[i]

Gouty Arthritis.

Note large tuberous swellings on knuckle and metacarpo-phalangeal joints due to uratic deposits.

[ii]

[iii]

GOUT

BY
LLEWELLYN JONES LLEWELLYN, M.B. Lond.

GOVERNOR AND SENIOR PHYSICIAN, ROYAL MINERAL WATER HOSPITAL, BATH;
FELLOW OF ROYAL SOCIETY OF MEDICINE; AUTHOR OF “ARTHRITIS DEFORMANS”;
CO-AUTHOR OF “FIBROSITIS”; CO-AUTHOR OF “MALINGERING, OR THE SIMULATION
OF DISEASE”; CO-AUTHOR OF “PENSIONS AND THE PRINCIPLES OF THEIR
EVALUATION”; CONTRIBUTOR TO LATHAM AND ENGLISH’S “SYSTEM OF TREATMENT,”
ALSO TO “OXFORD ENCYCLOPÆDIA OF TREATMENT” AND TO “STUDENT’S
TEXT-BOOK OF SURGERY.”

WITH A SECTION ON
OCULAR DISEASE IN THE GOUTY
BY
W. M. BEAUMONT

CONSULTING OPHTHALMIC SURGEON TO THE SOUTH-WESTERN
REGION OF THE MINISTRY OF PENSIONS; AUTHOR OF “INJURIES
OF THE EYES OF THE UNEMPLOYED, PROBLEMS IN PROGNOSIS,” ETC.

ST. LOUIS
C. V. MOSBY COMPANY
1921

[iv]

Printed in Great Britain.

[v]

Dedicated
TO
MY WIFE

[vi]

“A knowledge of the real nature of gout ... is, in my opinion, at the very foundation of all sound pathology,” wrote Todd many years since; and the passing years have but invested his reflection with deeper significance and something of prophetic insight. For who can doubt that he who would elucidate the pathological groundwork of gout must be at once a clinical physician, a bio-chemist, a bacteriologist, a morbid anatomist? and well may we ask, Who is sufficient for all this?

How vivid the light thrown upon the problems of clinical medicine by the bio-chemists! The story of the fate of protein and purin substances in the animal body, at one time a medley of guesses and gaps, is gradually evolving into one of relative certitude and completeness. Revolutionary, in truth, the change, and many a cherished shibboleth has been ruthlessly cast aside! With admiration not unmingled with awe we see them laying well and truly the foundations upon which in the ultimate scientific medicine must inevitably rest.

Of these the very corner-stones are chemical physiology and chemical pathology, the rapid evolution of which is profoundly altering our conceptions of health and disease. Those vital processes of the organism that but yesterday we saw “as through a glass, darkly,” are now in great part illumined, and the distortions wrought in them by disease made more manifest.

How pregnant, too, with warning their findings! Processes that to our untutored minds seem simple are revealed as infinitely complex. Through what a maze must we thread our way if we would disentangle the intricacies of metabolism! Intricate enough, forsooth, in health, but how much more so in disease! For, as Sir Archibald Garrod eloquently phrases it, “it is becoming evident that special paths of metabolism exist, not only for proteins, fats, and carbohydrates as such, but that even the individual primary fractions of the protein molecule follow their several katabolic paths, and are dealt with in successive stages by series of enzymes until the final products of katabolism are formed. Any of these paths may be locked while others remain open.”

It is with chastening reflections such as these that we may best approach our study of gout, that riddle of the ages upon which so many physicians from time immemorial have expended their dialectic skill. But, vast though the increase in our knowledge[viii] of the chemical structure of uric acid and its allies, uncertainty still dogs our steps, and, doubtful of the pathway to solution of the pathological mystery of gout, we must perforce approach the problem in a more strictly catholic attitude.

Uric acid has apparently failed us as the causa causans. Neither this substance nor its precursors can be held responsible for the fever, local inflammation and constitutional disturbances in gout, being, as they are, practically non-toxic. Albeit, though I hold this view, I do not for one moment suggest that uric acid has nothing whatever to do with gout. The fact that tophi, its pathognomonic stigmata, are compounded of biurate of soda, would per se stamp such an attitude as untenable. On the other hand, uric acid must be viewed at its proper perspective as a concomitant or sequel of gouty inflammation, the essential cause of which must be sought elsewhere.

“The old order changeth, giving place to new,” and happily with the advent of bacteriology our views, or rather our hazards, as to the nature of joint diseases underwent profound modification. But, strange to say, though quick to apprehend the significance of infection, its causal relation to other joint disorders, we still seem unaccountably loth to discard our timeworn conception of “gouty” arthritis as of purely metabolic origin. This to my mind is the more remarkable in that the onset, clinical phenomena, and course of acute gout, and no less the life history of the disorder as a whole, are emphatically indicative of the intrusion of an infective element in its genesis.

The extreme frequency with which infective foci are met with in the victims of gout, the frequency, too, with which exacerbations of the disorder are presaged by acute glandular affections of undeniably infective source, is by no means adequately realised. For our forefathers gout began, and, forsooth, often ended, in the “stomach,” or it was the “liver” that was impeached. But the portal to the alimentary canal was for them only a cavity, the contained structures of which, albeit, to their mind often betrayed evidences of a “gouty diathesis.” They distinguished “gouty” teeth, “gouty” tonsillitis, “gouty” pharyngitis, even “gouty” parotitis; but all these they classed as tokens or sequelæ of gout, not possible causes or excitants thereof.

Now as to the true significance of these acute glandular affections held by clinicians of repute to be of “gouty” origin. What of “gouty” tonsillitis, pharyngitis, parotitis? Still more, what of our deductions regarding the relationship of these same when met with in association with non-gouty forms of arthritis? Do we not hold them each and all as evidences of infection? and, we may well ask, why not in gout?

[ix]

The marvel then is that even to-day many still hold that the tonsillitis, pharyngitis, even the gingivitis, like the subsequent articular lesions, are one and all attributable to the underlying gout. We certainly should not do so in the case of any arthritis other than “gouty,” and to my mind the time is ripe for a change of attitude.

The “gouty” throats, like the “gouty” teeth, should be regarded not as symptomatic of gout, but etiologically related thereto. We should cease to talk of “gouty” throats, teeth, etc., should renounce the prefix, for there is nothing specific of gout either in the tonsillar, pharyngeal, or dental lesions. We should instead view these various local disorders in their true perspective as foci of infection, causally related to the subsequent and secondary “gouty” arthritis.

Similarly, when we come to analyse the component elements of an acute paroxysm of gout, how strongly indicative of the intrusion of an infective element the following features: the onset, temperature curve, character of local articular changes of the disorder, the presence of leucocytosis, with secondary anæmia and enlargement of the lymphatic glands! Again, how suggestive the occasional complication of acute gout by lymphangitis and phlebitis! Of like significance, too, the paroxysmal nature and periodicity of the disorder, and the compatibility of the morbid anatomical changes and the cytological content of the aspirated joint fluid with their genesis by infection.

As to correlation of the metabolic phenomena of gout with the postulated infective element, I would suggest that, although abnormalities of metabolism form an integral part of gout, they are of themselves inadequate to achieve its efflorescence. As we shall see when we come to consider those elemental manifestations of gout, i.e., uratic deposits, or tophi, neither the purely physical nor the purely chemical theory of their origin will suffice, nor, for that matter, can any solution of their formation be gleaned from even a blend of the twain. In short, such hypotheses are too mechanical.

The intrusion of some other factor, “something vital, something biological,” seems essential for the elucidation of uratosis, i.e., uratic deposition. For this, not uricæmia, is the specific characteristic phenomenon of gout. If we cannot explain uratosis on physical or chemical grounds, then how much less, in view of the non-toxicity of uric acid, can we on this basis account for the inflammatory phenomena of the disorder!

Now inflammatory reaction is, I hold, an invariable antecedent in all gouty processes, whether of articular or ab-articular site. Granted that inflammatory reaction is a necessary prelude, the[x] specificity of gout is attested by the fact that the same is followed by local deposition of urates. But while this sequential uratic deposition invests all forms of “gouty” inflammation with a specific character unshared by any other disease, it follows that the cause of the said inflammation must, if possible, be ascertained.

Now, as I believe, “gouty” subjects are ab initio victimised by innate tissue peculiarities, doubtless reflected in corresponding obliquities of tissue function and metamorphosis, and through their medium the general resistance of the body to invasion by infections is lowered; in other words, under the influence of these morbific agencies the latent morbid potentialities of the gouty become overt and manifest. For in the gouty, as Walker Hall observes, “a slight injury or indiscretion of diet, an overloaded intestine, or increased toxicity of the intestinal flora, may be followed by a disturbance of the general nuclein metabolism and a local reaction in certain tissues.”

Enough has been said to disclose the dominant trend of this work, and although there are many aspects of the subject in regard to which I hold somewhat iconoclastic views, yet exigencies of space forbid me even to allude to them in this foreword. I hasten therefore to discharge the pleasing duty of acknowledging my great indebtedness to the acumen and discrimination which has been brought to bear on this subject by a long succession of eminent physicians, in proof of which I need only adduce the names of those giants of the past the illustrious Sydenham, Sir Thomas Watson, Sir Charles Scudamore, Jonathan Hutchinson, not to mention Trousseau, Charcot, Lecorche, and Rendu. But I should fail in my duty did I not in a special sense express my deep indebtedness to the classic and epoch-making work of Sir Alfred Garrod. For the rest, too, I have derived much enlightenment from Sir Dyce Duckworth’s treatise and the various works on the subject by Luff, Lindsay, and others.

From the bio-chemical aspect I owe much to the researches of Walker Hall, and to those of our American confrères Folin, Denis, Benedict, Pratt, McLeod, Walker Jones, Gideon Wells, etc.

Reverting to my own colleagues at the Royal Mineral Water Hospital, Bath, I would tender my deep thanks to the Honorary Physicians, Drs. Waterhouse, Thomson, Lindsay, and King Martyn, for the uniformly generous manner in which they afforded me opportunities for studying cases under their care.

To Dr. Munro, our senior pathologist, I am especially beholden for invaluable, nay indispensable, help in the matter of blood examinations, the cytological study of joint fluids, and the microscopic verifications of tophi. To Dr. MacKay also my[xi] cordial thanks are due for the skiagraphs contained in this work.

For the section dealing with the ocular disorders met with in the gouty my most sincere thanks are due to Mr. W. M. Beaumont, of Bath, whose singularly wide experience in this sphere renders him unusually equipped to deal with this highly controversial aspect of gout. To Drs. Cave and Gordon, of Bath, also I am indebted for many valuable suggestions kindly afforded me while writing this volume. To my brother Dr. Bassett Jones I am under deep obligation for unwearying assistance in our joint endeavour to ascertain the exact relationship of gout to lumbago, sciatica, and other types of fibrositis.

For the preparation of the index of this work I would proffer my grateful thanks to Mr. Charles Hewitt and to Miss Donnan and Miss Crosse for having undertaken the arduous task of typing the manuscript thereof.

Lastly, I would express my thanks to my publisher, Mr. Heinemann, for much consideration and many courtesies.

LL. J. LL.

31, Upper Brook Street, W. 1.

[xii]

The Antiquity of Gout

“Teeth, bones, and hair,” quoth the Sage of Norwich, “give the most lasting defiance to corruption,” and were it not that “Time which antiquates antiquities and hath an art to make dust of all things hath yet spared these minor monuments,” it might perhaps have been inferred that gout was the primordial arthritic disease that afflicted mankind.

That it was the first articular affection to achieve clinical individuality may be allowed, but, from the aspect of antiquity, gout is relatively modern—the appanage of civilisation. True, Hippocrates, discoursing in the famous Asclepion at Cos, enunciated his aphorisms on gout some 300 years before the Christian Era, the dawn of which moreover found Cicero in his discussions at Tusculum lamenting its excruciating tortures “doloribus podagræ cruciari” and the peculiar burning character of its pains “cum arderet podagræ doloribus.”

But what of that? For did not Flinders Petrie in the hoary tombs of Gurob (dating back to the 28th Dynasty 1300 B.C.) find in mouldering skeletons of bygone civilisations unequivocal evidence of osteoarthritis.[1] But despite these sure though silent witnesses of the prevalence of this disorder among the ancient people of Egypt, yet in contrast with gout, no hint transpires in the writings of Greek or Roman physicians, nor those of much[2] later date, that the condition was recognised clinically, as a joint disorder, distinct from others of the same category.

Small call to marvel thereat, for how much more arresting the clinical facies of gout, with its classic insignia—tumor, robor, calor, et dolor—than of osteoarthritis, its etiolate tokens indicative rather of infirmity than of disease. Apart from this, it may well be that the early Egyptians owed their relative immunity from gout, and alike their proneness to osteoarthritis, to living hard laborious days, unenervated by that luxury and sloth, which in the first century A.D. drew upon the ancient Romans the caustic reproofs of Pliny and Seneca. For the old philosophers lamented the growing prevalence of the disorder, almost unknown in the early, more virile days of the Empire, rightly seeing in it but another harbinger of impending decadence, clearly attributable as it was to riotous living and debauchery.

Indeed, we have it on the authority of Galen that “In the time of Hippocrates there were only a few who suffered from podagra, such was the moderation in living, but in our own times, when sensuality has touched the highest conceivable point, the number of patients with the gout has grown to an extent that cannot be estimated.”

Nothing, in truth, seems more clearly established than this, that gout is the Nemesis that overtakes those addicted to luxurious habits and dietetic excesses. On the testimony of eminent travellers we are assured that amongst aborigines the disease is unknown. The indigenous native tribes of India are immune, but not so the immigrant flesh-loving Parsees. Strange to relate, Anglo-Indians of gouty habit, while resident in the Orient, seem exempt, some say, owing to cutaneous activity, but more probably because quâ Rendu “these are countries in which we cannot survive unless we are frugal.”

Nations too, like individuals, when fallen on hard times, lose their gout. Thus the Arabs, at the zenith of their mediæval Empire, were prone thereto, but in these latter days are almost exempt from its ravages. But, on the other hand, if we are to believe Professor Cantani, in no other disorder are the “sins of the fathers visited upon the children” with such pertinacity, claiming as he does that its marked incidence in Southern Italians is a direct heritage from the ancient Greeks and Romans.

Prevalence of Gout in the Anglo-Saxon Period

Reverting to our own country, what evidences as to its antiquity are forthcoming? This much may at any rate be affirmed, that according to Mason Good “Gout is one of the maladies which seem to have been common in England in its earliest ages[3] of barbarism. It is frequently noticed by the Anglo-Saxon historian, and the name assigned to it is Fot-adl.”

Cockayne, in his “Leechdoms Wortcumming and Starcraft,” of early England, has it that the word “addle” appears to have been a synonym for ailment, thus “Shingles was hight circle addle.” That gout should have flourished so among our Anglo-Saxon forbears is perhaps a matter for regret but not for astonishment, when we recall their coarse Gargantuan feasts, washed down with doughty draughts of ale, “sack and the well spic’d hippocras.”

Gout, we see then, even in our own land, is full ancient, and the word, as Bradley as shown, may be traced in the English tongue right through the literature of the various periods.[2] This not only in the brochures of physicians, but also as in the days of Lucian in the works of historians, and the satires of poets, which indeed abound with allusions to the disease.

Views of the Humoralists

The Greek physicians, quite familiar as they were with the overt manifestations of gout, did not, as far as its nosology was concerned, commit themselves to any appellation that might imply their adherence to any theory as to its causation. They contented themselves with a mere topographical designation, terming the affection, podagra, chirargra, etc., according as foot or hand was the seat of the disorder, while for polyarticular types the generic term arthritis was invoked.

Nevertheless the old Greek physicians had their views as to its pathology. Thus the source of the peccant humours resided for them in the brain, which they had invested with all the functions of an absorbent and secreting gland. This hypothesis in time was displaced by the true humoral theory, according to which the[4] bodily fluids, those found in the alimentary canal, the blood stream, and the glandular organs, were the primordial agents of disease. No need, albeit, for gibes on our part, for how true much of their conception of the genesis of disease even to-day. Indeed, what else than a fusion of the foregoing views? the modern theory of Sir Dyce Duckworth, who would ascribe gout to the combined influence of neural and humoral factors. And now to consider briefly the individual views of the fathers of medicine.

The Aphorisms of Hippocrates

In the eyes of the pioneer priest-physician, the disorder was attributable to a retention of humours, and many of his dicta have stood the corroding test of time. He noted, like Sydenham, its tendency to periodicity, its liability to recur at spring and fall. Also that eunuchs are immune and youths also, ante usum veneris, while in females its incidence is usually delayed until after the menopause.

The curability of the disease in its earlier stages was affirmed, but that after the deposit of chalk in the joints it proved rebellious to treatment, which for him resided in purgation and the local application of cooling agents.

In the first and second centuries Celsus, Galen, and Aretæus the Cappadocian recounted their views as to its nature and therapy, while the Augustan poet in his Pontic epistles, like Hippocrates, laments that his gouty swellings defy the art of medicine.

To Celsus, venesection at the onset of an attack seemed both curative and prophylactic. Corpulence of habit a state to be avoided, and conformably he prescribed frugality of fare and adequate exercise. Galen (130-200), more venturesome than his contemporaries, voiced his belief that tophi were compact of phlegm, blood, or bile, singly or in combination. For the rest, he enjoined bleeding and purgation and local applications, contravening, by the bye, Hippocrates’ claim as to the immunity of eunuchs in that in his (Galen’s) day their sloth and intemperance were such as readily begat the disorder.

About this period Lucian of Saramosta enumerated the various anti-gout nostrums vaunted as specifics in his day. Though in his comic poems, the Trago-podagra and Ocypus he rightly holds up to scorn the charlatanism rampant at the time, still it is quite clear that he possessed no mean knowledge of the clinical vagaries of gout and was quite alive to the mischief of too meddlesome treatment thereof.

[5]

Said the hero of the Trago-podagra:

Again, Seneca, in a jeremiad on the decadent habits of Roman ladies of the patrician order, observes: “The nature of women is not altered but their manner of living, for while they rival the men in every kind of licentiousness, they equal them too in their very bodily disorders. Why need we then be surprised at seeing so many of the female sex afflicted with gout.” That the old philosopher’s misgivings were but too well founded is obvious when we recall that so widespread were the ravages of gout among the Romans in the third century that Diocletian, by an edict, exempted from the public burdens those severely crippled thereby, in sooth a blatant illustration of political pandering to national vice.

But to return to the researches of physicians, those of Aretæus seem to have been the most enlightened of his time. A succinct account of the mode of invasion of gout and its centripetal spread in later stages to the larger joints is followed by enumeration of the exciting causes of outbreaks. Anent these, he quaintly notes the reluctance which the victims display to assigning the malady to its true cause—their own excesses—preferring to attribute it to a new shoe, a long walk, or an injury. Noting that men are more liable than women, he tells us, too, that between the gouty attacks the subject has even carried off the palm in the Olympic games. The white hellebore, to his mind, at any rate in early attacks, was the remedy par excellence. But, for the true nature of the disease, he, with humility and piety, avows that its secret origin is known only to the gods.

Not so his successor Cælius Aurelianus, who affirmed it to be not only hereditary but due to indigestion, over-drinking, debauchery, and exposure. Under their maleficent influence morbid humours were generated which sooner or later found a vent in one or other foot, with a predilection for tendons and ligaments; these structures he averred being the locus morbi. An abstemious dietary with exercise was his sheet anchor in therapy, with local scarification in preference to cupping and leeching, but violent purging and emetics he decried, and drugs to him made little appeal.

More ambitious than his predecessors, Alexander of Tralles, in the sixth century, held that there were many varieties of gout, some due to intra-articular effusions of blood, reminding us of Rieken’s view (1829) that hæmophilia is an anomalous variant of gout. Other cases, Alexander averred, were the outcome of[6] extravasation of bile or other peccant fluids between tendons and ligaments. Abstinence, especially from wine and blood-forming foods, was enjoined and a plentiful use of drastic purgatives, elaterium, etc., with local sinapisms and blisters. For the absorption of chalk stones he commended unguents containing oil, turpentine, ammoniacum, dragon’s blood, and litharge.

Aetius, a contemporary, is noteworthy in that during the intervals of attacks he highly eulogised the use of friction while, like Alexander of Tralles, he seems to have been much impressed with the virtues of colchicum, of which he says, “Hermodactylon confestim minuit dolores.” Planchon, in 1855, in his treatise, “De hermodactes au point de vue botanique et pharmaceutique,” claims to have proved that the hermodactylon of the ancients was Colchicum variegatum, of similar properties to the Colchicum autumnale.

Paulus Ægineta, like most of his confrères, regarded gout and rheumatism as the same disorder, differing only in their location. He subscribed whole heartedly to the prevailing humoral theory, but inclined to think the site of the discharged humours was influenced by weakness or injury of the parts. He noted, too, that mental states, sorrow, anxiety, etc., might act as determining causes.

Nor will any historical résumé rest complete without a reference to the numerous works of the Arabian physicians—Avicenna, Rhazes, Serapion, and Haly Abbas—who one or other all maintained gout to be hereditary, rare in women and due to peccant humours, developed in the train of depletions, debaucheries, and the like.

Introduction of the Word “Gout”

In the thirteenth century the Greek terms “podagra,” “chirargra,” etc., were to a large extent abandoned, and following Radulfe’s lead gave way to the use of the generic term “gout,” derived from the Latin “gutta.” Its adoption was doubtless traceable to the prevailing humoral views of the origin of the disorder, as due to some morbid matter exuding by “drops” into the joint cavities. Indeed, according to Johnson, the word “gut” was used as a synonym for “drop” by Scottish physicians even in his day.

In any case, the term found little difficulty in installing itself among all nations, taking in French the form “goutte,” in German “gicht,” in Spanish “gota,” etc. Trousseau thought it “an admirable name, because in whatever sense it may have been originally employed by those by whom it was invented, it is not now given to anything else than that to which it is applied.” In contrast[7] therewith, that trenchant critic Pye-Smith complained of the laxity with which the Germans invoked the word “gicht.” He says it is popularly credited with all the pains which are called “rheumatics” in England. “Sometimes ‘gicht’ is nothing but bad corns and is rarely true gout.” Albeit, Pye-Smith did not, as we shall see later, hold even his English confrères in this respect void of offence.

From these remote times onwards through the Middle Ages to the present day, an almost continuous series of historical records testify that not only has gout always been with us, but that its clinical characters throughout the ages have remained unaltered, conforming ever to the primitive type. During the seventeenth and eighteenth centuries many physicians, both British and continental, ventilated their views as to the nature of gout, all swearing allegiance to the old humoral pathology, notably Sydenham, Boerhaave, Van Swieten, Hoffmann, Cadogan, etc.

The English Hippocrates, as Trousseau christened the illustrious Sydenham, displayed his catholic outlook by the pregnant words: “No very limited theory and no one particular hypothesis can be found applicable to explain the whole nature of gout.” A live-long martyr himself thereto, he brought all the strength of his dominating intellect to bear upon its elucidation. As to its causation, he held it to be due to a “morbific matter,” the outcome of imperfect “coctions” in the primæ viæ and in the secondary assimilating organs. He refrained from speculating as to the constitution of the materia peccans, but as Trousseau observes, “he made his morbi seminium play the part which modern chemistry attributes to the products it has discovered. Take it all in all,” he says, “the theory of the great English physician is much more medical than the theories of modern chemists.”

Early Views as to the Nature of Tophi

The word “tophus” or “tofus,” the Greek τοφος, seems to have been applied to rough crumbling rock, the disintegrated volcanic tufa. As to its constitution it is clear from the above quotation that Virgil evidently associated it with chalk, a shrewder guess than the fanciful hypothesis of Galen, though the views of Paracelsus (1493-1541) enunciated some centuries subsequently, were even more grotesque, a “mucous essence,” a “Tartarus” burning “like hell fire.”

Nevertheless, our contempt need be chastened when we recollect[8] that, up to the latter half of the eighteenth century, equally weird assumptions found acceptance. By some “various excrementitial humours,” by others “checked and decomposing sweat” were deemed the basis of tophi.

A mucilaginous extract, derived from the solid and liquid intake, appealed to some as an explanation of their formation, while to others, tophi were compounds of subtle and penetrating salts.

But the later view, doubtless the reflex of etiological hypotheses, was that tophi were of tartareous nature, closely similar to that encrusting the interior of wine casks. Hoffmann declared that the materies morbi actually was a salt of tartar circulating in the blood. His investigations of tophi and also of the stools, saliva, and urine of gouty subjects, convinced him that the peccant matter was tartar of wine.

Hoffmann’s views, however, were laughed to scorn by M. Coste as being obviously absurd, inasmuch as gout was not uncommon amongst those who had never partaken of wine, ergo, never of tartar. How infinitely more physicianly the inference of Sydenham, who, like some of the older humoralists held the tophus to be “undigested gouty matter thrown out around the joints in a liquid form and afterwards becoming hardened.”

So it went on until, alchemy being displaced by chemistry, uric acid was in 1775 discovered by Scheele, and in 1787 Wollaston established its existence in tophi, and to the further elaboration of our knowledge of this substance we shall allude later. Here we would only observe that Wollaston’s researches marked the coming substitution of the humoral and solidist theories by a chemical hypothesis as to the etiology of gout.

The “Honour of the Gout”

The absurd delusion, not wholly dissipated even to-day, that to have the gout, “Morbus Dominorum,” was highly creditable, a mark of good breeding, was firmly ingrained in our forefathers. We all recall the story of the old Scottish gentlewoman who would never allow that any but people of family could have bonâ fide gout. Let but the roturier aspire to this privilege, and she scouted the very idea—“Na, na, it is only my father and Lord Gallowa’ that have the regular gout.” As to the origin of this mistaken ambition, it most probably was the outcome of the fact that it was peculiarly an appanage of the great, the wealthy, and alas! those of intellectual distinction!

Statesmen, warriors, literary men and poets loom large amongst its victims. Lord Burleigh suffered greatly therefrom, and good[9] Queen Bess on that account always bid him sit in her presence, and was wont to say, “My Lord, we make much of you, not for your bad legs, but for your good head!” With more humour, Horace Walpole complained, “If either my father or mother had had it I should not dislike it so much! I am herald enough to approve it, if descended genealogically, but it is an absolute upstart in me, and what is more provoking, I had trusted in my great abstinence for keeping it from me, but thus it is!”[3]

Of warriors, Lord Howe, Marshal Saxe, Wallenstein, and Condé were among its victims; while of literary men and poets thus afflicted may be mentioned Milton, Dryden, Congreve, Linnæus, Newton, and Fielding. Of physicians, the great Harvey was a martyr to gout, and was wont to treat it after the following heroic fashion. Sitting, in the coldest weather, with bare legs on the leads of Cockaine House, he would immerse them in a pail of water until he nearly collapsed from cold. Mrs. Hunter, wife of John Hunter, in a letter to Edward Jenner about her distinguished husband, dated Bath, September 18th, 1785, laments that “He has been tormented with the flying gout since last March!” In short, the disorder, with a notable frequency, figures in the life history of some of the ablest men in all ages, hence the complacency with which lesser men, often without good reason, affect to have the gout.

“But nothing,” as Sir Thomas Watson says, “can show more strongly the power of fashion than this desire to be thought to possess, not only the tone and manners of the higher orders of society, not their follies merely and pleasant vices, but their very pains and aches, their bodily imperfections and infirmities. All this is more than sufficiently ludicrous and lamentable, but so it is. Even the philosophic Sydenham consoled himself under the sufferings of the gout with the reflection that it destroys more rich men than poor, more wise men than fools.”

The Scotch at one time regarded gout as fit and meet punishment for the luxurious living of the English. But, as was pointed out, the cogency of the moral was somewhat spoilt by the fact that the disorder was found to exist even among the poor and[10] temperate Faroe Islanders. In truth, although “the taint may be hereditary, it may be generated by a low diet and abstinence carried to extremes.”

That Gout confers Immunity from other Disorders

The fallacy that longevity and freedom from other maladies was ensured by gout was prevalent among our forefathers. In satire of this, one Philander Misaurus issued a brochure entitled “The Honour of the Gout,” and purporting to be writ, “Right in the Heat of a violent Paroxysm; and now publish’d for the common Good” (1735). “Bless us,” says he, “that any man should wish to be rid of the Gout; for want of which he may become obnoxious to fevers and headache, be blinded in his understanding, loose the best of his Health and the Security of his Life”; and forthwith in his zeal for the common good gives us the following invocation:—

He quaintly suggests that Paracelsus, if he would ensure men against death, had but to inoculate them with gout. Gout, indeed, was held to be a jealous disorder, intolerant of usurpation by any other disease, recalling the remark of Posthumus to his gaolers:—

Still the fallacy that gout was salutary died hard, and although it seems incredible, yet, Archbishop Sheldon is said not only to have longed for gout but actually to have offered £1,000 to any one who would procure him this blessing; for he regarded gout as “the only remedy for the distress in his head.” How ingrained the notion may be gathered from the fact that in the early part of the last century, M. Coste in his “Traité Pratique de la Goutte,” observed: “A popular error, which I wish to expose in a few words, is this prejudice, which has already lasted more than two[11] thousand years, and which has reached even the thrones of princes, where the disease commonly shows itself, viz., that gout prolongs life (que la goutte prolonge la vie). This error,” says he, “has taken the surest method of introducing itself, by making flattering promises, by persuading its victims that there is a singular advantage in having gout, and that the malady drives away all other evils, and that it ensures long life to those whom it attacks.”

In like refrain, our own countryman Heberden deplores that people “are neither ashamed nor afraid of it; but solace themselves with the hope that they shall one day have the gout; or, if they have already suffered it, impute all their other ails, not to having had too much of that disease, but to wanting more. The gout, far from being blamed as the cause, is looked up to as the expected deliverer from these evils.” Such deluded views being prevalent, it is hardly a matter for surprise that misguided persons deliberately courted a “fit of the gout” by resorting to excess and intemperance.

But alas, while the initial visitations of gout, after their passing, may leave behind them a renewed sense of well-being, it is no less certain that, when once installed, the intervals of respite grow shorter and shorter. Crippledom grows apace, the general health breaks and untimely senescence overtakes the worn-out victim, and, as Heberden puts it, “that gout causes premature death, when all the comforts of life ...

are destroyed, and the physical powers either insensibly undermined or suddenly crushed by an attack of paralysis or apoplexy, should hardly be reckoned among the misfortunes attending the disease.”

But for our encouragement it may be observed that not always does gout carry with it such a terrible Nemesis. “Gout is the disease of those who will have it,” said a wise physician, and though the inbred gouty tendency may be so strong as to cast defiance at abstinence, yet it is by no means always so. A man may inherit gout, but he need not foster it by self-indulgence. Much less need he, as so often happens, acquire it by depraved habits of life. In no disease do sobriety and virtuous living ensure so great a reward. As Sir Thomas Watson long since said to those inheriting this unwelcome legacy: “Let the son of a rich and gouty nobleman change places with the son of a farm servant, and earn his temperate meal by the daily[12] sweat of his brow, and the chance of his being visited with gout will be very small.”

Growing Infrequency and Attenuation of Gout

So accurate and graphic were the clinical pictures of gout depicted by the ancient physicians that there is no doubt the gout of to-day conforms to the primitive type as met with among the Greeks and Romans. This certainly as regards the arthritic phenomena of the disease; for in those remote ages little or no account seems to have been taken of its irregular or ab-articular manifestations. While disregard of the latter group renders more credible their claims as to the widespread prevalence of the affection, nevertheless, I think there can be no doubt that the frequency of gout amongst the ancient Greeks and Romans was probably over-estimated.

Can it be questioned that a large percentage of the cases of gout in those bygone times consisted of undifferentiated infective forms of arthritis. Syphilis and gonorrhœa must have existed then as now, and their specific forms of arthritis, how easily confused with “rich man’s gout!” Surely too, they, like ourselves, must have suffered with states of oral sepsis, pyorrhœa alveolaris, etc., not to speak of infective disorders, with their correlated arthritides. In short, the differentiation of arthritic disorders was then hardly in its infancy, and it is in light of this disability that we must appraise their clearly extravagant assertions as to the widespread ravages of gout in their day.

But passing to more recent times, there is little doubt that the classical type of podagra is very much rarer to-day than, say, in the time of Sydenham. Indeed, it may be said to be becoming progressively infrequent. Thus, writing in 1890, Sir Dyce Duckworth tells us that some twenty-six years prior to that date, Sir George Burrows informed him that “he then saw fewer cases of acute gout than he was accustomed to see in his earlier practice.” It may be recalled, too, that Sir Charles Scudamore, in retrospect of his own experience, of still earlier date, was led to much the same conclusion. Moreover, not only is the disorder less frequent, but its virulence seems to have suffered attenuation, and this to a marked degree.

Again, Ewart, writing in 1896, observed that “goutiness” is becoming relatively more common than declared gout. This, he thought, by reason of the increasing attenuation in transmission of the “gouty” taint. In this, as well as the more mitigated[13] character of the arthritic manifestations, he saw hope of “an ultimate extinction of the bias in ‘gouty’ families.” For, as he rightly says, side by side with “the tendency to a reproduction of morbid parental peculiarities, there is a yet stronger tendency in Nature to reproduce the healthy type of the race in each successive generation.”

But while there is a general consensus of opinion as to the growing rarity of acute regular gout, on the other hand, many, as if loth to part with the disorder, claim that pari passu with the decline of regular types the incidence of irregular manifestations grew proportionately.

In my experience the incidence of regular gout has appreciably diminished during the past twenty years. Moreover, such examples as one has met with incline much more in character to the asthenic than to the sthenic variety of podagra. But, in contrast to many, I have observed no increase in the irregular manifestations of gout. On the contrary, a steady diminution in the nebulous content of this category, but to this vexed subject we shall recur in a subsequent chapter dealing with the propriety or not of retaining this ill-defined term in medical nomenclature.

My conclusion, then, is that not only is arthritic gout becoming less prevalent, but that the type of the disease also has suffered attenuation. Probably this dual change is the outcome of many factors, not the least of these an increase in national sobriety. For as Sir Alfred Garrod long since observed, “There is no truth in medicine better established than the fact that the use of fermented liquors is the most powerful of all the predisposing causes of gout; nay, so powerful, that it may be a question whether gout would ever have been known to mankind had such beverages not being indulged in.

Under the vague term “articulorum passio” or “arthritis” the physicians of antiquity handed down to posterity the clinical description of a disease in the varied symptomatology of which we may descry at one time the features of gout and anon those of rheumatism. But centuries had to elapse before gout became differentiated from rheumatism. For there is no doubt that not only the Greek and Roman physicians, but those also of the Græco-Arabian school, confounded these two disorders, or more accurately failed to differentiate rheumatism.

So it is that Charcot, reviewing the antiquity of gout, while he pays a graceful tribute to the ancient physicians for their masterly disquisitions thereon, at the same time deplored their silence on the subject of articular rheumatism.

This absence of allusion thereto is the more remarkable in that the term “rheumatism” or “rheumes” dates from a very remote period. Both words, in truth, were indifferently enlisted to denote all those diseases deemed attributable to the defluxion of some acrid humour upon one or other part of the body. Used by the ancients more in accordance with its etymological sense, the term “rheumes” or “rheumatism,” finds a place even in the writings of Pliny and Ovid. But our modern conception of the disorder differs widely from “the flux of humours” which the Greeks named rheumatism, or “the sharpe and eager flux of fleam” which for them characterised an attack of the “rheumes.”

The early English authors, too, invoked the word as a general term descriptive of various forms of disease. Sir Thomas Elyot, in his “Castel of Health,” so scoffed at by the faculty in his day, inculcates abstemiousness in those afflicted with the “rheumes,” and in “Julius Caesar,” Brutus is warned by Portia not to tempt “the rheumy unpurged ayre of night,” a clear indication that the term was used as a synonym for fluxions, humours and catarrhs of all sorts. But as to the malign articular forms of the affection, never a word; and this almost inexplicable silence led Sydenham, Haecker and Leupoldt to surmise that articular rheumatism was a modern disease unknown amongst the ancients.

[15]

Isolation of Acute Articular Rheumatism From Gout

Hallowed by tradition, this erroneous conception of the identity of gout and rheumatism endured until 1642, when Baillon, in his treatise “De Rheumatismo et Pleuritide,” effected a cleavage, at any rate between the acute varieties of these two diseases.

Dissociating the term “rheumatism” from its primitive interpretation, Baillon restricted its usage to that particular group of symptoms we now call acute articular rheumatism. In the same century Sydenham, in his “Classical Observations,” materially clarified the existing clinical confusion, defining with his customary lucidity the essential differences between the two disorders.

Tardy Dissociation of Chronic Gout From Chronic Rheumatism

Bearing in mind the centuries that elapsed before the acute articular forms of gout and rheumatism were dissociated, one ceases to marvel that the task, incomparably more difficult, of discriminating between the chronic forms of these diseases is even now barely accomplished.

“Rheumatissimus agnatus podagræ” said our forefathers, the axiom postulating not the actual identity of the two affections, but a near relationship, and in this non-committal phrase we may, I think, descry the birth of that modern term “L’arthritisme,” so beloved of the French physicians. Even as late as the beginning of the nineteenth century Chomel at the Saltpetrière taught his pupils that gout and rheumatism were but clinical variants of an underlying “arthritic diathesis,” his successor Pidoux being still more insistent that the two disorders sprang from one common root. Even Charcot and Trousseau, convinced as they were of the essential distinctness of the two disorders, nevertheless admitted that at the bedside their chronic manifestations were with difficulty dissociated, the former pointing to the terms “rhumatisme goutteux” and “rheumatic gout” as tacit acknowledgments of our impotence.

Nor did this view that gout and alike rheumatism are the outcome of a basic arthritic diathesis fail of doughty supporters in this country. Thus Hutchinson, in his “Pedigree of Disease,” observes “gout is but rarely of pure breed, and often a complication of rheumatism. It so often mixes itself up with rheumatism, and the two, in hereditary transmission, become so intimately united, that it is a matter of considerable difficulty to ascertain how far rheumatism pure can go ... when this complication exists. It shows its power, we may suspect, by inducing a permanent modification of tissue, and it is to this modification that[16] the peculiarities in the processes (transitory rheumatic pains in joints, fasciæ, and muscles, chronic crippling arthritis, destructive arthritis with eburnation, lumbago, sciatica) are due. Hence the impossibility under many conditions of discriminating between gout and rheumatism.”

Laycock also subscribed to Charcot’s view, and Sir Dyce Duckworth confesses that the conception of “a basic diathetic habit of body called arthritic has well commended itself to my mind,” while as to the clinical commingling of the two disorders Sir Charles Scudamore spoke with no uncertain voice. That an individual may in youth suffer from acute articular rheumatism, and later in life develop gout, is undeniable, as also the reverse, that a gouty subject may be harassed by manifestations of chronic rheumatism or fibrositis. But this mutual trenching of the one upon the clinical territory of the other must not be allowed to impair our views as to the essential distinctness of gout and rheumatism. It is undeniable that the difficulty of differentiating between the chronic forms of these two disorders is great, for not even the revelations of skiagraphy, in the absence of a clinical history, will suffice to effect a discrimination. But to a further consideration of this vexed matter we refer the reader to the coming chapters on Diagnosis.

Identification of Muscular Rheumatism

But to resume our thread, one great step forward we owe to Cullen, who not only differentiated acute from chronic articular rheumatism, but also clearly portrayed the clinical distinctness from both of muscular rheumatism. In so doing, he materially assisted in the differentiation of these same disorders from gout. But at the same time, owing to his immoderate advocacy of “chill” as the one great cause of rheumatism in all its forms, he undoubtedly retarded progress. For immediately there arose a cloud of witnesses who claimed a “rheumatic kinship” for a myriad visceral disorders, the victims of which had suffered exposure. Thus throughout the seventeenth and eighteenth centuries many of the conditions now assigned to irregular gout were affiliated instead to rheumatism.

Differentiation of Chronic Gout From Arthritis Deformans

Apart from Cullen’s contribution the eighteenth century was unmarked by any further advance in differentiating the mass of heterogenous joint affections, indifferently classed as gout and[17] rheumatism. The physicians of this period, indeed, appear not only to have done little themselves, but had omitted to utilise the useful indications furnished by their predecessors.

Thus how much more swiftly would the clinical distinctness of chronic articular gout from rheumatoid arthritis have been realised had Sydenham’s dicta in the seventeenth century regarding this intricate problem been duly appreciated. Up to his time, the clinical descriptions of rheumatoid arthritis appeared now under gout, now under rheumatism. As for Sydenham himself, he placed the disorder, nosologically speaking, under chronic rheumatism, of which he believed it to be an apyretic variety. But the importance of his researches resides in this—he pointed out that it differed essentially from gout, but that, in resemblance thereof, it might endure throughout life, its course diversified by remissions and exacerbations. Also he tells us that its excruciating pains, even when of prolonged standing, sometimes cease spontaneously, noting also that the joints are, so to speak, turned over, and that there are nodosities, especially on the inside of the fingers.

Nevertheless, if we except Musgrave’s work (1703), “Arthritis ex Chlorosi,” which included some undoubted examples of rheumatoid or atrophic arthritis, no note was taken of Sydenham’s contention until a century afterwards. True, John Hunter in 1759 described the morbid anatomy of osteoarthritis or the hypertrophic forms of arthritis deformans, but not until 1868 was the true significance of Sydenham’s work appreciated, a most generous tribute being then accorded him by the great French physician Trousseau.

In 1800 Landre Beauvais published his clinical description of rheumatoid arthritis under the title “goutte asthenique primitif.” That Beauvais, as Sir Archibald Garrod contends, included under this title some cases of true gout is beyond doubt. But the words “Doit admettre une nouvelle espèce de goutte,” go far to justify Charcot in his claim that Beauvais, despite the title of his brochure, fully realised that the disease differed from gout.

A few years later (1804-1816), Heberden, in his Commentaries, insisted on the essential distinctness of rheumatoid arthritis from gout. Thus he wrote, “The disease called chronical rheumatism, which often passes under the general name of rheumatism and is sometimes supposed to be gout, is in reality a very different distemper from the genuine gout, and from the acute rheumatism, and ought to be carefully distinguished from both.” As to its salient features he noted its afebrile nature, the lack of redness in the skin over the affected joints, the relative absence of pain, and that it displayed no special tendency to begin in the feet. It was further marked by a protracted course involving severe crippling,[18] while the peculiar nodosities on the fingers are still associated with his name.

In 1805 Haygarth published his classical essay, “A Clinical History of the Nodosity of the Joints,” the opening sentence of which shows that, comparably with his successors, he lamented the laxity with which the term “rheumatism” was invoked and applied “to a great variety of disorders which beside pain, have but few symptoms that connect them together.” A purist in nosology, he equally deplored the term “rheumatick gout” as tending to perpetuate its confusion with gout and rheumatism, and suggested the term “Nodosities,” in the hope that “as a distinct genus it will become a more direct object of medical attention.”

Alas, even as late as 1868 Trousseau deplored the retention of the term “rheumatic gout” by Garrod and Fuller and his own countryman Trastour. But, in common justice to Garrod, it must be allowed that in the third edition of his work he definitely applied the term rheumatoid arthritis to the disorder in question. Nor can we refrain from recording Fuller’s words that “the natural history of rheumatic gout accords but little with that of acute rheumatism, and is equally inconsistent with that of true gout.”

Cleavage of Arthritis Deformans into Two Types

In reviewing the researches of the foregoing writers it will be clearly seen that though they did yeoman service in differentiating broadly gout from the disorders grouped under Arthritis Deformans, there is little doubt that not for many years afterwards was their distinctiveness sufficiently realised. This may be in large part attributed to the fact that they still awaited the next great process of fission as applied to chronic joint disorders.

I allude in the first place to Charcot’s momentous discovery of the nerve arthropathies, and secondly, to the cleavage of arthritis deformans into the rheumatoid or atrophic, and the osteoarthritic or hypertrophic varieties.

It is to Vidal that we are indebted for the first clinical description of the atrophic type. Charcot in his lectures refers to it as the “Atrophic form of Vidal,” noting that in this variety “induration of the skin, a sort of scleroderma develops, the cutaneous covering is cold, pale, smooth, polished, and will not wrinkle, adding also that in such cases atrophy of the bones and muscles accompanies the wasting of the soft tissues.”

Notwithstanding this, Charcot, to our mind, unquestionably refers to the category of chronic articular gout certain of these examples of Vidal’s atrophic type of arthritis deformans. The[19] reasons he adduces for their gouty nature are, to say the least of it, both conflicting and unconvincing. On the one hand, he admits that they are clinically indistinguishable from Vidal’s type, in respect of their pronounced atrophic changes; on the other, he postulates them as gouty even though the uratic deposits “either do not exist at all, or only mere traces of them, or when only the articular cartilages are invaded by the urate of soda.” It must be conceded that chronic articular gout and rheumatoid or atrophic arthritis are totally distinct affections.

Now as to the hypertrophic variety, or osteoarthritis, which, of the twain, more closely resembles gout, and whose confusion therewith is far from infrequent even at the present time. Sir Dyce Duckworth, while he recognises with Charcot a tophaceous form of chronic articular gout, postulates the existence of another type, arthritis deformans uratica. Unlike Charcot, however, he seems only to have included under this term instances of the osteoarthritic or hypertrophic variety. But like Charcot, his claim that this particular variety is of gouty nature seems to rest on equally frail foundations, as witness his statement that they “may be complicated with visible or invisible tophaceous deposits!”

That osteoarthritis and gout may coexist in the same individual is certain, and equally sure is it that uratic deposits may supervene in joints the seat of osteoarthritis. But it is now, I think, generally conceded that, despite these coincidences, gouty arthritis and osteoarthritis are wholly distinct disorders, of wholly different origin.

At this period of our historical résumé we see that by the withdrawal of these three great groups—rheumatism, the nerve arthropathies and arthritis deformans—the domain of gout has, through these several allotments, undergone substantial shrinkage.

Elimination of the Infective Arthritides

Yet again was the territory of gout destined to undergo further restriction, and this largely owing to the rise of the science of bacteriology. For in light of recent improvements in diagnostic methods, who can escape the conviction that under the term “gout” had been wrongfully included many forms of arthritis, now known to be due to specific infections. What, for example, of Hippocrates’ aphorism that gout was unknown in youths—ante usum veneris—who can doubt that some of his reputed cases of gout were examples of gonococcal or syphilitic arthritis?

What, too, of all the other infective arthritides—influenzal, pneumoccocal, scarlatinal, typhoidal, meningococcal—to mention only those actually affiliated to some specific organism. For gout,[20] be it noted, confers no exemption from other arthritic diseases, but how in time past were such to be differentiated therefrom?

Again, gouty subjects, as has been recently emphasised, are notoriously prone to pyorrhœa alveolaris, and how difficult, given the supervention of an arthritis in such to define the causal agent—gout or sepsis, which? Small wonder then, that the clinical content of gout, not only to ancient, but also to latter day physicians, loomed large, swollen as it undoubtedly was by the inclusion of infective arthritides, not to mention those of traumatic or static origin.

That more of these alien joint disorders—les pseudo-rheumatismes infectieux, as M. Bouchard terms them, were relegated to the “rheumatic” than to the “gouty” category, may perhaps be allowed, but still gout was undoubtedly allotted its full share and to boot. Moreover, if to “rheumatism” was wrongly affiliated the lion’s share of the infective arthritides, on the other hand to “gout” accrued a host of unrelated visceral disorders, not to mention affections of the nervous and vascular structures, etc.

In endeavouring to summarise the results of our brief retrospect, the somewhat chastening fact emerges, viz., that the isolation of articular gout has been achieved not so much by an increase in our knowledge as to what is gout, but through our growing perception of what is not gout. For of the causa causans of gout we are still as ignorant as in the days of Sydenham. But, in contrast, our enlightenment as to the clinical and pathological features of other forms of arthritis has steadily progressed. In this way, shorn of many alien joint disorders, gouty arthritis has slowly but surely asserted itself as a specific joint affection, distinct both from rheumatism and arthritis deformans.

In the course of our sketch, too, we have traced the evolution of the modern opinion that at least two separate conditions, “rheumatoid arthritis” and “osteoarthritis,” are comprised under arthritis deformans. This most tardily arrived at differentiation has done more than any other to clarify our conceptions as to what constitutes true “gouty arthritis.”

If to this be added the further differentiation, not only of the nerve arthropathies, but also of the infective arthridites—both specific and undifferentiated forms—it will be seen that the term “gouty arthritis,” once the most comprehensive perhaps in all medical nomenclature, has now been brought within, at any rate, reasonable distance of more or less exact definition.

The fanciful views of the humoralists as to the etiology of gout exercised almost undisputed sway up to the latter half of the eighteenth century. At that time the great Scottish physician, Cullen, took up arms against a doctrine which appeared to him unjustifiable in conception and baneful in practice. He inclined to the solidists rather than to the humoralists, claiming that gout was the outcome of a peculiar bodily conformation, and more especially of an affection of the nervous system. While he categorically denied that any materia peccans was the cause of gout, he yet admitted that in prolonged cases a peculiar matter appeared in gouty patients. But, in view of latter day revelations, Cullen, with singular prescience, maintained that the said matter was the effect and not the cause of gout.

Albeit, notwithstanding the almost universal deference accorded to Cullen, his theory, promulgated in 1874, though previously adumbrated by Stahl and afterwards reinforced by Henle, secured but few adherents. The source of this was not far to seek. For ever since the discovery of uric acid by Scheele in 1776, and its detection in tophi by Wollaston, an increasing body of opinion inclined to the view, that in some obscure way the life history of gout was bound up with that of uric acid.

Still, despite able advocacy in this country by Sir Henry Holland, Wollaston, and others, not to mention Continental authorities, such as Cruveilhier, it was felt that scientific proof of the truth of their contention was still lacking. But not for long were they left in doubt. For, in 1848, Sir Alfred Garrod’s momentous and epoch-making discovery of the presence of uric acid in the blood of the victims of gout allayed all doubts, and seemed then and for long after an all-sufficient explanation of the protean manifestations of the disease.

This distinguished physician enunciated his views in a series of propositions which embodied the result of his researches and incidentally laid the foundations of the uric acid theory.

[22]

Garrod’s Theory

This great physician held that, in true gout, uric acid in the form of urate of soda was, both prior to and during an attack, invariably present in the blood in abnormal quantities, and was moreover essential to its production; but with this reservation, that occasionally for a short time uric acid might be present in the circulating fluid without exciting inflammatory symptoms. This comparably with what obtains in lead poisoning, and on this account therefore he did not claim that the mere presence of uric acid therein would explain the occurrence of the gouty paroxysm.

He further averred that gouty inflammation is always accompanied by a deposition of urate of soda, crystalline and interstitial, in the inflamed part. Also that “the deposited urate of soda may be looked upon as the cause and not the effect of the gouty inflammation. Moreover, that the said inflammation tends to destruction of the urate of soda not only in the blood of the inflamed part, but also in the system generally.”

In addition, Garrod postulated implication of the kidneys, probably in the early, and certainly in the chronic stages of gout; and that the renal affection, though possibly only functional at first, subsequently became organic, with alterations in the urinary secretions.

As to the anomalous symptoms met with in gouty subjects, and alike those premonitory of a paroxysm, he ascribed them to the impure state of the blood, and due principally to the presence therein of urate of soda. Of causes predisposing to gout, if we except those attaching to individual peculiarities, they are either such as will lead to increased formation of uric acid or to retention of the same in the blood.

On the other hand, the determining causes of a gouty fit are those which induce a less alkaline condition of the blood, or which greatly augment for the time the formation of uric acid or such as temporarily check the eliminating powers of the kidneys. Lastly, his final axiom was that—in no disease but true gout is there a deposition of uric acid.

No tribute to Garrod’s masterly achievement could err on the side of generosity. A truly scientific physician, he built on the rock of sound clinical and pathological observations. For measured restraint, he stands out in pleasing contrast to those who, lacking his clinical acumen and sound judgment, brought not grist to the mill, but vain imaginings based on Garrod’s hard-won facts. His researches in truth constitute a landmark in the history of the pathology of gout, with their substitution of facts for pure hypotheses. True, though it was that, for half a century[23] before, there was a growing suspicion that lithic (uric) acid was the malign factor in the induction of gout, still it was not till Garrod’s discovery of uric acid in the blood and tissues of the “gouty,” that any definite step towards the elucidation of the problem presented by gout was attained.

Antagonistic Views

One aspect of Garrod’s theory that much exercised the minds of his contemporaries was that for him uric acid was the alpha and omega of the disease, and as Ewart remarks, “If we are not over-anxious as to the stability of this mid-air foundation, everything is evolved smoothly from it on the lines of the theory.” Fortunately, however, for the progress of the art of medicine, men were over-anxious as to the why and wherefore of that accumulation of uric acid in the blood which Garrod held to be a necessary antecedent of gout. He himself, as we know, attributed it to a functional renal defect which may be inherited or acquired. To others, however, this assumption of renal inadequacy was not wholly satisfying, hence the origin of the many widely differing hypotheses from time to time advanced as to the pathogeny of the disorder.

Broadly speaking, the various conceptions proffered as to the causation of gout fall into one or other of the following categories. The primary alteration in gout is variously assumed to be:—

(1) In the blood or tissues, the so-called histogenous theories.

(2) In the bodily structures, either inborn or induced.

(3) In hepatic inadequacy.

(4) In hyperpyræmia.

(5) In the nervous system.

Histogenous Theories

In his classic work, “On Urine” (1860), Parkes expressed his scepticism as to the valency of Garrod’s assumption of a primary renal inadequacy. In shrewd forecast of latter day views he was of opinion that both uric and phosphoric acids existed in some untoward combination in the blood or organs, and that this same impeded its excretion. As he says, “If this be the case, the deficient elimination is, as it were, only a consequence of more important antecedent aberrations in metamorphosis of which impeded excretion is a natural sequence. What these are, however, is quite unknown; but an unnatural formation of uric acid, either from food or tissues, may possibly be part of them.”

In 1866 Barclay lodged another objection to Garrod’s hypothesis, viz., that the baneful influence of uric acid was exercised passively and physically. Not only did he regard it as “far too mechanical,” but he also strongly dissented from his axiom that[24] gouty inflammation was invariably attended by uratic deposits. Thus he asks, “Must we of necessity find urate of soda in the stomach and the bronchi before we can admit gouty gastritis, or gouty bronchitis?” Seemingly he believed in the existence of these two clinical entities, and inasmuch as urate of soda had not been detected in situ in these disorders, he felt justified in denying that “true gouty inflammation is always associated with, or caused by, the deposit.” Moreover, this conclusion, he considered, derived colour from the fact that, “though the deposit and the inflammation were associated together in the joints, the urate of soda was seen in other parts without any evidence of its exciting inflammation there.”

His own view was that the primary change lay in the blood corpuscles, this being induced by the serial ingress of “gout producing elements” into the blood stream. As to the retention of uric acid, he deemed it not the cause, but merely a symptom, a consequence of gout. Thus he says, “The good living and the stimulants do not simply cause an excess of uric acid to form, but they end by causing some more permanent change, and probably one affecting the blood globules, which reacts on the kidney, putting a stop to the excretion of uric acid, and causing its retention in the serum, where, passing in the round of the circulation, it is very apt to become deposited as urate of soda.” Moreover, his observations of the effect of colchicum in checking a gouty paroxysm, seem to indicate, “that there is a disease to which the name ‘gout’ is applied, distinct from the excess of uric acid in the blood serum which attends its progress.”

The imaginative insight of Barclay is very remarkable. If we substitute the white for the red corpuscles we see how closely his views accord with those prevalent at the present time, when so important a rôle in the genesis of gout is attributed to the leucocytes. Moreover, as Ewart observed, the views of Barclay and Parkes approximate in principle to those afterwards propounded by Ord and Ebstein, that the bodily tissues “take an active share in determining the deposition of uric acid.”

It is, however, but fair to note that, long prior (1854) to Barclay, Gairdner held that “the disappearance of urea and uric acid in the urine and their accumulation in the blood” was but symptomatic and not causative of gout, coupling with it the suggestion that there was some antecedent nerve influence at work.

Laycock, too, it may be noted, considered Garrod’s theory inadequate, adding that “Gout is characterised not by urates in the blood but by the genesis of uric acid in the tissues, and its action thereon, and is especially characterised by peculiar changes in the innervation of the individual.”

[25]

Antecedent Structural Changes

In 1872 Ord took up the novel standpoint that there was an inborn tendency in the fibroid tissues of gouty subjects to undergo a special type of degeneration, which same might be inherited or acquired. Also that this innate peculiarity was attended by excessive formation of urate of soda in these tissues, and which subsequently gaining entry therefrom into the blood, was deposited promiscuously in the body with a predilection for relatively non-vascular structures, viz., cartilages.

As to the local inflammations typical of gout, Ord’s attitude was somewhat ambiguous. Thus he maintains, “The local inflammations do not necessarily depend upon the deposit of urate and the deposit is not a consequence of inflammation; at the same time, it is probable that excess of urate in the blood produces irritation of tissues.” Neither did he believe that the local inflammatory reactions were of necessity in every instance specific, viz., due invariably to mechanical irritation by uratic deposits, but that they might be initiated by injuries, exposure to cold, etc. Lastly, as to the migration of the disorder from place to place, he believed that for its explanation direct or reflex nervous agencies had to be invoked, for he held the opinion that the local gouty “degeneration and inflammation tend to infect the rest of the system through the blood, and to set up similar actions elsewhere through reflex nervous influence.”

We see, therefore, that for Ord gout, as Ewart observes, was “a mode of decay” or a “disease of degenerations.” “The local tissue degeneracies supply a basis for the uratic deposits and the general degenerative changes multiply the sites exposed to an infiltration from the contaminated blood; whilst reflex mechanisms step in as additional determining agents.”[4]

Reminiscent of Ord’s view is the hypothesis associated with the name of Ebstein. As the outcome of experimental study he arrived at the conclusion that the primary factor in the causation of gout was a disturbance of tissue nutrition culminating in death or necrosis of the damaged textures. The initial nutritional derangement was ascribed by him to the irritant effect of soluble neutral sodium urate. This necrotising agent, following the development of “free acid” during the process of necrosis, was transmuted into the acid urate. Subsequently this same was deposited in crystalline form in the necrosed area. He held these areas of necrosis quite as typical of gout as the uratic deposits, and postulated their combinations to be necessary for the production[26] of a true gouty focus, claiming that he had detected such foci in cartilage, tendons, kidneys, and connective tissue.

Experimentally, Ebstein endeavoured to induce a gouty condition in fowls by ligaturing both ureters, thus thrusting upon the circulation the dammed-up uratic secretion. In other instances he administered to the same animals subcutaneous injections of neutral chromate of potassium, attributing to this substance the power of inhibiting the excretion of uric acid viâ the kidneys through its action on the renal parenchyma. Subsequently, after death he noted the incidence of uratic deposits in joints, muscles, tendon sheaths, and liver, the same being more copious in those animals subjected to chromate injections.

His conclusions were: (1) That necrosing and necrotic processes are developed in various organs as a result of some irritant. (2) That uratic deposits occur in the necrosed area resembling those met with in gouty subjects. (3) That an inflammatory reaction with small cell infiltration ensues in the vicinity of such necrotic areas.

But, in regard to these experimental investigations, they are obviously incomparable to the morbid processes that presumably occur in gout in man. Moreover, as shrewdly pointed out by Levison, experimental ligation of both ureters would certainly engender uræmia rather than anything approximating to gout.

Again, his experiments with urates and uric acid, by which he claims to have demonstrated their action as chemical irritants capable of inducing necroses in tissues, have proved fallacious. This, for the very cogent reasons pointed out by Luff, which run as follows: “Not only is there no proof that the neutral sodium urate upon which he depends for the starting of the gouty changes, ever exists in the human body, but, on the other hand, very strong evidence to show that it never can exist in the human body.”... “The neutral sodium urate is an extremely caustic and unstable compound, and is decomposed in the presence of carbonates, so that it is impossible for it to exist in the blood. The first factor upon which Ebstein relied for his theory for the causation of gout therefore disappears.”

Again, Ebstein’s fundamental proposition that in gout uric acid was produced in many tissues not normally concerned in its production, was ruled out by Horbaczewski’s establishing the fact that in health uric acid is a by-product of the metabolism of almost all tissues. Lastly, the strong toxic properties accredited by him to solutions of the urates was disproved by Pfeiffer’s experiments. This observer showed that urates, in such degrees of concentration as may exist in the human body, are incapable, when injected into the tissues, of inducing necrosis.

[27]

In summarising the doctrines of Ord and Ebstein, it may be observed that if the latter’s contentions have been disproved, Ord’s claim that the tissues of gouty subjects exhibit a specific tendency to degeneration has also as yet not been substantiated. Albeit, we must not forget that in 1883 Ralfe subscribed to Ord’s views as to the tendency to textural degenerations in gouty subjects, either through heredity or acquirement. For this observer, however, the basal factor in the production of the disease was a diminished alkalinity of the blood, due to a surcharging of it with acid and acid salts. Disagreeing with Garrod’s assumption that deficient renal elimination was the prime cause of the retention of uric acid, he was of opinion that “the first step in the process lies in the failure of the tissues to reduce the acid, as it occurs in health.”... “In the large glands or where the current of the circulation is free, the uric acid is carried into the blood and gradually reduced to urea; in tissues outside the current of the circulation, the insoluble uric acid is not so readily carried off, and so on the slightest disturbance is deposited, as is the case in cartilages of the joint, the ear, etc.” As to the determining cause of the gouty attack, he invokes the agency of the nervous system to explain its incidence, for he held it probable that the primitive failure of the tissues to reduce uric acid eventually led to derangement of some special nerve centre, which disturbance occasioned the gouty outbreak, with resultant “accumulation of uric acid in the blood and deposition of urate of soda in the tissues.”

In 1895 Berkart propounded a mode of genesis which may be regarded as a variant of Ord’s theory. The severity of the symptoms of acute gout were such as he deemed incompatible with their production as a result of simple mechanical irritation by crystals of biurate of soda. Uric acid, he held, must be afforded a humbler rôle than that of a proximate cause. It was, for him, but an epi-phenomenon, the accompaniment of a panarthritis, the origin of which was as follows:—

While not postulating the identity of rheumatoid arthritis in gout, he yet held that both disorders originated in some obscure form of atrophy of the bone substance, and that the degenerative change also overtook the cartilages and fibrous tissues of the joints. Subsequently, there ensued a necrosis in the tissues in and around the joint. The degeneration and subsequent necrosis, he held, were the outcome of a profound “vice of nutrition.” The pain, inflammatory reaction, œdema, and cuticular desquamation were the direct result, he thought, of the necrosis. The excess of uric acid in the blood he referred to leucocytosis, and in part to disintegration of the tissues.

[28]

Hepatic Inadequacy

That some obscure connection obtained between gout and hepatic disorder has been for long an axiom in high favour, with both clinicians and pathologists. This hypothesis found its chief exponents in Murchison and subsequently Latham, and to discussion of their individual views we now proceed. The first named authority held gout to be either merely a result or a variety of what he termed lithæmia. In other words, gout was the outcome of a depraved condition of the blood, due to faulty digestion and functional disturbance of the liver.

Now the conditions that lead to functional derangement of the liver are in the main such as favour the development of gout. Nevertheless, such hepatic disturbances do not inevitably culminate in outbreaks of gout, at any rate of classical type; but, unquestionably, such may eventuate in symptoms currently recognised as distinctive of incomplete gout, e.g., headache, palpitation, cramps, dizziness, sleeplessness, etc. Moreover, if the faulty habits leading to such hepatic derangement be persisted in, they are but too likely to induce outbreaks of frank gout. “Articular gout,” said Murchison, “is so to speak a local accident which, though sometimes determined by an injury, yet may occur at any time in persons in whom the normal process by which albuminous matter becomes disintegrated in the liver into urea is persistently deranged.” Following such hepatic disturbance, the secretion of bile decreased with resultant abnormal metabolism of proteins, and in this way was produced an accumulation of uric acid. This, moreover, according to Murchison, was, especially in the later stages of gout, reinforced by the concurrence of renal inadequacy, which he also postulated as a factor in the production of the disorder.

The tendency to lithæmia Murchison held to be hereditary, and in this was supported by Goodhart, who, discussing its occurrence in young children, was strongly of the opinion that it was due not to dietetic irregularities but to a “constitutional tendency on the part of the individual”; a conclusion, as he thought, strongly supported by the fact that it is more commonly met with in the children or descendants of the “gouty.”

But we have to recollect, as Duckworth observes, that lithæmia, “even when persistent and not due to accidental causes, is not by itself gout.” Moreover, gout is not the only morbid condition in which urates are in excess in the blood, for such obtains, e.g., in leukæmia, pneumonia, anæmia, Bright’s disease, etc. Also, underlying Murchison’s theory is the further unwarrantable assumption, viz., that the “gouty” diathesis is identical with the “uric acid” diathesis.

[29]

Now, as we hope to show later, whatever be the proximate cause of gout it is at any rate not uric acid. The fact, too, that higher degrees of lithæmia are to be met with in conditions, not even remotely connected with gout, renders it impossible to accept the view that the excess of urates in the blood is responsible for all the varied symptoms accredited by Murchison and his followers to lithæmia. For the same reason, it is difficult to uphold the hypothesis that “the tendency to lithæmia in early life may be an early expression of the ‘gouty’ diathesis.”

In short, excess of uric acid in the blood or lithæmia is not pathognomonic of gout, much less of “potential” gout. But further discussion of this assumed relationship of lithæmia to gout may well be postponed until, in the light of recent blood analyses, we come to consider more narrowly the contention at one time widely held, that lithæmia is an irregular manifestation of gout.

If we are compelled to adopt a more judicial attitude in regard to lithæmia, what of the similar assumptions as to the relationship of lithuria or lithiasis to gout? Now lithuria, like lithæmia, was and probably still is by some held to be an inherited “gouty” proclivity. Sufferers in youth from lithiasis were deemed likely to develop gout in later years. Not only was lithiasis observed to precede but also to be a concomitant or sequel to gout. Nevertheless, although uric acid, gravel and calculi, sometimes arise in those of “gouty” diathesis, these instances are but isolated, so rare indeed as to entitle them to be regarded as mere coincidences. Moreover, when we recall the fact that the formation of calculi takes place in the urinary passages, i.e., outside the economy, it renders even more improbable the hypothesis that the two morbid phenomena are diverse expressions of the “gouty” diathesis.

As a matter of fact, the large bulk of “gouty” subjects are immune from gravel. Conversely, only a negligible percentage of the victims of gravel develop gout. The geographical distribution of the two disorders is wholly distinct one from the other. The Indian native is a martyr to stone, but notably exempt from gout. Coming nearer home, we find stone relatively common in Scotland, but gout rare. Plowright’s researches, too, revealed no correspondence between the incidence of gout and the prevalence of stone in the several counties of England. In some counties in which the mortality from gout was high that from stone was low, and Norfolk, the one most prolific of stone in England, enjoys comparative immunity from gout.

Reverting now to Latham’s views as to the hepatic origin of gout, we find them very similar to those formulated by Murchison. He held that the defective transmutation of glycocine into urea was[30] responsible for the occurrence of uric acid in the urine. These chemical irregularities were attributed by him to functional disturbance or partial suspension of the normal hepatic metabolism. This, again, was referred back by him to some obscure change in the central system, viz., that part of the medulla oblongata from which the vagus takes origin.

Hyperpyræmia

Excess of carbonaceous materials in the blood was considered by Hare to be an essential, though by no means the sole factor in the genesis of gout. This same “hyperpyræmia,” as he terms it, was also, he believed, responsible for migraine, asthma, epilepsy, and other paroxysmal neuroses. For the alternation of attacks of acute articular gout with paroxysms of migraine, asthma, and epilepsy, seemed to him to indicate a kindred origin. The same inference, also, he deemed might be drawn from the well-ascertained fact that the temporary or even permanent cessation of long standing asthma, migraine, and epilepsy, might exactly coincide with the onset of acute gout.

These alternations and substitutions seem to suggest that the preceding alterations in metabolism are similar in nature, finding expression indifferently in gout, asthma, epilepsy, etc. Carbon foods, he considered, are much more likely to accumulate in the blood than the nitrogenous. Ingestion of the latter is swiftly reflected in increased elimination of nitrogenous excreta. On the other hand, following the intake of carbonaceous foodstuffs, no such rapid and proportionate increase in the excretion of carbonic acid ensues. In other words, the capacity of the organism to deal with or katabolise in response to the absorption of excess of carbon foods, is strictly limited. Muscular exercise and exposure to cold, factors which but slightly influence protein katabolism, are largely responsible for adequate carbon katabolism. Accordingly, given deficient exercise, excess of carbonaceous food and a warm temperature, an accumulation of the carbon content of the blood is favoured.

Hare considered that present day habits of warm clothing, warm rooms combined with excessive intake of starch and sugar, are precisely the favourable conditions for producing a state of hyperpyræmia. Increased fat formation would of course tend to diminish such a tendency to carbon accumulation, but this capacity in many subjects is conspicuously lacking, and may already have attained its limit.

Hare contended also that excessive intake of starch and sugar by inducing a state of “glycogenic distension” of the liver, might[31] through compression of the intra-hepatic portal capillaries, lead to congestion of the retro-hepatic portal venous system, and sequentially of the gastric and intestinal mucosa. Through consequent inhibition of digestion and absorption, a condition of hyperpyræmia is induced. This, under varying conditions, may eventuate in acute gout, the coincident pyrexia of which is curative of the underlying hyperpyræmic state, and of all those hyperpyræmic manifestations (irregular or suppressed gout) which so often are the harbingers of an on-coming articular outbreak.

Nervous Theories

It may be noted en passant that the influence of the nervous system was frequently invoked directly or indirectly in many of the theories already discussed. Stahl, it will be recalled, was the pioneer in this direction, and later Cullen and Henle propounded the view that “the origin of the affection was probably to be found in the central nervous system.” Gairdner, too, by implication, as also Laycock, postulated a neural origin for at any rate some of, the phenomena of gout.

But it was reserved for Edward Liveing (1873) explicitly to advocate the nervous origin of the disease, his reflections on the paroxysmal nature of the attacks, its tendency to periodicity leading him to suspect its kinship with other neuroses.

Those inclining towards the neural conception were later strengthened in their convictions by Charcot’s momentous identification of the nervous origin of certain arthropathies. Accordingly, in 1880, we find Sir Dyce Duckworth advocating the view that gout was “a primary neurosis,” “a functional disorder of a definite tract of the nervous system.”

The gouty neurosis, Duckworth contended, may “be acquired, intensified, and transmitted; also that it may be modified variously and commingled with other neuroses; that it may suffer metamorphic transformations, or be altogether repressed.” Arguing by analogy, Duckworth saw in the paroxysmal attacks, the tendency to periodicity and alternation in the manifestations, evidence of an alliance between gout and the various neuroses.

He further postulated that “this diathetic neurosis determined a disorder of nutrition and led to the perverted relations of uric acid and sodium salts in the economy.” He also held that the localisation of attacks, and the determination of urate of soda to the affected part was also due, in all probability to nervous influence. And the temporary renal incapacity for excretion of uric acid was also attributed by him to the same nerve inhibition.

We see, therefore, from the above, that Duckworth was well[32] justified in describing his view as a combine of the humoral and neural hypotheses. His pathological differentiation between primary or inherited gout and secondary or acquired gout is as follows: In the primary type “the toxæmia is dependent on the gouty neurosis ... and is therefore a secondary manifestation.”

In secondary or acquired gout, “the toxæmia is directly induced by such habits as overload the digestive and excretory organs, and consequently prevents complete secondary disposal of nutritional elements of food; that if, together with such toxæmia, distinctly depressing and exhausting agencies, affecting the nervous system, come into operation, the special neurotic manifestations of the gouty diathesis will occur, and be impressed more or less deeply upon the individual and his offspring.” It is generally conceded that Duckworth’s theory as to the genesis of gout is pre-eminently catholic in conception, because, as Ewart rightly remarks, “it represents the most complete theory published in this country on the general pathology of gout,” and because “the able advocacy of its propounder has given it the support of arguments derived from pathological analogy and from clinical influence which will demand careful examination and searching criticism before they can be either disproved or adopted.”

Albeit, it must be frankly admitted that Duckworth’s perception of gout as a tropho-neurosis of central nervous origin has never gained wide acceptance; this no doubt largely because it was insusceptible of proof. In an endeavour to remove this reproach. Sir Willoughby Wade promulgated the view that the causal change in gout was partly in the central nervous system, partly in the peripheral nerves of the inflamed limb. In other words, he regarded gouty arthritis as the outcome of a local neuritis, this latter being set up in the first instance by the faulty blood state, viz., uricæmia. On the other hand, the central nerve centres might occasion or aggravate the general gouty tendency through their influence over “recognised seats of metabolic activity.” Also the same might, through the medium of the vaso-motor nerves, determine the incidence of local attacks. It will be seen that Wade’s theory is but a variant of that propounded by Duckworth, viz., neuro-humoral.

Growing Scepticism as to Garrod’s Pathogeny of Gout

It will be recalled that as far back as 1889 Duckworth displayed disquietude as to the adequacy of the purely chemical or purely physical view of the pathogeny of gout, as sufficing for an explanation of all its varied phenomena. Thus he writes: “It is incumbent, I believe, to invoke not only a chemical and physical basis for gouty disease, but to include also, in a comprehensive view,[33] the marked determining influence of the nervous factor in the problem.”

Whether we agree or not with Duckworth’s view of gout “as a diathetic neurosis, due to a central neurotic taint, and originating from prolonged toxæmia,” it does, I think, mark the dawn of a reaction from the uric acid theory of its causation. Still, this latter conception continued to dominate the field until seriously called in question by the results of Magnus Levy’s researches. His revelations were, in truth, almost revolutionary, and doubts now accumulated as to the propriety of the terms “uric acid diathesis,” “uric acid intoxications,” “lithæmia,” etc., so long credited as being responsible for not only nearly all the minor ailments flesh is heir to, but especially those relating to joints and muscles, all alike attributable to the presence of excess of uric acid or urates in the blood.

To hasten the process of disillusionment there came from the side of the physiologists the announcement, almost unanimous, that uric acid, though in minimal amounts, is a normal constituent of the blood, organs, and tissues. Thoroughly purged now of their obsession as to the pathological potency of uric acid, there awoke a spirit of inquiring scepticism. On all sides it was felt that the whole problem must be looked at afresh, untrammelled by previous conceptions, no matter how high the sanction. How else, indeed, could the chaff be winnowed from the grain, the illusions born of inaccurate observations be replaced by the substantial form of truth?

Still, it would be ungracious to withhold our due meed of admiration for the masterly manner in which the views of the earlier physicians as to the causation of gout were elaborated, the shrewd and often prophetic inferences, well buttressed by arguments based on clinical and pathological analogies; these the more wonderful when we recall the meagreness of the positive material at their disposal, and that little, alas! how often ambiguous!

In light of latter day views, too, we may well admire the swiftness with which the inadequacy of Garrod’s theory to explain all the protean phenomena of gout was realised. Like Duckworth, they rightly apprehended gout to be “something beyond the resultant effects of aberrant relations of uric acid; that it consists in something more than a perversion of animal chemistry; that it is not to be explained as a mere outcome of gastric or hepatic distemper; and that it is not the appanage only of the middle-aged or elderly high liver, and intemperate drinker, because, as is well known, it affects also sometimes in early life the high thinker and the laborious bread-winner.”

That the uric acid theory should more than any other have found[34] ready acceptance, is not so much to be wondered at. The one solitary pathological fact that emerged out of the mist of hypotheses was that established by Garrod, viz., the excess of uric acid in the blood. It survived and still survives the corroding test of time. Surely such must be the fons et origo mali, and how obtrusive the uratic deposits, so ready to hand, objective affirmations of the truth of their contention.

This apparent simplicity how delusive! yet not wholly unprofitable. For if in these latter days our knowledge of the life-history of uric acid and purin bodies in the organism has evolved from “a state of chaos and guesswork to one of system and scientific accuracy,” the seeds thereof were sown by these hardy pioneers, their, to us crude, researches in the dark regions of bio-chemistry.

Here it would appear opportune to outline our plan of procedure in approaching this abstruse subject—gout. In the coming chapter we shall attempt to define and classify the various types of the disorder before passing on to discuss its etiology and morbid anatomy.

Now all will agree that the more recent revelations of chemical physiology and chemical pathology have an intimate bearing on the problem to be considered. We shall therefore, before proceeding to the more purely clinical aspects of the disease, deal with the modern conceptions of protein and purin metabolism, more especially the latter. Subsequently our scrutiny will be narrowed to consideration of the chemical structure of uric acid, its solubility, sources, mode of formation and destruction. In possession of these facts the relationship of uric acid to gout will be dealt with, in regard to respectively uric acid excretion, uricæmia, and uratosis.

The inadequacy of the uric acid theory of the causation of gout will then be discussed and the possible intrusion of an infective element in its genesis advocated. This accomplished, we shall proceed to the section dealing with the clinical aspects of the disorder, its regular and so-called irregular manifestations. Thence we shall proceed to the diagnosis of gout, while the terminal chapter will be devoted to that all-important subject—the prophylaxis and treatment of the affection.

Definition and Classification

Said Locke long since, “There are some words which will not be defined,” and surely of these is gout; for reflection upon the proffered definitions thereof is apt to leave one with the depressing impression that the disorder is both “incomprehensible and infinite.”

But have we not by unjustifiable and unwarrantable assumptions deliberately complicated the issue, in recklessly relegating to the gouty category a myriad affections of the intimate nature of which we are as ignorant as we are of gout? Doubtless, this is in part the outcome of a too slavish adherence to tradition, an undue reverence for authority. In all deference, our forefathers were somewhat too hasty in their speculations as to the causation of gout. Dominated by the prevalent philosophy of their days, they strove to interpret the phenomena of gout through its lights, endeavouring to reduce the study of its pathology to philosophical order when the very elements of philosophical order were lacking.

The same is reflected in the earlier, and to a lesser extent in the latter day definitions or descriptions, as some of them more aptly may be designated, notably that put forward by Sir Charles Scudamore.

For myself, I would proffer the following definition, which, of course, the reader must accept provisionally, viz., pending the perusal of subsequent chapters, dealing with the pathology and clinical features of gout, and the inferences drawn therefrom as to the nature of the disease.

Definition.—Gout is an hereditary disorder, the intrinsic element of which is an inborn instability of nuclein metabolism which may remain latent, but under the influence of extrinsic factors, infections, becomes manifest, as betokened by local inflammatory tissue reactions in joints or elsewhere the specific character of which is attested by the associated uratic deposition.

Classification

At the present time, under the most liberal interpretation, the word “gout” comprises the following conditions, viz., acute and chronic articular gout, and the so-called ab-articular forms. But it is clear that not only the latter or irregular manifestations, but even the former or regular varieties of the disorder seem destined to undergo considerable pruning.

As to the classical podagra—acute articular gout—no question can arise as to the propriety of its retention in this category. But as to the chronic articular types we are on less certain ground, and to discussion of this vexed question we now proceed.

Let us take, for example, Sir Dyce Duckworth’s classification of the arthritic types of gout. He distinguishes the following forms:—

• (1) Acute articular gout.
• (2) Chronic articular gout

the latter (2) further subdivided into—

• (a) the “tophaceous” variety.
• (b) the “deforming” variety.

[37]

Of these twain the “tophaceous” form need not detain us, and why? Simply and solely this—the uratic deposits stamp the seal of specificity on the disorder. In short, the presence of tophi places the “gouty” origin of the arthritis beyond the pale of cavil.

Now, if we accept, as we must, the fact that uratic deposition is the solitary unequivocal clinical criterion of gout, we are not, I contend, justified in classing any chronic arthritis as “gouty,” the victim of which does not exhibit tophi of articular or ab-articular site, either clinically demonstrable or deducible from skiagraphic revelations.

Nevertheless, be it noted tophi do but bespeak the “gouty diathesis,” not necessarily the “gouty” nature of an associated arthritis. For clearly tophi, of ab-articular location, may coexist with an arthritis of gonococcal or other origin. But given uratic deposits, either in the joint proper or its related structures, all reasonable doubts as to the true “gouty” nature of the arthritis are disposed of. On the other hand, in the absence of tophi, the diagnosis of an arthritis as “gouty” is presumptive, not absolute. This even in acute classical outbreaks in the big toe, viz., pending the finding or subsequent eruption of tophi.

In saying this, I do not for one moment depreciate the diagnostic value of the clue afforded by location of the initial outbreak of the disorder, in the vast majority of instances, in the big toe. It is an invaluable, but not an infallible clue; for, unfortunately, acute arthritic diseases other than gout may elect to announce themselves in the great toe.

Moreover, there is nothing specific in the external characters of acute “gouty” inflammation, nothing in the objective changes which would stamp them on sight as “gouty,” save only their location in the great toe; nothing distinctive about the angry blush, œdema, and engorged veins, all of which may be met with in infective arthritis. There may be, as Garrod with good reason affirms, a local intra-articular deposit of urate of soda, but this lies beyond our ken, presumptive but undemonstrable.

Let but the initial outbreak of gout occur elsewhere than at the big toe, say, e.g., in the wrist, hand, ankle, or knee, and we are at once, diagnostically speaking, en l’air. In this impasse how impotent are we, and how painfully we realise that our diagnosis of acute gout is largely topographical, not etiological! Not, strictly speaking, etiologically diagnosable pending the eruption and detection of tophi. In short, location per se in the big toe is strongly suggestive but not diagnostic of “gout.” (Vide Chapters on Diagnosis.)

If this be done in the green, what then shall be done in the dry?[38] In other words, if so precarious our diagnostic foothold in acute, how much more so in chronic articular gout! for in the latter even topography may wholly fail us, what then our diagnostic criterion?—tophi and tophi alone—aye, and demonstrable at that.

Yet both Charcot and Duckworth would have us recognise not only a tophaceous but a non-tophaceous variety of chronic articular gout, for that is what it amounts to. They apparently feel justified in labelling a chronic arthritis as “gouty” even though tophi “may not exist” or “be invisible”! Deformity, say they, is its hall-mark, not tophi, and its character forsooth, they add, is not only not peculiar to gout, but clinically indistinguishable from the similar defacements met with in arthritis deformans. Nor is Duckworth alone in his contention, for both Ewart and Luff also recognise what they term “chronic deforming gout.”

Tophi, I contend, notwithstanding, are essential for the diagnosis of gout. In their absence, the designation of an arthritis as “gouty” is unjustifiable. Either tophi are, or tophi are not the sole pathognomonic feature of gout. If the latter, then gout ceases to exist as a clinically recognisable entity.

Holding tophi indispensable for the diagnosis of gout, I maintain that Charcot and Duckworth’s plea for the recognition of a chronic type of articular gout, apart from the tophaceous variety, is untenable. Fraught, moreover, with risk, as I am satisfied that their so-called, “deforming” type is largely made up of the atrophic and hypertrophic forms of arthritis deformans.

Suggested Classification of Articular Gout

For myself, as to the classification of the articular types of gout, I would divide them into:

• (1) Acute articular gout.
• (2) Chronic articular gout.

Under the first group I would place not only the acute localised type, but also those acute varieties of polyarticular distribution. As to the second category, I would exclude therefrom, for the reasons cited, the so-called “deforming” varieties of chronic articular gout, recognising only the so-called tophaceous form. But I would place a different interpretation on this term in opposition to that generally accepted; for, by most writers the word tophaceous is apparently limited in its application to examples which, so to speak, exhibit tophi of phenomenal size or number. Scudamore was the chief offender in this respect. As a consequence, he found tophi in only 10 per cent. of his cases of gout. Accordingly, he went so far as to postulate for such victims as did present this peculiarity an idiosyncratic tendency to chalk-stones![39] In other words, he would seem to suggest that there is a gout within gout, that one displays chalk-stones, the other not. By inference, Duckworth and his followers, by differentiating tophaceous gout, tacitly concur, and so “confusion twice confounded” results.

This usage of the term “tophaceous” is unjustifiable and misleading. The significance of tophi is qualitative not quantitative. One tophus bespeaks the “gouty diathesis” as surely as a myriad concretions. Solitary though it be, the same, given elimination of all other sources of arthritis, will suffice to establish the “gouty” nature of an associated joint disorder. It is in this more catholic sense that I would translate the term “tophaceous gout.” The conclusion, then, to my mind, is obvious—there is but one form of articular gout, and one only, viz., an arthritis, the victim of which exhibits uratic deposits in situ or elsewhere in his body. On this and on no other grounds can a chronic arthritis, with any show of certitude, be certified as truly “uratic” or “gouty.”

This rigid attitude may not commend itself to some, but I feel convinced that, only by holding on grimly to the tophus, shall we steer a safe course through all the pitfalls that beset the diagnosis of the chronic arthritides. Only in this way, too, can we preserve for ourselves a clear conception of gouty arthritis as a specific disorder, the which otherwise loses its identity, submerged in a medley of joint diseases. Prior to the differentiation of gout, on the one hand, from rheumatism and arthritis deformans, and on the other from the nerve arthropathies and the infective arthritides, such laxity might be condonable, but not, we think, in the present stage of our knowledge.

In drawing to a close my remarks on the classifications of articular gout, it will be noted that I have made no reference to that variety known as retrocedent gout, but to this I shall allude at a more favourable juncture, viz., in the chapter devoted to the clinical account of articular gout. Conformably, too, it will, I think, be more convenient, to defer any criticisms of the term “irregular gout” to the chapter I purpose devoting to consideration of the varied clinical content of the same.

Etiology and Morbid Anatomy

To the antiquity of gout and no less its distinctive clinical facies, when of classic type, we owe not a little. Its salient phenomena have endured unchanged from the time of Hippocrates onward through the ages. So it is that, even allowing for the enhanced powers of discrimination of latter days, we are in no doubt that the gout of the ancients is the gout of to-day. How signal the advantage thus accruing, when we come to consider the conditions[40] which engender or tend to engender the disease! For, quâ its broad etiological factors, we find ourselves in accord with the physicians of old, our experience a confirmation of their old-time findings.

Our forefathers, like ourselves, realised the innate complexity of the problem, that in the development of the disorder both heredity and environment played a rôle. In other words, that in the genesis of gout not only intrinsic but extrinsic agencies were concerned. Of the intrinsic influences the most important are age, sex, heredity, bodily conformation, and individual peculiarities.

Age.—Gout is slow in evolution, tardy of appearance, confined in the main to the middle and declining years of life. Said Sir Thomas Browne, “Leprosie awakes not sometimes before forty, the gout and stone often later.” Experience but confirms the dictum, for, as Cullen long since observed, it rarely declares itself under the age of five-and-thirty. This relative immunity of youth is not the least striking feature of the disorder; whence the Hippocratic aphorism, “Puer non laborat podagra, ante veneris usum.” Both Sydenham and Heberden were also doubtful of its occurrence before the age of puberty. Gairdner, however, records the incidence of fits of gout even in infants at the breast! and in one death therefrom. Garrod, too, met with two cases of classical type in girls, both of them under ten years of age. But Scudamore states that he never witnessed more than one example of a first attack before twenty, or any after sixty-six.

For myself, I have never seen a case under thirty-five years of age, and am sceptical as to the occurrence of infantile gout of regular type, believing with Scudamore that “the commonly asserted cases which represent the existence of the gout in very early youth are really examples of rheumatism.” Nor am I less but more inclined to cavil at the claims of Comby and others, as to the frequency in children of irregular manifestations. As Osler dryly observes, “The tendency in some families is to call every affection gouty. Even infantile complaints such as scald-head, naso-pharyngeal vegetations, and enuresis, are often regarded, without sufficient grounds, I believe, as evidences of the family ailment.”

To sum up, the majority of cases of gout ensue between thirty-five and fifty years of age. But, given a strong hereditary taint, it may break out in youths and young adults, or haply even in children. But such, in my experience, are phenomenally rare. Indeed, it may be said of gout that only exceptionally is it met with at either extreme of life; though Garrod records several examples in which the initial attack was postponed until nigh eighty years of age;[41] while in one instance, a lady experienced her first classical attack of podagra in her ninety-first year.

Sex.—In the matter of liability to gout the sexes stand in marked contrast, the disorder being infinitely more common in males. Out of eighty cases submitted to the French Academy, seventy-eight were men and only two women; but according to other authorities, this is an under-estimate. Thus in James Lindsay’s series of cases of gout, 84·7 per cent. were males, 15·3 per cent. females, percentages which he notes “are in accordance with the observations of other writers.” J. Lambert, out of 125 examples of gout, noted that 102 were men, i.e., 81·6 per cent., twenty-three women, i.e., 18·4 per cent.

From my own experience, the figures submitted to the French Academy probably represent the ratio of incidence in males as opposed to females. This certainly, if regular, in opposition to “irregular,” types of gout be the criterion; for it must be admitted that regular gout does occur in women, though exceptionally rare either prior or subsequent to the climacteric.

As to the current opinion that the regular manifestations of gout in women are of asthenic as opposed to sthenic character, this has, I think, often proved a source of fallacy. At any rate, in many of these cases the assumed gouty inflammation resolves itself into one of inflamed bunion. Again, in but too many instances, women, showing Heberden’s nodes, are held to have gout or “rheumatic gout.” The latter term, as Pye-Smith observed, “is a bad name for osteoarthritis,” to which category Heberden’s nodes belong.

Judged by the one unequivocal diagnostic criterion, i.e., tophi, gout in women is extremely rare. If to this be added the further fact, viz., the rarity in their sex of classical attacks in the great toe, we see clearly that the diagnosis of gout in women is often a matter of assumption rather than of certitude.

Moreover, having regard to the fact that the diagnosis of gout in women is frequently based on so-called “masked and irregular manifestations,” I must admit that, to my mind, statistics, purporting to indicate the percentage incidence of gout in women and men, are not very convincing.

As to the why and wherefore of the relative immunity of women it may be due to the fact that their habits and mode of life are less calculated to evoke the disorder. There is also the further possibility that the catamenial discharges to a certain extent are protective against gout, for most authorities support Hippocrates’ aphorism, “Mulier podagra non laborat nisi ipsi menstrua defecerint.”

Heredity.—By the ancient physicians gout was held to be[42] hereditary, and even to-day most will agree that “From father to son its seeds are transmitted, and bear fruit in exact proportion to the degree in which circumstances prove favourable to their growth.” Cullen, indeed, went further and held it purely hereditary; but, on the other hand, the belief, that it is often acquired is widely countenanced.

That gout is an hereditary disease is, I think, beyond question, and certainly, of all arthritic disorders, gout furnishes by far the greater number of instances in which parents and children are victimised by the same articular affection. Scudamore in 522 cases found that 332 could trace their disease to the father, mother, grandfather, grandmother, or aunt. But in the remaining 190 no evidence of the existence of gout in their forbears could be elicited. Out of eighty examples submitted to the French Academy an hereditary predisposition was established in thirty-four, and in the residue it appeared to have been acquired. Garrod found that 50 per cent. of his hospital examples of gout were hereditary, and of his private patients nearly 75 per cent. came of gouty stock. Again, Sir William Roberts found that “fully three-fourths of the cases of gout occurring among the easy classes, can be traced back distinctly to a gouty ancestry.” Luff’s estimate is even higher, inasmuch as analysis of a series of 300 examples disclosed a “definite family history of gout in 81·3 per cent.”

Nevertheless, Garrod’s experience, he tells us, convinced him that “in this country gout is frequently acquired even at a moderately early age, for in many most inveterate cases not the least hereditary influence could be discovered.” For myself, I find it difficult to appreciate the attitude of those who, like this observer, postulate innate or static morbid proclivities on the part of the “gouty,” and in the same breath, as it were, are equally insistent that it may be “acquired” de novo. Now, in the taking of family histories positive evidence is more valuable than negative. Surely, therefore, in the light of Garrod’s and Luff’s findings, it is obvious that heredity plays not merely an important, but an essential and indispensable rôle in the genesis of gout. To my mind, accordingly, the balance of evidence is more in favour of the same ancestral taint, though apparently undiscoverable, being present in the remaining 20 or 25 per cent., than that the disease in their instance was wholly and newly acquired.

Personally, I therefore question whether the alleged acquisition de novo of gout is not apparent rather than real. My own opinion is that the innate predisposition thereto is always inherited, and the predisposing factors, that we presume may originate gout, are in reality merely excitants or determining agents. In other words,[43] the remote, the primary or essential cause of gout, is an inborn morbid tissue potentiality, and in the absence of this intrinsic warp the various contributory or exciting causes are impotent to evoke the disorder.

Apart from statistical proof of heredity, how else, save on the basis of an organic predisposition to the disease, can we explain the fact that of a large number of individuals, of slothful habit, and given to alcoholic and dietetic excesses, not one may get gout; while others who lead literally “a godly, sober, and righteous life,” become martyrs thereto. How escape then the conviction that in gout “breed is stronger than pasture”? for, apart from gluttony and indolence, gout is much more prone to arise in persons in whose pedigree it can be traced than in others.

It is not gout, but the predisposition thereto, that is inherited. This proclivity, moreover, may descend to the children of those who, in their own persons, have never suffered from the disease. In Luff’s series it was so in 27 per cent. of the cases, i.e., the disease was transmitted from grandparents to grandchildren without the fathers or mothers suffering from “active gout.” In other words, the morbid potentiality may lie latent until evoked. Thus, the females of “gouty” families, infinitely more often than not, escape overt gout, but hand on nevertheless their inborn liability thereto to their offspring. Looked at in this light, I see no difficulty in accepting the fact that gout may skip a generation. The son of a gouty parent, happily warned by the excesses of his father, may remain immune, while in turn his son, forgetful of his evil heritage, may bring it again to fruition.

The more one reflects on the essential cause of gout, the more inevitable seems the conclusion that gouty individuals, as Walker-Hall contends, “possess some inborn defect or alteration of nuclein metabolism.” And the vague phrases “constitutional” or “nutritional,” as applied by older writers to the disorder, are only explicable on the basis of inherited structural peculiarities, with their correlated perversions of tissue function.

That such constitute the pathological groundwork of gout, is, I think, further indicated by the fact that “gouty” inflammation, in virtue of its associated uratic deposition, is sui generis. No tissues, other than the gouty, react in this specific fashion. Does not this seem to indicate that the inborn tissue peculiarities dictate, so to speak, the character of the pathological reaction; this indifferently, whatever the nature of the so-called predisposing causes which, if our assumption be correct, are merely provocative of gout, in other words, do but evoke or make manifest what is already latent.

[44]

To sum up, on statistical, and more cogently, general clinical and pathological grounds, my own conclusions are that—

Bodily Conformation and Individual Temperament.—Of the hereditary character of gout no doubt remains, but as to the influence of physical build and temperament no such certainty prevails. Said Cullen, “Gout attacks especially men of robust and large bodies, men of large heads, of full and corpulent habit, and men whose skins are covered with a thicker rete mucosum, which gives a coarser surface.” Doubtless, in its more sthenic form, gout affects persons like Falstaff, of sanguine temperament and corpulent habit. But its milder or more asthenic manifestations occur often in men like Cassius, of lean and nervous type.[5]

Of objective stigmata, I know of none, save tophi, that can be[45] truly regarded as pathognomonic of the outward semblance of the “gouty.” The skin of the face may be coarse, unctuous, and studded with ramifying venules. Such appearances, though not always, betray the tippler. Indeed, such stigmata as these are only of value as indicating the habits of the individual, favourable or not, to the development of gout.

Again, it has become a tradition with us that gout produces characteristic teeth. The mere fact that they are “ground down” so as to display the dentine in section is held as evidence of a “gouty” diathesis, or of lithæmia. The teeth of the gouty, it is true, often appear long and square-topped; but the gouty, no more than others, are immune from early recession of the gums. Again, we must recollect that there are several causes which may lead to the teeth being worn down more quickly than normally. Thus the formation of the jaw may be such that the upper and lower incisors meet edge to edge instead of overlapping. This so-called “edge to edge bite” subjects the incisors to marked attrition. Also we must recall that these effects may be aggravated by the nature of the diet. All of us are familiar with the fact that in old horses the teeth are ground down to the gums. The same also is observed in races condemned to live on coarsely prepared flour and hard vegetable food.

In conclusion, having regard to the marked frequency with which disorders leading to early recession of the gums are met with in the “gouty,” and the ease with which the early attrition of the teeth is explicable on tangible mechanical reasons, I am inclined to refer such changes to their combined agency, rather than to the nebulous “gouty” diathesis.

Again, despite Duckworth’s assertion that “the gouty throat is like no other,” I am convinced that it presents no specific appearances. Nor have I been able to satisfy myself that striated and fluted nails of, it is usually affirmed, exceptionally brittle nature, are distinctive of gout any more than the premature whitening of the hair so frequently accredited to the subjects of this diathesis.

One point, however, I would emphasise is, the frequency with which potentially gouty persons suffer from local syncopes and asphyxias of the hands. They are precisely similar to those met with in rheumatoid or atrophic arthritis, certain cases of which, as we shall see later, have another affinity with gout, viz., retardation in the output of exogenous purin.

Locality, Race, Climate, etc.—As to the geographical distribution of gout, the salient fact would appear to be the almost complete restriction of the disorder to the temperate zone. Among the natives of Africa gout, according to Livingstone, is unknown.[46] Neither apparently is it to be met with in Turkey, China, Japan, Peru, and the Brazils. The indigenous peoples of India, and the East Indian Archipelago, also seem exempt, though the immunity does not extend to Europeans resident in these tropical climes.

It is significant that Duckworth, inquiring of practitioners from foreign parts as to their experience of gout, found that little or none was forthcoming “save where Europeans have formed part of the community.” This statement, to my mind, does but add cogency to my contention that gout is always hereditary.

If we restrict our purview to the British Isles and the Continent, we find that as a nation we have achieved the unenviable distinction of being facile princeps in point of the liability to and incidence of gout. The bulk of examples, too, are met with in England, the disorder being much less frequent in Scotland and Ireland. Moreover, in the two latter countries, the disorder is practically restricted to the upper classes. By contrast, in England it has extended to the lower orders also, in respect of which peculiarity we stand unique as compared with all other countries.

Reverting to the Continent, gout appears to be more common in France than in Germany, Austria, and Italy. Indeed, it is said to be endemic in Normandy, Burgundy, and the Rhone Valleys. In Holland, according to Duckworth, there is practically no gout, and the same is true of Russia, save in Petrograd and the Baltic Provinces.

In Belgium, also, gout is not common, and in Greece it is much less prevalent than in France or England.

In regard to the incidence of gout, its greater prevalence in temperate as opposed to tropical climes, and the disparities between different countries, it would be unsafe to assume that the variations are the outcome solely of climate. Thus the immunity of, e.g., strict Mohammedans is attributable in part to their sobriety and the less highly nitrogenous character of their food. But, if seduced into the ways of the “infidel,” their exemption, it is said, ceases. Europeans, of “gouty” heritage, may, if temperate, escape gout when resident in the tropics, otherwise they fall victims thereto just as surely as at home.

Gout, indeed, is more a matter of morals than climate. In the palmy days of the Roman Empire, when luxury and indolence were rampant, gout flourished, but declined following the installation of a republican form of government. In like fashion and for similar reasons, the inhabitants of modern Greece suffer infinitely less from the ravages of gout than of yore. In short, the climate of Italy and Greece has presumably endured unchanged, but the “habits” of their peoples have altered.

Formerly it was held that the incidence of gout in any country[47] or district varied according as to whether the population drank wine and malt liquors, or distilled spirits. Where the taste for the latter predominated, the disease was relatively rare, whence the comparative immunity of Scotland, Russia, Poland, and Denmark. But what of the rarity of gout in the wine-producing country Spain? Nor for that matter have I ever seen it claimed that gout was especially prevalent in Portugal, the home of “port,” that bête noir of the “gouty.” In truth, dogmatism is here out of place, for though overeating and overdrinking are undeniably important factors in eliciting gout, they are not the sole factors.

In reviewing the statements made as to the geographical distribution and the race incidence of gout it is but too manifest that they are largely provisional; indeed, such information as we do possess as to its relative frequency in various countries, must be taken cum grano salis. Thus, who can doubt that the various affirmations must have been very largely influenced by the “personal equation,” that what one authority would define as gout would by another be deemed inadmissible to this category. Moreover, many of the original statements were made at a time when the differentiation of arthritic disorders, as we now know it, was but in its infancy. For obvious reasons, therefore, no researches in this sphere can ever be satisfactory, until the opinion of the profession at home and abroad be crystallised into some definite pronouncement, some precise definition, of the exact criteria by which the diagnosis of gout stands or falls.

In justification of these strictures, may I cite some opinions as to the frequency of gout in the United States. In 1890, Sir Dyce Duckworth affirmed that in America gout was “practically unknown.” But a few years later, we find Sir William Osier convinced that gout was often unrecognised in the United States. More pertinent still, only twenty years after Duckworth’s affirmation, Luff quoted the statistics of the Johns Hopkins Hospital, Baltimore, from which it appeared that during a period of fourteen years 0·26 per cent. of the total admissions thereto were examples of gout. This he contrasts with the number of cases of gout admitted to St. Bartholomew’s Hospital, London, during a similar period. Mirabile dictu, the percentage was only 0·37, but a third more than that of the Johns Hopkins Hospital!

Yet again, J. H. Pratt, of Boston, writing in 1916, observes “the greatest confusion exists in the minds of many practitioners in America to-day regarding this disease (gout) and its diagnosis. In some parts of the country the diagnosis is frequently made in conditions that are not gout; in other sections there seems to be a skepticism in the minds of many practitioners regarding the[48] existence of such a disease. In New England I have found that chronic gout, even when tophi occur, is often mistaken for rheumatism or arthritis deformans. Some physicians of large experience assert that they see gout frequently. Enquiry has shown that they mistake typical cases of arthritis deformans for gout, and the swellings about the joints and even Heberden’s nodes for ‘gouty’ deposits.”

Can it for one moment be denied that even to ourselves, living in England, the so-called “home of gout,” these trenchant criticisms are but too applicable. So long, then, as such confusion exists as to what does and what does not constitute gout, how can we, with any show of scientific precision, presume to discuss, much less lay down, dogmatic statements as to the geographical distribution and the race incidence of gout?

Food, Drink, and Occupation.—Gout, it has been well said, is the “Nemesis of high living,” for, unquestionably overeating is most fertile in evoking any latent tendency thereto. Attempts to throw all the blame on particular foodstuffs, e.g., red meats, etc., on the ground that these highly nitrogenous substances engender excessive formation of uric acid, have failed of their object. Even the much-maligned “purin bodies” have of late been largely absolved of blame, and the virtues of a “purin-free” diet, e.g., milk, are probably referable to the intestinal asepsis that such a regimen promotes.

My experience, like that of others, is, that it is not the quality, but the quantity of the food that is responsible. Moreover, I believe that the toxicity of the blood plasma thus produced exerts its evil effects indirectly, viz., by lowering the vis resistantiæ of the individual to microbic invasion. Nor have I any doubt that it is this same but too common tendency to gluttony on the part of the “gouty” which is in part responsible for the cardio-vascular, hepatic, and renal changes so frequently associated with gout in its later stages.

Reverting to alcohol, there are many who regard it as par excellence the predisposing cause of gout, and some even question whether gout would have evolved had alcohol been unknown to mankind. But the interesting point is, that all forms of alcohol are not equally pernicious in this respect, and the difference in their potency in this direction is apparently little or at all referable to their percentage content of alcohol. Port, madeira, sherry, burgundy, strong ales, and stout are far more provocative of gout than distilled spirits. In England, where gout is prevalent, malt liquors are the common drink, whereas in Scotland, where the predilection is for whisky, the disorder is much more rare, and the same applies to Ireland. In the Burgundian province of[49] France gout is common, but exceptional in the Rhenish district of Germany, where hock is largely consumed. The why and the wherefore of these vagaries is not as yet explicable; but of those forms of alcohol, most conducive to gout, neither their acidity, sugar content, etc., can be impeached as imparting to the alcohol its predisposing influence in this direction. Incidentally, to those who advocate the primary renal origin of gout, one would propound the question, why is it that distilled spirits are less provocative of gout than wines, seeing these particular liquors are so fruitful of granular kidney?

Again, if alcohol be such a potent factor in gout, why is it so rarely met with in habitual drunkards, and how account for the comparative rarity in gouty subjects of hepatic cirrhosis, or for that matter of other disorders of alcoholic origin? Beset by these eccentricities of behaviour, Sir William Roberts was tempted to regard gout as “rather an incident of the legitimate dietetic use of alcoholic beverages.”

The relationship of alcohol to gout is as erratic as it is to atrophic cirrhosis. Thus an individual may drink hard through life, and escape cirrhosis; another luckless wight, though he be quite temperate, yet falls a prey thereto; still another, who may never have tasted alcohol, acquires cirrhosis; lastly, cirrhosis is occasionally met with in the lower animals, into whose diet alcohol does not enter.

In like fashion, an habitually intemperate man may pass through life without incurring gout. Another, handicapped by his heritage, though he be strictly abstemious, yet falls a prey thereto. Even a total abstainer, when coming of gouty stock, may develop gout, haply through overeating.

To my mind, the only supposition deducible from these facts is that some individuals are born with a tendency to gout, and that this tendency may never assert itself as actual disease; that in others the dormant proclivity, under the influence of alcohol, forthwith becomes manifest; lastly, in some again, so nicely poised is the equilibrium of their nuclein metabolism, that the most venial alcoholic indulgence suffices to evoke an outbreak.

I incline, therefore, to the view that alcohol per se is not a cause of gout; in other words, alcohol will not, in the absence of a gouty heredity, produce gout. On the other hand, given an innate proclivity thereto, alcohol, especially certain forms of it, will almost infallibly evoke the disease; this often though the subject be conspicuously moderate in its use.

That alcohol will produce the disorder even more swiftly and surely if reinforced by overeating also, cannot, I think, be gainsaid. As to the modus operandi of alcohol in inducing gout, I believe that[50] it acts indirectly, viz., by slowly sapping the protective mechanisms of the body, and so paving the way to infections.

Much stress has been laid on the fact that certain occupations conduce to gout; but, if we exclude plumbers, painters, or other workers in lead, no other callings in life can be held to entail a specific predisposition to its development, save in so far as they promote overeating, overdrinking, and inactivity.

It is well established that workers in lead are specially prone to develop gout. I take pride in noting that two of my predecessors at the Royal Mineral Water Hospital, Bath, William Falconer (1772) and Caleb Hillier Parry (1807), drew attention to the frequent occurrence of gout in those exposed to the action of lead; nevertheless the major part of our knowledge of lead as a predisposing cause of gout we owe to Sir Alfred Garrod (1854). This authority noted that at least one out of every four gouty patients that had come under his care at King’s College Hospital had at some time in their lives been the subjects of plumbism, and for the most part were plumbers or painters. Out of 136 undoubted examples of gout, Sir Dyce Duckworth noted that of these twenty-five males showed signs of lead poisoning, and were either plumbers, painters, compositors, or workers in lead mills. My colleague, James Lindsay, out of a total of 482 instances of males afflicted with gout, found that 108, or 22·4 per cent., were workers in lead.

In light of these findings the question naturally arose as to whether lead impregnation per se could produce gout. It was then elicited that the association of lead with gout was noticeably less frequent in Scotland and in the North of England than in London. On this interesting point Dr. T. Oliver observes, “We do not see in the north that intimate relationship between gout and saturnine poisoning. Workmen from the south develop it in the North of England. The natives of the north, though equally exposed, seldom become gouty even when the kidneys are affected.” Again, Osler tells us that in America lead-gout is comparatively rare, though chronic lead poisoning is frequently met with in that country in association with arterio-sclerosis and contracted kidneys. Again, Frerichs, out of 163 cases of plumbism in the Berlin Hospital, found not a single case of true gout.

Some remarkable instances illustrating the influence even of medicinal doses of lead in determining outbreaks of gout are on record. In a man aged 25-30, suffering from chronic diarrhœa, Sir Lauder Brunton prescribed lead and opium pills. In less than ten days he returned with gout in one of his joints, though he had never previously suffered from an attack. My colleague, Dr. Munro, tells me of an even more striking case. A lady under his[51] care had used a hair wash, for many years, with apparently no ill effects. She recommended a friend of hers to try the same lotion, and within a few days she developed acute arthritic gout, though she had never previously experienced the disorder. Analysing the preparation, Dr. Munro found the clue in the contained lead.

As to proffered explanations of lead-gout some have sought it in the production by this poison of arterio-sclerosis and chronic nephritis. But this is scarcely satisfying when we contrast the frequency of chronic plumbism and associated arterio-sclerosis and contracted kidneys with the relative rarity of lead gout.

The balance of evidence would appear to be in favour of the view that lead per se cannot produce gout. For the incidence of lead-gout is scarcely appreciable, save in a population amongst whom from other causes gout is prevalent. In short, lead in the absence of an hereditary bias, is impotent to evoke gout.

As to its modus operandi, I think it exerts its effect through derangement of the intestinal secretions, and so favours the migration inwards into the system of pathogenic bacteria.

As for occupations other than those concerned with lead, it is certainly notorious that gout is extremely frequent in those that are rich in opportunities for overeating, overdrinking, and sluggish habits. This point has never been more clearly illustrated than by James Lindsay, whose analysis I take the liberty of transcribing.

Thus, out of 482 males the victims of gout, eighty-one were cabmen, coachmen, grooms, stablemen, and bus drivers; fifty-one were draymen, publicans, barmen, cellarmen, potmen, innkeepers, maltsters, coopers, storekeepers, brewers’ travellers, and brewers’ labourers; twenty-five butlers, men servants, ship’s stewards, and hotel servants; while forty-five were labourers, and of the residue, although all kinds of trades and occupations were represented, yet no other class reached ten in number.

Of these various stations and occupations, it cannot be held that, in themselves, these callings necessarily contain the “seeds of the gout.” The banefulness resides in the associated habits of living; for but too frequently repletion, intemperance, and indolence go hand in hand with these vocations. In other words, dietetic excesses, overloaded intestines, and too much alcohol, what more likely to impair the digestive functions, to increase the toxicity of the intestinal flora, and in turn to upset the equilibrium of general nuclein metabolism, with its associated specific local reaction in certain tissues?

Mental and Physical Over-exertion, etc.—Sydenham said of gout that it destroys “more wise men than fools,” and in a letter to Dr. Short, he complains, “I send you a short tract upon Gout and[52] Dropsy instead of the thicker volume, which in my own mind I had determined on, viz., a history of such chronic diseases as my practice has most especially met with. By applying my mind, however, to its utmost, and by bringing all my powers of thought on the subject, I brought on a fit of gout, such as I had never before suffered from; so that the fact itself warned me to lay aside, even against my own will, such lucubrations, and to take care of myself; well satisfied with having, in some measure, dealt with these two diseases. Whenever I returned to my studies, gout returned to me.”

It is doubtful if, in the absence of an hereditary proclivity, intellectual strain would promote the development of gout. On the other hand, there is, I think, no doubt that immoderate mental exertion will indirectly precipitate an outbreak. I can well understand that the illustrious Sydenham, absorbed in his life study, forgot to take a normal amount of exercise. Perhaps, like the renowned Jenner, he would have said, “I never walk at all except from my house into my carriage. I hate walking, and if I could, I would get my servants to carry me to bed.” Nevertheless, I doubt not that Sydenham’s intellectual efforts necessarily entailed sedentary habits, which brought in their wake digestive and intestinal derangements, whence his occasional gouty outbreaks.

Gout, indeed, has taken its full toll of the “Intellectuals.” Thus Scudamore tells us that “The late Mr. Pitt and his father had gout at a very early period of life. The father was never a votary of Bacchus, and neither of Venus (as we are told), but both were ardent students.” Probably, in many instances, however, the evils of immoderate study are reinforced by more reprehensible excesses. The ancients insisted on sexual debauchery as favouring outbreaks of gout. Whence the Latin verse:

Doubtless, in some instances of this supposed origin, a gonococcal arthritis was confused with gout. Doubtless sexual neurasthenia with diatetic excess favours the onset of gout. In the same way grief, anxiety, and other depressing emotions are provocative of gout in that they impair the digestive functions, lead to hepatic torpor, and sluggish bowels.

Summary

In conclusion, we have now dealt with those factors currently regarded as predisposing causes of gout. Personally, as I have before said, the differentiation of the foregoing from the so-called[53] exciting causes of gout is purely arbitrary. Thus even those who countenance such division are forced to admit that many of the predisposing causes will, “if at any time suddenly increased,” immediately excite a fit of gout.

In other words, the difference is quantitative rather than qualitative. Thus, a moderate drinker, if perchance he exceed his usual limits, pays the penalty by an outbreak. Another habitually addicted to the fleshpots eclipses himself, and a similar retribution is exacted. Or, he exposes himself to a chill, with subsequent gastro-intestinal or hepatic functional derangement. Yet again, the cessation of wonted exercise, and more often the taking of it when unaccustomed, may determine the onset of a paroxysm.

But far more arresting are the numerous and well authenticated instances in which local trauma not only determines an outbreak but also its locality. How frequently, too, have blows, strains, sprains, fractures, dislocations, or other trivial or severe injuries, been the signal for an attack. Now, as we hope to show later, local foci of infection are extremely common in the gouty. Such are especially frequent in the teeth, tonsils, naso-pharynx, etc. Is it not then extremely probable that organisms may, viâ the blood-stream, find their way to a joint, the resistance of whose tissues has been lowered by a trauma, however slight its degree? This I apprehend to be the true explanation of the undoubted intimate connection between traumatisms and arthritic outbreaks of gout.

Of similar significance, too, the numerous instances on record in which acute attacks of gout have followed acute tonsillitis, acute pharyngitis, acute parotitis, etc. How frequently, also, competent observers, such as Garrod, noted that boils and carbuncles frequently appeared to be excitant of acute attacks. But to this important point, the intrusion of an infective element in the genesis of gout, we shall return in a later chapter entitled “Gout as an Infection.” It will suffice here if we record our belief that—

Morbid Anatomy

It has been truthfully affirmed that we know more of the results or products of gout, and less of its essential nature, than of almost any other disease. Thus the post-mortem history of the disorder is concerned almost exclusively with more or less graphic[54] accounts of the uratic deposits, their sites of predilection, and the changes that they induce. Hence it is that the morbid anatomy of gout relates for the most part to its regular or articular manifestations, for it is in and around the joint structures that the deposits for the main part occur.

As to the assumed localisations of the disease in the internal organs, there is no anatomical evidence that they are due to an invasion of the “gouty” inflammation. Not even the renal changes, despite the attestation, as it were, of the gouty process by uratic deposits in the papillæ, can be held as distinctive of gout. Norman Moore found them present in only twelve out of eighty cases. As Osler said, “The presence of uratic concretions at the apices of the pyramids is not a positive indication of gout. They are not infrequent in this country [U.S.], in which gout is rare.... It is not possible to say in a given case that the condition has been due to gout unless marked evidence of the disease co-exists.”

If, then, nothing distinctive can be claimed of the renal, how much less can we construe as “gouty” the anatomical alterations that may or may not be met with in other organs in this disorder. In short, it may be said of the renal as well as the other visceral lesions, so often met with in association with gout, that they are met with even more frequently in its absence, and most certainly fail to attest their “gouty” nature by the appearances which they present.

The only morbid structural changes, therefore, that can legitimately be defined as specific of gout relate to its regular or articular lesions. As to the anatomical alterations in the articulations, their specificity depends essentially on the uratic deposits, rather than upon the associated inflammatory and degenerative processes.

Given death during an acute paroxysm, examination reveals the usual tokens of inflammation, hyperæmia, effusion, and swelling of the ligamentous tissues. The synovial lining is injected and spongy, while the exuded fluid is thick, scanty and turbid, containing polymorphonuclear leucocytes as well as crystalline deposits. Charged therewith, not only is the synovia thick, but of a milky appearance. Examined microscopically, it is found to contain the acicular crystals of sodium biurate. The synovia has occasionally been found covered with blood, but no pus formation has ever been known to occur in uncomplicated acute gouty arthritis. The reaction of the synovial fluid is generally neutral or alkaline, but exceptionally Garrod found it acid.

Uratic deposit has a predilection for cartilage, and in some instances is strictly confined thereto; but in the more chronic forms it permeates all the component elements of the articulation. In the synovial membrane and fringes deposition takes place in[55] the subepithelial and subserous layers. It invades also the ligaments, the tendons, and even the periarticular fibrous tissues become impregnated with biurate. Moreover, like the synovial sheaths of the tendons, the neighbouring bursæ are specially prone to deposits, which again encroaching upon the subcutaneous connective tissues, infiltrate the skin itself, forming chalk stones or tophi.

Inspected after death, the articular cartilages are seemingly overlaid with a white mortar or chalk-like material, i.e., sodium biurate. Their surfaces, however, though defaced by stains, streaks, or dull patches, nevertheless, at any rate at first, retain their pristine smoothness. This because closer scrutiny reveals that the deposit is not in reality upon the surface of the cartilage, but is located interstitially in its substance.

Microscopic examination of a vertical section, taken at the site of the deposit, shows clearly that it is composed of felted masses of acicular crystals. Lying in the matrix of the cartilage, they are more densely packed just below its free surface. The crystals do not penetrate further than one-third or one-half of the depth of the cartilage. Becoming more and more sparse towards the deeper layers, those near the bone are entirely free from deposit. This clearly indicates that the uratic matter originated from the synovial fluid bathing the articular ends and was precipitated therefrom.

As to the primary site of the deposition, it usually takes place at the centre of the articular cartilage. Opinions differ as to whether the cartilage cells are foci of deposition. Garrod thought so, but Duckworth found no relationship between it and any histological elements, while others locate it in the matrix.

While, as before stated, the cartilage at first retains its smoothness, later it becomes pitted in patches. Ultimately the cartilage, through atrophic changes and erosions, may disappear, the joint cavity becomes filled with a plaster-like material, and the joint structures undergo more or less disorganisation. Pari passu with the central atrophy of the cartilage, hypertrophic outgrowths form at its free margin. In late stages the bones, too, undergo changes; their outer layers become more dense through proliferative osteitis, while their spongy tissue becomes rarefied, and the cells of the marrow fatty. Duckworth held that uratic deposits might occur primarily in the bone without any similar implication of the related cartilage. On the other hand, Garrod dissented, claiming that when the bone was involved, it was only secondarily to uratic deposition in the cartilage, of which indeed it was but an extension.

In reviewing the foregoing findings, it must be admitted that[56] morbid anatomy fails to shed light on the essential cause of gout. This, at any rate, is true of the older studies with which, up to the present, we have been engaged. Still, as Berkart’s more recent researches show, our knowledge of even the morbid anatomy of gout is as yet but in its infancy.

Histological examination of the articular ends adjacent to gouty joints reveals the presence of certain cystic changes in the diaphyses. Thereupon Berkart propounded an hypothesis, explanatory of the acute phenomena of a paroxysm of gout. His view was that these cysts in the bone, at first minute, gradually enlarge. Ultimately, through concomitant thinning of the surface bone, there comes a day when the cyst bursts into the joint, its content voided into the cavity thereof.

An interesting point noted by Berkart was that in many cases of “acute” gout the articular cartilage was found apparently normal and devoid of uratic deposits, and this although the attack had been sufficiently severe. This would appear to contravene Garrod’s dictum that “gouty inflammation is invariably attended with deposition of urate of soda.” The same inference was drawn from a case of Sir Dyce Duckworth’s. The subject had had two attacks of gout in the right great toe joint. Yet at the autopsy neither toe joint contained a speck of uratic deposit. Nevertheless, this does not prove that uratic deposition had not ensued during the gouty attacks. All it can be held to prove is, that such deposits are not always permanent, and that, under certain conditions, they may undergo resolution. That this is so is almost certain, seeing that tophi in the ear have been seen to come and go, and equally certainly, after an acute attack, tophi in the neighbourhood of a joint may lessen even though fresh ones form coincidently at another site.

Albeit, the importance of Berkart’s hypothesis and histological findings resides in the fact that they suggest strongly that a pathological process, more vital and biological than the mechanical uric acid theory, is at the root of the clinical phenomena of a gouty paroxysm. It does not put out of court Garrod’s assumption that uric acid is an invariable accompaniment of acute gouty inflammation, but it militates strongly against his contention that uric acid deposition is the cause of acute gouty inflammation. It indicates the reverse, viz., that the uratic deposition is the consequence of a more vital underlying morbid process.

Let us revert now more in detail to Berkart’s findings. The bones adjacent to gouty joints were fully prepared for microscopic examination. Investigation of the first metatarsals, and in some instances of the phalanges also, revealed the presence of cystoid degeneration. Its starting point is in the epiphyses. Thence[57] it extends to the articular cartilage, through which it bores at one or more points. The contents of the cyst then find their way into the joint through the fistulous openings in the cartilage, with a resultant acute “perforative synovitis.”

The cysts, at first minute, may be either single or multiple. Small in size, they are easily concealed by the fat marrow, unless the bone is properly prepared for microscopic examination. The isolated cysts eventually coalesce, and so lead to considerable excavation.

As to the contents of the cysts little is known, as, save through accidents or surgical operations, they are rarely available for examination. When of relatively recent origin they apparently consist of a coagulable substance which later on become serous or hæmorrhagic. So long as the fistulæ thus formed in the cartilage remain pervious, a direct way into the articular cavity is provided, and through this, if of sufficient calibre, the necrotic matter periodically gains entry into the joint, with ensuing periodic outbreaks of acute synovitis. In other instances in which the cysts are located in proximity to, or within, the diaphysis they may fail to extend to the cartilage, and no perforation ensues. In this event, through accumulation of its contents, the cyst enlarges, and the bone is gradually expanded through pressure.

Berkart holds that the histological changes in the affected epiphyses indicate that the cystoid degeneration is the outcome of an anomaly of the vascular and osseous structures. The degenerative area contains an abundance of dilated and thin-walled veins, evidence of a condition of chronic congestion. In consequence thereof, the trabeculæ undergo decalcification, and the adjacent fat marrow becomes fibrous. The areas of fibrosis thus formed, owing to thrombosis of the related veins, become softened and transmuted into cysts.

Now, as we all know, some persons, after indulging in wine, almost immediately experience sharp twinges in the small bones of their hands or feet. Garrod attached diagnostic importance to such swift response as a sign of gout. These pains he attributed to uric acid deposition. In contrast, Berkart attributes the twinges to atony and consequent over-distension of the related vessels, which lack the normal support afforded by the osseous trabeculæ.

As far as we are aware, these findings of Berkart’s are as yet unconfirmed. Nevertheless they provide us with a much more probable explanation of the phenomena of acute gout than the older uric acid theory, which, not to mention the many other obstacles to its acceptance, has always laboured under the aspersion of being too “mechanical” in conception.

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Moreover, his studies clearly indicate that not only the intra-articular surfaces but the adjacent bone-ends and marrow must, as the somewhat rare opportunities present themselves, be exhaustively investigated. For myself, I cannot believe that so passive an agent as an “anomaly of the vascular and osseous systems” is the fons et origo mali in gout. Some more vital element must, I feel convinced, intrude, and I incline to think an infection. Berkart himself brings forth evidence in favour of this contention, inasmuch as he noted the frequent co-existence of lymphangitis, so pronounced that the whole of the affected leg became the seat of a leuco-phlegmatic œdema.

Not only is the proximate cause of gout unknown, but the essential nature of the disease is still shrouded in obscurity; for the obliquity in trend of protein metabolism, manifested though it be by striking phenomena, is clearly only the outcome of some, as yet undetermined, derangement in the mechanism of intermediary metabolic or bio-chemical change.

This is, of course, but to restate the problem we are confronted with. Wholly to solve the enigma would postulate ability on our part to trace ingested foodstuffs through all their vicissitudes from the moment of entry into the blood or lymph-stream till flung out as effete matter through the various avenues of excretion; but, unhappily, we know the story only in part, its beginning and end, but not what lies between.

We know much of the complex changes that take place in food prior to absorption, and of the modus operandi of the latter not a little. Comparably, too, we can gauge the quality and quantity of end-products, the chemical outcasts, as they escape in the urine, sweat or breath, and largely how achieved; but of the intermediate steps between absorption and excretion we catch but a glimpse here and there. The sequestered path by which the inanimate molecules of food uprise to Life, and anon go down to decay and death, are still hidden.

In other words, little do we know of the relationship of labile, or food-protein, to tissue protein. True, the coarse fact of abnormal protein loss in renal disease may be revealed in the urine, as likewise the waste of albumoses in myeloma, etc., and the incidence of amino-acids in disease of the liver. Similarly, the appearance of cystin or of alkapton in the urine bespeaks flaws in protein metabolism, failures in the normal disruption of amino-acids. All these are of the grosser anomalies of protein metabolism, but more subtle those of gout!

Complex, in truth, the problem here presented, than which none more subtle exists in the realm of bio-chemistry. True, quantitative variations in the content of the urine as to urea, uric acid, etc., undoubtedly bear a direct relation to protein metabolism, but they give us little, if any, substantial clue as to the particular[60] metabolic warp responsible. We see this particularly in regard to uric acid, so long accredited with an essential rôle in gout.

Thus we cannot, on the basis of the variations in its excretion only, presume to diagnose “gout.” This because even more extensive variations occur in healthy persons. On the other hand, attacks of gout never occur when urates are absent from the blood. To reduce the amount of these urates is clearly then of importance, and obviously to this end a knowledge of their source is essential. We have an analogy to hand in diabetes, in which the somewhat similar problem relating to glycosuria has been partially solved.

Revelations of the Bio-Chemist

But before proceeding to the more strictly biological aspect of the relationship of uric acid to gout, we must, as in the study of any other problem of metabolism, place ourselves in possession of the main facts relating to the chemistry of protein, and more particularly of purin or nuclein metabolism; for it was just this same lack of even the most rudimentary facts, especially regarding the chemistry of uric acid, that vitiated the conclusions arrived at by the earlier workers in this sphere. Disabilities of technique of necessity rendered inaccurate the results obtained by these pioneers in research, while the significance of the facts they laboriously gleaned was likewise misinterpreted.

But with the advent of highly trained organic chemists, well skilled in the investigation of bio-chemical problems, a basis of accurate chemical facts was established. The story of the fate of protein and purin substances in the animal body, at one time a medley of guesses and gaps, was brought to one of relative certitude and completeness. The change involved has proved in truth revolutionary, and many the cherished shibboleth that has been ruthlessly cast aside.

How vivid the light thrown upon the problems of clinical medicine by the bio-chemists! With admiration not unmingled with awe we see them laying well and truly the foundations upon which in the ultimate scientific medicine must inevitably rest. Of these the very corner stones are chemical physiology and chemical pathology, the rapid evolution of which is profoundly altering our conceptions of health and alike disease. Those vital processes of the organism that but yesterday we saw “as through a glass darkly,” are now in great part illumined, and the distortions wrought in them by disease made more manifest.

How pregnant, too, with warning their findings! Processes that, to our untutored minds, seemed simple are revealed as infinitely complex. Through what a labyrinth must we thread[61] our way if we would unravel the intricacies of metabolism! Intricate enough, forsooth, in health, but how much more so in disease!—for as Sir Archibald Garrod eloquently phrases it, “It is becoming evident that special paths of metabolism exist, not only for proteins, fats and carbohydrates as such, but that even the individual primary fractions of the protein molecule follow their several catabolic paths, and are dealt with in successive stages by series of enzymes until the final products of catabolism are formed. Any of these paths may be blocked, while others remain open.”

It is with chastening reflections such as these that we may best approach our study of gout, that Riddle of the Ages, upon the elucidation of which so many physicians from time immemorial have expended their dialectic skill. Would that we could affirm that the bio-chemists of to-day had found the “Open Sesame!” But, alas, it is not so! The chamber is still sealed.

Vast though the increase in our knowledge of the chemical structure of uric acid and its allies, uncertainty still dogs our steps. Doubtful of the pathway to solution of the pathological mystery of gout, we must perforce approach the problem in a more strictly catholic attitude. Uric acid has apparently failed us as the causa causans. We can, therefore, no longer restrict our enquiry to purin, but must take cognisance of protein metabolism as a whole, for some, perhaps not unnaturally despairing of the uric acid hypothesis, are turning therefrom to other end-products of metabolism, e.g., creatinine. In keeping with this altered outlook, it will not be out of place if we, at this juncture, allude, though in brief, to the later revelations as to protein metabolism, before we pass on to more detailed consideration of those relating to the purin bodies.

Protein Metabolism

No longer can we, like the older physiologists, envisage protein as being absorbed as such from the alimentary canal and forthwith incorporated with the body tissue, for the researches of Fischer have revealed that the complex protein molecule must previously undergo complete disruption into the a-amino-acids, its ultimate “building stones,” this through the hydrolytic action of the digestive enzymes of the alimentary tract. The fact that Fischer[6] was able to maintain nitrogen equilibrium in animals[62] fed with completely digested protein mixtures is, of course, direct evidence in favour of his contention, viz., that proteins undergo disruption into amino-acids.

The Formation of Urea

The question as to whether urea, the end-product of general nitrogenous catabolism, was derived from the amino-acids, brought in the portal blood to the liver, was for long a vexed one. This because the earlier attempts to detect amino-acids in the portal blood, during the digestion of copious amounts of protein, proved futile. On the other hand, the same workers found that free ammonia was present in greater amounts in the portal vein than in the systemic circulation.

This, to their mind, seemed to indicate that the amino-acids, during their passage through the intestinal mucous membrane, underwent deaminisation. According to this view the ammonia, thus split off from the amino-acids, was the precursor of urea.

But the claim that more free ammonia was present in the portal vein than in the systemic circulation was disproved by Folin and Denis. Invoking more delicate methods of hæmo-analysis, they found that the amount of ammonia and urea in the portal blood was not increased during the absorption of amino-acids from the lumen of the intestine. Moreover, they found that the ammonia present was of minimal amount, produced in the main by putrefactive bacteria. Lastly, they discovered that amino-acids were actually present in the portal blood.

Fate of the Amino-Acids

In the gastro-intestinal tract the complex food proteins, under the hydrolytic action of enzymes, break down into a variety of substances, all of which belong to the group of a-amino-acids. These same absorbed from thence into the blood are transported to the various organs and tissues. Arrived thither the amino-acids are subjected to a process of sifting. Thus some are invoked for the reconstruction of broken down proteins, i.e., are re-synthesised into the body’s own characteristic tissues.

The surplus amino-acids, viz., those not required for purposes of cell repair, undergo deaminisation. Two residues then result,[63] one represented by ammonia, and the other by the remaining relics of the amino-acid molecule. The former is excreted as urea and the latter is oxidised to produce energy.

But there is yet another source of amino-acids, viz., the disintegration of tissue protein. To this end almost all bodily tissues possess intracellular enzymes capable of converting their proteins into the same simple products from which they took origin.

Comparably with those of exogenous origin, these amino-acids of endogenous formation undergo a like deaminisation; in other words, the bulk of their carbon, oxygen, and hydrogen is oxidised to form CO₂ and water, the residue combining with nitrogen to form urea, etc.

The main end-product, then, of protein metabolism is urea, with traces of its forerunner ammonia. But there are also other waste nitrogenous metabolites. Thus, of the various amino-acids that become built up into tissue protein, some subsequently break down into products not belonging to the amino-acid category, viz., creatine and creatinine. Some of the amino-acids, too, are excreted unchanged in the urine. Lastly, to these must be added those closely related substances, the purin bodies, the end-products of nuclein as opposed to general protein metabolism, of which latter urea is the terminal product. To sum up, in a man on ordinary diet about 90 per cent. of his total nitrogen is excreted as urea, about 3 per cent. as ammonia, the residue of the nitrogen appearing in the form of other nitrogenous metabolites.

Seat of Formation of Urea

The liver, it is generally held, is the main centre wherein urea is produced from the amino-acids; but not exclusively so, for it has been definitely established that, even after removal of the entire liver in animals, its production may not cease.

Moreover, some researches of Otto Folin and W. Denis into urea formation seem to indicate that the older views call for revision. Experimenting on cats, they injected them with alanine and glycocoll nitrogen and other amino-acids as well as Witte’s peptone. They were able to prove definitely that, at the end of an hour or more, the formation of urea from the absorbed amino-acids was unmistakably demonstrable. Also they noted that interesting fact, that the “urea nitrogen obtained from the hepatic blood is not larger than the urea in the blood obtained at about the same time from the iliac artery.” This they claim indicates that “the liver has not brought about any demonstrable specialised deaminisation.”

The experimental data forthcoming in their researches, while[64] they prove that the absorption of amino-acids is very swiftly followed by the formation of urea, does not afford any definite evidence as to the site of urea formation; but, as they rightly contend, we have no satisfactory proof that deaminisation and urea formation is localised. Consequently “we are not justified in assuming that the process is a specialised process in the sense of being confined to some particular organ.”

Indeed, they bring forward evidence that the process of urea formation, far from being localised to any particular organ, i.e., the liver, is almost ubiquitous.

Thus, experimenting with the injection of alanine, they noted that prior to the same the muscle content of non-protein nitrogen and urea nitrogen was respectively 194 and 26 mg.; but 180 minutes after the injection the non-protein content in muscle had risen to 232 and that of urea nitrogen to 41 mg. Working with glycocoll, the non-protein and urea nitrogen in muscle before injection of the same was 248 and 42 mg. respectively, while 240 minutes after injection the figures were 304 and 54 mg.

The significance of these figures is more striking when contrasted with the fact that in the same subjects the urea nitrogen content of the hepatic blood did not exceed that obtained almost simultaneously from the iliac artery. The deduction made by Folin and Denis is that—

(1) “The urea-forming process is one characteristic of all the tissues, and by far the greatest amount of the urea is, therefore, probably formed in the muscles.”

(2) “The negative results, so far as any localised urea formation is concerned, is almost satisfactory proof that there is none, for if there were one central focus from which all or nearly all of the urea originated we could scarcely fail to find it.”

Amino-Acids in Relation to Gout

The vista opened up by these advances in physiology suggested investigations into the amino-acids, their association with the output of uric acid in gouty patients. No less than eighteen different amino-acids enter into the constitution of protein, but of these the most interesting from our point of view is glycocoll or amino-acetic-acid. Now, glycocoll plays a great rôle in the organism as a detoxicating agent, rendering innocuous, e.g., benzoic and cholic acids by transmuting them into hippuric and glycocholic acids. In short, the body always has glycocoll at its disposal for coupling or combination purposes.

Now it appears likely that glycocoll can be split off from all the amino-acids, a probability reinforced by the results of the[65] researches of Embden and Reese and Lipstein, these observers having shown that amino-acids are present in all urines to about 1 per cent. of the total nitrogen output.

Ignatowski, working with the urine of gouty patients, found amino-acids present in large amounts; not that it was peculiar to such subjects, for he found it in other diseases, but only traces were detectable in the urine of healthy individuals. Again, Walker Hall, investigating urines drawn from the subjects of gout, the victims of other diseases, as well as healthy and diseased children, determined the presence of glycocoll in about 70 per cent. of the cases. His researches, to his mind, confirmed the conclusion that “normally a certain amount of glycocoll escapes through or is eliminated by the renal filter.”

Burger and Schweriner, from their researches on gouty subjects, have confirmed Walker Hall’s findings as to the excretion in excess of amino-acids, especially glycocoll. Lastly, Almagia has in gouty urines detected the presence of glyoxylic acid. What its significance may be is uncertain, but it is at least interesting to note that, as MacLeod suggests, the synthetic formation within the body of glycocoll may very probably result from the interaction of ammonia and glyoxylic acid.

The Glycocoll Theory of Gout

Excessive meat feeding in dogs, according to Kochmann, induces degenerative changes in the liver and kidneys. Similar tissue alterations were noted by Walker Hall in rabbits, after injection with hypoxanthine, while the same was observed by Kionka in mice. These findings suggest that, although anatomical lesions are not apparent in the livers of “gouty” men, it is at least probable that functional damage results from the overeating of meat.

Now, if glycocoll be added to a solution of (neutral) dialkali-urate, it expedites the appearance of the (acid) mono-alkali-urate, a reaction more noticeable with the sodium salt. Urea, in contrast to glycocoll, markedly inhibits the formation of the acid salt. But if glycocoll be added to a solution of the (neutral) dialkali-urate and urea, the latter parts to some extent with its powers in this respect, and the mono-alkali-urate is deposited.

It is reasonable, then, to suppose that if, as testified by Ignatowski and Walker Hall, glycocoll is present in gouty urine, it is also present in the tissue fluids of the gouty individual, and so the precipitation of uric acid is favoured. Glycocoll, normally, is almost entirely transmuted into urea by the urea-forming ferment of the liver.

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Impressed by these considerations, Kionka advances the hypothesis that gout is due to:

In other words, given deficient action of the urea ferment in the liver, then more glycocoll will be present in the blood-stream, and the uric acid may be thrown out of solution.[7]

For it is possible, as Kionka suggests, that normally uric acid, on its way to urea, may pass through a glycocoll stage. Now, in the gouty individual the glycocoll may not be entirely transformed to urea, and its excess in the tissue fluids may lead to uric acid deposits. Perhaps, as Walker Hall observes, “since hepatic deficiency is generally admitted in the gouty, diminished destruction of uric acid and glycocoll may go hand in hand.”

In healthy cartilage glycocoll is undemonstrable. But, according to Kionka, if bruised or damaged, a considerable amount thereof is formed. Now, when blood, rich in uric acid, circulates through injured cartilage, the presence of glycocoll favours precipitation of the urates, a possible explanation of the formation of tophi. Unfortunately for the valency of this theory, Aberhalden and Schittenhelm show that the methods employed by Frey, to isolate glycocoll from cartilage, were such as yield errors which would quite account for the amount obtained by this worker. They, therefore, deny the presence of glycocoll in damaged cartilages. But, in conclusion, Kionka’s plea for a primary hepatic functional disability derives colour from the fact that the drugs which have gained most approval in the treatment of gout are those which increase the quantity of bile without augmenting the amount of bile acids; and the which are excreted in combination with glycocoll, for instance, salicyclic acid combines with glycocoll, and is excreted as salicyluric acid, and benzoic acid, which combines with glycocoll to form hippuric acid. Albeit, we must not overlook the fact that the presence of glycocoll is not peculiar to gouty urine, but, as shown by Walker Hall and Embden, is met with in other disorders. The glycocoll hypothesis as to the origin of gout is, though attractive, therefore still unproven.

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Urea Excretion in Gout

According to Tilden Brown, the rhythm of urea excretion constitutes a warning as to the approach of gout. A very lowered elimination thereof he holds to be an excellent and pathognomonic symptom. The excretion of urea may at times run so low as to lead to a suspicion of renal disease. He considers that this sign may find a place in the prophylaxis of gout, a signal for the initiation of treatment with the object of lessening the severity of symptoms (viz., extent of toxic action as manifested by destruction of proteid, etc.).

This point was advanced by Brown (1905) during a discussion at the Harvard Medical Society, but as far as we know it has not been confirmed. Presumably it rested upon the assumed existence of a normal ratio of uric acid elimination to that of urea with the corollary that every deviation therefrom was due to a pathological cause. Haig held this view, which was, however, disproved by Herringham, Groves and Luff. The latter authority estimated the daily eliminations of uric acid and urea in a healthy adult man on a mixed diet for a period of fifty days, and clearly showed that no constant ratio exists in a given individual between the excretion of uric acid and urea.

Also, it is obvious that, before attaching any valency to Tilden Brown’s dictum, it is essential that it be established that the cases were instances of pure gout, unaccompanied by nephritis. Moreover, modern workers tend more and more to rely not on analyses of the urine but of the blood, especially in the unravelling of so-called metabolic disorders. Also, it may be added, that their findings in this sphere indicate no harmony between the urea and the uric acid content of the blood. Thus, Otto Folin observes, “One most interesting fact which we constantly meet with in blood analysis is that there is no correspondence between uric acid and the total non-protein nitrogen in the blood. In gout or lead poisoning, or leukæmia, the blood is uniformly rich in uric acid, yet the total non-protein nitrogen or urea nitrogen may be normal.”

Creatine and Creatinine

As before pointed out, it has been suggested that these substances may be in some obscure way related to the genesis of gout. To this end a great amount of research has been expended on the metabolism of creatine and creatinine. But although, as far as I am aware, the revelations hitherto forthcoming have disclosed no link between these substances and the development of gout, still, by reason of the potentialities possibly resident therein, a brief digression is permissible.

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The exact origin of creatine and creatinine is still obscure. All we know is that they are, in the main, the outcome of chemical processes in the tissues, viz., products of endogenous metabolism. Also of the creatine and creatinine present in food a moiety may appear as creatine in the urine.

Creatinine occurs in the urine of adults, and is practically independent of the protein intake. The amount excreted varies with the size, and not with the weight of the body. In other words, it varies with the volume or mass of the voluntary muscles, which structures have the highest content of creatinine and creatine. MacLeod, discussing this relationship, tells us that, “in the muscular atrophies creatine excretion is distinctly below normal.” It must, he adds, be the “mass of the muscles rather than their activities that is the determining factor, for the creatine excretion does not become increased by muscular exercises.” Otto Folin, discussing the clinical application of pathological chemistry, observes, “Nothing definite is as yet known concerning the creatinine output in abnormal metabolism, except that in fevers and other diseases there is an increase, sometimes a very large increase.” But this much we do know that creatine, after ingestion, is almost quantitatively excreted in the urine. Creatine, in considerable amount, is a normal constituent of children’s urine, but in normal adults hardly a trace occurs, though in some diseases it is met with even in their case. In boys it gradually dwindles and disappears at about seven years of age. On the contrary, in girls creatine is excreted until puberty. Subsequently, its presence in the urine is intermittent, its incidence confined to the menstrual cycles, the period of pregnancy, and for some days after parturition.

From our point of view, the most interesting of the above revelations is the fact that the largest percentage amount of creatine and creatinine is located in the muscular tissues. On this point we cannot do better than quote the following words of Otto Folin:—

“It is to be noted that we are as yet entirely ignorant of the origin and significance of the creatine which is so abundant in muscles, and it is scarcely to be doubted that fundamentally important metabolism problems somehow are connected with the muscle creatine and urinary creatinine, but these are as yet problems of normal metabolism, and it is too early to say whether, or in what way, light may be thrown on clinical problems by studies of these products. The fact that the muscles of mammals, including man, contain 0·3-0·4 per cent. of creatine, and only traces of the chief nitrogenous waste product urea, constitutes to my mind strong presumptive evidence that creatine serves some important function, and it is quite conceivable that metabolism[69] diseases of one kind or another may be associated with this curious substance, but investigations rather than hypotheses are needed in the study of such obscure problems.”

Inborn Errors of Metabolism

Apart from its intrinsic fascination, the tracing out of analogies, clinical or pathological, between diseases apparently diverse has often proved a fruitful source of enlightenment, for the natural history of disease is such that one disorder trenches upon the clinical territory of another, symptoms overlap and similarity if not community of origin is revealed.

Few will gainsay that gouty individuals are the victims of some inborn defect or eccentricity of metabolism, and instinctively the thought arises, are there no other disorders of like character? Immediately we bethink ourselves of alkaptonuria, cystinuria and pentosuria. Sir Archibald Garrod, as we know, classed these disorders as “chemical malformation” of hereditary origin. In other words, all are the outcome of an abnormality in intermediary metabolism.

In alkaptonuria the metabolic warp concerns the aromatic groups, in cystinuria the sulphur-containing radicles of the protein molecule. On the other hand, in pentosuria the origin of the endogenous pentose is variously ascribed to the nucleo-protein of the cell nuclei or to galactose. Lastly, in gout it is in the metabolism of nucleo-protein, or rather of the nucleic acids of the cell nuclei that the flaw resides.

We see, therefore, that Langdon Brown, discussing gout, is well justified in observing that, “We may look upon a person who is readily poisoned by purins in the same light as the person who has cystinuria, alkaptonuria, or pentosuria, i.e., they all lack a link in the chain of protein katabolism, so that intermediate products appear in the urine instead of the usual end-products.” In other words, they all display a pathological kinship, viz., in that they are all due to inborn errors of metabolism.

Certain broad clinical resemblances also obtain. All members of the group, including gout, display hereditary tendencies. All occur much more often in males than in females. They all alike tend to persist through life. Lastly, their distinctive chemical products, including uric acid, are all apparently of low toxicity.

But when we pass to the realm of their symptomatology, resemblance, if it does not cease, becomes relatively obscured. Cystinuria and pentosuria appear to be “harmless anomalies,” and the same is true of alkaptonuria. The cystinuric, albeit, does suffer with[70] urinary concretions, and we may recall that some authorities hold that gout and uric acid calculi are not unrelated. As to alkaptonuria, it has this attenuated link with gout that in its later stages the victims thereof tend to develop a degenerative type of arthritis, while the frequently associated pigmentary change, ochronosis, has a predilection for deposition in the cartilages of the ears and joints.

But how colourless the clinical features of alkaptonuria, etc., as contrasted with the vivid arresting phenomena of gout! how remote the latter disorder from these “harmless anomalies”!

Apart from this general distinction, before gout could with justice be relegated to the same category of disorders, it would be necessary to prove that uric acid was an intermediary and not a terminal product of metabolism. All modern research, however, tends to indicate that uric acid is an end-product, and, moreover, that there are no uricolytic ferments within the body whereby its destruction can be accomplished. The term “chemical malformation,” therefore, though strictly applicable to alkaptonuria, cystinuria, etc., is inapplicable to gout. In other words, though, for example, the homogentisic acid met with in alkaptonuria is a “chemical malformation,” uric acid cannot be regarded as such. We see, therefore, that though gout may, superficially regarded, appear to have kinship with alkaptonuria and its congeners, yet in reality there is a profound and essential difference between it and this fascinating group of disorders.

No hard and fast line can be drawn between the metabolism of protein and that of nuclein. For though, morphologically speaking, the nuclei of cells are sharply differentiated from the circumambient cytoplasm, and exhibit equally distinct staining reactions, yet, chemically, the differences between them are quantitative rather than qualitative.

But while, as far as chemical changes are concerned, nuclein metabolism is comparable with that of protein, nevertheless the former in respect of its “energy” and its bearing upon growth and production, is infinitely more vital, incomparably more active; for it is in nuclear changes that we may best discern evidence of the initiation of oxidation processes and other varieties of enzymatic activity. Moreover, as Walker Hall points out, “the presence of masked iron phosphorus and certain forms of fat in the cell nucleus strengthens this view, and thus we are led to recognise the important part played by the nucleus in the life of the cell, and to appreciate the influence of nuclein heredity in cellular exchanges.”

So much by way of prelude, but the story of the growth of our knowledge of nuclein as opposed to protein is so fascinating as to be worthy of a slight digression.

The Isolation of Nucleic Acid

Functionally regarded, the nucleus is the essential element of the cell. Embedded within the cytoplasm, its isolation therefrom, and this in quantities sufficient for analysis, may well have dismayed the earlier workers. But the resources of Friedrich Miescher were equal thereto. Treating surgical bandages soaked with pus with a dilute solution of sodium sulphate, he extracted the heavy pus cells. These, then, by careful decantation, were easily disengaged. The pus cells, still intact, were then subjected to the digestive action of artificial gastric juice. The protoplasm was thus dissolved, but not the more resistant nuclei, which remained as an insoluble grey powder. In this manner cell nuclei, free from protoplasm, became available for chemical analysis. Treating the insoluble nuclei thus obtained with dilute sodium carbonate, a solution was formed. Acetic acid added thereto produced[72] a flocculent precipitate which was found to contain phosphorus, and responded to protein colour tests. This substance Miescher christened by the name of nuclein. Subsequent observers prepared nuclein from the nuclei of yeast cells and the red blood corpuscles of birds. All nucleins are insoluble acids which form soluble salts with sodium. But while they respond to protein colour reactions they differ from protein in that they contain phosphorus and resist the solvent action of artificial gastric juice.

Migrating some ten years afterwards (1897) from Tubingen to Basle, Miescher entered upon his celebrated researches into the habits of the Rhine salmon. He found the belief had long been current that the fish, during their passage from the sea up the Rhine to their spawning haunts, never partook of food. That this belief was well founded he was able to prove; for, saving isolated and easily explicable exceptions, he noted that their alimentary canal was devoid of food débris, while their digestive juices were as a rule inert. One startling change he noted, that while, on the one hand, their muscular tissue profoundly wasted during their migration, their organs of reproduction enlarged enormously, the inevitable conclusion being that eggs and spermatozoa had been created from muscle protein.

Researches on Spermatozoa

Struck by the opportunities for scientific investigation during the spawning season, Miescher determined to resume his work upon nuclein. Spermatic fluid or lachsmilch, being readily obtainable in great quantities, he had to hand a mass of material admirably adapted for chemical examination of the cell nucleus. The conclusion that the heads of the spermatozoa might be regarded as a metamorphosed nucleus seemed obvious, and the opportunity too good to be lost.

On examination he found the “sperm heads” protein-free, made up almost entirely of a single chemical entity, a salt of an organic base rich in nitrogen and an organic acid containing phosphorus. The former was protamine, the latter nucleic acid.

The presence of this salt protamine nucleate led to the conclusion that nuclein was merely a salt of protein and nucleic acid.

The Discovery of Purins

Miescher, who had already isolated nuclein and nucleic acid, came nigh to one other equally important discovery. Heating a specimen of protamine with nitric acid, he noted that a yellow spot formed which turned to bright red when moistened with alkali.

Alive to the import of the reaction, Miescher requested Piccard[73] to examine salmon sperm for purin bases. Extracting the same with hydrochloric acid, Piccard found guanine, and what he thought was hypoxanthine, but which was in truth adenine.

Another distinguished worker in this sphere, Kossel, noted that, subjected to the action of hydrolytic agents, nucleins always yield purin derivatives; also that the same were derived, not from the protein of the nuclein, but from the nucleic acid. Thus it was to Kossel that we are indebted for the discovery of the purin bases, hypoxanthine, xanthine, guanine, and lastly adenine. It was, indeed, through his brilliant achievements that nucleic acid became recognisable as a definite entity, distinguishable from proteins and other body elements, this latter differentiation by token of the purin bases which are contained in nucleic acid.

Moreover, it led to the dissipation of the old belief that uric acid was an intermediate product of protein metabolism, for the revelation of purin bases as decomposition products of nucleic acid carried with it the inference that uric acid also had chemical affinities therewith. The chemical structure of the purin bases and that of uric acid betrayed a common likeness, and, therefore, a presumptive physiological connection; in other words, that a chemical nexus obtained between the cell nucleus or nucleic acid and uric acid.

The physiological derivation of uric acid from nucleic acid did not long lack experimental proof. In 1886 Minkowski found that, given extirpation of their livers, the urine of birds contained ammonium lactate, evidently a substitute for the uric acid normally present, notwithstanding the uric acid never entirely disappeared from the urine. This indicated the derivation of uric acid from two sources:—

• (1) Conversion in the liver of ammonium lactate into uric acid.
• (2) Some other, though unknown, process of formation.

To clear up the obscurity regarding the latter, V. Mach, after extirpating the livers of geese, injected them subcutaneously with hypoxanthine, finding that the same was converted into uric acid, which was excreted in the urine. In this way the capacity of the organism to elaborate uric acid from a purin precursor was demonstrated.

Uric Acid a Derivative of Nucleic Acid

Despite V. Mach’s revelation, the origin of uric acid from nucleic acid was still to seek. In the year following (1889) Horbaczewski traced it to this source, and in the following manner. Mixed with water, the pulp of the calf’s spleen was put to digest at 50° until putrefaction began. The fluid was then sterilised[74] with a solution of lead acetate, and arterial blood being added it was kept at 50°, a current of air meanwhile being passed slowly through the mixture. Subsequently the fluid was found to contain uric acid; but the experiment being repeated, without the passage of air, xanthine and hypoxanthine and not uric acid resulted.

While Horbaczewski’s experimental findings were amply confirmed, some of his deductions therefrom were subsequently proved faulty. (Thus, he thought putrefaction an essential factor; also he believed that the formation of uric acid ensued before the purin groups were disengaged from the nucleic acid, and definitely affirmed that the uric acid was not produced by the oxidation of free xanthine or hypoxanthine.)

But, nevertheless, this pioneer established that in both man and rabbits uric acid was derived from nucleic acid. Also, having observed that when after starvation the food intake was resumed, a leucocytosis occurred, he announced his belief in the following theory. Thus, he noted that leukæmics, whose blood showed a high leucocyte count, excreted an unusually large amount of uric acid; consequently, he came to the conclusion that uric acid was formed from defunct leucocytes. Also that nuclein-rich food, when ingested, contributed to the formation of uric acid only in so far as it induced leucocytosis. Hence the origin of the increased uric acid excretion which occurs when feeding is resumed after starvation.

This increased excretion of uric acid after the ingestion of food rich in nucleic acid has been amply confirmed; but all the earlier attempts to achieve an increased excretion by the ingestion of free purin bases, as opposed to the combined purin bases, existing as such in nucleic acid, failed, although tried repeatedly.

So much for the various stages by which our knowledge of the purin derivatives of nucleic acid has been gradually acquired, for though purin bases had, from early times, been known to exist in animal tissues, their presence there could not be rationally accounted for prior to the discovery of nucleic acid.

It still remains for us to deal in detail with the further developments of our knowledge which concern the disruption of nucleic acid in the body and the process by which uric acid is derived therefrom.

But before proceeding to consider in detail the complex series or enzymatic transformation that this entails, it will, I think, be wiser to deal first with the chemistry of uric acid, its solubilities, and its sources, whether exogenous, endogenous or synthetic.

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The Chemistry of Uric Acid and the Purin Bodies

Much of the vague philosophy of disease in past times may fairly be attributed to the complexity and mystery of action inherent in living matter. The subjects of physics, chemistry and biology, in their wider acceptation, were unevolved, and scientific pathology, the offspring of this ancestry, was yet unborn. How much we owe to physics, chemistry, and biology, those handmaids of medicine, is inestimable! But something at least of our debt thereto will be revealed in the following pages.

Of the purins in human urine, the most important is uric acid, and far behind comes xanthine, while traces of hypoxanthine, guanine, and adenine are also detectable. Some years ago the current view was that the metabolism of any protein gave rise to uric acid. This assumption has now proved to be erroneous, for it is known that only certain foodstuffs lead to an increase in the uric acid excretion; in other words, on a diet rich in purin the output thereof is considerably higher than on a purin-free diet, this being due to the large amount of nuclein and purin bases in flesh foods, especially those containing glandular substances. Under ordinary conditions the excretion of uric acid ranges from 0·3-1·2 gm. per diem, or 0·02-0·10 per cent. The oscillations in output vary with the state of health, diet, and personal idiosyncrasy.

Chemical Constitution

The empirical formula of the uric acid molecule, C₅H₄N₄O₃, has for long been known, but it was reserved for Emil Fischer to reveal the chemical structure thereof. Through his labours we now know that uric acid is one of a group of substances which owe their kinship to their possession in common of the heterocyclic ring termed by Fischer the “purin nucleus” (1898).

The intimate relations of the purins of bio-chemical interest to the purin nucleus, and alike to each other, will be rendered more intelligible by examination of their structural formulæ as hereafter given. All, as will be seen, are derivatives of a synthetically formed body purin which, though unimportant in itself, is yet interesting in that it is the basic substance from which the following take origin:—

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It now devolves upon us to note the arrangement of the atoms in the purin nucleus. To each atom is affixed a number indicating the exact location of the various atoms and groups attached to the said nucleus. The manner in which the various purin bodies are built up around the purin nucleus C₅N₄ will become apparent from a study of the following structural formulæ culled from Wells’ “Chemical Pathology”:—

Structural Formulæ

To describe the individual derivatives of purin we have to indicate to which particular atom of the purin nucleus the combining groups are attached. Thus, for example, adenine in structure is classed as a 6-amino-purin, and accordingly has the following formula:

Other important bodies built up round the purin nucleus C₅N₄, variously designated as xanthine, alloxuric and nuclein bodies:—

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It will be seen that the purin bases stand in very close chemical relationship to uric acid in that the latter also is marked by the possession of a group called the purin nucleus; indeed, the relationship of uric acid to the purin bases is more intimate than to urea (CON₂H₄), close though this latter be as may be seen from the study of its constitutional formula. (For uric acid may be regarded as composed of two urea radicles, linked by a tricarbon chain. By oxidation and hydrolysis, two molecules of urea may be obtained from one of uric acid, and conversely uric acid is produced by the condensation of urea with hydroxy acids).

The first product of the oxidation of purin is hypoxanthine, long recognised as a constituent of meat extracts. Adenine, the amino derivative of hypoxanthine, is met with in combination with other substances in nuclear material. The second oxidation product of purin is xanthine, and its amino derivative guanine, both of which are found in the same substances as hypoxanthine and adenine. Further oxidation of purin gives rise to uric acid. We have to recognise, also, that in addition to the purins of animal origin there are some also derived from vegetables, viz., the methyl purins, caffeine, theobromine, and theine.

Now, as will be seen later, certain compounds, containing nitrogen and phosphorus, constitute the chief, if not the exclusive, source of uric acid. These substances, long known as nucleins or nucleo-proteins, exist in the animal tissues, and in special abundance in those largely made up of cell nuclei, viz., thymus, lymph-glands, etc. The important and, indeed, the distinguishing component of the nucleins or nucleo-proteins is nucleic acid. This, in that through the action of ferments, it is from the nucleic acids that uric acid and the purin bases are derived.

But, apart from this, we have to recollect that nucleic acids yield constituents other than purin bases, viz., the pyrimidine bases, phosphoric acid, and a carbohydrate group. From a study of the structural formulæ of the pyrimidine bases it will be seen that they are closely related to the purin bases, lacking, however, one of the urea radicles. Moreover, it is believed that, though included[78] in the makeup of nucleic acid, they are not derived from purin but are primary products.

To sum up, the characteristic constituents of nucleic acid are the purin bases (adenine, guanine, hypoxanthine, and xanthine), pyrimidine bases (uracil, cytosine, thymine), phosphoric acid and a carbohydrate group.

We have now discussed the chemical structure of uric acid and its relationship to the purin bases; but before proceeding to consider the various sources from which uric acid is derived, it will I think be convenient to consider (1) the physical properties of uric acid and (2) the condition in which it circulates in the blood.

Properties of Uric Acid

When pure, uric acid is white in colour and crystallises in rhombic form. In contrast to urea it is very insoluble, but much less so in blood serum than in distilled water, viz., ⅟₄₀₀₀₀ of water as opposed to ⅟₁₀₀₀ parts of plasma. It yields with alkalies two series of salts, viz., the biurate or mono-basic, and the so-called neutral or bi-basic urate, the latter of which is much more soluble. In water the mono-basic urate forms a colloidal solution from which the crystalline salt gradually precipitates.

The greater solubility of uric acid in blood plasma was, by Garrod and Haig, attributed to the alkalinity of the plasma. But it must be recalled that the earlier workers in this sphere judged of the alkalinity of the plasma by its reaction to litmus, a crude procedure as compared with the use of phenol-phthalein, and Frankel’s electro-potential measurements. Working with these as criteria, it has been shown that blood is normally alkaline in only a minority of cases, and indeed, according to Flack and Hill, the plasma is in reality neutral.

In the urine uric acid and the urates are held in solution by the neutral phosphates. This because the decomposition of the urates into uric acid by the acid salts of the urine is inhibited by the di-sodium phosphate present therein. Its maintenance in solution is possibly also reinforced through the influence of other constituents in the urine, notably, the urinary pigments and sodium chloride.

Uric Acid in the Blood

As to the form in which uric acid circulates in the blood, Sir William Roberts believed that when dissolved in blood serum it was transformed into the relatively soluble sodium quadriurate.[79] This authority held that in gout, either through deficient excretion or over-production, the quadriurate accumulates in the blood. Circulating therein, in a medium rich in sodium carbonate, it takes up an additional atom of the base, and is transmuted into the biurate, which is less soluble and less easily excreted by the kidneys; consequently, the biurate is hoarded up in the blood, at first in gelatinous, and later in an almost crystalline form, when its precipitation is imminent or actually ensues. This, moreover, was apt to occur at sites where the circulation was poor, the temperature low, and more particularly in regions in which the plasma contained a relatively high percentage of sodium chloride, e.g., synovial sheaths.

But, unfortunately for the valency of this otherwise plausible theory, it was proved by Tunnicliffe, Rosenheim, and others, that quadriurates do not exist as definite chemical compounds; in short, it is generally conceded that their existence should no longer be accepted.

Gudzent and Schade’s Theories

Gudzent was of opinion that uric acid can only exist in the blood as the mono-sodium-urate, of which there are two isomeric varieties, the easily soluble unstable lactam, and the stable relatively insoluble lactim urate. It is the former, or lactam, variety that accumulates in the blood in gout and, according to Gudzent, it is the transmutation thereof into the lactim modification that determines the precipitation of urates in the tissues. The lactim urate is soluble only to the extent of 8·3 mg. per 100 cc. serum, whereas the lactam form is soluble up to 18 mg.

Others, like Bechhold, maintain that the urates are present in the blood in a colloidal form, impossible of excretion by the kidneys. Thus Schade contends that, in the presence of alkalies (hydrates), uric acid or its salts may pass into a state in which it is far more soluble than usual. Moreover, on its path to crystallisation from this over-saturated solution, it passes through a colloid stage in which it is relatively stable. The maintenance of this colloid stage and consequently the retardation of precipitation is promoted by certain substances, i.e., glycerine, urea, serum, albumen, nucleic acid, etc. But hitherto the therapeutic possibilities suggested have not been invoked.

Organic Combinations

It will be recalled that purin bodies cannot be detected in the blood in health, though their administration by the mouth results in an increase in the excreta. Minkowski, to account for this, suggested that the purins in the blood were circulating in a combination[80] which prevented them from giving the usual reactions, typical of their presence therein. We have an analogy in the masking of arsenic and iron in the cacodyl compounds and the ferrocyanide ion.[8]

The explanation proffered by Minkowski was elaborated by Von Noorden. His view was that lying at the disposal of the normal organism are a certain number of organic substances. These latter can combine with uric acid and render it soluble. It is then in this form passed through the blood in the kidneys, which eliminate from it the uric acid. Now, in gout these organic substances are deficient or wanting, and the result is that the uric acid is passed into the blood in the form of urates, the elimination of which only proceeds with difficulty; in other words, the purins normally circulate in organic combination and abnormally as salts of sodium.

It is worthy of note that, from a solution containing albuminous substances, Burian and Walker Hall found that while it was easy to remove the bulk of the purins, a certain percentage always remained which it was difficult to extract.

The view that uric acid is probably carried in the blood in combination with some other organic body and not, as was formerly supposed, with sodium salts, rapidly gained adherents, but the nature of the organic complex is still not accurately known. Many believe that at least a moiety of the uric acid circulates in combination with nucleic (thyminic) acid, but no such compound has yet been isolated from the blood. Nevertheless, as MacLeod suggests, this theory, were it proved correct, would account for the fact that some purins at least are katabolised in the body when they are given in a combined state, as thyminic acid, but are excreted unchanged when ingested in a free state. Thus, certain purins, e.g., adenine, when given freely, cause inflammation and calculous deposits in the kidneys of dogs which, however, does not ensue when they are fed with thymic acid.

But Walker Hall, discussing the good results obtained by Schmoll and Fenner from the administration of thyminic acid,[81] states that his experiments do not indicate that the improvement is at all associated with any change in the uric acid excretion.

To sum up, it is obvious, from the mere variety of the hypotheses advanced, that we are still much in the dark as to the actual form in which uric acid circulates in the blood. While on the one hand the quadriurate theory appears no longer tenable,[9] on the other the nature of the suggested uric acid organic complex is still unknown.

Nay, more, Walker Hall, writing in 1913-14, states “there are many who consider that the sodium mono-urate is the only possible compound;” while Wells, in his “Chemical Pathology” (1918), claims that the best evidence points to uric acid existing in the blood “in a free state and not combined, as was at one time urged by several students of gout.”

Complexity of the Problem

How complex, indeed, the task of the bio-chemist may be gathered from some reflections of Walker Hall. He reminds us that the oxidation and deaminisation of the nuclein derivatives, nucleins, nucleotides and nucleosides, is never complete. For purin bases and pyrimidin bases run side by side in the blood-stream together with uric acid. Also, that the unstable but soluble biurate is constantly changing into a less soluble type, viz., from one isomer to another. Moreover, since the red blood corpuscles abound in potassium, urates of potassium must also occur, and to these may be added, too, ammonium and calcium compounds in small quantities.

But more striking is his inference that the occurrence of isomeric forms of uric acid suggests that isomers of purins and pyrimidins also may occur. For the purin ring or pyrimidin nucleus, with their numerous receptors for the linking up of other substances, offer wide potentialities in the direction of isomerism.[10] Some of these, he hazards, may be born of one type of cell nucleus, some of another, while it is not inherently improbable that, “In[82] response to abnormal stimuli or excessive demand, other isomers may be formed.”

Now, though uric acid and the urates can be extracted from the blood, it does not, as he remarks, necessarily follow that they circulate as such in vivo; for, despite modern achievements, “the best of the existing methods for the determination of uric acid in the blood are nearly barbarous in their crudity and intensity.” The various procedures available for such estimates fall short of distinction between the several tautomeric forms of uric acid, much less do they furnish any information as to the associations or combinations of purins or pyrimidins with other substances.

For himself, recognising the generally more complex nature of biological processes, he considers that “the circulation of the purins as sodium mono-urate and its simple extraction by kidney cells, seems almost too simple to be true.”

As to the solubilities of uric acid and urates in gouty blood he points out that the suspension capability of the blood-stream for uric acid much transcends the highest amount of uric acid as yet found in the gouty subject. Accordingly, to him, therefore, it seems that “neither chemical nor physico-chemical processes suffice to explain the problem. There must be something more, something vital, biological.”

Having ascertained as far as possible the measure of our knowledge in regard to the foregoing points, we shall, in the succeeding chapter, proceed to discuss the sources of uric acid, whether of intrinsic or extrinsic origin.

Uric acid, like the “purin bodies” (xanthine, hypoxanthine, guanine, and adenine), is derived from nucleins, i.e., from the breaking down of tissues rich in cells. The end-product of purin or nuclein katabolism uric acid represents but a further stage in the oxidation of the purin bodies. To the serial enzymatic transformations that mark its derivation from nucleic acid we shall allude later, but at this juncture we are concerned not with the mode of formation of uric acid, but with the sources thereof.

In this sphere we are greatly indebted to the pioneer researches of Burian and Schur. These observers noted that on a diet rich in nucleins (sweetbreads, liver, kidneys) the total daily excretion of uric acid was considerably higher than on a milk or purin-free diet. This difference in response to varying dietaries, in respect of the excretion of uric acid, led Burian and Schur to the conclusion that the purins excreted must be partly of exogenous and partly of endogenous origin; in other words, the exogenous purins are derived from the nucleins ingested in the food, whereas the endogenous are the outcome of the breaking down of the cellular tissue of the organism itself.

Here it may be noted that all the ingested purins are not excreted in the urine as uric acid, for some pass away as purins. Moreover, the amount excreted will vary with the kind of purin ingested, and also with the species of the animal that consumes it. Thus, in man “only one half of the hypoxanthine administered as such appears as uric acid in the urine, and but one fourth of the purin in nuclein when that is fed. In the dog, compared with man, about ten times as much purin disappears in its passage through the organism; in the rabbit, about three times” (Flack and Hill).[11]

In amount about 0·4-0·7 gramme of uric acid is excreted in human urine daily, and the purin bodies, hypoxanthine, xanthine, and adenine, in small quantities.

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Beyond exogenous and endogenous purins there is yet one other possible source of uric acid, viz., its synthetic formation within the organism. This supposition took origin in Horbaczewski’s discovery that in the laboratory he was able to produce uric acid by the interaction of urea and glycocine, a finding afterwards confirmed by Latham. The theory was then advanced that a similar synthesis might be effected by the kidneys; but it was found that glycocine and urea, even when given in excess to mammals, caused no change in the uric acid excretion.

So much by way of preface to our detailed discussion seriatim of the various sources of uric acid, and to which we now pass on.

Exogenous Purins

The foodstuffs that cause an increase in purin excretion are divisible into three groups:—

• (a) Amino-purins.
• (b) Oxy-purins.
• (c) Methyl-purins.

Amino-purins.—In man the taking of food rich in nucleated cells and therefore in nucleo-protein and nucleins, increases the quantity of uric acid in the urine. Thymus gland, pig’s pancreas, and herring roe, containing the characteristic conjugated proteins of nuclei, or Liebig’s meat extract, rich in purin bases, when ingested, lead to a distinct increase in purin excretion.

The researches of Kossel and Horbaczewski showed that such augmentation was mainly due to the production of uric acid from the nuclein substances of the food; in other words, it was due to the katabolism of nuclein, the cleavage products of which comprise adenine derived from thymus, and guanine from the pancreas, both of these bodies being amino-purins. According to Burian and Schur, of the amino-purins ingested, a fourth is excreted as purin.

Oxy-purins.—To this group belong xanthine and hypoxanthine. These substances occur in muscle, and in great abundance in meat extract, and Minkowski noted that the ingestion of xanthine bases markedly augmented the amount of uric acid excreted. In man, given ingestion of hypoxanthine as such, only one half thereof appears as uric acid in the urine. It may here be mentioned that not all the purin bases ingested exist bound up in the nuclein substances. An appreciable amount is present in the tissues in a free state, e.g., hypoxanthine in the muscles; consequently, a moiety of the intake of purin bodies, especially in the animal constituents of the food, is to hand ready formed, and does not require the disruption of nucleic acid for its liberation.

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Methyl-purins.—The nuclei of vegetable cells also contain nucleo-protein, and, therefore, can add their quota to the purin intake. The most important are caffeine, theobromine, and theophyllin, the active principles of tea, coffee, and cocoa. It may here be recalled that of the purins administered in food, not all are excreted as uric acid, but some as purins. Now it is doubtful whether the methyl-purins lead to the formation of uric acid in the organism, or whether they are excreted as purin bases in the urine. According to Stewart, a fractional part of the purin bases in the urine is composed of heteroxanthine, 1-methyl-xanthine, and paraxanthine derived from the active principles of coffee, tea, and cocoa when consumed as beverages. As stated by Burian and Schur, one third of the methyl-purins ingested is excreted as purin.

From the foregoing data it will be obvious that the exogenous urinary purins are derived from nuclein and certain free xanthine bases, and that the influence of other nitrogenous foodstuffs in this direction is practically negligible.

Exogenous Uric Acid Excretion

As to the amount of exogenous purins that, when administered orally, can be recovered from the urine, it would appear that a certain rough parallelism obtains between the purin content of the food and that of the urine. The amount of the exogenous urinary purin differs for different forms of food, a variation well illustrated by the following table, giving the results of Burian and Schur’s researches.

Walker Hall, experimenting with various purin-containing foods, found that (1) with chicken 54·4 per cent., (2) with plaice 58·7 per cent., (3) with beef 47·4 per cent., (4) with haricot beans 55 per cent. of the food purin appears in the urine as exogenous purin. These findings of Walker Hall’s, like Burian’s and Schur’s,[86] reveal that, roughly speaking, 50 per cent. of the purin content in food is excreted in the urine.[12]

These figures must be taken as a broad average relating only to healthy individuals upon diets capable of perfect assimilation.

More recently, Mendel and Lyman found that about 60 per cent. of injected hypoxanthine, 50 per cent. of xanthine, 19-30 per cent. of guanosine, and 30-37 per cent. of adenine were excreted in the form of uric acid. While this is true of free purins, on the other hand, when bound purins, i.e., nucleins are administered, only a small proportion thereof appears as uric acid in the urine. But before proceeding to canvass the fate of the missing purin, it will, we think, be helpful if we interpolate here a table (Taylor and Rose), illustrative of the variations in uric acid excretion that attend a purin as opposed to a purin-free diet.

The subject of the experiment was, for three days, fed on a purin-free diet of milk, eggs, starch and sugar. At the end of this period a portion of the total nitrogen (3 grams) was administered in the form of sweetbreads, thymus gland, etc., with a high percentage content (0·482) of purin nitrogen. During the succeeding four days still more (6 grams) of the total nitrogen was replaced by sweetbread nitrogen. Subsequently the person was placed on the original purin-free diet.

From a study of the table it will be noted that, following the introduction of sweetbreads rich in nucleins, the uric acid content of the urine markedly increased, to sink again when a purin-free diet was substituted. But it will be seen also, as MacLeod points out, that “the increase of uric acid accounted for less than half of the purin nitrogen ingested. This appeared as uric acid, the excretion of purin bases being practically unchanged.” In other words, a moiety of the bound purins, i.e., nucleins ingested, appears as uric acid in the urine.

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Fate of the Unexcreted Purin

As to what becomes of that portion of the ingested purin that, so to speak, disappears in the body, is largely a matter of speculation. As MacCallum states, “the liberation of guanine and adenine is well in the line of uric acid formation,” but “the fate of the pyrimidin groups, thymine and cytosine, is still uncertain.” According to this observer, Levene has hitherto been unable to find an enzyme which will decompose the nucleoside in which they occur, and that since they cannot form uric acid, they are possibly excreted as urea or in other forms. He adds that only 50 per cent. of the nucleic acid nitrogen can be counted on for the production of uric acid, viz., that in the guanine and adenine groups.

MacLeod, discussing this same point, suggests that some of the unrecovered purin may undergo decomposition in the intestine, but why so much should, after absorption of the blood, disappear is, as he remarks, difficult of explanation; for while uricase, which can decompose uric acid, exists in the tissues of the lower animals, no such ferment is found in man, and uric acid is excreted as such. According to MacLeod, too, “the destroyed purins cannot be shown to influence any of the other well-known nitrogenous metabolites of the urine.”

Lastly, Stewart, discussing the ultimate destiny of the absorbed products of nucleic acid digestion, suggests that, when undergoing further cleavages, “they may be in part utilised for the synthesis of nucleo-proteins, replacing those destroyed in the process of cell metabolism;” or, that it is “possible that they may be wholly disrupted into their components, and these again re-synthesised.”... “Finally, and this fate is probably not long delayed in the case of the surplus of purin compounds contained in ordinary dietaries, both the purins of the food and the purins arising from the waste of the tissues, are for the most part converted into uric acid and excreted in the urine.”

Also, it should be recollected that the purin bases normally found in human fæces are in part of exogenous origin, and are increased in amount after the ingestion of meat extract or thymus.

Endogenous Purins

Even if we entirely eliminate all purin substances, by restricting the diet to purin-free foodstuffs (bread, milk, cheese, eggs and butter), purin in the form of uric acid is still excreted in the urine.

To this moiety the term endogenous purin is applied; for the continued excretion of purin on such a diet is explicable only on the view that they are derived from the waste of the tissues, the[88] daily “wear and tear” of cells. In other words, it is the outcome of the katabolism of the nucleo-protein of the body tissues.

Source of Endogenous Purins

Is the nuclear destruction of localised or generalised distribution?

Mares (and subsequently many other observers), having noted that, following the ingestion of purin-free protein food, a marked increase in endogenous uric acid excretion ensued, suggested that the said augmentation was the outcome of the “wear and tear” entailed upon the nuclear material of the secretory glands of the gastro-intestinal tract, following such intake.

The effects yielded on uric acid excretion by those antithetic drugs, atropine and pilocarpine, certainly seem to lend colour to Mares’ hypothesis.

Following the injection of atropine, the rise in uric acid output, that normally follows the ingestion of protein, was inhibited. But in sequence to pilocarpine, an excitant and not like atropine, a depressor of secretory activity, a marked increase in uric acid excretion followed. The contrast in response was naturally translated as striking evidence of the important rôle played by the digestive glands on uric acid excretion; in other words, it was held that the major portion of the endogenous uric acid was the reflex of such intensified glandular action.

In opposition, however, Burian, as the outcome of his experimental studies, maintained that a fractional portion only of the endogenous uric acid could be derived from the nucleo-protein of the body cells. This, inasmuch as it would entail a far too extensive katabolism of nuclear substance. Accordingly he propounded the view that the endogenous uric acid in the main was derived from the hypoxanthine of the inosinic acid present in muscular tissue. In this connection it may be noted that, on a diet approximating to Voit’s standard, 0·5 gram of purin is excreted daily. This, it is calculated, is equivalent to nearly 100 grams of thymus or allied tissue, which probably far exceeds the amount that could be gleaned from cellular katabolism.

Proteins and their Derivatives

A comparison of the influence of proteins as contrasted with that of their digested products, the amino-acids, it was thought, might furnish a clue as to the extent of which the alleged activity of the digestive glands was responsible for the increased uric acid output that followed the intake of non-purin protein food.

Such was the supposition entertained by H. B. Lewis, M. S. Dunn, and E. A. Doisy. Alive, moreover, to the deficiency of[89] the older procedure in use for the determination of small amounts of uric acid, Lewis and his collaborators invoked the more accurate colorimetric method of Folin and Denis (as modified by Benedict and Hitchcock).

The experiments were conducted with great care, and with as complete control as possible of the variable factors concerned. The investigators realised that, if any significance was to be attached to fluctuations in uric acid excretion following the intake of proteins and their derivatives, it was essential that accurate information be obtained as to the extent of the variations to be expected normally in the subjects when fasting. “Controls,” therefore, in which no food was consumed throughout the experiments, were instituted at frequent intervals so as to make sure that the level of endogenous uric acid metabolism was not altered by the long-continued purin-free diet.[13]

Passing now to the results obtained, it was noted that, after the intake of three types of purin-free protein food (egg white, cottage cheese, and glidine), there ensued a rise in uric acid output, reaching its maximum during the third or fourth hour after their intake. No quantitative differences in the uric acid output after ingestion of these three types of protein were observed; in short, the findings did but confirm what had been repeatedly demonstrated, viz., that the excretion of the endogenous uric acid is increased by purin-free protein food.

Amino-Acids and Dicarboxylic Amino-Acids

But the further interesting fact emerged, viz., that glycocoll and alanine, end-products of protein digestion, also augmented uric acid excretion; moreover, this even more swiftly than proteins, the maximum being reached within two hours after their intake.

In addition, like results followed the ingestion of the dicarboxylic amino-acids (glutaminic and aspartic acids), the increase in endogenous uric acid excretion being even more pronounced than with glycocoll or alanine.

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Now, it must be recalled that the amino-acids represent the end-products of protein digestion. Accordingly, Lewis and his co-workers argue that “since no digestive processes are required for the utilisation of amino-acids, it can hardly be considered that the rises in endogenous uric acid observed following the ingestion of four different amino-acids can be attributed to the work of the digestive glands.” The effect, they held, is more probably attributable to “a direct stimulation of the body cells by amino-acids or their katabolism products, a stimulation of nuclear metabolism,” for it is known that amino-acids disappear very swiftly from the blood-stream to be stored up temporarily in the tissues.

The question that now confronted the observers was whether the stimulation of nuclear metabolism was an inherent property of amino-acids. If so, “substituted amino-acids might be expected to exert a similar influence.” But, if on the contrary, it was due not to the amino-acids as such but “either to the cellular work of their katabolism or to the intermediary products of their breakdown, a substituted amino-acid which does not follow the normal path of amino-acid catabolism would in all probability be devoid of the power of stimulation.”

To this end, they selected sarcosine or methyl-glycocoll to elucidate the point at issue; this, inasmuch as it has been found to pass through the organism for the most part unchanged. The result justified their inference, for no perceptible influence on uric acid excretion was noted. Hence, on the basis of this experiment, they inferred that the stimulation of uric acid metabolism was not an inherent property of amino-acids; in other words, that if an amino-acid when ingested does not undergo disruptive katabolism, it is without effect on uric acid excretion.

Now deaminisation is the first stage in the katabolism of amino-acids, yielding as products ammonia and a-ketonic or hydroxy acids. The ammonia thus formed normally undergoes conversion into urea and is excreted as such. In order to ascertain whether the ammonia stimulated uric acid excretion, ammonium chloride was administered, but no rise in the uric acid output above the normal level ensued. Also, the ingestion of urea seemed to entail no appreciable increase in the uric acid elimination; in other words, these katabolic products of the nitrogenous moiety of the amino-acids are without effect. As to the non-nitrogenous intermediary products of the katabolism of amino-acids, i.e., the a-ketonic or hydroxy acids, it was impossible to investigate the influence of these on the endogenous uric acid elimination.[14]

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Lusk also has brought forward evidence that in the presence of amino-acids cellular activities are intensified markedly. According to Taylor and Rose, too, not only nuclear katabolism, but also nuclear anabolism, may be accelerated by the presence of large amounts of amino-acids.

Lewis and his collaborators consider that the results of their researches militate against Mares’ hypothesis, viz., that the origin of the increased amounts of endogenous uric acid that follow the intake of purin-free protein stuffs is referable to intensified activity of the digestive glands.

They hold that “it can be accounted for equally well as the result of a general stimulation of all cellular metabolism by the products of digestion of proteins the amino-acids.”

The recorded increases in endogenous urinary purin are, they consider, far too great to be the outcome of the stimulation of so small a proportion of the cells of the body as those of the digestive tract. On the other hand, they do not deem it necessary to assume that the whole of the endogenous uric acid is the outcome of nuclear disruption, concurring with Burian’s view, that a moiety thereof may be derived from the hypoxanthine of muscular tissue.

Endogenous Uric Acid Excretion

The researches of Leathes and his collaborators permit the deduction that endogenous uric acid excretion bears a definite relation to the activity of cellular processes. Given unchanged physiological conditions, e.g., muscular exercise, the amount of the endogenous uric acid excreted is, for the same individual, fairly constant, and this irrespective of diet; but it is not the same for different individuals, even those of identical body weight.

According to MacLeod, the endogenous excretion in an adult man fluctuates between 0·12 and 0·20 per cent. purin nitrogen. The average daily endogenous uric acid output of a normal adult, as stated by Walker Hall, is about 0·5 gram, while that of a gouty individual is 0·45 gram.

Now Burian and Schur’s original contention was that, in a given individual on a purin-free diet, the endogenous purin output was constant, and this despite marked variations in the amount of the purin-free food digested.

Recent researches, however, of Folin and of Hopkins and Hope, indicate that this dictum must be modified to this extent, viz.,[92] that although it is true that the endogenous excretion continues remarkably constant, with moderate variations in the amount of purin-free food, it is not so in the presence of marked variations.

The subject (Hopkins and Hope), after a fast of six hours, was given a meal of bread and potatoes, and at every subsequent hour estimates were made of the amount of urea and uric acid excreted in the urine.

It is clear from the results obtained that a very definite increase of endogenous purin excretion ensued, and that the said increase occurred sooner as regards uric acid than urea. This bears out what Mares demonstrated many years ago, viz., that the greatest increase in uric acid excretion occurs in a few hours after a meal, whereas the increase in the case of urea comes more tardily, not reaching its maximum until some hours after.

Horbaczewski referred such increase in uric acid excretion to a digestive leucocytosis; in other words, that the uric acid was the outcome of destruction of the leucocytes, and consequent formation of purin from the released nucleic acid. Unfortunately for this theory, the period of most marked augmentation in uric acid excretion ensues when the leucocytes are most in evidence in the blood-stream, not after they have disappeared, as would be the case if uric acid was derived from the purin product of the nucleic acid liberated by leucocytic destruction. We have a parallel instance in the case of pneumonia, in which it has been shown that the elimination of uric acid and other purins is at its acme when the leucocytes are most abundant; in other words, the highest uric acid output coincides with the period of most marked leucocytosis, whereas during the post-critical stage, viz., when leucocytes are being destroyed in great numbers, the output of uric[93] acid is very markedly lowered. Discussing Horbaczewski’s theory in light of the above criticisms, MacLeod suggests, “that the facts appear to indicate that the purin substance is a metabolic product of the living leucocytes,” and not, so to speak, the chemical outcast of their disruption and death.

Lastly, Walker Hall, discussing endogenous uric acid excretion, emphasises the necessity of discriminating between the uric acid output and the total purin output. He reminds us that the actual cell nucleins belong chiefly to the group of amino-purins, i.e., guanine and adenine, and that the oxypurines, xanthine and hypoxanthine, are intermediate products on their way to excretion, another and more advanced intermediate product being uric acid. Now, only a proportion of these intermediary products appears in the urine, this commonly cited to be approximately 50 per cent.

But this, as Walker Hall states, must be taken only as a very broad estimate, for in the same individual the output varies with the number of conditions, not as yet fully determined. But the point most emphasised by him is, that though “the uric acid output varies considerably, the total purin output does not show similar variations; for when the uric acid excretion wanes that of the purin bases usually rises. As a consequence, the total purin output is more constant, less influenced by circumstances, than the output of uric acid.”

This being so, we shall now pass on to consider other conditions influencing endogenous uric acid excretion.

Factors Influencing Endogenous Uric Acid Excretion

The output of endogenous uric acid excretion is influenced by (1) Physiological conditions, (2) Pathological states, and (3) The ingestion of certain drugs.

Physiological Conditions

It is now recognised that the purin bases of the body exist not only in the bound form (nucleic acid), but also free, especially in muscular tissue. Also, that from such free purin bases uric acid can be readily formed as from those liberated by the disruption of nucleic acid. Thus, inosinic acid, a nucleotid first isolated from meat extract, yields phosphoric acid and the purin base, hypoxanthine. In possession of these facts, we shall be better able to appreciate the significance of the researches of Burian and others.

(a) Muscular Exercise.—According to Burian a large increase in the excretion of uric acid was found to follow muscular exercise. The same observer also noted the presence of hypoxanthine in[94] defibrinated blood after its perfusion through the hind legs of a dog whose muscles had been thrown into tetanus. Moreover, subsequent to contraction, the muscles themselves contained an increased amount of oxypurine. From these findings Burian concluded that hypoxanthine was a product of muscular action, and that this substance or its precursor, inosinic acid, was an important source of endogenous uric acid. The uric acid thus formed by oxidation was then partly destroyed in the liver and partly excreted by the kidneys. But Burian noted also during activity of the muscles that a certain amount of the purin bases failed of oxidation, and consequently a larger amount of the same, as compared with uric acid, passed into the circulation.

Kennaway, discussing the effect of muscular exercise on the excretion of endogenous purins, noted that during unaccustomed exercise the uric acid output of the kidneys diminished, but that of the purin bases is relatively augmented, but, on the whole, he found that the total purin output (bases plus uric acid) was not very much increased.

Leathes and others, investigating the effects on uric acid excretion of strenuous exercise, established the occurrence of a distinct increase. Given that the same kind of exercise is practised on the day following, the said increase is much less marked. If, however, some different form of muscular activity is undertaken, another increase in uric acid follows. It would appear, therefore, that, despite conflicting evidence, the balance of opinion favours the view that muscular activity does lead to increase in endogenous uric acid excretion.

(b) Periodic Variations.—Leathes noted diurnal and nocturnal variations in the excretion of endogenous uric acid, the maximum occurring within the early waking hours, and sinking to a minimum towards the evening. His experiments, he held, indicated a variation in the actual formation of endogenous uric acid at different periods of the day. Rockwood also found that an increase occurred during the daytime, and Pfeil, that there was a morning rise in the amount of uric acid passed. The fact that doubt still obtains as to whether muscular exercise has any effect on endogenous uric acid excretion, renders explanation of this diurnal variation difficult. This especially as there are no fluctuations in the urinary functions that could in any way account for it.

Pathological States

Endogenous uric acid is increased under certain pathological conditions. Leathes’ recent work confirmed the view that there is an increased production of nitrogenous waste in fevers. After taking a large dose of anti-typhoid serum his temperature rose to 103° F. Experimenting on himself, he found his output of urea, uric acid, and creatinine all increased, but of all[95] three uric acid showed the most marked alteration. The question now arises as to whether such is due to increased production or diminished destruction. Some further experiments conducted by Leathes on himself may serve to elucidate this point. Subjecting himself for a prolonged period to cold baths, a similar increase in his uric acid output ensued. This would appear to indicate that, through increased loss of heat, the bodily processes of combustion were augmented to maintain the body temperature, with, as a consequence, increased uric acid excretion.

In leukæmia protein-destroying forces are at work, and the urine contains large quantities of uric acid. The same is attributed to the formation and destruction of enormous numbers of leucocytes, but the urinary findings in this respect have been extremely variable. While increased uric acid elimination has been vouched for by many authors, some have noted increase in the purin bases, sometimes with, and sometimes without increase in the uric acid; while others again have even noted a decrease in uric acid and phosphoric acid excretion.

Apart from these contradictory findings, it would appear, according to Magnus-Levy, that in acute leukæmias the relation between the number of leucocytes and the uric acid output is most variable. Lastly, the different types of leukæmia present differences in regard of their uric acid output, the increase in the myelogenous variety being much more marked than in the lymphatic form.

Wells, discussing these conflicting data, considers that they are but the reflex of the “known fluctuations in the course of the pathological processes of leukæmia; the number of leucocytes, the size of the lymphatic organs, and the general condition of the patient all vary greatly from time to time, often with remarkable rapidity and the excretion of products of metabolic activity must vary likewise.” Continuing, he observes that the enormous increase in the amount of lymphoid tissue in the body and blood must give rise to a greatly augmented nuclein katabolism, with sequential appearance of uric acid, purin bases, and phosphoric acid in the urine. This he holds to be well demonstrated by the increased elimination of uric acid and purin bases, together with a general increase in the nitrogen output such as has been frequently noted in sequence to the therapeutic use of X-rays in leukæmia, this attributable to the increased autolysis known to be induced by X-rays.

As to this question of the relationship of leucocytosis to uric acid excretion, it must be borne in mind that the number of leucocytes and the excretion of uric acid do not always vary directly. Parallel studies of the blood and urine have shown that leucocytosis does[96] not invariably accompany increased uric acid excretion. Indeed, Hutchison and MacLeod have recorded cases of leucopenia without any reduction in the amount of uric acid eliminated.

Also, we have to recall that on a purin-free diet the amount of endogenous uric acid is more than can come from nuclein destruction in the body. As suggested by Burian, some may be derived from the hypoxanthine in muscular tissue. In short, while nuclein disintegration is the outstanding source of endogenous purin, yet, for the reason cited, it cannot be regarded as the sole source, for the exact origin of all the endogenous purin is not as yet established.

In conclusion, it would appear that some drugs influence more or less markedly the excretion of endogenous uric acid, notably, atophan; but discussion of these will, we think, be best postponed to the section dealing with the medicinal treatment of gout. Meanwhile we shall proceed to consider the vexed question of the formation within the organism of uric acid by synthesis.

Synthetic Formation of Uric Acid

Birds eliminate most of their nitrogen in the form of uric acid, and, undoubtedly, in their instance synthetic formation of uric acid in the liver takes place on a large scale. Thus, when blood containing ammonium lactate is perfused through the liver of the goose, an increase in the uric acid content of the blood occurs. Also the ingestion of lactic, pyruvic and other organic acids leads to augmented output of uric acid; in short, it is generally agreed that in birds synthesis is the chief mode of formation of uric acid, homologous with the formation of urea in the liver of mammals.

If this be true of birds, on the other hand, splitting and oxidation of nucleins is in mammals the most important source of uric acid, but there is evidence that it cannot all be accounted for in this way. As before remarked, the old belief that purin excretion remains almost constant on a purin-free diet, despite great variations in the amount of the ingests, is not strictly true. Thus, using swifter and more reliable methods for the estimation of nitrogenous metabolites, Folin noted, on an absolutely purin-free diet, that an increase in purin excretion ensued, given marked variations in the intake of food. Again, the Dalmatian dog, as we have seen, excretes uric acid in his urine. S. R. Benedict was therefore able to demonstrate that a very distinct increase in his uric acid output ensued in sequence to increase in the amount of his non-purin food; moreover, that even when such non-purin foods were continued for a year, “the total amount of uric acid excreted was at least ten times greater than could have come from the traces unavoidably included in the food” (MacLeod).

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Also Ascoli and Izar, experimenting with dog livers, noted on incubation thereof and passage through the same of oxygen that the uric acid disappeared; but on the substitution of carbon dioxide an accumulation thereof ensued. Wells, however, was unable to confirm this re-synthesis of uric acid by dog livers, and Spiers also failed to corroborate their findings.

On the other hand, there is evidence pointing to the fact that a certain small percentage of synthetic formation does take place in the organism. Thus certain chemical substances, and these not purin, do cause an appreciable though slight increase in the purin excretion of mammals, and a very marked augmentation of the same in birds, viz., lactic, tartronic and B-oxybutyric acids.

But, as MacLeod, discussing these experimental and clinical findings, observes, there are to hand even more direct proofs that purin synthesis occurs in mammals. Thus, as McCallum has pointed out, we cannot escape the admission that young mammals are able to synthetise the purins essential for their growth, and this from food containing no purin, e.g., milk. Again, prior to incubation, a hen’s egg contains practically no nucleic acid, whereas after development its content in the same increases by great strides. The eggs of insects, too, with the progress of development, amass purin very rapidly.

Again, Miescher noted long since that salmon, on leaving the sea to ascend rivers for the object of spawning, have at that time well-developed muscles; but on arriving at the upper reaches, marked muscular wasting ensues, while the testes undergo enormous enlargement. MacLeod, reflecting on these observations, argues that, “as the fish takes no food during the migration, there must be conversion of the protein of the muscles into the cellular tissue of the sexual glands, and nucleic acid must be produced.” MacLeod’s conclusion is that “Purin synthesis undoubtedly occurs in the mammalian body, but it is difficult to recognise in metabolism investigation, because it is a slow continuous process ... whether or not changes in the activity of purin synthesis occur in conditions of disease, is a question which awaits investigation.” Lastly, the opinion of most authorities is that, while they concede the possibility of synthetic formation, the amount of uric acid produced in this manner is negligible, and that by far the most important mode of formation in mammals is by the splitting and oxidation of nucleins; in other words, that uric acid in the main is derived from the amino-purins by deaminisation and subsequent oxidation, and from the oxy-purins directly by oxidation.

The chemical structure and sources of uric acid having been dealt with, we are now in a position to resume our narrative, and to take up the thread at the point when Horbaczewski revealed the derivation of uric acid from nucleic acid. It now devolves upon us to scrutinise more narrowly the process by which the formation of uric acid from nucleic acid is achieved. Incidentally, it will not be unprofitable to note, if only briefly, the steps by which the necessary expansion of our chemical and physiological knowledge of nucleic acids has been acquired.

As may be imagined, the primary difficulty was to prepare nucleic acids of such purity as admitted of their elementary chemical analysis. The necessary researches were to a large extent confined to two types of nucleic acid, one derived from yeast, and the other from the thymus gland; in other words, to representatives of the only two nucleic acids in nature, one derived from the nuclei of animal cells, the other from the nuclei of vegetable cells.

A feature common to nucleic acids of animal and vegetable origin is that, on hydrolysis with boiling mineral acid, they yield two purin derivatives, guanine and adenine, and a pyrimidin derivative, cytosine. From thence as regards their remaining constituent elements they display distinctions. Thus animal nucleic acids yield thymine, and contain a hexose group in their molecule. On the other hand, vegetable nucleic acids give forth uracil and possess a hexose group.

To sum up, nucleic acid is a chemical complex, made up of phosphoric acid with purin bases, pyrimidin bases and carbohydrate radicles. Moreover, nucleic acids, whatever their source, show a striking similarity in structure, containing always two amino-purins (adenine and guanine), two pyrimidines (either cytosine and uracil, or cytosine and thymine), and a carbohydrate. Now, while purin bases are always present, yet, in respect of their carbohydrate group, nucleic acids display variations; this, according as they are of animal or vegetable origin. If the former, the carbohydrate group is a hexose (contains six carbon atoms) with thymine. If the latter, it contains pentose (five carbon atoms) with uracil.

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The constancy in the content of the various nucleic acids is such that Levene and Jacobs have felt justified in putting forward the following provisional formula as to the constitution of a nucleic acid of animal origin.

Structural Formula of Nucleic Acid

Distribution of the Enzymes

The enzymes responsible for the disruption of the nucleic acid complex are not to be found in all the body tissues. Moreover, the distribution of the enzymes in the various organs and tissues varies in different species of animals. Of the various organs the liver, spleen, thymus, and pancreas more particularly contain enzymes in abundance. As to their varied location in different animals, it may be noted that the enzyme responsible for the oxidation of xanthine into uric acid, viz., xanthine-oxidase, is found in man only in the liver. In other animals, also, it is of localised distribution, being as a rule only found in the liver or in the liver[100] and kidney. The dog, however, appears to be an exception, xanthine-oxidase being found in a variety of its tissues.

Adenase, the deaminising enzyme, is not to be found in any organs in man. Neither does it exist in any of the tissues of the rat. Consequently, if adenine be injected subcutaneously in rats, it undergoes oxidation, without abstraction of its amino group.

On the other hand, guanase, also a deaminising enzyme, is in man to be detected in the kidney, lung, and liver, but not in the pancreas or spleen. In the pig, however, guanase is lacking, and its absence no doubt explains why deposits of guanine may occur in the muscles constituting the so-called guanine gout met with in swine. It is worthy of note also that in pigs’ urine the content of purin bases exceeds that of uric acid.

To sum up, in man the enzyme, xanthine-oxidase, which forms uric acid from xanthine, is located chiefly or exclusively in the liver. This, of course, represents the final stage of purin metabolism, but the antecedent chemical processes involved in the disruption of nucleic acids are initiated by the action of enzymes in the intestinal juices and wall, and to a consideration seriatim of these changes we now proceed.

Stages in Disruption of Nucleic Acid

As might be expected from the complex structure of the nucleic acid molecule, a number of ferments are concerned in its disruption. The gastric and pancreatic juices contain not a trace of any enzymes. Thus, when nucleo-protein is subjected to the gastric juice a moiety of protein is readily split off and hydrolysed to peptone and other products of proteolysis.

But the nuclein element remains unacted upon until it comes under the action of the pancreatic juice. Hydrolysis then ensues, and the ingested nuclein is broken down into nucleic acid and protein. The nucleic acid remains unaffected by the pancreatic juice, but, coming in contact with the succus entericus, it undergoes partial decomposition through the action of a ferment called nuclease or nucleic-acidase. Under its disruptive effect the nucleic acids or poly-nucleotides are further split up into groups known as nucleotides. The two pyrimidine nucleotides split off and undergo no further change. But, through the action of another ferment, nucleotidase, the purin nucleotides are further decomposed to yield nucleosides (substances of the glucoside class made up of a combination of a purin base with a carbohydrate group of the nucleic acid with which also phosphoric acid is linked).

No further stage in hydrolysis of nucleic acid occurs in the intestine, but the nucleosides are again in turn split up after reaching the tissues, particularly in the spleen, liver, and thymus. This,[101] under the action of specific enzymes, nucleosidases, which succeed in breaking the nucleosides down into the so-called “building stones” of the nucleic acid molecule, phosphoric acid group, carbohydrate group, pyrimidine and purin bases, especially adenine and guanine. The adenine and guanine thus formed are, by the action of the ferments adenase and guanase, converted and, by the removal of their amino group, transformed, adenine into hypoxanthine, and guanine into xanthine, thus:—

By the action of oxidases also present in the tissues hypoxanthine is changed into xanthine and xanthine into uric acid (trioxy-purine), this by a specific ferment xanthine oxidase.

Scheme Illustrating the Probable Stages in the Passage of Purin through the Body (Walker Hall)

It will be seen that the disintegration of nucleic acid involves many stages, and its complexity is such that we make no apology for drawing upon the masterly monograph of Walter Jones for[102] further elucidation of this intricate question. In relating the history of nucleic acid in the animal body Jones has found it convenient to introduce certain terms wherewith to designate the various elements of the nucleic acid molecule. Thus, the molecule in its entirety is termed a tetra-nucleotide. The cleavage of this complex is initiated by the action of two specific enzymes. Through their agency the tetra-nucleotide is first cloven into two di-nucleotides, which immediately divide up into four mono-nucleotides. These ferments are:—

(1) Phospho-nuclease (which splits off the phosphoric acid radicle, leaving a nucleoside, guanosine or adenosine).

(2) Purin-nuclease (which splits off the purin radicle, viz., separates out both phosphoric acid and carbohydrate groups, leaving free purin bases).

Now, in sequence to either of the foregoing cleavages by the phospho- or purin-nucleases another set of enzymes come into the field. Under their deaminising effect the amino group is abstracted, with the formation of either free oxy-purins or oxy-purins still bound in glucoside-like combination with sugar.

If the oxy-purins are free, the following is the reaction:—

Should, however, the guanine glucoside be present:—

In the latter instance a hydrolysing enzyme, xanthosine-hydrolase, by its action, splits off xanthine. We see, therefore, that by either route the end-product is the same. Following a like series of changes, the adenine radicle is transmuted into hypoxanthine. This either directly by the action of adenase:—

or indirectly through the agency of adenosine-deaminase, the hypoxanthine-glucoside (inosine) is formed, and subsequently the hypoxanthine is split off.

[103]

Xanthine and hypoxanthine are, therefore, now to hand, and given the presence of oxygen, their oxidation to uric acid ensues:—

Now, in man and the anthropoid apes, uric acid is the end-product of purin catabolism. In contrast therewith in most mammals only a minimal amount of the exogenous or endogenous purins escapes in the urine as uric acid. Most of it undergoes further oxidation into allantoin,[15] this change taking place in most mammals chiefly in the liver. According to Schittenhelm, if nucleic acid be given to dogs, pigs or rabbits, from 93-95 per cent. thereof appears in the urine as allantoin, and only 3-6 per cent. as uric acid, and 1-2 per cent. as purin bases.

Disruption of Nucleic Acid Molecule (Amberg and Jones).

[104]

In man, as in most mammals, uric acid is formed chiefly in the liver from purins, and in the preceding table Amberg and Walter Jones schematically represent the various steps by which disruption of the nucleic acid molecule is attained, and uric acid formed.

Destruction of Uric Acid

Uricolysis, or the destruction of uric acid, is, in most mammals, achieved through the agency of the oxidising enzyme uricase, which oxidises uric acid to allantoin. Consequently, in their instance, purin bases, ingested as such or set free in the tissues, appear in the urine, not as uric acid, but in the form of allantoin. On the other hand, both in man and in the anthropoid apes, this particular enzyme uricase is absent. In accordance therewith, only a trace of allantoin is to be found in the urine of man and the higher apes, while in the lower animals, e.g., dogs, pigs, and rabbits, a large proportion of the purin excretion assumes this form.

Now, the absence of uricase, in man, is held to be proved by the fact established by Wiechowski and others, viz., that uric acid, if injected subcutaneously, may be almost wholly recovered in the urine, and moreover, unchanged. On the other hand, the total excretion of uric acid and the other purin bodies by no means tallies exactly with the amount of the uric acid ingested as purin bases in the food and that produced from the tissues; in other words, it has been found that, when given by the mouth, nucleic acid or purins are by no means quantitatively excreted in the urine, even though not only uric acid, but also allantoin and the purin bases, are included within the estimate. According to most experiments, a considerable proportion of the purin-nitrogen intake, about 50 per cent., is excreted as urea.

The question then arises as to what becomes of that moiety of the food purins which fails to appear in the urine as uric acid. Now the amount of allantoin that appears in the urine is negligible. Moreover, Ackroyd, having shown that the organism cannot destroy allantoin, it is possible that the minimal amounts excreted thereof in the urine are all derived from the food.

Accordingly, if, as experimental feeding with purins or nucleic acid appears to indicate, purins are destroyed in the body they[105] “pass through some other route than allantoin, and possibly, that part of the purin which is destroyed does not pass through the stage of uric acid.” Such is Wells’ opinion, and he reminds us that in vitro the destruction of uric acid can be attained by other routes than through allantoin. Thus, it can be broken down into glycocoll, ammonia, and CO₂, or by another method of disintegration it furnishes first alloxan (C₄H₂N₂O₄), then parabanic acid (C₃H₂N₂O₃), which in turn yields oxalic acid and urea.

But while it is probable that there is more than one way in which uric acid can be decomposed in the body, nevertheless there is, according to Wells, no evidence that either of the alternative routes above suggested is ever affected in the animal body. In this impasse Siven suggests the further possibility, viz., that the moiety of the food-purins which fail of recovery from the urine undergo partial destruction in the intestine by bacteria.

Stewart, however, in his “Physiology,” discussing uricolysis, maintains that a considerable destruction of uric acid and other purin bodies goes on in the body and mainly in the liver. He reminds us that when uric acid is heated in a sealed tube with strong hydrochloric acid, it breaks down into glycin, carbon-dioxide and ammonia, and he maintains that “there are grounds for believing that a similar decomposition takes place in the body, and that the products are then transformed into urea in the liver”; this, through the agency of a special ferment called the uricolytic enzyme.

Also, Flack and Hill, discussing the metabolism of nuclein, hold that some of the uric acid thus formed may be transmuted into urea by an uricolytic ferment present in the liver, muscles, and kidneys. This same agent they consider “probably destroys a considerable amount of the uric acid formed in the body. Indeed, uric acid, even when given in the food, owing to the presence of this enzyme, causes no increase in the uric acid output of the body.”

On the other hand, Wells, discussing the destruction of uric acid, observes that repeated investigations show “that the tissues of man have no power whatever to destroy uric acid in vitro; the earlier reports of positive uricolysis undoubtedly being erroneous.” His final conclusion, after weighing all available evidence, is that it is highly probable that in man “most of the purin absorbed from the food, and practically all the purin from cell metabolism, is converted into uric acid and excreted as such.” MacLeod, however, reflecting on the fact that uric acid is not destroyed when extracts of the organs are incubated at body temperature with uric acid or its precursors, bids us bear in mind that, “although the uric acid is thus shown not to[106] be destroyed in vitro, it may nevertheless be destroyed in the living animal.”

We see, therefore, that the question, Whether uric acid can undergo destruction in the human body? is still a matter of dispute, and must, pending further investigation, remain sub judice. Still, despite the conflict of evidence, clinicians have felt justified in assuming that one of the factors in the genesis of gout may be an entire absence or a diminution in the amount or activity of this uricolytic ferment.

But the awkward fact remains that all researches up to date have failed to establish the presence in the human body of any enzyme which can decompose uric acid. Should, therefore, future investigators place beyond the reach of cavil the claim that no uric-acid-destroying enzyme exists in the body, it would seem that, ipso facto, man, through lack of this capacity for rapid oxidation of uric acid, is, by this same disability, rendered a potential victim of uric acid retention and deposition.

Elucidation of this vexed point seems more probable in view of the striking discovery recently made by R. Benedict, viz., that in one particular breed of dog, the Dalmatian, uricase is wholly absent. In respect of this lack of a uric-acid-destroying ferment, the Dalmatian breed of dog has a purin metabolism apparently identical with that of man.[16] Thus, if fed on a purin-free diet, he passes large quantities of uric acid, and if the latter be injected subcutaneously, elimination in quantity as such ensues; this, in striking contrast to what obtains in all other animals in whom, as before noted, uric acid is mostly oxidised to allantoin before excretion. Now, as MacLeod observes, investigation into the metabolism of nucleic acid has, in man, been hampered greatly, in that the absence of uricase from his tissues, prior to Benedict’s discovery, rendered experimental researches on the lower animals valueless. But, in light of the above revelation later by R. Benedict, it may reasonably be hoped that in the near future our knowledge as to the location and nature of the intermediary chemical processes occurring in the metabolism of nucleic acids may be materially clarified.

It will be recalled that at the close of our chapter on Pathogenesis we referred to the growing scepticism of Garrod’s views as to the pathogeny of gout. Still, if we except Edward Liveing’s pertinent observation that uricæmia was not peculiar to gout, naught, save alternative hypotheses, unsupported by pathological data, was advanced. Consequently, Garrod’s facts never being seriously called in question, his position remained unassailable, until, in the year 1898, his original observations as to the lowered alkalinity of the blood in acute gout, and the increased uric acid content thereof during the same, were definitely contradicted by Magnus Levy.

Working with more modern and more reliable methods of technique, this observer, in a series of seventeen cases of acute gout, found no evidence of any lessening in alkalinity of the blood or of any augmentation of its uric acid content as compared with the inter-paroxysmal period.

Again, as to Garrod’s claim that there was a diminished excretion of uric acid during the attack, this also, while supported by Minkowski, was called in question by Pfeiffer, Levy, and Badt, who found the reverse to be the case, i.e., a notable increase in the excretion of uric acid during the paroxysm.

These results were again in 1900 confirmed by Chalmers Watson. An exhaustive study of a series of cases of acute gouty polyarthritis convinced him that:—

The iconoclastic revelations of the foregoing researches may[108] well form a preface to our discussion of gout from the triple aspect of:—

• (1) Uric acid excretion.
• (2) Uricæmia.
• (3) Uratosis.

Uric Acid Excretion in Gout

The earlier investigations as to the behaviour of uric acid in the organism were necessarily restricted to the noting of any variations in the uric acid output in the urine. That the findings and, alike, the deductions proved bewilderingly contradictory is not to be marvelled at when we recall the many factors that govern the amount of uric acid excreted in the urine.

How fallacious, it now transpires, were the assumptions based upon the mere uric acid output in the urine, and how little understood even to-day the many conditions that determine its variations.[17] But, fortunately, we can now to some extent control and review our urinary findings in light of the uric acid content of the blood. But we anticipate, and meanwhile let us confine our discussion to the variations in uric acid excretion that occur in gout, and this as revealed by more modern students of the disease. This will be more conveniently dealt with if we consider first the oscillations in uric acid output in relation to acute attacks of the disorder, and subsequently the same as met with in its more chronic manifestations.

Uric Acid Variations in Acute Gout

Generally speaking, there appears to be a consensus of opinion on the following points:—

To sum up, during an attack of acute gout the uric acid output stands at a relatively low level between the paroxysms. But one or two days before the oncoming attack a diminution in uric acid output ensues. In contrast with the outbreak of the attack, the uric acid excretion increases markedly, this enduring for a week or more, when the output again declines. The augmented output during the paroxysm is more constant than the diminished excretion antecedent thereto. Now, while it may be taken that the foregoing variations in uric acid output, prior, during, and subsequent to, acute attacks, obtain as a general rule, such behaviour is not invariable; for, unfortunately, as Wells reminds us, instances are met with in which “the uric acid excretion shows no variation from that of normal persons.”

Uric Acid Variations in Chronic Gout

It must never be forgotten that the elimination of uric acid displays wide variations, this even when the subject under investigation is on a constant diet. Consequently, as Folin has pointed out, “even in the case of gout, which is distinctly associated with uric acid, it is an extremely difficult matter to prove by means of urine analyses that the uric acid elimination is not entirely normal.” And he adds, “If it had not been for the fact that uric acid, because of its insolubility, is so easily found in the joints, it would unquestionably have been a very long time before any definite relationship between uric acid and gout could have been established.”

None can gainsay the truth of these reflections, for, when placed on a fixed diet, the uric acid output in the victims of chronic gout differs but little from that of normal individuals on a similar regime; save in this respect, that, following the intake of purin-containing substances, the period of augmented uric acid excretion that ensues is prolonged as compared with the normal.

Retarded Exogenous Uric Acid Output

In 1901 Vogt showed that in gout the excretion of exogenous purins was not only delayed but diminished. Giving simultaneously to a gouty subject and a healthy individual a diet rich in purins, he found that, in the former, retention and delayed[110] excretion of purins ensued. Vogt’s findings were confirmed by Reach, Soetbeer, Pollak, Mallory, and others.

Brugsch and Schittenhelm also observed that, following the intake of purin-containing substances, the exogenous uric acid excretion was retarded and reduced; in other words, the percentage of exogenous nitrogen excreted as uric acid nitrogen is less than in normal individuals, although the increased elimination extends over a longer period of time.

On the other hand, Walker Hall finds that, though there is retardation, there is no diminution in the output in gouty subjects. Thus he states: “When an adult takes a meal consisting of half a pound of beef and a quarter of a pound of sweetbread, containing about 0·620 gram purins, the moiety which usually occurs in the urine, say 0·300 gram, is not fully excreted until 6-10 hours have elapsed. When a similar meal is taken by a gouty individual the full 0·300 gram is eliminated, but the rate of output is delayed, some 48-72 hours being necessary.”

The same observer states that, given intravenous injection of acid into a normal man, its elimination is spread over several days, and the total amount injected fails to appear in the urine. But if the injection be administered during a course of atophan, then the uric acid excretion is completed within twenty-four hours, and the whole amount injected can be recovered from the urine. Now if in a gouty subject the same method of procedure be adopted, the sequence of events is precisely similar, and like results have been reported, following the administration of sodium salicylate to vegetarians of five or more years’ standing. To sum up, the above findings would appear to indicate that:—

But, unfortunately for the diagnostic valency of this symptom[111] in gout, viz., retarded exogenous purin output, it has not been found to be invariable. Thus Magnus Levy has shown that, in some instances of gout, the elimination of exogenous purin is neither reduced nor protracted. Pratt, too, has confirmed this observer’s findings, while, as we shall see later, this authority, also McClure, Mallory, and others, have placed on record the still more disconcerting fact, viz., that a diminished and retarded output of exogenous purin is not peculiar to gout.

The inference then would appear to be that:—

Lowered Endogenous Uric Acid Output

As a rule, gouty subjects, on a purin-free diet, excrete less endogenous uric acid than normal persons. Thus, according to Walker Hall, the average daily endogenous urinary uric acid output of a normal adult is about 0·5 gramme, while that of a gouty subject is about 0·45 gramme. Brugsch and Schittenhelm hold that in about 80 per cent. of cases the average endogenous excretion is lower than normal.[19]

According to these same observers, “the maximum fluctuation during attack-free periods was at first believed to be less than in the normal cases; more recent examinations, however, have shown that in the same case of gout there may be periods of high, and periods of low, endogenous uric acid excretion.” These variations, they hold, are not to be accounted for by either mild or severe attacks of gout, for they occur in the attack-free period.

Again Laird, investigating the elimination of endogenous uric acid in a case of chronic gout, noted that the output thereof was sub-normal, and, as Brugsch and Schittenhelm observed, the same presented marked variations. The leucocyte counts he found normal, but the phosphorus output and the acidity were sub-normal. Bloch again, while he agrees that endogenous purin excretion is usually below the average in gouty subjects, found that the output thereof is at its minimum before an acute attack of gout.

The foregoing observations would suggest that the retention[112] or delayed excretion of uric acid applies both to exogenous and endogenous purins. But, when we come to analyse the foregoing findings as to the variations in uric acid output, both in acute and chronic gout, one feels inclined to agree with O. Folin, “that the clinically useful contributions obtained by urine analysis have not been very numerous.” Thus we cannot, on the basis of the variations in uric acid excretion, presume to diagnose gout; in other words, if we take urine analysis alone, it is extremely difficult to prove that the uric acid elimination in gout is really and truly abnormal. Our uncertainty, moreover, is the more pronounced when we realise that in some cases of rheumatoid arthritis, etc., there is a disturbance of purin metabolism which in some of its features is reminiscent of that obtaining in typical gout. But, before proceeding to discuss this interesting resemblance, it will, we think, be convenient here to recall that the obliquities in metabolism found in gout are not wholly restricted to uric acid.

Other Anomalies in Excretion in Gout

As Levene and Kristeller have shown, side by side with the delayed excretion of ingested purins, there occurs also a tardy elimination of the other nitrogenous products of protein food. Vogt observed that fluctuations in nitrogen retention and nitrogen loss are quite typical of gouty subjects. As to the why and wherefore, however, of this variability, it remains a mystery. Nor do we know the form in which the nitrogen is retained, though Vogt maintains that the uneliminated moiety takes the form of purin bodies. According to Brugsch, it is during the acute attacks of gout that the nitrogen loss reaches its zenith, and he suggests that the nitrogen retention in the inter-paroxysmal periods is in part compensatory. On the other hand, the gain in weight that ensues is not adequate to account for the sum total of the nitrogen retention; while, as before observed, in gout there occurs, not only retarded elimination of exogenous purins, but also of other nitrogenous products of protein food. Yet, according to Heffter, the ratio of purin bases to uric acid is unaltered in the urine of gouty subjects.

Again, all nucleins contain a phosphoric acid group, and Futcher found that the curve of the uric acid output ran in a striking parallel with that of phosphoric acid. But the attempts of subsequent investigators to show that the two end-products of nuclein disintegration—uric acid and phosphoric acid—go hand-in-hand prove contradictory. Hence Wells, in regard to phosphoric elimination, observes that, “it seems probable that it shows no characteristic alterations in gout.” Lastly, we will[113] recall to the reader that in the chapter on protein metabolism it was pointed out that the amino-acids, especially glycocoll, are found in excess in “gouty” urines.

In conclusion, it must, we fear, be admitted that the results of urinary analyses have proved insufficient of themselves to unravel the intricacies of metabolism in gout, and, after a brief digression, we shall proceed to ascertain whether, on the other hand, chemical analysis of the blood by modern methods can in any way shed further light on this obscure problem.

Purin Metabolism in other Disorders

Working at the Research Hospital for the Study of Special Diseases at Cambridge, Strangeways (1910) commented on the striking resemblance that obtained between certain cases of so-called rheumatoid arthritis and gout, as evidenced by X-ray findings and section of the joints. Their similitude in these respects suggested that the nature of the apparent kinship of the two disorders might be elucidated by a study of purin metabolism in instances of rheumatoid arthritis.

To this end Ackroyd studied the purin metabolism in eleven persons, the victims of rheumatoid arthritis. His conclusion was that there was no important variation from the normal. To quote his own words, he states that “it may be (1) completely normal, or (2) while normal as regards endogenous excretion, the period of increased uric acid excretion which follows the administration of hypoxanthine may be prolonged for more than four days. It is more likely that this effect is individual, than that it is characteristic of any particular form of the disease, excepting those cases in which the prolongation is accompanied by active manifestation of the disease.”

W. J. Mallory, critically analysing Ackroyd’s cases, points out that he used only hypoxanthine in his studies; also that, while hypoxanthine has this advantage, that it is of definite and known chemical composition, furnishing a known quantity of basic nitrogen, it labours under this drawback: “It is by simple oxidation converted into uric acid, and probably calls into action only a limited part of the ferment system concerned in the formation of uric acid.” As a consequence, therefore, the amount of information on metabolism that can be gleaned through its usage is more restricted than if nucleinic acid were invoked in its place; for this substance, on the other hand, calls into action all the various enzymes concerned in the disruption of nuclein or nucleic acid.

Alive to these advantages, Mallory, in addition to hypoxanthine,[114] used nucleinic acid in his investigations of purin metabolism in a series of eight “undoubted cases of so-called rheumatoid arthritis.” The value of the inclusion of nucleinic acid is revealed by the fact that some of the cases, when given exogenous purin in the form of hypoxanthine, showed no deviation from the normal. On the other hand, when given nucleinic acid, a prolongation of the period of increased uric acid excretion ensued; this even though the total amount of basic nitrogen in nucleinic acid is less than in hypoxanthine. Thus 4 grams of nucleinic acid have 0·2632 gram of basic nitrogen, while 0·75 gram hypoxanthine has 0·309 gram of basic nitrogen.

Apart from his own series of cases, Mallory analysed those of other observers, and his conclusions are as follows: “Of nineteen cases of rheumatoid arthritis in which the purin metabolism has been studied by three different observers, nine cases, or 47·3 per cent., show a marked variation from the normal in their reaction to purin-containing substances while they are on a purin-free diet.

“In these cases the period of increased uric acid excretion which follows the administration of purin-containing substances is much prolonged. Following the administration of purin-containing substances, a considerable number of cases suffer from attacks of sub-acute arthritis, accompanied in some cases by an increased uric acid excretion.”

It will be seen that in virtue of:—

certain cases of rheumatoid arthritis manifest a certain resemblance to gout, though, as Mallory remarks, “other features characteristic of that disease are lacking.”

It may be observed that the attacks of sub-acute arthritis that ensued in rheumatoid subjects followed the administration of hypoxanthine, as shown in Ackroyd’s series. That this reaction to exogenous purin is suggestive of a relationship between rheumatoid arthritis and gout derives colour from the fact that it has been repeatedly induced in gouty subjects by the same means. Thus, Brugsch and Mallory (1910), after giving 0·5 gram of hypoxanthine to a gouty patient, noted a typical outbreak of gout. Again, Brugsch and Schittenhelm, in the same year, reported attacks of arthritis following the administration of nucleinic acid to gouty subjects.

Another feature worthy of note is that, in the cases of rheumatoid arthritis investigated by Ackroyd and Mallory, the percentage of[115] exogenous purin nitrogen excreted as uric acid nitrogen largely exceeds that observed in any case of gout available for comparison by these authors.

Mallory’s final conclusions were that “there seemed to be sufficient data to show that, in certain cases of so-called rheumatoid arthritis, the purin metabolism is not normal. Whether these cases are real gout, or only resemble that disease in certain features, must be determined by further studies.”

Purin Metabolism in Chronic Alcoholism and Plumbism

Quoting from Mallory’s contribution, we note that Pollak investigated the purin metabolism in a series of cases of chronic alcoholism. In five of the examples a marked derangement of purin metabolism was noted and manifested, “partly in retention, and partly in delayed excretion, or a combination of the two.” Having observed these variations in cases of what he considered were non-gouty alcoholics, Pollak felt justified in attaching but limited diagnostic import to the results of the examination of uric acid metabolism in gout, this though he realises the importance of alcoholic excess as a cause of disturbed purin metabolism.

Mallory’s observations, too, on uric acid excretion in gout complicated by lead poisoning are highly interesting. In two cases of this nature he noted that the percentage of uric acid nitrogen excreted was relatively small—in this respect in full accord with previous observations of Brugsch and Schittenhelm on a gouty patient with a history of plumbism, with this reservation, that in the latter observers’ example there were indications of early renal disease, while in Mallory’s two cases such was absent, the urine being normal, and likewise the blood pressure.

Again, Pollak in a case of lead gout noted an extremely low endogenous average, viz., a daily average endogenous excretion of 0·06 gram uric acid in a period of five days. Eschemburg, quoted by Pollak, has recorded an instance of gout with plumbism in which the excretion fell as low as 0·02-0·04 grams. It may be noted that Pollak’s was the victim also of incipient renal disease.

Reverting to Mallory’s conclusions, this observer’s studies of examples of gout with lead poisoning seem to indicate that “these cases differ from normal persons to a greater degree than do other cases of gout.” It may, he thinks, be affirmed that the subjects of gout and plumbism, as a rule, show “some or all of the following characteristics in a much more marked degree than do cases unassociated with lead”:—

[116]

To sum up, then, we see that poisons, other than those responsible for gout, may engender obliquities of general metabolism, with disturbances of purin assimilation and output, viz., lead, alcohol, and the causa causans of rheumatoid arthritis. Also, in respect of lead poisoning and alcoholism, further affinities with gout are discernible in that, like the latter disorder, they tend in their later stages to be associated with arterio-sclerosis and renal inadequacy.

Infantile Gout

Apart from the fact that gouty arthritis may occur in young children, Comby and other observers have noted that children born of gouty parents display a tendency to inflammatory changes in the cutaneous tissues and also in the mucous membranes.

These proclivities are difficult of explanation, but some further observations by Czerny, Paltauf, Escherich, and Pfaunder are also worthy of note. Under the headings of “exudative diathesis” or “neuro-lymphatismus” they have described a symptom complex marked by lymphatism with asthma, occasional vomiting, defective nervous equilibrium, and eosinophilia. These varied phenomena also are common in the descendants of gouty, diabetic, and arthritic subjects.

The clue to the true nature of these phenomena may possibly reside in the fact noted and emphasised by Uffenheimer, viz., that these children exhibit a purin metabolism identical with that met with in gouty patients.

From the foregoing consideration it is clear that further observations are called for in the sphere of purin metabolism, and it is, perhaps, not too much to hope that extended investigations of the uric acid content of the blood may clarify and illumine the conflicting results obtained by urine analysis.

As before stated, we had intended in the next chapter dealing with the question of “Uricæmia in Gout,” but on second thoughts it appears desirable to us to interpolate a chapter devoted to discussion of the primary renal origin of gout; for we take it that, with the phenomena of uric acid excretion in gout fresh in our minds, it will be more easy at this juncture to attempt solution of this very intricate problem. This achieved, we shall resume our thread and pass to the consideration of uricæmia and subsequently uratosis in gout.

This time-worn hypothesis as to the pathogeny of gout has, perhaps, provoked more controversy than any other etiological problem in the sphere of clinical medicine. Nor, unfortunately, despite the endless laborious research expended upon its solution, the dialectic skill exercised in attempts at its elucidation, can we claim even to-day that its complexities have been wholly unravelled. But, perhaps it will be wiser to postpone decision, pending detailed analysis of the several grounds upon which the theory of the primary renal origin of gout rests.

Broadly speaking, the arguments adduced tend to concern themselves with or rather to arise out of certain apparent abnormalities in uric acid excretion, currently held distinctive of gout, certain resemblances also suggestive of a hidden nexus between gout and renal disorders, viz.:—

(1) Anomalies in uric acid excretion in gout.

(2) Uricæmia, a condition common to gout and nephritis.

(3) Uratosis, a feature also common to both disorders.

(4) Occasional co-existence of gout and nephritis.

Anomalies in Uric Acid Excretion in Gout

As to the variations in purin excretion that occur in gout, it must be admitted that, notwithstanding the magnitude of the researches, no very striking departures from normal have emerged. Such as have been elicited occur in relation to (a) the acute paroxysm, (b) the excretion of exogenous purin.

The Acute Paroxysm.—Garrod, it will be recalled, claimed that during an acute attack of gout the excretion of uric acid was diminished, and that coincidently therewith the uric acid blood content rose. But these findings in the blood and urine, which constituted the basis of his hypothesis that gout was due to renal inadequacy, have, as previously noted, been categorically disproved.

Turning to the more modern findings upon which such refutation of Garrod’s view was achieved, one point emerges that appears to favour the assumption of renal block. It is that, one or two days prior to an acute attack, an appreciable decline in the output of uric acid occurs.

[118]

But this, be it noted, is neither so marked nor so constant as the subsequent increase; in short, at the zenith of an acute attack, an augmented output of uric acid ensues. At the very time when presumably the alleged functional renal impediment would be most pronounced, the impermeability of the organs for uric acid accentuated! Surely such behaviour seems scarcely compatible with the supposition that there is even a temporary diminution in the capacity of the kidney to excrete uric acid. Does it not in truth constitute strong proof of the reverse? Moreover, the said vagaries that herald the oncoming and that chequer the course of the paroxysm are not invariable, an obvious caveat against hasty etiological inferences therefrom. Any tendency thereto should also be curbed by the reflection that, viewing the character of the uric acid excretion in gout as a whole, the variations therein are not more extensive than in healthy individuals, and assuredly, on the mere basis of the fluctuations in uric acid excretion, no diagnosis of gout is possible.

Retarded Purin Elimination.—The mainstay in argument, however, as advanced by more modern advocates of the renal theory of gout, is that a retarded output of exogenous purin is typical of this disorder; but, here, again, there is no room for dogmatism. Thus Walker Hall reminds us that “the quantity of purins present in the food does not overstep the solubility of urates in the blood-stream, for once the material is metabolised and ready for removal the amount of blood, so far as solubility goes, places the whole amount of purins within the reach of the renal cells in less than twenty-five minutes.” We see, therefore, as far as rapidity of transport to the kidneys is concerned, there is no delay in presentation of the opportunity for the excretion of exogenous purin. While the alleged tardiness of output is attributed to defective action of the kidneys, it is at least equally possible that the delay, as Walker Hall states, “may be due to a defective or idiosyncratic nuclear metabolism, which results in the formation of isomeric purins or incomplete purin combination, and which makes greater demands upon the selective activities of the renal cells;” for it must be recollected that as yet we are ignorant as to the exact form in which uric acid circulates in the blood-stream, whether as sodium mono-urate or in organic combination.

Moreover, experimental injections of uric acid into the tissues or veins show no impairment in the elimination capacity of the kidneys for uric acid. Thus, Wells cites evidence that “the kidney in gout shows no lack of ability to excrete uric acid injected into the tissues.”

Again, given intravenous injection of uric acid into a normal man, its excretion occupies several days, and it fails to appear quantitatively[119] in the urine. But if administered during a course of atophan, then the whole amount injected is excreted within twenty-four hours. If the same procedure be followed in a gouty individual, precisely the same results are obtained; in other words, both normal and gouty kidneys react in identical fashion to atophan. Given an inherent functional defect, quâ uric acid excretion, in the gouty kidney, one would scarcely expect a wholly normal reaction thereto. Surely some disparity would be disclosed, some aberration in response as compared with normal renal organs.

Again, while McLester and others claim that atophan exerts “a selective stimulating influence on uric acid excretion,” it is quite possible that its rôle may be otherwise explained. May it not influence the actual formation of uric acid, or, failing this, the form in which it is presented to the kidneys for excretion? Nicolaier and Dohrn, indeed, believe that atophan influences in some way purin metabolism within the muscles and so leads to increased formation and excretion of uric acid. At any rate, whatever be the explanation of the action of atophan, the fact that healthy and gouty kidneys react alike thereto cannot be interpreted as proof of defective capacity for uric acid elimination in gouty subjects, indeed the reverse.

Moreover, in all our attempts to saddle the kidneys with the responsibility for the delay in exogenous purin excretion, we are for ever hampered in that we know not whether the alleged renal impairment is primary or secondary to the gout. That the kidneys are frequently functionally inefficient in the later stages of gout may be conceded. But what of the initial phases of the disorder? Some talk very glibly of subjects who are, they say, “potentially gouty.” But has the rate of disposal of ingested purins been investigated in persons suffering from so-called “goutiness,” or, perhaps more pertinently, in those individuals, not uncommon, who, while exhibiting auricular tophi, have yet experienced no frank attack of gout?

In this connection we may note that McClure has recently emphasised the fact that the kidneys, in the later stages of gout, are often functionally deficient, and that, accordingly, the faulty elimination of exogenous uric acid by gouty persons may be simply the result of such functional renal depression; in other words, not due to gout, but to the secondary or associated renal deficiency. Hence, having regard to the frequency with which renal inefficiency is met with in gout of any standing, he is inclined to discount the value of studies of exogenous uric acid elimination as an aid to the diagnosis of gout. Consequently, he holds that before the diagnostic status of retarded[120] purin elimination, as a symptom of gout, can be established, an investigation of the output of uric acid in the different types of nephritis is essential.

From the foregoing it will be seen that we stand in urgent need of further studies of early or oncoming gout and of early nephritis before we can with certitude impeach the kidneys as responsible for the delay in exogenous purin output. Meanwhile, too, we must be careful not to overlook the further disconcerting fact, previously adverted to, that the retardation and diminution of exogenous purin output is not invariable in gout. Nor, for that matter, is it peculiar to gout, considerations both of which, if confirmed, will still further discount the diagnostic significance of this phenomenon.

Uricæmia in Nephritis

Von Jaksch and Klemperer noted long since that in chronic interstitial nephritis urates are always present in the blood. Now, according to Folin and Denis, human blood contains 1·5-2·5 mg. of uric acid per 100 c.c.; but if the eliminating powers of the kidney be deficient, the uric acid content thereof rises, sometimes to as high as from 15-20 mg. per 100 c.c.

But more interesting still the fact noted by Fine, viz., that even in early interstitial nephritis the same feature is well marked, i.e., the blood may contain 4-8 mg. of uric acid per 100 c.c. Indeed, according to this authority, increase in the uric acid content of the blood is the first signal of impaired renal efficiency. This, be it noted, without any coincident proportional increase in the blood content of urea or creatinine. The sequence would appear to indicate that the damaged organ encounters greater difficulty in excreting uric acid than these other metabolites.

But, pari passu with the advance of the renal disease, retention of urea is superadded, and still later creatinine. So constant, indeed, the sequence that, by determining the percentage amount of these three metabolites in the blood, the measure of the renal mischief may be gauged.

But of striking significance is the further point established by Myers and Fine, viz., that the blood content, in respect of uric acid, urea, and creatinine, in early nephritis, is an almost exact replica of that met with in typical cases of gout. The same is well illustrated in the following table, in which the blood content, in respect of these three metabolites, in cases of gout and early and late nephritis is contrasted. The percentage of the retained metabolites in relation to the severity of the case is gauged by the blood pressure findings.

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Uric Acid, Urea N, and Creatinine of Blood in Gout and Early and Late Nephritis

(Myers and Fine: “Arch. Int. Med.,” 1916.)

The salient feature of the table is, however, the fact that in early interstitial nephritis the retention of uric acid precedes that of urea or creatinine.

Its importance resides in the reflection that it lends support to those who contend that renal change, leading to failure of excretion of uric acid, is the primary cause of gout; in other words, it gives colour to Magnus Levy’s contention that the phenomena of[122] gout are referable to “a deficient and restricted secretory power of the kidney.” The existence of such a selective excretory incapacity, i.e., for uric acid, does not, he considers, predicate a genuine nephritis. He maintains that such disability on the part of the kidney for uric acid excretion may exist without morphological change; in other words, he thinks it conceivable that a single function of the kidney can become almost exclusively insufficient, though later real damage to the organ and a nephritis frequently follow.

Reflecting on the above theory, it is obvious that, if carried to its logical conclusion, it would appear to postulate that gout is nothing more than a form of renal disorder, marked simply by functional inability to excrete uric acid. The postulate is no mean one, for, as Sir Archibald Garrod says, “If the fault is in the kidneys alone, gout must be removed once and for all from the category of metabolic disorders, and placed among the sequelæ of renal inadequacy, at least in so far as the uric acid phenomena of the disease are concerned.”

Furthermore, Levy’s hypothesis involves the assumption that the excreting functions of the kidney for uric acid and urea are separate and independent of each other, and to discussion of this we now pass on.

The Relationship, if any, between the Amounts of Uric Acid and of Urea, and Total Non-Protein Nitrogen in Human Blood

Taking samples of human blood from (1) unselected insane subjects and (2) chronic nephritics, Folin and Denis determined the amounts therein of urea, total non-protein nitrogen, and uric acid. The figures obtained showed that “there is apparently no relationship between the amount of uric acid and the amount of urea or total non-protein in nitrogen, in human blood.”

That such a discrepancy should obtain is doubtless of profound though as yet imperfectly grasped significance. These authorities rightly assume that, since the kidney is practically the sole avenue for nitrogenous waste excretion, it follows that the urea and total non-protein nitrogen of the blood must in the main be inversely proportional to the general efficiency of the renal organs. Then, obviously, the same law, too, should, in lack of some other plausible explanation, govern the excretion of uric acid also. But, as the above generalisation portends, it is apparently not so.

Fortunately, Folin and Denis prosecuted their study still further, taking in examples of gout (with and without clinically recognisable nephritis), also instances of leukæmia and lead poisoning.

[123]

The blood, again, in these disorders betrayed the same peculiarity, viz., that while containing an excess of uric acid, it did not contain correspondingly large amounts of urea or other waste nitrogen; in other words, the findings in the blood in gout were in full accord with the above generalisation, i.e., the apparent lack of any relationship between the amount of uric acid and that of urea or total non-protein nitrogen in the blood.

Now in leukæmia the cause of the uricæmia is over-production of uric acid, but in this instance the same is correlated with an increased elimination of uric acid by the kidneys.

Turning to lead poisoning, the medicinal administration of lead acetate results in a great diminution of uric acid excretion, a response consistent with the view that lead inhibits the excretory power of the kidney for uric acid, the change, at first functional, becoming later organic; for it is held that the uricæmia, associated with plumbism, proves that the action of the lead is not due to inhibition of the formation of uric acid.

Lastly, as to gout, opinion still wavers as to whether or not the excretion of uric acid in this disorder is appreciably lowered. On the other hand, it is significant that the reverse is never claimed, viz., that in gout the uric acid output is abnormally raised. Now, as we saw in leukæmia, the high uric acid blood content is accompanied by a correspondingly high uric acid output; but, on the contrary, in gout, despite the accumulation of uric acid in the blood, there is no parallel increase in its elimination.

Reflecting on the above considerations, Folin and Denis claim that “the mere fact that the uric acid may accumulate in the blood of the gouty without being accompanied by an increased elimination constitutes definite proof that the gouty kidney is damaged with reference to its ability to eliminate uric acid.”

In all deference, we doubt the legitimacy of the inference, if only for the very excellent reason that, to quote Von Noorden’s words, even to-day “it remains uncertain whether the retention of urate arises because the outlet is blocked, or because the uric acid is held fast by chemical affinities.”

Apart from this, there are several objections to Folin and Denis’ assumption.

Uricæmia not Necessarily Due To Renal Defect

Thus Pratt, in some examples of his cases of gout, found that there was no apparent diminution or delay in the output of exogenous purin in the urine. On the other hand, he observes that “our study of the blood shows that a marked increase in retention of uric acid in the blood may result from the ingestion of purin bases even when no evidence of retention is found on examination[124] of the urine.” This would appear to indicate that the uricæmia, sequential to exogenous purin intake, ensues independently of and apparently despite the absence of any delay or diminution in uric acid elimination.

Again, Walker Hall, discussing the metabolism of exogenous purins, reminds us that a gouty subject excretes an excess thereof as completely as a normal individual, with only this difference, that he takes a longer time to do so; but even this disability is removed by a simultaneous intake of atophan. His comment is that “the gouty kidney, therefore, is not poisoned beyond compensating for and responding to an extra load.” “Perhaps,” he says, “the situation may be summed up in the observation that the uricæmia of the gouty is maintained in spite of a fair renal elimination.”

Uricæmia not Peculiar to Nephritis

Again, a grave obstacle to the acceptance of Folin and Denis’ inference is that uricæmia, though incidental to nephritis, is not peculiar thereto.

Thus Roy Upham and Higley noted its presence in 85·6 per cent. of their cases of nephritis; but, on the other hand, they found that no less than 40 per cent. of another series of clinical cases, not suffering from nephritis, also showed uricæmia.

This would appear to indicate that, while uricæmia is an exceedingly common symptom of early chronic interstitial nephritis, it is by no means specific for that disorder; in other words, its diagnostic valency as a symptom of nephritis is distinctly limited.

Reverting now to gout, what evidence is there that the uricæmia therein is due to defective eliminatory capacity on the part of the kidney for uric acid? Certainly there is no proof that the kidney, at any rate in the initial stages of gout, suffers from this particular functional disability. Indeed, the fact that, at the very acme of an acute attack, the output of uric acid is not only not diminished, but actually increased, constitutes strong proof of the reverse.

Again, as modern investigations show, the variations in the uric acid content of the blood, re the incidence or intensity of attacks, are most erratic. Far from its being essential that uricæmia be present, acute attacks may occur with even a sub-normal uric acid blood content; in short, the variations are so erratic as to seem quite out of keeping with the assumption that the uricæmia in gout is primarily of renal origin.

If it were so, one would expect no such vagaries in the uric acid content of the blood. One would rather, given the existence ab initio of a renal functional defect, look for not only a permanent uricæmia, but further, from time to time, augmentations and[125] diminutions thereof, synchronising with the rise and wane of gouty paroxysms; in other words, that in gout the clinical course and crises of the disorder would be linked up with harmonious variations in the degrees of uricæmia.

Uricæmia does not Necessarily Portend Gout

If it were so, why does not every case of nephritis develop gout? The researches of Myers and Fine have shown that uric acid is the nitrogenous metabolite that first accumulates in the blood in early interstitial nephritis. Only in its later stages do urea and other waste nitrogenous products undergo like retention therein.

Now let us review these findings, re nephritis, in light of another statement by Folin and Denis, which runs as follows:—

“In pure gout, unaccompanied by any abnormal urea retention in the blood, the kidney is damaged (so far as we yet know) only with its function of removing down to the normal level the uric acid of the blood.”

Is it not clear, then, that in the early stages of nephritis, viz., prior to retention of urea and other waste nitrogen, we have precisely that isolated functional renal disability, i.e., inability to excrete uric acid, that we postulate to be in operation in the initial stages of gout?

Yet, notwithstanding this similitude in the blood content of the two disorders, cases of nephritis do not necessarily develop gout. Indeed, as a matter of fact, examples of nephritis, of all grades and intensities, may run to their full end without manifesting any symptoms even remotely reminiscent of gout. Even Magnus Levy, ardent advocate as he is of the primary renal origin of gout, could not but admit that this salient clinical obstacle barred the way to acceptance of his otherwise plausible view. However, he fails to proffer any other solution of the problem.

To our mind, albeit, the disparity carries with it the inevitable postulate that in gout some other factor intrudes, some tertium quid, something vital, something biological, haply an infection. For even if we grant, for the sake of argument, that renal retention, if it were proved, might explain such anomalies in the excretion of uric acid and other nitrogenous metabolites as occur in gout, yet, nevertheless, no one could possibly contend that this factor alone could explain the nature of gout, could adequately account for its dramatic and protean phenomena.

To what may be Ascribed the Deficient Eliminating Capacity of the Kidney for Uric Acid?

Naturally the advocates of the renal theory had to account in some way for the alleged functional disability of the kidney. Thus,[126] Sir Dyce Duckworth, recalling the occasional occurrence in hysteria of anuria, held that, judging from the general phenomena of acute gout, “the influence of the nervous system ... must not be left out of account as a possible determining factor for renal inadequacy.”

Others, with whom Duckworth disagreed, propounded the view that the deposition of urates in the renal tissues was essential for the initiation of a nephritis in the gouty. Duckworth, on the other hand, held that nephritis could develop in their absence.

Croftan considers the renal changes in gout identical with those of chronic plumbism. From experiments with hypodermic injections of xanthine and hypoxanthine over a prolonged period, he concludes that the presence of minute quantities of purin bases in the circulation is capable of producing marked renal changes. On the other hand, uric acid, injected into the circulation of healthy animals for a period of over three months, produced no renal change whatever.

As to this possibility, viz., that the circulating uric acid might lead to nephritis in the gouty, some reflections of Folin and Denis are instructive. Normal blood, according to these observers, contains not less than from 1-2 or 2-5 mg. per 100 grams, while that of gouty blood does not, in their experience, exceed 6 mg. Continuing, they observe, “There is, however, no reason to suppose that a uric acid concentration of 4-6 mg. per 100 grams of blood is very much more irritating or stimulating to the kidney than the somewhat more dilute solution represented by normal blood. Disregarding the insolubility of uric acid, the elevation of its threshold of elimination from 2-4 or 6 mg. (per 100 grams of blood) is certainly a small one. Kidneys in which the threshold of elimination for urea has risen by 10-20 mg. (per 100 grams), or even more, are extraordinarily common.”

While they consider that such urea and total nitrogen retention may possibly bespeak latent or incipient nephritis, they recognise that no appreciable effects on health have as yet been determined in connection therewith. But more pertinently to our point, they make the further pregnant observation, “In the case of uric acid it seems to be purely a matter of insolubility that corresponding or even smaller degrees of kidney insufficiency with slight uric acid accumulation should result in all the serious consequences involved in the development of gout”!

Again, some have attempted to account for the assumed renal incapacity as being part of the tissue peculiarity of the gouty subject. “Without doubt,” says Duckworth, “there are peculiarities of tissue in the gouty, and with this may very possibly be associated peculiarities of tissue function and metabolism.”

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Naturally this suggests the further question, Are there any distinctive histological changes in the gouty kidney? On this point Walker Hall has some apposite reflections. Taking Folin’s figures as a basis, it transpires that in acute and chronic nephritis, also in arterio-sclerosis, there is an average content of 2·5 mg. uric acid per 100 grams of blood. Now, notwithstanding the fact that in these conditions an appreciable quantity of the renal tissues is, functionally speaking, temporarily or permanently out of action, nevertheless “the extraction of uric acid from the blood and its subsequent excretion are practically normal.” The inference is that a relatively small moiety of renal tissue suffices for the excretion of the daily quantum of uric acid in the urine.

Now in contrast thereto, the blood content in gout and lead poisoning is about 4·5 mg. uric acid per 100 grams of blood, or “an increase of about 50 mg. in the total blood-stream at any one moment (an increase from the normal 70 up to 120 mg.).” Continuing, Walker Hall observes that “the gouty kidney per se, even when arterio-sclerotic conditions prevail, does not show anything like the amount of cellular damage which occurs in acute or chronic diffuse nephritis.” Thence he argues if histological changes be taken as a criterion of functional efficiency, then the gouty kidney should be more capable of excreting freely than the diffuse nephritic organ.

How does this work out in actual daily life? he asks. “0·5 gram, in a normal adult, represents the average daily endogenous uric acid excretion in the urine, while that of a gouty subject is about 0·45 gram. Now, assuming that the type and extent of the endogenous metabolism is identical in each instance, then the balance, i.e., 0·05 gram, is distributed between the uric acid pent up in the tissues and the uratic deposits, i.e., tophi.” Walker Hall tells us it has been stated that about 0·01 gram suffices to cover the amount deposited as tophi every twenty-four hours. The residual 0·04 gram runs to swell the amount in the blood and lymph-streams. “The increase is 0·0114 to 0·0118 gram per litre of blood; in other words, the actual increase of uric acid circulating through the kidneys is about 0·00047 per hour,” which, as Walker Hall contends, “seems to be a very trifling difference, especially as it is one of amount and not a type.” In other words, it is quantitative, not qualitative. But, trivial as the disparity is, to what may it be referred? To Walker Hall’s mind, if we are to appreciate the standpoint of those who maintain that the gouty uricæmia is referable to renal inadequacy, it is necessary to postulate the presence of a poison acting upon the renal tubules specifically.

In the gouty uric acid excretion is maintained at a “low physiological level to the very end,” and it is easier, he thinks, to adopt the[128] above hypothesis as to its cause than “to conceive of a poison acting upon the nuclear processes in such a way as to induce a persistently low uniform level” of purin excretion.

This view, viz., of a toxin acting specifically upon the uric acid excreting cells of the kidney, seems to be the only reasonable assumption available. But even this is difficult of adherence when we recall the fact that the effect of the toxin is so readily neutralised by a few grains of atophan. Always we have to recollect, too, that under normal conditions, even given a constant diet, the elimination of uric acid displays wide variations. Also the uric acid output in the subjects of chronic gout, when placed on a fixed diet, differs but little from that of normal individuals on a like dietary. At most the excretion but tends to fall to, or slightly below, the lower normal limits of uric acid elimination.

From the foregoing considerations it is but too obvious that those who render obeisance to the primary renal origin of gout have not only yet to prove that the functions of the kidney are defective, but also upon them lies the onus probandi why gouty subjects should exhibit, or acquire, such a disability.

Uratic Deposits in Nephritis

Here, again, we light upon another point of contact between gout and nephritis, for an interesting feature of the latter disorder is that the retained uric acid, purins, and other excretory products are deposited in cartilage and serous membranes. At these sites they are frequently detected post mortem, though they fail of ante-mortem recognition.

Impressed by the fact that, at post-mortems, uratic incrustation of the articular cartilages was frequently observed in persons who had never suffered from overt gout, Ord and Greenfield sought to ascertain the frequency with which such uratic deposits were associated with renal disease. Out of ninety-six cases presenting renal lesions, no less than eighteen exhibited uratic deposits in the joints.

A still more elaborate research in this sphere was undertaken by Norman Moore. Out of forty-nine cases of chronic interstitial nephritis, uratic deposits were present in twenty-two instances. Again, out of nine cases of chronic parenchymatous nephritis, deposits were found in the joints in two cases. With respect to the first group he observes that “chronic interstitial nephritis is not invariably accompanied by deposits in the articular cartilages, though usually accompanied by traces of degeneration in some of the articular cartilages.”

Levison, too, an ardent supporter of the primary renal origin of gout, noted that all the subjects dying at the Communal[129] Hospital, Copenhagen, of granular kidney disease (during a period of fourteen months) exhibited uratic deposits in one or other of their joints, although they were never known to have had any definite attack of gout.

Luff, in the following table, shows the results of the examination of the joints in seventy-seven cases of granular kidney disease.

Of the ten cases known to have suffered from gout, the renal condition was in every instance defined as “markedly granular,” or “fairly granular.” Uratic deposits were invariably present in one or more joints. Of the sixty-seven examples not known to have had gout, uratic articular deposits were found in 46 per cent., which approximates, more or less closely, to Norman Moore’s findings. It is noteworthy that in several of the instances, lacking uratic deposits in the joints, the kidneys were described as “slightly granular,” or “faintly granular.”

If of the sixty-seven cases there be selected only those described as “markedly granular,” or “typical granular kidneys,” the incidence of uratic deposits in the joints, as revealed by the second table, reaches no less a figure than 77 per cent.

Another authority, discussing the frequency of incidence of uratic deposits in the joints in cases of chronic interstitial nephritis, states that, at post-mortem, from 50-80 per cent. show their presence—this, moreover, in cases known not to have had gout.

Differentiation of Uratic Deposits in Gout and Nephritis

Uratic deposits, it is true, occur in both these disorders. But it is with a difference. In gout the uratic deposit assumes the[130] form of tophi, whereas in nephritis it is not so. In the latter the uratic deposit is in the nature of a passive deposition—an uratic incrustation of the articular cartilages.

Again, in gout the deposition is sudden and associated with an acute paroxysm; while in nephritis it is gradual and unassociated with inflammatory reaction.

In gout the uratic deposits are overt, manifest as tophi; in nephritis, occult and unrevealed (ante-mortem).

Uratic deposits in the form of tophi occur in gout, in the absence of clinically recognisable interstitial nephritis. But tophi do not occur in nephritis if uncomplicated by gout.

In conclusion, the mere fact that uratic deposits affect such widely disparate forms in these two disorders is to our mind a sure indication that their mode of origin and formation is equally diverse—the one vital, biological; the other passive, mechanical.

Clinical Associations of Gout and Granular Kidney

It cannot be denied that gout and granular kidney are frequently met with in close association. But neither can it be disputed that in these disorders, as in many others, their outward affinities do but hark back to inward disparities. The occasional overlapping of the two affections, the trenching of the one upon the clinical or pathological territory of the other, must not blind us to the essential distinctness of the two morbid entities. Doubtless to the earlier advocates of the renal theory their not infrequent co-existence bespoke some hidden nexus, and at least seemed confirmatory of their views as to the pathogeny of gout. But, even if we allow that the connexion between the two disorders seems superficially intimate, it cannot be gainsaid that it is neither constant nor essential. For we have to recollect that—

Also we have to recall that—

Apart from the difficulty of reconciling these disparities, we cannot overlook the fact that both gout and granular kidney are very common diseases, sufficiently common, as Samuel West pointed out, to be not infrequently associated accidentally, without any cause or connection. Again, both affections, be it observed, are prone to develop in the middle and later decades of[131] life. In light of this, is it not readily conceivable that both may arise independently, mere coincidences, both evidences of pre-senilism? Hastings Gilford, indeed, classes gout with syphilis, lead, and alcohol as amongst “the chief promoters of pre-senility.”

Again, certain toxic agents which predispose to or initiate renal mischief also favour apparently the incidence of gout, e.g., lead and alcohol. Samuel West, discussing the relationship of both gout and lead to granular kidney, maintains that, though each may produce chronic change in the kidney, neither of them causes granular kidney. But the presence of granular kidney, he holds, greatly enhances the liability of the victim to gout on the one hand and plumbism on the other; also, to both together and in each affection alike markedly increases the gravity and the risk.

Sir William Roberts, too, has some wholly relevant observations on this point. Thus all will agree with him that “it is difficult to conceive that plumbism induces the same constitutional diathesis as that which obtains in true gout.” He held that gout and plumbism, though they differ in all other respects, yet have one point in common, a tendency to uratic deposition. But such precipitation, he contended, was the outcome of a gouty tendency, reinforced by lead poisoning; or if, on the other hand, uratic deposits occurred in plumbism, the same had but accentuated a pre-existing gouty diathesis. In this connexion, too, it should be recalled that the frequent association of gout and lead poisoning which exists in London is not seen in the North of England or in North America.

Is it not clear, then, that reflection on the broad clinical affinities exhibited by gout and granular kidney does but emphasise the essential distinctness of the two morbid entities? Inferentially, too, it lends no colour to the assumption that gout is of primary renal origin.

That the victim of gout, despite uricæmia and those unequivocal tokens, tophi, may, notwithstanding repeated arthritic outbreaks, be in the intervals in sound if not exuberant health, is a clinical truism. His kidneys, too, may, as far as can be ascertained, be normal; and his blood pressure not beyond what might be expected at his age. His output of uric acid may but touch the lower normal limit or a little less, and his metabolism of purin-rich foods be but a little protracted. Thus he runs his course, more frequently than not a strenuous one, chequered by occasional outbreaks which not seldom he regards as salutary rather than otherwise. Then, sooner or later, in one, two, or even three decades, that Nemesis of age, arterio-sclerosis overtakes him with its correlated chronic nephritic change.

Is not this very reminiscent of what Walker Hall reminds us of,[132] the sequence of events in lead poisoning and alcoholism? “These poisons affect the general metabolism adversely and are connected with disturbances of purin assimilation and output. At a later stage they produce arterio-sclerosis and renal insufficiency.” And as he shrewdly observes, “It is, therefore, of importance to exactly appraise the stage of the disease when interpreting the results of experiments upon gouty individuals. When this obtains widened application, many generally accepted statements will have to be re-written.”

In conclusion, therefore, we see that the weight of clinical evidence is against the primary renal origin of gout, for not only are renal changes frequently slight, but they are often entirely lacking in gout. Confronted with these difficulties, the question inevitably rises as to whether there does not exist a special morbid entity, gout, which develops independently of renal abnormalities?

In the summer of 1848, Garrod made his momentous announcement that “the blood in gout always contains uric acid in the form of urate of soda, which salt can be obtained from it in crystalline state.” Some eleven years later in his classic work on gout, he reiterated his affirmation, but appended thereto the words, “in abnormal quantities.” Garrod’s analyses were mainly qualitative, but, at any rate, in one instance, he obtained from a gouty patient the equivalent of 5 mg. of uric acid per 100 gm. of blood serum, maintaining, however, that this amount was much below that really present.

But not until 1895 was a series of quantitative estimates undertaken when Klemperer in three gouty subjects passing through an attack found the blood content of uric acid to be 6·6 mg., 8·8 mg., and 9·5 mg. per 100 c.c. of blood. Some years later, Magnus Levy, investigating seventeen gouty individuals, found that the amount of uric acid in the blood ranged from 2·1-9·5 mg. per 100 c.c.

Brugsch and Schittenhelm noted that, in gouty victims, uric acid was still present in the blood even when they had been on purin-free diet for weeks or months. They held endogenous uricæmia to be a constant symptom in gout. Even as late as 1913 the former investigator contended that, in a healthy person on a purin-free diet, the presence of uric acid in the blood cannot be satisfactorily demonstrated. But it must be recollected that the precipitation (ammonical silver and cupric bisulphite) method was beset with disadvantages. An approximate estimate only of the blood content of uric acid was with difficulty to be achieved even when large quantities were available.

Fortunately, however, our powers of analysis in this direction became greatly enlarged with the introduction in 1913 of the colorimetric method of Folin and Denis.

Folin and Denis’s Method

This colour reaction is so sensitive that one part of uric acid in a million parts of water can be detected. Moreover, unlike the older methods which required from 75-100 c.c. of blood or more, determinations can be made with 20 c.c., and if the blood be rich in uric acid only 10 c.c. Walker Hall observes that the procedure “has many advantages and does not take up much more time than[134] some of the qualitative methods when once the technical difficulties are overcome.” He described it as follows:—

Twenty cubic centimetres of blood are withdrawn into a wide-mouthed, tared bottle containing 0·1 gramme of finely-powdered potassium oxalate. The flask and contents are then weighed. Five times the weight of n/100 acetic acid is heated to boiling. The oxalated blood is poured into the boiling acetic acid solution, and the heating continued until the solution has begun again to boil. The mixture is filtered hot. The clear filtrate and wash waters are acidified (0·5 c.c. of 50 per cent. acetic acid) and evaporated to 3 c.c. Five drops of a 3 per cent. silver lactate solution, two drops of magnesia mixture, and ten to fifteen drops of strong ammonia hydrate are next added. The mixture is centrifugalised. The supernatant fluid is removed. To the residue five drops of freshly-saturated hydrogen sulphide water and one drop of strong hydrochloric acid are added. The tube is placed in a beaker of boiling water for ten minutes in order to remove the hydrogen sulphide. The supernatant fluid is added to 2 c.c. of a solution containing 100 grams of sodium tungstate and 80 c.c. of 85 per cent. phosphoric acid in 1,000 c.c. of water and 10 c.c. of a saturated sodium carbonate solution. The resultant blue solution is then compared with a standard uric acid solution, and the result obtained by the following formula:—

(20V)/(RW) mg. of uric acid per 100 grams blood,[20]

where 20 represents depth in millimetres of standard solution,

• R, the depth of unknown solution,
• V, the volume to which the unknown solution is diluted,
• W, the weight of blood taken for the determination.

[135]

Uric Acid a Normal Constituent of Blood

Up till quite recently it was held that in normal persons the amount of uric acid in the blood was too small to be detected; also that uric acid was not demonstrable in the blood of normal individuals when on a purin-free diet. On the other hand, if the subject’s blood was found to contain uric acid, while on a purin-free diet, it was held a characteristic feature of gout and of prime diagnostic import.

But, since the introduction of Folin and Denis’s method, it has been established that uric acid is constantly present, in demonstrable amounts, in human blood. These authorities, using their colorimetric method, found that the uric acid content of the blood ranged from 0·7-3·7 mg. per 100 grams. They believe that 1-2 mg. of uric acid per 100 grams of blood is well within the normal variations, but “are not prepared to say that they represent the full variations.”

However, before applying their colorimetric method to human subjects, Folin and Denis conducted some researches into the uric acid blood content of a variety of animals, the results of which appear in the following table:—

Uric Acid, Total Non-Protein Nitrogen and Urea Nitrogen in Blood

(The Figures represent Milligrams per 100 grams of Blood.)

The most striking feature of these findings is the marked contrast between the uric acid blood content of mammals as opposed to avians. In the former the amount is minimal—0·2 mg. or less per 100 grams of blood. On the other hand, in the blood of birds, in whose instance the origin of uric acid is so different, it is present in relatively large amounts. As Folin and Denis observe, the[136] small amounts of urea in the blood of birds, as compared with that of mammals, is also worthy of note.

Reverting now to the findings in human subjects, as observed by Folin and Denis, these have been summarised as follows by Walker Hall:—

Uric Acid, Total Non-Protein Nitrogen and Urea Nitrogen in Blood

(The Figures represent Milligrams per 100 grams of Blood.)

Interesting and valuable as are the above findings, Folin and Denis are careful to point out that, even as regards the first three groups in the above table, “the figures can scarcely be said to represent the strictly normal variations, for no attempt was made to select physically normal persons.” The samples of blood were drawn from patients newly admitted to the Boston Psychopathic Hospital.

It may be noted that of all the mammals examined the blood of man contains by far the greatest amount of uric acid. Also that in humans the uric acid blood content varies in different persons, and, moreover, as Walker Hall points out, “the figures lend support to the view that there may be groups or families exhibiting similar features.” It will be seen, too, that the blood uric acid in gout and lead poisoning stands at a high level, though not so elevated as was formerly maintained. From the figures, too, it may be gleaned that apparently no relationship obtains[137] between the amount of uric acid and that of the urea or total non-protein nitrogen in the blood.

At the same institution in Boston, Adler and Ragle conducted a similar series of investigations, though on a more extended scale. These observers, taking 156 unselected psychopathic patients, found that in 107 examples the uric acid content of the blood was from 1-2 mg., in thirty-eight more than 2 mg., and in eleven instances less than 1 mg. To sum up, the uric acid content varied from 0·7-4·5 mg. per 100 grams of blood, an average of 1·7 mg.

As before stated, it was until recently maintained that in the blood of normal individuals, on a purin-free diet, uric acid was undemonstrable. But McLester, utilising Folin’s method, found uric acid in the blood of fifteen healthy individuals, who had been on a purin-free diet for at least three days, and this in amounts ranging from 0·5-2·9 mg. per 100 grams of blood, an average of 1·4, as contrasted with 1·7, the average amount in Adler and Ragle’s series. Pratt, discussing these findings, considers that the fact that the average amounts approximate so nearly in the two series is worthy of emphasis. This especially as all McLester’s examples were young healthy adults on a purin-free diet, while the patients studied by Adler and Ragle were of all ages and on a mixed diet.[21]

Effect of Exogenous Purines

As we are aware, the amount of uric acid excreted in the urine increases markedly on a purin-rich diet. But recent researches[138] appear to raise doubts as to whether the uric acid content of the blood rises correspondingly. Thus, according to Walker Hall, “a state of uricæmia is said to exist if the amount of uric acid in the blood exceeds 0·8 mg. per 100 c.c.” The figure he considers is probably too low for, after an average meat breakfast, the blood uric acid rises to 1 or 2 mg. per 100 c.c. in normal adults, or even higher after an excessive intake of purin-rich foods.

On the other hand, Denis, investigating the effect of ingested purin on the uric acid content of the blood, found that in normal individuals no increase in the circulating uric acid follows the intake; in other words, the kidney, in normal persons, is quite capable of excreting any excess of uric acid presented to it, thereby keeping the uric acid of the blood at the same level as obtains when only the endogenous moiety thereof has to be eliminated.

Moreover, another factor, according to Folin and Denis, that operates in the same direction is the binding capacity of the tissues for uric acid. Pratt of Boston’s observations, too, appear to indicate “That the uric acid derived from exogenous purin does not accumulate in the blood unless there is a disturbance in the uric acid metabolism.”

On the other hand, given damage to the kidney (even when this has not progressed to the point when nitrogen retention is apparent, as shown by the non-protein nitrogen values), an accumulation of uric acid takes place in the blood after a short period of purin feeding.[22]

Now, as to the second regulating factor, the retention capacity of the tissues for uric acid, it may be said that the amount, in normal subjects, would appear to be small. But Fine, it may be noted, found that the uric acid content in divers tissues was relatively proportionate to that of the blood, whether normal or increased in amount.

But, to resume, Denis also demonstrated that the uric acid content of the blood in patients suffering from various chronic diseases other than gout was also not increased on a purin-rich diet. To sum up, the researches of Denis would appear to indicate that:—

[139]

In amplification of the second of the foregoing postulates some observations by Pratt may be quoted. This authority is of opinion that the low amount of uric acid present in the blood of unselected psychiatric patients on a mixed diet (Folin and Denis, Adler and Ragle) shows that a retention of uric acid in the blood in any considerable amount for twenty-four to twenty-eight hours rarely occurs. For, as he informs us, these patients at the Boston Psychopathic Hospital, when on ordinary diet, are eating purin-containing food daily, and they might take as much or more purin during the forty-eight hours preceding the blood analysis as is contained in a single sweetbread meal. Now, as Pratt argues, if the uric acid thus derived accumulated in the blood, the amount found would be considerably greater than that of individuals on a purin-free diet. But, on the contrary, it transpires that the average amount of uric acid found by Adler and Ragle in the blood of patients on an ordinary diet was only 0·3 mg. more than that found by McLester in normal individuals on a purine-free diet. The diagnostic significance of these observations will be better appreciated when we come to discuss the sequential increase of the uric acid content of the blood in gouty subjects after the ingestion of purin-rich substances.

Uric Acid Content of Blood in Gout

Taking 1-3 mg. per 100 c.c. as the normal, the uric acid content of the blood, in typical cases of gout, according to MacLeod, rises to nearly 10 mg. Gudzent, from his studies, maintains that the blood, in almost all cases of gout, contains as much or even more mono-sodium urate than it can hold in solution (1-8 mg.), in other words, it is in effect a supersaturated solution of the relatively insoluble lactim urate.

Pratt, working in Folin’s laboratory, investigated a series of cases of gout, selecting only those in which (1) Tophi were found, (2) A history of characteristic attacks of acute gout was obtained, or (3) Typical symptoms developed while under observation.

At the time of examination the average uric acid content, irrespective of the diet or condition, was 3·7 mg. In three patients on ordinary diet, who were seen during attacks, the amounts were 4·5, 4·8 and 5·7 mg. of uric acid. In two other patients, also seen during attacks, and while on a purin-free diet, the uric acid in four estimates ranged from 2·4-5·1 mg., viz., an average of 3·6 mg. None of these patients were taking atophan.

Seven patients, on a mixed diet, and free at the time from symptoms of gout, contained on the average 4·3 mg. of uric acid in their blood.

On the other hand, examination of the blood in six patients on a[140] purin-free diet, at the time manifesting no acute symptoms of gout, revealed an average uric acid content of 3 mg.

From the foregoing considerations it may be deduced that:—

Hyper-Uricæmia in Non-Gouty Arthritis

Pratt, of Boston, has found that a condition of hyper-uricæmia is sometimes demonstrable in joint disorders other than gouty; but he maintains that the following distinction obtains, viz., that while in gout the hyper-uricæmia is generally constant, in other forms of arthritis it appears to be transient.

He cites a case of infective arthritis, not exhibiting the clinical features of gout, in which the first analysis of the blood by Denis revealed a uric acid content of 7·6 mg.; but on a subsequent examination, seven months later, only 0·8 mg. was found, this, though the patient at the time was on a purin-rich diet. This difference is response to exogenous purins in gouty, as opposed to non-gouty arthritics, is well illustrated in the following table.

As Pratt points out, if the figures in the two tables be compared, it will be seen that, prior to the sweetbread meal, the average uric acid content of the blood in the gouty and the non-gouty patients was identical. But twenty-four hours to three days, after the purin intake, the average uric acid content of the blood in the gouty was 5·1 mg., while in the non-gouty subjects it was only 2·2 mg.; in other words, in the five gouty individuals a pronounced hyper-uricæmia was produced from one to three days after a purin meal. On the other hand, in the non-gouty subjects the uric acid content was found to be practically unaltered twenty-four to forty-eight hours after the same purine intake.

It would seem, therefore, that some diagnostic importance may be attached to the hyper-uricæmia that is induced in gouty subjects[141] after exogenous purines, as compared with its non-occurrence in non-gouty subjects.

Another interesting point elicited by Pratt was that in his gouty examples, although, after a purin meal, the uric acid content of the blood rose markedly, yet there was no apparent delay or diminution in the output of exogenous purin in the urine. Thus, in one example, after the intake of 190 grams of thymus gland, the uric acid in the blood, in the first twenty-four hours, rose from 2·2 mg. to 4·4 mg., reaching, on the third day, a maximum of 8·7 mg., which, on the fourth day, sunk to 2·7 mg. Nevertheless, 26·2 per cent. of the ingested purin nitrogen was excreted as uric acid. Now, as pointed out in the preceding chapter, it has been shown by many observers that in gouty subjects the excretion of exogenous purin is diminished and retarded. But Pratt’s study of the blood shows that a marked increase and retention of uric acid in the blood may result from the ingestion of purin bases, even when no evidence of retention is found on the examination of the urine.[23]

The clear inference from this is that it is desirable that our urinary findings in respect of uric acid should be reviewed and controlled in light of blood examinations to the same end.

[142]

Variations in Uric Acid Content of Blood Independently of Diet

Considerable variations in the uric acid content of the blood, according to Pratt, may occur both in gouty and non-gouty subjects, and which cannot be attributed to any purin intake. Such oscillations, moreover, may ensue within a short time. A patient of his, admitted to hospital suffering from a severe attack of gout, was placed upon a purin-free diet. Twenty-four hours afterwards examination revealed only 2·7 mg. of uric acid in his blood. Subsequently, after having had no food containing purins for fifteen days, it contained 5·1 mg.

Marked variations in the uric acid content of the blood may likewise occur in non-gouty subjects. After being on a purin-free diet for two days, a patient of Pratt’s, with recurrent iritis, had 2·2 mg., while a few months after, when on a mixed diet, his blood contained only 0·8 mg.

Again, great oscillations in the blood content of uric acid, independent of diet, are sometimes found in cases of non-gouty arthritis. Thus, in one chronic case of this nature, the blood when first examined contained 7·6 mg. of uric acid, but a few months later, when on a purin-rich diet, only 0·8 mg. were present. In another instance of primary polyarthritis the same was strikingly exhibited. Aged twenty-two years, the subject in October was on ordinary diet. His blood at that period showed 2·7 mg. of uric acid per 100 mg. of blood; in December, on a purin-free diet, 5·0; and in May, on a similar dietary, 1·6 mg.

As to whether in healthy individuals, on a purin-free diet, similar variations in the uric acid content of the blood occur, is not sufficiently ascertained. The solitary example that may be[143] cited is by McLester, who, as a result of four examinations of the blood in a normal person on a purin-free diet, found that its uric acid content was practically constant.

The deductions that may be drawn from the foregoing findings are:—

What Relation, if any, Exists between the Uric Acid Content of the Blood and Attacks of Gout?

If uric acid be causally related to gout, it would seem reasonable to expect that the blood content thereof would stand in some clear relation to the incidence or intensity of attacks.

But, according to Pratt and others, no variations indicative of such a relationship obtain. For, independently of acute attacks, and, moreover, in the absence of any pronounced renal inadequacy, the blood of gouty subjects, even on a purin-free diet, contains, as a rule, 4-9 mg. of uric acid.

More pertinently to our point, in the experience of Daniels and McCrudden, it transpires that, contrary to the usually accepted teaching, typical acute attacks might occur without any variation in the uric acid content of the blood or its excretion.

Nor did their iconoclastic findings cease here, for, mirabile dictu! attacks ensued even when the uric acid blood content was at a sub-normal level; this latter, owing to the victims being at the time on atophan, which increases uric acid elimination. In this connection it is worthy of note that, according to Pratt, the uric acid content of the blood may at times be low, even when atophan has not been taken. In one of his cases, on a purin-free diet, only 1·7 mg. was present, and in another case, on a mixed diet, 1·9 mg.

Daniels and McCrudden, too, note that the uric acid content of the blood in gouty subjects may be persistently lowered, even under the normal average. His, again, has recorded an instance of a gouty subject, with multiple tophi, whose blood did not contain an excess of uric acid. Bloch, also, took 200 c.c. of blood from a man, aged twenty-five, suffering at the time from a typical attack of gout in the big toe; but uricæmia was not present.

Bass and Herzberg injected uric acid into the blood of gouty[144] subjects until its content thereof reached 10 mg. per 100 c.c., this without any joint symptoms supervening. The same observers, aspirating joint fluids in non-gouty subjects, noted that the uric acid content was approximately the same as that of the blood. But, in contradistinction thereto, in two gouty subjects, victims of uræmia, they found in the joint fluids 18·5 and 20·8 mg. of uric acid, while the blood content was only 10 mg. and 8·2 mg.

Furthermore, intravenous injection of uric acid engendered a lesser degree of uricæmia in the gouty—this despite impaired renal excretion. To their mind, therefore, the inference was that the bodily tissues in gout display an enhanced capacity for taking up uric acid.

Lastly, Walker Hall, discussing the question as to whether any relation obtains between the degree of uricæmia and the onset of acute attacks, observes that, “the evidence is more general than specific.” Thus he reminds us that excessive intake of purin food has sometimes been followed by, or associated with, an acute outbreak. Also, that the leucocytic destruction which occurs during acute lobar pneumonia and after the use of X-rays has occasionally coincided with an acute paroxysm. To this, again, must be added the fact that atophan curtails the duration of acute attacks, apparently by exciting an increased uric acid output. Superficially regarded, these facts might appear to be conclusive; but, as Walker Hall states, it must be recalled that overeating, overdrinking, trauma, mental disturbances, atmospheric vicissitudes, and bacterial infections have also preceded acute outbreaks.

To sum up, the main conclusions deducible from the foregoing clinical and experimental findings would appear to be that:—

Discussion of the Foregoing Data

While the researches of the past decade have proved distinctly encouraging, yet we must not blind ourselves to the fact that the foregoing findings, and alike our deductions therefrom, are largely provisional; for we stand in grave danger of over-emphasising the[145] significance of the results forthcoming from the investigation of isolated samples of blood from different individuals. The recorded estimates of the uric acid content of the blood in strictly normal persons are all too few, the findings in diseased subjects too conflicting, to warrant dogmatic inferences, wide generalisations. In truth, the problem is by no means as simple as may at first sight appear, and this but a slight digression will suffice to make clear.

The Significance of Uricæmia.—It is generally maintained that the blood content of uric acid in gout is above normal. Yet the excretion of uric acid, save during acute attacks, rests within physiological limits. Again, à propos of our claim that the blood is surcharged therewith, we have the awkward fact, as yet inexplicable on chemical or physico-chemical grounds, that the blood-stream can hold in suspension far more uric acid than has ever yet been met with in gout, according to Bechhold and Ziegler no less than 50 mg. of uric acid per 100 c.c. of blood serum before deposition tends to occur. On the other hand, urates are less soluble therein, not exceeding 2·5 mg. per 100 c.c. How remote from the limit of saturation the highest figures observed in gout! What a large margin of solubility is still available!

Again, the uric acid blood content in gout is far less than was formerly thought. Only by a few milligrams does it transcend that found in normal individuals. Can this slight disparity have such profound potentialities as to determine the incidence or not of gout? and this with the saturation point still so remote. The urates, too, being practically non-toxic, how difficult to conceive that the almost trivial excess of the uric acid blood content over the normal is adequate to produce the fulminant and dramatic phenomena of acute gout.

Again, though we speak of uricæmia as a dominant characteristic of gout, we are uncertain whether the alleged increase in the uric acid content of the blood is real or merely apparent. We can, it is true, extract uric acid and urates from the blood-stream, but it does not necessarily follow that it is as such that they circulate in vivo. We need walk circumspectly here for, despite the most modern methods of blood analysis, we are still ignorant as to the exact form in which uric acid exists in the blood-stream; whether the purins of the food appear in the blood-stream as sodium monourate, or in organic fusion. Accordingly, in the interests of progress, it were well to bear in mind the pitfalls that beset uric acid estimation, the insufficiently eclectic capacity of even the most modern tests, and to consideration of these more chastening aspects we now proceed.

Sources of Fallacy in Uric Acid Estimation.—With Folin’s findings as his basis, Walker Hall estimates that, excluding the[146] lymphatics and lymph spaces, the entire blood-stream contains normally 70 mg. of uric acid, i.e., 2 mg. of uric acid per 100 grams of blood, 3,500 c.c. (total quantity of blood).

Thence he argues that, inasmuch as about 1 litre of blood traverses the kidney per minute, the total content thereof of uric acid would gain access to the renal organs in three and a half minutes. Now the average total output of the kidneys is 500 mg. per twenty-four hours. Accordingly, assuming that the blood arriving at the kidneys contains as a constant the above 70 mg. uric acid, the total daily output would pass through these organs in twenty-five minutes.

Now, given immediate extraction of all the uric acid by the renal cells, then the blood in the renal veins will become free of uric acid. If so, the estimates of the uric acid content of the blood will reflect exactly the measure of the endogenous or exogenous nuclein metabolism. But, “if the renal vein blood is not purin-free, then the estimations will fail to yield a true picture of the activities of nuclein exchange.”

Again, as to the precise import of isolated estimates of the uric acid blood content, we must recollect that the excretion of purins is not distributed evenly over the twenty-four hours, varying as it does under the influence of food, exercise, sleep, and other factors. A propos of this, Pratt’s observations clearly show that both in gouty and non-gouty subjects fluctuations in the uric acid blood content also occur, and this independently of diet. To what, then, may these variations be referred? Obviously a question of great moment, especially when we recall the eccentric behaviour of the blood uric acid in relation to the incidence of acute gouty attacks. For, until the inward meaning of these vagaries is revealed, the value of recorded estimates must necessarily be discounted considerably.

We must recall, too, that a certain moiety of the purins derived from nuclein metabolism lags in the lymph spaces and lymphatics, and this, as Walker Hall reminds us, must reduce the quantity present in the blood-stream at any one time. Also, as the same authority reflects, the lymph stream being probably richer in sodium ions than the blood, the entry of the nucleins therein may be retarded and so lead to a still further reduction of the blood content.

There is yet another possibility, he reminds us, viz., “that the purin content of the blood varies in the peripheral pulmonary hepatic and osseous streams, and that, while in some parts the purins are being carried to the kidneys for excretion, in others they are being transported from one organ to another for further metabolism.”

[147]

For, as before pointed out, the enzymes responsible for the ultimate disruption of the nucleosides are scattered in different organs, and Walker Hall suggests that “a transport of half metabolised nucleotides from one organ to another may form a part of the normal processes of nuclein metabolism.” This may well lead us on to consider the limitations that beset even the most modern tests in use for uric acid determination.

Disabilities of Modern Tests.—With all its outstanding advantages, even the Folin method of uric acid estimation has its drawbacks. As Curtman and Lehrman have pointed out, different workers have, even on identical blood samples, arrived at results which vary widely. Nor, disconcerting though it be, do the limitations of this mode of hæmo-analysis cease here.

Thus we know from Gudzent and Apolant that the soluble but unstable biurate is constantly being transmuted into an insoluble stable type, in other words, metamorphosis from one isomer into another. But, unhappily, the tests to hand fail of differentiation of the several tautomeric forms of uric acid. Also, as isomers of uric acid actually exist, then quâ Walker Hall, why not isomers of purins and pyrimidins also? But here again our tests are insufficiently eclectic. They give us no clue as to the affinities or blends of purins or pyrimidins for or with other substances.

Again, as our criteria fall short of identifying the exact form of the “purin combinations” it follows, therefore, that they tell us nothing as to whether “the increase is due to a more active transport of purins from one organ to another for further metabolism or simply to a transport to the kidneys for elimination.”

In other words, hampered by the above disabilities in our tests, it is beyond our power to determine whether “the increases denote a supernormal nuclein metabolism or an unusual type of nuclein cleavage.” Should it ultimately transpire that the increase in the purin blood content is a real one, viz., made up of “an excess of normally formed and normally bound purins,” a great step forward will have been achieved. For, to account for the same it will, as Walker Hall observed, be necessary to postulate a supernormal nuclear activity of generalised or localised distribution.

Need for Further Investigations.—While none can doubt that, by means of chemical investigation of the blood, the clinical problem of gout will be elucidated to a much greater extent than has been possible by means of urine analysis, still much remains to be done before recent findings can be applied to the solution of the etiology of gout.

The results of blood analyses up to now have afforded us no clue as to the intimate nature of the warp in nuclein metabolism. At[148] the most, the researches in this sphere do but make it increasingly clear that uricæmia is not the cause but the result of gout.

Albeit, this conclusion does not justify us in putting out of court all thought of uric acid in connection with gout. Any tendency thereto will be immediately checked when we recall that uratic deposits, i.e., tophi constitute the solitary unequivocal token of gout, and to this aspect of the question the ensuing chapter will be devoted.

Meanwhile, systematic investigations of the purin content of the blood, not only in gouty but in normal subjects, would surely dissipate much of the obscurity that envelops this complex question. It were well, too, that blood and urine analyses go hand in hand in our investigations. How illumining these have been in connection with atophan, the increased urinary output of uric acid having been found to be correlated with a simultaneous sinking in the level of the uric acid of the blood.

Again, the excretion of urinary purin ebbs and flows with the intake of food and the degree of muscular activity, while sleep also exerts an influence, not to mention constitutional disturbances, e.g., fever infections, etc.

Can it be doubted that the blood content of uric acid varies with these same vicissitudes? Walker Hall tells us that the data to hand, “as to the rapidity of the appearance of purins in the blood-stream after food, infections, fever, etc.,” though few in number, yet suggest that “the excretion by the kidney is tidal in character, and that the blood uric acid has similar characteristics.” In light of these possibilities, we may well pause before attempting to appraise exactly the significance of isolated blood examinations.

What, too, as the above authority observes, of the influence on the gouty uricæmia of infancy, puberty, the menopause, and for that matter the pre-senile and senile periods of life with their associated vascular lesions? The researches of Uffenheimer prove that even in young children the disorders of purin metabolism distinctive of gout are to be met with, i.e., “infantile gout.”

We stand also in urgent need of knowledge as to the uric acid blood content in the early as opposed to the late stages of gout; in need, too, of further examinations of the blood to this end, not only during the passage of acute attacks, but even more under those conditions which are presumed to determine their incidence.

But, despite these gaps in knowledge, these disabilities of technique, there is no need for despair. “It is a slow progress along the zigzag which leads to the centre of the ‘gouty maze,’ but the researches of the last decade have opened up many new and possible pathways thereto.”

The two salient features of the gouty diathesis are:—

With the former we have dealt, but before passing to discuss the latter, it will, we think, be advisable to review both these morbid tendencies in relation to gout.

Hyper-uricæmia and uratosis, though they both occur in gout, are by no means of identical pathological valency or significance. In hyper-uricæmia the uric acid, either in a free state or combined, circulates in the blood and lymph. In uratosis the uric acid is anchored in solid form in the substance of the tissues. In the former, then, the uric acid, if it be noxious, acts as a chemical poison, in the latter as a mechanical irritant.

But the more striking contrast is that while hyper-uricæmia is not restricted to gout, but occurs in many other disorders; on the other hand, uratosis is absolutely confined to the gouty state, constituting its pathognomonic stigma.

Again, hyper-uricæmia may exist for prolonged periods without producing uratosis. But uratosis cannot, as far as is ascertained, occur without a co-existing hyper-uricæmia. From these disparities it may legitimately be inferred that the factors responsible for the genesis of hyper-uricæmia and of uratosis, are not identical; in other words, that in uratosis some other agency or agencies are at work over and beyond those that beget hyper-uricæmia.

Lastly, inasmuch as uratosis stamps the seal of specificity upon gout, it follows, from this and the above considerations, that there is a more intimate relation between gout and uratosis than between gout and hyper-uricæmia, and that the factors which make for uratosis have a more intimate bearing upon the pathogeny of gout than those which lead to hyper-uricæmia.

Constitution of Tophi

The view that tophi were composed of chalk prevailed for centuries. As we see such was the conception of Virgil, and in our[150] own country John Hunter entertained the same erroneous notion, while amongst the laity this view as to their nature is held widely even to-day as it was in the time of Dryden.

Albeit, the term “chalk-stones” is a misnomer, as tophi, when pure, may be wholly devoid of lime. Modern analyses, too, have failed to demonstrate the presence of calcium carbonate, the essential ingredient being urate of soda.

On the authority of Rendu, we have it that Tennant and Pierson were the first to demonstrate the presence of uric acid in gouty deposits, which discovery was later confirmed by Fourcroy and Wollaston (1797), these latter observers showing that they consisted almost exclusively of urate of soda.

Subsequently to Wollaston’s day, many analyses have been conducted, by Marchand, Lehmann, Wurzer, and Langier, L’Heretier, Ebstein and Sprague. Of the various findings we append those by Marchand, Lehmann and one of later date by Ebstein and Sprague.

Marchand’s Analysis

Lehmann’s Analysis

Ebstein and Sprague’s Analysis

[151]

It will be seen that all of them agree more or less closely as to the essential ingredients being uric acid and soda. According to Ebstein and Sprague they consist usually of almost pure biurate of sodium and potassium. But, as a rule, after a time calcium salts are deposited. Dunin, it may be noted, has found deposits resembling gouty tophi, which contained only calcium salts. Kahn, again, claims that tophi do not always consist solely or even largely of urates, but that these may be replaced by calcium salts. It may be added, too, that M. B. Schmidt has recorded, under the designation of “Calcium gout,” a case in which there existed a generalised deposition of calcium, and this in tissues other than those usually involved in “metastatic calcification.” But, to sum up, although there may be admixture of lime salts and organic matter, the salient chemical constituent of tophi is biurate of sodium.

Mode of Formation

Gouty tophi, like all pathological concretions, are laid down in accordance with a definite law. In the first instance, a central nucleus is essential. To this must be added a “binding substance” or structural framework of different nature from the main mass of the concretion.

Garrod, discussing the intimate structure of “chalk-stones,” observes that, “the large amount of phosphate of lime occasionally met with is probably derived not only from the tissue in which the chalk-stones have been developed, but likewise from secondary deposition, the result of ordinary inflammation around the original nucleus (urate of soda) which acts as a foreign body.”

It is, however, quite possible that some substance other than urate of soda constitutes the primary nucleus, for, as we now know, concretions most frequently gather around masses of mucin, clumped bacteria, desquamated cells, precipitated proteins, etc. Thus, the renal uric acid infarcts, supposed to result from disruption of the nucleo-proteins of the fœtal nucleated red corpuscles, take origin around injured epithelial cells, which latter form the nucleus.

As to gouty tophi, too, it has been suggested that they form in response to any toxin, resistance to which may involve death of the tissue cells with consequent disruption of their nucleins and formation of urates. Such was the view held by Woods. Hutchinson, who also thought that the calcareous accretions might be regarded as “protective,” analogous to the formation of shells in the invertebrates, the process here consisting in the deposition of lime salts in cells already saturated with uric acid and urates.

In any case, whatever be the exact nature of the nucleus, the[152] urate of soda collects thereupon, the acicular crystals tending to assume the form of radiating needles. But the successive depositions not being of regular incidence, the surface of the crystals, in the intervals of quiescence, becomes covered by mucin, animal or earthy matter. Hence, the concretions display not only a radiating, but a concentric or laminated structure.

The mucin acts as the “binding substance,” the crystals lying in its meshes, and, moreover, remaining as the framework of the concretion even after the crystals are dissolved out; in other words, the gouty tophus is made up of a blend of crystalloids and colloids, evolved from solutions of the same character.

The importance of recognising the true nature of this binding substance, i.e., mucin, merits a brief digression, in light of Ebstein’s view that local tissue necrosis is a necessary antecedent to uratic deposition. Now, exhaustive studies of the histology of uratic deposits, both those experimentally induced and of spontaneous gouty origin, have been conducted by Freudweiler, His, Krause, and Rosenbach.

All their results, according to Gideon Wells, “indicate that uric acid and urates excite some slight inflammatory reaction, cause a slight local necrosis, and seem to act as a weak tissue poison.” According to Rosenbach, however, this sequence is not invariable, inasmuch as he noted that such deposits may occur without inducing necrosis. More pertinently to our contention, however, is it that Krause’s experience seems to indicate that errors of interpretation were possible. Thus, he suggests that part of the material in the areas of uratic deposits merely constituted the framework of a crystalline deposit, though such were currently regarded as strands of necrotic tissue.

But, to resume, tophi being blends of crystalloids and colloids, we must recollect that the suspension capacity of colloidal solutions for crystalloids is much superior to that of simple solutions, by reason of the fact that at the surface of each colloidal particle there exists a zone in which the crystalloids are much more closely aggregated than elsewhere, thus permitting more crystalloids to be dissolved in the solvent between the colloidal particles. But, be it noted, this same tendency to concentration of the crystalloids at the surface of the colloidal elements leads to the colloids acting as determinants of precipitation when crystalloids are in excess. Accordingly, when the crystalloids pass out of solution, they form crystals or precipitates intimately blended with the colloids. Thus, for example, when uric acid crystallises out of urine it carries with it the colloidal pigments. On the other hand, if the colloids are precipitated, the solvent capacity of the solution being[153] consequently depreciated, the crystalloids are deposited in intimate relation with the colloids.

Again, Schade has pointed out that colloids may precipitate in reversible form or not. If in irreversible (e.g., fibrin) form, the concretion will remain permanent. But if the colloidal precipitate is reversible, it may be redissolved, as happens with the uric acid infarcts of the infant’s kidney. In conclusion, we see, therefore, re crystalloids and colloids in animal juices, that the conditions of their solubility are most complex, and though they do not explain the nature of gout, the variations doubtless stand in intimate relation to the formation of tophi.

Localisation of Uratic Deposits

Uratic deposits evince a decided predilection for cartilages, tendons, muscles, and skin. This localised distribution of the depositions would seem to suggest their dependence on local tissue peculiarities. Now the presence of sodium salts in a solution diminishes the solubility of urates therein. Consequently, in seeking to explain the incidence of tophi, it was suggested that cartilage and tendons, being richer in sodium ions than the blood, this might account for the fact that urates tend to be precipitated in these particular structures.

Again, Almagia, working in Hofmeister’s laboratory, noted that thin sections of cartilage, if left for some hours in a solution of sodium urate, will take up uric acid. Direct inspection readily reveals the presence of white foci and diffuse opacities due to uratic deposits. The marked affinity of normal cartilage for uric acid is again attested by the fact that, given injection thereof in quantity into the peritoneal cavity of rabbits, the uric acid may often be detected by the murexide reaction in joint cartilage, though apparently not in other tissues.

This behaviour would appear to justify the conclusion that the observed accumulation of uric acid in the cartilages in the presence of states of uricæmia, may be explicable on this same basis. In any case, this marked affinity of even normal cartilage for uric acid seems to disprove the necessity of Ebstein’s postulate, viz., that the dissolved uric acid sets up inflammation, and that an antecedent necrosis precedes the deposition of urates. Still, even if we concede the fact that normal cartilage has a marked affinity for uric acid, how is it that in leukæmics, despite their high blood content of uric acid, no uratic deposits ensue? Does not such disparity seem to indicate that in gout some other factor intrudes? in other words, that the excess of sodium ions in particular tissues, while it may favour deposition therein, is[154] inadequate of itself to actually determine the formation of tophi.

The Causation of Tophi

Many and divers are the theories that have been propounded to account for the genesis of tophi. For some their incidence would appear to predicate something abnormal in the conditions of uric acid solution and circulation. Others have pinned their faith to some affinity on the part of the bodily tissues for uric acid—an enhanced retention capacity on their part for this substance. Some again, impressed by the objective changes that mark the clinical evolution of tophi, have been led to regard them as concomitants or sequels of gouty inflammation. But, be the true explanation what it may, we may well preface our discussion of the various theories by the obvious comment, viz., that the origin of tophi must doubtless depend in the ultimate upon constitutional or systemic, as well as local, factors.

Solubilities of Uric Acid

In the older conceptions of the pathology of gout the hypothesis that found most vogue was that the separation of uric acid from the blood into the tissues was due to diminished alkalinity of the blood and tissue juices; but, as before pointed out, it has been established that the alkalinity of the blood is not reduced, and the theory has consequently been abandoned.

But, with the advent of Gudzent’s findings, viz., that uric acid existed in two forms—one soluble and unstable, and the other insoluble and stable, and that the former is constantly changing into the latter—another conception of the origin of tophi arose. It was supposed that, by reason of the disparity in solubility of these tautomeric types of uric acid, the blood in gouty subjects must at times be in a state of super-saturation with uric acid; and, moreover, that equilibrium could only be restored through abstraction of the urates by crystallisation.

Unfortunately for this theory, it has been shown that the blood of gouty subjects is not super-saturated therewith; indeed, over and above the highest increments hitherto met with in gouty blood, a considerable margin of solubility for uric acid is still available. In truth, the problem is by no means so simple; for the conditions governing the solvency of uric acid in the blood are bewilderingly complex, subject as they are to the manifold variations in solubility exhibited by crystalloids in the presence of the many divers colloids.

But, to resume, Minkowski, it will be recalled, noted that[155] from a mixed solution of uric and nucleinic acids the former cannot be precipitated by either acetic acid or alkaline ammonio-silver-magnesia mixture. Accordingly he advanced the view that uric acid “primarily exists in the blood and the tissue juices in combination with nucleinic acid, and that, not only the conversion of the purin bases into uric acid, but also the solubility and transportation, as well as the further changes of the uric acid in the living body, is regulated by this linking with a nucleinic acid rest.”

But, unfortunately for the value of this hypothesis, there is no proof that nucleinic acid is actually present in the blood; for, as Fürth remarks, is this inhibition of the precipitation of uric acid, in the presence of nucleinic acid, “necessarily indicative of a true acid combination with nucleinic acid,” “but such inhibition of precipitation is rather to be referred to the general group of variations of solubility which are manifested by crystalloid substances in the presence of all sorts of colloids.”

Complex phenomena of solubility of this nature must be considered in connection with the circulating uric acid. Nucleinic acid is not the only important substance, but “the general mass of the blood proteins must be particularly thought of.”

Continuing, Fürth reminds us that uric acid is much more soluble in blood serum than in water, and forthwith envisages this disparity in light of the factors that affect solubility of uric acid in the urine. The latter is markedly influenced by the presence of urea and di-sodium phosphate, and the relation of this to mono-sodium phosphate. Nor, he reflects, is there any doubt “of the importance of such inter-relations, too, in the formation of uric acid deposits in the tissues.” But he adds, “Although the importance of these complex conditions of solubility as they prevail among colloid and crystalloid substances in the animal juices may be accepted in relation to the formation of uric acid concretions, there is no real reason for seeking the explanation of gout in this sphere.”

Tophi in Relation To Uricæmia

It might be thought that some relationship might be established between uratic deposits and the degrees of uricæmia, but the data to hand give no countenance to the assumption. Thus, His has recorded the case of a gouty subject with multiple tophi whose blood did not yield an excess of uric acid. Pratt, again, could trace no relation between the amount of uric acid in the blood and the severity or character of the disease. Two of his patients had[156] numerous and widely distributed large deposits of sodium urate beneath the skin, yet the blood content of uric acid in both was less than the average amount found in gout. Thus, on a purin-free diet, one had 2·4, the other 2·2 mg. These findings, he considers, show that the presence of multiple tophi is no indication that a state of hyper-uricæmia exists.

Walker Hall, discussing this same question, holds that there is but little evidence “as to the relation of uricæmia to the formation of tophi.” He asks the question whether the deposition is the outcome of abnormal purin combination in the blood and lymph stream? which latter at present, he states, are regarded as passive carriers of the urates. For, he says, the small purin increase in gouty blood cannot surely make all the difference, seeing the large volume of solubility still available. The physico-chemical hypothesis, he claims, is inadequate to explain the relationship between uricæmia and the tophi, and hazards the suggestion that after all it may be that “the uricæmia plays little or no part in the depositions, and that these are due to the defective removal of substances resultant from local nuclear activities.” He asks, moreover, whether such substances differ in type from those of normal nuclein metabolism and so fail to be suspended in the surrounding lymph in such a way as to ensure their entrance into the blood-stream? Like others, he notes that atophan brings about a removal of some of the deposited urates. But such diminution of the tophi may, of course, he says, be due to increased flow of serum to the inflamed part; though, on the other hand, the more massive deposits “are surrounded by layers of young granulation tissue and phagocytes and peritophal fibrous tissue, and these in turn offer some hindrance to the permeation of serum or drugs.”

In reviewing the foregoing views as to the formation of tophi, it is obvious we stand in urgent need of more knowledge. Neither the chemical nor the physical theory or a combination of the twain seems adequate. This for the salient reason that, as far as the existing evidence permits us to draw conclusions, it would seem probable that not only local but constitutional or systemic conditions play an important rôle in tophi formation.

But as far as our discussion has advanced, we may, we think, be justified in the following deductions:—

It will be seen from these conclusions that the proximate cause responsible for the genesis of tophi is yet to seek, and in pursuance of our quest we turn to another aspect of this complex subject.

Tissue Affinities for Uric Acid

Injecting uric acid intravenously into gouty subjects, Umber noted that at times the whole was retained, but on some occasions was excreted in fractional portions. On the other hand, a normal individual under similar circumstances eliminates it completely. In explanation thereof, he proffered the opinion that this failure on the part of gouty persons to excrete exogenous uric acid was due to a special affinity of their tissues for uric acid.

As to intravenous injection of uric acid, however, modern investigation has established that, both in normal as well as gouty subjects, its excretion is spread over several days, and the whole is not recoverable from the urine. Now this incomplete excretion or retention of uric acid was attributed to defective elimination by the renal cells; but, as shown in a previous chapter, this conception fails of demonstration. Nor, for that matter is there any proof either that the retention is due to fixation of the uric acid in the blood serum. Accordingly, to our minds, it is permissible then to canvass the further possibility adumbrated by Umber, viz., that an increased affinity of the tissues for uric acid may haply account for the diminished purin excretion, the excess of uric acid in the blood, lymph, and tissues, and that these same may lead to uratic deposition.

This last hypothesis derives colour from the findings of Schmoll, Magnus Levy, Vogt, Reach and Bloch, who noted that, after giving thymus to gouty persons, they found far less uric acid in the urine than in the case of normal subjects. Also, that the ingestion of thymus by the victims of chronic gout repeatedly resulted in acute outbursts of the disease. Moreover, as we saw when discussing the sources of uric acid, there are cogent reasons for avoiding a too restricted conception which would make the leucocytes, the muscles, or the digestive glands alone responsible for the endogenous production of uric acid; in other words, that a more catholic attitude on our part is indicated, one which would envisage it as the outcome of continuous and general cellular wear and tear. That an increased cellular destruction, as induced experimentally, e.g., by exposure to Röntgen[158] rays, is capable of raising the blood content of uric acid in a gouty subject, and of precipitating a gouty paroxysm, may be inferred from the researches of P. Linsen.

Retention Capacity of Tissues for Uric Acid

It may be recalled that Wiechowski and others observed that in man, of parenterally introduced uric acid, 80-90 per cent. reappears in the urine. Accordingly, Schittenhelm and Wiener argued that, if uric acid is indestructible in the human body, then, given retarded elimination, the tissues should contain considerable quantities thereof. Subsequently, in 1914, they sought to investigate human tissues as to their content of uric acid. Their studies were conducted on three examples, a case of anuria, one of pernicious anæmia, and one of gout.

The case of anuria occurred in a male, aged sixty-two, in sequence to thrombosis of both renal veins following operation. Two-hundred gram samples of the following tissues, lung, heart, spleen and liver, were examined for uric acid with wholly negative results. The residue of the organ was worked up together, but only 0·01 gram of uric acid was isolated.

In the case of pernicious anæmia no uric acid was demonstrable. The gouty subject had for twenty-five years suffered from typical attacks and exhibited many auricular tophi. The following organs, in their entirety, were analysed, the liver (1,550 gram), no uric acid; spleen (290 gm.), 10 mg. uric acid (3·5 mg. per 100 gm.); kidney (270 gm.), no uric acid; lung (930 gm.), 15 mg. uric acid (1·6 mg. per 100 gm.); muscle (440 gram), no uric acid; and intestine (420 gram), no uric acid.

It will be seen that uric acid was either absent or present in minimal amounts, and these results Schittenhelm and Wiener interpreted as confirming their long advocated contention as to the destructibility of uric acid in the human organism.

Morris S. Fine, from the results of similar investigations, considered the failure of these observers to isolate uric acid in these cases of anuria and gout as most remarkable. He considers “their results may in part be ascribed to the use of hot sodium hydroxide previous to the precipitation of the proteins in the extraction of the tissues, as the instability of uric acid in alkaline solutions is a well-known property.”

In this criticism Fine would appear to be fully justified, in view of the marked contrast between the findings of Schittenhelm and Wiener, and his own data is recorded in the tables on p. 159.

While it is unfortunate that Fine’s theory contained no instances[159] of gout, his findings are a definite proof that, to quote his own words, uric acid can be demonstrated in considerable concentrations in human tissues. Incidentally, also, his tissue analyses are flatly contradictory to Schittenhelm and Weiner’s persistent contention, viz., that the human organism can decompose uric acid.

Gideon Wells states that in normal individuals the tissues contain but little uric acid, and this not in quantities sufficient to permit readily of its isolation in a pure state. Albeit, Wells found considerable amounts of uric acid in the tissues of a young woman who, in sequence to poisoning with HgCl₂, died after complete suppression of urine for nine days.

Table I.—Concentration of Uric Acid in Human Tissues and Fluids per 100 Grams of Material

Table II.—Concentration of Uric Acid in Miscellaneous Human Tissues per 100 Grams of Material

Again, as before alluded to, Bass and Herzberg found that[160] intravenous injection of uric acid caused less uricæmia in the gouty, despite diminished renal excretion. Hence, they concluded that in gout the retention capacity of the tissues for uric acid is augmented.

Fürth, an ardent advocate of Umber’s hypothesis, emphasises the fact that Wiechowski was never able to detect any evidence of uricolysis in the human body. Continuing, he observes, if we reject all idea of uric acid retention in the tissues, “It would be a particularly difficult thing to understand why gouty patients do not simply expel by a compensatory hyper-excretion the uric acid which is accumulated from a supposed failure of uricolysis; precisely as in leukæmia the patient compensates simply by an exaggerated excretion of the excessive uric acid which is mobilised in the body from the excessive purin decomposition.” His conclusion, therefore, is that, “In the gouty individual there must exist some cause which makes a compensatory uric acid excretion impossible; and that is plainly a retention affinity of the tissues, because of which the uric acid is actually held in the tissues.”

In light of Fine’s revelations the retention capacity of the bodily tissue for uric acid may, we take it, be considered as fairly well established. But, in view of the precipitation or anchoring of urates in the tissues in gout it is most desirable that further investigations be made to discover whether in gouty subjects the tissue retention capacity for uric acid is enhanced.

“The impression,” says Fürth, “grows on one that this hitherto little considered factor, of an increased affinity of the tissues for uric acid in the gouty subject is very much closer to the real kernel of the gout problem than, for example, the question of the fixation of uric acid in the blood about which there has been so much contention, and with which of necessity we are compelled, at least, to some little extent to concern ourselves.” The results of modern researches tend to support this more catholic conception. We would recall that Lewis and his co-workers, seeking the source of the increased endogenous purin excretion that follows ingestion of purin-free food, were forced to reject the view that it was solely derived from katabolism of the nuclear substance of the digestive glands, and to refer it instead to “wear and tear” of the body cells as a whole. Precisely the same change in attitude, we may remind our readers, has overtaken us in regard to the site of urea formation, viz., that not only the liver cells, but those of the muscles also participate in its production.

While admitting that dogmatism is out of place, still to our mind this theory of tissue retention makes strong appeal. In light of it the nebulous “gouty diathesis” seems on its way to become incarnate in some inborn peculiarity of tissue-function, a falling[161] short of full physiological activity, or, as M. Rendu termed it, a “primordial vice of nutrition.”

In other words, in gout there is no rift nor lack of finish in the orderly sequence of enzymatic reactions that eventuate in uric acid. Uric acid is formed and, as far as we know, after a normal fashion. But, here comes the flaw, viz., the uric acid, when formed, fails of transport and elimination. It is precipitated and anchored in the tissues, from whose grip it fails to detach itself. In short, it is not the formation of uric acid, or its failure of further metamorphosis, but the retention of uric acid, and more pertinently, its fixation in the tissues that constitutes the salient feature of gout.

Now, all modern research tends to indicate that uric acid is not an intermediary, but a terminal product of metabolism, and, moreover, that there are no uricolytic ferments within the body whereby its destruction can be accomplished.

If we grant that—

then it follows that man, ipso facto, is potentially liable to uric acid retention and deposition, the same objectivated as tophi. In this innate potentiality of and to uratosis resides the “gouty” diathesis.

If the postulates (1) and (2) be established, then, though it sound rank heresy, it follows that gout is not, chemically speaking, an “error of metabolism.” Not, at any rate, in the ordinary acceptation, viz., not a failure in the transmutation of uric acid into urea and intermediate products. If uric acid be an end-product, then no further cleavage into urea, etc., occurs, and in this connection the failure to discover uricolytic enzymes is significant.

We have before proffered the suggestion that not only local, but constitutional, or systemic influences also play a part in the origin of tophi. Provisionally, therefore, we would infer that—

In other words, we have in these two elements haply the constitutional and local factors that we postulate as essential to the formation of tophi. Albeit, they represent but latent tissue[162] potentialities, inadequate of themselves to determine the eruption of tophi.

Moreover, be it recalled that the causa causans of gout must be responsible not only for the incidence of tophi, but also for the more dramatic features of gout, its arthritic outbreaks, etc. To dissociate the cause or causes of the uratic deposits from that of the joint inflammations would indeed appear impermissible.

But, taking this view, it is clear that, apart from the constitutional and local factors above postulated, tophi and, alike, the arthritic phenomena of gout, demand for their production the intrusion of some further element, some tertium quid, vital and biological. To this end, therefore, we purpose reviewing tophi in their clinical aspects, as herein possibly we may find some further clue to their exact mode of genesis.

Clinical Evolution of Tophi

As to the clinical characters that mark the genesis and maturation of tophi not a little conflict of opinion seems to obtain. Do tophi arise painlessly or not? Do the uratic depositions occasion any local inflammatory reaction? Or, are they merely concomitants or sequels thereof?

With what wearisome iteration has the same question been propounded in regard of gouty arthritis. Are the attacks of pain and inflammation due to deposits, or do the deposits take place at the site of inflammation?

But, restricting our enquiries to tophi, we may remind the reader that Aretæus, writing in the second century, A.D., made the following observations: “Callosities also form in the joints; at first they resemble abscesses, but afterwards they get more condensed, and the humour being condensed is difficult to dissolve; at last they are converted into hard white tophi (Πῶροι στερροὶ λευκοὶ), and over the whole there are small tumours like vari and larger, but the humour is thick white and like hailstones” (Περὶ Αρθριτιδος). To our mind, it would be difficult to emulate, much less to surpass, the succinct and, as we believe, accurate picture here drawn of the various stages that mark the life history of tophi. It will be noted that Aretæus says that in their initial stages they “resemble abscesses,” and, turning to the writings of the elder Garrod and others, we find abundant evidence that it is so.

Discussing the more frequent incidence of tophi in the hands than in the feet, Garrod describes the physical characters presented by tophi in the making as seen in one of his examples of gout. “On the dorsal surface of the second phalangeal joints of three fingers, small rounded protuberances were observed, the[163] skin over them being red; these bulgings appeared soft, as if containing a thick fluid, but not the slightest indication of white matter could be seen through the skin; they might have been either gouty concretions in their early stage of formation or some other form of swelling; from a simple inspection I could form no opinion as to their true nature, but their history convinced me that they arose from a deposit of urate of soda. Upon puncturing one of the little swellings, full light was thrown upon the case, as a thick white fluid immediately exuded, a drop of which placed, under the microscope, with the use of polarised light, gave the appearance represented in Fig. 1; the crystals were proved by analysis to consist of urate of soda.”

We see, therefore, that Aretæus and Garrod were at one in their observation that tophi in their initial stages are betokened by small red swellings; in other words, as Aretæus says, they “resemble abscesses.” Garrod also held that uratic deposits probably form during an attack of gout, but occasionally they appear shortly afterwards. Thus, in one of his cases no auricular tophi were found when the subject left hospital, but within ten days, on re-examination, a deposit was detected. “Perhaps,” he reflects, “some fluid was effused during the fit, but being at first transparent, could not easily be distinguished.”

That Garrod held the swellings to be inflammatory in nature is clear from his writings. Thus, he says, “When tissues little liable to take on inflammatory action become infiltrated (with urate of soda), but slight vascular disturbance is produced. This is especially the case with the fibro-cartilage of the ear, and although we now and then meet with patients aware of the formation of these little nodules, who experience in fact a gouty fit in the ear, yet in the majority of cases attention has never been directed to the part, so slight has been the inflammation caused by the effusion.”

Again, James Moore, whose graphic description of tophi formation is quoted by Garrod, also held that “this process is usually preceded and accompanied by inflammation.” Hilton Fagge, too, says, “it appears probable that the deposition of lithate of soda causes inflammation in other tissues besides the joints. It does, as we have seen, in the ear and occasionally in the skin.” But, he also states, “in the pinna of the ear, in fact, gouty concretions commonly form without any indications of previous inflammatory action. In some instances the patient experiences sensations of heat and pricking, and the part is tender, but more often he is quite unconscious of the fact that such concretions in the pinna are present.”

Duckworth also noted that uratic deposits are not always painless[164] during their formation, and he noted that not only may auricular tophi be painful at this stage, but that, following the subsidence of acute gout in a joint, painful swellings may develop in its vicinity, which subsequently proved to have been tophi in process of formation.

For myself, I am of opinion that each and every process of tophus formation is preceded by local inflammatory reaction of varying grades of severity. In a matter of this sort, positive is more valuable than negative evidence. We see that all the authorities quoted admit that tophi are associated with inflammation and some measure of pain, though they add the reservation that in many instances, if not the majority, these phenomena have apparently been absent. Apparently, we say advisedly, for conceding that the pain attending the formation of auricular tophi is but slight, how all too easy for the subject to have wholly forgotten it when he comes later under notice. By this time the tophi, from being latent, have become overt. The initial soft red swellings, their nature probably misinterpreted at their initiation, are now transmuted into pearly concretions of hard or semi-solid consistence. Small wonder, then, that attempts to elicit the history of slight pain and pricking or tenderness often prove barren; for, be it noted, tophi take months to mature, as Garrod long since pointed out.

Moreover, we would emphasise the fact that tophi, more often than is thought, occasionally precede by some years the outbreak of arthritic attacks. Both Duckworth and Garrod are quite definite on this, and we can confirm them.

In such instances, then, even granted that our attention be drawn to them in their initial stages, how easy to misinterpret their true nature! Thus, we have known tophi in their early stages of formation confused with chilblains. In this connection we might remind the reader that, according to Duckworth, amongst the peculiarities of tissue in those goutily disposed is feebleness of the peripheral capillary circulation, “a condition leading to disorders of chilblain-type, the vessels filling slowly after being emptied.”

We repeat that the cause or causes of tophi and, alike, of the arthritic phenomena of gout are, and must be, one and indivisible, for the process of tophus formation is but an attack in miniature of gout. Although he may never have had an arthritic outbreak, the individual who exhibits a tophus undeniably has gout. More certainly so than if he had had an inflammatory outbreak in his great toe; for this, at any rate, may be of non-gouty origin, but the tophus, never!

Reflecting on the foregoing considerations, we would submit—

[165]

The question that now thrusts itself upon us is,—What, then, is the cause of the inflammatory phenomena which determines the eruption of tophi, and alike of the arthritic outbreaks?

The Cause of the Inflammatory Phenomena

Garrod’s discovery that uric acid was present in the blood in gout not unnaturally led to the assumption that herein lay the origin of its symptomatology, and what else than confirmatory could be the deposition of uratic deposits here and there in the body. The corollary seemed obvious that, given the presence of a certain proportion of uric acid in the blood, then gout must result. But, unfortunately, it was not so; for, lo! and behold, an excess of uric acid in the blood is in no sense pathognomonic of gout.

Thus, the blood in leukæmia contains a high percentage of uric acid, in some cases exceeding that found in gout, and enduring, moreover, for a longer period. Yet no symptoms distinctive of gout appear, nothing that can be referred to uric acid. But it was contended the reason why gout does not ensue is because simultaneously with increased formation there is increased elimination of uric acid. But, unfortunately, despite augmented excretion, the percentage of uric acid in the blood is still maintained at a high level, and still no gout occurs.

Moreover, it is met with also in nephritis, simple and pernicious anæmia, intestinal inflammation, certain fevers, notably in malaria between attacks, and in typhus after the febrile stage, pneumonia, plumbism, etc. Indeed, the ubiquitousness with which uric acid is found in the blood, and this in conditions wholly distinct from gout, would of itself seem sufficient to dissipate any lingering doubts as to its being anything more than a symptom of gout and not its proximate cause.

Obviously, with these revelations the uric acid theory was within measurable distance of being uprooted. Deposed from its high[166] estate as a causal agent, and accredited with only a symptomatic value, the question arose whether indeed this bogey, “uric acid,” was even capable of fulfilling a minor rôle, of originating any symptoms, much less gout, in its entirety. In other words, is uric acid toxic or non-toxic?

Non-Toxicity of Uric Acid

The adherents of the uric acid theory did not hesitate to attribute to its toxic action, not only the severe phenomena of acute attacks, but even all the functional disorders of so-called irregular or visceral gout. By the more ardent advocates, such as Haig, we were treated to a word picture of how solid crystals of uric acid erupted out of the blood-stream, and anchoring themselves in nerve sheathes, the renal substance and the mucous membrane, gave birth to chronic neuralgias, nephritis, rhinitis, and so forth. But, alas, there is very serious doubt as to whether uric acid or the urates are capable of acting even as mechanical, much less as true toxic irritants.

Perhaps the most cogent evidence of the slight toxic effects of uric acid or urates is that derived from a study of the uric acid infarcts so frequently noted in infants dying within the first two weeks of birth. According to Gideon Wells, “little or no change occurs in the renal tubule as a result of these depositions, except such as can be attributed to their mechanical effect.” This same observer, discussing this question of the toxicity of uric acid, observes, “It may be safely stated that at the present time there exists no good evidence which makes it probable that uric acid is responsible for any pathological conditions whatever, except uric acid calculi, uric acid infarcts in the kidneys, and certain manifestations of gout.” His further conclusion is that uric acid possesses but a very slight degree of toxicity, and that an actual intoxication of the organism with this substance probably never occurs.

Again, we have the fact that in instances of malnutrition in children excess of uric acid may occasionally be found in the blood. Yet no symptoms comparable to gout occur, even though uric acid calculi form. Also, as has been pointed out, showers of uric acid may be present in their urine, and yet no symptoms arise, save those referable to mechanical irritation of the renal or vesical tissues.

Turning to experimental researches, the evidence is cumulative as to the non-toxicity of uric acid. Rabbits and dogs seem quite irresponsive, either to its ingestion in large quantities in their food, or to repeated intravenous injections of 1 or 2 grammes[167] thereof, save only that the urine showed a large increase in uric acid.

Again, Ransom, of New York, found that no systemic disturbance ensued in two cases of chronic nephritis, following the taking by the mouth of 3 grammes of uric acid per diem for three days in succession. All that resulted was a notable increase in the uric acid output. In one case, he went further, and on the fourth day administered 6 grammes, but nothing happened.

Walker Hall, with commendable devotion, took large doses of uric acid with resultant headache and malaise, which endured for some hours. But as Luff shrewdly observes, “almost any substance, however (common salt for example), will produce toxic effects if taken in very excessive quantities.” Despite his brief indisposition, Walker Hall maintains that uric acid is rather a symptom of, than the precise materies morbi in gout.

Nor, apparently, even in gouty subjects can aggravation of the condition be induced by intravenous injection of uric acid. Bass and Herzberg did so until the blood content of uric acid reached the high level of 10 mg., and yet no joint attack supervened. Neither, for that matter, has it been possible to establish any relationship between degrees of uricæmia and the incidence or severity of gouty paroxysms.

Again, taking a typical instance of acute gout in the big toe, how difficult to conceive that the same owes its origin to uric acid circulating in the blood especially when we realise that the blood content of uric acid in gout exceeds but by a few milligrammes that in normal blood. Moreover, if it does so, then why does it fail to ensue in leukæmia and in other states associated with uricæmia. Also, we like to think that the penchant of acute gout for the toe is that the circulation is inefficient at this peripheral site. But how often is the circulation all too vigorous in gout, and for that matter frequently feeble in leukæmia and in ill-nourished children. But, notwithstanding that in the two latter conditions, uricæmia exists yet, despite favouring circulatory conditions, they develop no gout.

Garrod contended that the violent pain, intense inflammation, and profound constitutional disturbance of acute gout were due to mechanical irritation occasioned by the sudden deposition of biurate crystals in the delicate interior of the implicated joint. Also, that the absence of constitutional disturbance in the inter-paroxysmal periods was because the deposition of urates, being gradual, the tissues acquired tolerance, and yet, forsooth, this same substance is held responsible for the fulminant outbreak that ensues anon.

But it is, as Ringrose Gore shrewdly observed, “against the[168] usual laws of nature that, if an irritant foreign body remains in any organ the symptoms should quickly subside, while the irritant actually increases, for after each attack, and during the intervals between the attacks, the deposits of such biurate enlarge.” In conclusion, is it not infinitely more probable, as Gore states, that the inflammatory reaction precedes the deposition of urates and that these latter, in short, are the consequence and not the cause of the gouty arthritis?

Reverting to tophi, their experimental production, it is claimed, has been achieved by His.[24] Administering alcohol to dogs and simultaneously injecting them locally with sodium mono-urate, he produced deposits which seemed identical with tophi produced spontaneously in gout. But, unfortunately, up to the present, it has been found impossible to induce their formation by flooding the circulation with urates. The utmost, indeed, that His and other workers in this sphere feel able to postulate is that uric acid is a “weak tissue poison.”[25] Scarcely the words in which to describe the poison responsible for gout! for, as we have before stated, the agent that is responsible for tophi must also be capable of inducing the arthritic phenomena and other features of the disorder.

The sum of our reflections is that the toxicity of uric acid has been grossly over-estimated, and that, like its relative urea, it is practically non-irritating and inert; in other words, it cannot any longer be regarded as the essential cause of the acute or chronic forms of gout, whether of articular or ab-articular site. Moreover, far from its presence in excess in the blood being pathognomonic of gout, it must, as Walker Hall contends, be held merely “as symptomatic of conditions which help or prevent its solubility and excretion and does not itself cause lesions which accompany uricacidæmia.”

Are the Precursors of Uric Acid Toxic?

Naturally the upholders of the uric acid theory were loth to find their fetish uric acid was allotted a meaningless rôle. That it should be deemed inert was to dislodge the very corner-stone of the imposing superstructure they had been at such pains to raise. Uric acid not responsible for the genesis of gout! But, haply, maybe their position was still unassailable; for what of the purin bases, the forerunners of uric acid? Might not the blame lie with these?

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Straightway xanthin, hypoxanthin, adenin, etc., were credited with pernicious potencies.[26] Nor did they lack apparent support from the experimental side. Thus, Mandel affirmed that purin bases, apart from infection, might originate pyrexia. Others, again, noted that in dogs and rabbits fed on adenin, degenerative changes in the kidneys ensued, with deposits resembling uric acid and urates in their substance. The fact, too, that guanin-gout was occasionally met with in swine, also lent colour to their views.

Moreover, that ingestion of these congeners of uric acid led in animals to renal lesions, seemed to support the contention of many, that renal disorder might be the primary cause of gout. But, unfortunately, Kolisch and Weintrand’s assertion that the alloxur bases were found in increased quantities in the urine of gouty patients was contradicted by Schmoll, His, Laquer, and others.

Still more cogent, apparently, the announcement in 1910, by Brugsch and Mallory, that they had seen a typical attack of gout ensue in a gouty patient in sequence to a dose of 0·5 gram of hypoxanthin. Nor did this reaction of gouty persons fail of confirmation, as in the same year, Brugsch and Schittenhelm, in gouty patients, noted attacks of arthritis, after the administration of nucleinic acid.

Nevertheless, we must beware of laying too much stress on isolated experiments of this nature, so hypersensitive are some of the victims to any strange or unaccustomed ingesta. Were all the myriad other determinants of gouty attacks eliminated, over-drinking, trauma, mental disturbances, etc.? for be it recollected, all the victims of these experiments with hypoxanthin and nucleinic acid were gouty subjects, i.e., potentially liable to attacks at any moment.

Even admitting the ingestion of, e.g., hypoxanthin was followed by a gouty outbreak, it must be insisted that mere sequence does not establish causation. Clinically, on the whole, there is little or nothing to support the contention that the purin bases have much to do with the pathogeny of gout. “The proof of the pudding is in the eating,” and contrary to the view, at one time so prevalent, that purin foodstuffs were most deleterious, it has been found that, for the average gouty person, a purin-free dietary is not only not essential, but prejudicial. Those, therefore, who may be inclined to see in the above sequence proof of a causal connection, would do well to recall Bacon’s dictum that “there is in the[170] human mind a peculiar tendency to dwell on affirmative and to overlook negative instances.”

In conclusion, we must affirm our belief that neither uric acid nor its precursors is responsible for the fever, local inflammation, and general constitutional disturbance in gout, for uric acid and the urates are themselves practically non-toxic. Albeit, though holding this view, I do not for one moment suggest that uric acid has nothing whatever to do with gout. The fact that tophi, its pathognomonic stigmata, are compounded of biurate of soda, would per se stamp such an attitude as untenable. On the other hand, uric acid must be viewed in its proper perspective as a concomitant or sequel of gout, the essential cause of which must be sought elsewhere.

With the abandonment of the uric acid theory of the causation of gout we see a reversion, curiously enough, to the hypothesis held by the ancient physicians as to its pathogeny. Like Cælius Aurelianus and Paulus Ægineta, we now incline to refer the origin of the disorder to some derangement of the gastro-intestinal tract. This conception indeed endured up to the latter half of the eighteenth century, and was definitely maintained by Van Swieten in his commentary on the aphorisms of his great preceptor, Boerhaave. For him the fons et origo mali in gout was disturbance of the functions of the alimentary tract.

The English Hippocrates, too, Sydenham, in his classic treatise observes: “The more closely I have thought upon gout, the more I have referred it to indigestion, or to the impaired concoction of matters both in the parts and juices of the body.”

Not only in regard of the initial site are we reverting to the views of old-time physicians, but the tenor of our reflections upon the nature of the disorder exhibits a like trend. Thus the older physiologists, doubtless impressed by its fulminant onset and clinical features, ranked gout amongst the fevers, describing it indeed as a “tertian fever terminating in fourteen days.”

Indeed, the great Boerhaave avowed his belief that gout was contagious—a forecast, we may take it, of the modern theory of infection. Subsequently his pupil, Van Swieten, went a step further, maintaining that sometimes wives, while nursing husbands afflicted with gout, contracted the malady!

Passing now to relatively modern times, it will be noted that in 1864 Laycock classed acute gout with rheumatic fever as an “excretory fever,” while Parkes even prior to this, in 1860, wrote: “I define gout after Garrod as a febrile infection with inflammation about the joints leading to a deposition of urate of soda.”

But it must be freely acknowledged that, subsequent to Garrod’s discovery of uric acid in the blood in gout, the spell exercised by the uric acid theory was such that it dominated medical thought almost to the exclusion of all other possibilities.[172] All energies were forthwith centred upon endless laborious researches into possible modes of uric acid formation, but which, alas, did little to purge men’s minds of their obsession that uric acid was the proximate cause of gout.

Still it would be unfair to infer that the disabilities attaching to the uric acid hypothesis were wholly unrealised. Indeed, it may be fairly said of Duckworth’s reflections on the pathogeny of gout that they definitely foreshadowed the infective theory. His views postulated what may be termed a toxic tropho-neurosis, wherewith to explain the paroxysmal nature, the periodicity and protean symptomatology of the disorder.

But in the early part of 1900 we may, I think, discern in some words of Chalmers Watson a change coming over our thoughts as to the pathology of gout, this as the result of some studies of a series of examples of acute gouty polyarthritis. The results of his researches were such that he challenged the accuracy of Garrod’s original observations as to the lowered alkalinity of the blood during acute attacks, also his claim that the uric acid content of the blood was increased and the uric acid excretion diminished during the paroxysm. If these points be accepted, he says we must start de novo in search of the cause of the acute paroxysm.

He noted also the interesting fact that during acute attacks of gout a very marked leucocytosis was present. Another outstanding feature was the presence in large numbers of peculiar myelocyte-like cells, half as many in number as the ordinary finely granular oxyphil leucocytes. Reflecting on these findings, he observes: “It would, I think, be well if much less attention were centred on the excretion of uric acid alone as the all-important factor in the disease, whether in its acute or chronic form. The results obtained by the line of investigation here followed suggest the advisability of more attention being devoted to the histo-chemical characters of the blood, the ratios of uric acid to other important products of metabolism, and, if opportunity be afforded, an examination of the bone marrow.”

To other interesting features of these researches of Watson’s we shall allude later, but, concerned here more with tracing the evolution of the infective theory of gout, we would hasten to add that in September of the same year Ringrose Gore, discussing the inadequacy of the uric acid theory, boldly avowed and ably propounded his belief in the infective origin of the disorder.

Thus he writes: “I consider a toxin to be the cause of this disease. If so, such toxin must be formed in the intestine. As the symptoms of gout are constant, it must be a definite toxin, the product of a definite bacillus acting upon the intestinal secretion.[173] As gout is capable of being caused in any subject, it must be one of the bacilli normally found in the intestinal canal.”

Nor did Gore lack supporters in his suggestion that the alimentary tract was the primary source of the changes in the metabolism of gout. For in the same year Minkowski, Le Gendre, and in this country Watson, hazarded the view that intestinal derangements, through the medium of their resultant toxins, initiate disturbances in the liver, and these in turn determine those obliquities of metabolism typical of gout.

At the same time their contentions derive colour from the researches of Grübe, who, despite traditional views, maintained that in gout the hydrochloric acid of the gastric juice, far from being increased, was in most cases diminished or wholly lacking, while, on the other hand, lactic acid was present in some instances.

In 1903 Woods-Hutchinson ably contended that “gout and lithæmia are mere symptom names for a miscellaneous group of chronic toxæmic processes of widely varied origin, characterised by the production of uric acid and the urates.” He held that the uric acid in gout as well as the associated phosphoric acid are merely a criterion of the measure to which the nucleins of the body cells (chiefly probably of leucocytes) have undergone destruction in consequence of their invasion by a toxin or toxins of organic or inorganic nature. He furthermore contended that the rôle of the liver in gout was purely negative, consisting in its inability “to absorb or transform into harmless excretory substances the excess of toxins brought to it by the portal vein.”

In 1904 Falkenstein furnished collateral evidence that the starting point of gout lay in a diseased condition of the gastric glands, those responsible for the secretion of hydrochloric acid. The supply of hydrochloric acid being deficient in the gouty, their digestive capacity is distinctly lowered. Abnormal fermentation ensues with insufficient oxidation, and “the substances containing quantities of nuclein are partly prevented from being further split up, and partly favour the synthetic formation of uric acid.” He would thus refer the excessive formation of this latter directly to the diseased glands. He further observes that, despite the deficiency of hydrochloric acid, the gastric juice is often hyperacid, this being due to the presence therein of organic acids, such as butyric, lactic, and acetic acids.

In the same year Chalmers Watson, as the outcome of investigations into gout as it occurs in the fowl, held that:—

He concludes that the last-mentioned point clearly proves that:—

He then proceeds to inquire as to the nature of the toxic principles in the blood, and the factors that influence their passage thence into the tissues. In connection with these queries he emphasises the necessity of envisaging the all-important part played by the alimentary canal, holding that herein doubtless resides the clue to the solution of the problem.

Post-mortem examination of the fowl revealed marked catarrh of ileum, duodenum and large intestine, while the pancreatic duct was filled with catarrhal products. The congested spleen, apart from proliferation of its endothelial elements, exhibited a marked increase in the number of granular leucocytes in the capillaries and sinuses as compared with the features of the control sections, which, as Chalmers Watson observes, is the characteristic reaction of this organ to invasion by bacteria or their products. The kidneys on examination revealed here and there uratic deposits surrounded by inflammatory tissue. The relationship of these to the inter-lobular arteries was such as to suggest an infection by the blood stream.

The collecting tubules in the deeper part of the cortex and medulla were markedly dilated and choked with granular leucocytes. Sections of the organs were examined bacteriologically by Muir, the necrosed areas revealing the presence of “rod-like bodies of the size of large bacilli massed together in dense clusters; the appearance suggested that these rods were either degenerated cell products of an unusual character, degenerated bacteria, or crystalline in nature.” Examination of the same by polariscope by Marshall disposed of the possibility that they were crystalline. Finally it was thought that the appearances generally favoured the view that the rods in question were bacteria which had lost their reaction to bacterial stains owing to bacteriolytic or other changes.

As to the inference that the defunct fowl fell a victim to acute gout, Watson based it on the existence of the uratic deposits in the tissues, the changes in the synovia, the widespread thromboses, and the renal necroses. As to the other lesions, the chief interest centres in those located in the intestine, pancreas and kidney. The state of the pancreatic duct raises the question as to whether it points to any connection between these changes and the common occurrence of glycosuria in gouty subjects. The alteration in the leucocytes merits notice in that similar changes were found[175] by Watson in the blood in acute gouty polyarthritis, the same, moreover, being subsequently confirmed by Bain.

Chalmers Watson’s final conclusion was that “the clinical features of gout—regular or irregular, acute or chronic—are more adequately explained by the light of our present knowledge of infections, relapses, and immunity than by any other theory. The distinctive feature of this infection in gout is that the toxin or toxins have a special property of disturbing nitrogenous metabolism in a manner favourable to the deposit of uric acid in certain tissues.”

Suggestion of a Specific Infection

It will have been noted that, despite the growing number of adherents to the infective theory, no attempt had been made to saddle any particular organism with the responsibility of initiating gout. But in 1905 Trautner, holding mucous colitis to be one of the initial manifestations of gout, affirmed his belief that the bacillus coli communis was the responsible microbic agent.

He claimed that this particular organism, during its passage through the system, gives rise to a reducing agent which is subsequently transmuted into xanthin and uric acid. This is, of course, but a variant of Gore’s original view that the toxin of gout is a product of certain bacteria normally present in the intestine, but which under certain conditions take on a pathogenic action.

The microbic theory fast gained ground. Thus Luff, who in the first edition of his work advocated the renal origin of gout, subsequently renounced the same in favour of its infective origin. To sum up, the opinion generally was that it was more than probable that gastro-intestinal derangements, with their altered secretions, exert an influence on the intestinal flora with resultant formation of toxins, and that these same, acting chiefly on the liver, put in motion those obliquities of metabolism which eventuate in gout.

Sikes, however, in 1907, discussing the rôle of gastro-intestinal disorders, expressed a doubt as to whether the same are primarily or secondarily related “to the actual chemical processes at the base of the disease.”

He thinks it at least as probable that the gastro-intestinal disorders are due to an alteration in the intestinal secretions from an internal cause as that they are due to bacteria in the formation of toxins, or, he suggests, to some alteration in the epithelial cells, so that they take up chemical compounds of different nature from the ordinary. To him it does not seem at all probable[176] that gout will ever be found affiliable to any specific micro-organism, inclining rather to the belief that a solution of the riddle will only be found in a closer and more extended study of that most difficult subject, the actual chemistry of the cell protoplasm.

“The old order changeth, giving place to new,” and the uric acid theory having failed us, it is essential that we cast round for some other solution of the problem, carrying with us, however, this guiding principle, that uric acid, having lost its etiological status, be viewed in its right perspective as not the cause, but the consequence, of gout.

Happily, with the advent of bacteriology our views, or rather our hazards, as to the nature of joint diseases underwent profound modification. But, strange to say, though quick to apprehend the significance of infection, its causal relation to other joint disorders, we still seem unaccountably loth to discard our time-worn conception of “gouty” arthritis as of purely metabolic origin. This, to my mind, is the more remarkable in that the onset, clinical phenomena, and course of acute gout, and no less the life history of the disorder as a whole, are emphatically indicative of the intrusion of an infective element in its genesis.

In developing this hypothesis I purpose devoting the present chapter to consideration of the frequency with which local foci of infection are met with in gout, the frequency, too, with which exacerbations of the disorder are presaged by acute glandular affections of undeniably infective source. The latter part of the text will concern itself with the rival claims of auto-toxæmia and infection or sub-infection. In the subsequent chapter we shall analyse critically the component elements of the acute paroxysm of gout, their compatibility or not with an infective origin. The affinities between gouty arthritis and the specific infective arthritides will then be noted, and, finally, an endeavour made to link up the specific stigmata of gout—its uratic deposits—with the postulated infective element.

Local Foci of Infection

The extreme frequency with which infective foci are met with in the victims of gout is by no means adequately realised. Moreover, we are only now beginning to appreciate the grave significance of such “nests” of infection and how devious are the ways in which they work their malign influence. For our forefathers gout began, and, forsooth, often ended, in the “stomach,” or it[178] was the “liver” that was impeached. But the portal to the alimentary canal was for them only a cavity, the contained structures of which, albeit, to their mind often betrayed evidences of a “gouty diathesis.” They distinguished “gouty” teeth, “gouty” tonsillitis, “gouty” pharyngitis, even “gouty” parotitis; but all these they classed as tokens or sequelæ of gout—not possible causes or excitants thereof.

Nevertheless, their observations on “gouty” teeth are of deep interest, though their significance was misinterpreted.

Thus, Duckworth, for example, wrote: “The tendency to shed sound teeth has been noted with some frequency in middle or later life in goutily disposed persons, and they are more than others liable to occasional and fugitive attacks of pain in several sound teeth at a time, with a sensation as if these were starting from their sockets, being tender to bite upon.” In truth, a succinct picture of pyorrhœa alveolaris, of unprejudiced source, hence the more valuable.

Garrod again tells us that he saw an initial attack of gout supervene after extraction of a tooth, a sequence attributed by him to loss of blood. How interesting this, in light of the fact that exacerbations of joint disease have frequently been seen to follow the removal of septic teeth. The same authority also noted the incidence of a primary attack of gout following epistaxis, and the same after copious hæmatemesis, and Todd several times observed such articular outbreaks after venesection.

Lastly, says Garrod, “cases illustrative of the effects of the suppression of an habitual hæmorrhoidal discharge are by no means uncommon, and ... numerous instances arising from boils and carbuncles have come under my notice.” By Garrod and his contemporaries all these various determinants of gouty paroxysms, i.e., loss of blood, etc., were believed to exert their influence viâ the nervous system, with consequent disturbed equilibrium of nutritive processes throughout the body. But while it may be admitted that depression of the vis resistantiæ plays a part, it does so, I believe, by favouring the occurrence of infection.

Let us turn now to modern findings, and we shall see that they do but confirm those of the older clinicians. Lambert in 125 cases of gout found the teeth unsound in 82 per cent. of males and 1 per cent. of females, while in 9 per cent. of the former and 17 per cent. of the latter there was associated chronic dyspepsia. Two years after (1909) Wynn, Wirgman and Turner noted the invariable correlation of gout with local foci of infection. In the majority, pyorrhœa alveolaris was present. Tonsillar sepsis, too, was not uncommon, and much more rarely nasal disorders.[179] Again, out of fifty-two examples of so-called “gouty” throat Edward McCracken found pyorrhœa alveolaris to be present in thirty-nine, and Fenner also tells us that this affection is common in the subjects of gout.

In truth, the victims of gouty arthritis are no more immune from dental lesions than those of other types of joint disease. Thus, Mr. Macdonald, dental surgeon to the Royal Mineral Water Hospital, Bath, informs me that this form of oral sepsis is extremely common in gouty individuals, and in my experience it is but rarely that evidences of its presence are not forthcoming in these subjects. The desirability of early recognition of such foci—in light of their highly probable etiological significance—can scarcely be overestimated. For their consequences, both local and remote, are of paramount importance.

Thus, G. I. Stewart’s recent observations have conclusively demonstrated that “bad teeth” are causally related to tonsillar affections. How illumining this, in view of McCracken’s experiences in “gouty throats.” As we saw, pyorrhœa alveolaris was present in more than half the examples. But, more pertinently to the point at issue, he comments on the frequency with which the victims of gout develop acute tonsillitis, of lacunar or parenchymatous type, also that such attacks frequently precede outbreaks of arthritic gout. Duckworth again noted the same liability of the gouty to unsound teeth and tonsillitis, and that the latter was often followed by articular outbreaks. Luff also observed that “gouty” tonsillitis was occasionally a precursor of articular gout, always subsiding on the appearance of the latter complication.

Again, acute and chronic pharyngitis are proverbially common in “gouty” subjects. Moreover, in both types the subsidence of the throat affection has frequently been signalised by an articular outbreak of classic site. Parotitis, too, has been repeatedly met with in gout, and, according to Luff, “rapidly subsides on the appearance of regular gout in one or more joints.”

In truth, whether we peruse recent or older works on gout, we cannot fail to remark the unanimity of opinion as to the frequency of incidence of these glandular affections—these states of oral sepsis—in the subjects of gout. Equally noteworthy is their insistence on the constancy with which such local affections have proved harbingers of oncoming articular outbreaks. Lastly, the mere fact that our forefathers dignified these local disorders with special appellations, “gouty” tonsillitis, pharyngitis, etc., is cogent proof that they regarded them as among the integral features of gout.

Now, as to the true significance of these acute glandular affections,[180] held by clinicians of repute to be of “gouty” origin. What of “gouty” tonsillitis, pharyngitis, etc.? Still more, what of our deductions regarding the relationship of these same when met with in association with other joint disorders? Do we not hold them each and all as evidences of infection—“acute rheumatism,” “gonorrhœal arthritis,” etc.?—and we may well ask, Why not in gout?

Says Duckworth, “Angina tonsillaris—very painful but not suppurating—may in the gouty suddenly yield to an acute articular attack.” Is it not here more than likely that the tonsil was the initial site or portal of infection, and the arthritis secondary thereto? Is not this same interpretation in all probability true also of all forms of “gouty” throats when followed by arthritic outbreaks?

The marvel, then, is that not only have we held, but apparently many still hold, that the tonsillitis, pharyngitis, even the gingivitis—like the subsequent articular lesions—are one and all attributable to the underlying gout. We certainly would not do so in the case of any arthritis other than “gouty,” and to my mind the time is ripe for a change of attitude. The “gouty” throats, like the “gouty” teeth, should be regarded not as symptomatic of gout, but etiologically related thereto. We should cease to talk of “gouty” throats, teeth, etc., should renounce the prefix, for there is nothing specific of gout either in the tonsillar, pharyngeal, or dental lesions. We should instead view these various local disorders in their true perspective as foci of infection, causally related to the subsequent and secondary “gouty” arthritis.

Gastro-Intestinal Disorders.—It is a matter of common experience that acute attacks of gout are often preceded by or associated with flatulence, heartburn, acidity, loss of appetite, confined bowels, scanty, high-coloured urine, and a feeling of lassitude. In short, nothing is more certain than that exacerbations or relapses very commonly follow symptoms referable to gastro-intestinal and hepatic disorders.

How well established is it that these subjects after unusual, though not necessarily excessive, indulgence at the table, almost inevitably, and sometimes almost immediately, suffer twinges in the big toe, if not frank outbreaks of gout. Such reaction seems to indicate clearly that the functional disturbances in the alimentary tract stand in some causal relation to the subsequent arthritic phenomena. The assumption gains colour, too, from the very certainty with which freedom from such gouty manifestations is attained by abstinence from, or more moderate indulgence in, articles of diet predisposing to such ebullitions.

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So much by way of prelude as to the probability—attested by clinical observation and the results of treatment—that the intestinal canal is often the source of the responsible microbe or toxin. Let us now pass to consider what factors other than an oral sepsis may favour the incidence of functional disorders of the alimentary tract.

Variations in Free HCL.—Some years ago Grübe and Falkenstein found that in gout the hydrochloric acid of the gastric juice, far from being increased, was in most cases diminished or wholly wanting.

Now, as we know, the gastric juice when of normal acidity is quite capable of dealing with moderate quantities of pathogenic bacteria. But in the presence of oral sepsis it is probable that a greater number are swallowed than can be satisfactorily coped with.

Given therefore excess of pathogenic organisms and relative insufficiency of free HCL, conditions favourable to the growth of bacteria ensue, while incidentally the chance of such reaching the intestine is materially enhanced.

When, however, the defensive barrier is wholly withdrawn, viz. when there is an absence of free HCL, then of course the necessary inhibition of microbic growth fails of achievement. Moreover, also owing to diminished acidity, ill-digested protein substances gain access to the intestine, and their subsequent putrefaction is favoured.

In opposition to the foregoing, many hold that an excess of free HCL in gout is not uncommon, and unquestionably some are thus troubled. The pernicious effects of the hyperchlorhydria are accentuated by the fact that intestinal indigestion ensues secondarily, owing to the acid chyme completely antagonising pancreatic secretion and thus impairing digestive capacity.

Intestinal rather than gastric indigestion is, I think, more typical of the gouty subject. It will be recalled that the food nucleins are unaffected by the gastric juice, and though the protein moiety is split off from the nucleinic acid by the pancreatic ferments, yet neither the poly- nor the mono-nucleotides are thereby acted upon. It is in truth the succus entericus with its nucleotidase that plays the most important digestive rôle as regards nucleins, breaking them up into nucleosides which are, to a large extent, absorbed as such.

To resume, this condition of intestinal indigestion may arise from a variety of causes: excess or deficiency of gastric juice, defective motility, and diminished secretion of intestinal juices, and in all cases improper food may determine such intestinal derangement.

The clinical features presented are very variable. It is often[182] difficult, if not impossible, on the basis purely of the subjective symptoms, to decide in any given instance how far the symptoms are referable to intestinal stasis, or to a chronic infection, with a resultant catarrhal state of the mucosa, or to both causes combined in varying proportions.

But, be the explanation what it may, in our experience the most common antecedent or concomitant of gout is intestinal dyspepsia. Its secondary consequences are far reaching, especially if the small bowel be involved, catarrh of which may lead to reduction in the secretion of bile and pancreatic juice.

How commonly in these cases do we meet with symptoms indicative of sluggishness of the hepatic functions, such as turbidity of the urine, a pale or abnormally dark colour of the alvine evacuations. Also, whatever be its true etiology, they exhibit not so uncommonly sugar in the urine, the so-called “gouty” glycosuria.

Now, as a mere glance will show, diminution and impairment of the biliary and pancreatic secretions have far-reaching consequences. Foodstuffs undergo abnormal changes, are less easily absorbed, and simultaneously chemical products are formed which irritate the intestinal mucosa. Nor do the baneful effects cease here, for, owing to the unusual nature and reaction of the intestinal content, the bacterial flora in the bowel undergo modifications.

Thus, organisms normally present only in small numbers in the small intestine find the altered medium more suitable for their growth and multiplication; while others, whose usual habitat is the large bowel, migrate upwards, and infect the ileum and duodenum, and ultimately the biliary and pancreatic passages.

In the presence of such deficiency in the intestinal juices, proteins are imperfectly digested, and putrefaction under microbic action favoured. At the same time the digestion of carbohydrates is impaired, organic acids are formed, and gases in larger amounts liberated. Ultimately, owing to absorption of these irritating products, a condition of chronic toxæmia results.

Summary

It now devolves upon us to decide whether the phenomena of gout are best explicable as the outcome of auto-intoxication, or of infection or sub-infection. The uric acid theory was in truth one of auto-toxæmia, the varied manifestations of gout being attributed to mechanical or toxic irritation by uric acid, the end-product of purin metabolism. But, as we hope to have shown conclusively, uric acid is not toxic, and per se is apparently as innocuous as those other and intermediary products of metabolism which give rise to cystinuria and alkaptonuria.

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The question then arises, Is gout haply due to a retention of other metabolites? That outbreaks of gout follow fast on the heels of dietetic irregularities is proverbially true. But there is no certain evidence that the symptoms generally ascribed to auto-toxæmia are referable to substances derived from the foodstuffs under the action of the digestive juices. Toxic as are peptones and primary proteoses when they gain direct access to the tissues, the symptoms produced in no way resemble those affiliated to alimentary toxæmia, much less those of gout. Rather, according to Adami, do they approximate to those typical of anaphylactic shock.

Normally, too, the mucous membrane proves an efficient barrier, these poisonous bodies during their passage through it being transmuted into harmless substances. Nor can we refer the symptoms of gout to a toxæmia secondary to intestinal stasis or other causes. In other words, it cannot be attributed to assumed toxic action on the part of the intermediary and terminal products of protein disintegration. For seemingly these chemical outcasts of the economy become progressively less toxic on their downward path to effete matter.

The diamines, too, produced by bacterial action on foodstuffs, are so minimal as to be negligible, while the toxicity of cholin and neurin is unestablished; and as for indol and skatol, they are with difficulty absorbed from the healthy colon. Experimental researches on carbohydrate and fatty disintegration have likewise proved sterile, while there is no evidence that the anaerobes present in the digestive tract produce ecto-toxins, or undergo lysis with release and absorption of their endo-toxins.

In short, it is but too clear from the foregoing brief résumé of recent experimental findings that, if uric acid cannot be held responsible for the causation of gout, there is no evidence likewise that the disorder owes its genesis to any other of the as yet isolated chemical products of gastro-intestinal digestive activities. Having dealt with this aspect of the question, we shall now pass on to consider whether the phenomena of gout can be more adequately explained on a basis of infection or sub-infection.

Infection or Sub-infection.—Our knowledge as to the exact manner in which local foci of infection work their malign effects almost daily undergoes expansion. It will be recalled that Stewart has shown that “bad teeth” are often etiologically responsible for tonsillar inflammation. It further is well established that streptococci are of common incidence in the tonsils, and Rosenow and Brown from experimental observation have established that these hemolysing organisms, migrating viâ the blood stream, exhibit a marked predilection for forming a fresh nidus in the gall bladder. Here they may initiate a cholecystitis, and secondly[184] gallstones, and in sequence thereto the symptoms associated with gall-bladder-dyspepsia. The same formidable list of sequels may follow infection of the gall bladder from the teeth, stomach, or intestines, notably from the vermiform appendix.

In like fashion the origin of appendicitis may be traced back to septic foci in the mouth, tonsils, naso-pharynx, or to the gastro-intestinal tract. Here again there ensue the symptoms of so-called appendix-dyspepsia. As in the case of the gall-bladder variety, the primary lesion in the appendix may be latent, and the exact diagnosis may be a matter of great difficulty, often indeed only to be achieved retrospectively, viz., when abatement of the symptoms follows ablation of the appendix.

We see, therefore, how far-reaching are the consequences of local foci of infection in the mouth or elsewhere. Now, the gouty subject enjoys no immunity from the remote sequels of local sepsis. But as a rule, unfortunately, whatever be the nature of his dyspeptic symptoms, they are, like his dental anomalies, his tonsillar inflammations, forthwith dismissed as symptomatic of gout, not etiologically related thereto.

Now, I have seen pyorrhœa and chronic appendix-dyspepsia running side by side in the same subject with recurring classical attacks of gout in the big toe. The faulty teeth were extracted, and later the chronically inflamed appendix removed; and though he had an attack of gout shortly after the operation, there has as yet been no recurrence thereof.

Again, by the older writers “gout in the liver” was most firmly believed in—as one authority puts it, “a subacute catarrh of the intrahepatic biliary system which may lead to a subacute parenchymatous hepatitis”! But more pertinent to my point is the insistence of older authors upon the frequent association of gout and gall-stones. Senac, of Vichy, claimed indeed that out of 166 cases of biliary lithiasis 95 had gout or an hereditary predisposition thereto. Judging by modern experience, this is probably a gross over-estimate. In contrast, our own countryman Murchison dwelt upon the frequency of jaundice in gout independently of biliary colic. And, as we shall see later, Brinton held that many of the dramatic phenomena accredited to “retrocedent gout” were unrecognised examples of biliary colic.

But, controversy aside, the point I would lay stress on is, that we should refrain from labelling offhand “dyspeptic” symptoms in a “gouty” subject as gouty, this when we are so constantly confronted with local foci of infection in the mouth, or elsewhere, which afford us an explanation of the gastro-intestinal symptoms at once more obvious and more rational. This also the more[185] especially in that—as far as subjective symptoms go—those deemed typical of so-called “gouty” dyspepsia are indistinguishable from those met with in appendix- or gall-bladder-dyspepsia. Indeed, I might go further and point out that the variations in free HCL in the gastric juice—as observed in gout—conform to those met with in the above disorders. Thus, in “gouty” dyspepsia, the free HCL may be normal, in excess, or wholly absent, as in gall-bladder or appendix-dyspepsia. I would therefore plead that in any “dyspepsia” arising in a genuinely gouty subject we endeavour to elucidate the exact nature of the underlying lesion, but to this we shall return again when discussing diagnosis.

Again, the fact that gall-bladder or appendix lesions may be the outcome of septic foci in the mouth enables us the more easily to explain the not infrequent co-existence of gout and glycosuria. For an infected gall-bladder may by extension determine a chronic pancreatitis.

Lastly, what of the relationship of local foci of infection to “gouty” synovitis and arthritis? Is one focal infection more than another particularly related to arthritides? Whatever be the true inference, if we take arthritides as a whole, nothing seems so efficient a cause of their production as oral sepsis. Accordingly, some are inclined to think that organisms, e.g., streptococcus viridans, at the roots of the teeth or others in the tonsillar crypts, pass, viâ the blood-stream, direct to the joints. Others, again, hold that, given oral sepsis, infection of the stomach and lower levels of the alimentary tract and its accessory cavities ensues. And in sequence thereto infection of the joints may take place from local foci throughout gastro-intestinal tracts.

Those who favour the view that direct infection viâ the blood from foci of oral sepsis is the more probable modus operandi are wont to produce the following points in support of their view. Arthritis, they say, is relatively rare in enteric fever. In yet another disorder, dysentery, which gives every chance of absorption from the intestine, arthritis when it occurs is seldom very acute, while in appendicitis it is distinctly uncommon.

On the other hand, we must recall that even in normal animals the alimentary and respiratory tracts, and alike the liver and kidneys, constantly afford cultures of pathogenic and non-pathogenic bacteria. Such was established by Adami and his co-workers, who moreover found that such organisms, through the agency of leucocytes, continually pass into the system, where subsequently in the healthy animal they as constantly undergo destruction.

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If, however, inflammatory processes are at work, their migration into the tissues is favoured. For under such conditions leucocytes aggregate at the reactive focus, and concurrently, their migration being more active, larger numbers of bacteria achieve entry into the system. The subsequent course of events is determined by the number and virulence of the organisms that effect a lodgment in the tissues, where under favourable conditions they originate other foci of infection or sub-infection.

By sub-infection is understood the fact that microbes carried into the system undergo slight, if any, numerical increase, and do not set up foci of suppuration. Here we may note that “gouty” inflammation, however intense, never ends in pus formation. But, to resume, the bacteria, instead of multiplying, undergo lysis, and, their endo-toxins being released, the more highly specialised tissue cells in the vicinity are destroyed. Coincidently the lower grade connective tissue elements are by the self-same poisons stimulated to proliferate, and an area of chronic interstitial fibrosis is formed.

Incidentally this is interesting, inasmuch as the visceral organs in gout evince a tendency to fibrosis. But, as Gideon Wells observes, “the actual increase of uric acid in the blood and tissues in gout is so slight that we are not warranted in saying that the usual tendency to sclerosis in all the organs in gout is due to the action of uric acid rather than to some other unknown agent or agents.” In view of these revelations, is it not infinitely more likely that the chronic interstitial fibroses in gout are the outcome of such sub-infection?

The assumption gathers weight in light of the experimental proof adduced by Adami that not only tubercle bacilli, but streptococci and other organisms, taken orally, can gain an entrance into the system. Upon this basis we get a clear conception of the possible relationship of gout to local foci of infection. Thus, whether it be a condition of oral sepsis—pyorrhœa alveolaris, tonsillar sepsis, sinus disease, intestinal disorders, constipation, and so forth—we see that it is highly probable that organisms at any one of such infective foci may gain access to the blood-stream with subsequent installation of local lesions in joints or other structures.

Now, as pointed out, inflammatory states or functional derangements of the alimentary tract, whether focal or diffuse, favour the ingress into the tissues of organisms. Is it not reasonable, therefore, we ask, to suppose that the functional derangements which so commonly precede or accompany gout may modify the character of the intestinal flora, and promote their migration inwards in greater numbers? The inevitable swiftness with which relapses[187] or exacerbations of this disorder follow even venial dietetic indiscretions distinctly favours this assumption, one, moreover, substantiated by the amelioration or immunity which follows abstention from the offending foodstuffs. The often prolonged course, too, of gout, and its marked liability to periodic recurrence, would be explicable as the outcome of a continued or intermittent series of sub-infections.

My conclusions then are that:—

Analysis of the Acute Paroxysm

If we reflect on the general features and local characters of an initial outbreak of gout they are precisely such as would, did they occur anywhere but at the classic site, the big toe, suggest an infection. The abrupt onset, the local signs, the crisis, and no less the subsequent swift restoration to health, how strikingly reminiscent of an exanthematous fever! Moreover, does not this outward clinical resemblance seem to predicate an inward pathological similarity? And now to scrutinise more narrowly the component elements that make up the content of a paroxysm of gout.

Its fulminant onset, with shivering, if not a definite rigor, in a person in sound and sometimes exuberant health, irresistibly reminds one of the sudden onfall of an infective disorder. Doubtless, as Duckworth says, “the conditions leading up to the attack have been some time previously in operation.” But, as he rightly contends, “some determining factor must now be invoked to explain how, as it were, the train is fired.” Quite so, and what more likely to call into the open these latent morbid potentialities than an infection?

The constitutional disturbance is often profound, certainly out of all proportion to the severity and extent of the local phenomena. Especially prominent are the nervous concomitants—the excruciating pain, the irascibility, etc. Viewing these in light of the paroxysmal nature and periodicity of gout, Duckworth postulated a kinship between the disorder and the paroxysmal neuroses. But, given an infective element, what more plausible than to attribute the nervous phenomena of gout to the simultaneous action of its toxins on the higher centres?

The temperature curve, again, is obviously compatible with this conception. It begins abruptly, its course punctuated by daily remissions. No specific peculiarities apparently differentiate it from other arthritides of established or assumed infective origin, but its relatively low grade pyrexia recalls that typical of gonococcal[189] arthritis. Its most striking feature, however, is the disproportion between the level of the pyrexia and the intensity of the general and local phenomena. Moreover, the temperature is not only low, but relatively ephemeral in duration, while the inflammatory reaction in its violence emulates that of the most sthenic forms of arthritis.

Albeit both the febrile disturbance and the local reaction display infinite grades of severity. Thus, acute gouty polyarthritis may be afebrile and the asthenic varieties of the affection marked by little inflammatory reaction. All these vagaries, however, are quite compatible with infection—the reflex, as it were, of varying degrees of toxæmia.

Says Duckworth, “The pyrexia proper to acute gout is paroxysmal with remission, and the pain of gout is likewise paroxysmal. One is reminded of the influence of marsh poison upon the nervous centres. This paroxysmal no less than periodic element in gout stamps a nervous character upon the malady and binds it in alliance with other well-recognised neuroses.”

How interesting these reflections by this distinguished physician in light of latter-day revelations! For, in so far as these features in gout are reminiscent of malaria, they disclose an affinity, not for a malady of nervous, but one of established infective, origin.

Simultaneously with the onset of pyrexia the pulse quickens. The blood shows that increase in fibrin characteristic of inflammation, a fact noted by Gulland, Cabot, Buchanan and others. But more significant is the presence of leucocytosis. It may be of high grade. In a case of acute gouty polyarthritis recently under my care the leucocyte count reached 27,000. Even in a subacute example of the classic monarticular type the leucocyte count attained 25,920. It was of leucoid type and attended by moderate anæmia due to deficiency of red corpuscles.

Nor is leucocytosis restricted to the periods of exacerbation, but it may be met with in the inter-paroxysmal stages. In my experience, even in cases of definitely chronic type it may reach 14,000. The higher grades of leucocytosis are obviously very suggestive of an infection, and that lesser degrees should be encountered in examples of definitely chronic type seems to point to gout being of the nature of a chronic or serial infection.

I would here add also that the converse of leucocytosis, viz., leucopenia, is sometimes met with in chronic cases. Dr. Munro and I have met with two instances of such in chronic gout in the intervals between paroxysms. This decrease in the number of leucocytes (leucopenia) is, of course, deeply interesting and, needless to say, quite compatible with infections, e.g., enteric,[190] malaria, tuberculosis. In fact, it suggests that gout may be the outcome of divers infections, and not due to any specific organism.

Enlargement of the lymphatic glands was, by older authors, believed not to occur in gout. But obviously the lack of macroscopic evidence does not exclude the possibility of microscopic changes in these structures. The likelihood of such, moreover, is enhanced by the occasional occurrence of lymphangitis in connection with the inflammatory articular lesions. Buzzard, indeed, long since claimed that there was “clinical evidence of subacute gouty inflammation of lymph spaces in certain regions due to uratic deposit and influence.”

As a matter of fact, enlargement of the lymphatic glands does occur. Thus, my colleague James Lindsay cites an instance thereof. The subject, a painter, fifty-three years of age, had gout of some three years’ standing. During an acute paroxysm thereof “there was a mass of glands in the right groin, synchronous with an acute inflammation affecting the right knee and periarticular tissues. On the subsidence of the gouty inflammation the glands became smaller, but never entirely disappeared during the four weeks he was subsequently under observation.”

Splenic enlargement, states Duckworth, has been met with in many cases of gout, and occasionally infarcts. But such splenic enlargement is, he thinks, not specifically related to gout, but is due to associated conditions. Personally, I have not as yet met with splenic enlargement in gout.

This aside, is it not palpably significant of infection that Paget, Garrod, and others, repeatedly noted the incidence of acute phlebitis in a limb the seat of acute articular gout? Did we observe such a complication in any arthritis other than gouty, should we not inevitably regard it as indicative of the spread of an infection from the joint to the related veins?

Reverting to the local articular phenomena, they are not only compatible with, but emphatically suggestive of, an infective source. The typical signs of inflammatory reaction are swiftly installed in acute classical gout, and this with an intensity unrivalled save by the most sthenic types of acute arthritis. Witness how insistent were our forefathers, e.g., Scudamore, on the differentiation of acute gout, not so much from acute rheumatism as from erysipelas or phlegmon. Garrod, indeed, held that “if a medical man, by chance entirely ignorant of the nature of gout, were to see a toe affected by this disease in its full intensity, swollen, hot, red, and tender, he would probably think that the affection must of necessity terminate in suppuration, yet I believe this never happens as the result of simple gouty inflammation.” This leads us to note a salient[191] feature of gouty inflammation, viz., it never results in pus formation. Now, allowing for the increased powers of discrimination that happily to-day are ours, is it not, I ask, significant that the disorders deemed most likely of confusion with acute gout belong to the frankly infective category?

That Garrod’s caveat was not uncalled for I feel sure, having myself known an acute gouty arthritis incised in the hope of evacuating pus. Sometimes the error in judgment is reversed and pyæmic or septic conditions in or near the great toe joint confounded with gout. Thus, Sir James Paget tells of an instance in which a pyæmic abscess forming near the great toe and consequent upon ligaturing of piles was thus confused. I recall, too, another example in which the supposed gouty arthritis of a great toe was of pyæmic nature, the outcome of a suppurating otitis media. Garrod, it may be recollected, ranked pyæmia as one of the disorders to which gouty subjects were especially liable.

Gouty inflammation resembles most other forms of the same morbid change, but some, however, contend that the association of œdema therewith is pathognomonic. Indeed, by some of the older authors this concomitant feature of gouty inflammation ranked as a criterion differentiating it from “true rheumatic inflammation.” Œdema, of course, is not distinctive of gouty as opposed to other forms of inflammation. But its occurrence therein is, we would submit, but another token of its affinity with the infective arthritides. We need but recall the constancy with which local œdema is met with in, e.g., gonococcal arthritis. More typical of gout, however, is the desquamation of the cuticule that follows the subsidence of the acute arthritis. Here we are reminded of the similar peeling of the skin that occurs in another infective disorder associated with arthritis, i.e., scarlatina.

Acute gout is definitely paroxysmal. The attack, at any rate when primary, is relatively ephemeral, lasts but a few days, and after it has passed, as Cullen says, “leaves the person in very perfect health, enjoying greater ease and alacrity in the functions of both body and mind than that for a long time before experienced.”

In short, acute gout would appear to be a self-delimited disease, its fleeting duration predicating that if an organism be responsible, the same is short-lived. Even in chronic gout, though it never quite loses its grip of those it has made its prey, yet nevertheless there are intervals of respite between the attacks, however long the latter may be. In other words, the disease never loses its paroxysmal character, which to my mind is very suggestive of a serial infection.

The periodicity of gout was, as we have seen, well known to the[192] ancients. Its recurrence in early spring and late autumn has even been celebrated in verse:—

Scudamore referred its prevalence at these particular seasons to their attendant vicissitudes of heat and cold (the strongest of all the exciting causes of gout). Trousseau states that “gout with successive paroxysms shows itself early or late in the year, at the beginning of spring or late autumn, the wherefore I know not.”

This tendency on the part of acute gout to seasonal rhythm is ultimately lost. For, once the disorder is established, no period of the year confers absolute immunity. Whatever be the explanation of the vernal and autumnal incidence of gout in its early stages, this peculiarity is at any rate not incompatible with its infective origin. In this connection it may be recalled that it was once described as “a tertian fever terminating in fourteen days.”

Again, further evidence may be obtained from the action of colchicum, our sheet-anchor in the treatment of gout. Thus, Dixon and Malden have shown that colchicine has no action on the metabolism of purins or on the kidney. On the other hand, it causes a primary diminution followed by a marked increase in the number of leucocytes, which suggests the possibility that it exerts its beneficial effects by combating infection.

Lastly, turning our attention to the anatomical changes as disclosed after death during an acute articular paroxysm, these present appearances quite compatible with their infective origin. Dr. Munro, in one of my examples of acute gouty polyarthritis, aspirated the knee joint. The results of cytological examination were precisely such as are deemed characteristic of arthritides of infective source.

The results of our analysis of the component elements of an acute paroxysm of gout are, for the following reasons, strongly indicative of the intrusion of an infective element:—

The Evolution and Life History of Gout

If the onset, phenomena, and course of acute gout are reminiscent of infection, so, also, does a review of the life history of the disease, as a whole, carry with it the same inference.

For the course of gout, like other arthritides of chronic type, is not one of steady, uninterrupted progress, but one marked rather by periodic or intermittent advances, as if seemingly due to a series of successive infections or sub-infections. One is reminded of gonococcal arthritis in its more severe forms, the acute exacerbations which chequer its course being generally referred to intermittent absorption of fresh doses of the toxin from some smouldering infection in the prostatic urethra.

Now, if the general course or evolution of gouty arthritis is notably similar to that of the specific infective arthritides, so, also, do the clinical features approximate. Thus its onset, more often than not, is abrupt and attended by pyrexia of irregular or septic type, with an occasional leucocytosis.

Again, that not all cases of gout are of acute fulminant type may be admitted. We know that it may assume the guise of a fleeting arthralgia or “flying gout,” a transient synovitis, as well as an acute arthritis of mono-, oligo-, or poly-articular extent. This same polymorphism in respect of the joint lesions in gout is a replica of that met with in the specific infective arthritides. The milder varieties betokened by arthralgia or synovitis tend commonly to disappear, as it were, spontaneously in precisely the same manner as the arthralgias or synovites that follow the exanthemata, and we presume that, comparably with these latter, the source of infection dries up and restitutio ad integrum of more or less completeness follows.

But with repeated attacks, as in the specific infective arthritides, progressive infiltration and thickening of ligaments, capsule, and related tendinous and aponeurotic structures ensue. As far as these anatomical changes are concerned, gouty arthritis and the specific arthritides are at one, but with this outstanding difference, the associated uratic deposition. Save in respect of this last, the analogy is complete, and herein resides the specificity of gouty arthritis.

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Chalmers Watson, from his observations of “gouty deposits” in human subjects in their relation to tendons, cartilage, and bone, came to the conclusion that the tout ensemble of the pathological lesions was very reminiscent of that typical of the more chronic types of infective disorders. Thus necrotic areas in gouty tendons stood in such clear relationship to the vascular supply as to suggest some infection viâ the blood-stream. Again, areas of erosion in the cartilage were found to be due, not to uric acid, but to the disintegrating action of small round cells of the nature of granulation tissue.

As to uratic deposits located in the bones, it was noted that their vicinity was characterised by marked vascularity, the existence of giant cells, and an accumulation of the small round cells so commonly correlated with the action of bacterial toxins.

In reviewing the foregoing clinical and pathological data and, alike, the inferences as to their significance, it cannot, we think, be gainsaid that, collectively, they are more readily explicable as being due to an infection than to any other morbid source.

Analogies between Gout and the Specific Infective Arthritides

A striking parallel can be drawn between the varied manifestations of gout and those met with in specific infections. But, to begin with, we must recall that our attitude towards infective disorders, e.g., acute rheumatism, gonorrhœa, etc., is altered in that we regard them now, not as local, but general, systemic infections.

Thus, following the revelations of bacteriologists, we now, for example, recognise that in gonococcal infection not only may there be articular involvement, but that muscular and nervous lesions may be associated therewith. This same, also, in acute articular rheumatism. True, its causal organism is still sub judice, but data accumulate as to the frequency with which the muscles are involved, and, to a less extent, the sheaths of nerves.

Take dysentery, again; it, too, as Sydenham pointed out, may be complicated, not only by arthritis, but by myalgias, while more recent experience emphasises the frequency with which neuralgias are associated therewith. In syphilis, also, the association of articular, muscular, and nerve lesions is well attested; and by French physicians it is insisted that, in tubercle, myalgias and neuralgias, as well as joint disorders, are infinitely more common than is generally realised.

To sum up, this triad of arthritic, muscular, and nerve lesions, either serially or simultaneously, is the most common complication[195] of specific infections. Now, is not this same congeries of articular, muscular, and nerve disorders precisely the clinical content of gout?

Thus its articular manifestations constitute the most striking feature of the disease. As to the muscular troubles, there is a consensus of opinion as to their relative frequency. Inflammatory foci with associated uratic deposit have been found in muscles and tendons. We may here recall that the purin bases of the body exist, not only in the bound form (nucleic acid), but also free, especially in muscular tissue, also that from such free purin bases uric acid can be as readily formed as from those liberated by disruption of nucleic acid.

Clinically, one meets with all forms of fibrositis in actual association with acute articular gout. Such may affect either the neck, shoulder, loin, or sciatic nerve. In their work on “Fibrositis,” Bassett Jones and Llewellyn have shown that the disorder develops with significant frequency in the victims of gout. This but confirms the conviction held by Gowers, Garrod, Hilton Fagge, and others, viz., that the muscular and nervous types of fibrositis are frequently and obviously related to gout.

How noteworthy the well-established proclivity of gout to involve bursæ, tendon sheaths, and fasciæ, especially the plantar! Is not this exactly paralleled in certain infections? Note the predilection of post-scarlatinal rheumatism for bursæ and tendon sheaths; that of the gonococcus for these structures as well as fasciæ, not to mention the frequency with which bursal enlargements are traceable to syphilitic, tuberculous, and other infections.

We see, therefore, that in virtue of its tendency, not only to arthritic, but also to muscular and nerve disorders, gout falls into line with the specific infections. Its predilection for bursal and fascial structures is but another evidence of affinity with this group of disorders. In view of these similitudes, one may well ask, Are not these gouty manifestations, all of them, susceptible of a like explanation, viz., that they are the outcome of an infection?

For, in reviewing the foregoing analogies, it cannot, we think, be denied that in the aggregate they are emphatically suggestive of an infective origin.

Correlation of the Metabolic Phenomena of Gout with the Postulated Infective Element

In essaying this difficult task, we must recall to the mind of the reader our findings or deductions from the data disclosed in preceding chapters.

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The outstanding conclusions that we felt justified in formulating were that:—

In other words, we suggest that, although abnormalities of metabolism form an integral part of gout, they are of themselves inadequate to achieve its efflorescence. Thus, when we came to consider the elemental manifestations of gout, i.e., uratic deposits or tophi, we saw that neither the purely physical nor the purely chemical theory of their origin would suffice, nor, for that matter, could any solution of this complex problem be gleaned from even a blend of the twain. In short, such hypotheses are too mechanical. The intrusion of some other factor, “some vital something biological,” seems essential for the elucidation of uratosis, i.e., uratic deposition. For this, not uricæmia, is the specific characteristic phenomenon of gout. If we cannot explain uratosis on physical or chemical grounds, then how much less, in view of the non-toxicity of uric acid, can we, on this basis, account for the inflammatory phenomena of the disorder?

Inflammatory reaction is, we hold, an invariable antecedent in all gouty processes, whether of articular or ab-articular site. Granted that inflammatory reaction is a necessary prelude, the specificity of gout is attested by the fact that this same is followed by the deposition of urates. But while the sequential uratic deposition invests all forms of “gouty” inflammation with a specific character, unshared by any other disease, it follows that the cause of the said inflammation must, if possible, be ascertained.

For Walker Hall “the contention that gout lowers the general tissue resistance, and so opens the way to bacterial infections, is so obvious that it need hardly be formulated.” In light of this, we need have the less diffidence in hazarding our opinion that the morbific agent responsible for “gouty” inflammation is an infection or sub-infection. Now, in all forms of arthritis other than gouty, the intrusion of a germ is held to be self-explanatory and final; in short, all the local morbid changes and constitutional disturbances are held satisfactorily accounted for by the organism or its toxins.

The problem of gout, however, is not so simple. Its arthritis is peculiar in that it is always accompanied or followed by uratic deposition, which, be it noted, is not an ordinary sequel of inflammation. It is, in short, the outcome of inflammation supervening in an individual of gouty diathesis. What do we know of this latter?

The researches of the bio-chemists reveal that uric acid is the[197] end-product of nuclein metabolism—the summation of a long chain of enzymatic reactions. Some indeed have thought to find an adequate explanation of gout in enzymatic abnormalities. Thus, Adami and McCrae suggest that gout is the outcome of insufficient oxidation, whereby the precursors of uric acid and similar bodies are not fully oxidised, and, by their accumulation and toxicity, set up morbid changes, and the uric acid formed is, in its turn, imperfectly oxidised and accumulates. This diminished oxidation is due to a constitutional deficiency of oxydases, inherited or acquired.

This opens up the old problem as to whether uric acid is an intermediary or a terminal product of metabolism. But, from evidence cited in preceding chapters, it appears probable, if not certain, that uric acid is an end-product. Moreover, as Gideon Wells observes, “the failure of recent studies on the enzymatic transformation of purins to locate anywhere in the human body an enzyme-destroying uric acid makes hazardous the attempt to explain gouty metabolism as a result of enzymatic abnormalities.”

Indeed, in view of this, as hitherto ascertained, absence of uricolytic enzymes, there can, as Wells says, “be little doubt that the fundamental reason for the existence of uric acid gout in man lies in the inability of the human organism to destroy uric acid. Consequently, inasmuch as man, unlike other mammals, cannot destroy uric acid rapidly by oxidation, he is always a potential victim of uric acid retention and deposition.”

Now we have, we hope, shown that there is no evidence that the uric acid retention in gout is due to functional inability on the part of the kidney to excrete uric acid. This being so, we have, as Von Noorden rightly says, no right to do violence to the facts by assuming that, in a case lacking any other evidence of nephritis, a condition of “latent nephritis” is the cause of the uric acid retention and deposition.

Similarly, there is at present no evidence forthcoming that the retention of uric acid is due to abnormal purin combinations in the blood. Nay, according to Wells, on the best evidence obtainable, uric acid exists in a free state in the blood, and not combined, as has been urged by many workers in this sphere.

But if the cause of uric acid retention lies neither in the kidneys nor in the blood, there must exist something abnormal in the gouty individual which renders impossible what may be termed a compensatory uric acid excretion. Now, as disclosed in the previous chapter, experimental research, in diseases other than gout, has shown that the bodily tissues have an appreciable capacity for retention of uric acid (Fine). This, moreover, gains probability from the fact that Wiechowski, in his prolonged studies as to the[198] possibility of uric acid decomposition in the human body, was never able to detect any evidence of uricolysis. Furthermore, on the clinical side, the fact that intravenous injection of uric acid does not produce a corresponding degree of uricæmia seems, as Bass and Herzberg suggest, to indicate that in gout the retention capacity of the tissues for uric acid is augmented. Lastly, in the precipitation and anchoring of urates in the tissues in gout, we have objective proof, i.e., tophi, that the uric acid is actually held in the tissues.

Does not this seem to indicate that there are peculiarities of tissue in the gouty? What, then, the subtle change that determines the retention and deposition of urates in the tissues in gout?

May we not, with Walker Hall, hazard the reflection that there may be differences between the nucleotides of normal and gouty tissues? For, doubtless, if there be peculiarities of tissue in the gouty, these will be reflected in abnormalities of tissue function and metamorphosis.

Gowlland Hopkins, discussing the metabolism of purins, holds that in gout there is some disturbance or defect in the fermentative functions of the tissues. Of a verity the range of intranuclear activities offers scope enough when we recollect that the cells of all tissues contain not only nucleinase, but also nucleotidase and nucleosidase. Even so, the resultant nucleins, the nucleotides, and nucleosides, have still further changes of deaminisation and oxidation to undergo, these carried out in the liver and elsewhere!

We may talk of defects in the enzymatic functions of the tissues, but, viewing gout clinically, and more particularly the hypersensitiveness of its victims to the most varied stimuli, dietetic and other, one inclines rather to predicate in their instance an inherent instability of nuclein metabolism. For in the gouty, as Walker Hall observes, “a slight injury or indiscretion of diet, an overloaded intestine, or increased toxicity of the intestinal flora, may be followed by a disturbance of the general nuclein metabolism, and a local reaction in certain tissues.”

With this pronouncement all clinicians will be in accord, and herein, too, we may, I think, discern how the latent tissue idiosyncrasies of the gouty are evoked, i.e., by infection; in other words, that, under the influence of these morbific agents, the innate morbid potentialities of the gouty become overt and manifest.

The exact modus operandi whereby the assumed organisms or their toxins determine the efflorescence of gout is uncertain. We know that, following the intake even of non-purin-containing foodstuffs, an increase in uric acid excretion ensues, and that the same is the outcome of the stimulation of general nuclein metabolism.[199] Is it not conceivable that the responsible toxin acts in like fashion, and haply by disturbing the orderly sequence of those exquisitely delicate enzymatic reactions which culminate in the formation of uric acid, and with which potentialities every living cell in the organism is dowered? Further than this we, pending future researches by the bio-chemists, may not go, for “the positive material is much too insufficient, and much too ambiguous.”

In conclusion, I would postulate that in gouty subjects:—

Acute Localised Gout

If we would clarify somewhat the obscurity that enshrouds the genesis of disease, our watchword must here, as in other spheres, be “Despise not the day of small things.” We know not the proximate cause of gout, it is true, nor the exact modus operandi of those agents, infective or other, which bring to fruition the latent morbid potentialities of its victims. But, even if so handicapped, we should be quick to descry those portents of the coming storm, those minor backslidings from physiological righteousness, that doubtless foreshadow the outbreak of the disorder.

For it cannot be doubted that the evil potentialities which make for gout are for long in operation before their definite installation in its chosen seat, the joints, ensues. As Trousseau puts it, “The diathesis is in action before there is time for the local affection to show itself in a precise form.” In short, given imminence of an attack, the whole system is charged with gout, or, as Sydenham laconically expressed it, “Totum corpus est podagra.”

Prodromal Symptoms

While we recognise that local inflammatory reaction in the joints is more particularly characteristic of gout, it is no less necessary that we take cognisance of the general precursory symptoms that often, if not always, usher in its onfall. Gout begins in a disorder of function.

Uncomfortable sensations may obtain days and weeks before the incidence of the fit. To old time sufferers they are sufficiently alarming. But their significance, as heralds of an initial attack, by victim and too often by physician also, is usually only appreciated when the threatened fit becomes an actuality. Speaking of premonitory phenomena in gout, Sydenham remarked, “Its only forerunner is indigestion and crudity of the stomach, of which the patient labours some weeks before,” and doubtless this is in the main true.

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As Trousseau long since observed, the patient’s appetite often becomes capricious. He likes his meat strongly spiced, and craves for acids. But his satisfaction is short-lived. For eating is followed by drowsiness, feelings of oppression and fulness, with unpleasant eructations, or more rarely definite retching. The bowels are generally costive, but in exceptional instances diarrhœa has been noted. The state of the urine is variable. Generally scanty and high-coloured, it may in some be copious and pale.

Uneasiness in the right hypochondrium and even slight swelling of the liver was noted by Trousseau and also by Scudamore. Such congestion of the portal system and hepatic enlargement may be only fugacious, but often the same is permanent, a penalty of the same cause—free living—which leads to the production of gout. For in many instances but too true is it that “for years together,” as Sydenham said, “a man has drunk and feasted, has omitted his usual exercise, has grown slow and sluggish, has been over-studious or anxious, in short, has gone wrong in some important point of life.”

But more palpable to his friends than to himself are the concomitant changes in his disposition and character. From being good-natured and easy-going he becomes morose and irritable. The irascibility of the gouty is proverbial, and the explosive mental outbursts to Duckworth appeared at times to be “a metamorphic substitution for a more overt and regular attack,” or, as Sydenham expressed it, “Non rectius podagræ quam iracundiæ paroxysmus omnis dici potest.”

Sometimes his mental vagaries are exchanged for or accompanied by neuralgia, painful cramps in the limbs, etc. In truth, the premonitory phenomena of gout are protean, inasmuch as, given any prior weakness or functional derangement of any viscus, the symptoms of oncoming gout are masked by aggravation of the same, it may be by cardiac irregularities, vesical irritability, or in an old bronchial subject by increase of cough, etc.

But it may be objected, there is nothing specific about these various functional disturbances. They are not more common in the gouty than in others. Moreover, the habits of life productive of gout favour the development of gastric and hepatic derangements. The mental irritability, the gastric disturbances, etc., may be quite as well accounted for by overeating and overdrinking as by gout.

Now, if there be nothing specific of gout in these so-called prodromata—“heartburn, acidity, flatulence, etc.”—then what is their true significance? For, obviously recognition of their true import is most essential. Now to my mind the said “dyspeptic”[202] symptoms should be regarded not as symptomatic of gout, but as etiologically related thereto.

For, though the etiology of gout is still much debated, the same obscurity will certainly not be clarified, if we merely content ourselves with dubbing such “dyspeptic” symptoms as “gouty.” On the other hand, if we, at this early stage, endeavour to elucidate the true origin of the “dyspeptic” symptoms, who will deny that this is the more rational and scientific mode of procedure? The timely elimination of septic foci in the mouth, tonsils, and naso-pharynx conjoined with modification or restriction of food intake and recognition betimes of the signs of intestinal infection and constipation would perhaps stave off or avert the threatened articular outbreak.

It has been suggested that there is some statistical evidence that “acute rheumatism” has declined in frequency since the introduction of tonsillectomy. In the same way, I cannot help thinking that the growing infrequency and attenuation of gout is in part due to increasing appreciation by the laity and the profession of the vital importance of oral hygiene and timely and radical treatment of local foci of infection. The fact that in children, victims of so-called infantile gout, the purin metabolism may show those same derangements held typical of the subjects of gout, is surely an indication that the disorder begins betimes, and that we too must not tarry if we would prevent these evil potentialities coming later to fruition.

Now, if there be nothing specific of gout in the “dyspeptic” derangements held prodromal thereof, the reader may well ask the pregnant question, Are there any symptoms or signs that will enable one to identify the victim of these minor discomforts as being “actually” or “potentially” a “gouty” subject? In attempting to answer this reasonable query one would emphasise the fact that tophi in the ears or at other sites sometimes antedate articular outbreaks.

Now given that an individual exhibits auricular tophi, one or many, can anyone deny that he is “gouty,” nay more, that he has gout, this even though he never has had, or may never have, an articular outbreak? In truth, the eruption of a tophus in the ear is as essentially a “fit of gout” as if it had occurred at the classic site, the big toe.

How vivid the light then thrown upon the import, the etiological significance, of otherwise inexplicable functional derangements! How grim the potentialities of, e.g., “dyspeptic” symptoms as revealed by detection in the subject of a tophus! Whether viewed from the diagnostic or prognostic aspect, its importance cannot be overestimated. For let us not forget that the tophus is the one[203] incontrovertible token of the “gouty diathesis.” This morbid localisation is the sole outward expression of the inward and dominant pathological trend.

The great Charcot did not despise its aid. He narrates the case of a man thirty-five years of age, a sufferer for some months from “acid dyspepsia,” in whom he predicted a fit of gout from noting an uratic concretion in one ear. Is not the moral obvious that in an individual complaining of gastric or hepatic disturbances, etc., we should, at any rate, examine the ears for tophi?

For, far more often than is currently realised, their eruption antedates the articular outbreaks.[27] Moreover, they may not be solitary, but numerous, the cutaneous gravel of older authors. In truth, these cases of tophi, uncomplicated by articular lesions, seem to merit some distinguishing term, representing as they do a purely ab-articular form of gout.[28] They constitute what might be termed primitive elemental gout, of which the subsequent articular outbreaks are but an extension, a further manifestation of the “gouty diathesis.” For it is just this same tendency to uratosis or deposition of sodium biurate, and this alone, that to our mind constitutes gout, this “primordial vice of nutrition,” not the congeries of distempers that with the passing ages have clustered around the primitive gout, well-nigh submerging its identity.

Premonitory Symptoms of Tophus Formation.—While tophi may antedate articular attacks, we do not always meet with them as mature concretions easily recognisable as such. We must have regard therefore to the symptoms and signs indicative of their impending eruption. Consequently in a patient complaining of the various functional disturbances that so frequently anticipate gout we should never dismiss as trivial any complaints of pricking or tenderness in the ears.

Sometimes the pain in the ears is acute, the tenderness such as forbids their pressure on a pillow. Graves, of Dublin, not only noted that the pain in some instances was agonising, lasting a few hours, but he himself suffered also from such attacks of auricular pain, which only disappeared when gout supervened in his fingers. I have myself frequently known the pain and soreness referred to chilblains, though later their tophaceous nature was disclosed.

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Given such auricular pain and tenderness, we should examine the pinna for small red swellings.[29] These, when definitely localised, should be punctured and the thick white fluid which exudes examined microscopically for urate of soda crystals. In some instances the creamy-like exudate does not yield a crystalline deposit, and Dr. Munro and I are inclined to believe that there is a pre-uratic stage in the evolution of tophi. We have observed this absence of crystalline deposits in apparently unmistakable tophi, as evidenced by the usual pearly white concretions in the rim of the ear. I recollect that the late Sir William Osler, when visiting our laboratory, was deeply interested in this possibility, as suggested by Dr. Munro, of a pre-uratic stage. Needless to say, all local sources of fallacy—Woolner’s tip, fibroid nodules, sebaceous cysts—were excluded, while, in the lack of crystalline proof, the evidence in favour of the associated arthritis being gouty rested on its being at the classical site, the great toe. Moreover, as an alternative explanation we have the possibility of reabsorption. We may recall Duckworth’s well-known example where a man had two attacks of gout in the right great toe joint, yet autopsy revealed no speck of uratic deposit. We know, too, that, following an acute attack, tophi may diminish in size or even disappear, while coincidently fresh tophi form at other sites.

Premonitory Articular Pains.—Again, when, in association with indigestion or other premonitory symptoms, twinges in the toe recur from time to time, especially after consuming wines or certain articles of food, these same are very suggestive of impending gout. Garrod is very definite on this point: “I have no doubt that many persons experience extremely slight attacks of gout before the development of the affection in an acute form, and several of my patients have assured me that for years before their first severe attack in the great toe they have felt slight periodic twinges. I am of opinion that when such twinges occur deposition has already taken place.”

In conclusion, we would urge that, given gastric or hepatic disturbances, etc., in a subject predisposed by heredity or habits to gout, we should note the presence or absence of the following:—

Further signs that may be sought for in cases of doubtful nature, i.e. unevidenced by tophi, would be:—

To take up the thread of our narrative regarding the prodromal symptoms which at any moment may give place to an articular outbreak. The determinants or exciting causes having been already dealt with in the section on etiology, we shall here only note those symptoms or signs that portend the imminence of the paroxysm. These are very variable. But it is suggestive if without any change in the habits the “dyspeptic” symptoms abate somewhat or disappear.

Indeed, it is well recognised that, whatever the nature of the prodromal phenomena, they all tend to cease just before the oncoming attack. Occasionally a pre-existing depression gives way to a feeling of exuberant health or well-being. We recall the instance of a celebrated physician whose lectures always just prior to an attack took on an added brilliance.

Reverting to more definite harbingers, it has been noted that the urine becomes scanty, and its content of uric acid much diminished, some three or four days before the paroxysm, though such is not invariable. Easier of note and widely recognised is the fact that in those exhibiting tophi pricking pains or tenderness are experienced at their site. Scudamore, Garrod, and Duckworth are all agreed on this point. Another sign noted by Sydenham was that the veins of the part about to be affected become engorged—a feature confirmed by Trousseau and others.[30]

The Acute Paroxysm

A brief interlude, lasting a few hours or a day, frequently intervenes between cessation of the prodromal discomforts and the onset of the attack. This delusive sense of well-being deceives none but the uninitiated, for to the old time sufferer it is but the truce before the threatened assault.[31]

Still the subject feels better and more placid than his wont, seeks his bed, and sinks to sleep (“sanus lecto somnoque committur”).[206] But suddenly, more commonly an hour or two after midnight, he awakes to a pain in the foot, usually in the ball of the great toe, though more rarely in the heel, instep, or ankle. Simultaneously he becomes chilly, shivers, or has a rigor. But as the pain, at first bearable, grows in intensity, these feelings lapse, giving way to feverish restlessness. Posture after posture is renounced, but, toss as he will, he strives in vain to find a place[207] of ease for the tortured limb. Even the pressure of the bedclothes is intolerable. But towards morning (“sub galli cantu”) the pain remits as suddenly as it began. Anon the sufferer breaks into a gentle sweat, falls asleep, and wakes to find the painful part red, swollen, tense, and shiny, surrounded with œdema and turgid veins.

The same series of events recurs, though often in mitigated form, for some days and nights. During the day his pain is lulled, but towards evening it gathers in intensity to cease or diminish towards morning. The cycle continues from eight to ten days; then pain ceases, redness fades, œdema subsides, and the inflamed cuticle peels, with itching. The temperature meanwhile has sunk to normal, the local tenderness and stiffness gradually pass off, and health is restored. “Gout is the cure of the gout,” said Mead long since, and certainly recovery from the first attack of gout is usually speedy and complete. A renewed sense of bien-être ensues, free from the discomforts that led up to the outbreak. Indeed, in exceptionally rare instances the disease seemingly exhausts itself in a single paroxysm, or decades may pass before another visitation. Sir William Roberts tells of a Yorkshire squire who sustained a classical attack in his twenty-seventh year, the next in his eighty-ninth year. Frequently a second attack may not occur for one, two, or even three years. But the tendency to recurrence usually becomes more and more pronounced as the years roll on, and eventually the gouty man resigns himself to the doleful expectation of an attack once or twice a year, during spring or fall, with some approach to periodic regularity.

Initial attacks of gout are usually monarticular, but consideration of the polyarticular variety will best be postponed until we come to consider acute gouty polyarthritis. Also we think it will be more convenient for us to defer discussion of retrocedent gout to the chapter dealing with the irregular or anomalous types of the disorder. Meanwhile we will now proceed to detailed description of the individual phenomena that make up the clinical content of acute gout.

Detailed Consideration of Phenomena

Onset.—From Sydenham’s classical account it might be inferred that the onfall of gout is always fulminant. But this is far from being the case. For I find myself in agreement with Hilton Fagge that in many, if not the majority of instances, even the initial outbreak of the disorder is installed in a far less dramatic manner. Certainly in not a few cases its manner of approach is insidious, not to say stealthy. At onset then the nature of the case is therefore frequently misinterpreted both by victim and physician. The free liver, fearing that Nemesis has overtaken him, is fertile[208] in suggestion. He has overwalked, his boot pinched him, or it is a sprain. Local appearances may be non-committal. There may be no swelling nor redness, and no access of pain at night. Still there is discomfort when he walks. The so-called sprain lingers, and one morning the great toe, instep, or ankle, is swollen, tender, flushed, and the victim’s fears and the physician’s suspicions are converted into certainty: it is gout!

Still in this matter of the onset I must not overlook the findings of my colleague James Lindsay. In 569 cases, the onset was sudden in 458, and in the remaining 111 examples gradual. It was noted that only 14·5 per cent. of the male cases were of gradual onset. But no less than 47·1 per cent. of the female cases developed after this fashion.

Again to resume, it is by no means invariably the case that the onset is nocturnal. For, as Duckworth has pointed out, many attacks begin during the day, and this is perhaps more often the case after the disorder is fully established.

Locality.—Gout in its classical form is monarticular in distribution. In 375 out of 512 initial seizures, Sir Charles Scudamore found that the metatarso-phalangeal joint of the great toe of one or other foot was the joint affected. Garrod, too, noted that, excluding the great toe, in not more than 5 per cent. were other joints implicated. As to the frequency of incidence in joints other than the big toe, opinions differ. For Scudamore it is the ankle, for Garrod the instep, and afterwards the outer side of the foot and the knee. In contrast, Hilton Fagge holds that next to the great toe gout vents its initial fury with greatest frequency upon the metacarpo-phalangeal joint of the index finger, adding, “certainly not the thumb.” Most authorities however agree that gout in its early stages rarely attacks the joints of the upper limb, and even in its most inveterate form the shoulder and hip joints are immune. Personally, I have never seen a case of gout in the shoulder or hip; such cases are usually examples of osteo-arthritis.

Exceptionally, even in first seizures, more than one joint may be affected. Thus it may migrate from one big toe to its fellow, or travelling further afield, may invade ankle, knee, wrist, or elbow, or small joints of hand. W. Gairdner held that in gout the joints of the left were more commonly attacked than those of the right limb. But James Lindsay’s figures would appear to indicate precisely the reverse, viz. a predilection for the right side of the body.

Pain.—If we may accept the lurid imagery of its victims, even the tortures of the Inquisition failed to transcend in agony the—

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Sydenham said that at its onset the pain was as that of a dislocation (ossium dislocatio). At its zenith it was as if the flesh was being gnawed, squeezed in a bootscrew, or scalded by molten lead or boiling water. Sensory perversions are superadded, and, as Ambrose Paré said, “some patients say they burn, while others complain of icy coldness.”

Its peculiarly exasperating nature is well illustrated by Hosack, an old time Professor of Medicine of New York, who thus delivered himself: “Some compare it with the gnawing of a dog, the pressure of a vice, or the pain of the actual cautery; this probably is not far from the truth, judging from the anecdote I have heard of a man subject to gout. This man falling asleep barefooted before a large fire, the fire fell, and a large coal found its way to his foot; half awake and half asleep, he cried out: ‘There’s that d——d gout again!’ He at length awoke, when he found a large coal frying his great toe. The sensation of the two evils was probably the same.”

The pain is aggravated in that frequent “startings” of the limb prevent the victim keeping the foot at rest. The slamming of a door, or the incautious shaking of the bed, so quickens its throbbing intensity as provokes a literal frenzy of rage. But fortunately it is not always so. For though the pain of gout is unquestionably severe, at times excruciating, yet it presents infinite grades of severity. Also one must recollect that but too many of its victims are already in a high state of irritability before the outbreak. Moreover, their powers of self-control are too often sapped by unbridled self-indulgence, and they have but slight reserves of patience and fortitude to draw upon.[32]

Apart from the personal factor, in subacute cases the pain is notably less severe than in the acute sthenic form. The pain of gout, as a rule, is more intense than that of acute rheumatism, and, I fancy, than that of all other varieties of acute arthritis.[33] Sir Thomas Watson in his fascinating lectures tells of a witty Frenchman who, comparing acute gout and acute rheumatism in respect of pain intensity, remarked: “Screw up the vice as tightly as possible, you have rheumatism; give it another turn, and that is gout.”

Lastly, in respect of the duration of the pain, it is not always true that it wholly intermits at the approach of dawn. It does so frequently, it is true, but in some instances pain, more or less severe, continues during the day as well as the night. Occasionally,[210] on a crescendo scale, it continues increasing almost up to the crisis. Generally speaking, too, the shorter the duration of the paroxysm the more intense the pain, and the more prolonged the less the degree of suffering.

Following the crisis, the pain gradually becomes less and less, giving place to a feeling of numbness of the toe, which in older subjects may endure for some days.

General Phenomena.—Symptoms, other than those referable to the affected part, vary widely in different cases. In this respect the acute sthenic forms contrast with the acute asthenic types. In the former the pulse quickens; the temperature rises, but rarely exceeds 101°-102°, though Garrod saw it reach 104°. The tongue is furred, the breath foul, with anorexia and thirst. Though the appetite is frequently impaired or lost, yet in some instances it is retained. Dyspeptic symptoms, hiccough, eructations, etc., are sometimes prominent, but often wholly lacking. The bowels are constipated, as a rule, the stools pale, or dark and extremely offensive. The urine is generally scanty, high-coloured, with a lateritious sediment on cooling. It may contain a trace of albumen. Severe cramps affecting muscles of the leg, thigh, and upper parts of the body, are more or less prominent symptoms in a considerable number of instances.

The pyrexia appears to be symptomatic, more or less in proportion to the acuteness of the local phenomena. Comparably the highest temperatures are usually met with in sthenic forms in relatively young or robust middle-aged subjects. Duckworth noted the interesting point that “a preliminary rise is commonly noted for one, two, three or four days before a joint is actively involved.” With the articular outbreak the febrile movement becomes more active. The temperature runs up to 100° or over, but with the morning abatement sinks to normal or nearly so. The following evening it rises again frequently to a higher level, 102° with a morning remission, and so it continues for a variable number of days, it may be only two or eight to ten. It then subsides, and frequently for a few days remains sub-normal. Lastly, the acute asthenic forms, that occur often in women (Garrod), may be wholly afebrile.

Changes in the Blood.—Apart from its increased content of uric acid, further morbid changes take place in the blood in gout.

Neusser in 1894 described what he termed “perinuclear basophilic granules” over and about the nuclei of the leucocytes in the blood of gouty patients. He held that the dark granules constituted the mother substance from which uric acid was derived, and that their presence in the blood was distinctive of the “gouty diathesis.” Subsequent researches, however, by Futcher and[211] others appear to have shown the absence of any interrelationship between the amount of these granules and uric acid elimination, though Neusser claimed that cases showing them excreted uric acid in excess.

More significant, however, is it that the blood in acute gout may show a high grade leucocytosis with secondary anæmia.

In a case under my care of acute gout at classic site, though by no means of unusual severity, the following was the content of the blood picture:—

Uric Acid Excretion.—If when on a purin-free diet a gouty subject develops a paroxysm, the curve of uric acid excretion in the urine is so characteristic as to be almost pathognomonic of the disorder. As His pointed out, immediately before the onset of the paroxysm the endogenous uric acid sinks to a lower level (termed by Umber the anacritical stage of depression). With the onset of the attack the uric acid content of the urine quickly increases, to reach its zenith on the second or third day. F. Pfeiffer, who first noted this point, termed it an uric acid wave. Subsequently, with the gradual subsidence of the paroxysm, it again drops into what Umber termed the post-critical stage of depression. While this curve of endogenous purin excretion may be modified by oft recurring exacerbations, still Umber holds that nevertheless it is of decided value in differential diagnosis.

Local Phenomena.—The site and character of the pain having been dealt with, we now pass on to consider the objective changes in the affected part. The local engorgement of veins that precedes the articular outbreak becomes more pronounced, extending from the vicinity of the painful joint as far as the leg. The overlying[212] skin of the joint quickly becomes red and tumid. It is not a bright, but a dark red, the superjacent skin taking on a shining smoothness that has been compared to the peel of an onion. Indeed, in its more violent form it resembles but too closely the ordinary appearance of an abscess, over which the skin is becoming thin. The redness is not strictly confined to the surface of the joint, but spreads a little beyond, and where it ceases œdema is perceptible.

The redness in its intensity attains its zenith in from twenty-four to forty-eight hours, and then in hue becomes more violaceous. On the other hand, the œdema may go on increasing for some days. At first, owing to tension, the presence of œdema may not readily be elicited. But with the subsidence of inflammation the swollen parts readily pit on pressure. It is scarcely possible to detect intra-articular effusion unless it be the ankle joint that is involved.

According to Duckworth, in the more sthenic forms there may be local ecchymoses. With the crisis the redness, œdema, and venous turgescence die down. The previously distended skin becomes wrinkled, and with complete subsidence of inflammation desquamation ensues. This process is generally attended with troublesome itching. It is most noticeable about the feet and hands, but more rare at other sites. Scudamore said that in seventy-eight out of 234 cases no peeling occurred, but, as Garrod observed, it may readily be overlooked unless especially sought for.

The exquisite sensitiveness of the parts, as before noted, gives way to numbness. The diminished sensibility, coupled with stiffness of the joint, renders walking difficult for some days, and, indeed, a month or more may elapse before the joint, even in favourable cases, recovers its customary mobility.

In acute asthenic forms great contrasts appear. Pain and tenderness in the toe may be moderate, but there may be little local heat or redness and no pyrexia. But œdema is generally in evidence, and the usual desquamation of skin follows.

Tophus Formation.—To the local changes that mark their eruption at ab-articular sites we have already alluded. Here we would only reiterate that their formation follows the local joint inflammation. Consequently if a few days after the attack local pain or tenderness, with or without swelling in the vicinity of the joint, should be complained of, it should not be dismissed as of no account, but the affected parts should be scrutinised carefully and, where possible, at short intervals. This in the interests of diagnosis of a joint affection which may at the time have been of doubtful nature, more especially if the primary attack occur elsewhere than at the classical site. Some observations of[213] Trousseau are well worth quotation: “Physicians who have watched the progress of the evolution of tophus believe that it is formed during the paroxysm of gout. They are mistaken: the deposit appears during the interval between attacks, or at least when the attacks have not been of long duration, and when they do not recur in such rapid succession as to run into one another, in which cases their secretion has commenced during the preceding and continued during the succeeding attack.”

Acute Generalised Gout

While gout may throughout its life history confine its ravages to the foot, if not solely to the toe joints, it may, even in the initial attack, involve many articulations. Such cases usually, if not always, occur in persons of marked gouty heredity. In its simplest forms the orthodox monarticular seizure is simply exchanged for a sequential implication of each big toe joint. If so, as Trousseau pointed out, the joint that is the last to be involved is least affected, and the soonest to get well again, while the accompanying œdema is of shorter duration. But in more severe cases not only the big toe, but the tarsal joints, the knee and the hand, may be invaded in the first attack. Occasionally, too, the disorder displays concomitantly its tendency to involve other structures, tendons and aponeuroses, e.g., the tendo Achillis, plantar fascia. Such widespread initial involvement is usually preceded by prodromal phenomena of unusual severity and prolonged duration. These initial attacks of polyarticular distribution are extremely rare.

Far more commonly acute gouty polyarthritis supervenes after several attacks of classic location have been suffered. The gouty inflammation in these cases invades the joints after a serial fashion. But each joint as it becomes involved goes through the same painful cycle. Thus, for five or six days the pain goes on increasing, then abates, and finally the wished-for crisis comes. So it happens that the gout may be raging simultaneously in several articulations, though in each at different stages of evolution. Consequently the symptoms do not pursue an even tenor, but are made up rather of a series of little attacks—series et catena paroxysmulorum, to invoke Sydenham’s expression.

Frequently periods of apparent recovery take place. The temperature remains normal for some days, and welcome convalescence seems established, when, to the victim’s despair, the temperature again rises, and the same weary cycle, though perhaps shorter, is yet to be endured. Running this chequered career, the disorder may last for six weeks or two or three months.

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In such attacks not only the feet, knees, hands, and elbows, may be promiscuously involved, but often also the ligaments, bursæ, tendon sheaths, and aponeuroses. The suddenness with which the disorder shifts its seat from one joint to another, or from joints to bursæ or muscles, often leads to its confusion with acute rheumatism. In other words, that fixity distinctive of gout in its monarticular forms is here exchanged for mobility, that specific quality of acute rheumatism.

Naturally, the implication of so many varied structures casts its impress on the clinical picture, inasmuch as the physical characters vary with the different textures involved, their capacity for inflammatory distension, etc. On the dorsum of the hand and foot redness and œdema will be prominent, and Scudamore noted that the flush might be widely diffused, simulating erysipelas, with here and there small ecchymoses.

When structures more deeply placed, i.e., tendon sheaths at ankle, knee, and wrist, are singled out for attack, swelling is less marked and redness of the skin more patchy in distribution. The bursæ at the elbow or back of the knee may swell with extraordinary rapidity. The parts become exquisitely tender and painful, while the overlying skin takes on an angry blush. They may subside, but more often continue permanently enlarged, defiant of reduction.

Involvement of the olecranon bursa is very typical of gout. Pratt, of Boston (1916), tells of a case in which the subject had during twenty-seven years suffered from recurring attacks of acute gouty polyarthritis. The eight or ten physicians who had treated him had all regarded the disease as rheumatic fever. Pratt himself observes: “I did not feel sure of the diagnosis until I saw the swelling on his elbow, which presented the typical picture of a chronic gouty olecranon bursitis.”[34] Occasionally the bursæ when filled with uratic deposit undergo suppuration following injuries. The bursa in connection with the great toe frequently becomes acutely inflamed, and Scudamore in a gouty hand saw an old ganglion take on the same inflammatory reaction.

The tendon sheaths when involved lead to great disablement, as even the most tentative attempts at movement give rise to sudden and agonising cramp. The tendo Achillis is a favourite site, or the tendons of the wrist, or the ligament of the patella. The same is true of the aponeuroses, the predilection being for the lumbar or gluteal fascia, in which instance it may extend to the sheath of the sciatic nerve. These extensions of gout to[216] tendon and nerve sheaths frequently outlast the articular lesions, and may become the dominant element in the clinical picture.

Naturally, when not only joints, but bursæ and other structures, are involved and implicate both upper and lower limbs, the victim presents a pitiful spectacle, one of almost complete helplessness. Œdema and general venous turgescence may be very pronounced in one or more members, giving a subjective sensation of almost overwhelming weight in the limb.

Reverting to the constitutional symptoms, the outstanding feature is that, notwithstanding the widespread involvement of joints with manifest local inflammatory reaction, the pyrexia is of moderate grade, and so frequently, indeed, is it afebrile that this peculiarity is of diagnostic significance.

Changes in the Blood.—The findings are extremely interesting in view of the high grades of leucocytosis to be met with both in pyrexial and apyrexial examples.

In a case of acute gouty polyarthritis under my care the blood picture was a very striking one. The patient had suffered from gout for some eleven years, with recurrent acute exacerbations. There was widespread involvement of the joints both in upper and lower limbs. On the dorsum of the mid-phalangeal joints small semi-solid swellings were present, the exact nature of which was somewhat puzzling. But inasmuch as the pinna in both ears was studded with tophi, this seemed to provide a clue. The auricular tophi were verified microscopically. The extra-articular phalangeal swellings were then aspirated with a hypodermic syringe. A turbid straw-coloured fluid issued, which microscopically was found to contain biurate crystals. His temperature rose nightly from 101° up to 102° F., with morning remissions. The left knee and wrist were the seat of effusion, and some of the small finger joints were inflamed.

Blood Count.

Differential Count.

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The left knee joint was aspirated by Dr. Munro. A clear fluid of straw yellow tint was withdrawn, which yielded some fibrin on standing. The cytological examination gave the following results:—

Total Count.

Differential Count.

Attempts at culture on broth and agar proved sterile. In addition three separate blood cultures, taken at intervals of a few days, on agar slopes and broth, all gave negative results.

In another instance of polyarticular distribution the subject was seen during the inter-paroxysmal period. He displayed auricular tophi, the crystalline content of which was verified microscopically.

Blood Count.

Differential Count.

Chalmers Watson some years previously investigated the blood in cases of acute gouty polyarthritis both during an exacerbation and in the inter-paroxysmal period. His findings were as follows:—

During the attack the films showed very marked leucocytosis. Also there was present a large number of peculiar myelocyte-like cells, these more than half as numerous as the ordinary finely granular oxyphil leucocytes.

Shortly after Chalmers Watson, Bain published his results of blood examination in acute gouty polyarthritis. He also noted the presence of a distinct leucocytosis. A differential count disclosed a marked increase of the eosinophil cells, and he adds: “There was present a moderate number of the peculiar myelocyte-like cells originally described by Chalmers Watson.”

Dr. Munro, though he carefully examined the gouty blood films to this end, was unable to identify the myelocyte-like cells noted by these observers.

Recently, through the kindness of my colleague Dr. Waterhouse, Dr. Munro and I had again an opportunity of examining the blood in a case of this kind during the inter-paroxysmal period. The subject, a male, had had repeated attacks at the classic site, with subsequent extension to other joints. Multiple tophi were present in both ears, and the crystals of uric acid were demonstrated microscopically.

Blood Count.

Differential Count.

The blood picture, it will be seen, is one of erythræmia—a marked leucocytosis, a normal differential percentage count, pronounced secondary anæmia.

Da Costa also notes, in a case of gout, erythræmia (7,125,000) with a leucocyte count of 14,000. Ewing, too, records an instance[219] of chronic gout with huge tophi, seen in an acute exacerbation, in which the blood gave a leucocyte count of 21,000 with 70 per cent. hæmoglobin. In another severe instance of subacute type the same observer again met with leucocytosis (15,000).

In regard to these interesting blood findings, it is to be cordially hoped that as the somewhat rare opportunities occur they will be taken full advantage of.

As to the other general clinical features the nervous system, as might be expected, is often greatly perturbed, and the mental distress and anxiety in some instances appear to cause even more irritation than the bodily pain. Febrile movement when present accords with that observed in monarticular sites, save only in the tendency to relapses. Sweating is not a common feature, as in acute rheumatism. Neither does acute endocarditis occur in gout. On the other hand, as this acute polyarticular form may recur throughout years, it may in its later stages be complicated by nephritis.

Furthermore, in its differentiation from acute rheumatism the more advanced age of the sufferer, always over thirty-five and more often nearer fifty or over, will be of help. The presence of an hereditary taint, the nature of the occupation and personal habits, and more pertinently the history of a classical attack in the great toe, may give a clue.

But in this, as in all other varieties of gouty arthritis, the one and only unequivocal objective proof of the nature of the disorder is the presence of tophi. Lamentable indeed is the frequency with which this fact is forgotten, to our confounding and the patient’s detriment. As Hilton Fagge, discussing the diagnosis of gout, long since observed: “All those parts which are apt to be the seat of tophi should be examined. If a single deposit of urate of soda can be found it settles the question.”

In conclusion, before passing to consideration of chronic articular gout, it will be convenient here to discuss certain concomitant phenomena of the acute types. We refer to the muscular and nerve forms of fibrositis, which, we hasten to add, are of common occurrence also in the chronic types of articular gout.

Collateral Phenomena of Gout

The liability of acute articular gout to be complicated by muscular and nerve disorders has already been briefly alluded to. Also it was pointed out that in respect of this tendency gout displayed an analogy with the specific infections, viz., in that these latter too are prone not only to arthritic, but to muscular and nerve, lesions also.

Our forefathers, greatly exercised by this apparent overlapping[220] of “gout” and “rheumatism,” in their efforts at discrimination drew fanciful contrasts between the subjective sensations produced by gout and rheumatism, but all to no end, for said Heberden, “It must be owned that there are cases in which the criteria of both are so blended together that it is not easy to determine whether the pain be gout or rheumatism.”

Gradually, however, a change in attitude made itself felt. It became no longer customary to regard such examples as blends of gout and “rheumatism,” but to hold the muscular and nerve disorders as also attributable to the underlying gout. Thus, so impressed was Garrod with the frequency of the incidence of lumbago and sciatica in gouty subjects that he was doubtful as to whether they ought to have been classed by him as among the “diseases to which gouty persons are particularly liable.” He thought “they might perhaps have been properly classed among the forms of irregular gout.”

Duckworth, again, felt sure “that much so-called ‘muscular’ rheumatism is really gouty,” and forthwith ranked its manifestations among the irregular forms of gout. Hilton Fagge was likewise convinced that the muscular types of fibrositis are frequently and obviously related to gout; while Sir William Gowers, discussing this same muscular fibrositis, is even more explicit: “It is currently associated with gout, and the truth of the belief is soon impressed upon the practitioner. But it is gout with a difference: it may occur in those who are gouty in the common sense of the word, but some of the most severe cases I have seen, especially the brachial form, have been in those who have inherited a tendency to gout, but have not merited its development.”

Turning to the nerve manifestations, Charcot long since pointed out that gout and sciatica might co-exist, while Gowers is insistent that “underlying most cases of sciatica is either the state of definite gout, or that ‘rheumatic diathesis’ in which the fibrous tissues suffer, especially those that are connected with the muscles, a form closely connected with common gout by co-existence or descent.”

As to my own opinion, I have, in collaboration with Bassett Jones, discussed in detail this relationship of gout to fibrositis in our monograph on the latter disorder, and I shall largely transcribe our remarks therein on this vexed point.

Of all the conditions reputed to be etiologically related to fibrositis, in none of them is the connection more obvious or more easily traceable than between this affection and gout. Whether or no the hyperplasia of the connective tissues be directly due to the gouty toxin must perforce for the present remain uncertain. But there is no doubt as to the relatively frequent incidence of[221] fibrositis in “gouty” subjects. It is as true to-day as when Scudamore wrote it that occasionally “a patient when he has gout in the regular situations suffers, in consequence of some partial exposure to cold, a rheumatism in other parts, as in the muscles of the neck, or in the shoulder joints; and a seizure of lumbago at the time of the invasion of the gout is also not uncommon.”

Apart from the simultaneous incidence of gout and fibrositis in the same subject, it is equally certain that the victims of a “gouty” heritage are unusually prone to develop fibrositis.

Thus, in a series of 1,000 cases hereditary or acquired gout was present in no less than 281—viz., a percentage incidence of 28·1. While this taint was more in evidence in fibrositis of the joints, it obtained appreciably in regard to all muscular types of the affection, more especially lumbago, its influence also being very obvious in the case of sciatica and other types of nerve sheath involvement.

In light of this, we must admit being somewhat nonplussed by those who confidently affirm that “gout” plays little or no part in the production of “fibrositis.” Speaking from an extensive experience, we confidently believe the reverse is the case, and that the gouty element is but too frequently overlooked in examples of this affection.

Approaching another aspect of this vexed question of the relationship of gout, what of the ambiguous attitude of those who, while denying it any share in the causation of lumbago and other types of muscular fibrositis, yet at the same time attribute to gout an important etiological rôle in the allied conditions sciatica and brachialgia?

Thus, they maintain that the fleeting attacks of lumbar fibrositis or lumbago which ensue after dietetic indiscretions have no relation to gout, but are simply indicative of some digestive disability on the part of the individual for certain articles of diet. Hardly to our mind a satisfactory mode of differentiation; much less can it be held to put out of court the influence of gout. For are not the gouty precisely the very persons who display this inability to cope satisfactorily with unusual or excessive meals? Hence the frequency with which in their instance attacks of lumbar fibrositis, often transient, almost invariably ensue when any unwonted excess of purin-containing food has to be disposed of, and especially when at the same time katabolic changes have been stimulated in the body by the ingestion of alcohol, not necessarily excessive in amount.

That the lumbar regions should have been singled out is the more remarkable, for, if there be one form of fibrositis more than another prone to be associated with gout, it is precisely lumbago.

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Our difficulty, moreover, in appreciating the cogency of this plea for excluding the influence of gout in muscular fibrositis is the more accentuated in that those who advocate it claim that this very gout is the salient etiological factor in sciatica and brachialgia.

This position is untenable, and for the following reasons: the pathological lesion in both instances is the same—viz., fibrositis; in lumbago and deltoid rheumatism it implicates the sheaths and interstitial tissues of the muscles, in sciatica and brachialgia the similar investments of the nerves.

Strictly speaking, therefore, any differentiation that we can effect between muscular and neuralgic types of fibrositis is perforce merely topographical. To draw etiological distinctions is well-nigh impossible, for the very continuity of the fibrous tissues favours the passage of one type into the other. Hence clinically we find that the bulk of our cases of sciatica are preceded by lumbago, and similarly many cases of brachial neuralgia or neuritis develop by extension out of a pre-existing deltoid fibrositis.

In light of such transitions of muscular into neuralgic types of fibrositis, it seems inconsistent to postulate a gouty origin for the latter and at the same time to deny it any share in the production of the former. For ourselves, we fully recognise gout as the most potent predisposing factor in sciatica and brachialgia, and ergo in the closely associated and often antecedent muscular types of fibrositis.

While insisting on the importance of gout as a predisposing factor in fibrositis, we feel called upon to emphasise the fact that we are not sheltering ourselves under that nebulous term “latent” gout, for our contention is based on the ground that in the vast majority of the cases for which we claim a gouty origin unequivocal proofs of gout, such as tophi, etc., were present.

Incidence of Gouty Stigmata in Various Types of Fibrositis

Out of 343 instances of fibrositis of the joints such stigmata of gout were present in 118 males and nine females. Of muscular types, taking as our example lumbago, we find that out of twenty-seven examples no less than ten displayed definite evidences of a gouty taint. Similarly, out of thirty-eight cases of lumbago complicated by other manifestations of fibrositis eleven males and one female were of gouty habit. Also in twenty-three cases of lumbago associated with arthritic fibrositis six males, but no females, displayed the same[223] proclivity. Lastly, out of thirty-eight cases of lumbago complicated by right or left sciatica ten were of the same diathesis.

Passing in turn to consider this same factor in relation to sciatica, we note that out of 142 examples twenty-four men and three women were gouty. Occasionally, too, apart from glycosuria, it appears to be responsible for bilateral sciatic pains, for in three examples of this nature gout was present.

James Taylor is also very definite on this point, that, glycosuria aside, affections of individual peripheral nerves occur frequently in the gouty. There is little doubt, he says, that sciatica is “frequently present in the gouty and is sometimes directly due to that state.” While admitting that in many, if not most, cases of sciatica there are associated arthritic changes in the hip joint, he yet affirms his belief that “there are some in which the neuritis is a primary condition.”

With this statement my own experience accords, but with a reservation, viz., that the sciatic neuritis is apparently secondary to a lumbar or gluteal fibrositis, with sequential involvement of the sciatic nerve sheath and extension to the nerve trunk.

Taylor holds also that anterior crural and brachial neuritis may be directly due to gout. As to brachial neuritis, he says: “I have known it occur apart from any recognisable arthritic change in a patient who was the subject of gout.”

Having regard to the flippant manner in which the term “neuritis” is but too frequently bandied about, it is refreshing to note that in all Dr. Taylor’s cases “the existence of the neuritis” was shown “by the tenderness of the nerve trunks, the spontaneous, often severe, pain, and atrophic changes both in the skin and the muscles—the glossy skin and atrophied muscles.”

As for the involvement of other nerves, trigeminal neuralgia is held to be the most common; but, for myself, I have never felt justified in claiming any such example as gouty. Nor am I satisfied that persons of gouty habit are more prone than others to attacks of migraine.

Lastly, I cannot confirm out of my own experience Duckworth’s statement that “herpetic attacks in all varieties of ‘gout’ are common.” Nor have I seen shingles co-exist with acute gout, neither have I come across any examples of so-called gouty spinal meningitis!

In conclusion, I would submit that:—

In regard of this last postulate, it is well known that gouty persons who contract gonorrhœa are more prone than the non-gouty to develop gonorrhœal rheumatism, in other words, to sustain a widespread infection involving the fibrous tissues, not only of the joints, but of the muscles and even of the nerve sheaths. With this concrete example to hand, is it not reasonable to suppose that such a constitutional taint will favour the incidence also of other infections or sub-infections, and that this may explain the relative frequency of fibrositis, not only in the actually gouty, but in those of gouty heritage, this the more cogently having regard to the fact that so much exact evidence is forthcoming in favour of local infection as the cause of all types of fibrositis?

Chronic Articular Gout

In delineating the features of the acute polyarticular variety, we have to a certain extent trenched on the clinical territory of the chronic form; this is scarcely avoidable, inasmuch as the line drawn between acute and chronic gout is purely arbitrary. Thus one authority remarks of acute gout: “If the disease continue beyond three or four weeks, it is to be considered as persistent or chronic” (Flint). Trousseau, again, discussing the acute variety, more particularly the acute polyarticular type, states that it “may last for some weeks, or even for three months,” adding: “Should it extend beyond that period, it is no longer acute gout; it is chronic gout.”

The truth is that articular gout in this respect is very prone to vagaries. Thus, in rare instances an attack of acute or sub-acute gout, more particularly the latter, may merge without break into the chronic form of the disease.[35] Far more commonly the tragedy is more slowly played out. The unfortunate victim, after passing through several more or less classical attacks, finds that the intervals become shorter and shorter until they merge, as it were, one into the other. Fortunately its course is not one of continuous uniform severity. Remissions, but not complete intermissions, occur, and every now and again intercurrent acute attacks take place.

But, the reader may observe, surely this is very reminiscent of acute gouty polyarthritis, with its serial content of acute paroxysms?[36] Quite so; but there is this difference, that, although such may last six weeks or three months, still there is a period put to the sufferings. A respite of months or years of immunity, and relative health may then supervene.

Not so, unfortunately, when such paroxysmal waves sweep over the subject of long-standing or chronic gout. Not only do the[226] recurrent acute outbreaks occur with increasing frequency, but also with increasing length of duration. It is here no longer a question of the intercurrent acute attack lasting days, but weeks. Also during such exacerbations either four, five, or six joints are simultaneously attacked, or in such rapid sequence that before one joint is free another is involved.

But a word here as to the variations in distribution of the articular lesions in chronic gout. The well-marked penchant of acute gout for the great toe continues throughout the life history of the disorder, the predilection for this site being equally a characteristic of the chronic type. As to the subsequent articular involvement, Garrod held the sequence to be as follows: heels; ankles; knees; the smaller articulations of the hands; lastly, the shoulders and hips. It has never been my lot to see either the shoulders or hips involved; but I have seen osteo-arthritis of the hip in men displaying auricular tophi, and I am inclined to think that, in the presence of the latter, it has sometimes been assumed that the hip mischief was of gouty nature—the “hip gout” of the older authors.

Moreover, the order of sequence is by no means invariable, for oftentimes a local circumstance, i.e., injury or sprain, determines the location. Again, chronic gout is very erratic in respect of the number of joints implicated. In some almost all the joints may be affected, while in others, no matter how ancient the disorder and how oft its recurrence, it remains localised to but a few joints; or it may progress after a leisurely fashion, with each attack invading different joints in succession.

Naturally, if the disorder confine itself to a few joints, and these, and these alone, are the seat of the oft-recurring attacks, permanent changes sooner or later make their appearance. Nor are the morbid effects limited to the joints, but they invade the continuity of the limb, for the oft-repeated inflammatory reactions lead to engorgements of persistent nature. The contour of the affected members is distorted by the œdematous tumefaction, which, more pronounced at the level of the joints, extends in lesser degree beyond their confines. The skin, too, especially over the fingers, undergoes a change in texture, often becomes smooth and glossy, and through its dusky pink subjacent uratic deposits may be discerned.

Old gouty subjects are often of sallow or parchment-like complexion. The blood in these cases of polyarticular gout conforms in attenuated degree, in the matter of leucocytosis and secondary anæmia, to that observed in the more acute types, as witness the following blood pictures.

All were males, the subjects of chronic articular gout of many[227] years’ standing. They all exhibited tophi, which were verified microscopically. The examinations were conducted during the inter-paroxysmal periods.

(1) Blood Count.

Differential Count.

(2) Blood Count.

Differential Count.

(3) Blood Count.

Differential Count.

In these chronic forms, save during exacerbations, there may be little or no febrile movement, and local pain, heat, and redness may be slight or wholly lacking. But the articular swellings never wholly disappear, and the mobility of the joints is never entirely regained. The articulations, few or many, become stiff, ankylosed, and deformed, by the growth of tophaceous deposits. But to detailed description of these latter we shall return later.

In inveterate cases of this nature the victim grows more and more crippled and infirm, the inroads of the disease upon the constitution more and more palpable. Pelion is heaped upon[228] Ossa, as one ailment sets in after another, now of the digestive organs, now of the heart, or of the kidneys. These subjects of chronic gout are more often than not dyspeptic, show signs of arterio-sclerosis. Their blood pressure is raised, their vessels tortuous and thickened, and the left ventricle enlarged.

As to the variations in uric acid excretion, these, as before remarked, show no appreciable deviation from normal. Occasionally, however, there is a tendency to uric acid gravel. Of more sinister significance, albeit, is the fact that in many of these cases the urine is copious, of low density, paler than normal, and shows a trace of albumen with hyaline casts.

As the disease marches to its fell end the appetite becomes impaired, gastric catarrh and diarrhœa may sap the waning strength, or palpitations, fits of dyspnœa, or angina-like attacks, sometimes fleeting, but often of organic source, may portend a fatal issue. Ripe for the sickle, a kindly “stroke” perchance puts an end to his protracted misery. Or symptoms, long since manifest, of progressive renal failure may usher in the closing scene, and happy the victim if he pass muttering, half conscious, into that dream-like stupor drifting by insensible graduations to death.

So much in attempted portraiture of the long-drawn-out tragedy of inveterate chronic gout. But, fortunately, it is not always thus, and nowadays, at any rate, the evils wrought on the constitution by the malady are seldom so malignant. For not only, as before stated, has gout become less frequent, but its virulence also much attenuated. States of so-called “gouty cachexia” were, however, more familiar to our forefathers. It more commonly ensues in subjects of strongly hereditary tendency, and particularly in those in whom the initial attacks ensue before thirty years of age. I recall the instance of a colonel who sustained his first attack of gout when a subaltern of but eighteen, brought on, as he thought, through exposure while shooting snipe in Peshawur. It is in such cases that this so-called “gouty cachexia” may overtake a man while yet in his prime, and vest him untimely “with all the characters of age.”

As to the milder types of regular chronic gout, such usually arise, not in youth, but in men past the meridian of life. In their instance the recurrence of gouty paroxysms is often erratic. Periodicity becomes less pronounced or wholly lost. The life[229] history of the disease may be summed up in a few sporadic outbreaks, occurring irregularly throughout a long life. Even when at first the attacks occurred regularly in the spring and fall the rhythm of incidence becomes broken. An attack comes before its time, is belated, fails of appearance wholly, or an intermediate paroxysm comes as a surprise. Moreover, in many such the gouty manifestations with the passing years tend to become more and more attenuated, maybe even to extinction. Thus, a man who in the middle decades was a martyr to gout in old age gains freedom from its visitations, the disease having apparently exhausted its vicious potentialities.

Reviewing articular gout as a whole, one cannot but realise that it does in respect of the recurrence of gouty paroxysms exhibit inexplicable vagaries, inexplicable in that, as Sir William Roberts long since said, “in many instances they are dependent neither upon medical treatment nor upon altered dietetic habits, but are due to spontaneous changes in the constitution. They form part of the natural history of gout; and it is important to bear their existence in mind when we seek to estimate the value of therapeutic means in order to prevent ourselves from becoming the dupes of misinterpreted sequences.”

Albeit, we would not end on too sombre a note. For, in respect of the graver consequences of gout, it is unquestionable that right living, aided by efficient therapy, may arrest the course or mitigate the severity of the disorder. Moreover, as long as the attacks do not follow quick upon each other, but are separated by long intervals, there is little fear of a cachectic condition supervening. Life may not be appreciably shortened, and such textural degenerations as may ensue, though frequently attributed to gout, may often with at least equal plausibility be assigned to advancing years, but this with reservation, for, as Duckworth says, “the wilful libertine is likely soon to become cachectic, while the prudent man may altogether avoid this state or avert its evils for many years or decades of years.”

The Joint Deformities of Chronic Gout

The palpable changes in the affected joints differ widely in different cases, and why is not apparent. Thus, the first attack, if of prolonged duration, may bequeath a legacy of crippledom comparable to that met with after repeated paroxysms. On the other hand, some, although they have suffered from the disorder off and on throughout their lives, yet escape those consecutive deformities which in others deform and cripple the hands and feet, though the disease may be of relatively brief duration.

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But in the less fortunate cases the continued ravages of gout lead to a pitiful disablement of the affected limbs, reaching its acme in the hands and individual fingers, flail-like and semi-paralytic as they so frequently become.

Not only are the digits variously distorted, their joints more or less ankylosed, but the overlying skin, distended by the ever increasing subjacent uratic deposits, becomes thinned and purplish red in hue, and occasionally ulcerates. Similarly at ankle, knee, wrist and elbow thickening and deformity ensue as the concretions accumulate in and around the affected joints, these further accentuated by the correlated inflammatory and degenerative processes. Coincident deposits in the tendon sheaths and related bursæ contribute their quota, and at knee and elbow the bursal masses may reach extraordinary dimensions. Not only do the joints become deformed, but distorted also, through reflex muscular spasm and instinctive adoption of unnatural attitudes for the avoidance of pain.

So much for the broad outline of the picture presented, but a still closer scrutiny is called for. The deformities produced are the outcome of uratic deposits, which, as Charcot long since pointed out, take on the shape of “irregularly rounded or ovoid swellings, bunched, and either large at the base or just the opposite, i.e., provided with a pedicle.”

As shown in the coloured plate, the favourite site for their development is the dorsum of the hand or the vicinity of the metacarpo-phalangeal or mid-phalangeal joint. The resultant disfigurement of the hand is very characteristic. Irregular tuberous swellings surmount the knuckles, and spreading laterally, obliterate the fossæ between them and their fellows. The same extend forward over the first phalanges, from nigh the distal end of which again arise similar bossy excrescences over the mid-phalangeal joints. Encroaching thus upon the length of the first phalanx from either end, but little of its shaft is ultimately left exposed. In like fashion the mid-phalanx may be buried in uratic deposits, its contour wholly lost; and, the terminal phalanx participating, the digits become almost pedunculated, the nails projecting from the ends thereof—the “parsnip hand” of Sydenham. Such is the appearance presented in inveterate chronic gout.

Fortunately such examples are relatively rare, and a study of the condition in its earlier stages reveals some interesting features. The uratic deposits, it is important to note, are not located exactly at the level of the articulation. Unattached as they are to the articular ends, they are not compelled to, nor do they in any way, adapt themselves, as it were, to the contour or shape thereof. In short, the tophaceous formations are erratic, are not like[231] osteo-arthritic nodules, erupted from and continuous with the articular bone ends. Again, relatively independent of the contiguous tissues, they, unlike osseous outgrowths, are slightly movable in lateral directions.

When of recent incidence, their consistence is soft, and, be they never so ancient, they do not attain the density and hardness of bony outgrowths. The overlying skin, to which they are sometimes adherent, takes on a peculiar glossy and satin-like texture, its dusky pink blotched with spots of dead white colour, i.e., subjacent uratic deposits.

In other particulars also they differ from bony outgrowths. The tophaceous masses may soften and disappear after exacerbations of arthritis, and others may form at different sites. Following such absorption or difference in their location, some increase in joint mobility may happily ensue. This same fortunate occurrence may follow discharge of the uratic masses through ulceration and perforation of the skin.

Tophi: Their Evolution and Distribution

In our chapter on Uratosis we dealt with the chemical nature and mode of formation of tophi. Also we affirmed our belief that tophi, whether articular or ab-articular in site, were always preceded by local inflammatory reaction, and to the clinical tokens of their impending eruption we need not recur. Albeit this point, i.e., antecedent inflammation, is of such prime importance that we have not hesitated to append to our text a lengthy footnote,[37] this because, as Garrod, who quotes the same in extenso,[232] rightly claims, the genesis and evolution of tophi has never been so graphically depicted as in Moore’s description.

It will be seen that this observer holds that tophus formation “is usually preceded and accompanied by inflammation.” Garrod, as we know, believed uric acid to be the cause, and not the consequence, of gouty inflammation. But he emphasises the fact that the phenomena attendant on the eruption of auricular tophi are “exactly the same as when a joint is affected, and constitute, in fact, a true gouty paroxysm, commencing with infiltration of the tissue and subsequent inflammation.” Still, though venturing to differ as to the sequence of events, we gladly invoke this authority’s observations in proof of the fact that the inflammation even in the ear is not always of negligible grade: “I have seen many cases in which the ear symptoms have proved very annoying, so that patients have been unable to rest their ears on the pillow.”[233] Subacute gout sometimes occurs in the ears, says Duckworth, who furthermore believed that the indurations in the cartilage observed by him in gouty subjects were the outcome of such attacks. Laycock, too, long before noted that the ears of gouty subjects often appeared to be “soldered.”

Pain or discomfort in auricular tophi often presages an oncoming articular paroxysm. “Those gouty persons,” said Scudamore, “who are affected with concretions (chalk-stones), experience for a short time before the fit pricking pains in the parts where they are situated. This is described even by those who have minute points of concretions in the lobes of the ears and in no other parts of the body.” Hence tophi have a prognostic as well as diagnostic valency in that the incidence of pain at their site may foretell the oncoming of articular outbreaks.

While, as before emphasised, the eruption of tophi may antedate the occurrence of articular gout, on the other hand tophi may be present at the joints, but lacking in the ears and all other ab-articular sites. Auricular tophi, extracted occasionally by patients, are sometimes shed spontaneously. According to Duckworth’s statistics, in one-third of all well-marked cases of gout the ears present tophi in the helix, the anti-helix and its fossa and the lobule, and in some cases they may be situated on the posterior surface of the pinna.

Other Sites of Tophi

Apart from the external ears, tophi are apt to form in various localities. Most frequently they are situated in the vicinity of the joints and bursæ, especially that over the olecranon. As attack follows attack at short intervals the tophaceous matter is heaped up around the joint, and in this way many articulations may be involved, even all of them, says Trousseau, “as happened to Gordius, who composed on himself the following jocular epitaph:—

Uratic deposits sometimes attain a prodigious size. I have seen them the equivalent of a small hen’s egg. The largest tophi are invariably found in the neighbourhood of some joint, and the upper extremities furnish the most marked examples. But even when of considerable magnitude they may be non-adherent, the skin gliding freely over their surface. As John Hunter wrote: “The chalk shall remain for years without producing inflammation, and seldom produces it at all but from quantity.”

Often, however, their presence at length induces irritation of the[234] overlying integument. As they approach the surface the skin assumes a purple hue, becomes thin, and ulcerates. The uratic ulcers thus formed have generally an indolent fungous base. As the deposits extrude or are removed they are continually redeposited, and in this manner ounces of urates may be discharged. The same is followed by great relief and diminution of deformity.

Discussing such lesions, John Hunter tells us that “when the interior surfaces are exposed they hardly take on common inflammation and suppuration, healing more readily than a sore of the same magnitude from any other cause; even a joint shall be exposed, yet common inflammation shall not come on, nor shall it suppurate: only a watery fluid shall come out, bringing the chalk with it occasionally, and it shall heal up kindly.”

A glance, too, at the preceding footnote shows that Moore also agreed with Hunter as to the absence of common inflammation and suppuration. Moreover, even of recent years it has been suggested that, because gouty tophi do not suppurate even when ulcerated through the skin, the urates have antiseptic properties. But Bendix (Zeit. klin. Med., 1902) failed to demonstrate such qualities experimentally. The truth would appear to be that, though gouty inflammation never ends in suppuration, yet abscess formation very commonly occurs in the peri-tophal tissues. Such more often ensues in subjects of frail health or of definitely cachectic type. Garrod saw as many as five or six open at one time in each hand, and others on the feet. In his experience they give rise to but little constitutional disturbance. Scudamore, speaking of the same, says the sores produced are “unusually tender, aching, and sometimes very painful as the fit is making its approach.”

Ultimately the gouty ulcers thus formed dry up, and this indifferently whether or not the uratic deposits are wholly extruded in the discharging pus. The wound then closes, leaving a small scar, which, however, given a fresh attack of gout, is but too likely to break down, and this process may occur repeatedly. Bursal sacs containing tophi not infrequently suppurate, constituting abscesses containing urates.

An interesting fact noted by Garrod was that so long as such abscesses were discharging freely the subjects enjoyed comparative immunity from overt gout. But, given healing of the same, in several instances he had seen it the signal for a sharp outbreak. Duckworth, too, states that “whenever ulceration and flow of tophaceous matter occurs it is rare to meet with paroxysmal attacks anywhere in the body. With the cessation of the discharge renewed fits may intervene.”

While they tend to aggregate themselves round the joints, yet[235] tophi sometimes invade the integument of the limbs. They have been seen in the skin over the ulna and tibia, and commonly over the olecranon and patella. Pye Smith recalls the instance of a man in whom a number of small ulcers, discharging urate of soda, formed in the middle of his thighs and legs. The case is not an isolated one, but the incidence of subcutaneous uratic deposits in the limbs, save over articulations, is exceptional.

In the palms of the hands and the pulps of the fingers, the knuckles and phalanges, tophi are found not infrequently; and Trousseau tells of a lady of sixty in whom the cutaneous palmar folds of both hands were “marked with radiating white lines such as are seen in those who have long been employed in tempering plaster.”[38] Similar deposits have been noted in the plantar surface of the feet.

Reverting to the trunk, uratic deposits have been found in the scapular region, also in the perineum. I have twice seen tophi in the corpora cavernosa of the penis. In the face, apart from the ears, they have been found in the alæ of the nose. In the eyelids Duckworth noted uratic deposits in streaks resembling xanthoma; they were chemically tested, and proved to be of this nature. Speaking of “gout in the eye,” Garrod states: “I have witnessed many cases in which conjunctivitis and sclerotitis appear to be distinctly connected with the gouty diathesis, and in two cases there existed deposits of urates on the surface.”

As before stated, we recognise only one type of gout, viz., the tophaceous variety. But even so it must be noted that in some instances the process of tophus formation is greatly accentuated. In other words, the tophi may not only be of prominent size, but of unusually widespread distribution. Indeed, poetic exaggeration has it that one Baylas and one Acragas were entombed while alive in their own uratic deposits. But, apart from such imaginative flights, there are unquestionably some cases in which tophi are most widely diffused. Thus Plater tells of a patient whose whole body, even the eyelids, was studded with them: “ex toto corpore, per poros, adeo ut etiam palpebræ oculorum non exemptæ fuerint, ejusmodi materia gypsœa, circa poros cutis mox in tophos mutata, prodisset.”

These cases of multiple tophi are far more common in men. Duckworth met with some well-marked cases in women. They may occur also in persons who have been lifelong abstainers. Sometimes trauma seems to have played a part in determining their localisation. Garrod held that, given prodigious uratic[236] deposition, the kidneys might be held as unsound and undergoing sclerosis; and, according to Duckworth, the rule commonly holds good.

Affinities Between Gout and Other Diseases

Whatever be the explanation, no fact in practical medicine is better established than this, viz., that certain disorders are peculiarly liable to arise in gouty subjects. Of these the more noteworthy are glycosuria, phlebitis, certain cutaneous disorders, and nephritis. While, for myself, I prefer to regard these affections as merely diseases to which the gouty are especially subject, nevertheless each and all of them, by one authority or other, have been classed as among the irregular manifestations of gout.

This, on the assumption that these several morbid entities may precede, alternate with, or follow arthritic seizures, frequently also on the basis of their alternation in hereditary transmission with arthritic gout. Thus, in a family of marked gouty proclivity, while one son, despite a temperate life, may have severe articular gout, on the other hand his brother may suffer only with irregular manifestations, i.e., phlebitis, eczema, etc.

As to whether these particular disorders, phlebitis, glycosuria, etc., are directly caused by the toxin of gout, or whether their not infrequent association with gout is merely accidental, is a moot point. But to the sources of fallacy in this connection we shall allude more in detail when dealing later with irregular gout. Meanwhile extended knowledge of the intimate etiology of phlebitis, glycosuria, etc., tends to an attitude more critical than that of our forefathers, who, faute de mieux, relegated a large number of conditions whose pathology was inexplicable to the nebulous domains of irregular gout.

Gout in Relation to Glycosuria

That some obscure link existed between glycosuria and gout was long since suspected. Prout noted it as far back as 1843, and Bence Jones discussed the subject under the title “Intermitting Diabetes” (1853), while in the following year Gairdner announced that he had long surmised the kinship between the two disorders. About the same time Claud Bernard remarked that gout and glycosuria might alternate, and so did Trousseau, and many since that day have ranked glycosuria as one of the forms of irregular gout, whether legitimately or not is an open question, but at any rate it does not affect the established clinical fact that glycosuria occurs with significant frequency in gouty individuals.

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Gouty glycosuria is more common in males than females. The subjects are usually robust, middle-aged, and of full habit. Sugar is found intermittently in their urine in small amounts, but no acetone bodies. It is as a rule unaccompanied by thirst or wasting. It quickly responds to dietetic restrictions. As Gull long since observed, gouty glycosuria does not “discover itself,” but is “not uncommonly discovered.” This tersely sums up the clinical difference between this affection and true diabetes, albeit, as in all glycosurias, there is always the risk that carbohydrate excess, mental strain, or other adverse circumstances may aggravate the disorder and the case merge into one of true diabetes.

Following the installation of glycosuria, the tendency to paroxysmal articular outbreaks often ceases. The converse also has been observed, viz., that when, in sequence to dietetic restrictions, the sugar disappears, the articular pains may reappear. The fact that attacks of glycosuria may alternate with attacks of gout led to the assumption that a positive antagonism existed between the two disorders. Hence the phrase “the more sugar the less gout,” and vice versâ. This, however, with reservations, for a fugitive glycosuria has been seen during an acute articular paroxysm, and a classical outbreak in the toe has been known to supervene in the course of a well-established glycosuria.

It is generally held that glycosuria is most commonly associated with irregular forms of gout. But, in view of our ignorance of the intimate nature of even regular gout, I should myself deprecate affixing the prefix “gouty” to any glycosuria other than one that has supervened in sequence to, or alternates with, gouty arthritic seizures. Moreover, the glycosuria of gout is usually the alimentary glycosuria of fat elderly people, in whom the sugar excreted represents the unconsumed surplus of carbohydrate food. But fat elderly people are not necessarily “gouty,” neither is every so-called benign glycosuria inevitably linked on to a gouty diathesis. In fact, the relegation of glycosuria to the gouty category is but too often not a matter of diagnostic certainty, but rather an inference. Hence my plea that the prefix “gouty” would best be restricted to glycosurias occurring in individuals who suffer regular attacks of gout, or those displaying those objective tokens pathognomonic of the disorder, i.e., tophi.

Again, James Taylor has recently reminded us that, if nerve affections are relatively common in true diabetes, the same may be met with in gouty glycosuria, even when of temporary duration. Thus symptoms indicative of peripheral neuritis may occur, i.e., lost knee jerks, paræsthesiæ, and paresis of the lower limbs. Now, as this authority pertinently observes, the subjects of gouty glycosuria are frequently given to alcohol. Consequently the question[238] whether or not the symptoms are due, not to sugar, but to alcohol, arises forthwith.

In some undoubtedly the alcoholic factor plays a rôle, but such symptoms may, on the contrary, arise in very abstemious individuals. This notwithstanding, James Taylor holds that the clinical complex differs substantially from that met with in true alcoholic neuritis. It is slighter in degree, the paresis usually restricted to lower limbs, while the exquisite tenderness to pressure on nerve trunks so typical of alcoholic neuritis is little or not at all in evidence. Nor is there the same tendency to contractures in muscles as met with in the alcoholic variety, and withal there is an absence usually of the mental changes—loss of memory—associated therewith. Accordingly Taylor holds that we must recognise the existence in the gouty of a true glycosuric peripheral neuritis quite independent of alcoholic peripheral neuritis.

Other concomitant nerve troubles noted in this association are severe intercostal neuralgia and, even more commonly, neuralgia of the fifth nerve, and to this may be added migraine and that other neurosis asthma. Intense mental irritability and depression is not an infrequent sequel in gouty glycosuria. According to James Taylor, melancholia even may result, especially if the glycosuria have merged into true diabetes—a sequel, he says, especially prone to occur in Jewish subjects.

Having seen and suffered many painful disillusionments through too flippant relegation of neuralgias or neuritides to diatheses “gouty” or “rheumatic,” I would emphasise the necessity for great caution. In other words, before labelling a neuralgia or neuritis as “gouty,” all possible causes, infective or other, should be excluded, this always, but pre-eminently so in brachialgia, sciatica, and trigeminal neuralgias. Nor even, should there be a history of classic outbreaks or blatant tophi present, should we be less vigilant.

By all means recognise the gouty diathesis. It often avails much in treatment, but not if, e.g., dental caries, antral disease, cervical rib, or pelvic growth be overlooked, not to speak of recent or concurrent sources of infection or toxic absorption.

Lastly, we should always recollect that gouty glycosuria, as Gull said, “does not discover itself”; it is not writ large on the subject like true diabetes. But given the incidence of nerve troubles in a gouty person, i.e., a paræsthesia, itching, neuralgia, etc., we should always suspect its presence.[39] Incidentally our search may reveal not only sugar, but also albumen, and the latter may explain much that appeared inexplicable.

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Gout in Relation to Phlebitis

It is to Sir James Paget that we are indebted for recognition of the fact that phlebitis occurs with significant frequency in gouty subjects. This great surgeon held that the disorder was the outcome of a modification or transformation of gout, the result of “morbid conditions changing and combining in transmission from parents to offspring.” At the present time some regard it merely as a complication of gout, others as one of the irregular manifestations of the disease.

It occurs most commonly in men, women being rarely the subjects of gouty phlebitis. It may install itself insidiously with but mild local discomfort, and yet on examination a cord-like hardness is detected. In others it announces itself with pain, in rare instances intense, this more commonly if the deep veins of the calf are its seat.

Its predilection is for the veins of the lower extremity, the superficial rather than the deep vessels. If the former, a faint blush over the affected veins may be seen, but if the deep veins, then œdema and tenderness may be the sole token of its presence.

Frequently the phlebitis is patchy in distribution and migratory. Thus, as Paget says, it may on one day be located in a short length of the saphenous vein, flitting the next day to some other portion thereof, or, it may be, to the corresponding vein of the opposite limb. This tendency on its part to metastasis and symmetry led Paget to the conclusion that “the essential and primary disease is not a coagulation of the blood, but an inflammation of portions of the venous walls.”

Its duration is not uncommonly prolonged, and it displays a marked tendency to recurrences, the latter determined by blows, unusual exertion, or, according to some, exposure to cold. Most cases end favourably, but death from embolism sometimes occurs. Occasionally, given occlusion of the large veins, some degree of swelling lingers permanently.

The instances most indicative of a gouty origin are those in which the veins of a limb, the seat of acute gout, are simultaneously attacked by phlebitis. In three cases of this nature recorded by Garrod, the subjects, despite their suffering from acute articular gout, persisted in leaving their beds to record their votes in the parliamentary election of 1884. This type of case, according to Garrod, is usually confined to men, and, with the exception of the cases above noted, a varicose condition of the veins of the legs of long standing existed in his series of examples.

Garrod recognises in addition a second type, in which phlebitis,[240] “usually of a much less acute character, ensues without the previous development of gouty inflammation in the neighbourhood of the part.” Here we may recall that, according to Paget, the incidence of phlebitis in an elderly person without any external cause warrants the suspicion of gout. Perhaps the chief justification for such an assumption rests on the fact that phlebitis appears sometimes to be hereditary. Paget cites the instance of a man who suffered from phlebitis of both saphenous veins during an attack of acute gout. On the maternal side his mother, two uncles, a grandmother, and two cousins had been the subjects of phlebitis.

In conclusion, for myself, I would suggest that the term “gouty” phlebitis be restricted to those instances in which a limb, the seat of acute articular gout, is complicated by phlebitis of the veins of the affected part. Here we are dealing with what is palpably an extension of the gouty inflammation from the affected joint to the veins, and which, I venture to assert, is strongly confirmatory of the view that an infective element intrudes in “gouty” arthritis. We may recall that, e.g., gonorrhœal phlebitis of the lesser saphenous veins is not so uncommon, while the frequency with which phlebitis complicates infections calls for no emphasis.

Leaving aside these rare instances of acute gout complicated by acute phlebitis, I think there is a too flippant tendency to regard any phlebitis occurring in middle-aged or elderly subjects as being of this nature, this often in the absence of any evidence, hereditary or other, of a gouty element in the case. Frequently, too, the subjects are women with varicose veins of long standing, and ipso facto potentially liable to phlebitis. But why, in the absence of ancestral or acquired gout, dub such cases forthwith as “gouty”? We may, it is true, as in Paget’s classical instance, elicit a familial tendency to phlebitis, but even so I doubt the legitimacy of the inference that the phlebitis is necessarily “gouty.” Is it not equally true that the tendency to varicose veins is hereditary, and ergo predicates an enhanced liability to phlebitis?

Cutaneous Disorders

The incidence of tophi in the skin naturally engendered the conception that gout was responsible for many and diverse types of cutaneous affections. In accordance with this, every effort was made to prove that they were the outcome of uratic infiltrations, but in vain.

Objective proof of this nature being lacking, the older clinicians found their justification in the alternation of arthritic attacks with cutaneous disorders, and their alternation in inheritance was laid great stress upon, this especially by French dermatologists,[241] notably Bazin, but at the present day Jacquet’s non-committal pronouncement is probably representative of the attitude of the French school as a whole towards “arthritic” affections of the skin: “Le lien admis entre le groupe de maladies dites arthritiques est très mal connu dans son essence, mais il serait tout aussi contraire à l’esprit scientifique de le nier avec rigueur que de l’affirmer avec presomption.”

As to the skin disorders associated with acute types of gout, perhaps the most interesting and well ascertained is herpes. It may precede an acute attack, may alternate with it, or be a sequel thereof. Rendu noted that acne, boils, and carbuncles also might occur prior to, in alternation with, or in sequence to acute attacks, and Scudamore noted the same in respect of erysipelas.

The noteworthy liability of the gouty to these disorders is but another proof that gout predisposes its victims to infections. The fact that acute gouty arthritis might follow acne, boils, etc., lends colour to our contention that the same may be of infective origin. But unfortunately the suspicion also intrudes that some of the arthritides occurring in such association may, on insufficient grounds, have been diagnosed as “gouty,” this especially if the joint disorder were located anywhere save at its classic site, the big toe.

Passing to skin affections associated with chronic gout, it must be admitted that as a whole the contention that they are “gouty” in origin is, to say the least of it, doubtful. French dermatologists claimed that the cutaneous eruptions of the “gouty” might be recognised by their polymorphism, circumscribed location, etc., but these are no more distinctive peculiarities than the concomitant pricking, hyperæsthesia, and hyperalgesia upon which Bazin laid such emphasis in their diagnosis.

In short, sequences, coincidences, and alternations are the basis of much that has been written upon so-called “gouty” cutaneous affections, criteria all of them fruitful sources of fallacy.

As to psoriasis, I have met with it so frequently in association with non-gouty arthritides that I have never felt justified in claiming any example as “gouty.” So-called “gouty” pruritis and prurigo, these when they occur in the “gouty” are frequently referable to an associated glycosuria, and when this is not the case, it is frequently a senile prurigo. The claim that urticaria is “gouty” may be dismissed without comment.

As to frequency of incidence in the “gouty,” eczema undoubtedly must be awarded the palm. But whether the scaliness of skin on extensor surfaces of arms and legs and back of neck, which ultimately, under the influence of skin infection through scratching, develops into a dermatitis which assumes the character of eczema,[242] can be, strictly speaking, held as of “gouty” origin, is questionable. Certainly, whatever be the origin of the pruriginous scaliness of the skin, there can be no doubt that the later dermatitis is the outcome of infection by skin organisms. Frequently the presumption that the eczema is “gouty” rests upon general rather than specific grounds, on “goutiness” rather than “gout.” Accordingly I think it would be wiser to regard eczema as an occasional complication of gout rather than an integral element thereof.

Lastly, there can be no doubt that many of the so-called “gouty” cutaneous disorders ensue at what may be called the arterio-sclerotic stage of life. It is when renal and cardio-vascular changes are present that we meet with exudative erythema, pityriasis, exfoliative dermatitis, and purpuric eruptions. All these have at one time or another been foisted upon gout, whereas they are far more closely related to the cardio-vascular and renal changes with which the disorder is so frequently associated.

Gout and Nephritis

The association between gout and renal disease is admittedly intimate, in so far as gouty subjects often have granular kidneys, while gout is a frequent complication of this type of renal disorder. Nevertheless, the clinical relation between the two diseases is ill defined and, moreover, somewhat erratic. In most instances the renal defect is engrafted upon the antecedent gout, or the sequence is reversed; and, again, the two conditions may arise contemporaneously. Lastly, in sharp and disconcerting contrast to this mutual overlapping of the two disorders, we have the awkward fact that more commonly gout and granular kidney run to their fell end quite independently of each other.

Thus, Sir William Roberts observed: “It is quite common to see articular gout, even of chronic and inveterate character, run its entire course without any accompanying signs of structural disease of the kidneys.” The same, to be sure, is equally true of granular kidney, which may pass to its close without any suspicion of gout.

Now, as we have seen, the primary renal origin of gout fails of demonstration. Is gout, then, causally related to granular kidney, or is there some less direct relation between them?

As to this, to begin with, it is extremely rare that a “gouty” subject develops acute nephritis. In the exceptional instances when it does occur it is either purely accidental or else the outcome of an exacerbation of a previously existing interstitial nephritis.

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The question then arises, Can gout when long continued originate per se the condition we are pleased to term “gouty kidneys”? As seen above, such renal lesions are by no means an inevitable sequel or concomitant of long-standing gout. Moreover, there is nothing specific of gout in the so-called “gouty” kidney. It is an interstitial nephritis, which may assume the appearances of the ordinary “contracted kidney” or the “arterio-sclerotic” type. There may be uratic deposits at the apex of the pyramids, or even an uric acid calculus; but even so that of itself constitutes no proof of the renal changes being “gouty” in origin. In short, the prefix “gouty” as applied to these types of renal lesion is just as unscientific and unwarrantable as used in regard of “phlebitis,” “eczema,” and so forth.

Nor, quâ gout as a causal factor, are we in better case if the renal disorder be of the “arterio-sclerotic” type. No direct relationship is established between gout and arterio-sclerosis beyond the fact that both are usually met with in middle-aged or elderly people. Moreover, a man may develop arterio-sclerosis and arterio-sclerotic kidneys, yet never have any vestige of gout.

There being nothing specific of gout in the lesions of so-called “gouty” kidneys, we must revert to the clinical findings to refute or establish any causal connection between gout and the renal disorder. Now, gout is a disease of middle and late life, and rarely of itself proves mortal. On the other hand, it appears increasingly probable that the seeds of granular kidney are laid in earlier life, and, on the average, its course is shorter than that of gout. Also the two disorders have clinical facies absolutely distinct the one from the other.

From the above considerations it is, I think, clear that, whatever the hidden nexus between gout and “granular kidney,” it is neither essential nor constant. It is rather, I believe, of the nature of a coincidence. Furthermore, as applies to so many problems pertaining to gout, and, for that matter, to “granular kidney” also, we labour under the grave disability that both terms are, especially “gout,” very vaguely applied and when used are often a matter of personal opinion. Consequently, as Samuel West shrewdly observes, “it is difficult to discuss satisfactorily the relation of two conditions to each other when neither condition admits of precise definition, for some authorities are more easily satisfied in the diagnosis of gout than others; and, while some place all forms of chronic interstitial nephritis in one and the same category, others are not so comprehensive, and regard granular kidney as a definite clinical disease, of which the interstitial nephritis is only a part.” Under these circumstances, the[244] need for further and more exact researches in this sphere is but too obvious.

Meanwhile, accepting the general opinion as to the frequency of the co-existence of gout and granular kidney, is there any explanation thereof? For myself, I am inclined to believe that the common overlapping of the two disorders is in large measure due to this, that the factors, i.e., excess in alcohol, overeating, etc., that make for the eruption of gout, are largely identical with those that promote the development of granular kidney. Hastings Gilford holds “there is very little doubt that syphilis, lead, and gout do not so much originate Bright’s disease as excite it into activity when it already exists in a smouldering or latent condition.”

With this view I feel much in accord, and if to the malign effects of gout be superadded the effects of alcohol or, haply, lead also, how incalculably greater the chances of fanning into flame any latent tendency to nephritis—a legacy, perhaps, of some long bygone infection.

Prognosis in Gout

Gout per se rarely, if ever, proves fatal. Certainly, as Sir Thomas Watson long since said, “gout in the extremities is not a mortal disease.” When death did occur during or in close relation to an acute paroxysm, it was by our forefathers attributed either to its retrocession or to some misplaced or irregular manifestation. Indeed, their attitude was very much that of the French physician who observed: “La goutte articulaire est celle dont on est malade, et la goutte interne est celle dont on meurt.”

But, as we shall see later in our chapter on Irregular Gout, most, if not all, of their instances of the assumed translation of the materies morbi of gout to some vital organ are without foundation. The demise, often dramatically sudden, was not due to gout, but to some insidious, unguessed-at organic degeneration, or to one of the accidental intercurrent maladies to which these subjects seem especially liable. To sum up, the immediate danger to life from regular gout when uncomplicated is slight.

Not that gout is salutary, lessens the liability to other diseases, or promotes longevity. Very much the reverse—“a tendency to recurrence is a law of the disease.” Broadly speaking, the more pronounced the tendency to recurrence of articular outbreaks, the more protracted the isolated paroxysms, the worse the outlook, the more sombre, too, the greater the number of joints involved. Conversely, if the disease, though it recur, restrict itself to the classic site, the big toe, the longer, as a rule, the intervals of[245] freedom, the brighter the prospects of long life. Lastly, the more the subject is crippled, the more pronounced the tendency to tophaceous deposits, the more likely is the disease to pursue a downward course, the greater the risk of associated degenerations in renal and vascular tissues.

While these reflections are in the main, we think, justifiable, we must recollect that in gout, as in other maladies, the elements of prognosis reside in the individual, not the disease. Does he come of a long-lived stock?—not uncommonly a feature of gouty families. If so, the outlook is favourable. If he come of a short-lived breed, then in all probability, no matter how carefully he lives, he will not likely make “old bones,” this, certainly, if the gout makes its appearance early in life, say under thirty.

As to the axiom, generally accepted, that the earlier in life gout makes its début, the more unfavourable the outlook, there are exceptions. Where longevity marks the stock, they usually are true to type. Thus, even if the first outbreak occurs in the twenties, I have known them reach the allotted span and over. Nor if their urine show traces of albumen is this necessarily of grave import, for these gouty veterans may for many years, even to old age, exhibit traces of albumen without apparently developing genuine Bright’s disease.

“There dies not above one of a thousand of the gout, although I believe that more die gouty,” wrote Graunt long years since; and this contains a kernel of truth, for the prognosis of gout rests in the main not on the gout, but the conditions correlated therewith—the absence or not of complications. For, be it always remembered, gout, though it may appear in youth, is chiefly an appanage of the middle and later decades, in short of the regressive period of life.

This last is, I think, apt to be forgotten, and gout vicariously saddled with all the infirmities of age. Thus, out of 2,680 examples of arterio-sclerosis Huchard held gout and lithiasis responsible for no less than 693. An appalling indictment, but what of the long arm of coincidence? For age unquestionably is the chief factor in the production of arterio-sclerosis, though many allot gout a dominant rôle in its genesis. This certainly is by no means proven. Still, whatever be the relationship, gout and arterio-sclerosis are very often found in association. If so, the prognosis will obviously rest, not on the gout, but on the vascular disease—the pulse tension. If therewith be correlated albuminuria and a displaced apex beat, the outlook is unfavourable.

Again, is the subject lean or obese? If the former, so much the better, for corpulency and gout are a sinister combination.[246] Gout in itself, as previously observed, favours microbic invasion, and obesity accentuates the liability. Moreover, the gouty obese are prone to arterio-sclerosis and granular kidneys, with sometimes a superadded glycosuria, or even true diabetes. In such subjects also the presence or absence of signs of cardiac mural degeneration must enter into our forecast, which at best is but gloomy.

Apart from arterial degeneration, we have to recollect the tendency to phlebitis of recurrent type. This when present always carries with it the risk of embolism and sudden death. Cases therefore displaying this proclivity to phlebitis must be judged accordingly. The gouty glycosuric, too, is always subject to the risk that the condition may develop into one of true diabetes. The absence of response to dietetic restrictions, viz., persistent sugar in the urine, the onset of thirst, polyuria, or other concomitants of diabetes, will darken the prognosis.

Also I myself believe that the presence of local foci of infection gravely prejudices the course of gout, accentuates any tendency to recurrence of the attacks, and incidentally reinforces any latent proclivity to vascular and visceral degenerations.

Last, but not least, what of the subject’s habits? The “internal environment” of the tissue cells of the gouty is presumably of itself none too good; but if to this be added the poison of alcohol, lead, or the toxic products of gluttony, it is incalculably worse. The painter or the plumber, if he can, would be wise to change his calling. If the alcoholic be deaf to remonstrance or the glutton continue to gorge, their chances of life dwindle proportionately, and if given to both vices, still more so.

In conclusion, the prospects of long life in gout depend in the main on the presence or absence of associated morbid states. If there be no complications such as I have indicated, the disease, in my experience, is not likely to shorten life materially, always provided that the victim is amenable to what should be the watchword of the gouty,—

Articular Gout

The intimate cause of gout is unknown—a humiliating reflection, albeit salutary, if it but engender a more catholic attitude on our part when seeking to unravel the nature of this obscure joint affection. For, to secure ideal ends, diagnosis must be, not only clinical, but etiological. This is the more likely to be attained if we shed all preconceived ideas and prejudices.

Etiological Diagnosis

Confronted, then, with a suspected case of gout, whether acute or chronic, what shall be our way of approach? Not the easy and hazardous path of lightning diagnosis affected by those who plume themselves on their so-called clinical “instinct,” but the slow, laborious route of clinical “observation,” that leads more surely to the vantage ground of truth, this assuredly in all diseases, but in none more so than in joint disorders, whose outward resemblances so oft hark back to inward disparities.

First, as to the manner of man, while one would not decry the hints obtainable from physiognomical peculiarities, it is often hard, if not impossible, to fit the subject to the so-called “gouty diathesis.” They are not all of the John Bull type; not a few are spare in build. Hence the danger of too ready inference from so-called “gouty” traits, to be regarded rather as ancillary to, but not substitutes for, more exact criteria.

Now, as to heritage, for, despite the fallacies that surround inquiries into family predispositions, they often furnish valuable hints as to the metabolic trend of the stock. True, ancestral stories often prove indefinite, but fortunately less so in the “gouty” than in those of “rheumatic” tendency. For, as Sir Dyce Duckworth points out, even the laity are quick to recognise what they term “chalky” gout, and so “if a history be given of ancestors or relatives thus affected, there need be no hesitation in pronouncing for true gout amongst them, and for the probably gouty nature of such arthritic ailments as may be complained of by the patients under examination.”

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Turning to the individual himself—for the subjects of regular gout are rarely women—what is his age? If he is over thirty-five and has never previously had an arthritic disorder, it is much more likely to be gout than rheumatism, this only as a broad generalisation.

What occupation does he follow? What are his habits? Is he of the “idle rich” who “fare sumptuously every day”? Is he a plumber, a painter, or a butler, coachman, or club waiter, these last being men who, as Sir Thomas Watson observes, “often live more luxuriously and more idly a great deal than their masters”? In short, we must search for any evidence of overeating, overdrinking, and indolence. For of this triad of vices is gout too oft begotten.

As to illnesses, his past may tell of classic outbreaks, one or more in the great toe, and if to this be added a visible tophus, we stand face to face with a “gouty diathesis.” More eloquent this than a “cloud of witnesses” as to previous attacks of migraine, asthma, eczema, etc. All these and more may emerge during the subject’s recital, and by all means let them be ascertained. But forget not that they often arise in the non-gouty. Above all, though, miss not the significance of heightened blood pressure, a cardiac lesion of degenerative type, sugar or albumen in the urine. For these are of the things that will out, but let it not be to our discomfiture!

Even presuming that all facts and observations up to now point to a “gouty” origin of the arthritis, the end is not yet. What has evoked the arthritis? We seek a cause. For to call an arthritis “gouty” is but to restate the problem. How clear the need then for a meticulously careful investigation, in the hope of achieving not a merely nosological, but an etiological, diagnosis.

To narrow our field, we should, in the first place, exclude gonococcal infection, and failing this, influenza, syphilis, or any of the zymotic or other disorders prone to be followed by or associated with joint affections.

If none of such be forthcoming, we should search for local foci of infection. The mouth and its accessory cavities first claim attention. It should be closely scanned for the presence of oral sepsis, the most fruitful source of which is pyorrhœa alveolaris. If dentures are worn it is wise not to take the subject’s word that all his teeth have been extracted. Like others, I have in such found the broken-off stumps still in situ. The condition of “bridges” should be noted, fruitful sources of sepsis as they are. Clinical examination of the mouth may prove inadequate, as buried roots, cysts, or abscesses, not to mention alveolar rarefaction, etc., demand for their detection radiographs.

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The pharynx and tonsils should be thoroughly investigated, for disorders of these same are by no means uncommon in “gouty” subjects. Any history of aural or nasal discharges demands the same careful local examination; and, needless to say, the same course must be pursued in regard of any local infections of the genito-urinary passages. In short, in gouty, as in non-gouty, forms of arthritis, thorough and routine examination of every patient by modern bacteriological methods is imperative.

Ignorant of the precise etiology of gouty arthritis, we can ill afford to overlook any associated infective foci which may prejudice the well-being of the victim, as, for aught we know to the contrary, we may be overlooking the very fons et origo mali. Compare our attitude towards other arthritides of cryptic origin, how systematic our search for infective foci, and what a light has thereby been shed on their intimate etiology!

Here may we lodge a plea for routine examination of the blood in all cases of gout? For, as shown, the findings, leucocytosis, etc., have doubtless some profound significance. Apart from this, the routine employment of complement-fixation tests for the organisms responsible for local infections might illumine the obscurity that overhangs this complex problem of their relationship to remote pathological lesions.

If up to now our search for local foci prove futile, it remains for us to note the presence or absence of functional derangements of the alimentary tract, or its accessory glands. We must not, because we think perhaps that the patient “looks gouty,” assume that his dyspeptic symptoms are of like origin. It is our duty to ascertain, if possible, the precise nature and origin of the dyspepsia.

We know that, given oral sepsis, sequential infections of the appendix and gall bladder are not uncommon. Recently it has been remarked that many gouty patients suffer with attacks of pain in the region of the appendix, and simultaneously tenderness over the gall bladder. That the subjects of gout enjoy no immunity from appendix or gall bladder disorders is certain, and at this we need not be surprised, seeing the frequency with which they suffer from alleged causes thereof, i.e., dental sepsis, etc.

But what we would insist upon is that we should not be content merely with dubbing these symptoms “gouty,” as they are much more likely to be, not symptomatic of gout, but etiologically related thereto. If then we are to arrive at the exact nature of the underlying lesion, the probable site of infection or toxic absorption, we must invoke all modern methods of investigation. Thus, how valuable the existence of an X-ray barium or bismuth meal in furnishing positive evidence of gastric or duodenal ulcer on the one hand or of gall bladder or appendix disease on the other. What[250] an aid to the location of adhesions the demonstration of ileal and cæcal stasis, etc.!

In obscure cases the fæces may have to be scrutinised for evidences of pancreatic inefficiency, viz., bulky pale stools, undigested meat fibres, and excess of neutral fat. Their bacterial content, too, if abnormally high, should be noted. As in other arthritides of unknown origin, the results following the administration of vaccines prepared from the predominant organisms have been such as to suggest a causal connection.

The urine should be subjected to chemical and bacteriological examination. As to uric acid, the delusion still widely prevails that gouty subjects excrete large amounts thereof. How frequently is “the degree of acidity” of the urine or “its content of uric acid” held to justify a diagnosis of gout. The deduction is quite unjustifiable. Equally so the assumption that the reverse, a defective excretion of uric acid, is an invariable feature of the gouty diathesis. For though when on a purin-free diet the output of uric acid in the gouty is low, it rarely, if ever, falls below the level of normal. The truth is that we cannot on the mere basis of the variations in uric acid excretion in the urine presume to diagnose gout.

To have any semblance of diagnostic value, the patient should be on a purin-free diet, and a long series of exact quantitative examinations made. C. v. Noorden, to gauge the limit of tolerance of his patients, gives them increasing amounts of purin, and so determines the quantity the subject can deal with without showing retention. But, as Von Fürth satirically observes, “when a physician allows a quantitative analysis to be made of any arbitrarily collected specimen of urine of his patient and then makes a diagnosis of the presence or absence of a ‘gouty diathesis’ after a glance at the list of data of the analysis, he is really not proving by his actions his possession of diagnostic acumen as much as he is laying bare his total ignorance of bio-chemical matters.”

So much for the diagnostic valency of uric acid estimates in chronic gout, but if the patient be on purin-free diet, and an acute attack ensue, the curve of uric acid excretion is fairly characteristic. In other words, for a day or two preceding the outbreak, the uric acid output falls below the usual level, but early in the attack rises markedly, to be followed by a secondary fall.

Some aid in diagnosis has been afforded by the fact that after ingestion of purin-containing food the gouty individual does not, like a normal person, eliminate the excess of uric acid, but the excretion is “spread out over a number of days.” But this retardation and diminution in the excretion of exogenous purins[251] has been seen in non-gouty forms of arthritis, not to mention some cases of nephritis and chronic alcoholism. Hence delayed nuclein exchange, though highly suggestive of gout, is not infallibly diagnostic thereof.

As to uric acid in the blood, it will, I fear, not for long, if ever, be easy to prevail on patients to submit to withdrawal of the amount of blood necessary, even by modern methods, for its estimation. Fortunately, our American confrères appear to be more successful in securing such opportunities. Pratt states that in his twenty-one cases of genuine gout the uric acid content of the blood, irrespective of diet, was 3·7 mg. per 100 grams, as opposed to 1·7 mg., the average amount in 156 non-gouty cases studied by Adler and Ragle. Still Pratt noted that in a few cases of undoubted gout the uric acid content of the blood was within normal limits, though it never fell, even on a purin-free diet, below 1·4 mg. Nevertheless he holds that there is conclusive evidence that the uric acid content of the blood is in gouty individuals notably increased both in the intervals and during attacks.

He has found the sweetbread meal an aid in diagnosis, and the following is his method of procedure: “The patient is placed on a purin-free diet, and the daily output of uric acid in the urine determined. After having been on this diet for at least four days the blood is analysed for uric acid, and 150 to 300 grams of sweetbread (weighed raw) are fed. The purin-free diet is then resumed. The blood of gouty subjects forty-eight to seventy-two hours after the sweetbread meal has shown in every case examined an abnormally high amount of uric acid, while in control subjects this was not found. It is not improbable that this rise in the uric acid content of the blood may occur in certain cases of nephritis and other pathological conditions.”

A bacteriological examination of the urine should be undertaken. Trautner held mucous colitis as one of the initial manifestations of gout, and believes that the bacillus coli communis is the primary agent in gouty affections. He suggests that it produces a reducing substance which during its passage through the body is transmuted into xanthin and uric acid. Be this as it may, there is increasing evidence that an etiological potency may attach to coliform bacilli, streptococci, and other organisms. Dr. Munro in his researches at the Royal Mineral Water Hospital, Bath, noted that the blood serum in one of my cases of acute gout agglutinated B. coli. He has also found streptococci in the urine in acute gout, and these subjects certainly enjoy no immunity from other forms of bacteriuria.

It is beyond the scope of this volume to outline the methods of differentiating and determining the exact organisms which may[252] be responsible for gouty arthritis. But if we aim at rational as opposed to purely haphazard serum or vaccine therapy, we must effect a differential specific diagnosis in a bacteriological sense. How searching our investigations must be in these cases we learn from Adami’s brilliant address on sub-infection when he laid down the axiom that in all cases “there ought to be routine blood cultures, routine examination and reports on the stools and their predominant bacterial types, blood counts, hæmoglobin examination, in fact the full clinical study of each case, so that nothing is neglected.”

No apology is needed for our insistence on the imperative necessity of routine systematic investigation from all sides of these cases of gouty arthritis. For its origin still remains hidden, and who can doubt that, to remove this long-standing reproach, we must approach our study of these cases in a more catholic attitude of mind, one bent on etiological, not merely nosological, diagnosis?

Clinical Diagnosis

Introductory Remarks

The word gout itself is void of offence, innocent of scientific pretensions, neither expressing nor violating any article of pathological belief. But let us not forget that the term is neither self-explanatory nor final. Derived through the French goutte from the Latin gutta, it but expresses laconically the fanciful doctrine of those who so christened it.

What the old humoralists saw was the tophus, and would that they had clung more steadfastly to this as their sheet anchor in diagnosis! but casting their moorings, they launched forth on the uncharted seas of abstract philosophy. Even in the writings of the nineteenth century physicians we trace the influence of their disquisitions, and we are tempted to think that some even of our day still bide beneath their thrall.

But, with the advance of pathology to the dignity of a natural science, we must assert our independence of misty hypotheses, rendering obeisance only to facts. What then, may we ask, is the outstanding fact of the “gouty diathesis”? It is, in a word, the tophus! Even as the vague and shadowy constitutional warp known as the “rheumatic diathesis” finds expression, or rather becomes incarnate, in fibrous nodule and induration, so also does the equally nebulous “gouty diathesis” become objective, crystallised in the tophus.

The Diagnostic Status of Tophi

This problem calls for more critical consideration than is usually accorded thereto. The tophus is, in truth, the touchstone[253] of gout, yet not a little controversy obtains as to the frequency of its incidence in “gouty” subjects.

At one extreme we find Sir Charles Scudamore maintaining that tophi have occurred in only a few individuals “of particular ‘gouty’ idiosyncrasy,” in, according to him, less than 10 per cent. of the victims. At the other Sir Alfred Garrod, discussing these figures, observes: “From my own experience I consider these numbers far below the real proportion, from their being deposited in parts of the body scarcely to be expected.”

Now as to these distinguished physicians, who shall doubt that of the twain Garrod stood on firmer ground than his predecessor? In arriving at their diagnoses of gout, Scudamore rested on clinical “instinct,” Garrod on clinical “observation.” To the more scientific mind of the latter the tophus appealed with all the insistence of a fact, while the former was yet in bondage to abstract philosophy, dominated too much by crude and unproven hypotheses.

Given the presence of tophi, the diagnosis of a “gouty diathesis” is assured; in their absence it is but speculative.

It is upon this dictum that we would take our stand, and this without depreciating in any way the pioneer researches of Garrod. For it must be recognised that the increasing differentiation of joint diseases has proceeded apace. How many are now affiliated to specific germs, not to mention the undreamt-of light thrown on their inward characters by X-rays! Scudamore’s work appeared exactly a century ago, Garrod’s in 1876. The conclusion then seems inevitable that many of their alleged cases of gout—at any rate, those unattested by tophi—would now be relegated to widely different categories.

But this zeal for infinite cleavage and subdivision, so characteristic of the modern school, far from diminishing, does but accentuate, the diagnostic valency of the tophus. It still remains the infallible criterion of diagnosis, and, for myself, I feel convinced that infinitely more good than harm would ensue if we refuse to recognise any individual as being of the “gouty diathesis” unless he exhibit these objective stigmata thereof.

Of course to some such a rigid attitude will spell anathema. I hear them say in oracular tones: “Never forget gout, or awful indeed will be your awakening.” More harm, say they, is wrought by failure to recognise gout than by diagnosing gout where none is. Doubtless they are right in counselling us not to forget gout, but not to the exclusion of all else. For, at issue with them, I hold it better to miss gout than to miss syphilitic, gonorrhœal, and other forms of arthritis.

“A name being so readily found for an obscure disease, the[254] practitioner considers himself as excused from the difficult task of nicer discrimination.” Thus wrote Scudamore a century since, a rebuke and a warning for all time.

Tophi in Relation to Arthritis

How elated we are, and rightly, when in an obscure form of arthritis we pounce on these objective criteria of gout, how apt to deem our diagnostic quest as ended, and with what fatal glibness the time-worn “gout” slips from our lips, sure, alas, of ready and almost complaisant acceptance. Fallacious inference, all too prevalent, that the presence of tophi stamps any concomitant arthritis as “gouty.”

True, tophi are pathognomonic of gout, but their existence does not confer on their host immunity from all other forms of arthritis. In view of the increasing light shed upon joint disorders, who can doubt that (and this not only for our forefathers) the tophus has too often proved a veritable snare, allaying all diagnostic doubts, lulling us into false security? For an individual may, for example, exhibit auricular tophi and be the victim also of an arthritis, but the latter is not inevitably “gouty.” All that can be assumed at sight is merely that the joint disorder, whatever its nature, has ensued in a subject of “gouty diathesis.”

For it may be of specific infective origin, gonococcal, syphilitic, pneumococcal, etc. Quâ a concomitant arthritis, then, the diagnostic significance of tophi, at any rate when of ab-articular site, must not be overrated. It is at once a beacon and a warning. In other words, the diagnosis of a co-existent arthritis as “gouty” should not be entertained pending the exclusion of all other forms of arthritis.

Conversely, in the absence of tophi, the diagnosis of an arthritis as “gouty” is not absolute, but presumptive.

For in the lack of these objective stigmata how can the authenticity of our diagnosis be established? Is it not when achieved a nosological rather than a diagnostic feat? Put otherwise, is not our diagnosis, especially in initial attacks, largely topographical? Not that we would for one moment decry the advantage of realising the predilection of certain organisms for this or that particular joint: of the gonococcus for the sterno-clavicular, of typhoid for the hip, post-scarlatinal rheumatism for the phalangeal joints, etc. But we would drive home the fact that our diagnosis in initial attacks of “gout” is very largely topographical. Let but inflammatory trouble ensue in the big toe, and forthwith we assume it gout, as if, forsooth, this particular joint were immune from all other forms of disease, this, too, while in the same[255] breath we comment on its extreme liability to injury. So, indeed, we maintain, is the marked predilection of gout for the toe joint explained. Is not this a little crude? Does not the same circumstance increase its liability to infection and, we may add, not less important, its proneness to static deformities? But to this we shall recur when discussing differential diagnosis.

To return, how often, apart from the above pitfalls, is the diagnosis “gout” arrived at without any search for tophi wherewith to support the assumption. Our contention is that even in primary attacks of gout our search for tophi should be exhaustive. If undiscoverable, why not be honest with ourselves and recognise that our diagnosis is presumptive pending their development?

Sir William Roberts on this point observes: “As a rule, diagnosis of acute articular gout is easy, but exceptional cases of difficulty occur. The gouty character of the inflammation is affirmed by the discovery of uratic concretions in the rim of the ear or elsewhere.”

Again, Sir William Osier, discussing the diagnosis of acute gouty polyarthritis, remarks: “We have had of late years several cases admitted for the third or fourth time with involvement of three or four of the larger joints. The presence of tophi has settled the nature of a trouble which in previous attacks has been regarded as ‘rheumatic.’”

One may, we think, gather from these two statements the inference that both these distinguished authorities hold tophi to be the only infallible criterion upon which to base a diagnosis of gouty arthritis. In my own practice I must affirm that I never feel justified in christening any arthritis as gouty unless I have discovered tophi, and then only when to the best of my ability all other known causes of arthritis have been excluded.

Frequency of Tophi in True Gouty Arthritis Underestimated

In reviewing the statistics of authors as to the frequency of the incidence of tophi in their cases of assumed gouty arthritis I am inclined to think their relative infrequency is apparent rather than real, in other words that many of their cases of alleged “gouty” arthritis which lack tophi would, if investigated by modern methods, have been shown to be due to other causes of arthritis, this especially as regards their assumed cases of chronic gout. For who can doubt that prior to the discovery of X-rays many cases of osteoarthritis, etc., were thus erroneously labelled? Nor indeed, as we hope to show later, is it improbable[256] that similar fallacies obtained even in regard to acute types of gout, particularly when of polyarticular distribution.

It will be noted that we confine our criticisms to those examples of “gouty” arthritis unassociated with tophi. But if, as we maintain, our scepticism be justifiable, then it follows that it diminishes to an unknown extent the percentage of cases of genuine “gouty” or uratic arthritis which lack tophi.

Difficulty of detecting Tophi

Apart from the probability of such erroneous relegation to the “gouty” category of non-gouty arthritides, there remains this further consideration, the ease with which tophi, even when superficial, may be overlooked. We look for pearly white concretions, and if none are seen we straightway assume that tophi are absent. This, I am sure, is a very common pitfall. At their inception tophi are neither white nor hard. They are largely fluid and soft to touch. The skin over them may be unchanged in colour or reddened. Only when mature, and the overlying skin is thin, do they assume the ordinary aspects of a tophus. These observations apply not only to tophi in the ears, but to those in the vicinity of the small joints of the hands and feet or elsewhere. I would urge that in the case of all soft localised swellings of dubious nature in the neighbourhood of the phalangeal joints aspiration with a hypodermic syringe will often prove very helpful. If fluid can be withdrawn and the same microscopically examined, it will more often than is supposed reveal the presence of biurate crystals.

More information is badly needed as to the relationship of their formation to acute attacks of gout. Garrod on this point remarks: “The deposits are probably formed during an attack of gout, but occasionally they appear shortly afterwards. In one case, of which I have notes, the ears were carefully examined without result when the patient left the hospital, but within ten days, on re-examination, a deposit was found. Perhaps some fluid was effused during the fit, but being at first transparent, could not be easily distinguished.” Sir Dyce Duckworth, too, observes: “After acute attacks of gout have passed off there may follow renewed pain in the neighbourhood of the joint, and later there is discovered a nodular or soft swelling. In the latter case there may be fluctuation, indicating a liquid collection of urates. This should never be opened. In a few weeks this tumour tends to indurate, grow more compact, and a so-called ‘chalky’ concretion is established.”

Reflection upon the foregoing considerations leads me to the[257] conclusion that not only was Garrod right in his affirmation that “gouty inflammation is invariably attended with the deposition of urate of soda,” but more that examples of true uratic arthritis which lack tophi are exceptional, and that in their absence their diagnosis as such cannot be with certitude established.

We have now, we trust, sufficiently defined our attitude towards the tophus, the salient objective stigma of a “gouty diathesis,” and the indispensable rôle it plays in enabling us to establish the diagnosis of articular gout.

Acute Articular Gout—Localised Variety

The nonchalance with which not a few writers dismiss the diagnosis of acute gout when located in the great toe or elsewhere in the foot is, to say the least of it, somewhat remarkable. “It is a very easy matter,” say they, and as an earnest of their good faith are silent as to the many pitfalls that await the unwary. Should they deign to differential diagnosis, they are at pains to discriminate between it and acute articular rheumatism, which re classical outbreaks in the toe seems a little superfluous! But not a word of traumatic lesions, infective processes and static deformities, all infinitely more likely stumbling-blocks.

Did all cases conform to the classic type, acute sthenic gout, it might be held relatively easy. But such are not, to say the least of it, common nowadays. More often than not our examples are, as Garrod terms them, of acute asthenic character. As he observes: “There may be indeed pain and tenderness in the toe, and some amount of swelling, but accompanied with little heat or redness, and all febrile disturbance may be absent; still œdema is generally observed and itching and desquamation follow.”

That diseases, like their victims, alter with environment is but too clear. Who can doubt that the gout of the Regency has to-day assumed a milder clinical facies? Physicians of those days were haunted with the fear of confounding it with erysipelas and phlegmon. Still, while no such fears apparently beset us to-day, it were well to walk circumspectly.

Thus, recently a friend of mine came across an instance of what he deemed acute gout in a metacarpo-phalangeal joint. Its failure to respond to colchicum and the growing intensity and extent of the local inflammation suggested incision, when, lo, pus issued, to the subject’s comfort, but to his own chastening!

There are, however, many more likely sources of fallacy, these, too, of the most diverse type, inasmuch as they differ according to the exact location in the foot of the assumed gouty process. For while the big toe is the site of predilection for the initial manifestation, it is not always so. The primary outbreak may be located in any of the smaller joints of the foot, or outside them in related structures: in the heel, the sole, or the tendo Achillis.[259] These vagaries greatly enhance the difficulties of diagnosis. For the process of differentiation will vary according to the particular joint or structure involved, the predilections of certain infective processes, not to mention the marked liability of the foot to painful disturbances of static origin.

Differential Diagnosis

Inasmuch as the primary outbreak may be located in any part of the foot, we purpose, for reasons just cited, dealing seriatim with gout in (1) the big toe; (2) the instep; (3) the heel; (4) the sole.

Gout in the Big Toe

Infections.—There is no â priori reason why any of the infections may not find a nidus in the first metatarso-phalangeal joint. Thus, Garrod, as we know, held gouty subjects specially liable to pyæmia. In rare instances, the primary focus has been in or near the great toe, and has consequently been mistaken for gout. The rapid progress of the disease would of course soon clear up the nature of the case. But if the subject has previously suffered from gout, such a diagnostic error at first sight is quite excusable. Accordingly, as a safeguard in all doubtful cases, inquiry should be made as to the existence of bladder troubles, piles, etc., especially any recent operation in this or other regions.

Again, while gout in its articular form is rarely, if ever, met with in children, it must be recalled, on the authority of Sir James Goodhart, that rheumatism in their instance is occasionally limited to one joint. Moreover, this distinguished physician actually saw it localised in the great toe, “in a case in which the subsequent course of the disease showed that it was acute rheumatism.”

Acute Gonococcal Arthritis.—We may recall that Van Swieten, a disciple of Boerhaave, held that sometimes a wife while nursing her gouty husband had contracted the same disorder. A tribute, we fear, to Van Swieten’s diplomacy rather than to his clinical acumen—an euphemism for gonorrhœal rheumatism!

Of course in adolescents or in young adults monarticular pain, with or without swelling, heat, or redness, should not suggest “gout,” but an infective disorder either in the joint or the related bone-ends. At the same time middle-aged men enjoy no immunity from gonorrhœa, and we may add that gonococcal infection of the metatarso-phalangeal joints is not so uncommon. When located in that of the great toe, it is easy to see how readily the acute arthritis may be confused with gout. But, unlike the latter, its duration is measured by months or weeks rather than[260] by days. It is well to recollect, too, that “gouty” persons are more prone to develop arthritis following gonococcal infection. Given therefore a history even remote, we should in doubtful cases recall the longevity of the organism, its persistence in the prostatic recesses, and the need for bacteriological investigation.

Traumatic Lesions.—Its exposed situation renders the big toe very liable to trauma. Often, too, the injury being slight, and not followed by any immediate consequences, the connection may easily be overlooked. A blow or a fall may readily bruise the synovial membrane without at first any external sign. But given trivial hæmorrhage into the cavity or subjacent tissues, an acute synovitis with effusion is induced.

Again, joint disorder following injury is usually monarticular, whereas the same when the outcome of so-called “constitutional” causes is generally oligo- or poly-articular. The relevancy of this is obvious when we recall that initial attacks of gout are monarticular. Accordingly, given a history of definite injury to the toe joint, the question arises, Is it acute gout or acute traumatic arthritis? this especially if the subject has not had a previous attack of gout at this site.

Here I would lay stress on the fact that indirect rather than direct traumatisms are more common antecedents or determinants of gout, viz., sprains or strains. Moreover, in reviewing the writings of the older physicians one is driven to the conclusion that frequently a septic cellulitis, synovitis, or a frankly traumatic arthritis was confused with acute gout.

The following examples cited by Scudamore are, we contend, susceptible of such an explanation: “A gentleman much subject to gout, when considering himself unusually well, underwent the slight operation of having the nail of the great toe cut on account of its improper growth. The toe was much pressed, and gouty inflammation was the immediate consequence.” In another case “the patient, never before having suffered the gout, tore off a broken portion of the thumb-nail, so as to make the part tender. Very soon the thumb and part of the hand put on a swollen and shiny appearance, and was exquisitely painful. A poultice was applied. Suddenly on the third evening the pain quitted the thumb and seized the toe, next the ankle, then the knee, and lastly the great toe of the other foot. Throughout he secured ease and sleep till the first light of the morning appeared, and hence facetiously observed that the gout in this respect assumed all the behaviour of a ghost.” Was not this probably a case of septic absorption with cellulitis and a mild degree of sapræmia, evoking arthralgic pains?

In conclusion, without denying the potentialities of trauma,[261] whether direct or indirect, in determining an outbreak of gout, we would submit that its diagnosis under such circumstances should not be hastily arrived at, but by the slower process of elimination, this especially if the trauma has involved slight abrasions with the possibility of sepsis. A quick response to colchicum would of course be highly suggestive of gout.

Acute Osteoarthritis.—It is perhaps not so widely recognised as it should be that osteoarthritis not uncommonly attacks the metatarso-phalangeal joint of the great toe. It becomes enlarged owing to the hypertrophy of the articular ends. Like similar lesions in the small joints of the hand, the big toe joint from time to time undergoes exacerbation, with increased vascularity and local heat, which, though of minor degree, may by a superficial examiner be readily misinterpreted as gout. The parts are painful, somewhat swollen, hot, and tender, but the local symptoms are never intense, and constitutional disturbance is lacking. The presence of osteoarthritic lesions elsewhere and the revelations of skiagraphy will suffice for differentiation of such cases from asthenic articular gout.

Static Foot Deformities

Hallux Valgus with Inflamed Bunion.—Scudamore in his “Treatise on Gout” observes that “the bursal disease over the first joint of the great toe, which is familiarly known as bunion, is a very common complaint with gouty persons.” In view of the fact that no reference is made in the context to the absence or presence in such cases of a condition of hallux valgus, one is led to believe that Scudamore overlooked the deformity and regarded the local bursitis as the outcome of a gouty inflammation of this structure.

Bradford and Lovatt, discussing hallux valgus, observe: “There may be pain and irritability in the great toe joint, and in severe cases extreme pain and difficulty in walking, which is usually attributed by the patient to gout.” We would only qualify this statement by the fact that the local heat, redness, and swelling that in this condition so often follow slight injuries or excessive walking is not only so interpreted by the patient, but far too frequently also by his medical attendant.

Routine examination of the bare foot will minimise the chance of such a fallacy, though of course it must be borne in mind that a gouty subject may present this deformity. But when we recollect that hallux valgus of slight degree “is almost universally present after middle childhood,” we see that, given the presence of this static foot deformity, any inflammatory process in the[262] superjacent structures is infinitely more likely to be due to an inflammatory bursitis than to a gouty arthritis.

Given an inflamed bursa with cellulitis spreading over the dorsum of the foot, confusion with acute sthenic gout is all too easy. But in our experience, mirabile dictu, the ordinary more or less chronic circumscribed redness over the bunion is but too commonly misinterpreted as gout, this particularly in women, despite the rarity with which gout attacks their toe and the frequency with which their footgear is precisely adapted to produce hallux valgus. Given therefore the presence of this static foot deformity, we should in the absence of objective stigmata of gout, viz., tophi, suspend our diagnosis pending observation of the results obtained by local treatment of the displaced toe.

Hallux Rigidus.—This deformity is but too often overlooked, and if marked by pain and more or less rigidity of the first metatarso-phalangeal joint, it may, in lack of adequate examination, be flippantly dismissed as “gout,” this more particularly in its later stages, when, in addition to pain and stiffness therein, the joint is swollen, tender to the touch, and the bony ends actually enlarged. Here again local examination, if carefully carried out, will suffice to obviate such errors, while the quick response to rest and appropriate applications, with correction of the frequently associated sunken arch, will sufficiently attest its true nature.

Metatarsalgia.—As pointed out in our previous work on Fibrositis, “this painful condition is more often than not confused with rheumatism or gout.” We have known subjects wander to nearly every spa on the Continent under such a misconception. Not to mention the financial expense, the dietetic penances imposed, the consequences of such faulty diagnosis, are by no means trivial, for the intensity of the suffering may reduce the walking capacity to a minimum.

The neuralgic pain radiates into the toes and often upwards into the leg, usually comes on while walking, and is relieved by the removal of the boot. For its detection any altered relationship in the position of the third, fourth, and fifth metatarsals, especially their displacement to a lower level than normal, should be noted, and any limitation of the power of dorsal flexion of the foot likewise estimated. The presence of callosities under the heads of the metatarsals is very suggestive of this painful condition.

Gout in the Instep

Next to the metatarso-phalangeal joints, the tarsal articulations are the most frequent site of initial attacks of gout. Here again we would insist on the necessity of excluding infections of[263] the tarsal joints or shafts and even more important, static foot deformities.

Gonococcal Arthritis.—In a table compiled by Garrod from those of Foucart, Brandes, Rollet, and Fournier, the relative frequency of the implication of individual joints in gonorrhœal arthritis shows that out of a total of 119 the tarsus and metatarsus were attacked in five instances. In the more acute cases the periarticular swelling, local heat, and pink blush may be confused with acute gout. The resemblance is enhanced in that, as in gout, the overlying tendon sheaths are liable to become inflamed and distended with fluid.

Tuberculous and Syphilitic Disease of the Tarsal Joints or the Related Joints.—In cases of obscure pain and inflammatory trouble in the instep the possibility of arthritic and bony lesions of this nature should not be overlooked, especially if there be suggestive lesions elsewhere, or if the history afford evidence of the possibility of such contingencies.

Pes Planus.—In all cases of pain and swelling, with or without redness, in the instep, it is well to recollect that, though flatfoot may for a long time exist without giving rise to symptoms, it frequently happens that, in sequence to some unusual strain on the plantar arch, the static disturbance in the foot enters quite abruptly on a painful phase. Congestion and swelling of the foot is common, and actual teno-synovitis of the tibial and peroneal muscles is not infrequent. Tenderness, too, at points of ligamentary strain is almost always present, and more or less constant pain.[40]

The frequency with which the local and referred pains of flatfoot are misinterpreted as “gout” and dietetic restrictions and other useless and uncalled-for methods of therapy enjoined is well exemplified by a case which has just left our consulting room.

The subject, a middle-aged spinster of lean kind, came to Bath for treatment of her supposed gout, and for which indeed she had previously received spa therapy. Her feet when bared showed a condition of double hallux valgus with related bursal thickenings.[264] The occasional inflammation of these latter structures and the recital of doubtful ancestral proclivities were the sole evidence on which was based the diagnosis of gout. In addition, as is so frequent in hallux valgus, there was associated therewith a bilateral flatfoot, and it may be added that in the left foot a hammer-toe had been removed some years since. Unfortunately the neglected symmetrical flatfoot had, as so frequently happens, initiated, through the erroneous deflection of a body weight, a condition of chronic villous synovitis in both knees. This again was misinterpreted as but another proof of her assumed “gouty” diathesis. Reflecting upon human nature, how curious the reluctance with which such subjects elect to part with their “gout.” Women especially hold tenaciously thereto, even those of austere type, clinging to the taint handed down to them from some far-off ancestor whose “superfluity of naughtiness” was a by-word among his generation. To exchange gout, morbus dominorum, for “flatfoot” and inflamed “bunions,” savours of degradation, and to couple it with aspersions on their footgear is well-nigh insupportable. Nor are the “lords of creation,” we fear, exempt from this failing. We recall during the War being consulted by a highly placed officer who complained of gout. A well-preserved man of nigh sixty years of age, he obviously prided himself on being immaculately booted. As such patients frequently do, he brought his own diagnosis of “gout.” Removing his footgear, manifestly too small, his crucified toes stood out with bunions in a state of hot resentment. But impeachment of his boots was too much for him. Persuasion and argument were futile, and I doubt not he walks to-day stiff, a martyr to his vanity. “Il faut souffrir pour être belle.”

Gout in the Heel

In some instances the first manifestations of gout occur in the heel, while in others the sheath of the neighbouring tendo Achillis is the part first invaded. Probably there is no region of the foot in which there exist more pitfalls, and doubly careful should we be before concluding that any painful or inflammatory condition thereof is one of “gout.”

Referred Pain.—Pain in the heel affords many loopholes for misinterpretation. It may, as Sir James Paget pointed out many years ago, be symptomatic of a renal calculus. In my own experience it is sometimes complained of by the subjects of internal hæmorrhoids, the pain waxing and waning with the variations in the rectal trouble, and only disappearing permanently when the piles have been radically treated. It is, again, a[265] symptom sometimes complained of by the victims of enlarged prostate.

Local Sources of Fallacy

If the pain and tenderness be located on the under-surface of the os calcis, there are several misconceptions possible.

If the pain and tenderness be located on the posterior surface of the os calcis, or in the tendo Achillis, the following should be excluded before assigning the trouble to “gout”:—

Gout in the Sole

There is a wide disposition to regard all painful or unpleasant sensations in the sole of the foot as evidences of “goutiness.” It may be recalled that Strabo, according to Plutarch, apostrophised heat or itching of the feet at night as “the lisping of the gout.” Duckworth, too, emphasised the frequency of this symptom in the gouty, and Sir Charles Scudamore also held heat and dryness of the sole as frequent harbingers of acute attacks. Now, did we[266] but confine our hazards as to gout only to cases marked by heat or itching in the sole, possibly little harm might result; but unfortunately there is a flippant readiness to relegate all obscure pains or abnormal sensations in the sole to the “gouty” category. Needless to say, this is quite unjustifiable. We need not reiterate the bounden necessity of excluding all static foot deformities, but we should in addition recall the various types of plantar neuralgia.

Plantar Neuralgia.—Occasionally, as we have pointed out elsewhere, the pain is of almost unendurable severity. It constitutes one of the types of so-called partial sciatica, the pain and paræsthesia being confined to the plantar nerves. Indeed, pain, numbness, hyperæsthesia, or sweating of the sole are often symptomatic of a definite neuritis. Such may follow typhoid fever or caisson disease, and in this latter be of aggravated type. When we realise that the pain in these cases may be limited to the tips of the toes or the ball of the great toe, we see how readily it may be confused with “gout.” Fortunately plantar neuralgia is exceptionally rare; but even after exclusion of the foregoing causes we should, before pronouncing any such neuralgia to be “gouty,” recollect that plantar neuralgia or hyperæsthesia is very common in alcoholism and hysteria.

Erythromelalgia.—Among the exceptional cases that find their way to spas are examples of this rare disorder. Almost invariably they come under the diagnosis of “gout” or “rheumatism.” When we reflect that in the majority of instances the initial burning pain typical of the disease is located in some part of the sole of one foot, and that the associated redness and vascularity may be delimited to the ball of the great toe, the heel, or outer or inner side of the foot, we see the danger of its being too easily referred to “gout.”

If seen at the zenith of an attack, the severe pain, the local heat, the intense purplish redness, the distension of the veins, and in some instances œdema, how close the resemblance to gout! Precisely also, as in gout, the simulation of a deep-seated inflammatory process is very pronounced. Indeed, in not a few examples of erythromelalgia fruitless incisions have been made. Accordingly in all cases of pain, redness, and swelling in the sole of the foot, we should canvass the possibility that we may be face to face with an instance of erythromelalgia, a disorder which, like gout, is most frequently met with in men of middle age.

In drawing to a close our remarks on the diagnosis of acute gout in the foot, we would emphasise the fact that in all such cases the bare feet should be thoroughly examined. For, apart from infective and traumatic lesions, the frequency with which the various static foot deformities are confused with “gout” is[267] incredibly common. That gout may co-exist with hallux valgus or other distortion we readily admit, but this does not absolve us of our responsibility—correction of the static deformity. Combine this, if you will, with constitutional treatment if there be evidence, i.e., tophi, of a “gouty” diathesis, but, we repeat, correct the mechanical defect. For gout may come and go, but static errors remain. In so doing, the victim will be saved much preventable suffering, and, for aught known to the contrary, the removal of irritation and local congestion may haply minimise the chances of subsequent gouty outbreaks.

Anomalous Sites for Initial Outbreaks

While primary attacks are in the vast majority of instances localised to the foot, if not actually to the toe, it is well to recollect that very rarely the knee, the wrist, elbow, or ankle may be the chosen spot. In such cases there is need for exceptional caution before committing oneself to a diagnosis of gout. Certainly not until all other known causes of acute arthritis of monarticular type have been excluded.

If in the knee or wrist, any possibility of injury or strain should be thoroughly canvassed. To make assurance doubly sure, a radiograph should always be taken. Specific infective forms of arthritis then call for careful elimination—i.e., gonococcal, etc. If there be no history of such, a painstaking search should be made for any local foci of infection, e.g., mouth and accessory cavities. If any be found, they should be radically treated, as it is much more likely that the arthritis is due thereto than to gout.

If, notwithstanding a meticulously careful investigation, no cause can be assigned, we may entertain the possibility of its being gout, the more legitimately if the subject be a middle-aged man coming of gouty ancestry and exhibiting himself tokens of this diathesis, i.e., tophi. It would be confirmatory, too, if, apart from its exceptional localisation, the joint disorder in its course conformed to that typical of gout in the toe, in other words if it was of sudden nocturnal onset, showed marked daily remissions in temperature and pain, responded swiftly to the action of colchicum, and was not protracted beyond the usual week or ten days.

Sir Hale White, discussing the diagnosis of acute gout of unusual localisation, remarks: “The real difficulty in acute cases comes when it is suggested that an acute arthritis with pyrexia and swelling and redness of a joint other than that of the great toe is caused by gout. I have recently seen the difficulty in one patient in the wrist, in another in the knee. Such cases, if they are not gout, are some bacterial arthritis.”

Acute Gouty Polyarthritis

In the pathways of medicine, as in other walks in life, we are apt to become stereotyped, to fall into grooves, and sooner or later the inevitable rude awakening comes. Thus, so prone are we to think of gout as belonging, so to speak, to the foot, that when it erupts elsewhere it is often the last contingency to dawn upon us. If we diagnose it too often and too readily in the foot, we do so too seldom when it appears in joints remote.

Now, while in initial outbreaks of gout it is exceptional for more than one joint to be affected, it is not always so. For sometimes in those strongly predisposed by heredity not one, but many joints, may be implicated in the primary attack. Such cases, however, are extremely rare.

As a rule, this acute gouty polyarthritis occurs in individuals who have already experienced articular paroxysms at the classic site; but in the subsequent polyarticular attacks the toe joints are often unimplicated, and the disease is located in the larger articulations—the knees, ankles, wrists, or elbows. Herein resides the difficulty of diagnosis in these cases: the likelihood of confusion with other polyarthritides.

Confronted then with an acute polyarthritis of obscure nature marked by pain, redness, swelling, and pyrexia, what are the points necessary to establish it as being of gouty origin?

The sex and age should be noted, also the heritage, habits, and occupation. A history of previous attacks located in the big toe would be of prime value. The presence of a cardiac valvular lesion, while it would suggest a previous attack of acute rheumatism, would in no wise negative the possibility of the subject developing gout in later life. Here I may say that if the subject is over thirty-five and has never had acute rheumatism or acute gout, it is much more likely at his time of life that his acute polyarthritis is of gouty than of rheumatic origin.

As to the character of the pyrexia, it is usually of low grade; but if the condition be afebrile, it is even more suggestive of a gouty arthritis. But recollect, too, that the pyrexia in gonococcal arthritis is also of low grade or absent.

[269]

There is nothing distinctive of gout either in the character or distribution of the articular lesions. The ankles, knees, hands, wrists, are most commonly involved, much more rarely the elbows, shoulders, or hips. Naturally the local changes will differ according to the joint involved and the structures implicated; but these local variations in appearance, including œdema, may all be met with in any form of infective arthritis.

As to uric acid excretion, Osler, who was deeply interested in this type of arthritis, held that any lowering of the ratio of the uric acid to the urea excretion would be significant of gout. Also we should, as these cases of acute gouty polyarthritis are of the nature of successive paroxysms (“series et catena paroxysmulorum,” to use Sydenham’s expression), note any variations in the uric acid output ensuing pari passu with their rise and wane.

Last, but most important of all, a thorough search must be instituted for tophi, not only in the ears, but elsewhere. If anything could emphasise the indispensable rôle played by tophi in the diagnosis of gout, it would be our utter inability to effect in their absence a diagnosis of these acute types of gouty polyarthritis. The establishment of the existence in situ of such articular uratic deposits disposes forthwith of all possible doubts as to the true nature of the case; but if, as so frequently happens, the tophi when present are of ab-articular site, then we must withhold our decision pending the exclusion of certain other joint disorders, to the differentiation of which we now proceed.

Differential Diagnosis

The class of disorders that call for discrimination are those of infective origin. In the first place, acute articular rheumatism must be excluded; nor is it less necessary that we should eliminate gonorrhœal and syphilitic types; while, last, but not least, that vast group, the undifferentiated infective arthritides, is but too often a source of confusion.

Acute Articular Rheumatism

Unquestionably many cases of acute gouty polyarthritis have been confounded with acute articular rheumatism, and vice versâ. Garrod on this point remarks: “That many cases of acute gout have been mistaken for acute rheumatism I do not doubt, and, on the other hand, that some few cases of acute rheumatism have been regarded as of a gouty nature I am no less certain. I may refer to the oft-quoted case related by Dr. Haygarth in which[270] gout was supposed to have been transferred from the extremities to the heart as an example of the latter error.”

It is only, of course, with that type of acute gouty polyarthritis accompanied by pyrexia, and not the afebrile variety, that confusion with acute articular rheumatism is possible. What then are the points of discrimination?

Acute Gonococcal Arthritis

This disorder, as we know, is sometimes of oligo- or poly-articular distribution. Moreover, as the attendant pyrexia may be slight or absent, it may readily be confounded with the afebrile variety of acute gouty polyarthritis. Osier, discussing diagnosis of the latter condition, observes: “A patient with three or four joints red, swollen, and painful in acute rheumatism has fever,[271] and while pyrexia may be present, and often is, in gout, its absence is, I think, a valuable diagnostic sign.”

This is of course true, but it still remains necessary, for reasons above cited, to eliminate acute gonorrhœal arthritis. The tendency to such confusion has been emphasised by Sir Rose Bradford and Sir William Roberts, and I would urge the necessity of being alive to this possibility even in middle-aged men. One thing is certain, viz., we should be extremely chary of pronouncing any coincident urethral discharge to be a so-called “gouty urethritis”; nor should we translate any coincident conjunctivitis or iritis as further evidence of the articular affection being “gouty.” It is far more likely to be gonococcal. Apart from these inflammatory ocular affections, the relics also of previous attacks—viz., irregularity in contour or inequality in size of the pupils—have before now put me on the right track in obscure types of polyarthritis.

To sum up, the following are distinctive characters of generalised gonorrhœal arthritis:—

Etiology.—History or presence of urethral discharge and isolation of the gonococcus.

Onset.—Insidious, seldom acute.

General Symptoms.—Absent or slight relatively to extent and severity of joint mischief. Pyrexia, low grade or absent.

Distribution of Lesions.—Preference for large joints. Special liability of sacro-iliac, chondro-costal synchondroses, sterno-clavicular, tibio-fibular, and temporo-maxillary joints.

Local Characters.—Persistent passive effusion or peri-articular boggy swelling, with redness and local heat. No tendency to migrancy. Joint swelling very persistent.

Associated Phenomena.—Involvement of fasciæ, especially plantar, and of tendon sheaths, very distinctive, while coincident iritis or conjunctivitis is almost diagnostic.

Secondary Syphilitic Arthritis

The ease with which a subacute arthritis of this nature may be confounded with “gout” or “rheumatism” calls for comment. We have met with cases despatched to spas under this impression. The customary intermittent fever of secondary syphilis is usually present. The detection of periosteal nodes in addition to the joint swellings should arouse suspicion, while the presence of secondary syphilides and the rapid response to specific treatment will be confirmatory.

I well recollect some years ago a young farmer being sent to me by a medical man as suffering from gouty arthritis with gouty[272] eczema. The eruption was a typical roseola, and the condition promptly cleared up under anti-syphilitic treatment.

Acute Rheumatoid or Atrophic Arthritis

While the old term “rheumatic gout” still clings to this affection, it has now achieved its isolation from gout on the one hand and rheumatism on the other. The fact that it occurs in young women in whom gout never occurs, and has a very marked clinical facies of its own, should almost preclude the possibility of its being a source of confusion. Still, for the sake of completeness, we append its chief characteristics.

Age and Sex.—Most common in young women.

Onset.—More or less acute.

General Symptoms.—Continuous low grade pyrexia, quick pulse, and rapid emaciation, and commonly concomitant gastro-intestinal derangements.

Distribution of Lesions.—Polyarticular. Beginning in the small joints, it spreads centripetally, with a tendency to symmetry. No migrant trend, but a steady, progressive involvement of joint after joint, including temporo-maxillary and cervical articulations.

Local Characters.—Overlying skin of affected joint white or semi-asphyxial in tint. Contour spindle-shaped, but in terminal stages shrinkage from atrophy of articular structures sets in. Muscular wasting and contracture conspicuous features.

Associated Phenomena.—Trophic and vasomotor changes prominent, but no tendency to cardiac lesions.

Infective Arthritis of Undifferentiated Type

It were well in approaching any acute polyarthritis of obscure nature to bear in mind the axiom that any or all infections may be complicated by arthropathies, also that if the said polyarthritis does not respond quickly to colchicum or salicylate of soda we are almost certainly dealing with an infective arthritis either of specific or undifferentiated type. The specific forms of infective arthritis, as far as seems necessary, have been dealt with, but those rarer forms not referred to, viz., influenzal, pneumococcal, dysenteric, meningococcal, etc., have also to be borne in mind, if the history reveal any recent occurrence of these disorders.

Still far more common than any of these are the acute infective arthritides of undifferentiated type. As we before remarked, an extraordinary general clinical resemblance obtains between these types of joint disorder and acute gouty polyarthritis. Indeed, in the absence of tophi, their differentiation is well-nigh impossible.[273] Even the blood picture in both types of the disorder is strikingly similar in the matter of leucocytosis and secondary anæmia.

Recently Dr. Henry A. Christian, lecturing at a clinic of the Harvard Medical School, emphasised this clinical similarity and the difficulty of discriminating between these two types of joint disorder. As he rightly says, “while there is a definite acute gouty polyarthritis (as evidenced by external tophi or deposits in bone or cartilage with variations in uric acid output) and also an equally definite infective arthritis, yet between those two there is a very considerable number of cases that present some of the factors suggestive of gout and other factors suggestive of an infectious arthritis, and there is where the difficulty comes.”

This is precisely the state of affairs, and one may well ask where gout ends and infection begins. Let us take an example. A man exhibiting tophi, the subject also of pyorrhœa alveolaris, develops an acute polyarthritis. What then is the nature of the joint disorder? There is a gouty element in his case, as attested by tophi, also an infective element, as evidenced by oral sepsis.

Now are we to regard such a case as one of infective arthritis of undifferentiated type occurring in a gouty subject, or are we to proceed on the assumption that the presence of tophi negatives the possibility of infection and forthwith to class it as a case of acute gouty polyarthritis of so-called metabolic origin?

This is no theoretical quibble. In the Royal Mineral Water Hospital, Bath, one constantly meets with cases in which the very elect would be puzzled as to whether they should be placed in the category of gouty or in that of infective arthritis. I have at present in my wards a middle-aged man, stout of body, rubicund of face, with well-marked auricular tophi and widespread arthritis. There are no tophi round his joints. On X-ray examination his phalanges show Bruce’s nodes, and his phalangeal joints show changes indistinguishable from those constantly met with in infective arthritides occurring in non-gouty subjects.

Indeed, this overlapping may proceed still further, the gouty and the infective characters neighbouring in such proximity as to suggest actual fusion, a community of origin. What else in truth can be the inference, when one meets with examples in which the peri-articular tissues are the seat of demonstrable uratic deposits, while the X-ray changes within the joint proper, the bone and cartilage, are typically those met with in infective arthritis?

Now, who will deny that if tophi were absent in such a case we should without hesitation hold the case to be one of infective arthritis? My own contention is that even in the presence of tophi the same appellation is indicated. In other words, I submit that acute gouty polyarthritis is itself but a form of infective[274] arthritis which derives its specific character from the associated uratic deposits.

As to differentiation of the latter from these cryptic infective arthritides, this will rest mainly on—

(1) The presence of tophi;

(2) A history of previous attacks in the great toe;

(3) A swift response to colchicum.

In addition, acute gouty polyarthritis is confined to middle-aged males, while no period of life is immune from infective arthritis, and both sexes are equally liable.

Again, acute gouty polyarthritis may be afebrile. Pyrexia when present is moderate in grade, its curve undulating as the paroxysms rise and wane. In infective arthritis the temperature curve is irregular and erratic.

Lastly, the uric acid output in acute gouty polyarthritis drops a day or two before the paroxysm, rises markedly after its inception, then sinks again. Also we may add that occasionally glycosuria or albuminuria is present.

In conclusion, I would allow myself a brief digression regarding these infective arthritides of undifferentiated type. They constitute the bulk of the cases of arthritis that find their way to the Royal Mineral Water Hospital, Bath, under one or other of the appellations “gout,” “rheumatism,” and “rheumatic gout.” It is within this category that most of the cripples met with at spas fall, and their obduracy to “drug” treatment accounts for their belated despatch thereto.

I would that I could sufficiently emphasise the imperative necessity of early recognition of the true nature of these cases. Colchicum is a most valuable drug, and so is salicylate of soda. But they have their limitations. They act swiftly or not at all. Persistence with them in the absence of any response is worse than futile: it is definitely prejudicial. Because of our unreasoning devotion, our almost fetishistic addiction, to these drugs, I often feel that these agents, especially salicylate of soda, have made more cripples than they have saved. For, unfortunately, unqualified reliance on these drugs is apt to blind us to the surgical necessities of these cases. Foci of infection pass unnoticed, joints stiffen at unfavourable angles, and not infrequently a potential bread-winner is lost.

I make no apology for this digression, for it is, strictly speaking, wholly apposite, this in view of the fact that failure of quick response to the action of colchicum or salicylate of soda, say within a week, speaks in favour of the infection having ensued in a non-gouty as opposed to a gouty subject.

Chronic Articular Gout

If the diagnosis of acute types of articular gout often presents difficulties, these same are, if anything, accentuated when we approach its chronic manifestations. For, apart from uratic deposits, the anatomical lesions that ensue in joints the seat of long-continued gout have no specific character. In short, there is nothing pathognomonic of gout in the changes produced, and which, as a matter of fact, we know to be capable of production, by many different morbid agencies. Surely this lack of specificity in its structural lesions should make us very chary of admitting to the category of chronic articular gout any examples of arthritis destitute of uratic deposits.

In our chapter on classification we emphasised the desirability of restricting the usage of the term chronic articular gout to that type long since known as tophaceous gout, this because there is little, if any, doubt that that variety known as chronic deforming gout (syn. arthritis deformans uratica) is largely made up of examples of rheumatoid or atrophic arthritis and hypertrophic arthritis or osteoarthritis.[41]

As to osteoarthritis, I do not for a moment deny that uratic[276] deposits may be met with in its victims. One frequently meets with patients, the subjects of osteoarthritis of the hip, who at the same time exhibit tophi in the ears.