Gouty Arthritis.

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

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

Printed in Great Britain.

Dedicated
TO
MY WIFE

PREFACE

“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 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?

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 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 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.

TABLE OF CONTENTS

CHAPTER I
HISTORICAL AND INTRODUCTORY

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 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 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 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.

“Tollere nodosam nescit medicina podogram.”

Ovid, Ep. ex Pont., I, 3, 23.

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.

Said the hero of the Trago-podagra:

“Irritantibus me

Soleo occupere multo iracundior

His vero qui cogitant nihil adversum mihi

Benignam adhibeo mentem, facilisque fio.”

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 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 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

“Et tophus scaber, et nigris exesa chelydris Creta.”

Georg., ii., 214.

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 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 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.”

“At vero (quod mihi aliisque licet, tam fortunæ quam Ingenii dotibus mediocriter instructis, hoc morbo laborantibus solatio esse possit) ita vixerunt atque ita tandem mortem obierunt magni Reges, Dynastæ, exercituum classiumque Duces, Philosophi, aliique his similes haud pauci.

“Verbo dicam, articularis hicce morbus (quod vix de quovis alio adfirmaveris) divites plures interemit quam pauperes, plures sapientes quam fatuos.”

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 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:—

“Blessed Gout, most desirable Gout, Sovereign Antidote

Of murdering Maladies; powerful corrector of Intemperance;

Deign to visit me with thy purging Fires, and throw off the

Tophous Injury which I may have suffer’d by Wine and Wit,

Too hard for the Virtue of a Devotee upon a Holy Festival.

But fail not thy humble Supplicant, who needs thy

Friendly Help, to keep his tottering Tenement in

Order: Fail him not, every Vernal and Autumnal

Æquinox.”

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:—

“Yet am I better

Than one that’s sick o’ the Gout: since he had rather

Groan so in perpetuity, than be cur’d

By the sure physician, death: who is the key

To unbar these locks.”

Cymbeline.

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 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 ...

‘Multæ formæ infortunatorum,

Meditatio pœnæ, et consuetudo,

Podagros miseros consolentur.’

Lucian.

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 sweat of his brow, and the chance of his being visited with gout will be very small.”

“O fortunatos nimium, sua si bona norint

Agricolas!”

Georg., ii., 458.

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 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.

“Αυσιμελου Βάκχου, και λυσιμελους Αφοδίτης,

Γένναται θυχατηρ, λυσιμελὴς, Ποδὰγρα.”

CHAPTER II
THE PEDIGREE OF GOUT

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.

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 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 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, 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 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, 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.

CHAPTER III
EARLIER THEORIES OF PATHOGENESIS

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.

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 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 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.”

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 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.

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.

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.

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 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 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 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, 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 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.

CHAPTER IV
DEFINITION, CLASSIFICATION, ETIOLOGY, AND MORBID ANATOMY

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.

“A constitutional disease, producing an external local inflammation of a specific kind; the susceptibility to it often depending on hereditary bodily conformation and constitution, but with great frequency wholly acquired; almost never occurring before the age of puberty, not frequently under the age of five-and-twenty, and most commonly between the ages of twenty-five and forty; affecting chiefly the male sex, and particularly persons of capacious chest and plethoric habit; in the first attack invading usually one foot only, and most frequently at the first joint of the great toe; but in its returns, affecting both feet or other situations, as the hands, knees, and elbows; and not only in the articular structure, but also in the other textures belonging to the moving powers, different parts being affected together or in succession; often accompanied with sympathetic inflammatory fever, which is usually marked by nocturnal exacerbations and morning remissions; much disposed to return at periodical intervals, and for the most part preceded by some premonitory symptoms.”

In extenuation of this prolixity, Scudamore observed that, “In an attempt to mark the general characters of gout, I feel the necessity of entering into a description rather in detail, instead of confining myself to a brief definition, because the disease is too complex in its nature to be distinguishable with certainty by a few signs alone.”

Trousseau, in his lectures on gout, refrains, perhaps wisely, from attempting any definitions of the disorder, resting content with the reflection that, “The production in excess of uric acid is a pathological phenomenon, inherent, like all others, in the disease, and, like all the others, it is dominated by a specific cause, which we know only by its effects, and which we term the gouty diathesis.”

Sir William Roberts defines gout “as a constitutional disorder characterised by paroxysmal attacks of inflammation of the joints, associated with the formation of chalk-like concretions in and about the joints.”

Sir William Osler regards gout as “a nutritional disorder, one factor of which is an excessive formation of uric acid, characterised clinically by attacks of acute arthritis, by the gradual deposition of urate of soda in and about the joints, and by the occurrence of irregular constitutional symptoms.”

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.

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? 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! 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 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; 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 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, 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.

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

(1) Gout is always an hereditary disease.

(2) The factors currently regarded as predisposing agencies are in reality merely determining agents, not the cause of gout, but the occasion of its appearance.

(3) In the absence of an hereditary taint, these same are powerless to evoke the specific manifestations of true “gouty” inflammation as estimated by associated uratic deposition.

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 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. 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 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 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 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 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 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 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:

“Ut Venus enervat vires, sic copia vini,

Et tentat gressus, debilitatque pedes.”

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 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—

(1) Heredity is the sole predisposing factor in gout.

(2) That the differentiation between the usually cited predisposing and exciting causes is unwarrantable.

(3) That both alike are merely determinants.

(4) That their influence as such in exciting outbreaks is exerted through the medium of infection, this achieved either directly or indirectly.

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 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 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 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 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.

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.

CHAPTER V
PATHOLOGY OF GOUT—PROTEIN METABOLISM

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 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 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 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, 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 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 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.

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

(1) Functional changes in the liver, a depressed urea-ferment action.

(2) A deficient uric acid excretion by the kidney, possibly due to the changed uric acid combinations in the blood.

(3) These pathological conditions may be “hereditary” or “acquired,” from overeating, alcohol, lead, etc.

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.

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.

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 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 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.

CHAPTER VI
NUCLEIN METABOLISM

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 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 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 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.

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:—

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:—

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 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. 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 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, 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 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.

CHAPTER VII
SOURCES OF URIC ACID

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.

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.

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, 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.

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 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 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.

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]

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., 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 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 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 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 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).

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.

CHAPTER VIII
FORMATION AND DESTRUCTION OF URIC ACID

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.

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 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, 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 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.

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).

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 “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 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.

CHAPTER IX
URIC ACID IN RELATION TO GOUT

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:—

(1) The alkalinity of the blood is not diminished during the attack.

(2) The excretion of uric acid is not lessened during the paroxysm, but the reverse; there is, therefore, no ground for the supposition that there is a temporary diminution in the capacity of the kidneys to excrete uric acid.

(3) The amount of the uric acid in the blood is not greater during the attack than in the intervening period, and if these points be accepted, we must start de novo in search of the cause of the acute paroxysm.

The iconoclastic revelations of the foregoing researches may 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:—

(1) That in the intervals between acute attacks of gout the elimination of uric acid lies within the normal limits, but that

(2) For one or two days prior to an acute attack an appreciable decline in the output of uric acid occurs. This, however, is not so marked as the subsequent

(3) Increased output of uric acid during the acute attack. According to Magnus Levy the increase may reach from 0·3-0·5 gram, daily, and more, and may sometimes last for a week or even two.

(4) Following attack a tardy decline in uric acid output to former level.

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 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:—

(1) A gouty subject can excrete exogenous purins as adequately as a normal man, but he takes longer to do so.

(2) If the extra purins be taken during a course of atophan, even this departure from normal is obliterated, i.e., the customary delay in excretion is obviated.[18]

But, unfortunately for the diagnostic valency of this symptom 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:—

(1) Reduction and retardation of the excretion of exogenous purin, though common in gout, is not invariable.

(2) The same is not peculiar to gout, but occurs in other disorders.

(3) Its diagnostic valency, as a characteristic feature of gout, is correspondingly depreciated.

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 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 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, 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:—

(1) The prolongation of the period of exogenous uric acid excretion, and

(2) Increased uric acid excretion during attacks of sub-acute arthritis,

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 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”:—

(1) Slight fluctuation in the endogenous excretion.

(2) Low endogenous average.

(3) Small percentage of exogenous purin nitrogen excreted as uric acid nitrogen.

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.

CHAPTER X
THE RENAL THEORY OF 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.

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 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 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.

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 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.

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 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 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, 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.”

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 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 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 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—

(1) Some gouty subjects never develop granular kidney.

(2) Some individuals with granular kidney never develop gout.

Also we have to recall that—

(1) Paroxysms of gout often occur for many years before the symptoms of interstitial nephritis develop.

(2) In persons of gouty stock acute attacks may ensue at an age at which nephritis is practically unknown.

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 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, 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?

CHAPTER XI
URICÆMIA IN GOUT

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 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.

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 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 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 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:—

(1) In normal subjects no increase in the uric acid content of the blood follows exogenous purin intake.

(2) The uric acid content of the blood in patients suffering from chronic diseases, other than gout or renal disease, is similarly not augmented on a purin-rich diet.

(3) The uric acid content of the blood is increased more or less markedly, after a short period of purin feeding, in the presence of defective renal elimination.

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 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:—

(1) In gout there is a condition not of uricæmia, but of hyper-uricæmia.

(2) That on the average the blood in gouty subjects contains twice as much uric acid as that of non-gouty subjects, as evidenced by comparison of the average uric acid content of the blood in Pratt’s series of gouty cases (4·5 mg.) with Adler and Ragle’s non-gouty examples (1·7 mg.).

(3) In contrast with non-gouty subjects, the uric acid content of the blood in gouty subjects is augmented on a purin-rich diet.

(4) Both in the inter-paroxysmal periods and during attacks the uric acid content of the blood, when on a mixed diet, is higher than when on a purin-free diet.

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.

According to Walker Hall, the following example illustrates the effect of purin-free as opposed to purin diet on the uric acid blood content in a gouty subject:—

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 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.

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 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:—

(1) That in gouty subjects pronounced variations of the uric acid content of the blood may occur which are not attributable to the purin content of the food.

(2) That in non-gouty arthritis similar fluctuations in the blood content of uric acid, irrespective of diet, also occur.

(3) That in normal persons, on a purin-free diet, the blood content of uric acid, as far as is ascertained, does not show such variations.

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 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:—

(1) No constant relation has as yet been established between the uric acid content of the blood and acute attacks of gout.

(2) No variations in the same apparently herald or accompany typical acute paroxysms.

(3) Attacks may occur with a sub-normal uric acid blood content.

(4) The tissues of gouty subjects apparently possess an enhanced binding capacity in respect of uric acid.

(5) Given impaired renal excretion in gouty subjects, the uric acid content of the joint fluid rises markedly, exceeding that of the blood.

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 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 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.”

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.