Opening
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.
I. HISTORICAL AND INTRODUCTORY
The Antiquity of Gout. Prevalence of Gout in the Anglo-Saxon Period. Views of the Humoralist. The Aphorisms of Hippocrates. Introduction of the Word Gout. Early Views as to the Nature of Tophi. The “Honour of the Gout.” That Gout confers Immunity from other Disorders. Growing Infrequency and Attenuation of Gout pp. 1-13
II. THE PEDIGREE OF GOUT
Tardy Dissociation of Chronic Gout. Identification of Muscular Rheumatism. Differentiation of Chronic Gout from Arthritis Deformans. Cleavage of Arthritis Deformans into Two Types. Elimination of the Infective Arthritides pp. 14-20
III. EARLIER THEORIES OF PATHOGENESIS
Garrod’s Theory. Antagonistic Views. Histogenous Theories. Antecedent Structural Changes. Hepatic Inadequacy. Hyperpyræmia. Nervous Theories. Growing Scepticism as to Garrod’s Pathogeny of Gout pp. 21-34
IV. DEFINITION, CLASSIFICATION, ETIOLOGY, AND MORBID ANATOMY
Definition. Classification. Suggested Classification of Articular Gout. Etiology and Morbid Anatomy. Bodily Conformation and Individual Temperament. Locality, Race, Climate. Food, Drink, Occupation. Lead Poisoning. Mental and Physical Over-exertion. Summary. Morbid Anatomy pp. 35-58
V. PATHOLOGY OF GOUT-PROTEIN METABOLISM
Revelations of the Bio-chemist. The Formation of Urea. Fate of the Amino-acids. Seat of Formation of Urea. Amino-acids in Relation to Gout. The Glycocoll Theory of Gout. Urea Excretion in Gout. Creatine and Creatinine. Inborn Errors of Metabolism pp. 59-70
VI. NUCLEIN METABOLISM
The Isolation of Nucleic Acid. Researches on Spermatozoa. The Discovery of Purins. Uric Acid a Derivative of Nucleic Acid. The Chemistry of Uric Acid and the Purin Bodies. Chemical Constitution. Properties of Uric Acid. Uric Acid in the Blood. Gudzent and Schade’s Theories. Organic Combinations. Complexity of the Problem pp. 71-82
VII. SOURCES OF URIC ACID
Exogenous Purins. Exogenous Uric Acid Excretion. Fate of the Unexcreted Purins. Endogenous Purins. Source of Endogenous Purins. Proteins and their Derivatives. Amino-acids and Dicarboxylic Amino-acids. Endogenous Uric Acid Excretion. Factors influencing Endogenous Uric Acid Excretion. Physiological Conditions. Pathological States. Ingestion of Certain Drugs. Synthetic Formation of Uric Acid pp. 83-97
VIII. FORMATION AND DESTRUCTION OF URIC ACID
Distribution of the Enzymes. Stages in Disruption of Nucleic Acid. Destruction of Uric Acid pp. 98-106
IX. URIC ACID IN RELATION TO GOUT
Uric Acid Excretion in Gout. Uric Acid Variations in Acute Gout. Uric Acid Variations in Chronic Gout. Retarded Exogenous Uric Acid Output. Lowered Endogenous Uric Acid Output. Other Anomalies in Excretion in Gout. Purin Metabolism in other Disorders. Purin Metabolism in Chronic Alcoholism and Plumbism pp. 107-116
X. THE RENAL THEORY OF GOUT
Anomalies in Uric Acid Excretion in Gout. Uricæmia in Nephritis. The Relationship, if any, between the Amounts of Uric Acid and of Urea, and Total Non-protein Nitrogen in Human Blood. Uricæmia not necessarily due to Renal Defect. Uricæmia not Peculiar to Nephritis. Uricæmia does not necessarily Portend Gout. To what may be ascribed the Deficient Eliminating Capacity of the Kidney for Uric Acid. Uratic Deposits in Nephritis. Differentiation of Uratic Deposits in Gout and Nephritis. Clinical Associations of Gout and Granular Kidney pp. 117-132
XI. URICÆMIA IN GOUT
Folin and Denis’s Method. Uric Acid a Normal Constituent of Blood. Effect of Exogenous Purins. Uric Acid Content of Blood in Gout. Hyperuricæmia in Non-gouty Arthritis. Variations in Uric Acid Content of Blood independently of Diet. What Relationship, if any, Exists between the Uric Acid Content of the Blood and Attacks of Gout. Discussion of the Foregoing Data. The Significance of Uricæmia. Sources of Fallacy in Uric Acid Estimation. Disabilities of Modern Tests. Need for further Investigations pp. 133-148
XII. URATOSIS IN RELATION TO GOUT
Constitution of Tophi. Mode of Formation. Localisation of Uratic Deposits. The Causation of Tophi. Solubilities of Uric Acid. Tophi in Relation to Uricæmia. Tissue Affinities for Uric Acid. Retention Capacity of Tissues for Uric Acid. Clinical Evolution of Tophi. The Cause of the Inflammatory Phenomena. Non-toxicity of Uric Acid. Are the Precursors of Uric Acid Toxic? pp. 149-170
XIII. THE RISE OF THE INFECTIVE THEORY
Boerhaave’s Forecast of the Infective Theory. Ringrose Gore on Infective Origin. Leucocytosis in Acute Gouty Polyarthritis. Chalmers Watson’s Researches on Gout in a Fowl. Trautner’s Suggestion of a Specific Infection pp. 171-176
XIV. GOUT AS AN INFECTION
Local Foci of Infection: Dental, Nasal, Pharyngeal, etc. Gastro-intestinal Disorders. Variation in Free HCL. Intestinal Disorders. Infection or Sub—infection pp. 177-187
XV. GOUT AS AN INFECTION (continued)
Analysis of the Acute Paroxysm. The Evolution and Life History of Gout. Analogies between Gout and the Specific Infective Arthritides. Correlation of the Metabolic Phenomena of Gout with the Postulated Infective Element pp. 188-199
XVI. CLINICAL ACCOUNT
Acute Localised Gout. Prodromal Symptoms. Dyspepsia. Premonitory Symptoms of Tophus Formation. Premonitory Articular Pains. The Acute Paroxysm. Detailed Consideration of Phenomena. Mode of Onset. Localisation. Nature of Pain. General Phenomena. Pyrexia. Changes in the Blood. Uric Acid Excretion. Local Phenomena. Tophus Formation pp. 200-213
XVII. CLINICAL ACCOUNT (continued)
Acute Gouty Polyarthritis. Mode of Invasion. Distribution of Lesions. Local Characters. Constitutional Symptoms. Changes in the Blood. Leucocytosis. Collateral Phenomena of Gout. Lumbago, Sciatica, etc. Incidence of Gouty Stigmata in Various Types of Fibrositis pp. 214-224
XVIII. CLINICAL ACCOUNT (continued)
Chronic Articular Gout. The Joint Deformities of Chronic Gout. Tophi: Their Evolution and Distribution. Other Sites of Tophi. Affinities between Gout and other Diseases. Gout in Relation to Glycosuria. Gout in Relation to Phlebitis. Cutaneous Disorders. Gout and Nephritis. Prognosis in Gout pp. 225-246
XIX. ETIOLOGICAL AND CLINICAL DIAGNOSIS
Articular Gout. Etiological Diagnosis. Clinical Diagnosis. Introductory Remarks. The Diagnostic Status of Tophi. Tophi in Relation to Arthritis. Frequency of Tophi in True Gouty Arthritis Underestimated. Difficulty of Detecting Tophi pp. 247-257
XX. CLINICAL DIAGNOSIS (continued)
Acute Articular Gout. Localised Variety. Differential Diagnosis. Infections. Acute Gonococcal Arthritis. Traumatic Lesions. Acute Osteoarthritis. Static Foot Deformities. Hallux Valgus with Inflamed Bunion. Hallux Rigidus. Metatarsalgia. Gout in the Instep. Gonococcal Arthritis. Tuberculosis and Syphilitic Disease of the Tarsal Joints or the Related Joints. Pes Planus. Gout in the Heel. Referred Pain. Local Sources of Fallacy. Post-calcaneal Bursitis. Synovitis of the Tendo Achillis. Gout in the Sole. Plantar Neuralgia. Erythromelalgia. Anomalous Sites for Initial Outbreaks pp. 258-267
XXI. CLINICAL DIAGNOSIS (continued)
Acute Gouty Polyarthritis. Differential Diagnosis. Acute Articular Rheumatism. Acute Gonococcal Arthritis. Etiology. Onset. General Symptoms. Distribution of Lesions. Local Characters. Associated Phenomena. Secondary Syphilitic Arthritis. Acute Rheumatoid or Atrophic Arthritis. Age and Sex. Onset. General Symptoms. Distribution of Lesions. Local Characters. Associated Phenomena. Infective Arthritis of Undifferentiated Type pp. 268-274
XXII. CLINICAL DIAGNOSIS (continued)
Chronic Articular Gout. Chronic Monarticular Gout. Monarticular Gout in Large Articulation a Rarity. Chronic Gout of Oligo-articular Distribution. Its Confusion with Chronic Villous Synovitis. Villous Synovitis Static and Non-gouty in Origin. Clinical Symptoms of Villous Synovitis. Bilateral Hydrarthrosis. Peri-synovial and Peri-bursal Gummata. Chronic Gout of Polyarticular Distribution. Differential Diagnosis. Osteoarthritis. Local Characters of Joint Swellings. Rheumatoid Arthritis. Local Characters of Joint Swellings. Nerve Arthropathies. Hæmophilic Arthritis pp. 275-285
XXIII. CLINICAL DIAGNOSIS (continued)
Skiagraphy. Significance of Local Areas of Rarefaction. The Radiographic Types of Gouty Arthritis. Differential Diagnosis. Infective Arthritis. Hypertrophic or Osteoarthritis. Rheumatoid or Atrophic Arthritis pp. 286-292
XXIV. IRREGULAR GOUT
Historical Account. Murchison’s Views. Retrocedent Gout. Gout in the Stomach. Cardiac and Cerebral Forms. Other Irregular Manifestations. Conclusions. Infantile Gout pp. 293-307
XXV. OCULAR DISEASE IN THE GOUTY
Evidence of Gout in the Eye. Deposition of Urates. Gouty Diathesis. Significance and Location of Tophi. Relative Incidence of Iritis. Metastasis. Arthritic Iritis. Gouty Iritis not a Clinical Entity. Ocular Symptoms in Hyperuricæmia. False Gout. Retinal Hæmorrhage. Neuro-retinitis. Glaucoma. Conclusions pp. 308-326
XXVI. TREATMENT OF GOUT
Radical Treatment of Local Foci of Infection or Toxic Absorption. Diet in Acute and Chronic Gout. The Fallacy of Fixed Dietaries. Thorough Physical Examination a necessary Prelude to Dieting. Need for Collaboration of Clinician and Bio-chemist pp. 327-341
XXVII. TREATMENT OF GOUT (continued)
Regulation of Diet in the Gouty. The Individual Foodstuffs, Proteins, Carbohydrates, Fats, Vegetables, Fruits, Condiments. Special Dietaries. Amylaceous Dyspepsia. Hyperchlorhydria pp. 342-371
XXVIII. MEDICINAL AND OTHER MODES OF THERAPY—ACUTE GOUT
Initial Purgation. Colchicum in Acute Gout. Method of Administration. Preparations and Dosage. Colchicine, Salicylate of Colchicine. Atophan. Alternative Remedies in Acute Gout. Salicylates. Alkalies. Quinine. Thyminic Acid. Anodynes in Acute Gout. Local Measures. Analgesics. Liniments, etc. Ionisation. Massage. Surgical Methods pp. 372-388
Chapter XXIX
MEDICINAL AND OTHER MODES OF THERAPY (continued)—INTER-PAROXYSMAL PERIOD
Prophylactic Measures. Treatment of Atonic Dyspepsia. Hyperacidity due to Organic Acids. Treatment of Hypochlorhydria. Alkalies, Atophan, and Colchicum as Prophylactics pp. 389-396
Chapter XXX
MEDICINAL AND OTHER MODES OF THERAPY (continued)—CHRONIC ARTICULAR GOUT AND ASSOCIATED MORBID CONDITIONS
Alkalies. Contrasts between Salts of Sodium and Potash. Differential Indications for their Usage. Alternatives. Salicylates. Benzoates. Hexamine. Iodides. Iodine. Albumen Compounds. Collosol Preparations of Iodine. Guaiacum. Local Measures in Chronic Articular Gout. Treatment of Tophi. Ionisation. Surgical Measures. Treatment of Associated Morbid Conditions. Fibrositis. Lumbago. Sciatica. Acute Brachial Fibrositis. Local Massage. Oxaluria. Glycosuria. Hyperchlorhydria. Gouty Phlebitis. Gouty Eczema. Gouty Nephritis pp. 397-417
XXXI. CLIMATO-THERAPY, HYDRO-THERAPY, ETC
Climate. Choice of Residence. Clothing. Exercise. Massage. General Hydro-therapy. Importance of thorough Physical Examination. Individual Reactive Peculiarities. Prophylactic Measures. Contra-indications and Untoward Complications. Methods of Application of General Hydro-therapy. Immersion Baths. Aix and Vichy Massage. Vapour Baths. Indications for Sub-thermal Baths. Local Hydro-therapy. Varieties of Douche. Treatment by Hyperæmia pp. 418-430
XXXII. MINERAL SPRINGS AND CHOICE OF SPA
Difficulties of Definition and Classification. Radio-activity. General Principles of Spa Treatment. Physiological Action of Radium Emanation. Activation of Body Ferments. Influence of Uric Acid Metabolism. Increased Excretion of Uric Acid. Subjective Phenomena of Gout in Relation to Blood Content and Excretion of Uric Acid. Therapeutic Action and Application. Alimentary Disorders. Glycosuria. Raised Blood Pressure. Choice of Spa. The Spare and the Obese. Waters Suitable for Various Types of Dyspepsia. Bickel’s Experiments. Mineral Waters in Associated Morbid Conditions. Glycosuria. Oxaluria. Phlebitis. Respiratory Disorders. Fibrositis. Gouty Eczema. Uric Acid Gravel. Arterio-sclerosis. Chronic Nephritis. Concluding Remarks on Spa Treatment pp. 431-465
INDEX pp. 457-469
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.”
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.
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.
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.
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.