Are the Precursors of Uric Acid Toxic?
Naturally the upholders of the uric acid theory were loth to find their fetish uric acid was allotted a meaningless rôle. That it should be deemed inert was to dislodge the very corner-stone of the imposing superstructure they had been at such pains to raise. Uric acid not responsible for the genesis of gout! But, haply, maybe their position was still unassailable; for what of the purin bases, the forerunners of uric acid? Might not the blame lie with these?
Straightway xanthin, hypoxanthin, adenin, etc., were credited with pernicious potencies.[26] Nor did they lack apparent support from the experimental side. Thus, Mandel affirmed that purin bases, apart from infection, might originate pyrexia. Others, again, noted that in dogs and rabbits fed on adenin, degenerative changes in the kidneys ensued, with deposits resembling uric acid and urates in their substance. The fact, too, that guanin-gout was occasionally met with in swine, also lent colour to their views.
Moreover, that ingestion of these congeners of uric acid led in animals to renal lesions, seemed to support the contention of many, that renal disorder might be the primary cause of gout. But, unfortunately, Kolisch and Weintrand’s assertion that the alloxur bases were found in increased quantities in the urine of gouty patients was contradicted by Schmoll, His, Laquer, and others.
Still more cogent, apparently, the announcement in 1910, by Brugsch and Mallory, that they had seen a typical attack of gout ensue in a gouty patient in sequence to a dose of 0·5 gram of hypoxanthin. Nor did this reaction of gouty persons fail of confirmation, as in the same year, Brugsch and Schittenhelm, in gouty patients, noted attacks of arthritis, after the administration of nucleinic acid.
Nevertheless, we must beware of laying too much stress on isolated experiments of this nature, so hypersensitive are some of the victims to any strange or unaccustomed ingesta. Were all the myriad other determinants of gouty attacks eliminated, over-drinking, trauma, mental disturbances, etc.? for be it recollected, all the victims of these experiments with hypoxanthin and nucleinic acid were gouty subjects, i.e., potentially liable to attacks at any moment.
Even admitting the ingestion of, e.g., hypoxanthin was followed by a gouty outbreak, it must be insisted that mere sequence does not establish causation. Clinically, on the whole, there is little or nothing to support the contention that the purin bases have much to do with the pathogeny of gout. “The proof of the pudding is in the eating,” and contrary to the view, at one time so prevalent, that purin foodstuffs were most deleterious, it has been found that, for the average gouty person, a purin-free dietary is not only not essential, but prejudicial. Those, therefore, who may be inclined to see in the above sequence proof of a causal connection, would do well to recall Bacon’s dictum that “there is in the human mind a peculiar tendency to dwell on affirmative and to overlook negative instances.”
In conclusion, we must affirm our belief that neither uric acid nor its precursors is responsible for the fever, local inflammation, and general constitutional disturbance in gout, for uric acid and the urates are themselves practically non-toxic. Albeit, though holding this view, I do not for one moment suggest that uric acid has nothing whatever to do with gout. The fact that tophi, its pathognomonic stigmata, are compounded of biurate of soda, would per se stamp such an attitude as untenable. On the other hand, uric acid must be viewed in its proper perspective as a concomitant or sequel of gout, the essential cause of which must be sought elsewhere.
CHAPTER XIII
THE RISE OF THE INFECTIVE THEORY
With the abandonment of the uric acid theory of the causation of gout we see a reversion, curiously enough, to the hypothesis held by the ancient physicians as to its pathogeny. Like Cælius Aurelianus and Paulus Ægineta, we now incline to refer the origin of the disorder to some derangement of the gastro-intestinal tract. This conception indeed endured up to the latter half of the eighteenth century, and was definitely maintained by Van Swieten in his commentary on the aphorisms of his great preceptor, Boerhaave. For him the fons et origo mali in gout was disturbance of the functions of the alimentary tract.
“Indigestio viscorum pro origine proxima hujus morbi habitur.”
The English Hippocrates, too, Sydenham, in his classic treatise observes: “The more closely I have thought upon gout, the more I have referred it to indigestion, or to the impaired concoction of matters both in the parts and juices of the body.”
Not only in regard of the initial site are we reverting to the views of old-time physicians, but the tenor of our reflections upon the nature of the disorder exhibits a like trend. Thus the older physiologists, doubtless impressed by its fulminant onset and clinical features, ranked gout amongst the fevers, describing it indeed as a “tertian fever terminating in fourteen days.”
Indeed, the great Boerhaave avowed his belief that gout was contagious—a forecast, we may take it, of the modern theory of infection. Subsequently his pupil, Van Swieten, went a step further, maintaining that sometimes wives, while nursing husbands afflicted with gout, contracted the malady!
Passing now to relatively modern times, it will be noted that in 1864 Laycock classed acute gout with rheumatic fever as an “excretory fever,” while Parkes even prior to this, in 1860, wrote: “I define gout after Garrod as a febrile infection with inflammation about the joints leading to a deposition of urate of soda.”
But it must be freely acknowledged that, subsequent to Garrod’s discovery of uric acid in the blood in gout, the spell exercised by the uric acid theory was such that it dominated medical thought almost to the exclusion of all other possibilities. All energies were forthwith centred upon endless laborious researches into possible modes of uric acid formation, but which, alas, did little to purge men’s minds of their obsession that uric acid was the proximate cause of gout.
Still it would be unfair to infer that the disabilities attaching to the uric acid hypothesis were wholly unrealised. Indeed, it may be fairly said of Duckworth’s reflections on the pathogeny of gout that they definitely foreshadowed the infective theory. His views postulated what may be termed a toxic tropho-neurosis, wherewith to explain the paroxysmal nature, the periodicity and protean symptomatology of the disorder.
But in the early part of 1900 we may, I think, discern in some words of Chalmers Watson a change coming over our thoughts as to the pathology of gout, this as the result of some studies of a series of examples of acute gouty polyarthritis. The results of his researches were such that he challenged the accuracy of Garrod’s original observations as to the lowered alkalinity of the blood during acute attacks, also his claim that the uric acid content of the blood was increased and the uric acid excretion diminished during the paroxysm. If these points be accepted, he says we must start de novo in search of the cause of the acute paroxysm.
He noted also the interesting fact that during acute attacks of gout a very marked leucocytosis was present. Another outstanding feature was the presence in large numbers of peculiar myelocyte-like cells, half as many in number as the ordinary finely granular oxyphil leucocytes. Reflecting on these findings, he observes: “It would, I think, be well if much less attention were centred on the excretion of uric acid alone as the all-important factor in the disease, whether in its acute or chronic form. The results obtained by the line of investigation here followed suggest the advisability of more attention being devoted to the histo-chemical characters of the blood, the ratios of uric acid to other important products of metabolism, and, if opportunity be afforded, an examination of the bone marrow.”
To other interesting features of these researches of Watson’s we shall allude later, but, concerned here more with tracing the evolution of the infective theory of gout, we would hasten to add that in September of the same year Ringrose Gore, discussing the inadequacy of the uric acid theory, boldly avowed and ably propounded his belief in the infective origin of the disorder.
Thus he writes: “I consider a toxin to be the cause of this disease. If so, such toxin must be formed in the intestine. As the symptoms of gout are constant, it must be a definite toxin, the product of a definite bacillus acting upon the intestinal secretion. As gout is capable of being caused in any subject, it must be one of the bacilli normally found in the intestinal canal.”
Nor did Gore lack supporters in his suggestion that the alimentary tract was the primary source of the changes in the metabolism of gout. For in the same year Minkowski, Le Gendre, and in this country Watson, hazarded the view that intestinal derangements, through the medium of their resultant toxins, initiate disturbances in the liver, and these in turn determine those obliquities of metabolism typical of gout.
At the same time their contentions derive colour from the researches of Grübe, who, despite traditional views, maintained that in gout the hydrochloric acid of the gastric juice, far from being increased, was in most cases diminished or wholly lacking, while, on the other hand, lactic acid was present in some instances.
In 1903 Woods-Hutchinson ably contended that “gout and lithæmia are mere symptom names for a miscellaneous group of chronic toxæmic processes of widely varied origin, characterised by the production of uric acid and the urates.” He held that the uric acid in gout as well as the associated phosphoric acid are merely a criterion of the measure to which the nucleins of the body cells (chiefly probably of leucocytes) have undergone destruction in consequence of their invasion by a toxin or toxins of organic or inorganic nature. He furthermore contended that the rôle of the liver in gout was purely negative, consisting in its inability “to absorb or transform into harmless excretory substances the excess of toxins brought to it by the portal vein.”
In 1904 Falkenstein furnished collateral evidence that the starting point of gout lay in a diseased condition of the gastric glands, those responsible for the secretion of hydrochloric acid. The supply of hydrochloric acid being deficient in the gouty, their digestive capacity is distinctly lowered. Abnormal fermentation ensues with insufficient oxidation, and “the substances containing quantities of nuclein are partly prevented from being further split up, and partly favour the synthetic formation of uric acid.” He would thus refer the excessive formation of this latter directly to the diseased glands. He further observes that, despite the deficiency of hydrochloric acid, the gastric juice is often hyperacid, this being due to the presence therein of organic acids, such as butyric, lactic, and acetic acids.
In the same year Chalmers Watson, as the outcome of investigations into gout as it occurs in the fowl, held that:—
(a) There is ample evidence to prove that the uric acid in the blood is not the primary factor in gout, and
(b) Uric acid can be deposited in cartilages and other tissues, even in considerable amount, without the association of any inflammatory phenomena.
He concludes that the last-mentioned point clearly proves that:—
(c) Uric acid is not the factor which causes the inflammatory phenomena characteristic of the acute attack.
He then proceeds to inquire as to the nature of the toxic principles in the blood, and the factors that influence their passage thence into the tissues. In connection with these queries he emphasises the necessity of envisaging the all-important part played by the alimentary canal, holding that herein doubtless resides the clue to the solution of the problem.
Post-mortem examination of the fowl revealed marked catarrh of ileum, duodenum and large intestine, while the pancreatic duct was filled with catarrhal products. The congested spleen, apart from proliferation of its endothelial elements, exhibited a marked increase in the number of granular leucocytes in the capillaries and sinuses as compared with the features of the control sections, which, as Chalmers Watson observes, is the characteristic reaction of this organ to invasion by bacteria or their products. The kidneys on examination revealed here and there uratic deposits surrounded by inflammatory tissue. The relationship of these to the inter-lobular arteries was such as to suggest an infection by the blood stream.
The collecting tubules in the deeper part of the cortex and medulla were markedly dilated and choked with granular leucocytes. Sections of the organs were examined bacteriologically by Muir, the necrosed areas revealing the presence of “rod-like bodies of the size of large bacilli massed together in dense clusters; the appearance suggested that these rods were either degenerated cell products of an unusual character, degenerated bacteria, or crystalline in nature.” Examination of the same by polariscope by Marshall disposed of the possibility that they were crystalline. Finally it was thought that the appearances generally favoured the view that the rods in question were bacteria which had lost their reaction to bacterial stains owing to bacteriolytic or other changes.
As to the inference that the defunct fowl fell a victim to acute gout, Watson based it on the existence of the uratic deposits in the tissues, the changes in the synovia, the widespread thromboses, and the renal necroses. As to the other lesions, the chief interest centres in those located in the intestine, pancreas and kidney. The state of the pancreatic duct raises the question as to whether it points to any connection between these changes and the common occurrence of glycosuria in gouty subjects. The alteration in the leucocytes merits notice in that similar changes were found by Watson in the blood in acute gouty polyarthritis, the same, moreover, being subsequently confirmed by Bain.
Chalmers Watson’s final conclusion was that “the clinical features of gout—regular or irregular, acute or chronic—are more adequately explained by the light of our present knowledge of infections, relapses, and immunity than by any other theory. The distinctive feature of this infection in gout is that the toxin or toxins have a special property of disturbing nitrogenous metabolism in a manner favourable to the deposit of uric acid in certain tissues.”