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.
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.
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 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.
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.
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.”
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.
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.
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.”
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.”
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.