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.