Uric acid, like the “purin bodies” (xanthine, hypoxanthine, guanine, and adenine), is derived from nucleins, i.e., from the breaking down of tissues rich in cells. The end-product of purin or nuclein katabolism uric acid represents but a further stage in the oxidation of the purin bodies. To the serial enzymatic transformations that mark its derivation from nucleic acid we shall allude later, but at this juncture we are concerned not with the mode of formation of uric acid, but with the sources thereof.

In this sphere we are greatly indebted to the pioneer researches of Burian and Schur. These observers noted that on a diet rich in nucleins (sweetbreads, liver, kidneys) the total daily excretion of uric acid was considerably higher than on a milk or purin-free diet. This difference in response to varying dietaries, in respect of the excretion of uric acid, led Burian and Schur to the conclusion that the purins excreted must be partly of exogenous and partly of endogenous origin; in other words, the exogenous purins are derived from the nucleins ingested in the food, whereas the endogenous are the outcome of the breaking down of the cellular tissue of the organism itself.

Here it may be noted that all the ingested purins are not excreted in the urine as uric acid, for some pass away as purins. Moreover, the amount excreted will vary with the kind of purin ingested, and also with the species of the animal that consumes it. Thus, in man “only one half of the hypoxanthine administered as such appears as uric acid in the urine, and but one fourth of the purin in nuclein when that is fed. In the dog, compared with man, about ten times as much purin disappears in its passage through the organism; in the rabbit, about three times” (Flack and Hill).[11]

In amount about 0·4-0·7 gramme of uric acid is excreted in human urine daily, and the purin bodies, hypoxanthine, xanthine, and adenine, in small quantities.

Beyond exogenous and endogenous purins there is yet one other possible source of uric acid, viz., its synthetic formation within the organism. This supposition took origin in Horbaczewski’s discovery that in the laboratory he was able to produce uric acid by the interaction of urea and glycocine, a finding afterwards confirmed by Latham. The theory was then advanced that a similar synthesis might be effected by the kidneys; but it was found that glycocine and urea, even when given in excess to mammals, caused no change in the uric acid excretion.

So much by way of preface to our detailed discussion seriatim of the various sources of uric acid, and to which we now pass on.

Exogenous Purins

The foodstuffs that cause an increase in purin excretion are divisible into three groups:—

• (a) Amino-purins.
• (b) Oxy-purins.
• (c) Methyl-purins.

Amino-purins.—In man the taking of food rich in nucleated cells and therefore in nucleo-protein and nucleins, increases the quantity of uric acid in the urine. Thymus gland, pig’s pancreas, and herring roe, containing the characteristic conjugated proteins of nuclei, or Liebig’s meat extract, rich in purin bases, when ingested, lead to a distinct increase in purin excretion.

The researches of Kossel and Horbaczewski showed that such augmentation was mainly due to the production of uric acid from the nuclein substances of the food; in other words, it was due to the katabolism of nuclein, the cleavage products of which comprise adenine derived from thymus, and guanine from the pancreas, both of these bodies being amino-purins. According to Burian and Schur, of the amino-purins ingested, a fourth is excreted as purin.

Oxy-purins.—To this group belong xanthine and hypoxanthine. These substances occur in muscle, and in great abundance in meat extract, and Minkowski noted that the ingestion of xanthine bases markedly augmented the amount of uric acid excreted. In man, given ingestion of hypoxanthine as such, only one half thereof appears as uric acid in the urine. It may here be mentioned that not all the purin bases ingested exist bound up in the nuclein substances. An appreciable amount is present in the tissues in a free state, e.g., hypoxanthine in the muscles; consequently, a moiety of the intake of purin bodies, especially in the animal constituents of the food, is to hand ready formed, and does not require the disruption of nucleic acid for its liberation.

Methyl-purins.—The nuclei of vegetable cells also contain nucleo-protein, and, therefore, can add their quota to the purin intake. The most important are caffeine, theobromine, and theophyllin, the active principles of tea, coffee, and cocoa. It may here be recalled that of the purins administered in food, not all are excreted as uric acid, but some as purins. Now it is doubtful whether the methyl-purins lead to the formation of uric acid in the organism, or whether they are excreted as purin bases in the urine. According to Stewart, a fractional part of the purin bases in the urine is composed of heteroxanthine, 1-methyl-xanthine, and paraxanthine derived from the active principles of coffee, tea, and cocoa when consumed as beverages. As stated by Burian and Schur, one third of the methyl-purins ingested is excreted as purin.

From the foregoing data it will be obvious that the exogenous urinary purins are derived from nuclein and certain free xanthine bases, and that the influence of other nitrogenous foodstuffs in this direction is practically negligible.

Exogenous Uric Acid Excretion

As to the amount of exogenous purins that, when administered orally, can be recovered from the urine, it would appear that a certain rough parallelism obtains between the purin content of the food and that of the urine. The amount of the exogenous urinary purin differs for different forms of food, a variation well illustrated by the following table, giving the results of Burian and Schur’s researches.

Walker Hall, experimenting with various purin-containing foods, found that (1) with chicken 54·4 per cent., (2) with plaice 58·7 per cent., (3) with beef 47·4 per cent., (4) with haricot beans 55 per cent. of the food purin appears in the urine as exogenous purin. These findings of Walker Hall’s, like Burian’s and Schur’s, reveal that, roughly speaking, 50 per cent. of the purin content in food is excreted in the urine.[12]

These figures must be taken as a broad average relating only to healthy individuals upon diets capable of perfect assimilation.

More recently, Mendel and Lyman found that about 60 per cent. of injected hypoxanthine, 50 per cent. of xanthine, 19-30 per cent. of guanosine, and 30-37 per cent. of adenine were excreted in the form of uric acid. While this is true of free purins, on the other hand, when bound purins, i.e., nucleins are administered, only a small proportion thereof appears as uric acid in the urine. But before proceeding to canvass the fate of the missing purin, it will, we think, be helpful if we interpolate here a table (Taylor and Rose), illustrative of the variations in uric acid excretion that attend a purin as opposed to a purin-free diet.

The subject of the experiment was, for three days, fed on a purin-free diet of milk, eggs, starch and sugar. At the end of this period a portion of the total nitrogen (3 grams) was administered in the form of sweetbreads, thymus gland, etc., with a high percentage content (0·482) of purin nitrogen. During the succeeding four days still more (6 grams) of the total nitrogen was replaced by sweetbread nitrogen. Subsequently the person was placed on the original purin-free diet.

From a study of the table it will be noted that, following the introduction of sweetbreads rich in nucleins, the uric acid content of the urine markedly increased, to sink again when a purin-free diet was substituted. But it will be seen also, as MacLeod points out, that “the increase of uric acid accounted for less than half of the purin nitrogen ingested. This appeared as uric acid, the excretion of purin bases being practically unchanged.” In other words, a moiety of the bound purins, i.e., nucleins ingested, appears as uric acid in the urine.

Fate of the Unexcreted Purin

As to what becomes of that portion of the ingested purin that, so to speak, disappears in the body, is largely a matter of speculation. As MacCallum states, “the liberation of guanine and adenine is well in the line of uric acid formation,” but “the fate of the pyrimidin groups, thymine and cytosine, is still uncertain.” According to this observer, Levene has hitherto been unable to find an enzyme which will decompose the nucleoside in which they occur, and that since they cannot form uric acid, they are possibly excreted as urea or in other forms. He adds that only 50 per cent. of the nucleic acid nitrogen can be counted on for the production of uric acid, viz., that in the guanine and adenine groups.

MacLeod, discussing this same point, suggests that some of the unrecovered purin may undergo decomposition in the intestine, but why so much should, after absorption of the blood, disappear is, as he remarks, difficult of explanation; for while uricase, which can decompose uric acid, exists in the tissues of the lower animals, no such ferment is found in man, and uric acid is excreted as such. According to MacLeod, too, “the destroyed purins cannot be shown to influence any of the other well-known nitrogenous metabolites of the urine.”

Lastly, Stewart, discussing the ultimate destiny of the absorbed products of nucleic acid digestion, suggests that, when undergoing further cleavages, “they may be in part utilised for the synthesis of nucleo-proteins, replacing those destroyed in the process of cell metabolism;” or, that it is “possible that they may be wholly disrupted into their components, and these again re-synthesised.”... “Finally, and this fate is probably not long delayed in the case of the surplus of purin compounds contained in ordinary dietaries, both the purins of the food and the purins arising from the waste of the tissues, are for the most part converted into uric acid and excreted in the urine.”

Also, it should be recollected that the purin bases normally found in human fæces are in part of exogenous origin, and are increased in amount after the ingestion of meat extract or thymus.

Endogenous Purins

Even if we entirely eliminate all purin substances, by restricting the diet to purin-free foodstuffs (bread, milk, cheese, eggs and butter), purin in the form of uric acid is still excreted in the urine.

To this moiety the term endogenous purin is applied; for the continued excretion of purin on such a diet is explicable only on the view that they are derived from the waste of the tissues, the daily “wear and tear” of cells. In other words, it is the outcome of the katabolism of the nucleo-protein of the body tissues.

Source of Endogenous Purins

Is the nuclear destruction of localised or generalised distribution?

Mares (and subsequently many other observers), having noted that, following the ingestion of purin-free protein food, a marked increase in endogenous uric acid excretion ensued, suggested that the said augmentation was the outcome of the “wear and tear” entailed upon the nuclear material of the secretory glands of the gastro-intestinal tract, following such intake.

The effects yielded on uric acid excretion by those antithetic drugs, atropine and pilocarpine, certainly seem to lend colour to Mares’ hypothesis.

Following the injection of atropine, the rise in uric acid output, that normally follows the ingestion of protein, was inhibited. But in sequence to pilocarpine, an excitant and not like atropine, a depressor of secretory activity, a marked increase in uric acid excretion followed. The contrast in response was naturally translated as striking evidence of the important rôle played by the digestive glands on uric acid excretion; in other words, it was held that the major portion of the endogenous uric acid was the reflex of such intensified glandular action.

In opposition, however, Burian, as the outcome of his experimental studies, maintained that a fractional portion only of the endogenous uric acid could be derived from the nucleo-protein of the body cells. This, inasmuch as it would entail a far too extensive katabolism of nuclear substance. Accordingly he propounded the view that the endogenous uric acid in the main was derived from the hypoxanthine of the inosinic acid present in muscular tissue. In this connection it may be noted that, on a diet approximating to Voit’s standard, 0·5 gram of purin is excreted daily. This, it is calculated, is equivalent to nearly 100 grams of thymus or allied tissue, which probably far exceeds the amount that could be gleaned from cellular katabolism.

Proteins and their Derivatives

A comparison of the influence of proteins as contrasted with that of their digested products, the amino-acids, it was thought, might furnish a clue as to the extent of which the alleged activity of the digestive glands was responsible for the increased uric acid output that followed the intake of non-purin protein food.

Such was the supposition entertained by H. B. Lewis, M. S. Dunn, and E. A. Doisy. Alive, moreover, to the deficiency of the older procedure in use for the determination of small amounts of uric acid, Lewis and his collaborators invoked the more accurate colorimetric method of Folin and Denis (as modified by Benedict and Hitchcock).

The experiments were conducted with great care, and with as complete control as possible of the variable factors concerned. The investigators realised that, if any significance was to be attached to fluctuations in uric acid excretion following the intake of proteins and their derivatives, it was essential that accurate information be obtained as to the extent of the variations to be expected normally in the subjects when fasting. “Controls,” therefore, in which no food was consumed throughout the experiments, were instituted at frequent intervals so as to make sure that the level of endogenous uric acid metabolism was not altered by the long-continued purin-free diet.[13]

Passing now to the results obtained, it was noted that, after the intake of three types of purin-free protein food (egg white, cottage cheese, and glidine), there ensued a rise in uric acid output, reaching its maximum during the third or fourth hour after their intake. No quantitative differences in the uric acid output after ingestion of these three types of protein were observed; in short, the findings did but confirm what had been repeatedly demonstrated, viz., that the excretion of the endogenous uric acid is increased by purin-free protein food.

Amino-Acids and Dicarboxylic Amino-Acids

But the further interesting fact emerged, viz., that glycocoll and alanine, end-products of protein digestion, also augmented uric acid excretion; moreover, this even more swiftly than proteins, the maximum being reached within two hours after their intake.

In addition, like results followed the ingestion of the dicarboxylic amino-acids (glutaminic and aspartic acids), the increase in endogenous uric acid excretion being even more pronounced than with glycocoll or alanine.

Now, it must be recalled that the amino-acids represent the end-products of protein digestion. Accordingly, Lewis and his co-workers argue that “since no digestive processes are required for the utilisation of amino-acids, it can hardly be considered that the rises in endogenous uric acid observed following the ingestion of four different amino-acids can be attributed to the work of the digestive glands.” The effect, they held, is more probably attributable to “a direct stimulation of the body cells by amino-acids or their katabolism products, a stimulation of nuclear metabolism,” for it is known that amino-acids disappear very swiftly from the blood-stream to be stored up temporarily in the tissues.

The question that now confronted the observers was whether the stimulation of nuclear metabolism was an inherent property of amino-acids. If so, “substituted amino-acids might be expected to exert a similar influence.” But, if on the contrary, it was due not to the amino-acids as such but “either to the cellular work of their katabolism or to the intermediary products of their breakdown, a substituted amino-acid which does not follow the normal path of amino-acid catabolism would in all probability be devoid of the power of stimulation.”

To this end, they selected sarcosine or methyl-glycocoll to elucidate the point at issue; this, inasmuch as it has been found to pass through the organism for the most part unchanged. The result justified their inference, for no perceptible influence on uric acid excretion was noted. Hence, on the basis of this experiment, they inferred that the stimulation of uric acid metabolism was not an inherent property of amino-acids; in other words, that if an amino-acid when ingested does not undergo disruptive katabolism, it is without effect on uric acid excretion.

Now deaminisation is the first stage in the katabolism of amino-acids, yielding as products ammonia and a-ketonic or hydroxy acids. The ammonia thus formed normally undergoes conversion into urea and is excreted as such. In order to ascertain whether the ammonia stimulated uric acid excretion, ammonium chloride was administered, but no rise in the uric acid output above the normal level ensued. Also, the ingestion of urea seemed to entail no appreciable increase in the uric acid elimination; in other words, these katabolic products of the nitrogenous moiety of the amino-acids are without effect. As to the non-nitrogenous intermediary products of the katabolism of amino-acids, i.e., the a-ketonic or hydroxy acids, it was impossible to investigate the influence of these on the endogenous uric acid elimination.[14]

Lusk also has brought forward evidence that in the presence of amino-acids cellular activities are intensified markedly. According to Taylor and Rose, too, not only nuclear katabolism, but also nuclear anabolism, may be accelerated by the presence of large amounts of amino-acids.

Lewis and his collaborators consider that the results of their researches militate against Mares’ hypothesis, viz., that the origin of the increased amounts of endogenous uric acid that follow the intake of purin-free protein stuffs is referable to intensified activity of the digestive glands.

They hold that “it can be accounted for equally well as the result of a general stimulation of all cellular metabolism by the products of digestion of proteins the amino-acids.”

The recorded increases in endogenous urinary purin are, they consider, far too great to be the outcome of the stimulation of so small a proportion of the cells of the body as those of the digestive tract. On the other hand, they do not deem it necessary to assume that the whole of the endogenous uric acid is the outcome of nuclear disruption, concurring with Burian’s view, that a moiety thereof may be derived from the hypoxanthine of muscular tissue.

Endogenous Uric Acid Excretion

The researches of Leathes and his collaborators permit the deduction that endogenous uric acid excretion bears a definite relation to the activity of cellular processes. Given unchanged physiological conditions, e.g., muscular exercise, the amount of the endogenous uric acid excreted is, for the same individual, fairly constant, and this irrespective of diet; but it is not the same for different individuals, even those of identical body weight.

According to MacLeod, the endogenous excretion in an adult man fluctuates between 0·12 and 0·20 per cent. purin nitrogen. The average daily endogenous uric acid output of a normal adult, as stated by Walker Hall, is about 0·5 gram, while that of a gouty individual is 0·45 gram.

Now Burian and Schur’s original contention was that, in a given individual on a purin-free diet, the endogenous purin output was constant, and this despite marked variations in the amount of the purin-free food digested.

Recent researches, however, of Folin and of Hopkins and Hope, indicate that this dictum must be modified to this extent, viz., that although it is true that the endogenous excretion continues remarkably constant, with moderate variations in the amount of purin-free food, it is not so in the presence of marked variations.

The subject (Hopkins and Hope), after a fast of six hours, was given a meal of bread and potatoes, and at every subsequent hour estimates were made of the amount of urea and uric acid excreted in the urine.

It is clear from the results obtained that a very definite increase of endogenous purin excretion ensued, and that the said increase occurred sooner as regards uric acid than urea. This bears out what Mares demonstrated many years ago, viz., that the greatest increase in uric acid excretion occurs in a few hours after a meal, whereas the increase in the case of urea comes more tardily, not reaching its maximum until some hours after.

Horbaczewski referred such increase in uric acid excretion to a digestive leucocytosis; in other words, that the uric acid was the outcome of destruction of the leucocytes, and consequent formation of purin from the released nucleic acid. Unfortunately for this theory, the period of most marked augmentation in uric acid excretion ensues when the leucocytes are most in evidence in the blood-stream, not after they have disappeared, as would be the case if uric acid was derived from the purin product of the nucleic acid liberated by leucocytic destruction. We have a parallel instance in the case of pneumonia, in which it has been shown that the elimination of uric acid and other purins is at its acme when the leucocytes are most abundant; in other words, the highest uric acid output coincides with the period of most marked leucocytosis, whereas during the post-critical stage, viz., when leucocytes are being destroyed in great numbers, the output of uric acid is very markedly lowered. Discussing Horbaczewski’s theory in light of the above criticisms, MacLeod suggests, “that the facts appear to indicate that the purin substance is a metabolic product of the living leucocytes,” and not, so to speak, the chemical outcast of their disruption and death.

Lastly, Walker Hall, discussing endogenous uric acid excretion, emphasises the necessity of discriminating between the uric acid output and the total purin output. He reminds us that the actual cell nucleins belong chiefly to the group of amino-purins, i.e., guanine and adenine, and that the oxypurines, xanthine and hypoxanthine, are intermediate products on their way to excretion, another and more advanced intermediate product being uric acid. Now, only a proportion of these intermediary products appears in the urine, this commonly cited to be approximately 50 per cent.

But this, as Walker Hall states, must be taken only as a very broad estimate, for in the same individual the output varies with the number of conditions, not as yet fully determined. But the point most emphasised by him is, that though “the uric acid output varies considerably, the total purin output does not show similar variations; for when the uric acid excretion wanes that of the purin bases usually rises. As a consequence, the total purin output is more constant, less influenced by circumstances, than the output of uric acid.”

This being so, we shall now pass on to consider other conditions influencing endogenous uric acid excretion.

Factors Influencing Endogenous Uric Acid Excretion

The output of endogenous uric acid excretion is influenced by (1) Physiological conditions, (2) Pathological states, and (3) The ingestion of certain drugs.

Physiological Conditions

It is now recognised that the purin bases of the body exist not only in the bound form (nucleic acid), but also free, especially in muscular tissue. Also, that from such free purin bases uric acid can be readily formed as from those liberated by the disruption of nucleic acid. Thus, inosinic acid, a nucleotid first isolated from meat extract, yields phosphoric acid and the purin base, hypoxanthine. In possession of these facts, we shall be better able to appreciate the significance of the researches of Burian and others.

(a) Muscular Exercise.—According to Burian a large increase in the excretion of uric acid was found to follow muscular exercise. The same observer also noted the presence of hypoxanthine in defibrinated blood after its perfusion through the hind legs of a dog whose muscles had been thrown into tetanus. Moreover, subsequent to contraction, the muscles themselves contained an increased amount of oxypurine. From these findings Burian concluded that hypoxanthine was a product of muscular action, and that this substance or its precursor, inosinic acid, was an important source of endogenous uric acid. The uric acid thus formed by oxidation was then partly destroyed in the liver and partly excreted by the kidneys. But Burian noted also during activity of the muscles that a certain amount of the purin bases failed of oxidation, and consequently a larger amount of the same, as compared with uric acid, passed into the circulation.

Kennaway, discussing the effect of muscular exercise on the excretion of endogenous purins, noted that during unaccustomed exercise the uric acid output of the kidneys diminished, but that of the purin bases is relatively augmented, but, on the whole, he found that the total purin output (bases plus uric acid) was not very much increased.

Leathes and others, investigating the effects on uric acid excretion of strenuous exercise, established the occurrence of a distinct increase. Given that the same kind of exercise is practised on the day following, the said increase is much less marked. If, however, some different form of muscular activity is undertaken, another increase in uric acid follows. It would appear, therefore, that, despite conflicting evidence, the balance of opinion favours the view that muscular activity does lead to increase in endogenous uric acid excretion.

(b) Periodic Variations.—Leathes noted diurnal and nocturnal variations in the excretion of endogenous uric acid, the maximum occurring within the early waking hours, and sinking to a minimum towards the evening. His experiments, he held, indicated a variation in the actual formation of endogenous uric acid at different periods of the day. Rockwood also found that an increase occurred during the daytime, and Pfeil, that there was a morning rise in the amount of uric acid passed. The fact that doubt still obtains as to whether muscular exercise has any effect on endogenous uric acid excretion, renders explanation of this diurnal variation difficult. This especially as there are no fluctuations in the urinary functions that could in any way account for it.

Pathological States

Endogenous uric acid is increased under certain pathological conditions. Leathes’ recent work confirmed the view that there is an increased production of nitrogenous waste in fevers. After taking a large dose of anti-typhoid serum his temperature rose to 103° F. Experimenting on himself, he found his output of urea, uric acid, and creatinine all increased, but of all three uric acid showed the most marked alteration. The question now arises as to whether such is due to increased production or diminished destruction. Some further experiments conducted by Leathes on himself may serve to elucidate this point. Subjecting himself for a prolonged period to cold baths, a similar increase in his uric acid output ensued. This would appear to indicate that, through increased loss of heat, the bodily processes of combustion were augmented to maintain the body temperature, with, as a consequence, increased uric acid excretion.

In leukæmia protein-destroying forces are at work, and the urine contains large quantities of uric acid. The same is attributed to the formation and destruction of enormous numbers of leucocytes, but the urinary findings in this respect have been extremely variable. While increased uric acid elimination has been vouched for by many authors, some have noted increase in the purin bases, sometimes with, and sometimes without increase in the uric acid; while others again have even noted a decrease in uric acid and phosphoric acid excretion.

Apart from these contradictory findings, it would appear, according to Magnus-Levy, that in acute leukæmias the relation between the number of leucocytes and the uric acid output is most variable. Lastly, the different types of leukæmia present differences in regard of their uric acid output, the increase in the myelogenous variety being much more marked than in the lymphatic form.

Wells, discussing these conflicting data, considers that they are but the reflex of the “known fluctuations in the course of the pathological processes of leukæmia; the number of leucocytes, the size of the lymphatic organs, and the general condition of the patient all vary greatly from time to time, often with remarkable rapidity and the excretion of products of metabolic activity must vary likewise.” Continuing, he observes that the enormous increase in the amount of lymphoid tissue in the body and blood must give rise to a greatly augmented nuclein katabolism, with sequential appearance of uric acid, purin bases, and phosphoric acid in the urine. This he holds to be well demonstrated by the increased elimination of uric acid and purin bases, together with a general increase in the nitrogen output such as has been frequently noted in sequence to the therapeutic use of X-rays in leukæmia, this attributable to the increased autolysis known to be induced by X-rays.

As to this question of the relationship of leucocytosis to uric acid excretion, it must be borne in mind that the number of leucocytes and the excretion of uric acid do not always vary directly. Parallel studies of the blood and urine have shown that leucocytosis does not invariably accompany increased uric acid excretion. Indeed, Hutchison and MacLeod have recorded cases of leucopenia without any reduction in the amount of uric acid eliminated.

Also, we have to recall that on a purin-free diet the amount of endogenous uric acid is more than can come from nuclein destruction in the body. As suggested by Burian, some may be derived from the hypoxanthine in muscular tissue. In short, while nuclein disintegration is the outstanding source of endogenous purin, yet, for the reason cited, it cannot be regarded as the sole source, for the exact origin of all the endogenous purin is not as yet established.

In conclusion, it would appear that some drugs influence more or less markedly the excretion of endogenous uric acid, notably, atophan; but discussion of these will, we think, be best postponed to the section dealing with the medicinal treatment of gout. Meanwhile we shall proceed to consider the vexed question of the formation within the organism of uric acid by synthesis.

Synthetic Formation of Uric Acid

Birds eliminate most of their nitrogen in the form of uric acid, and, undoubtedly, in their instance synthetic formation of uric acid in the liver takes place on a large scale. Thus, when blood containing ammonium lactate is perfused through the liver of the goose, an increase in the uric acid content of the blood occurs. Also the ingestion of lactic, pyruvic and other organic acids leads to augmented output of uric acid; in short, it is generally agreed that in birds synthesis is the chief mode of formation of uric acid, homologous with the formation of urea in the liver of mammals.

If this be true of birds, on the other hand, splitting and oxidation of nucleins is in mammals the most important source of uric acid, but there is evidence that it cannot all be accounted for in this way. As before remarked, the old belief that purin excretion remains almost constant on a purin-free diet, despite great variations in the amount of the ingests, is not strictly true. Thus, using swifter and more reliable methods for the estimation of nitrogenous metabolites, Folin noted, on an absolutely purin-free diet, that an increase in purin excretion ensued, given marked variations in the intake of food. Again, the Dalmatian dog, as we have seen, excretes uric acid in his urine. S. R. Benedict was therefore able to demonstrate that a very distinct increase in his uric acid output ensued in sequence to increase in the amount of his non-purin food; moreover, that even when such non-purin foods were continued for a year, “the total amount of uric acid excreted was at least ten times greater than could have come from the traces unavoidably included in the food” (MacLeod).

Also Ascoli and Izar, experimenting with dog livers, noted on incubation thereof and passage through the same of oxygen that the uric acid disappeared; but on the substitution of carbon dioxide an accumulation thereof ensued. Wells, however, was unable to confirm this re-synthesis of uric acid by dog livers, and Spiers also failed to corroborate their findings.

On the other hand, there is evidence pointing to the fact that a certain small percentage of synthetic formation does take place in the organism. Thus certain chemical substances, and these not purin, do cause an appreciable though slight increase in the purin excretion of mammals, and a very marked augmentation of the same in birds, viz., lactic, tartronic and B-oxybutyric acids.

But, as MacLeod, discussing these experimental and clinical findings, observes, there are to hand even more direct proofs that purin synthesis occurs in mammals. Thus, as McCallum has pointed out, we cannot escape the admission that young mammals are able to synthetise the purins essential for their growth, and this from food containing no purin, e.g., milk. Again, prior to incubation, a hen’s egg contains practically no nucleic acid, whereas after development its content in the same increases by great strides. The eggs of insects, too, with the progress of development, amass purin very rapidly.

Again, Miescher noted long since that salmon, on leaving the sea to ascend rivers for the object of spawning, have at that time well-developed muscles; but on arriving at the upper reaches, marked muscular wasting ensues, while the testes undergo enormous enlargement. MacLeod, reflecting on these observations, argues that, “as the fish takes no food during the migration, there must be conversion of the protein of the muscles into the cellular tissue of the sexual glands, and nucleic acid must be produced.” MacLeod’s conclusion is that “Purin synthesis undoubtedly occurs in the mammalian body, but it is difficult to recognise in metabolism investigation, because it is a slow continuous process ... whether or not changes in the activity of purin synthesis occur in conditions of disease, is a question which awaits investigation.” Lastly, the opinion of most authorities is that, while they concede the possibility of synthetic formation, the amount of uric acid produced in this manner is negligible, and that by far the most important mode of formation in mammals is by the splitting and oxidation of nucleins; in other words, that uric acid in the main is derived from the amino-purins by deaminisation and subsequent oxidation, and from the oxy-purins directly by oxidation.