A few preliminary remarks on purins and purin metabolism are necessary in order to form a due appreciation of the value of the purin-free diet. Purins are bodies with a base C5 N4 H4 (purin) and include : -
Hypoxanthin C5 N4 H4O.
Xanthin C5 N4 H4 O2.
Uric acid C6 N4 H4 O3.
Adenin C5 N4 H4 -NH (amide of hypoxanthin). Guanin C5 N4 H4 O-NH (amide of xanthin).
Methyl-purins Thein and Caffein C5 H (CH3)3 N4 O2 Theobromin C5 H2 (CH3)2 N4 O2.
Xanthin, hypoxanthin, adenin and guanin are called purin bases. The amount in the urine is estimated by the purino-meter. About 3 per cent of the nitrogen of the food appears in the urine as purin and 86 per cent as urea, in mammals, so purins are quite of secondary importance to urea. Mammals and birds are not comparable in their nitrogenous metabolism. In mammals uric acid by the mouth appears as urea in the urine; in birds urea, amido-acids, and ammonia appear as uric acid. Urea is an end product of metabolism in mammals, and never forms uric acid, but in birds it is converted into uric acid before excretion.
Laboratory experiments show that uric acid can be split up into alloxan and urea; that alloxan can be converted into parabanic acid and CO2; and that oxaluric acid is derived from parabanic acid and can be split up into oxalic acid and urea. Hence, uric acid appears to contain two urea molecules, one of which is easily liberated, while the other is only freed with difficulty. There is another way in which uric acid can be split up into the ultimate products, urea, oxalic acid and carbonic acid, but allantoin, a somewhat similar body to alloxan, is formed in the intermediate process. On mild oxidation uric acid yields allantoin and CO2. On powerful oxidation it splits up into oxalic acid and urea. By hydrolysis uric acid yields glycin (amido-acetic acid), ammonia and CO2. Glycin plus urea forms uric acid. Glycin is found in the tissues and is undoubtedly a decomposition product of purins in herbivora, and probably so in man. Allantoin and oxalic acid in minute traces are normal constituents of urine. Both glycin and allantoin can form urea. In cats and dogs the purin of purin decomposition is only oxidized as far as allantoin, while in man it is further changed into urea. Glycin, allantoin and oxalic acid may all be produced during the disintegration of purin.
Purins are called exogenous when they are taken into the body as food, and endogenous when they are formed in the body. Vegetable purins are said to be less injurious than animal ones. Exogenous purins are present in meat and meat extracts; glandular organs, especially the liver, thymus, pancreas and kidneys; many cereals; some fruits, e.g. strawberries; vegetables, such as peas, beans, lentils, spinach, asparagus and onions; fungi, e.g. mushrooms; malt liquors; tea, coffee and cocoa.
These exogenous purins are in the form of oxy-purins, amido-purins or methyl-purins, according to the food, and are combined or free. They vary in their effects. Any purin by the mouth increases the purin excretion and always to the same extent, varying with the nature of the purin. Thus, in man, about one-half of the oxy-purins ingested, pure or in muscle, liver or spleen, reappears in the urine as uric acid. In dogs only one-twentieth reappears in this form. Of the amido-purins one-fourth of the nitrogen reappears as uric acid. Of the methyl-purins one-third reappears as basic purin-N. These methyl-purins are peculiar in that they cause an increase in the excretion of purin bases, but not of uric acid. Yet they are oxidized into oxy-purins, and it is known that oxy-purins give rise to uric acid.
That portion of the exogenous purins which is not excreted must be either stored up or disintegrated. Probably it is disintegrated, for it has been found that when uric acid and hypoxanthin are injected subcutaneously, in each case one-twentieth part appears in the urine, although hypoxanthin is much more soluble than uric acid and ought to be much more readily excreted.
In order to study the metabolism of endogenous purins a purin-free nitrogenous diet must be given. On such a diet it is found that the excretion of endogenous uric acid remains stationary and uninfluenced by the nature or amount of the diet, provided that it be sufficient. But the amount of urea excreted varies with the amount of protein given. Therefore, the uric acid does not come from protein. The total purin excretion on the diet is practically that of endogenous purin and a measure thereof. It varies in different individuals, and is constant in the same individual under the same conditions. It is supposed to come chiefly from the muscles and to be increased by muscular work. Recent work by Spriggs has led him to maintain that the greater part of the endogenous uric acid does not come from the muscular tissue, but that endogenous creatinin is mainly, if not entirely, derived from muscle and is the product of its structural metabolism.
Nucleinic acid, from the nuclei of cells, is split up by a ferment (nuclease) into and sets free purin bases, especially adenin and guanin. The nucleins vary in the nature of the amido-purins to which they give rise. Adenin comes from the thymus, guanin from the pancreas, and both from salmon sperm. By means of a hydrolytic ferment adenin is converted into hypoxanthin and guanin into xanthin. Possibly there are two ferments, adenase and guanase; or only one, in which case guanin is more resistant than adenin to disamid-ation. Subsequently the xanthin and hypoxanthin are converted by oxidase into uric acid, perhaps in the muscles and before getting into the blood.
Part of this uric acid is destroyed by a ferment in the liver, undoubtedly the purin destructor in dogs, and part is excreted before it is transformed. Thus, the amount of endogenous purins excreted is likely to bear a definite relation to the amount produced in the tissues, as has already been stated to be the case. About half of both the exogenous and endogenous purins is disrupted in the tissues and sets free urea molecules.
We may conclude from the above statement, based on the most recent work on the subject, that the uric acid excretion bears no relation to protein metabolism; that in man it is increased by oxy-purins in the diet; that oxy-purins are derived from adenin and guanin, and these bodies from nuclein; that nucleins in the food give rise to uric acid in the urine, although adenin and guanin by the mouth have apparently little effect; and that the conversion of oxy-purins into uric acid is due to a ferment action.
The purin-free diet in gout is based on the theory that there is retention of uric acid in the system in consequence of abnormal chemical affinities or blockage of the excretory channels, the kidneys. Possibly gout depends on an abnormal endogenous metabolism of purins with which there may or may not be associated a specific insufficiency of the renal epithelium to excrete uric acid. It is difficult to accept the theory of renal inadequacy, for at times the gouty excrete uric acid extremely well. In favour of the retention theory are the presence of uric acid in the blood; the lessened elimination of endogenous uric acid and the large variations therein; the delayed reaction of the urine to the intake of purins; and the formation of tophi. Uric acid exists in the blood as a salt and also as a firm combination with some unknown substance. Possibly the formation of excretable uric acid depends on ferments, or the excess is due to deficiency of uric acid destroying ferment. In gout it is worth while to try the effect of a purin-free diet; to estimate the toleration for purins; and to regulate the intake of protein. The relief of gout by drugs, which prevent intestinal putrefaction or eliminate the products thereof, suggests that it is due to toxins. The large amount of indican often, but not always, present in the urine in acute gout supports the view that the toxaemia is due to intestinal putrefaction of protein.
A purin-free diet can be devised from a combination of the various purin-free foods. Nuts are the most nutritious and contain much fat; chestnuts being the most digestible. Macaroni, dates, raisins, and cheese are all purin-free and are mentioned in order of nutritive value. White bread, potato and milk contain minute traces, but so minute that they may be regarded as purin-free. Cream, butter, fats, eggs, apples, grapes, figs and honey are also purin-free. The fruits mentioned are those best for food. The following table shows what foods are rich in purin.
Sweetbread 70.43 Liver . 1926 Beefsteak 14.45 Sirloin . 913 Chicken . 9.06 Loin of pork 8.48 Veal . . 8.13 Ham. . 8.08 Mutton . 6.75
Halibut . 7.14
Plaice . 556
Cod . . 407
Beans . 4.16
Lentils . 4.16
Onions . 0 06
Porter. . 135
Ale . . 127
Lager beer 1.09
Coffee. . 1.70
Ceylon tea 1.21
Indian tea 1.05
China tea. 075
(Potts: Lancet, 1906, vol. ii, p. 933, based on Walker Hall's work).
The purin-free diet may be tried for gout and gouty conditions, renal disease, headaches and neuralgias, bilious attacks, recurrent vomiting, and chronic affections of all kinds. There is no proof that it is of any decided value, either in modifying or curing these constitutional states. Practically it will be found that the benefit derived from this diet is mainly dependent on its simplicity, on efficient mastication, on the limitation of intestinal putrefaction, and on the prevention of over-eating, which the return to a simple and limited diet involves. Too much, therefore, must not be expected, but it may be justly recommended in conjunction with other therapeutic measures. Even if we accept the view that gout is connected with anomalous purin metabolism, we must remember that this is due to a disorder of the tissues or special organs, and that it is a sequel, not a cause. There is no proof that either uric acids or purins by mouth can give rise to gout, or that they possess toxic properties of importance. On a purin-free diet indicanuria may disappear.