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Human Aberrations of Purine Metabolism and Their Significance for Rheumatology

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Human Aberrations of Purine Metabolism and Their Significance for Rheumatology Ann Rheum Dis: first published as 10.1136/ard.39.2.103 on 1 April 1980. Downloaded from Annals of the Rheumatic Diseases, 1980, 39, 103-117 Heberden oration 1979 Human aberrations of purine metabolism and their significance for rheumatology J. EDWIN SEEGMILLER University of California, San Diego, La Jolla, California 92093, USA It is an honour and privilege to be invited to address by the microbiologists Beadle and Tatum.4 From you this day. Returning to the city of my grand- these studies he also formulated the concept of father's birth is always a great personal pleasure. inborn errors of metabolism and thus laid the This relationship is symbolic also of the close groundwork for modern-day developments of our scientific and cultural heritage that we in America concept of hereditary diseases. The younger Garrod5 owe to this land. The origin ofmany ofour important classified gouty arthritis as one of the inborn errors medical and scientific concepts today stem from the of metabolism, but unlike other such disorders no germinal ideas and observations of British scientists single enzyme defect has been found to account and physicians of past ages who have contributed for the disease. However, the absence of the enzyme substantially to building the scientific base of the uricase in man and the higher apes, coupled with a clinical medicine of today. remarkably inefficient mechanism for renal excretion Not the least of these contributions has come from of uric acid, results in a mean plasma concentration detailed study of patients afflicted with very specific of urate in adult males of 5c 1 mg/dl-a value not types of arthritis. Although it was the Swedish far from the theoretical limit of solubility of urate chemist, Scheele, who first isolated uric acid from a in serum of 6 4 mg/dl. The lower mean serum urate http://ard.bmj.com/ concretion of the urinary tract in 1776, it was the of women of 4 - mg/dl, until after the menopause, British chemist, Wollaston, a nephew of William may well account for the far lower incidence of gout Heberden, who first demonstrated in 1798 the in women. The supersaturation of all hyperuricaemic presence of the same substance in a gouty tophus plasma sets the stage for the deposition of needle- which he is purported to have removed from his shaped crystals of monosodium urate monohydrate own ear. The subsequent demonstration of hyper- in and about the joints and in the parenchyma of the uricaemia in patients with gouty arthritis in 1848 by kidney which account for the major pathology in Alfred Baring Garrod provided the impetus for much this disease, as proposed by the elder Garrod over a on October 2, 2021 by guest. Protected copyright. more detailed study of the chemical factors causing century ago.2 Although his concepts languished disease, which has proliferated remarkably in the for over half a century, new evidence of the past 2 ensuing 132 years and continues today at an even decades has validated his major proposals.6-9 Only more accelerated pace.' 2 in the past decade and a half have specific enzyme From detailed studies of patients with another defects in purine metabolism responsible for this heritable form of arthritis, alcaptonuria with disease been identified. ochronosis, Archibald Garrod carried his father's Today I will review some of the circumstances concepts to a more fundamental basis with for- involved in the discovery of these enzyme defects mulation of a revolutionary new concept to account and also review the recent work in which other for the accumulation of large amounts of homo- specific inborn errors of purine metabolism have gentistic acid in these alcaptonuric patients. In his been found to be associated with deficiency of the Croonian lectures in 1908 he proposed that the immune function and the new insight into possible accumulation and excretion of homogentistic acid regulatory mechanisms of the immune system that in this disease is a direct result of a hereditary may well be affected by these enzyme defects. I want deficiency of the enzyme for its further processing to acknowledge the major contributions of the within the body.3 This concept of one gene being many young investigators who have worked with me responsible for one enzyme was thus formulated over in these studies. I also hope to enlist your support 30 years before its more detailed investigation in a systematic approach to the classification of our 103 Ann Rheum Dis: first published as 10.1136/ard.39.2.103 on 1 April 1980. Downloaded from 104 Seegmiller gouty patients that will greatly facilitate, not only Knowledge of the classification of the gouty our rational management of their problems by patient in regard to the degree of production of selection of the most appropriate therapeutic agents, uric acid can also be of practical help to the clinician but will also allow us to work together in their in the selection of the most appropriate drugs for further biochemical and genetic characterisation. management of the particular patient's disease. We Since it is a lifetime of treatment to which we are know that allopurinol, in addition to its primary committing the patient, the extra time it takes for action in blocking the enzyme, xanthine oxidase classification seems warranted and can also be responsible for the synthesis of uric acid, also has conveniently performed while awaiting for the a secondary beneficial effect in shutting off excessive patient to recover from an acute attack of gouty purine synthesis." It therefore becomes the drug of arthritis and before institution of treatment with choice for patients who have evidence ofan excessive a drug known to lower the serum urate concentration. rate of purine synthesis, uric acid lithiasis or impaired renal function. Classification of gouty patients Although some of the patients who show a uric acid excretion in the normal range may have modest The genetic heterogeneity of the gouty population degrees of overproduction of uric acid that is is readily revealed by the simple test I am proposing obscured by increased extrarenal disposal into we use on all our gouty patients-the determination tophi or by intestinal uricolysis, a substantial of the 24-hour excretion of uric acid for each of 3 portion of such patients show a diminished ability days after the patient has been equilibrated on a of the kidney to excrete uric acid as the cause of their diet virtually free ofpurines.10 The mean value found hyperuricaemia.8 1012 Therefore, uricosuric drugs in normal adult males is 425 mg/24 hours (Fig. 1) correct the primary abnormality and provide a with a spread that places the upper range of normal rational therapeutic approach for controlling their at 600 mg per day. The population of gouty patients disease. showed a mean value only slightly higher but the We have recently been using a total of 6 days on spread was much larger with around one-quarter the purine-free diet with collection of urine during of the gouty population showing production of the last 3 days as an abbreviated procedure more excessive quantities of uric acid in the 24-hour acceptable to the patients. Even this degree of co- period. As might be expected, the patients who had operation is often difficult to elicit. For detection substantial renal damage excreted smaller amounts of of patients with the most extreme degrees of purine http://ard.bmj.com/ uric acid than was found in the normal, indicating overproduction, a simple ratio of uric acid to the basis for the well-known accleration in rate of creatinine in the morning urine suffices. However, development of pathological changes of gout when it is not nearly as discriminating as the 24-hour renal impairment supervenes. collection when properly performed.13 A further 8 on October 2, 2021 by guest. Protected copyright. .7 C_ Non-op*oceos 34 Tophocos S RenMlMR rnolrnnt w Fig. 1 Uric acid excretion by normal and goutypatients after equilibration for 5 days on a diet 3 _ X - 111- virtuallyfree ofpurines. From cr Seegmiller et al.10 0 200 OR 250 300 350 400 450 500 550 600 650 700 750 800 OR UNDER AVERAGE 24 HOUR URINARY URIC OVER B ACID EXCRETION mg./24 HR. Ann Rheum Dis: first published as 10.1136/ard.39.2.103 on 1 April 1980. Downloaded from Human aberrations ofpurine metabolism and their significance for rheumatology 105 modification has been proposed in which the mg such as ketoacids in diabetic acidosis or in maple of uric acid excreted per ml of glomerular filtrate syrup urine disease for transport mechanisms.'6 is obtained by dividing the above ratio by the In type 1 glycogen storage disease, with its glucose- serum creatinine.14 6-phosphatase deficiency, both a lactic acidosis The origin and disposition of uric acid in the and an increased rate of purine synthesis are found."7 normal and gouty patients is shown in Fig. 2. Purines which give rise to uric acid can originate Lesch-Nyhan disease with severe deficiency of hypo- from purines in the diet or from those synthesised xanthine-guanine phosphoribosyl transferase (HPRT) endogenously in all nucleated cells. From either source the purines can be incorporated into cellular Clinical Presentation. The most extreme example of nucleotides such as ATP and nucleic acid. The excessive uric acid production has been found in the metabolic turnover of these purine-containing com- paediatric practice rather than in the rheumatology pounds gives rise eventually to uric acid. Around clinic. A haematuria and uric acid crystalluria first two-thirds to three-quarters of the uric acid formed brought a young boy with cerebral palsy to the each day is excreted unchanged in the urine, while attention of a medical student, Michael Lesch, and the remainder is excreted in intestinal secretions Dr W.
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