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Observations on Uric Acid Transport in Man, the Dalmatian and the Non-Dalmatian Dog Howard Duncan

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Observations on Uric Acid Transport in Man, the Dalmatian and the Non-Dalmatian Dog Howard Duncan Henry Ford Hospital Medical Journal Volume 19 | Number 2 Article 9 6-1971 Observations on Uric Acid Transport in Man, the Dalmatian and the non-Dalmatian Dog Howard Duncan April S. Curtis Follow this and additional works at: https://scholarlycommons.henryford.com/hfhmedjournal Part of the Life Sciences Commons, Medical Specialties Commons, and the Public Health Commons Recommended Citation Duncan, Howard and Curtis, April S. (1971) "Observations on Uric Acid Transport in Man, the Dalmatian and the non-Dalmatian Dog," Henry Ford Hospital Medical Journal : Vol. 19 : No. 2 , 105-114. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol19/iss2/9 This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. Henry Ford Hosp. Med. Journal Vol. 19, No. 2, 1971 Observations on Uric Acid Transport in Man, the Dalmatian and the non-Dalmatian Dog* Howard Duncan, M.D.** and April S. Curtiss, B.S.** The urinary output of uric acid from the purebred Dalmatian is similar in amount to that in man. Also, this breed of dog has a higher plasma uric acid level than other dogs and, like man, this hyperuricemia is accompanied more frequently with renal and bladder lithiasis. AUopio-inol is effective therapy in both man and dog. Study of the fate of uric acid in the Dalmatian shows that the liver does not oxidize the available uric acid completely although it is capable of doing so when liver homogenates are studied. Consequently, the hepatic cellular membrane appears impermeable, or partially so, to uric acid. The pos­ sibility of a general membrane transport problem similar to that encountered at the liver cell has not been confirmed with studies of red cells in the Dalmatian. This dog shows some similarities to certain rare clinical human diseases with deafness, cardiac arrhythmias and renal tubule leak of uric acid, all of which offer ample opportunity for close and detailed examination as clinical models in biochemical, physiological, pathological and genetic studies. Uric acid, the end product of purine clinical hazards. However, once a pa­ metabolism in man, and also the higher tient has been identified as a former of apes, is a highly insoluble and biologi­ uric acid stones, particularly in gouty cally benign material. It introduces a arthritis or with primary hyperuricemia, problem of excretion because its solu­ therapy aimed at correcting these prob­ bility in water at 40°C is only 50 mg lems has to be continued indefinitely. per liter. In urine the solubility is Man is not as fortunate as the lower slightly greater and the concentration animals, which are capable of handling is usuafly near saturation level. The uric acid in a more efficient manner. clinical problems of uric acid stone Further down the evolutionary scale, formation and obstructive uric acid the fish and amphibia excrete most of nephropathy develop as a consequence the nitrogen of protein metabolism as of this limited solubility. Uricosuric urea and ammonia and the mammals drugs (probenecid, salicylates, sulfin­ have also maintained this mechanism pyrazone, etc.) and more recently al­ as a major means of nitrogen excretion lopurinol (an enzyme inhibitor of uric (Fig 1). However, the reptfles and the acid oxidation) for the first time have birds developed a very clever water- successfufly controlled many of these conserving system whereby the last phases of breakdown from protein ni­ '•'Support for these studies was made pos­ trogen to urea were eliminated, and sible by grants from the Michigan Chap­ uric acid is the end-product. This ter of the Arthritis Foundation and Henry Ford Hospital (Grant #437). allowed twice the number of nitrogen • "•'Division of Rheumatology atoms to be excreted per molecule of 105 Duncan and Curtiss available water. In the bird the plasma converts the insoluble uric acid to the uric acid level is simflar to man (3-7 more soluble allantoin (Fig 1). Man, mg/100 ml) and the uric acid is con­ however, has not shared this bequest centrated three-thousand times in the from aquatic ancestors. Partly because tubular urine of the bird and secreted of these basic metabolic differences into the cloaca.^ From here, the water between man and dog, research into is reabsorbed by the cloacal membrane, the control of the uric acid problem and the uric acid in solution, already has been slow. These biological differ­ supersatured crystalizes and, with this, ences result in man having a serum becomes osmotically and finally bio­ uric acid level of around 3-7 mg/100 logically inactive. The insolubility of ml and he excretes some 500-700 mg this white uric acid paste can be seen of uric acid per day in the urine while on the superior aspects of our public the dog with a plasma uric acid level buildings and statues, which have been of less than 0.3 mg/100 ml has a daily visited by pigeons and starlings. 24-hour urine output of uric acid of In the dog and similar lower mam­ 10-60 mg. Consequently, the solubflity mals uric acid is effectively oxidized problems for the dog are negligible and by the hepatic enzyme uricase, which uric acid lithiasis is rare. PATHWAY OF PURINE DEGRADATION \ GLYCINE NUCLEOPROTEIN PURINES ADENOSINE GUANOSINE MAN, APES FISH HYPOXANTHINE * BIRDS MAMMALS i REPTILES XANTHINE I ./ URIC ACID _ i ALLANTOIN \ UREA, AMMONIA Figure 1 106 Uric Acid Transport in Man, the Dalmatian and the non-Dalmatian Dog The purebred Dalmatian (Fig 2) is nize its intermediate position, in the distinguished biochemically by its ex­ handling of uric acid, with man on the tremely high uric acid output (400-600 one hand incapable of oxidizing uric mg/24 hours in a 10 kgm dog). The acid and on the other the non-Dalma­ plasma uric acid level is two to four tian breeds oxidizing uric acid most times that of the mongrel dog and as a efficiently. For this and other reasons consequence the Dalmatian* pays the to be enumerated, this purebred dog penalty for his genetic abnormality serves us with a remarkable oppor­ with a very high frequency of renal and tunity to study the physiological, bio­ bladder stones. During the past four chemical and pharmacological actions years we have used allopurinol in the and reactions of uric acid. Even Dalmatian to control the uric acid though this biochemical attribute was production and reduce the uric acid recognized specifically in 1916,- the output in the same manner as we have amount of such investigation has been in humans with the same problems. singularly little. Only in recent times In this particular breed we recog- has there been sufficient interest in this particular breed to bring about the '•'The reason that the dog has been called by this name is uncertain. There is no establishment of the Dalmatian Re­ reason to believe that it derived from search Foundation in 1969.** Dalmatia (Yugoslavia) anymore than it Aside from the basic uric acid dis- was first bred in England or Bengal al­ though it has often been called an English "•'Through the efforts of a Dalmatian fan­ Coach Hound and the Bengal Harrier. cier: J.C. Lowery of York, Pennsylvania. ES S 107 \ Duncan and Curtiss turbances, there are other areas of deaf Dalmatians, it was noteworthy physiological, pathological, clinical and that this "syndrome" in the Dalmatians genetic significance known to be more resembled an unusual clinical picture common in this breed than others. also seen in man. In this syndrome, The main biological aberrations in offspring of cousin marriages developed the Dalmatian include: combinations of congenital deafness, (1) Unique urate metabolism in: pigment patches, bizarre electrocardio­ a. liver grams, renal disease, and sudden b. renal clearance death. To our knowledge, uric acid of (2) Congenital deafness these children is not abnormal. (3) Cardiac arrhythmias and arrest The deafness in these dogs is re­ (4) Heterochromia of the iris, china ported to be due to Vlllth nerve dam­ eye and walleye age, but degeneration of the organ of (5) Renal calculi, hematuria, pyelo­ Corti and coflapse of the cochlear nephritis duct and saccule have been described.'' (6) Pigment "patches" These defects seem unrelated to the (7) Recurrent dermatitis uric acid abnormality. While many of these characteristics Although the full uric acid story is are also seen in other pure-bred dogs not yet known, it is clear that in the and reflect the result of close inbreed­ Dalmatian at least two distinct ab­ ing—the uric acid disturbance is normalities exist. In the mongrel dog unique to the purebred Dalmatian. The and in the human, uric acid is filtered high level of uric acid in the urine and through the glomerulus and approxi­ plasma falls dramatically in the off­ mately 98%-100% of this is reab­ spring of a cross between a pure Dal­ sorbed by the proximal tubules and matian bred to any other strain. Even that which ultimately reaches the urine by careful "back breeding" of such is thought to be almost entirely secreted offspring into the original pure strain, by the distal tubule (Fig 3). In the Dal­ the uric acid abnormality reacts as a matian, there is no resorption of uric true recessive; even though the charac­ acid at the proximal tubule and a small teristic polka-dot pattern of the coat amount is secreted by the distal tubule. can be reconstituted, the uric acid ab­ Hence in the Dalmatian, the uric acid normality fails to reappear.3 The es­ clearance may be equal to or even sence of this study reveals that the greater than the creatinine and insulin spotting phenomenon of the Dalmatian clearances in the same animal.^ * and the uric acid abnormality are This renal abnormality in the Dal­ coded on different genes.
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