[Historical review of gout and hyperuricemia investigations].
Historical development of gout and hyperuricemia investigations was reviewed. Gout has been a recognized disease since the fifth century B.C. In 1683, Sydenham described the detailed clinical features of the disease based on his own condition. Leeuwenhoek (1679) first described crystals in a gouty tophus, which were identified as uric acid by Wollaston (1797). Since uric acid clearance of hyperuricemia was markedly lower than that in normal controls, early investigators considered that the main cause of hyperuricemia was urate underexcretion. However, in the 1940s, studies on uric acid metabolism using isotope tracer techniques demonstrated that a part of hyperuricemia resulted from urate overproduction, which was detected in approximately one-third of all gouty patients. In the 1970s, micropuncture, microinjection and microperfusion methods as well as stop-flow methods demonstrated that uric acid transports in nephron were suspected to consist of four steps, that were glomerular filtration, reabsorption, secretion and postsecretory reabsorption. The majority of filtrated uric acid was almost completely reabsorbed, followed by secretion and postsecretory reabsorption at a proximal site in the tubulus. Each proportion of transports to the glomerular filtration(100%) was estimated approximately 99%, 50% and 40%, respectively. Subsequently, about 10% of the filtrate was excreted in the urine. The authors (1999) suggested that the secretion rate of hyperuricemic patients was significantly lower than that of normal controls but postsecretory reabsorption was not. Therefore, the decrease in the secretion rate was suspected to be the main cause of underexcretion. Dunkan (1960) reported a family demonstrating hyperuricemia associated with severe renal damage that progressed rapidely. Currently, this disease is called familial juvenile hyperuricemic nephropathy (FJHN), and was recently found to be the result of a variation in uromodulin. Enomoto (2002) found a number of urate transporters in the cell surface of the tubulus, among which URAT1 was the most effective in reabsorbing urate from the tubulus lumen to the cells. The urate was released to the blood vessel side by the other transporter OAT. Therefore, URAT1 was suspected to be a cause of underexcretion. As the mechanism underlying overproduction of uric acid, de novo purine nucleotide synthesis has been shown to be increased. In some cases, the increase in de novo synthesis is the result of gene mutation in purine nucleotide synthesis enzymes, such as PRPP synthetase (Sperling, 1973) as well as hypoxanthine guanine phosphoribosylpyrophosphate synthetase (Seegmiller, 1967). However, the mechanism in majority of the overproduction has not yet been clarified and is currently under investigation.
Nakamura
Toru
T
Department of Internal Medicine, Fukui University.
D006073:Gout / Q000209:etiology / Q000266:history; D049670:History, 17th Century; D049671:History, 18th Century; D049672:History, 19th Century; D049673:History, 20th Century; D006801:Humans; D033461:Hyperuricemia / Q000145:classification / Q000175:diagnosis / Q000209:etiology / Q000266:history; D007668:Kidney / Q000378:metabolism; D009154:Mutation; D027361:Organic Anion Transporters / Q000235:genetics / Q000502:physiology; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000502:physiology; D012268:Ribose-Phosphate Pyrophosphokinase / Q000235:genetics / Q000502:physiology; D014527:Uric Acid / Q000378:metabolism
D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; D014527:Uric Acid; D012268:Ribose-Phosphate Pyrophosphokinase