Uric acid/urate overproduction

In humans, uric acid is the end product of the degradation of purines. It serves no known physiologic purpose and is regarded as a waste product. The size of the urate pool is increased severalfold in individuals with gout. This excess accumulation may result from either overproduction or underexcretion. 

Consider briefly the disease gout, which is characterized by the precipitation of urates in tissues and by the presence of hyperuricemia. Bauer and Klemperer state, 11 "The etiology of the disease is unknown." As has been pointed out by other writers, the presence of high concentrations of uric acid in the blood may be due to (1) overproduction, (2) lowered excretion, (3) lowered destruction, or, of course, any combination of the three. Let us consider two hypothetical individuals, A and B, 30 years of age who have exactly the same uric acid blood level (4 mg. per cent) and exactly the same amount of blood (8 liters). The total uric acid in their respective bloods is 320 mg. Let us suppose further that the rate of production of uric acid in the two individuals is continuously exactly the same, the rate of destruction in the two is continuously the same, and that they consume exactly the same food. One hypothetical individual, A, however, continuously excretes on the average 0.1 mg. less uric acid per day than the other. This is very little, compared with the usual total excretion of 700 mg. per day. In the course of 10 years, A s uric acid blood level will, however, have more than doubled, due to this increased retention, and he will be in the range of "gouty" as contrasted with "normal" individuals. This could happen by a very gradual increase, in one individual, of the renal threshold for uric acid. Whether excretion, production, or destruction is responsible for the difference between individuals, the total accumulation of uric acid in hyperuricemia is small. 

Hyperuricemia may be produced by overproduction of uric acid or under-excretion of uric add by the kidneys. Kyperuricemia may progress to acute and chronic gouty arthritis if uric acid (monosodium urate) is deposited in joints and surrounding soft tissue, where it causes inflammation, Uric add is produced from excess endogenous purines as shown in Figure 1-18-5, and is also produced from dietary purines (digestion of nucleic acid in the intestine) by intestinal epithe-lia. Both sources of uric acid are transported in the blood to the kidneys for excretion in urine. 

Gouty arthritis is an inflammatory response to the deposition of monosodium urate monohydrate crystals secondary to hyperuricemia. It is called monosodium urate crystal deposition disease. Hyperuricemia is a serum urate concentration > 7 mg% in males and >6 mg% in females. Hyperuricemia results from overproduction (10-15% of individuals) or a renal excretion of urate lower than 400 mg uric acid/24 hours (85-90% of individuals). The urate under-excretors have a urate clearance of <6 ml/min or a urate to creatinine clearance ratio of <6%. The combination of a relative excess of dietary purine consumption together with urate under-excretion is often the basis for hyperuricemia. 

Febuxostat is a potent and selective inhibitor of xanthine oxidase, and thereby reduces the formation of xanthine and uric acid. No other enzymes involved in purine or pyrimidine metabolism are inhibited. In clinical trials, febuxostat at a daily dose of 80 mg or 120 mg was more effective than allopurinol at a standard 300 mg daily dose in lowering serum urate levels. The urate-lowering effect was comparable regardless of the pathogenic cause of hyperuricemia—overproduction or underexcretion. 

A 42-year-old male cancer patient undergoing radiation therapy develops severe pain in his right big toe. Laboratory analyses indicate an elevated serum uric acid level and urate crystals in his urine. This patient s pain is caused by the overproduction of the end product of which of the following metabolic pathways ... 

In humans, uric acid is the end product of the degradation of purines. Uric acid serves no known physiologic purpose and therefore is regarded as a waste product. In lower animals, the enzyme uricase breaks down uric acid to the more soluble allantoin, and thus uric acid does not accumulate. Gout occurs exclusively in humans in whom a miscible pool of uric acid exists. Under normal conditions, the amount of accumulated uric acid is about 1200 mg in men and about 600 mg in women. The size of the urate pool is increased severalfold in individuals with gout. This excess accumulation may result from either overproduction or underexcretion. 

The pathophysiology of gout is understood poorly. While a prerequisite, hyperuricemia does not inevitably lead to gout. Uric acid, the end product of purine metabolism, is relatively insoluble compared to its hypoxanthine and xanthine precursors, and normal serum urate levels approach the limit of solubility. In most patients with gout, hyperuricemia arises from underexcretion rather than overproduction of urate. Urate tends to crystallize in colder or more acidic conditions. Neutrophils ingesting urate crystals secrete inflammatory mediators that lower the local pH and lead to further urate precipitation. 

Gout is a metabolic disease characterized by recurrent episodes of acute arthritis, usually monoarticular, and is associated with abnormal levels of uric acid in the body, particularly the presence of monosodium urate crystals in synovial fluid. Primary gout is a hereditary disease in which hyperuricemia is caused by an error in uric acid metabolism—either overproduction or an inability to excrete uric acid. Secondary gout refers to those cases in which hyperuricemia is caused by an acquired disease or disorder, such as chronic renal disease, lead poisoning, or myeloproliferative disorders. Gout generally occurs in... 

The initial plasma urate concentration (Table 1) was disproportionately high levels greater than 0.6-0.9mmol/l in cases of acute renal failure are rare. The plasma urate concentration remained high when renal function had returned to normal 115 ml/min) However, the urinary uric acid, hypoxanthine and xanthine were nomnal for age, as was the excretion of total oxypurines in relation to creatinine excretion on a millimolar basis. Only after clinical gout appeared two years later was purine overproduction demonstrated, with plasma and urinary urate increased, as were hypoxanthine and xanthine excretion. The oxypurine/creatinine ratio was raised. 

A group of patients forming calcium oxalate stones are hyperuri-cosuric and it is thought that their excessive urate excretion contributes to calcium-stones formationl. The pathomechanisms invoked are dietary purine excess and endogenous uric acid overproduction, being defective tubular reabsorption of urate "unattractive because uricemia was found to be normal in patients with recurrent calcium nephrolithiasis (RCN) and hyperuricosuria. Current studies were undertaken to define the incidence, role of diet, abnormalities of the renal handling of urate, and associated metabolic disturban-c"es in patients with RCN and hyperuricosuria. 

Renal Disease and Uric Acid Lithiasis in Urate Overproduction... 

Another patient with HGPRTase deficiency and minimal neurological signs presented with intractable gout at the age of 35 years and developed an episode of acute renal failure when his fluid intake was reduced below 3 litres/2U hours. This was attributed to the formation of uric acid crystals within his renal tubules so that an intense alkaline diuresis was instituted, resulting in a urine volume which, over one 2k hour period, exceeded 15 litres. This succeeded, however, in completely reversing his acute renal insufficiency and, when a regular urine volume of 5 litres/day was maintained, his renal function returned to normal. His usual 2k hour urinary urate excretion exceeded 2.5 g. Thus, an acute deterioration of renal function may occur in urate overproduction, which may be completely reversed by an intense diuresis (Observation k). 

Hyperuricemia, uric acid overproduction, and hyperuricosuria are frequent clinical features of sickle cell anemia. Uric acid overproduction may result in hyperuricemia in some patients with sickle cell anemia. However, in other patients, enhanced urate excretion permits maintenance of a normal serum uric acid despite uric acid overproduction. Hyperuricosuria in normouricemic patients with sickle cell anemia may result from enhanced tTobular secretion of urate but is more likely to represent diminished urate reabsorption at a post-secretory site. Hyperuricosuria may protect the young patient with sickle cell anemia from gouty arthritis and tophi but may also increase the risk of tubular deposition of urate and nephropathy. 

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