Uric acid overproduction

Allopurinol treatment alleviates the symptoms of uric acid overproduction but does not remedy the neurologic problems. 

The biochemical alteration includes overexretion of uric acid in urine (two or three times above normal). The hyperuricuria results from a massive overproduction of uric acid (two or three times above what is observed in gout patients). Studies of the incorporation of [ " Cjglycine into urinary uric acid clearly illustrate the uric acid overproduction, which is 100 and sometimes 200 times as great as in normal individuals. 

Evidence of purine overproduction in childhood has led to detection of superactive PRPP synthetases in 2 families which are of special interest for several reasons, First, the hemizygous affected males in these families show severe sensorineural deafness in addition to uric acid overproduction. Second, the mothers of these boys share both the metabolic and hearing abnormalities with their sons, and one of these women has had both acute gouty arthritis and uric acid urolithiasis. Finally, as discussed below, the functional derangement in the enzyme of one of the families is unusually marked with more severe metabolic consequences of PRPP synthetase superactivity which might explain the childhood clinical onset, the development of gout in the mother, and even the associated deafness. 

Despite structural diversity in the superactive enzymes of individual families, studies of PRPP and purine metabolism carried out both vivo and in cells cultured from affected hemizygous males support the idea that a common mechanism accounts for the association of PRPP synthetase superactivity with uric acid overproduction. Increased intracellular PRPP concentrations and rates of PRPP generation as well as increased rates of all PRPP-dependent purine nucleotide synthetic processes are constant accompaniments of enzyme superactivity. These findings suggest a scheme to explain the association of the enzyme defect with uric acid overproduction PRPP synthetase superactivity -> increased intracellular PRPP generation and concentration > increased rate of purine nucleotide synthesis excessive uric acid synthesis. 

For practical reasons, screening for abnormalities of PRPP synthetase will amost certainly continue to utilize hemolysates, with the use of fibroblast or lymphoblast samples remaining the province of a relatively few laboratories. From the above discussion, it is clear that enzyme activities should be measured under a variety of conditions. In our laboratory, screening of PRPP synthetase activity is carried out in dialyzed hemolysates from patients with uric acid overproduction as follows 1) as a function of Pi concentration (range, 0.2-32 mM) at saturating siabstrate and Mg " " concentrations ... 

EVIDENCE OF A NEW SYNDROME INVOLVING HEREDITARY URIC ACID OVERPRODUCTION, NEUROLOGICAL COMPLICATIONS AND DEAFNESS... 

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. 

Increased intracellular levels of PP-ribose-P have been implicated in the cause of certain hyperuricemic states associated with uric acid overproduction. Fibroblasts from two patients with the Lesch-Nyhan syndrome were found previously to have an elevated intracellular concentration of PP-ribose-P with a normal rate of PP-ribose-P production (Rosenbloom, et al., 1968). Green and Seegmiller (1969) subsequently reported a mean PP-ribose-P value of 47.1 in erythrocytes from seven patients with HGPRT deficiency. We have confirmed these elevated PP-ribose-P levels in three additional patients with the Lesch-Nyhan syndrome with values of 20.5, 39.4 and 49.5 juM (Table 1). The mothers of these patients are obligate heterozygotes and have normal PP-ribose-P levels. Two diseases associated with a deficiency of other PRT enzymes are not associated with altered erythrocyte PP-ribose-P levels (Table 1). PP-ribose-P levels were in the normal range in one patient with a partial deficiency of adenine phosphoribosyltransferase (APRT) and in one patient with orotic aciduria, which is due to a deficiency... 

Thus, there was an equal frequency of uric acid overproduction among normouricemic and hyperuricemic patients with sickle cell anemia. 

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. 

In the course of studying the synthesis of PP-ribose-P in a number of patients with gout and uric acid overproduction, we have foimd increased PP-ribose-P synthetase activity in erythrocyte lysates and cultured fibroblast extracts from two brothers (T.B, and H.B.) in whom the clinical characteristics of the disease are moderately severe in one brother but not unusually severe in the other and are unassociated with neurologic, mental or hematologic abnormalities (7),... 

Lesch-Nyhan syndrome, an overproduction hyperuricemia characterized by frequent episodes of uric acid hthiasis and a bizarre syndrome of self-mutilation, reflects a defect in hypoxanthme-guanine phosphoribo-syl transferase, an enzyme of purine salvage (Figure 34—4). The accompanying rise in intracellular PRPP results in purine overproduction. Mutations that decrease or abohsh hypoxanthine-guanine phosphoribosyltrans-ferase activity include deletions, frameshift mutations, base substitutions, and aberrant mRNA splicing. 

The increased serum uric acid involves either the underexcretion of uric acid (80% of patients) or its overproduction. The cause of overproduction or underexcretion of uric acid in... 

Acute uric acid nephropathy, which is characterized by the acute overproduction of uric acid and by extreme hyperuricemia, can best be prevented with which of the following ... 

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. 

The average human produces 600 to 800 mg of uric acid daily and excretes less than 600 mg in urine. Individuals who excrete more than 600 mg after being on a purine-free diet for 3 to 5 days are considered overproducers. Hyperuricemic individuals who excrete less than 600 mg of uric acid per 24 hours on a purine-free diet are defined as underexcretors of uric acid. On a regular diet, excretion of more than 1,000 mg per 24 hours reflects overproduction less than this is probably normal. 

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. 

Overproduction of uric acid and chronic gout are treated with allopurinol. 

In this connection, a specific loss of hypoxanthine-quanine phosphoribosyltransferase activity has been observed in cases of gout associated with the overproduction of uric acid [305] and in a neurological disorder, the Lesch-Nyhan syndrome [306]. Although a causal relationship has not been established, these disorders could be indicative of the importance of these enzymes. 

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 condition known as Lesch-Nyhan syndrome is one of the primary causes of gout. An X-linked recessive trait occurring in males, this condition involves a tremendous overproduction of uric acid due to a deficiency of one of the enzymes involved in purine metabolism, hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Other abnormalites lead to mental retardation and aggressive behavior. An obvious symptom of the condition is self-mutilation. 

Primary gout (hyperuricemia) is the form of the disease that is attributable to an inborn error of metabolism, such as overproduction of uric acid. 

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 ... 

Mechanism of overproduction of purine nucleotides in the congenital deficiency of hypoxanthine-guanine phosphoribosyltransferase. The loss of the transferase prevents the recycling of hypoxanthine and guanine. This increases uric acid production as well as the de novo synthesis of purine nucleotides. 

---