Hyperuricemia Secondary

Children Allopurinol is rarely indicated for use in children, with the exception of those with hyperuricemia secondary to malignancy or to certain rare inborn errors of purine metabolism. 

Therapeutic uses Allopurinol is effective in the treatment of primary hyperuricemia of gout and hyperuricemia secondary to other conditions, such as that associated with certain malignancies (those in which large amounts of purines are produced) or in renal disease. 

K20. Krakoff, I. H., and Balls, M. E., Allopurinol in the prevention of hyperuricemia secondary to the treatment of neoplastic diseases with alkylating agents, adrenal steroids and radiation therapy. Ann. Rheumatic Diseases 26, 651-654, 1966. 

Allopurinol (zyloprim, aloprim, others) is available for oral use and provides effective therapy for the primary hyperuricemia of gout and the hyperuricemia secondary to polycythemia vera, myeloid metaplasia, other blood dyscrasias, or acute tumor lysis syndrome. 

While purine deficiency states are rare in human subjects, there are numerous genetic disorders of purine catabolism. Hyperuricemias may be differentiated based on whether patients excrete normal or excessive quantities of total urates. Some hyperuricemias reflect specific en2yme defects. Others are secondary to diseases such as cancer or psoriasis that enhance tissue turnover. 

Children (6 to 10 years of age) - In secondary hyperuricemia associated with malignancy, give 300 mg/day those younger than 6 years of age are generally given 150 mg/day. Evaluate response after approximately 48 hours of therapy and adjust dosage if necessary. 

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. 

Allopurinol is an xanthine oxidase inhibitor. It reduces urate production and is used in primary and secondary urate overproduction. Therapy of hyperuricemia prevents recurring attacks of acute gouty arthritis. Allopurinol dosages are 300 mg/day for serum creatinine < 1.5 mg/dl and 100 mg/day for serum creatinine between 1.6-2.0 mg/dl. Reduction of tophi is slow with allopurinol, particularly in patients with giant tophi and renal insufficiency where drug dosage is limited. 

C. Pyrazinamide is known to cause hyperuricemia and precipitate gouty arthritis. Pyrazinamide-induced gouty arthritis does not respond to uricosuric therapy with probenecid but may respond to acetylsalicylic acid. Cycloserine (A) can cause headaches, confusion, tremors, and seizures, possibly secondary to low levels of magnesium in the cerebrospinal fluid cycloserine should be avoided in patients with epilepsy and mental depression. It is not associated with hyperuricemia. Thiacetazone (B) is an antibiotic that is rarely used in tuberculosis. The most common adverse reactions are general rashes and GI intolerance. Its use is not associated with hy-... 

Secondary hyperuricemia may be caused by other diseases, for example, cancer, chronic renal insufficiency, etc. 

Allopurinol is used not only in treating the hyperuricemia associated with gout, but also in the secondary hyperuricemia associated with the use of antineoplastic agents. However, allopurinol may interfere with the metabolism of antineoplastic agents such as azathioprine and 6-mercaptopurine. 

Allopurinol (4-hydroxypyrazolo [3, 4-d] pyrimidine) is an inhibitor of xanthine oxidase that was successfully introduced in the treatment of primary gout about 45 years ago [171]. Allopurinol continues to be accepted as standard therapy in the treatment of primary and secondary hyperuricemia. Adverse reactions occur in about 10% of patients treated with allopurinol and are relatively mild and self-limited [171,172]. A mild maculopapular eruption or gastrointestinal disorders are usually noted, which promptly regress with cessation of therapy. Isolated instances of allopecia [173], bone marrow depression [174], ocular lesions [175], acute cholangitis [176], various types of hepatic injuries [177,178] temporal arthritis [179], and xanthine stones [180] have been reported. Recently, LaRosa et al [180a] have reported a case of xanthine nephropathy during treatment of childhood T-cell ALL. 

Measurement of plasma uric acid is predominantly used in the investigation of gout, either as a result of a primary hyperuricemia or caused by other conditions or treatments that give rise to secondary hyperuricemias. It is also used in the diagnosis and monitoring of pregnancy-induced hypertension (preeclamptic toxemia). 

Secondary gout is a result of hyperuricemia attributable to several identifiable causes. Renal retention of uric acid may occur in acute or chronic kidney disease of any type or as a consequence of administration of drugs diuretics, in particular, are implicated in the latter instance. Organic acidemia caused by increased acetoacetic acid in diabetic ketoacidosis or by lactic acidosis may interfere with tubular secretion of urate. Increased nucleic acid turnover and a consequent increase in catabolism of purines may be encountered in rapid proliferation of tumor cells and in massive destruction of tumor cells on therapy with certain chemotherapeutic agents. 

Secondary gout develops as a complication of hyperuricemia caused by another disorder (e.g., leukemia, chronic nephritis, polycythemia). This type of hyperuricemia usually is associated with abnormally rapid turnover of nucleic acids. The rare cases of gout in adolescents and children are usually of this type. 

Hyperphosphatemia is not uncommonly observed in patients undergoing treatment for acute leukemia and lymphomas. Chemotherapeutic treatment of acute lymphoblastic leukemia may result in the release of large amounts of phosphorus into the systemic circulation secondary to lysis of lymphoblasts. Initiation of chemotherapy for Burkitt s lymphoma results in a rapid lysis of malignant cells, resulting in hyperphosphatemia, hyperuricemia, hyperkalemia, and hypocalcemia. This syndrome is commonly referred to as tumor lysis syndrome. ... 

Potential adverse effects with vitamin Bn replacement therapy are rare. Uncommon side effects include hyperuricemia and hypokalemia. Rebound thrombocytosis may precipitate thrombotic events. Another side effect of vitamin Bn therapy is sodium retention. This effect is more likely to occur in the patient with compromised cardiovascular status, because of an expansion in intravascular volume secondary to the sudden increase in the production of RBCs. Rare cases of anaphylaxis with parenteral administration of cobalamin have been reported. 

Myelosuppression low emetogenic potential rash, pruritus, skin hyperpigmentation hyperuricemia may occur with rapid cytoreduction secondary leukemias may occur with long-term use... 

Secondary (or acquired) gout is caused by seemingly unrelated disorders. These conditions may cause hyperuricemia by either overproduction of uric acid or its undersecretion by the kidneys. For example, leukemia patients overproduce uric acid either because of massive cell destruction or the chemotherapy treatment required to destroy the cancerous cells. Hyperuricemia also results when certain drugs interfere with the renal secretion of uric acid into the urine. Patients with lead poisoning are also likely to develop gout because of renal damage. 

The usual daily dose in children with secondary hyperuricemia associated with malignancies is 150-300 mg, depending on age. 

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... 

In familial gout and hyperuricemia renal uric acid clearance is diminished compared with normals. It can be concluded from this that the turnover rate of the miscible uric acid pool is also diminished in gout. Summarizing the literature on uric acid turnover studies, there was a mean turnover rate of 0.46 ( 0.11) pools/day in gout and hyperuricemia (n = 33), while in normal subjects (n = 38) it was 0.60 ( 0.14) pools/day (p < 0.001). However, data reported on renal function of the subjects were insufficient in some of these publications to exclude secondary renal disease. The difference might therefore be due, at least in part, to renal insufficiency in patients with gout. 

Is the secretory transport in man and chimpanzee quantitatively important The fact that in the chimpanzee, which normally excretes 10% of the amount filtered, it is possible to increase the fractional excretion to 150% by mersalyl (a mercurial diuretic) points to an important secretory capacity (Fanelli et al., 1973). In man, secretion, is required for maintaining urate homeostasis since patients treated with pyrazinamide for tuberculosis may develop hyperuricemia (Emmerson, 1978 review). Furthermore, a retention of urate is observed when diuretics are given over long periods. Part of the retention is secondary to volume depletion and a stimulation of reabsorption (Steele, 1978), but at least in the case of thiazides a direct inhibition of the secretory transport cannot be excluded (Emmerson 1978, review). Such an effect was shown to occur in the rat (Weinman et al. 1975, 1976). 

Allopurinol has been used for 16 years at doses ranging from 200 to 800 mg/day for the control of primary and secondary hyperuricemia. At the most commonly used doses of allopurinol (300-400 mg/ day) about 70% of the allopurinol is oxidized to oxipurinol, which is excreted in the urine. Urinary allopurinol and allopurinol riboside each account for about 10% of the dose. Since the degree of xanthine oxidase inhibition is dose-related, not only the oxidation of hypoxanthine and xanthine to uric acid, but also the oxidation of allopurinol to oxipurinol might be expected to be strongly inhibited at high doses of allopurinol. This would lead to increased levels of allopurinol, as well as allopurinol riboside, in plasma and urine. The extent to which this phenomenon occurs was investigated in several laboratory animal species and in man. 

We conclude that hyperuricemia related to ethanol consumption at lower blood ethanol levels (less than 150 mg/dl) results from increased production of uric acid probably secondary to accelerated degradation of adenine nucleotides. 

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