Uric acid overproduction is a less common cause of hyperuricemia. The primary form of hyperuricemia is usually of unknown cause (idiopathic). However, certain mutations in the gene for X-linked PRPP synthetase have been identified. These mutations can lead to increased enzyme activity, resulting in the overproduction of PRPP and subsequently, purine production. This leads to elevated levels of uric acid in the plasma. Lesch-Nyhan syndrome also causes hyperuricemia due to decreased salvage of hypoxanthine and guanine, leading to increased availability of PRPP. Secondary hyperuricemia is typically caused by an increased availability of purines, often seen in patients with myeloproliferative disorders or undergoing chemotherapy. It can also be associated with unrelated metabolic diseases such as von Gierke disease or hereditary fructose intolerance.

Certain dietary factors can increase or decrease the risk of gout. A diet rich in meat, seafood (especially shellfish), and ethanol is associated with an increased risk, while a diet rich in low-fat dairy products is associated with a decreased risk.

Treatment for acute gout attacks involves the use of anti-inflammatory agents such as colchicine, steroidal drugs like prednisone, or nonsteroidal drugs like indomethacin. These medications help alleviate symptoms but do not affect uric acid levels.

Long-term strategies for managing gout aim to lower uric acid levels below saturation point (6.5 mg/dl) to prevent the deposition of MSU crystals. Uricosuric agents like probenecid or sulfinpyrazone, which increase the renal excretion of uric acid, are used in patients who have decreased uric acid excretion. Allopurinol, a structural analog of hypoxanthine, inhibits uric acid synthesis and is used in patients who produce excessive amounts of uric acid. Allopurinol is metabolized into oxypurinol, a long-lasting inhibitor of XO, which leads to the accumulation of more soluble compounds like hypoxanthine and xanthine, reducing the likelihood of an inflammatory response. Febuxostat, a nonpurine inhibitor of XO, is another available option.

Adenosine deaminase deficiency is another condition related to uric acid metabolism.
Uric acid overproduction: A less common cause of hyperuricemia is from the overproduction of uric acid. Primary hyperuricemia is, for the most part, idiopathic (having no known cause). However, several identified mutations in the gene for X-linked PRPP synthetase result in the enzyme having an increased maximal velocity ([Vmax] see p. 57) for the production of PRPP, a lower Km (see p. 59) for ribose 5phosphate, or a decreased sensitivity to purine nucleotides, its allosteric inhibitors (see p. 62). In each case, increased availability of PRPP increases purine production, resulting in elevated levels of plasma uric acid. Lesch-Nyhan syndrome (see p. 296) also causes hyperuricemia as a result of the decreased salvage of hypoxanthine and guanine and the subsequent increased availability of PRPP. Secondary hyperuricemia is typically the consequence of increased availability of purines (for example, in patients with myeloproliferative disorders or who are undergoing chemotherapy and so have a high rate of cell turnover). Hyperuricemia can also be the result of seemingly unrelated metabolic diseases, such as von Gierke disease (see Fig. 11.8 on p.
130) or hereditary fructose intolerance (see p. 138).
A diet rich in meat, seafood (particularly shellfish), and ethanol is associated with increased risk of gout, whereas a diet rich in low-fat dairy products is associated with a decreased risk.
c. Treatment: Acute attacks of gout are treated with anti-inflammatory agents. Colchicine, steroidal drugs such as prednisone, and nonsteroidal drugs such as indomethacin are used. [Note: Colchicine prevents formation of microtubules, thereby decreasing the movement of neutrophils into the affected area. Like the other anti-inflammatory drugs, it has no effect on uric acid levels.] Long-term therapeutic strategies for gout involve lowering the uric acid level below its saturation point (6.5 mg/dl), thereby preventing the deposition of MSU crystals. Uricosuric agents, such as probenecid or sulfinpyrazone, that increase renal excretion of uric acid, are used in patients who are underexcretors of uric acid. Allopurinol, a structural analog of hypoxanthine, inhibits uric acid synthesis and is used in patients who are overproducers of uric acid. Allopurinol is oxidized to oxypurinol, a long-lived inhibitor of XO. This results in an accumulation of hypoxanthine and xanthine (see Fig. 22.15), compounds more soluble than uric acid and, therefore, less likely to initiate an inflammatory response. In patients with normal levels of HGPRT, the hypoxanthine can be salvaged, reducing the levels of PRPP and, therefore, de novo purine synthesis. Febuxostat, a nonpurine inhibitor of XO, is also available. [Note: Uric acid levels in the blood normally are close to the saturation point. One reason for this may be the strong antioxidant effects of uric acid.] 2. Adenosine deaminase deficiency