Uric acid and gout

Cameron JS, Simmonds HA. Uric acid, gout and the kidney. J CUn Pathol 1981 34 1245-54. 

Cameron, J.S., and Simmonds, H.A. Uric acid, gout and the kidney. J. Clin. Path. (In press). Ferro, A.J., Vandenbark, A.A., Marchitto, K. The role of 5 -methylthioadenosine phosphorylase in 5 -methylthioadenosinemediated inhibition of lymphocyte transformation. Biochim. Biophys. Acta., 588 294-301 (1979). 

Allopurinol (Zyloprim) reduces the production of uric acid, thus decreasing serum uric acid levels and the deposit of urate crystals in joints. The exact mechanism of action of colchicine is unknown, but it does reduce the inflammation associated with the deposit of urate crystals in the joints. This probably accounts for its ability to relieve the severe pain of acute gout. Colchicine has no effect on uric acid metabolism. 

In those with gout, the serum uric acid level is usually elevated. Sulfinpyrazone increases the excretion of uric acid by the kidneys, which lowers serum uric acid levels and consequently retards the deposit of urate crystals in the joints. Probenecid (Benemid) works in the same manner and may be given alone or with colchicine as combination therapy when there are frequent, recurrent attacks of gout. Probenecid also has been used to prolong the plasma levels of the penicillins and cephalosporins. 

Allopurinol is the antihyperuricemic drug of choice in patients with a history of urinary stones or impaired renal function, in patients who have lymphoproliferative or myeloproliferative disorders and need pretreatment with a xanthine oxidase inhibitor before initiation of cytotoxic therapy to protect against acute uric acid nephropathy, and in patients with gout who are overproducers of uric acid. 

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. 

Colchicine, an alkaloid obtained from the autumn crocus, has long been used and is relatively selective for the treatment of acute gouty arthritis. Unlike many of the newer agents for use in gout, colchicine has minimal effects on uric acid synthesis and excretion it decreases inflammation associated with this disorder. It is thought that colchicine somehow prevents the release of the chemotactic factors and/or inflammatory cytokines from the neutrophils, and this in turn decreases the attraction of more neutrophils into the affected area (Fig. 37.1).The ability of colchicine to bind to leukocyte microtubules in a reversible covalent complex and cause their depolymerization also may be a factor in decreasing the attraction of the motile leukocytes into the inflamed area. 

It is effective for treatment of acute attacks of gout. It has no effect on renal excretion of uric acid. It binds to tubulin, it interferes with function of mitotic spindles, causes depolymerization and disappearance of fibrillar microtubules in granulocytes. In gout, the useful of colchicine is due to the inhibition of the release of glycoproteins from granulocytes in inflamed joint thus preventing precipitation of uric acid crystals and release of lysosomal enzymes. 

Mercaptopurine and thioguanine are both given orally (Table 55-3) and excreted mainly in the urine. However, 6-MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation catalyzed by xanthine oxidase, whereas 6-TG requires deamination before it is metabolized by this enzyme. This factor is important because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used with chemotherapy in hematologic cancers to prevent hyperuricemia after tumor cell lysis. It does this by blocking purine oxidation, allowing excretion of cellular purines that are relatively more soluble than uric acid. Nephrotoxicity and acute gout produced by excessive uric acid are thereby prevented. Simultaneous therapy with allopurinol and 6-MP results in excessive toxicity unless the dose of mercaptopurine is reduced to 25% of the usual level. This effect does not occur with 6-TG, which can be used in full doses with allopurinol. 

However laboratory experiments showed that it did not in fact dissolve uric acid crystals, and its use started to decline. Uric acid also dropped out of fashion. However old ideas and practices can take a long time to die out. Lithium continued to be prescribed for gout, arthritis, rheumatism and other complaints. It was listed as a recommended treatment for these conditions until the 1930s in major pharmacopoeias. Even when these publications admitted there was no rational foundations for the use of these (lithium) salts, they still listed indications for lithium use and instructions on how to administer it... 

Losartan appears to be unique among the ARBs because it inhibits the urate anion transport in renal proximal tubuli hence, it increases uric acid excretion and decreases plasma levels of uric acid in hypertensive patients. This effect is not the consequence of AT] receptor blockade. Since high uric acid levels have been associated with cardiovascular morbidity/mortality, losartan may be the best ARB for patients with gout [7,30,31]. Moreover, losartan was found to decrease ocular pressure in normotensive as well as in hypertensive patients [32]. 

Case Conclusion In addition to having urate crystals present in the joint fluid aspirate, KM has met several criteria to support the diagnosis of gout. This acute gout attack is treated with high-dose ibuprofen, which is tapered over 7 days. Once the attack is resolved, maintenance therapy with allopurinol is initiated to lower uric acid levels and prevent future acute gout attacks. 

Gout is an inflammatory condition that attacks joints, tendons, and other tissues. The most common site is at the joint of the big toe. Gout is caused by problems metabolizing uric acid and purine, which is produced by proteins. The inability to metabolize uric acid and purine results in a buildup of urates (uric acid salts) and uric acid called hyperuricemia. Uric acid is also not cleared by the kidneys. Urate crystals form urate calculi known as stones that appear as tophi (bumps) in the subcutaneous tissue of earlobes, elbows, hands, and the base of the large toe. 

In view of the obvious relationship between high uric acid levels and gout there has been a great deal of interest in hyperuricemia, and relatively little consideration has been given to a possible significance of hypouricemia. Studies have revealed, however, that in addition to the greatly discussed hyperuricemias there exist a certain small but real number of individuals whose uric acid levels run from a third to a sixth of the normal value (E7, F6). 

The answer is d. (Murray, pp 375-401. Scriver, pp 2513-2570. Sack, pp 121-138. Wilson, pp 287-320.) Xanthine oxidase catalyzes the last two steps in the degradation of purines. Hypoxanthine is oxidized to xanthine, and xanthine is further oxidized to uric acid. Thus, xanthine is both product and substrate in this two-step reaction. In humans, uric acid is excreted via the urine. Allopurinol, an analogue of xanthine, is used in gout to block uric acid production and deposition of uric acid crystals in the kidneys and joints. It acts as a suicide inhibitor of xanthine oxidase after it is converted to alloxanthine. Guanine can also be a precursor of xanthine. 

Allopurinol is the antihyperuricemic drug of choice in patients with a history of urinary stones or impaired renal function, in patients who have lymphoproliferative or myeloproliferative disorders and need pretreatment with a xanthine oxidase inhibitor before initiation of cytotoxic therapy to protect against acute uric acid nephropathy, and in patients with gout who are overproducers of uric acid. The major side effects of allopurinol are skin rash, leukopenia, occasional gastrointestinal toxicity, and increased frequency of acute gouty attacks with the initiation of therapy. An allopurinol hypersensitivity syndrome characterized by fever, eosinophilia, dermatitis, vasculitis, and renal and hepatic dysfunction is a rare side effect, but is associated with a 20% mortality rate. ... 

Notwithstanding its obsolescence in the treatment of infectious diseases, probenecid found a very important place in the physician s armamentarium because of its uricosuric activity. Its interference with the reabsorption of uric acid through the renal tubular membrane was an unexpected observation. Probenecid is the first useful synthetic compound for the control of uric acid excretion and the age-old disease, gout. 

PRPP is an important intermediate in the de novo synthesis of purines pathway (Figure 22.4). Defects in PRPP synthetase may render it insensitive to feedback inhibition by purine nucleotides. Thus, purine nucleotides are overproduced, leading to excessive uric acid synthesis and gout (Figure 22.9). 

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