Hyperuricemia and Gout: A Review Article

Abstract

Uric acid is a chemical, created in the body by the breaking down of purines. It is excreted out of the body by the kidneys, through urine, after it dissolves in the blood. If it is not excreted out of the body properly, high levels of uric acid gets accumulated which causes gout and kidney stones. Hyperuricemia is usually caused due to the regular intake of food having high content of purine and conditions such as hypoparathyroidism, lead poisoning, renal failure and side effects of chemotherapy. Hyperuricemia occurs when serum urate levels exceed urate solubility, ie, at approximately 6.8 mg/dL. At serum urate levels above this threshold, manifestations of gouty arthritis may occur, although asymptomatic hyperuricemia often persists for many years. Intercritical asymptomatic periods follow the resolution of acute gout flares, but crystals remain in the joint during these intervals and further deposition may continue silently. Ultimately this may lead to persistent attacks, chronic pain, and, in some patients, joint damage. INTRODUCTION TO GOUT Gout, or gouty arthritis, is a relatively common metabolic disorder. It is characterized by a painful, inflammatory response to deposits of sodium urate crystals in the synovial fluid of the joints and surrounding tissue. This condition may also present as deposits of urate crystals in cartilage (i.e., tophi), interstitial renal disease, or kidney stones. Gout is a recognized complication of hyperuricemia. In the acute phase it is characterized by a monoarticular arthritis that remits after one to two weeks and recurs periodically. Joints of the lower extremity are most commonly affected. The periods between flares of the disease may shorten over time and attacks may become polyarticular. Chronic tophaceous joints develop after many years of recurrent attacks and are characterized by deposits of urate in the skin or bursa, referred to as tophi. Common sites for tophi include the pinna of the ear, the olecranon bursa and adjacent to the small joints of the fingers. GENETIC AND BIOCHEMICAL BASIS OF HYPERURICEMIA There are three different inherited defects that lead to early development of severe hyperuricemia and gout: glucose-6phosphatase (gene symbol = G6PT) deficiency; severe and partial hypoxanthine-guanine phosphoribosyltransferase (HGPRT, gene symbol = HPRT) deficiency; and elevated 5'phosphoribosyl-1'-pyrophosphate synthetase (PRPP synthetase, gene symbol = PRPS) activity. The familial association of gout was recognized hundreds of years ago but defining the exact genetic mechanisms was not possible until the advancement of modern genetic tools. Gout and Garrod have been linked in medical literature for more than a century. He identified uric acid as a normal constituent of the serum of healthy persons and devised a method for detecting its increased concentration in gouty subjects. Overactivity of PRS is also an X-linked dominant disorder that can produce hyperuricemia. It is characterized by an overproduction of phosphoribosyl pyrophosphate (PRPP) and uric acid, which can cause hyperuricemia, nephrolithiasis, and gout at an early age. Overactivity of PRS is related to an accelerated transcription of the PRS-I gene, acting as a major determinant of synthesis of PRPP, purine nucleotides, and uric acid. At least three different isoforms of PRPP synthetase have been identified and are encoded by three distinct, yet highly homologous PRPS genes, identified as PRPS1, PRPS2, and PRPS3. The PRPS1 and PRPS2 genes are found on the X chromosome (Xq22–q24 and Xp22.2–p22.3, respectively) and the PRPS3 gene is found on chromosome 7. The PRPS3 gene appears to be expressed exclusively in the testes. All three PRPP Hyperuricemia and Gout: A Review Article 2 of 6 synthetase isoforms differ in kinetic and physical characteristics such as isoelectric points (pI), pH optima, activators and inhibitors. Phosphoribosylpyrophosphate synthetase (PRS) superactivity is characterized by hyperuricemia and hyperuricosuria and is divided into a severe phenotype with infantile or early-childhood onset and a milder phenotype with late-juvenile or early-adult onset. Variable combinations of sensorineural hearing loss, hypotonia, and ataxia observed in the severe type are not usually present in the mild type. In the mild type, uric acid crystalluria or a urinary stone is commonly the first clinical finding, followed later by gouty arthritis if serum urate concentration is not controlled. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is an enzyme involved in the salvage of purine nucleotides. HGPRT catalyzes the following two interconversions: hypoxanthine + PRPP IMP + PPi guanine + PRPP GMP + PPi A complete or virtually complete loss of HGPRT activity results in the severe disorder, Lesch-Nyhan syndrome. Lesch-Nyhan syndrome is inherited as an x linked trait. Persons with this syndrome are missing or are severely lacking an enzyme called hypoxanthine guanine phosphoribosyltransferase 1 (HGP). The body needs this enzyme to recycle purines. Without it, abnormally high levels of uric acid build up in the body. Hyperuricemia results from a combination of increased generation and decreased excretion of uric acid which is generated when increased amounts of G6P are metabolized via the pentose phosphate pathway. It is also a byproduct of purine degradation. Uric acid competes with lactic acid and other organic acids for renal excretion in the urine. In GSD I increased availability of G6P for the pentose phosphate pathway, increased rates of catabolism, and diminished urinary excretion due to high levels of lactic acid all combine to produce uric acid levels several times normal. Although hyperuricemia is asymptomatic for years, kidney and joint damage gradually accrue.