Monday, 9 December 2013

GOUT AND HYPERURICEMIA


The term gout describes a disease spectrum including hyperuricemia, recurrent attacks of acute arthritis associated with monosodium urate crystals in leukocytes found in synovial fluid, deposits of monosodium urate crystals in tissues (tophi), interstitial renal disease, and uric acid nephrolithiasis. a urate concentration greater than 7.0 mg/dL is abnormal and is associated with an increased risk for gout.
Epidemiology:-
Population studies have shown that serum urate concentration (and consequently the risk of gout) correlates with age, serum creatinine level, blood urea nitrogen level, male gender, blood pressure, body weight, and alcohol intake. The incidence of gout varies from 20 to 35 per 100,000 persons, with an overall prevalence of 1.6 to 13.6 per thousand. Prevalence increases with age, especially in men.1 Men are affected by gout approximately 10 times more often than women.
Etiology and pathophysiology:-
In humans, uric acid is the end product of the degradation of purines. Uric acid serves no known physiologic purpose and therefore is regarded as awaste product. In lower animals, the enzyme uricase breaks down uric acid to the more soluble allantoin, and thus uric acid does not accumulate.
Overproduction of  uric acid:-
The purines from which uric acid is produced originate from three sources: dietary purine, conversion of tissue nucleic acid to purine nucleotides, and de novo synthesis of purine bases. The purines derived from these three sources enter a common metabolic pathway leading to the production of either nucleic acid or uric acid. Under normal circumstances, uric acid may accumulate excessively if production exceeds excretion. The average human produces about 600 to 800 mg of uric acid each day.
Two enzyme abnormalities resulting in an overproduction of uric acid have been well described. The first is an increase in the activity of phosphoribosyl pyrophosphate (PRPP) synthetase, which leads to an increased concentration of PRPP. PRPP is a key determinant of purine synthesis and thus uric acid production. The second is a deficiency of hypoxanthine guanine phosphoribosyl transferase (HGPRT).
HGPRT is responsible for the conversion of guanine to guanylic acid and hypoxanthine to inosinic acid. These two conversions require PRPP as the cosubstrate and are important reutilization reactions involved in the synthesis of nucleic acids. A deficiency in the HGPRT enzyme leads to increased metabolism of guanine and hypoxanthine to uric acid, and more PRPP to interact with glutamine in the first step of the purine pathway.4 Complete absence of HGPRT results in the childhood Lesch-Nyhan syndrome, characterized by choreoathetosis, spasticity, mental retardation, and markedly excessive production of uric acid.
Underexcretion of uric acid:-
Uric acid is eliminated in twoways. About two-thirds of the uric acid produced each day is excreted in the urine. The rest is eliminated through the gastrointestinal tract after enzymatic degradation by colonic bacteria. Adecline in the urinary excretion of uric acid to a level below the rate of production leads to hyperuricemia and an increased miscible pool of sodium urate. Almost all the urate in plasma is freely filtered across the glomerulus. The concentration of uric acid appearing in the urine is determined by multiple renal tubular transport processes in addition to the filtered load. Evidence favors a four-component model including glomerular filtration, tubular reabsorption, tubular secretion, and postsecretory reabsorption. Approximately 90% of filtered uric acid is reabsorbed in the proximal tubule, probably by both active and passive transport mechanisms. There is a close linkage between proximal tubular sodium reabsorption and uric acid reabsorption, so states that enhance sodium reabsorption (e.g., dehydration) also lead to increased uric acid reabsorption. The exact site of tubular secretion of uric acid has not been determined; this too appears to involve an active transport process. Postsecretory reabsorption occurs somewhere distal to the secretory site.