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.
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