Uric acid is the major breakdown product of the purines adenosine and guanosine. It is largely excreted in the urine and therefore, increased plasma urate is either due to increased production or decreased excretion.
Lesch Nyhan Syndrome
This is due to an inherited deficiency of hypoxanthine-guanine phosphoribosyl transferase (HGPRT) which is one of the salvage pathways for purines.
Hyperuricaemia is consistent in this condition and is probably due to the co-existence of hyperlactataemia which inhibits uric acid excretion. Other biochemical features include hypoglycaemia and increased plasma cholesterol, triglycerides, pyruvate and lactate. Gouty arthritis does not usually present until after the first decade.
Essential, or primary, hyperuricaemia is due to a combination of overproduction (10-20%) and underexcretion (80-90%) of uric acid. Uric acid clearance of <6 mL/min (normal 6-11) and daily excretion of <3.6 mmol/24 hours is suggestive of renal underexcretion. In subjects with raised plasma urate, the daily urinary excretion may be normal.
NB acute attacks of gout van be precipitated by therapy with allopurinol or probenecid.
Causes of secondary hyperuricaemia
Increased turnover of purines
- myeloproliferative disorders and chemotherapy resulting in massive cell breakdown eg lymphomas
Reduced uric acid excretion
- renal failure
- thiazide diuretics (which inhibit renal excretion of uric acid)
- pyrazinamide & ethambutol
- chronic lead poisoning
- increased plasma ketones and lactate
This is clinically similar to gout but the biochemical lesion is due to deposition of calcium pyrophosphate crystals
About 20% of subjects with clinical gout have urinary uric acid stones; and 10% of renal stones are composed of urate.
Fallacies about gout
Gout is due to the precipitation of uric acid crystals within a joint and the plasma urate concentration is of no diagnostic use in the differential diagnosis of a mono-arthropathy. It is useful in determining the therapeutic value of allopurinol and uricosuric agents.
The typical gout sufferer in 18th Century caricatures has a high alcohol and protein diet. This is a misleading picture. However, in a predisposed individual, diet may increase the likelihood of an attack since high protein diets do create a purine load to be metabolised and ethanol may be metabolised to lactate which inhibits uric acid excretion into urine.