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Gout : Pathophysiology-I

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The underlying metabolic abnormality in gout is hyperuricemia (plasma urate levels > 6.8 mg/dl) which causes deposition of monosodium urate (MSU) crystals in and around joints. Hyperuricemia results from either overproduction or decreased excretion of uric acid.

Uric Acid Metabolism: Uric acid is a heterocyclic compound that is produced by the breakdown of purine nucleotides. Purine nucleotides are synthesized from non-purine precursors (de novo pathway) as well as from free purine bases derived from catabolism of purine nucleotides and absorbed from diet (salvage pathway). Uric acid is filtered by the glomerulus and almost completely reabsorbed by the proximal tubule in the kidney. A small amount of uric acid is normally excreted in urine.

Uricase (Urate Oxidase): Humans are the only animal consuming meat in their diet that don't synthesize the enzyme uricase (urate oxidase). Humans and other higher apes do have the gene for uricase but it has become non-functional during the course of evolution. As a result, uric acid is the end-product of purine metabolism and cannot be degraded further to allantoin (which is water soluble and readily excreted in urine). Pegloticase - a recombinant uricase that catalyzes oxidation of uric acid to allantoin has been developed to lower serum uric acid levels in patients with gout.

About 90% of cases are primary gout and result from overproduction of uric acid due to unknown reasons. The symptoms of gout dominate the clinical presentation. In the remaining 10% of cases, hyperuricemia is secondary to an underlying disease (e.g. increased nucleic acid breakdown during chemotherapy for myeloproliferative disorders, or decreased uric acid excretion in chronic renal disease).

The image shows several large gouty tophi around elbow joint and extensor surface of the forearm in a patient with chronic tophaceous gout.

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