Gout: Cause, Diagnosis and Treatment
Gout is a metabolic disorder characterized by hyperuricemia, which is variably defined as a serum urate level greater than 7.0 mg/dl. Crystals of uric acid evoke a severe inflammatory response (acute gout), cause chalky deposits (tophi) and cause renal stones and/or renal tubular obstruction
Pathway for uric acid production and metabolism
Pathogenesis of Gout
If uric acid production is increased due to metabolic disorder or it's excretion is impaired due to renal disorder, the it's concentration in plasma increases and the pH of plasma decreases markedly. The uric acid then deposited in joints, kidney and tissues due to it's lower solubility in low pH level. The leukocytes then migrate to the joints and converted to macrophages to engulf the urate crystals. There are two consequences: the accumulation of cellular glycoproteins and the increased lactic acid production further reduces the pH of blood and aggravates gout by positive feedback mechanism. Deposition of glycoprotein causes the increased lysosomal activities in the affected area. The lysosome degrades the affected synovial cells along with the urate crystals, followed by the erosion of the joints. Macrophages also aggravate the inflammatory pathways followed by the gouty arthritis (redness, swelling and pain in the affected areas).
The causes of increased uric acid concentration in plasma
(i) Hyperactivity of PRPP, which is responsible for the uric acid production by de novo pathway (there is no interruption in uric acid production even when there is excess production).
(ii) Decreased activity of HGPRT or adenine phosphoribosyltransferase (APRT). These enzymes catalyse the salvage reactions (conversion of purine bases to their corresponding nucleotides), when there is excessive uric acid production.
(iii) Increased breakdown of tissue nucleic acids (myeloproliferative and lymphoproliferative disorders) also cause the overproduction of uric acid.
(iv) Dietary purines play an unimportant role in the generation of hyperuricemia in the absence of some derangement in purine metabolism or elimination.
(v) A decline 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.
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