HYPERURICEMIA and GOUT PATHOGENESIS

HYPERURICEMIA Plasma/serum urate concentration >408 mol/L (6.8 mg/dL) Present in between 2.0 and 13.2% of ambulatory adults, and is more frequent in hospitalized individuals Can result from increased production of uric acid decreased excretion of uric acid combination of the two processes Harrison’s Principles of Internal Medicine, 17 th edition

Pathophysiology occur because of decreased excretion (underexcretors), increased production (overproducers), or a combination of these two mechanisms. Underexcretion accounts for most causes of hyperuricemia

Hyperuricemia may be either exogenous (diet rich in purines) or endogenous (increased purine nucleotide breakdown) enzymatic defects – complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HGPRT) – partial deficiency of HGPRT – increased production of 5-phospho-alpha-d- ribosyl pyrophosphate (PRPP) activity

Decreased Excretion of Uric Acid Gouty individuals excrete ~40% less uric acid than nongouty individuals May result from decreased glomerular filtration decreased tubular secretion enhanced tubular reabsorption Alcohol consumption Harrison’s Principles of Internal Medicine, 17 th edition

Decreased Glomerular Filtration Does not appear to cause primary hyperuricemia, but contributes to the hyperuricemia of renal insufficiency Uric acid excretion per unit of glomerular filtration rate increases progressively with chronic renal insufficiency Harrison’s Principles of Internal Medicine, 17 th edition

Decreased Tubular Secretion Tends to be preserved with chronic renal insufficiency Harrison’s Principles of Internal Medicine, 17 th edition

Enhanced Tubular Reabsorption Mechanism of many agents Occurs from "priming" renal urate reabsorption through the Na-dependent loading of proximal tubular epithelial cells with anions capable of trans-stimulating urate reabsorption A transporter in the brush border of the proximal tubular cells mediates Na-dependent resorption of components recognized to cause hyperuricemia by renal mechanisms Harrison’s Principles of Internal Medicine, 17 th edition

Enhanced Tubular Reabsorption Low doses of salicylates promote hyperuricemia through this mechanism Harrison’s Principles of Internal Medicine, 17 th edition

Alcohol Consumption Causes hyperuricemia by increasing urate production and decreasing uric acid excretion Accelerates hepatic breakdown of ATP to increase urate production Can also induce hyperlacticacidemia, which blocks uric acid secretion Higher purine content in some alcoholic beverages (beer) may also be a factor Harrison’s Principles of Internal Medicine, 17 th edition

GOUT Metabolic disease most often affecting middle- aged to elderly men and postmenopausal women Result of an increased body pool of urate with hyperuricemia Characterized by episodic acute and chronic arthritis, due to deposition of MSU crystals in joints and connective tissue tophi, and the risk for deposition in kidney interstitium or uric acid nephrolithiasis Harrison’s Principles of Internal Medicine, 17 th edition