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
Harrisons Principles of Internal Medicine, 17th 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

Harrisons Principles of Internal Medicine, 17th 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

Harrisons Principles of Internal Medicine, 17th edition

Decreased Tubular Secretion
Tends to be preserved with chronic renal
insufficiency

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

Harrisons Principles of Internal Medicine, 17th 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
Harrisons Principles of Internal Medicine, 17th 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
Harrisons Principles of Internal Medicine, 17th edition