Gout and Hyperuricemia

DEFINITIONS
• The term gout describes a disease spectrum including hyperuricemia, recurrent
attacks of acute arthritis associated with monosodium urate crystals in
leukocytes found in synovial fluid, deposits of monosodium urate crystals in
tissues (tophi), interstitial renal disease, and uric acid nephrolithiasis.
• Hyperuricemia may be an asymptomatic condition, with an increased
serum uric acid concentration as the only apparent abnormality. A urate
concentration greater than 7.0 mg/dL is abnormal and associated with an
increased risk for gout.
PATHOPHYSIOLOGY
• In humans, uric acid is the end product of the degradation of purines. It
serves no known physiologic purpose and is regarded as a waste product.
The size of the urate pool is increased severalfold in individuals with gout.
This excess accumulation may result from either overproduction or
underexcretion.
• The purines from which uric acid is produced originate from three
sources: dietary purine, conversion of tissue nucleic acid to purine nucleotides,
and de novo synthesis of purine bases.
• Abnormalities in the enzyme systems that regulate purine metabolism may
result in overproduction of uric acid. An increase in the activity of
phosphoribosyl pyrophosphate (PRPP) synthetase leads to an increased
concentration of PRPP, a key determinant of purine synthesis and thus
uric acid production. A deficiency of hypoxanthine–guanine phosphoribosyl
transferase (HGPRT) may also result in overproduction of uric acid.
HGPRT is responsible for the conversion of guanine to guanylic acid and
hypoxanthine to inosinic acid. These two conversions require PRPP as the
cosubstrate and are important reutilization reactions involved in nucleic
acid synthesis. A deficiency in the HGPRT enzyme leads to increased
metabolism of guanine and hypoxanthine to uric acid and more PRPP to
interact with glutamine in the first step of the purine pathway. Complete
absence of HGPRT results in the childhood Lesch-Nyhan syndrome,
characterized by choreoathetosis, spasticity, mental retardation, and markedly
excessive production of uric acid.
• Uric acid may also be overproduced as a consequence of increased
breakdown of tissue nucleic acids, as with myeloproliferative and lymphoproliferative
disorders. Cytotoxic drugs used to treat these disorders can
SECTION 1 | Bone and Joint Disorders
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also result in overproduction of uric acid due to lysis and breakdown of
cellular matter.
• Dietary purines play an unimportant role in the generation of hyperuricemia
in the absence of some derangement in purine metabolism or
elimination.
• About two-thirds of the uric acid produced each day is excreted in the
urine. The remainder is eliminated through the GI tract after enzymatic
degradation by colonic bacteria. 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.
• Drugs that decrease renal clearance of uric acid through modification of
filtered load or one of the tubular transport processes include diuretics,
nicotinic acid, salicylates (less than 2 g/day), ethanol, pyrazinamide,
levodopa, ethambutol, cyclosporine, and cytotoxic drugs.
• The average human produces 600 to 800 mg of uric acid daily and excretes
less than 600 mg in urine. Individuals who excrete more than 600 mg after
being on a purine-free diet for 3 to 5 days are considered overproducers.
Hyperuricemic individuals who excrete less than 600 mg of uric acid per
24 hours on a purine-free diet are defined as underexcretors of uric acid.
On a regular diet, excretion of more than 1,000 mg per 24 hours reflects
overproduction; less than this is probably normal.
• Deposition of urate crystals in synovial fluid results in an inflammatory
process involving chemical mediators that cause vasodilation, increased
vascular permeability, complement activation, and chemotactic activity for
polymorphonuclear leukocytes. Phagocytosis of urate crystals by leukocytes
results in rapid lysis of cells and a discharge of proteolytic enzymes
into the cytoplasm. The ensuing inflammatory reaction is associated with
intense joint pain, erythema, warmth, and swelling.
• Uric acid nephrolithiasis occurs in 10% to 25% of patients with gout.
Predisposing factors include excessive urinary excretion of uric acid, acidic
urine, and highly concentrated urine.
• In acute uric acid nephropathy, acute renal failure occurs as a result of
blockage of urine flow secondary to massive precipitation of uric acid
crystals in the collecting ducts and ureters. This syndrome is a wellrecognized
complication in patients with myeloproliferative or lymphoproliferative
disorders and results from massive malignant cell turnover, particularly
after initiation of chemotherapy. Chronic urate nephropathy is caused
by the long-term deposition of urate crystals in the renal parenchyma.
• Tophi (urate deposits) are uncommon in gouty subjects and are a late
complication of hyperuricemia. The most common sites of tophaceous
deposits in patients with recurrent acute gouty arthritis are the base of the
great toe, helix of the ear, olecranon bursae, Achilles tendon, knees, wrists,
and hands.