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
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.
CLINICAL PRESENTATION
• Acute attacks of gouty arthritis are characterized by rapid onset of excruciating
pain, swelling, and inflammation. The attack is typically monoarticular
and then, in order of frequency, the insteps, ankles, heels, knees, wrists,
fingers, and elbows. Attacks commonly begin at night, with the patient
awakening from sleep with excruciating pain. The affected joints are erythematous,
warm, and swollen. Fever and leukocytosis are common. Untreated
attacks may last from 3 to 14 days before spontaneous recovery.
• Although acute attacks of gouty arthritis may occur without apparent
provocation, attacks may be precipitated by stress, trauma, alcohol ingestion,
infection, surgery, rapid lowering of serum uric acid by ingestion of
uric acid–lowering agents, and ingestion of certain drugs known to elevate
serum uric acid concentrations.
DIAGNOSIS
• The definitive diagnosis is accomplished by aspiration of synovial fluid
from the affected joint and identification of intracellular crystals of
monosodium urate monohydrate in synovial fluid leukocytes.
• When joint aspiration is not a viable option, a presumptive diagnosis of
acute gouty arthritis may be made on the basis of the presence of the
characteristic signs and symptoms, as well as the response to treatment.
DESIRED OUTCOME
• The goals in the treatment of gout are to terminate the acute attack,
prevent recurrent attacks of gouty arthritis, and prevent complications
associated with chronic deposition of urate crystals in tissues.
TREATMENT
ACUTE GOUTY ARTHRITIS
Nonpharmacologic Therapy
• Patients may be advised to reduce their intake of foods high in purines (e.g.,
organ meats), avoid alcohol, increase fluid intake, and lose weight if obese.
• Joint rest for 1 to 2 days should be encouraged, and local application of ice
may be beneficial.
Nonsteroidal Antiinflammatory Drugs
• Nonsteroidal antiinflammatory drugs (NSAIDs) are the mainstay of therapy
because of their excellent efficacy and minimal toxicity with shortterm
use. There is little evidence to support one NSAID as more efficacious
than another, and three drugs (indomethacin, naproxen, and sulindac)
have FDA approval for this indication (Table 1-1).
• Therapy should be initiated with maximum recommended doses for gout
at the onset of symptoms and continued for 24 hours after complete
resolution of an acute attack, then tapered quickly over 2 to 3 days. Acute
attacks generally resolve within 5 to 8 days after initiating therapy.
• The most common adverse effects involve the GI system (gastritis, bleeding,
and perforation), kidneys (renal papillary necrosis, reduced creatinine
clearance [CL
cr
]), cardiovascular system (sodium and fluid retention,
increased blood pressure), and CNS (impaired cognitive function, headache,
dizziness).
• Although the risk of GI complications is relatively small with short-term
therapy, coadministration with a proton pump inhibitor should be considered
in elderly patients and others at increased GI risk. NSAIDs should be
used with caution in individuals with a history of peptic ulcer disease, heart
failure, uncontrolled hypertension, renal insufficiency, coronary artery
disease, or if they are receiving anticoagulants concurrently.
• The efficacy and safety of cyclooxygenase-2 (COX-2) selective inhibitors
(e.g., celecoxib) have not been fully assessed in gouty arthritis, but they are
more costly than conventional NSAIDs and are unlikely to result in fewer
GI complications because of the short duration of therapy.
Colchicine
is an antimitotic drug that is highly effective in relieving acute
gout attacks but has a low benefit-toxicity ratio. When colchicine is started
within the first 24 hours of an acute attack, about two-thirds of patients
respond within several hours. The likelihood of success decreases substantially
if treatment is delayed longer than 48 hours after symptom onset.
• Oral colchicine causes dose-dependent GI adverse effects (nausea, vomiting,
and diarrhea) in 50% to 80% of patients before relief of the attack.
Non-GI adverse effects include neutropenia and axonal neuromyopathy,
which may be worsened in patients taking other myopathic drugs (e.g.,
statins) or in those with renal insufficiency. Colchicine should not be used
concurrently with macrolide antibiotics (especially clarithromycin) because
reduced biliary excretion may lead to increased plasma colchicine levels and
agranulocytosis.
Corticosteroids
• Corticosteroids may be used to treat acute attacks of gouty arthritis, but
they are reserved primarily for patients with a contraindication or who are
unresponsive to NSAID or colchicine therapy. Patients with multiple-joint
involvement may also benefit.
• The recommended dose is prednisone 30 to 60 mg (or an equivalent dose
of another corticosteroid) orally once daily for 3 to 5 days. Because
rebound attacks may occur upon steroid withdrawal, the dose should be
gradually tapered in 5-mg increments over 10 to 14 days and discontinued.
• A single intramuscular injection of a long-acting corticosteroid (e.g.,
methylprednisolone acetate) can be used as an alternative to the oral
route if patients are unable to take oral therapy. If not contraindicated,
low-dose colchicine can be used as adjunctive therapy to injectable
corticosteroids to prevent rebound flare-ups.
• Intraarticular administration of triamcinolone hexacetonide 20 to 40 mg
may be useful for acute gout limited to one or two joints.
Xanthine Oxidase Inhibitor
• Allopurinol and its major metabolite, oxypurinol, are xanthine oxidase
inhibitors and impair the conversion of hypoxanthine to xanthine and
xanthine to uric acid. Allopurinol also lowers the intracellular concentration
of PRPP. Because of the long half-life of its metabolite, allopurinol can be
given once daily orally. It is typically initiated at a dose of 100 mg/day and
increased by 100 mg/day at 1-week intervals to achieve a serum uric acid
level of 6 mg/dL or less. Serum levels can be checked about 1 week after
starting therapy or modifying the dose. Although typical doses are 100 to 300
mg daily, occasionally doses of 600 to 800 mg/day are necessary. The dose
should be reduced in patients with renal insufficiency (200 mg/day for CLcr
60 mL/min or less, and 100 mg/day for CLcr 30 mL/min or less).
• Allopurinol is the antihyperuricemic drug of choice in patients with a
history of urinary stones or impaired renal function, in patients who have
lymphoproliferative or myeloproliferative disorders and need pretreatment
with a xanthine oxidase inhibitor before initiation of cytotoxic
therapy to protect against acute uric acid nephropathy, and in patients
with gout who are overproducers of uric acid.
Uricosuric Drugs
• Probenecid and sulfinpyrazone increase the renal clearance of uric acid by
inhibiting the renal tubular reabsorption of uric acid.
