Chapter 167: Gout, Pseudogout, and Related Diseases



Gout is a metabolic disease most often affecting middle-aged to elderly men and postmenopausal women. Hyperuricemia is the biologic hallmark of gout. When present, plasma and extracellular fluids become supersaturated with uric acid, which, under the right conditions, may crystallize and result in a spectrum of clinical manifestations that may occur singly or in combination.


Uric acid is the end product of purine nucleotide degradation; its production is closely linked to pathways of purine metabolism, with the intracellular concentration of 5-phosphoribosyl-1-pyrophosphate (PRPP) being the major determinant of the rate of uric acid biosynthesis. Uric acid is excreted primarily by the kidney through mechanisms of glomerular filtration, tubular secretion, and reabsorption. Hyperuricemia may thus arise in a wide range of settings that cause overproduction or reduced excretion of uric acid or a combination of the two.


Monosodium urate (MSU) crystals present in the joint are phagocytosed by leukocytes; release of inflammatory mediators and lysosomal enzymes leads to recruitment of additional phagocytes into the joint and to synovial inflammation.


  • Acute arthritis: most frequent early clinical manifestation of gout. Usually initially affects one joint, but may be polyarticular in later episodes. The first metatarsophalangeal joint (podagra) is often involved. Acute gout frequently begins at night with dramatic pain, swelling, warmth, and tenderness. Attack will generally subside spontaneously after 3–10 days. Although some pts may have a single attack, most pts have recurrent episodes with intervals of varying length with no symptoms between attacks. Acute gout may be precipitated by dietary excess, trauma, surgery, excessive ethanol ingestion, diuretic medications, hypouricemic therapy, and serious medical illnesses such as myocardial infarction and stroke.
  • Chronic arthritis: a proportion of gout pts may have a chronic nonsymmetric synovitis; may rarely be the only manifestation. Can also present with periarticular tophi (aggregates of MSU crystals surrounded by a giant cell inflammatory reaction).
  • Extraarticular tophi: often occur in olecranon bursa, helix and anthelix of ears, ulnar surface of forearm, Achilles tendon.
  • Tenosynovitis
  • Urate nephropathy: deposition of MSU crystals in renal interstitium and pyramids. Can cause chronic renal insufficiency.
  • Acute uric acid nephropathy: reversible cause of acute renal failure due to precipitation of urate in the tubules; pts receiving cytotoxic treatment for neoplastic disease are at risk.
  • Uric acid nephrolithiasis: responsible for 10% of renal stones in the United States.


  • Synovial fluid analysis: should be performed to confirm gout even when clinical appearance is strongly suggestive; joint aspiration and demonstration of both intracellular and extracellular needle-shaped negatively birefringent MSU crystals by polarizing microscopy. Gram stain and culture should be performed on all fluid to rule out infection. MSU crystals can also be demonstrated in chronically involved joints or tophaceous deposits.
  • Serum uric acid: normal levels do not rule out gout.
  • Urine uric acid: excretion of >800 mg/d on regular diet in the absence of drugs suggests overproduction.
  • Screening for risk factors or sequelae: urinalysis; serum creatinine, liver function tests, glucose and lipids; complete blood counts.
  • If overproduction is suspected, measurement of erythrocyte hypoxanthine guanine phosphoribosyl transferase (HGPRT) and PRPP levels may be indicated.
  • Joint x-rays: may demonstrate cystic changes, erosions with sclerotic margins in advanced chronic arthritis.
  • If renal stones suspected, consider abdominal flat plate (stones often radiolucent), ultrasound, IVP, or CT.
  • Chemical analysis of renal stones.

Differential Diagnosis

Septic arthritis, reactive arthritis, calcium pyrophosphate dihydrate (CPPD) deposition disease, rheumatoid arthritis.

Treatment: Gout


As only ∼5% of hyperuricemic pts develop gout, treatment of asymptomatic hyperuricemia is not indicated. Exceptions are pts about to receive cytotoxic therapy for neoplasms.


Treatment is given for symptomatic relief only since attacks are self-limited and will resolve spontaneously. Toxicity of therapy must be considered in each pt.

  • Analgesia
  • NSAIDs: consider when not contraindicated.
  • Colchicine: generally only effective within first 24 h of attack; overdose has potentially life-threatening side effects; use is contraindicated in pts with renal insufficiency, cytopenias, LFTs >2 × normal, sepsis. PO—0.6 mg every 8 h with tapering or 1.2 mg followed by 0.6 mg in 1 h with subsequent day dosing depending on response.
  • Intraarticular glucocorticoids: septic arthritis must be ruled out prior to injection.
  • Systemic glucocorticoids: brief taper may be considered in pts with a polyarticular gouty attack for whom other modalities are contraindicated and where articular or systemic infection has been ruled out.
  • Anakinra, canakinumab (inhibitors of interleukin-1β) have been studied, and can be used when other treatments have failed or were contraindicated.


Indications for initiating uric acid–lowering therapy include recurrent frequent acute gouty arthritis, polyarticular gouty arthritis, tophaceous gout, renal stones, prophylaxis during cytotoxic therapy. Should not start during an acute attack. Initiation of such therapy can precipitate an acute flare; in pts without contraindications consider concomitant PO colchicine 0.6 mg daily until uric acid <6.0 mg/dL, then discontinue.

  1. Xanthine oxidase inhibitors (allopurinol, febuxostat): Decrease uric acid synthesis. Allopurinol must be dose-reduced in renal insufficiency. Both have side effects and drug interactions. Febuxostat has been associated with an increased risk of death (heart-related death and all-cause mortality) compared to allopurinol. The FDA recommends limiting use of febuxostat to pts not treated effectively or who have severe side effects with allopurinol.
  2. Uricosuric drugs (probenecid, sulfinpyrazone): Increases uric acid excretion by inhibiting its tubular reabsorption; ineffective in renal insufficiency; should not be used in these settings: age >60, renal stones, tophi, increased urinary uric acid excretion, prophylaxis during cytotoxic therapy.
  3. Pegloticase: Recombinant uricase that lowers uric acid by oxidizing urate to allantoin. Risk of severe infusion reactions. Should be used only in selected pts with chronic tophaceous gout refractory to conventional therapy.

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