• Clinical science

Gout and hyperuricemia

Abstract

Gout is a common inflammatory arthropathy characterized by painful and swollen joints resulting from precipitating uric acid crystals. Decreased renal excretion and/or increased production of uric acid leads to hyperuricemia, which is commonly asymptomatic, but also predisposes to gout. Acute gout attacks typically manifest with a severely painful big toe (podagra) and occur most often in men following triggers such as alcohol consumption. Diagnosis is based on clinical presentation and synovial fluid analysis, which reveals negatively birefringent monosodium urate crystals. Acute attacks are treated with nonsteroidal anti-inflammatory drugs (e.g., naproxen or indomethacin), while management of chronic gout includes lifestyle modifications and possibly allopurinol to control hyperuricemia.

Epidemiology

  • Sex: > (3:1)
  • Age of onset: 30–60 years
  • Prevalence: ∼ 8 million people in the US
  • Higher incidence in African Americans

References:[1][2]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Gout

Acute gouty arthritis is not always associated with elevated serum uric acid levels; it can also occur when serum uric acid is normal!

Hyperuricemia

  • Uric acid is an end-product of purine metabolism that is renally excreted.
  • Insufficient excretion or increased production of purines leads to hyperuricemia, possibly triggering a gout attack.
  • May be primary or secondary.

Primary hyperuricemia

  • Idiopathic extracellular supersaturation of uric acid
  • No history of comorbidities or medications that affect uric acid formation or excretion

Primary hyperuricemia is aggravated by poor dietary habits!

Secondary hyperuricemia

References:[3][1][4][5][6][7][8]

Pathophysiology

  • Uric acid has poor water solubility, even under physiological conditions. Factors that trigger urate crystal deposition include:
    • ↑ Uric acid levels
    • Acidosis
    • Low temperature (e.g., cool peripheral joints)
  • Supersaturation of uric acid in extracellular fluid → intraarticular uric crystal precipitation (coated by IgGs) → phagocytized by polymorphonuclear cells → release of inflammatory mediators and enzymes → local joint inflammation
  • Chronic effects: repeated attacks → aggregations of urate crystals and giant cells (tophi) → destruction of cartilage and bone in joints → deformities and arthritis

References:[1]

Clinical features

Asymptomatic stage

  • Hyperuricemia with no symptoms
  • May last up to 20 years or even longer

Acute gouty arthritis

  • Triggers: anything that leads to hyperuricemia (see “Etiology” above)
  • Arthritis: usually monoarticular during first attacks (in 90% of cases)
    • Acute severe pain with overlying erythema, decreased range of motion, swelling, and warmth; possible fever
    • More likely to occur at night, typically waking the patient
    • Symptoms peak after 12-24 hours; regression may take days to weeks.
    • The recovering joint may present with desquamation of the overlying skin.
  • Locations: Peripheral small joints in the lower extremities are especially affected.
  • Polyarticular gout may also occur. However, it is usually a flare-up occurring in untreated cases and not the first manifestation of gout.

Intercritical stage

  • Asymptomatic
  • May also last up to several years

Chronic gouty arthritis

References:[3][9][10]

Diagnostics

  • Arthrocentesis
    • Indications
      • New-onset acute gout attack
      • If past suspected gout attacks were not confirmed via polarized light microscopy
    • Polarized light microscopy findings: needle-shaped, negatively birefringent monosodium urate crystals
    • Synovial fluid: WBC > 2000/μL with > 50% neutrophils
  • Laboratory tests
    • ↑ Serum uric acid levels
    • Typical in acute attacks: WBC and ESR
    • Testing for ↑ renal uric acid may be indicated in some cases (see extra information for more details).
      • Indications:
        • First gout attack occurs before the age of 25
        • Renal calculi are present
        • Positive family history of gout
      • Treatment trial: colchicine in the case of unexplained monoarthritis; improvement supports the diagnosis of gout
  • Imaging
    • Ultrasound
      • "Double-contour" sign representing hyperechoic monosodium urate crystals covering hyperechoic bone contour
      • Tophus (a mixture of hyperechoic and hypoechoic structures)
    • MRI
      • Excellent measure to detect tophi formation
      • Method of choice to detect spinal involvement
    • CT: can detect bone erosions as well as tophi
    • X-ray
      • Acute gout attack: not useful, as early changes cannot be detected
      • Chronic gout: radiopaque soft tissue , punched-out lytic bone lesions with spiky periosteal appositions

References:[11][1][10]

Pathology

  • Foreign body granuloma
    • Due to urate crystal deposition in cutis and subcutis
    • Histology
      • Clusters of crystal deposits
      • Macrophages in the shape of epitheloid cells or polynuclear giant cells

References:[1]

Differential diagnoses

See differential diagnoses of inflammatory arthritis.

Pseudogout (CPPD)

  • Short description: paroxysmal joint inflammation due to calcium pyrophosphate crystal deposition (calcium pyrophosphate dihydrate)
  • Epidemiology
    • Sex: =
    • Age of onset: adults > 50 years of age
  • Etiology
  • Clinical presentation
    • Often asymptomatic
    • Acute (pseudogout attack): monoarthritis (rarely oligoarthritis), mostly affecting the knees and other large joints (e.g., hips, wrists, and ankles)
    • May become chronic (can affect multiple joints)
      • Osteoarthritis with CPPD (most common form of symptomatic CPPD): progressive joint degeneration with episodes of acute inflammatory arthritis typical of pseudogout attacks
  • Diagnosis
  • Treatment
    • Asymptomatic cases do not require treatment unless there is an underlying condition (e.g., hyperparathyroidism).
    • Symptomatic treatment (similar to gout)
    • Arthroscopic lavage may also be considered
    • Possible joint replacement


References:[3][12][13][14]

The differential diagnoses listed here are not exhaustive.

Treatment

Acute gout attack

The use of aspirin in acute gout attacks is contraindicated as it inhibits uric acid excretion, thereby delaying the cessation of symptoms.

Proton pump inhibitors should be given to patients being treated with both NSAIDs and glucocorticoids to avoid gastrointestinal ulcers.

Chronic gout

General measures

  • Weight loss (if applicable)
  • Purine-restricted diet (e.g., low-protein diet)
  • Reduce alcohol consumption
  • Sufficient/high fluid intake
  • Close management of diabetes and blood pressure
  • Consuming dairy products, vitamin C, and coffee can lower levels of uric acids and therefore prevent gout.

Medical therapy

  • Indications:
  • General approach:
    • Delay initiation of urate-lowering medication until ∼ 2 weeks after an acute attack has resolved
    • Despite their therapeutic effect, urate-lowering medications may trigger or prolong an acute gout attack.

First-line treatment: xanthine oxidase inhibitors (allopurinol)

Second-line treatment: uricosuric medications (benzbromarone, probenecid, lesinurad) Recombinant uricase (rasburicase)
Mechanism of action
  • Catalyzes the breakdown of uric acid to allantoin
Notable side effects

Indications

  • As an alternative to or in combination with allopurinol
Contraindications
  • Acute gout attack
  • Previous hypersensitivity
  • In kidney disease: dose adjustment (febuxostat is an alternative for patients with kidney disease)

Interaction

  • No particular drug interactions

The combination of allopurinol and azathioprine leads to increased bone marrow toxicity!

During the first 2 weeks of an acute gout attack, treatment with allopurinol should not be initiated or altered → can lead to urate crystal mobilization, which worsens the symptoms!
References:[3][1][5][10][15][16][17][18][19]

Complications

References:[6]

We list the most important complications. The selection is not exhaustive.