Gout is an acute, inflammatory, monoarticular arthritis due to the deposition of monosodium urate crystals intraarticularly. The most commonly involved joint is the first metatarsophalangeal (MTP) joint. The identification of urate crystals in joint aspirate or tophi is diagnostic. NSAIDs provide dramatic relief in an acute attack. In chronic cases, the crystals get deposited in other tissues such as cartilage, joints, subcutaneous tissue.

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Epidemiology, Etiology, and Risk Factors

Epidemiology

  • Occurs earlier in life in men than in women
  • Usually presents over 30 years of age
    • Rare in childhood

Etiology

  • Primary gout: enzyme defects such as Lesch-Nyhan syndrome, glycogen storage diseases
  • Secondary gout: etiologies such as drugs (see FACT mnemonic below), malignancies, psoriasis, etc.

Risk factors

  • Nonmodifiable
    • Advanced age
    • Male gender
    • Ethnicity
    • Genetics
  • Modifiable
    • Medications that alter urate balance
    • Obesity
    • Age-associated cardiovascular, metabolic, and renal diseases
    • Diets rich in meat and seafood content
    • Alcohol-containing beverages
    • Sodas and fruit juices high in fructose or sucrose content
    • Postmenopausal and organ transplant recipient status
    • Toxin exposure (e.g., lead)

Mnemonics

Drugs causing acute precipitation of gout – FACT
Furosemide diuretics
Aspirin/Alcohol
antiCancer drugs (e.g., Cyclosporine)
Thiazide diuretics

Pathophysiology

  • Uric acid is obtained either from the diet or via endogenous purine synthesis.
  • Uric acid is excreted mainly through kidneys.
  • Overproduction or underexcretion (more common) of uric acid → hyperuricemia → deposition of urate in tissues due to supersaturation
  • Deposits in the tissue (tophus) and synovium (micro tophus) get crystallized → form monosodium urate crystals → recurring monoarticular arthritis → contribute to chronic deforming arthritis
  • The precise relationship between hyperuricemia and gout is unclear
    • Majority of people with hyperuricemia do not have gout.
    • Normal/low uric acid does not rule out gout.

Summary of the pathophysiology and drugs used for gout. Image by Lecturio.

Video Gallery

Gout: History, Pathophysiology by Stephen Holt, MD, MS
Crystalline Arthropathies: Gout / Pseudogout by Carlo Raj, MD

Clinical Presentation

  • Gout flares
    • Typically monoarticular (less than 20% are polyarticular)
    • Commonly occurs in the lower extremities
      • Most often at the base of the great toe (first MTP joint, known as podagra) or the knee
    • Intensely inflammatory causing severe pain, redness, warmth, swelling, and disability peaking within 12–24 hours
    • Onset more often at night
  • Intercritical gout and recurrent gout flares
    • Upon resolution of an acute gout flare, patients enter an intercritical (between flares) period.
      • Most often entirely asymptomatic
      • Variable in duration
      • Crucial for establishing gout diagnosis, starting therapy, and patient education
      • Most patients left untreated will develop a recurrent flare within 2 years
      • Intermittency of flares still allows for tophaceous material deposition
  • Tophaceous gout
    • Nodular deposit of monosodium urate crystals associated with a foreign body reaction.
    • Found in cartilage, subcutaneous and periarticular tissues, tendon (Achilles), olecranon bursae, ear helix, kidney, and elsewhere
  • Associated renal complications
    • Nephrolithiasis
    • Chronic urate nephropathy

Video Gallery

Tophaceous Gout by Carlo Raj, MD

Diagnosis

  • Diagnosis is established via joint aspirate which shows

    Image: Monosodium urate crystals which are negatively birefringent from a patient’s joint aspirate, which is diagnostic of gout. By Ed Uthman. License: CC BY 2.0

    • Crystals of monosodium urate which are negatively birefringent (yellow when parallel to compensator filter) and needle-shaped
    • WBC > 2000/μL with > 50% neutrophils (inflammatory picture)
  • Early in the disease, X-Ray shows no changes.
  • As the disease progresses, punched-out erosions with an overhanging rim of cortical bone develop
  • Blood work may show hyperuricemia, elevated WBC, and ESR (erythrocytic sedimentation rate).

Video Gallery

Quick Review: Gout and Pseudogout by Stephen Holt, MD, MS
Gout: Diagnosis and Treatment by Stephen Holt, MD, MS
Gout Medication: Colchicine, Uric Acid, and More by Pravin Shukle, MD

Management

Management is divided into that of acute gout and chronic gout.

Algorithm for the management of acute gout. Image by Lecturio.

Acute gout: goal to reduce inflammation

  • NSAIDs: contraindicated in active peptic ulcer disease, impaired kidney function, congestive heart failure, and elevated INR (international normalized ratio)
  • Colchicine: contraindicated in severe renal or liver disease
  • Glucocorticoids
    • Can be given intravenous, intramuscular, oral, and intra-articular
    • Make sure to rule out septic arthritis before giving corticosteroids.
  • Antihyperuricemic drugs (Allopurinol and Febuxostat) are contraindicated in acute attack as they may cause the disease to flare up.

Chronic gout: goal to minimize urate deposition in tissues 

  • General measures
    • Weight loss to achieve BMI <25
    • Avoid foods with a high purine (e.g. seafood, meat, alcohol).
    • Avoid drugs that inhibit uric acid excretion from kidneys (FACT, pyrazinamide, ethambutol).
  • Medical measures
    • Indications to start medical management for chronic gout are recurrent attacks (>1/yr), tophi, and urate kidney stones
    • Antihyperuricemic drugs (allopurinol and febuxostat) decrease uric acid production by inhibiting xanthine oxidase (an enzyme involved in endogenous purine synthesis).
    • Uricosuric drugs (probenecid) are used very rarely.
    • Give prophylactic colchicine/NSAIDs prior to starting antihyperuricemic drugs to avoid the flare-up of the disease.

Relevance

The following conditions are differential diagnoses of gout.

  • Cellulitis: a common and painful bacterial skin infection that affects the deeper layers of the dermis and subcutaneous tissue. Cellulitis also presents with fever, pain, and warmth over the affected area but the joint mobility is usually preserved with cellulitis (unless involving skin over the joint).
  • Pseudogout: also presents with monoarticular arthritis but is distinguished by the identification of calcium pyrophosphate crystals which are positively birefringent. Pseudogout also has a characteristic radiographic appearance of chondrocalcinosis. 
  • Septic arthritis: an infection of a joint causing acute, inflammatory, asymmetric monoarticular arthritis resembling acute monoarticular gout. Extremely high white blood cell counts in synovial fluid (>100,000 cells/mL) are most supportive of a diagnosis of septic arthritis. Gram stain or synovial fluid culture confirms or excludes the diagnosis.
  • Trauma: a stress fracture or traumatic process in the bone or joint can mimic gouty flares.
  • Rheumatoid arthritis: an inflammatory polyarthritis caused by an autoimmune attack on joints. Tophi may be mistaken for rheumatoid nodules (and vice versa). In these circumstances, the asymmetry and asynchrony of joint involvement in gout, the presence of urate crystals in the nodular lesions, and the distinctive radiographic features will often suffice to distinguish between these disorders.
  • Dactylitis: severe inflammation of the finger and toe joints that can resemble tophaceous gout. It can usually be distinguished from gout based upon the history and physical examination.
  • Osteomyelitis: an infection of the bone that can mimic advanced expansive and destructive changes associated with tophaceous gout. Diagnosis needs to be confirmed by examination of a needle aspirate using polarized light microscopy for the detection of MSU crystals before erroneous amputation takes place.
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