Epidemiology and Etiology
- In the United States, the general prevalence is approximately 3%.
- Risk increases with higher body mass index (BMI): prevalence is 1%–2% in those with normal body mass index (BMI), and 5%–7% with class II or class III obesity
- Middle-aged to elderly men and postmenopausal women are most often affected.
- Rare in childhood unless there is an inherited enzyme defect or a malignancy
- Hyperuricemia (plasma urate > 6.8 mg/dL) is necessary but not sufficient for the development of gout.
- Only 10% of individuals with hyperuricemia develop gout.
- Elevated uric acid (UA) can result from reduced excretion (90%), overproduction, or both.
- Gout can occur in primary or secondary forms:
- Primary gout (90%):
- Unknown enzyme defects: usually due to decreased excretion of UA
- Known enzyme defects: e.g., Lesch-Nyhan syndrome and variants of hypoxanthine-guanine phosphoribosyltransferase deficiency (due to increased purine production), glycogen storage diseases (due to decreased excretion of UA)
- Secondary gout (10%):
- Increased nucleic acid turnover (e.g., leukemia), due to increased UA production
- Chronic renal disease (due to decreased excretion of UA)
- Primary gout (90%):
Risk factors that increase UA levels
- Rich in meat and seafood
- Beverages containing fruit sugar (fructose), alcohol
- Medical conditions: untreated high blood pressure, diabetes, metabolic syndrome, heart and kidney diseases
- Certain medications
- Thiazide diuretics
- Low-dose aspirin
- Anti-rejection/immunosuppressive drugs used in organ transplantation
- Family history of gout
- Age and sex: higher prevalence in middle-aged and older men, but UA levels in post-menopausal women approach those of men
- Recent surgery or trauma
Drugs causing acute precipitation of gout: FACT
F: Furosemide diuretics
C: Anti-Cancer drugs (e.g., cyclosporine)
T: Thiazide diuretics
- Purine compounds, whether they are synthesized in the body or come from eating high-purine foods, can raise UA levels.
- Uric acid is excreted mainly through the kidneys.
- Overproduction or underexcretion (more common) of UA can lead to hyperuricemia → supersaturation → deposition of monosodium urate (MSU) crystals in the tissues
- These MSU deposit in the soft tissue and synovium as MSU crystals (“tophi”).
- Can erode the bone and damage other tissues such as tendons and cartilage
- Cause recurrent monoarticular arthritis and chronic deforming arthritis
- The precise relationship between hyperuricemia and gout is unclear:
- The majority (90%) of people with hyperuricemia do not have gout.
- Normal or low serum UA levels do not rule out gout.
- However, all patients with gout will have hyperuricemia (> 6.8 mg/dL) at some point, although levels may fluctuate.
- Typically monoarticular (< 20% are polyarticular)
- Commonly occurs in the lower extremities, most often at the base of the great toe (first metatarsophalangeal [MTP] joint, or podagra) or the knee
- Intensely inflammatory, causing severe pain, redness, warmth, swelling, and disability
- Peaking within 12–24 hours and resolving within 3–10 days even without treatment
- Onset more often at night
Upon resolution of an acute gout flare, patients enter an intercritical (between-flares) period.
- Most often entirely asymptomatic
- Variable in duration
- Most patients left untreated will develop a recurrent flare within 2 years.
- Monosodium urate crystals may continue to deposit as tophi in various tissues.
- Nodular deposit of monosodium urate crystals associated with chronic inflammation with a foreign-body giant cell reaction
- Found in cartilage, subcutaneous and periarticular tissues, tendons (e.g., Achilles tendon), olecranon bursae, ear helix, kidney, and elsewhere
- Can cause destruction of bone and soft tissue
Associated renal complications
- Chronic urate nephropathy
- Diagnosis is established via microscopic analysis of the joint aspirate, which shows:
- Crystals of MSU, which are negatively birefringent (yellow when parallel to compensator filter) and needle-shaped
- WBC > 2,000/μL with > 50% neutrophils (an acute inflammatory synovial fluid)
- Shows no changes early in the disease
- As the disease progresses, punched-out erosions with an overhanging rim of cortical bone develop.
- Blood work may show:
- Hyperuricemia (may be normal or low during a flare; best to measure 2 weeks after flare)
- Elevated WBC
- Elevated erythrocyte sedimentation rate (ESR)
Management differs for acute and chronic gout.
The goal of management is to reduce inflammation.
- Nonsteroidal anti-inflammatory drugs (NSAIDs): contraindicated in active peptic ulcer disease, impaired kidney function, congestive heart failure, and elevated international normalized ratio (INR)
- Colchicine: contraindicated in severe renal or liver disease
- Glucocorticoids: can be given via IV, IM, oral, or intra-articular routes. Make sure to rule out septic arthritis before giving corticosteroids.
- Antihyperuricemic drugs (allopurinol and febuxostat) are usually contraindicated/not recommended in an acute attack as they may cause the disease to flare up.
The goal of management is to minimize urate deposition in tissues.
- Weight loss to achieve BMI < 25
- Avoid foods with a high purine content (e.g., seafood, meat, alcohol [varies among different beverages])
- Avoid certain medications that cause hyperuricemia
- Diuretics both increase urate reabsorption and decrease its secretion.
- Allopurinol is often administered to control gout if a diuretic is necessary.
- Indications to start medical management for chronic gout are recurrent attacks (> 1/year), tophi, and urate kidney stones.
- Antihyperuricemic drugs (allopurinol and febuxostat) decrease UA 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 flare-ups.
- Newer medication: pegloticase, a recombinant pegylated (i.e., linked to methoxy polyethylene glycol) uricase.
The following conditions are differential diagnoses of gout:
- Septic arthritis: an infection of a joint with extremely high WBC counts in synovial fluid (> 100,000 cells/mL) are most supportive of a diagnosis of septic arthritis. Gram stain and synovial fluid culture are performed for diagnosis.
- Calcium pyrophosphate crystal deposition disease (CPPD, pseudogout): positively birefringent crystals in synovial fluid. Calcium pyrophosphate crystal deposition disease also has a characteristic radiographic appearance of chondrocalcinosis.
- Trauma: a stress fracture or traumatic process in the bone or joint can mimic a gout flare.
- Cellulitis: a common and painful bacterial skin infection that affects the deeper layers of the dermis and subcutaneous tissue. Typical signs of acute inflammation (rubor, dolor, calor, tumor) are present but joint mobility is usually preserved.
- Rheumatoid arthritis: an autoimmune inflammatory polyarthritis. Tophi may be mistaken for rheumatoid nodules but the clinicoradiological presentation and the lack of crystals in the nodular lesions can differentiate the 2 conditions.
- Dactylitis: severe bacterial inflammation of the finger and toe joints that can resemble tophaceous gout with acute flare. The condition can usually be distinguished from gout based on the history and physical examination.
- Osteomyelitis: an infection (usually bacterial) of the bone. Diagnosis is made by noting deep bony tenderness and clinical signs of acute systemic inflammation; CBC and magnetic resonance imaging (MRI) are helpful if routine radiologic findings are not supportive.
- Basic calcium phosphate (BCP) crystal disease (hydroxyapatite [HA] crystal deposition disease): painful and probably underdiagnosed periarthritis or arthritis due to the deposition of BCP crystals in the synovium. The condition can cause severe joint damage, as in the Milwaukee shoulder syndrome seen in elderly women.
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