19.3 Gout & Calcium Pyrophosphate Deposition Disease

7. Crystal Arthropathies: Gout

Gout is a metabolic disorder characterized by the extracellular deposition of monosodium urate (MSU) monohydrate crystals in synovial fluid, articular cartilage, and soft tissues following chronic hyperuricaemia.

Pathophysiology of Hyperuricaemia

Serum urate saturation threshold in human plasma at 37 °C is 408 µmol/L (6.8 mg/dL); above this concentration, plasma is supersaturated, driving nucleated crystallization.

• Renal Underexcretion (90% of Patients): Defective renal tubular clearance of urate via URAT1, GLUT9, and OAT4 transporters. Exacerbated by chronic kidney disease, volume depletion, and pharmacological agents that inhibit tubular urate excretion: thiazide and loop diuretics, low-dose aspirin (< 2 g/day), ciclosporin, tacrolimus, pyrazinamide, and ethambutol. Alcohol (particularly beer rich in guanosine purines) generates lactic acid, which competitively inhibits proximal tubular urate secretion.
• Metabolic Overproduction (10% of Patients): Increased purine nucleotide degradation or turnover: myeloproliferative and lymphoproliferative neoplasms, cytotoxic chemotherapy (tumour lysis syndrome), extensive psoriasis, and rare X-linked enzyme deficiencies (hypoxanthine-guanine phosphoribosyltransferase [HGPRT] deficiency / Lesch-Nyhan syndrome, or phosphoribosylpyrophosphate [PRPP] synthetase superactivity).
• Inflammasome Activation: Free MSU crystals are phagocytosed by synovial resident macrophages, activating the intracellular NLRP3 inflammasome. This activates caspase-1, triggering massive cleavage and secretion of active interleukin-1-beta (IL-1β). IL-1β drives intense neutrophil recruitment into the joint space, releasing lysosomal proteases and reactive oxygen species.

Clinical Features & Radiography

• Acute Gout Attack: Excruciatingly painful, explosive inflammatory monoarthritis that reaches peak intensity within 6 to 12 hours. The joint is intensely erythematous, swollen, warm, and exquisitely tender (even light contact with bedsheets is unbearable). Overlying skin exhibits desquamation as inflammation subsides.
• Predilection: > 50–70% of initial attacks involve the first metatarsophalangeal (MTP) joint (podagra). Other sites: midfoot (tarsal joints), ankle, knee, and olecranon bursa.
• Chronic Tophaceous Gout: Untreated chronic hyperuricaemia leads to the formation of tophi—large, painless or destructive nodular aggregate deposits of monosodium urate crystals surrounded by foreign-body giant cell granulomas. Common locations: helix and antihelix of the ear, olecranon bursae, prepatellar bursae, Achilles tendons, and interphalangeal joints. Tophi can ulcerate through skin, extruding a white, gritty, chalk-like paste.
• Radiography: Early attacks show only soft tissue swelling. Chronic tophaceous disease displays pathognomonic punched-out, well-circumscribed marginal or juxta-articular bone erosions with sclerotic borders and "overhanging margins" (Martel's sign / rat-bite erosions). Joint space is preserved until very late stage, and periarticular osteopenia is absent.
• Arthrocentesis (The Gold Standard): Polarized light microscopy of aspirated synovial fluid demonstrates pathognomonic needle-shaped monosodium urate crystals exhibiting strong negative birefringence. Under a compensated polarized light microscope with a red compensator: crystals lying parallel to the axis of the compensator appear bright yellow ("yellow parallel"); crystals lying perpendicular appear blue.
• Serum Urate Trap: Serum urate levels may be completely normal or falsely low during an acute gout flare (in up to 30–40% of cases), driven by systemic IL-6-mediated renal uricosuria and cortisol release. Therefore, a normal serum urate during an acute flare does not rule out gout; levels should be repeated 2 to 4 weeks after complete resolution of the attack.

                         Polarized Light Crystal Microscopy
                                         |
     +-----------------------------------+-----------------------------------+
     |                                                                       |
1. Gout: Monosodium Urate (MSU)                                     2. Pseudogout: Calcium Pyrophosphate (CPPD)
   - Morphology: Needle-shaped, pointed ends                          - Morphology: Rhomboid-shaped, rectangular/rod
   - Birefringence: STRONGLY NEGATIVE                                 - Birefringence: WEAKLY POSITIVE
   - Parallel to compensator axis: YELLOW                             - Parallel to compensator axis: BLUE
   - Perpendicular to compensator: BLUE                               - Perpendicular to compensator: YELLOW

Acute Attack Management

• First-Line Options:
  1. NSAIDs: Rapid, high-dose oral NSAIDs (e.g. naproxen 500 mg BD, or indomethacin) co-prescribed with a proton-pump inhibitor. First-line in young patients without comorbidities.
  2. Colchicine: Oral colchicine 500 micrograms twice to three times daily. Binds tubulin, inhibiting microtubule polymerization and blocking neutrophil chemotaxis and NLRP3 inflammasome activation. Adverse effects: dose-dependent diarrhoea, nausea, vomiting. Requires dose reduction in CKD.
  3. Oral Corticosteroids: Oral prednisolone 30–35 mg daily for 5 days. Treatment of choice in patients with chronic kidney disease, congestive heart failure, active peptic ulcer disease, or anticoagulation, where NSAIDs and colchicine are contraindicated.
  4. Intra-Articular Corticosteroid Injection: Highly effective for large accessible joints (knee) once septic arthritis is definitively excluded.
• CRITICAL EXAM RULE: DO NOT initiate or discontinue allopurinol or other urate-lowering therapy during an acute gout flare! Rapid fluctuations in serum urate destabilize established intra-articular tophi, precipitating crystal shedding and dramatically prolonging the attack. If a patient is already taking established allopurinol prior to the flare, continue it at the same dose and treat the acute attack with NSAIDs, colchicine, or steroids.

Long-Term Urate-Lowering Therapy (ULT)

• Indications: Recurrent acute attacks (>= 2 attacks within 12 months), presence of tophi, chronic kidney disease (stage 2–5), history of uric acid urolithiasis, or radiographic evidence of joint erosions. Under modern UK (NICE NG219) guidelines, ULT can be offered to anyone after their first attack using shared decision-making.
• Timing: Initiate ULT 2 to 4 weeks after complete resolution of an acute flare.
• First-Line Agent: Allopurinol—a purine analog that competitively inhibits xanthine oxidase, preventing the conversion of hypoxanthine to xanthine and xanthine to uric acid.
  • Dosing Protocol: Start low at 100 mg daily (50 mg daily if eGFR < 30 mL/min) and titrate upwards by 100 mg every 2 to 4 weeks until the target serum urate level is achieved.
  • Target Serum Urate: < 360 µmol/L (< 6.0 mg/dL) for uncomplicated gout; tighten to < 300 µmol/L (< 5.0 mg/dL) for severe tophaceous gout, frequent flares, or persistent erosive disease to promote active crystal dissolution.
  • Prophylaxis Against Mobilization Flares: Dissolving crystal surface architecture triggers secondary acute flares during ULT titration. Therefore, mandatory co-prescription of low-dose colchicine (500 micrograms once or twice daily) or low-dose NSAID for 3 to 6 months is required when starting allopurinol.
  • Pharmacogenomics: Screen for the HLA-B*5801 allele in patients of Han Chinese, Korean, or Thai descent before starting allopurinol; HLA-B*5801 positivity confers a massive risk of Allopurinol Hypersensitivity Syndrome (Stevens-Johnson syndrome / toxic epidermal necrolysis).
• Second-Line Agent: Febuxostat—a potent non-purine selective inhibitor of xanthine oxidase. Used when allopurinol is not tolerated or contraindicated. No dose adjustment needed in mild-to-moderate CKD.
• Uricosuric Agents: Sulfinpyrazone, probenecid, benzbromarone. Inhibit URAT1 in proximal renal tubules, increasing urinary urate clearance. Ineffective if eGFR < 30 mL/min; contraindicated in nephrolithiasis.
• Recombinant Uricase (Pegloticase): Pegylated mammalian uricase that enzymatically converts insoluble uric acid into highly soluble allantoin; reserved for severe, refractory, eroding tophaceous gout.

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8. Crystal Arthropathies: Pseudogout (CPPD Deposition Disease)

Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease involves the precipitation of CPPD crystals in articular hyaline cartilage and fibrocartilage (chondrocalcinosis).

Clinical Manifestations

• Acute CPPD Crystal Arthritis (Pseudogout): Acute, inflammatory monoarthritis or oligoarthritis mimicking gout or septic arthritis. Reaches peak intensity over 12–24 hours.
• Joint Distribution: Strongly predilects large joints, with the knee involved in > 50% of acute attacks, followed by the wrist (specifically the radiocarpal joint and triangular fibrocartilage complex [TFCC]), shoulder, ankle, and symphysis pubis. (In stark contrast to gout, pseudogout rarely affects the 1st MTP joint).
• Crowned Dens Syndrome: CPPD crystal deposition around the odontoid process (dens) of C2 and the transverse ligament of the atlas; manifests as severe acute neck pain, occipital headache, neck stiffness, and high inflammatory markers in elderly patients, frequently misdiagnosed as temporal arteritis or meningitis.

Polarized Microscopy & Radiography

• Polarized Microscopy: Synovial fluid aspiration reveals rhomboid-shaped, rod-shaped, or rectangular crystals exhibiting WEAK POSITIVE BIREFRINGENCE. When aligned parallel to the slow axis of the red compensator, crystals appear blue; when perpendicular, they appear yellow (the exact inverse of monosodium urate!).
• Radiographic Chondrocalcinosis: Plain radiography demonstrates thin, punctate, linear radiodense opacifications within articular hyaline cartilage or fibrocartilage: classically within the menisci of the knee, the triangular fibrocartilage complex (TFCC) of the wrist, and the symphysis pubis.

Secondary Metabolic Associations (The 4 Hs)

While primary CPPD is common in the elderly (> 80 years) due to age-related chondrocyte cartilage degeneration, any presentation in a patient < 60 years mandates an exhaustive metabolic evaluation for secondary predisposing disorders:

1. Haemochromatosis: Iron overload mutates the HFE gene (C282Y homozygosity). Excess intra-articular ferric ions inhibit pyrophosphatase, promoting CPPD deposition. Classically causes arthropathy of the 2nd and 3rd metacarpophalangeal (MCP) joints with characteristic hook-like osteophytes.
2. Hyperparathyroidism (Primary): Hypercalcaemia and elevated PTH enhance calcium pyrophosphate nucleation.
3. Hypomagnesaemia: Magnesium is an essential cofactor for alkaline phosphatase and pyrophosphatases; low magnesium impedes crystal dissolution. Common in Gitelman's syndrome, chronic alcohol use, or loop diuretic therapy.
4. Hypophosphatasia: Rare autosomal recessive loss-of-function mutation in tissue-nonspecific alkaline phosphatase (ALPL).

• Other Associations: Wilson's disease, acromegaly.
• Diagnostic Screening Workup in < 60y: Serum ferritin and transferrin saturation, serum calcium, phosphate, magnesium, PTH, alkaline phosphatase, and liver function tests.

Management of Pseudogout

• Acute Attack: Joint aspiration and intra-articular corticosteroid injection (highly effective); oral NSAIDs; short course of oral colchicine (500 micrograms twice daily) or oral corticosteroids.
• Prophylaxis: Low-dose oral colchicine (500 micrograms once or twice daily) for frequent recurrent attacks.
• Crucial Contrast: Unlike gout, there is no disease-modifying urate-lowering equivalent that dissolves CPPD crystals once deposited.