What is the most likely cause of isolated right knee pain in a 30‑year‑old man with three months of recurrent joint pain, normal white blood cell count, high‑normal serum uric acid, and no fever or systemic symptoms?

Pseudogout (Calcium Pyrophosphate Deposition Disease)

In a 30-year-old man with three months of recurrent joint pain, high-normal serum uric acid (400 µmol/L), normal WBC, and no systemic symptoms, pseudogout is the most likely diagnosis—normal uric acid levels essentially rule out gout in this clinical context. 1

Why Gout Is Highly Unlikely

• The absence of hyperuricemia has a markedly low likelihood ratio for gout diagnosis, making it very unlikely in this patient. 1
• While serum uric acid can be normal in approximately 10% of acute gout attacks, this applies to acute presentations reaching maximum pain within 6-12 hours, not a 3-month history of recurrent episodes. 2, 1
• The European League Against Rheumatism explicitly states that normal serum uric acid levels essentially rule out gout in the clinical context of recurrent monoarticular knee pain. 1
• Hyperuricemia alone has only 53-61% specificity for gout, but its absence is highly predictive against gout. 2, 1
• Patients with recurrent episodes over 3 months without typical acute inflammatory presentation of gout (sudden onset, maximum pain within 6-12 hours, overlying erythema) are less likely to have gout. 3, 2

Why Pseudogout Is More Likely

• Calcium pyrophosphate deposition disease (CPPD/pseudogout) is the second most common crystal arthropathy and frequently affects the knee joint. 1
• The patient's age (30 years) is atypical for pseudogout, which usually occurs in older adults, but CPPD can occur in younger patients with underlying metabolic conditions (hyperparathyroidism, hemochromatosis, hypomagnesemia). 1
• The subacute presentation over 3 months with recurrent episodes fits pseudogout better than the classic hyperacute presentation of gout. 3

Definitive Diagnostic Approach

Joint aspiration with synovial fluid analysis is mandatory to confirm the diagnosis and exclude other conditions. 2, 1

Synovial Fluid Analysis

• CPPD diagnosis requires identification of calcium pyrophosphate crystals—these appear as rhomboid-shaped, weakly positively birefringent crystals under polarized microscopy. 1
• Gout would show needle-shaped, negatively birefringent monosodium urate crystals. 2, 4
• Gram stain and culture must still be performed even when crystals are identified, as crystal arthritis and septic arthritis can coexist. 3, 1

Imaging Studies

• Plain radiographs of the knee should be obtained to look for chondrocalcinosis—linear calcifications in the cartilage that appear on X-ray. 1
• Chondrocalcinosis is highly suggestive of CPPD, particularly in the knee menisci. 2
• Conventional radiography and ultrasound are the recommended initial imaging modalities for CPPD diagnosis. 1

Common Pitfalls to Avoid

• Do not diagnose gout based on "high-normal" uric acid alone—only 22% of asymptomatic patients with serum uric acid levels above 9 mg/dL (540 µmol/L) develop gout over 5 years, and this patient's level is well below that threshold. 2
• Do not assume normal WBC excludes crystal arthropathy—both gout and pseudogout can present with normal systemic inflammatory markers. 2
• Do not skip joint aspiration—clinical diagnosis alone is insufficient without crystal confirmation, especially when differentiating between gout and pseudogout. 3
• The absence of fever and systemic manifestations makes septic arthritis unlikely but does not exclude it; culture is still mandatory. 3, 1

Metabolic Work-Up for Young Patient with Pseudogout

Given the patient's young age (30 years), screen for underlying metabolic conditions associated with CPPD:

• Serum calcium and parathyroid hormone (hyperparathyroidism) 1
• Serum iron studies and ferritin (hemochromatosis) 1
• Serum magnesium (hypomagnesemia) 1