calcium pyrophosphate deposition disease

**Pathophysiology** - Excess extracellular inorganic pyrophosphate (PPi) combines with calcium to form calcium pyrophosphate dihydrate (CPP) crystals in articular cartilage (fibrocartilage and hyaline cartilage). - Crystals are shed into the joint space, where they are phagocytosed by neutrophils and macrophages. This activates the NLRP3 inflammasome, releasing IL-1β and causing acute inflammation. - Increased PPi arises from altered cartilage metabolism: increased ANKH (a PPi transporter) activity, increased NTPPPH activity, and decreased alkaline phosphatase (which normally degrades PPi).

**Risk factors and associations** - Age: prevalence rises sharply after age 60. Onset before age 55 should prompt a search for a secondary cause or familial disease. - Metabolic: the "4 H's" are Hemochromatosis, Hyperparathyroidism, Hypomagnesemia, and Hypophosphatasia. Others include hypercalcemia, Wilson disease, and gout. - Prior joint trauma or surgery, and osteoarthritis. - Familial CPPD: ANKH gain-of-function mutations (autosomal dominant). - Acute episodes are often triggered by surgery, trauma, or severe illness (e.g., MI, stroke).

**Clinical presentation** - Acute CPP crystal arthritis ("pseudogout"): sudden, painful, swollen joint, most commonly the knee, and also the wrist, shoulder, and ankle. Usually monoarticular. Fever is possible. The attack self-resolves over days to weeks. - Chronic CPP crystal inflammatory arthritis: can mimic rheumatoid arthritis. - Osteoarthritis with CPPD: involves atypical joints for OA, such as the wrist (radiocarpal), MCP joints (especially the 2nd and 3rd), elbow, and shoulder. - Less common: crowned dens syndrome (neck pain and fever from crystals around the odontoid process) and spinal stenosis. - Asymptomatic: chondrocalcinosis found incidentally on imaging.

**Diagnosis** - Arthrocentesis is the key test. - Synovial fluid: rhomboid-shaped (rod-shaped) crystals that are weakly positively birefringent. They appear blue when parallel to the compensator axis and yellow when perpendicular. - WBC count is usually 2,000–50,000/µL, mostly neutrophils. - Gram stain and culture must exclude septic arthritis. Crystals and infection can coexist. - Imaging: - X-ray shows chondrocalcinosis (linear calcification of fibrocartilage and hyaline cartilage), classically in the knee menisci, the triangular fibrocartilage of the wrist, and the pubic symphysis. - Ultrasound and dual-energy CT can also detect deposits. - Screen for secondary causes in patients under 55 or with a suggestive picture: ferritin and transferrin saturation, calcium, PTH, magnesium, phosphate, and alkaline phosphatase.

**Gout vs. pseudogout (high-yield comparison)** - Gout: needle-shaped, strongly negatively birefringent monosodium urate crystals (yellow when parallel to the compensator axis). It classically affects the first MTP joint (podagra), and X-ray shows punched-out erosions with overhanging edges. - Pseudogout: rhomboid, weakly positively birefringent CPP crystals. It classically affects the knee, and X-ray shows chondrocalcinosis.

**Treatment** - Acute attack: - NSAIDs (if no contraindication). - Colchicine. - Intra-articular glucocorticoid injection, which is preferred for a single joint after infection is excluded. - Systemic glucocorticoids if multiple joints are involved or NSAIDs are contraindicated. - Prophylaxis for recurrent attacks: low-dose colchicine or NSAIDs. - Treat the underlying metabolic disorder, though this often does not reverse the arthropathy. - Urate-lowering drugs (allopurinol, febuxostat) are NOT effective, because the crystal is not urate. - No therapy dissolves CPP crystals.

**Board pearls** - An older patient with acute knee swelling, rhomboid crystals with weakly positive birefringence, and chondrocalcinosis points to pseudogout. - A younger patient with CPPD should prompt an evaluation for hemochromatosis, hyperparathyroidism, and hypomagnesemia. - Always rule out septic arthritis in an acutely inflamed joint.