Pathophysiology of Pseudogout (CPPD)
Pseudogout is fundamentally caused by the deposition of calcium pyrophosphate dihydrate (CPP) crystals in articular tissues, particularly fibrocartilage and hyaline cartilage, with elevated inorganic pyrophosphate levels being central to crystal formation. 1, 2
Crystal Formation and Deposition Mechanism
The core pathophysiologic process involves:
- Elevated inorganic pyrophosphate levels are the central driver of CPP crystal formation in affected joints 1
- CPP crystals accumulate primarily in fibrocartilage and hyaline cartilage of joints, though ligaments, tendons, bursae, bone, and spine can also be involved 2, 3
- The crystals deposit systemically in articular and periarticular tissues, distinguishing this from localized processes 4, 3
Inflammatory Response
Once crystals form and deposit:
- CPP crystals trigger an acute inflammatory reaction when released into the joint space, causing the characteristic pseudogout attacks 2
- The inflammatory process can manifest as either acute attacks (pseudogout) or chronic inflammatory arthritis with persistent joint swelling, morning stiffness, and elevated inflammatory markers 2
- Interleukin-1 (IL-1) appears to play a key role in the inflammatory cascade, which is why IL-1 inhibitors are being investigated as potential treatments 1, 5
Metabolic and Regulatory Factors
Several metabolic factors influence crystal formation:
- Magnesium deficiency promotes CPP crystal formation, as magnesium normally solubilizes CPP crystals and inhibits their nucleation and growth 1, 6, 7
- Medications like furosemide can precipitate CPPD by causing magnesium depletion 6
- Metabolic conditions including primary hyperparathyroidism (OR=3.03), hemochromatosis, and hypomagnesemia predispose to CPPD development 1, 7
Relationship to Joint Degeneration
A critical unresolved question in CPPD pathophysiology:
- The relationship between osteoarthritis (OA) and CPPD remains unclear - it is uncertain whether CPP crystals directly cause joint degeneration or are simply a consequence of pre-existing OA 2
- This bidirectional relationship complicates understanding of disease progression and treatment targets 2
Key Pathophysiologic Distinctions from Gout
Unlike urate crystals in gout, there is currently no way to prevent CPP crystal formation or enhance their dissolution 1, 6
- This fundamental difference means CPPD treatment is restricted to symptomatic control rather than disease modification 1
- The mechanisms of CPPD remain incompletely understood despite its prevalence as one of the most common forms of inflammatory arthritis 1, 2
Clinical Pitfall
The pathophysiology can affect unusual locations: CPPD of the atlanto-occipital joint (crowned dens syndrome) causes acute cervico-occipital pain with fever and neck stiffness, which can mimic serious conditions like meningitis or aortic dissection 2, 4