Pseudogout, formally known as Calcium Pyrophosphate Deposition Disease (CPPD), is a form of inflammatory arthritis causing sudden, painful swelling in one or more joints. It is often called “false gout” because its acute attacks resemble those of gout, but the underlying cause is different. CPPD is characterized by the accumulation of calcium pyrophosphate dihydrate crystals within and around joint structures, rather than the uric acid crystals found in gout. Understanding CPPD involves examining the factors that lead to the formation and inflammatory shedding of these specific crystals.
Understanding Calcium Pyrophosphate Dihydrate Crystals
The fundamental mechanism of CPPD involves an imbalance in mineral regulation, leading to the formation of calcium pyrophosphate dihydrate (CPPD) crystals. These microscopic crystals primarily deposit in the cartilage, a process visible on X-rays known as chondrocalcinosis. Crystal formation is directly linked to the concentration of inorganic pyrophosphate (PPi) and calcium within the joint space. An altered ratio of PPi to calcium favors CPPD precipitation within the cartilage matrix.
The ANK protein regulates this process by transporting PPi from inside cartilage cells (chondrocytes) into the joint’s extracellular matrix. Excess extracellular PPi is a direct precursor for CPPD crystal formation when sufficient calcium is present. The acute, painful attack occurs when these crystals detach from the cartilage and are shed into the synovial fluid. Immune cells recognize the crystals as foreign invaders, triggering a rapid inflammatory response that causes severe pain, swelling, and redness.
Aging and Familial Predisposition
Advanced age is the greatest risk factor for developing CPPD, with prevalence increasing significantly over a person’s lifespan. CPPD is rare before age 60, but is found in nearly half of individuals who reach their 90s. This association is thought to be due to the cumulative effects of mechanical stress and biochemical changes in the cartilage over decades. As cartilage ages, chondrocytes undergo functional changes that may lead to increased production of PPi, promoting crystal formation.
In some cases, CPPD is caused by a familial or genetic predisposition, leading to an earlier onset of the disease. This hereditary form is often linked to mutations in the ANKH gene, which codes for the ANK protein responsible for transporting PPi. A mutation in ANKH can cause the protein to become overactive, resulting in an excessive efflux of PPi from the cells into the joint space. This elevated PPi concentration promotes widespread crystal formation, causing symptoms to appear as early as the 30s or 40s.
Associated Metabolic and Endocrine Disorders
Systemic medical conditions that disrupt the body’s mineral balance significantly increase the risk of CPPD. These disorders alter the chemical environment necessary for normal bone and cartilage function, making CPPD crystals more likely to form. Identifying and managing these underlying conditions is important, particularly in younger patients.
Hyperparathyroidism
This condition involves an overactive parathyroid gland producing excess parathyroid hormone, which regulates calcium levels. Overproduction results in hypercalcemia, or abnormally high levels of calcium in the blood. The elevated calcium concentration in the body, including the joint fluid, provides a necessary building block for the CPPD crystal structure, promoting deposition.
Hemochromatosis
Hemochromatosis, a genetic disorder characterized by the excessive absorption and storage of iron, is another strong risk factor for CPPD. Excess iron accumulates in various tissues, including the joints and cartilage, where it can cause direct cellular damage. High concentrations of iron are also thought to inhibit pyrophosphatases, the enzymes that break down PPi. This inhibition allows PPi to accumulate and combine with calcium to form crystals.
Hypomagnesemia
Low levels of magnesium in the blood are strongly associated with CPPD because magnesium plays a protective role in joint health. Magnesium acts as a cofactor for pyrophosphatases, meaning that low magnesium impairs the enzymes’ ability to break down PPi, contributing to its accumulation. Magnesium deficiency also makes CPPD crystals less soluble, increasing the likelihood they will precipitate out of the joint fluid and deposit in the cartilage.
Hypophosphatasia
Hypophosphatasia is a rare, inherited metabolic disorder involving a defect in the tissue non-specific alkaline phosphatase (TNSALP) enzyme. Since this enzyme normally breaks down PPi, its deficiency leads to a massive accumulation of PPi in the joints and tissues. The resulting high PPi levels overwhelm regulatory mechanisms, causing extensive CPPD crystal deposition.
Localized Joint Damage and Physical Triggers
While systemic factors set the stage for crystal formation, localized joint issues and physical events can promote deposition or trigger an acute flare. Severe osteoarthritis (OA) is a significant local predisposing factor. Damaged and degenerating cartilage provides a favorable environment for CPPD crystals to form and embed. The structural breakdown and cellular stress within the arthritic joint alter the local chemistry, encouraging crystal deposition in the damaged tissue.
Physical events also serve as immediate triggers for a pseudogout attack in a joint where CPPD crystals are already present. Joint trauma, such as a serious injury, a fall, or prior surgery, can destabilize existing crystal deposits. This mechanical disturbance causes the crystals to shed rapidly into the synovial fluid, immediately provoking the inflammatory cascade. Even an unrelated acute illness or medical stressor can sometimes precipitate an attack by briefly altering the joint’s internal environment.