Essentials of Diagnosis
- Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease can mimic gout, rheumatoid arthritis, or osteoarthritis.
- Pseudogout causes an intermittent monoarthritis, often of the knee or wrist.
- Diagnosis of pseudogout established by demonstrating CPPD crystals in joint fluid.
- CPPD crystal deposition disease is associated with other diseases, especially hemochromatosis and hyperparathyroidism.
General Considerations
Calcium pyrophosphate dihydrate (CPPD) deposition disease can be asymptomatic or may result in a variety of clinical presentations (Table 45–1). Although the term “pseudogout” is often used to represent the entire spectrum of CPPD, it accurately describes the acute gout-like attacks of inflammation that occur in some patients with CPPD crystal deposition disease. In fact, the name pseudogout was coined when it was discovered that a subset of patients believed to have gout actually had CPPD crystals in their synovial fluid, instead of uric crystals. CPPD deposition may give rise to clinical presentations that mimic septic arthritis, polyarticular inflammatory arthritis, or osteoarthritis (Table 45–1). In addition, CPPD crystals may coexist in synovial fluid with urate or basic calcium phosphate crystals in inflammatory and osteoarthritic-like diseases, as well as in Charcot joints.
Although the cause of CPPD crystal deposition is unknown, recent identification of mutations in the ANKH gene on chromosome 5p has been associated with familial chondrocalcinosis, probably through disordered inorganic pyrophosphate (PPi) transport mechanisms. Low ratios of inorganic phosphate (Pi) to inorganic pyrophosphate (PPi) favor CPPD crystal deposition in joints. Research also shows that the immune system may influence the development of pseudogout, through the secretion of interleukin-1 and other cytokines that facilitate local tissue inflammation.
Several risk factors for pseudogout have been identified. Perhaps the most important factor is aging. CPPD deposition will probably occur in everyone if they live long enough. Genetic factors also influence crystal formation, given that numerous familial cases of CPPD deposition have been described in many nationalities. Interestingly, the pattern of clinical manifestation differs from family to family. For example, disease may occur in some families at an early age that mimics a spondyloarthropathy. In other families, presentation occurs in later years with sporadic joint distribution. What is notable is the prevalence of CPPD deposition is greater in people who have suffered orthopedic trauma; symptoms may persist despite attempts to repair affected joints. Finally, several metabolic and endocrine conditions have been associated with an increased frequency of CPPD disease, including hyperparathyroidism, hemochromatosis, hypothyroidism, amyloidosis, hypomagnesemia, acromegaly, and hypophosphatasia.
Clinical Findings
Approximately 25% of patients with CPPD deposition disease exhibit the pseudogout pattern of disease. Signs and symptoms are characterized by acute, typically monoarticular inflammatory arthritis lasting for several days to 2 weeks. These self-limited attacks may vary in intensity but can occur just as abruptly as an acute gout attack. Between episodes, patients are usually asymptomatic. Nearly half of all attacks involve the knees, although pseudogout can affect other joints, including the first metatarsophalangeal joint, which is the most common site of gouty inflammation. However, attacks of pseudogout may occur spontaneously or be provoked by trauma, surgery, or severe medical illness. Differentiation of pseudogout from joint infection may be difficult and requires arthrocentesis with examination of synovial fluid for crystals and culture. Without appropriate analysis of synovial fluid, it may be impossible to differentiate pseudogout from septic arthritis.
Symptoms that mimic rheumatoid arthritis develop in nearly 5% of patients with CPPD deposition disease. These patients have low-grade inflammation in multiple, symmetric joints. Moreover, morning stiffness, fatigue, synovial thickening, joint contractures, and elevated erythrocyte sedimentation rate frequently accompany this form of arthritis. Fever and other constitutional symptoms may also be possible. Given these misleading findings, this particular variant of pseudogout is often misdiagnosed as rheumatoid arthritis. Making matters more confusing, a small percentage of patients with CPPD deposition have low titers of circulating rheumatoid factor.
Nearly half of patients with CPPD deposition have a progressive, degenerative disease termed “pseudo-osteoarthritis.” Although there is some overlap with the pattern of joint involvement in primary osteoarthritis, the distribution of joint degeneration with CPPD deposition may differ. The knees are most commonly affected, followed by the wrists, metacarpophalangeal joints, hips, shoulders, elbows, and ankles. While symmetric involvement is typical, deformities and flexion contractures of affected joints are not uncommon. Several cases have been reported of severe derangement and destruction, mimicking the findings seen in Charcot joint. Valgus deformity of the knees is especially suggestive of underlying CPPD crystal deposition, as is disease localized to the patellofemoral joint. Patients with this pseudo-osteoarthritic pattern may have intermittent episodes of acute joint inflammation of varying severity, superimposed on their baseline disease state.
Rarely, CPPD crystal deposition occurs in the axial skeleton, which may potentially lead to acute neck pain. The ligamentum flavum has been the most regularly reported site of CPPD crystal deposition in the spine. At times, neck pain may be accompanied by stiffness and fever, mimicking meningitis. Crystal deposits, ligament hypertrophy, and cartilage metaplasia contribute to encroachment of the spinal cord. Infrequently, lumbar spine involvement may produce an acute radiculopathy or neurogenic claudication resulting from spinal stenosis. Thus, signs and symptoms of neurologic long tract disease, directly resulting from CPPD deposition and its related changes, may develop in some patients.
That being said, many patients with CPPD crystal deposits lack joint symptoms. Even patients with classic osteoarthritic symptoms in some joints may have other joints with crystal deposition that are completely asymptomatic and clinically normal.
