Calcium Pyrophosphate Deposition Disease
Calcium pyrophosphate deposition disease (CPDD) is a metabolic arthropathy resulting from the deposition of calcium pyrophosphate dihydrate (CPPD) in and around joints, especially in articular and fibrocartilage. Although CPDD often is asymptomatic, with only radiographic changes (ie, chondrocalcinosis), various clinical manifestations may occur, including acute (pseudogout) and chronic arthritis. Although almost any joint may be involved, the knees, wrists, and hips are most commonly affected. This condition is the most common cause of secondary metabolic osteoarthritis.
Although the exact mechanism for the development of CPDD remains unknown, increased adenosine triphosphate breakdown with resultant increased inorganic pyrophosphate in the joints occurs as a result of aging, genetic factors, or both. Changes in the cartilage matrix may play an important role in promoting CPPD deposition. Rare hereditary forms of CPDD occur, generally inherited in an autosomal dominant mode.
Overactivity of enzymes that breakdown triphosphates, such as nucleoside triphosphate pyrophosphohydrolase, has been observed in the cartilage of patients with CPDD. Therefore, inorganic pyrophosphate can bind calcium, leading to CPPD deposition in cartilage and synovium. Hyaline cartilage is affected most commonly, but fibrocartilage, such as the meniscal cartilage of the knee, also can be involved.
Hypotheses based on in vitro studies propose that pyrophosphohydrolase activity and inorganic phosphate content, as noted above, are generalized phenomena that occur in fibroblasts. Although these phenomena are generalized, the reason they occur only in joints remains unknown.
Recently, genetic defects have been identified as specific gene mutations in a few kindred families. The mutation occurred in specific genes known as ANKH and COL, which may be involved in the crystal-induced inflammation. This is related to synovial tissue and direct cartilage activation, leading to the arthritis caused by CPPD. The ANKH gene has also been shown to be involved in cellular transport of inorganic phosphate.
CPDD is a common condition that occurs with aging in all races. Nearly 50% of people older than 85 years have radiologic evidence of chondrocalcinosis.
CPDD can be a cause of significant morbidity, either from the pain of an acute attack of pseudogout or the chronic symptoms associated with chronic arthropathy.
No particular race predilection exists for this condition.
Women have a slightly higher incidence than men, but the exact ratio is not known. The female-to-male ratio probably is 1.4-1.
CPDD usually occurs in patients who are in the fifth decade of life or older, with increasing prevalence as age increases. When it occurs early, before the fourth decade, it usually is associated with secondary causes such as an underlying metabolic disease or familial causes.
Clinical presentations can vary, but according to McCarty, 5 different presentations are most common, as follows:
This usually is associated with finding chondrocalcinosis on radiographs, without clinical manifestations. This may be the most common form of CPDD.
The classic radiologic findings include chondrocalcinosis of the hyaline cartilage and fibrocartilage of the knees, the fibrocartilage of the triangular ligament of the wrist, the fibrocartilage of the symphysis pubis, and the acetabulum labrum of the hips.
This is characterized by acute monoarticular or oligoarticular arthritis. Pseudogout usually involves the knee or the wrist, although almost any joint can be involved, including the first metatarsophalangeal (MTP) joint, as occurs in patients with gout. This form of CPDD occurs in 25% of patients.
Clinical manifestations are similar to acute gouty arthritis, typically presenting with an acute monoarthritis with pain and swelling, although generally not as intense. Polyarticular attacks may occur on occasion. Pseudogout may be precipitated by medical illness such as myocardial infarction, congestive heart failure, or cerebrovascular accident or may occur after surgery. Trauma also may be a precipitating factor. Events that affect serum calcium levels also may precipitate attacks of pseudogout.
Occasionally, pseudogout may present as a pseudoseptic syndrome with acute arthritis, fever, and leukocytosis with a left shift.
Aspiration of the fluid from affected joints during an acute attack usually yields mildly-to-moderately inflammatory fluid, with 10,000-50,000 WBCs/mcL, more than 90% of which are neutrophils.
Glucose levels usually are normal.
Characteristically, rhomboid-shaped, weakly positively, birefringent crystals are seen both intracellularly and extracellularly using compensated polarized microscopy. The presence of such crystals intracellularly is pathognomonic for acute pseudogout.
Septic arthritis must be excluded; therefore, a Gram stain of the fluid should be performed. The results of the Gram stain are negative unless a concomitant infection is present.
Pseudoosteoarthritis often involves the metacarpophalangeal (MCP) joints, wrists, elbows, and shoulders, joints unlikely to be involved with primary osteoarthritis. It affects the knees most commonly and can involve the proximal interphalangeal (PIP) joints and spine, as occurs in patients with primary osteoarthritis. This form of CPDD accounts for 50% of all patients. Approximately half of these patients also have associated pseudogout.
Hooklike osteophytes are a common radiological finding in patients with a pseudoosteoarthritis condition and usually are present along the second and third metacarpal heads.
The presence of chondrocalcinosis on radiographs is common.
The differential diagnosis includes hemochromatosis, hyperparathyroidism, hypothyroidism, and traumatic arthritis (as occurs in heavy equipment machinery operators).
This pattern is found in approximately 5% of patients with CPDD and is associated with symmetrical inflammation of the PIP and MCP joints.
Clinically, these patients complain of morning stiffness and joint swelling.
Radiologically, erosions can be observed but usually are associated with chondrocalcinosis.
The erythrocyte sedimentation rate (ESR) usually is elevated.
The older age at onset for this condition, the lack of rheumatoid factor, and the presence of chondrocalcinosis help differentiate it from true rheumatoid arthritis. However, rheumatoid arthritis can occur in older individuals. In addition, older individuals may have low-titer–positive rheumatoid factor. Thus, the diagnosis must be made with care.
Neuropathiclike arthropathy is observed in fewer than 5% of patients with CPDD, most commonly involving the knee. This is a severe destructive arthropathy. Unlike true neuropathic arthropathy, no clear underlying neurological disorder is present.
Again, the presence of chondrocalcinosis can help make the diagnosis.
Revised diagnostic criteria for calcium pyrophosphate crystal deposition disease were taken from the 1997 Primer on Rheumatic Disease and are used with permission from the Arthritis Foundation.
Criterion I – Demonstration of calcium pyrophosphate crystal deposition in tissue or synovial fluid by definitive means (eg, characteristic x-ray films, diffraction analysis, or chemical analysis)
Criterion IIa – Identification of monoclinic or triclinic crystals showing no or weakly positive birefringence by compensated polarized light microscopy
Criterion IIb – Presence of typical radiographic calcifications
Criterion IIIa – Acute arthritis, especially of knees or other large joints
Criterion IIIb – Chronic arthritis, especially of knee, hip, wrist, carpus, elbow, shoulder, or MCP joint, especially if accompanied by acute exacerbation; the chronic arthritis shows the following features, which are helpful in differentiating it from osteoarthritis:
Uncommon sites – Wrist, MCP joint, elbow, shoulder
Radiographic appearance – Radiocarpal or patellofemoral joint-space narrowing, especially if isolated (eg, patella wrapped around the femur)
Subchondral cyst formation
Severity of degeneration – Progressive, with subchondral bony collapse and fragmentation with formation of intraarticular radiodense bodies
Osteophyte formation – Variable and inconsistent
Tendon calcifications, especially triceps, Achilles, obturators
Definite disease: Criterion I or IIa plus IIb must be fulfilled.
Probable disease: Criterion IIa or IIb must be fulfilled.
Possible disease: Criterion IIIa or IIIb should alert the clinician to the possibility of underlying calcium pyrophosphate deposition.
A number of conditions have been associated with CPDD. When CPDD is diagnosed, especially in a patient younger than 60 years, a metabolic workup should be performed, including measurements of serum calcium, magnesium phosphorus, alkaline phosphatase, iron, total iron-binding capacity (TIBC), transferrin saturation and ferritin, and thyroid-stimulating hormone.
True associations – Familial (autosomal dominant), prior trauma or prior surgery, hyperparathyroidism, hemochromatosis, hypophosphatasia, hypomagnesemia, aging
Probable associations – Hypothyroidism, gout, familial hypercalciuria
Possible associations – Acromegaly, diabetes mellitus, ochronosis, Wilson disease.
The physical examination findings vary depending on the form of CPDD in a given patient, who may present with an acute arthritis or different patterns of chronic arthritis.
Acute pseudogout: Physical examination findings show an acutely inflamed joint with swelling, effusion, warmth, tenderness, and pain on range of motion similar to acute gouty arthritis. This typically occurs in the knee but may occur in the wrists, shoulders, ankles, hands, and feet.
Pseudoosteoarthritis: Physical examination findings show a picture similar to osteoarthritis, sometimes with unusual joint predilection. If a patient has osteoarthritis involving the MCP joints and wrists, consider CPDD associated with an underlying metabolic disease.
Pseudorheumatoid arthritis: Physical examination findings show a picture similar to rheumatoid arthritis with synovitis in a symmetrical polyarticular pattern, especially involving the wrists and MCP joints.