Key Points
Disease summary:
The diagnostic for calcium pyrophosphate dihydrate (CPPD) crystal deposition is given after the identification of CPPD crystals in synovial fluid (SF) or in tissue sections.
The terminology of CPPD-related diseases is still not uniform; the following definitions are the most commonly used:
Pseudogout—acute clinical syndrome of synovitis associated with CPPD deposition
Pyrophosphate arthropathy—structural abnormality of cartilage and bone associated with articular CPPD deposition
Chondrocalcinosis (CC)—radiographic observation of calcification of fibro and/or hyaline articular cartilage
CPPD deposition is the main cause of radiographic articular calcification of the knee, that is, CC. The deposition of other calcium salts, such as hydroxyapatite, can also be the cause of articular calcification.
Hereditary basis:
CPPD deposition disease (CPDD) can occur as a familial monogenic disorder showing an autosomal dominant pattern of inheritance.
Differential diagnosis:
Certain metabolic diseases predispose to CPDD deposition such as hemochromatosis, Gitelman syndrome, and hyperparathyroidism. It is possible to screen these disorders by laboratory hematologic testing and evaluate elevated serum calcium, decreased serum phosphate, elevated parathyroid hormone or parathormone, elevated alkaline phosphatase, and increased serum ferritin. However, it is important to refer that these disorders have strong genetic component themselves. In Table 143-1, it is possible to see how to perform a genetic differential diagnosis.
| Syndrome | Gene Symbol | Associated Findings |
|---|---|---|
Hemochromatosis | HFE, TFR2, HJ, HAM, SLC40A1 | Group of phenotypically and genetically heterogeneous disorders characterized by iron overload. CPPD-CC has a well-known association with hemochromatosis affecting about 67% of the patients. |
Gitelman syndrome | SLC12A3 | Variant of Barter syndrome in which patients present hypokalemic alkalosis in conjunction with hypocalciuria and hypomagnesemia. CPPD-CC has been widely associated with this syndrome affecting a large majority of these patients. |
Hypophosphatasia | ALPL | Heterogeneous biochemical and clinical features which include low levels of serum alkaline phosphatase, high levels of serum pyridoxal-5-prime-phosphate, early loss of teeth (odontohypophosphatasia), bowed legs, calcification of paraspinous ligaments, joint pains, and peri- and intra-articular calcifications of joints of the hands, feet, and knees and calcification of the anterior spinous ligament in the lumbar area. |
Hyperparathyroidism | MEN1, HPRT2, HRPT3 | This is the most common familial form of primary hyperparathyroidism. Primary chief cell hyperplasia is the main characteristic of this disorder. Many patients show hypercalcemia and radiologic changes characteristic of chondrocalcinosis. |
Familial hypocalciuric hypercalcemia, type I | CASR | This was the first disorder described where renal tubular defect in calcium reabsorption is independent of parathormone. A ratio of renal calcium clearance to creatinine clearance below 0.01 suggests FHH1. The only complications attributable to the hypercalcemia are pancreatitis and chondrocalcinosis. Both the kidneys and the parathyroid glands seem insensitive to chronic hypercalcemia in this disease. |
Diagnostic Criteria and Clinical Characteristics
At least two of the following
Demonstration of calcium pyrophosphate crystal deposition in tissue or SF by definitive means.
Identification of crystals showing weakly or no positive birefringence by compensated polarized light microscopy.
Presence of typical radiographic calcifications.
Acute arthritis, especially of knees or other large joints.
Chronic arthritis, especially of knee, hip, carpus elbow, shoulder, or metacarpophalangeal (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—or patellofemoral joint-space narrowing, especially if isolated
Subchondral cyst formation
Severity of degeneration—progressive, with subchondral bony collapse and fragmentation with formation of intra-articular radiodense bodies
Osteophyte formation—variable and inconsistent
Tendon calcifications, especially triceps, Achilles, obturators
Categories
Definite disease: I or IIa and IIb must be fulfilled
Probable disease: IIa or IIb must be fulfilled
Possible disease: IIIa or IIIb should alert the clinician to the possibility of underlying calcium pyrophosphate deposition
CPPD-CC is clinically heterogeneous, including
An asymptomatic presentation, common in elderly people, affecting mainly the knee by the deposition of CPPD crystals in articular hyaline and fibrocartilage (CC)
An acute form of CPPD arthropathy, known as pseudogout
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