Chondrocalcinosis 

Calcium pyrophosphate dihydrate deposition (calcium pyrophosphate deposition disease; CPPD) disease is an arthritis variant. CPPD is actually a chemical aberration that manifests as at least 4 separate, yet related, diseases. Chondrocalcinosis has been described as the streaking of soft tissues with calcium. The term chondrocalcinosis sometimes is misapplied as a synonym for CPPD disease, but technically, it refers to the visible presence of calcification within tissues on an imaging study.

The images below show various structures that may be affected by CPPD.

Richette et al summarized recent research (1998-2008) regarding the epidemiology of chondrocalcinosis (CC), including CC prevalence, association between CC and osteoarthritis (OA), and familial forms of CC and diseases associated with CC. The authors found that aging is the main risk factor for the occurrence of sporadic CC, with the prevalence of CC varying from 7-10% in persons approximately 60 years they age. They noted a positive association between CC and OA, and mutations in the ankylosis human (ANKH) gene have been identified as a cause of familial CC in some kindreds. There is good evidence that hereditary hemochromatosis, hyperparathyroidism, and hypomagnesemia predispose to secondary CC. Primary metabolic disorders or familial predisposition are uncommon but should be considered if CC occurs before 55 years of age or if there is florid polyarticular CC. After the age of 55 years, hyperparathyroidism should be considered in all patients.^[1]

Calcium pyrophosphate deposition disease (CPPD) consists of the deposition of calcium pyrophosphate crystals into soft tissue. They have been found in high concentrations in hyaline cartilage, synovial tissue, capsule, meniscus, labrum, ligamentum flavum, the soft tissue of the hand, and, rarely, the fibrocartilage of the temporomandibular joint.

Frequency

Estimates on the frequency of CPPD disease in the United States vary widely. Rates range from 4% to more than 25% of the population by age 80 years. Prevalence clearly increases with age.^[1] CPPD manifests clinically approximately half as often as gout in the typical practice setting. The male-to-female ratio is approximately 1.4:1.

See Pathophysiology.

The exact physiologic dysfunction is not clear, but studies appear to implicate the chondrocyte and surrounding matrix as the responsible agents. Some noxious event (perhaps chemical, perhaps physical) appears to incite a cascade that evolves toward the hypertrophy and degeneration of chondrocytes. Intracellular material escapes to the surrounding matrix and potentially alters the calcium-binding effect of the matrix proteoglycans. Calcium pyrophosphate crystals grow adjacent to these hypertrophic chondrocytes within the affected matrix. The breakdown of collagen cells has been proposed to be the source of the inorganic pyrophosphate.^{[2, 3, 4]}

Following are the 4 separate and distinct manifestations of this disease:

Pseudogout

An acute presentation appears very similar to gout. Technically, this is designated pseudogout, although the term is often used synonymously with all calcium pyrophosphate deposition (CPPD) diseases. Gout can be distinguished from pseudogout in that gout crystals (sodium urate) are needle shaped and have negative birefringence, while pseudogout crystals (calcium pyrophosphate) are rod or rhomboid shaped and have no or weak positive birefringence. Advanced techniques such as electron microscopy can be used for a definitive diagnosis.

Pseudogout is estimated to affect a small percentage (< 25%) of individuals with demonstrated CPPD disease. Onset is usually monoarticular or pauciarticular and is often preceded by injury or surgery to the area. Not infrequently, pseudogout has been identified soon after parathyroid adenoma excision.

The onset is aggressive, reaching a peak in hours, and creating pain, swelling, heat, and redness. Fever is present in approximately half the patients with pseudogout. The knee most often is affected. The shoulder, elbow, ankle, and familiar first metatarsophalangeal (MTP) joint are also frequently involved. The natural course is spontaneous resolution over a few days or, at most, weeks. Treatment accelerates recovery.

Tophaceous pseudogout

The calcium pyrophosphate material can deposit in large accumulations, producing a pseudotumor. These can be massive, with all of the consequences of any other space-filling lesion. They often are discretely painful. A review of the literature reveals reports of rare lesions in the temporomandibular joint, sternoclavicular joint, transverse ligament of C1, metatarsophalangeal joints, spinal facet joints, cubital tunnel, and other sites. Involvement in the spine is frequently associated with neural impingement symptoms and spinal stenosis, requiring surgical decompression.^{[5, 6, 7, 8]}

Familial calcium pyrophosphate dihydrate deposition

A familial pattern appears at a much earlier age, often as early as the third decade of life. It tends to be more aggressive, with a more ominous long-term prognosis. The longevity of satisfactory joint function is reduced in these individuals. Genetic studies have implicated a responsible gene with an autosomal dominant mode of inheritance. Families with a rate of sibling involvement as high as 70% have been documented.

Familial studies and mouse genetics have been used to identify a mutation in the ANKH gene, which, when present, significantly increases the risk of developing calcium crystal formation. The mouse homologue of the ANKH gene was shown to code for a protein necessary for transporting inorganic pyrophosphate across the cell membrane into the extracellular environment. Mutations in this gene result in increased intracellular inorganic pyrophosphate levels. The low extracellular levels of inorganic pyrophosphate permit hydroxyapatite deposition in and around the articular hyaline cartilage and fibrocartilage and, thus, promote calcium hydroxyapatite crystal formation in the mouse. The ANKH gene has clearly been linked to CPPD in humans, but the molecular dynamics are not as well understood.^{[9, 10, 11, 12, 13, 14, 15]}

Osteoarthritis

The most common presentation is that of osteoarthritis (OA) alone. Symptoms are identical to those of the typical patient with OA, with the exception that, at some point, the presence of calcium pyrophosphate crystals is appreciated. Most often, this is identified by the presence of chondrocalcinosis. Chondrocalcinosis increases in frequency with age. Injury and surgery may aggravate symptoms. Some reports of symptom onset following viscosupplementation injection also are recorded in the literature.^{[16, 17, 18]}

Most patients in the typical orthopedic practice are in the latter category. Associated with the general category of CPPD diseases and, therefore, presumably including all the presentations listed above, are other metabolic diseases. The incidence of CPPD is increased in persons with hyperparathyroidism, hemochromatosis, hemosiderosis, hypomagnesemia, and hypophosphatemia.^[1]

The persistence of symptoms despite aggressive nonsurgical management should be considered an indication for surgical evaluation and treatment.

An intraoperative photograph (see image below) demonstrates extensive precipitate deposition of the calcium pyrophosphate crystals in the articular cartilage, meniscus, and synovium of a knee.

Patients who demonstrate symptoms of OA or CPPD disease have no contraindications to performing arthroscopic surgery as needed. For persons with more advanced OA, the available surgical procedures, up to and including total knee arthroplasty, also are not contraindicated by the presence of this disease.^[19]