History and exam
Key diagnostic factors
common
painful and tender joints
Joints may be tender and painful.[11]
osteoarthritis-like involvement of joints (wrists, shoulders)
Involvement of joints not typically involved in osteoarthritis such as shoulders, wrists, or metacarpophalangeal joints in a patient with clinical osteoarthritis suggests CPP arthritis.[11]
sudden worsening of osteoarthritis
Patients with chronic CPP arthritis often have acute inflammatory episodes superimposed on daily noninflammatory-type pain.[11]
Other diagnostic factors
common
uncommon
fever and malaise
Nonspecific signs of inflammation, such as low-grade fever and malaise, may occur in older patients with acute CPP arthritis.[11]
Risk factors
strong
advanced age
Aging is the strongest known risk factor. Although CPPD is rare in patients aged <60 years, the prevalence of cartilage calcification doubles with each decade after age 60 years.[20] It is not known how aging predisposes to CPPD.
injury
Injuries or previous joint surgeries, particularly involving the meniscus of the knee, are strong risk factors for subsequent CPPD.[21] It is not clear how injury is related to CPPD.
hyperparathyroidism
CPPD is strongly associated with hyperparathyroidism, and 20% to 30% of patients with hyperparathyroidism have radiographic cartilage calcification.[22] The chronic hypercalcemia of hyperparathyroidism could contribute to the development of CPP crystals, but patients often continue to have clinical CPP arthritis long after their hypercalcemia is corrected.[23]
hemochromatosis
Small studies suggest that 50% of patients with hemochromatosis have arthritis and 25% have cartilage calcification.[24][25] The etiologic link between hemochromatosis and CPPD is unclear, but there is some suggestion that these patients may have an abnormality of parathyroid hormone metabolism, and perhaps these two metabolic conditions share a common link.[26] Iron itself may also directly affect pyrophosphate metabolism.[27]
family history of CPPD
Familial clusters of CPPD have been described worldwide, most prominently in younger individuals.[3] These families typically have premature disease, ranging from mild to severe. The most common inheritance pattern is autosomal dominant. Some families have been shown to have mutations of the ANKH gene, which codes for a protein involved in pyrophosphate metabolism.[4][28] Mutations in the TNFRSF11B gene, which codes for osteoprotegerin, have also been implicated in familial CPPD.[29][30]
hypomagnesemia
This is associated with CPPD. Causes of hypomagnesemia vary from renal disorders such as the Gitelman variant of Bartter syndrome to short bowel syndrome (from intestinal bypass surgery).[31][32] It is believed that magnesium is an important cofactor for enzymes that degrade pyrophosphate and that low magnesium contributes to excess pyrophosphate accumulation.
weak
gout
Gout is thought to be a weak to moderate risk factor for CPPD, and an estimated 2% to 8% of patients have both monosodium urate and CPP crystals in a single joint.[35] The nature of this association is unclear, but it is unlikely to be through a shared association with local factors that promote crystal formation.[36]
other metabolic conditions
Other metabolic diseases have been associated with CPPD.[2] Some, such as hypothyroidism, are so common in the population that they may co-occur by chance.[37][38] Other extremely rare conditions, such as hemosiderosis, ochronosis, spondyloepiphyseal dysplasia, rickets, and acromegaly, are associated with CPPD only through case reports.[37]
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