Calcinosis and CalciphyaxisDz

Synonyms: Calcinosis cutis, dystrophic calcification.

ICD-9 code: Calcinosis cutis, 709.3; tumoral calcinosis, 275.49; calciphylaxis, 440.23.

Definition: Cutaneous and subcutaneous deposition of calcium is often referred to as calcinosis cutis or tumoral calcinosis. Calciphylaxis is a rare disorder that affects patients with long-standing end-stage renal disease, many of whom have secondary hyperparathyroidism. This condition primarily manifests painful nodular lesions.

Etiology: There are five types of calcinosis cutis: metastatic calcinosis, dystrophic calcinosis, iatrogenic calcinosis, idiopathic calcinosis and calciphylaxis. Metastatic calcinosis results from hypercalcemia or hyperphosphatemia and affects the kidneys, lungs, stomach, and, less commonly, the finger tips and periarticular structures. Dystrophic calcification occurs as a result of previously damaged skin and tissues, spares internal organs, and has normal serum calcium and phosphate levels. Dystrophic calcification in the skin seems to correlate with MRI evidence of cutaneous edema or vasculitis, suggesting calcific change is a response to injury. Iatrogenic forms result from extravasation of intravenous agents containing calcium or phosphate. Idiopathic calcification occurs without apparent cause or tissue degeneration. Calciphylaxis is a life-threatening condition caused by progressive cutaneous necrosis caused by small vessel calcification. Calciphylaxis is rare, and typically occurs in patients with end-stage renal disease.

Pathology: Calcinosis may affect the skin, subcutaneous layers including the fascia and muscle. Calcific lesions are rich in hydroxyapatite but may also contain calcium oxalate and uric acid in crystalline form. Lesions are also rich in macrophages, IL-1, IL-6, and TNF.

Risk Factors: Dystrophic calcification commonly occurs in children (more so than adults) with dermatomyositis (DM) and in scleroderma (diffuse and limited) and is rare in mixed connective tissue disease (MCTD). Calcinosis cutis may also occur as a consequence of subcutaneous injections with heparin or other parenteral agents or as a response to trauma.

Cardinal Features: Calcinosis often manifests as painful new lesions in the skin. They appear insidiously such that calcinosis is often a late finding in juvenile DM, CREST syndrome, and diffuse scleroderma. Calcific deposits commonly are found over the fingers, forearms, elbows, knees, and buttocks. Calciphylaxis presents as plaque-like, nodular, or bullous lesions progress to necrotic, ulcerative, painful, nodular lesions on the digits, extremities, and trunk. Patients may develop gangrene of the digits, extremities, buttocks, or abdomen. Uncommonly, it manifests as painful myopathy or severe livedo reticularis that progresses to cutaneous gangrene.

Uncommon Findings: Tumoral calcinosis is an uncommon condition with large calcific masses affecting the soft tissues, bursae, and joints (knees, wrist, fingers, feet, temporomandibular joint). These need not be painful. Tumoral calcinosis is seen in patients with renal failure, hyperparathyroidism, myelitis, calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, sarcoidosis, trauma, or microtrauma. Also rare are “milk of calcium” effusions are nonseptic collections of noncrystalline calcium seldom found in joints and tissues.

Complications: Cutaneous calcific lesions may cause skin breakdown, with the release of a chalky exudate. Such open lesions are subject to secondary bacterial infection. Tumoral collections of calcium may cause local compressive effects leading to pain, nerve impingement, or even myelopathy. Complications of calciphylaxis include cutaneous gangrene and sepsis. Unfortunately, there is a very high mortality rate owing to secondary sepsis. Calcification of the lungs or ischemic infarction of major organs is rare. It may be associated with functional protein C or S deficiency.

Diagnostic Tests: Serum calcium, phosphate, and alkaline phosphatase levels are normal for most with calcinosis cutis. With calciphylaxis, parathyroid hormone levels are elevated in 90% of patients. Look for hypercalcemia and hyperphosphatemia. The calcium-phosphate product (Ca2+ X PO4) exceeds 70 in 80% of patients. Deep incisional biopsies are preferred over punch biopsies.

Imaging: Subcutaneous, fascial, and muscular calcification is usually identified by soft tissue radiographs but may also be found on a CT scan. Vascular calcifications are seen in calciphylaxis.

Keys to Diagnosis: The presence of tender, hard, bead-like or gravel-like lesions beneath the skin that may ulcerate. Diagnosis is confirmed by either soft tissue radiography or calcium exudates from eroded skin lesions. Vascular calcifications or painful nodules in patients with end-stage renal disease indicates the presence of calciphylaxis.

Differential Diagnosis: Calcific deposits are seldom confused with tophi, rheumatoid nodules, or xanthoma. Vasculitis, panniculitis, and type 1 primary hyperoxaluria must be distinguished from calciphylaxis.

Therapy: There is no proven effective therapy for cutaneous calcification. Anecdotal reports suggest that oral aluminum hydroxide; calcium channel blockers (e.g., diltiazem); and bisphosphonate (e.g., alendronate, pamidronate, rise- dronate) therapy may be effective in some. The use of colchicine and warfarin appears to be even less successful. There is no specific therapy for calciphylaxis other than proper wound care and antibiotics. Corticosteroids are not helpful.

Prognosis: Lesions tend to be chronic and less commonly are relapsing or remittent. Calciphylaxis has a significant mortality rate of 60% to 80%.

BIBLIOGRAPHY

Khafif RA, DeLima C, Silverberg A, et al. Calciphylaxis and systemic calcinosis. Collective review. Arch Intern Med 1990;150:956–959.PMID:2184792

Martinez S. Tumoral calcinosis: 12 years later. Semin Musculoskel Radiol 2002;6:331–339. PMID:12541190

Touart DM, Sau P. Cutaneous deposition diseases. Part II. J Am Acad Dermatol 1998;39:527–544.PMID:9777759