Calciphylaxis: Diagnosis and treatment

Advances in Skin & Wound Care,  Nov/Dec 2001  by Trent, Jennifer T,  Kirsner, Robert S

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unusual Wounds

Calciphylaxis is a rare, often fatal condition, characterized by progressive cutaneous necrosis that frequently occurs in patients with end-stage renal disease. Many eliciting factors have been suggested as its cause, but the most commonly linked phenomenon is the development of secondary hyperparathyroidism.1,2 This secondary hyperparathyroidism leads to an elevated calcium-phosphate product and development of vascular, cutaneous, and subcutaneous calcification, resulting in tissue death.

Calciphylaxis typically develops after the start of dialysis and is seen in approximately 1% of patients with chronic renal failure and 4.1% of patients receiving hemodialysis.3,4 The prognosis for patients who develop calciphylaxis is grim, with an estimated 5-year survival of less than 50%.3 In addition to skin involvement, the pathophysiologic process may occur within internal organs. This-along with sepsis from infected skin wounds-is a major cause of morbidity and mortality for these patients.2,5,6

Calciphylaxis was first reported by Bryant and White in 1898; however, it was not described in the literature until 1962 by Selyein.1,2 There are 2 clinical variants of calciphylaxis: distal and proximal lesions.4,7 The distal lesions occur mostly on the posterolateral calves, but also appear on the fingers, toes, and glans penis (Figure 1).This distribution accounts for one third of clinical presentations. Patients who present with distal lesions have a mortality rate of 42%.4 In patients with proximal involvement, lesions appear on the trunk, abdomen, buttocks, and proximal extremities. Two thirds of patients with calciphylaxis have proximal involvement. These patients have an even worse prognosis, with a mortality rate of 72%.

Clinical Presentation

The cutaneous manifestations begin as red or violaceous mottled plaques that may resemble livedo reticularis.2-4,8,9 This signifies a vascular pattern, with these early ischemic lesions often progressing to gangrenous, ill-defined, black plaques (Figure 2). With time, the gangrenous plaques will ulcerate (Figure 3) and become tender, indurated ulcers, or may lead to autoamputation.

The ulcers of calciphylaxis are usually bilateral and symmetric and may be quite deep, extending into muscle.10 Vesicles often appear at the periphery of the ulcers.8 Because of the loss of the cutaneous barrier and underlying immune deficiency secondary to chronic renal failure and/or diabetes mellitus, patients with calciphylaxis are predisposed to infection, subsequent sepsis, and death.

A number of risk factors are associated with calciphylaxis.3,9,11 Although incidence is not higher in any particular age group, women have a higher incidence of calciphylaxis than men.3,11 Other patients who have an increased risk include those who are immunosuppressed for other reasons, those who have diabetes mellitus as a cause of their renal failure, and those with a history of protein C and/or protein S deficiency (Table 1). 3,9,11

Pathogenesis

Calciphylaxis occurs in patients with end-stage renal disease, hyperparathyroidism (mostly secondary), advanced liver disease, Crohn disease, and extensive bowel resections.1,12 It is believed that patients develop this condition as a result of a hypersensitivity reaction.1,4-9,12 For example, in certain circumstances, a patient may be sensitized by a specific agent, such as parathyroid hormone, hyperphosphatemia, or hypercalcemia (Table 2). The sensitization time period is important because the clinical scenario must be appropriate for this sensitization to occur. Once a patient is sensitized, a hypersensitivity reaction is induced in response to the presence of a challenging agent, such as systemic steroid, infusion of albumin, iron dextran, immunosuppression, or trauma (Table 3).4-9 The hypersensitivity reaction leads to the development of calcinosis, inflammation, and sclerosis associated with calciphylaxis. The fact that the sensitizing agent and the challenging agent are often different substances supports the concept that the reaction is not an immune-mediated one.7

Diagnosis

Diagnosis of calciphylaxis can usually be made based on the patient's clinical condition. For example, calciphylaxis should be suspected for a woman with a history of renal failure secondary to diabetes mellitus who develops necrotic plaques and ulcers. A laboratory evaluation that shows the presence of elevated calcium and/or phosphate level, or an elevated calcium-phosphate product, an elevated intact parathyroid hormone level, radiographic evidence, and confirmatory histology would substantiate the diagnosis of calciphylaxis.4,6,8-10

In patients with calciphylaxis, calcium deposits outline the vessels and radiographic findings show pipestem calcifications (Figure 4).4 Even with treatment, which may be successful in reducing the calcium-phosphate product, there is typically little or no improvement in the radiographic findings of excessive calcification.

Incisional biopsies of the lesions are recommended to obtain an adequate sample of the epidermis, dermis, and subcutaneous tissue.8 Calcification of the intima and media of small and medium-- sized vessels in the dennis and subcutaneous tissue are characteristic of calciphylaxis.4 Septal fat necrosis, lymphohistiocytic infiltrate, thrombosed vessels, giant cells, and minimal inflammation are also seen in this condition.9,10 Small vessel calcification and recanalization of thrombosed vessels are highly suggestive of calciphylaxis.4