Calcinosis cutis

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

Because a secondary infection may have adverse consequences for a patient with calciphylaxis, treatment of infected ulcers is critical. Swab and tissue cultures from the wound may aid in guiding antibiotic therapy.9

Treatment

The treatments used to manage patients with calciphylaxis can be divided into medical and surgical therapies (Table 4).2,3,6,8-- 10,12 Often, these therapies are used in tandem. Medical therapies consist of phosphate binders, low-phosphate diet, reduced calcium in the dialysate (for patients undergoing dialysis), antibiotics for secondary infection, and diphosphonates.2,3,8,9 Diphosphonates may be used with patients at risk for calciphylaxis and have been shown to reduce its incidence.8 In addition, avoidance of challenging agents is important to reduce the incidence of calciphylaxis.

Hyperbaric oxygen and cimetidine have been used in certain cases with good results. Anticoagulation has been helpful in patients with protein C and protein S deficiencies.6 Use of cyclosporine to reduce the hypersensitivity reaction and stanozolol to aid in blood flow through its fibrinolytic properties have also been attempted to manage this condition; both therapies warrant further evaluation.

Surgical treatments include wound debridement, amputation, renal transplantation, and parathyroidectomy.2,3,8,12 In certain studies, parathyroidectomy has been shown to increase survival, as well as to relieve pain and to heal ulcers.3,11 Indications for this procedure include painful lesions, refractory severe hyperparathyroidism, and an elevated calcium-phosphate product.3 Subsequent to debridement, grafting with autologous skin and tissue-engineered skin have both been used to speed wound closure.

Calciphylaxis is an uncommon condition, most often seen in patients with end-stage renal disease undergoing dialysis. It represents a hypersensitivity reaction in sensitized patients leading to widespread calcification. Treatment is difficult and, as a result, calciphylaxis is associated with a high mortality rate.

References

1. Smiley CM, Hanlon SU, Michel DM. Calciphylaxis in moderate renal insufficiency: changing disease concepts. Am J Nephrol 2000;20:324-8.

2. Roe SM, Graham LD, Brock BB, Barker DE. Calciphylaxis: early recognition and management. Am Surg 1994;60:81-6.

3. Kang AS, McCarthy JT, Rowland C, Farley DR, van Heerden JA. Is calciphylaxis best treated surgically or medically? Surgery 2000;128:967-72.

4. Budisavjevic MN, Cheek D, Ploth DW. Calciphylaxis in chronic renal failure. J Am Soc Nephrol 1996;7:978-82.

5. Kent RB, Lyerly FIT. Systemic calciphylaxis. South Med J 1994;87:278-81.

6. Goyal S, Huhn KM, Provost TT. Calciphylaxis in a patient without renal failure or elevated parathyroid hormone: possible aetiologic role of chemotherapy. Br J Dermatol 2000;143:1087-90.

7. Goldsmith DJ. Diabetes, tissue infarction and calciphylaxis. Am J Med 1997;102:171-2.

8. Gilson RT, Milum E. Calciphylaxis: case report and treatment review. Cutis 1999;63:149-53.

9. Oh DH, Eulau D, Tokugawa DA, McGuire JS, Kohler S. Five cases of calciphylaxis and a review of the literature. J Am Acad Dermatol 1999;40:979-87.

10. Fischer AH, Morris DJ. Pathogenesis of calciphylaxis: study of three cases with literature review. Hum Pathol 1995;26:1055-64.

11. Hafner J, Keusch G, Wahl C, et al. Uremic small-artery disease with medical calcification and intimal hyperplasia (so-called calciphylaxis): a complication of chronic renal failure and benefit from parathyroidectomy. J Am Acad Dermatol 1995;33:954-62.

12. Fader DJ, Kang S. Calciphylaxis without renal failure. Arch Dermatol 1996;132:837-8.

Jennifer T. Trent, MD, is a Research Associate in the Department of Dermatology and Cutaneous Surgery at the University of Miami School of Medicine, Miami, FL. Robert S. Kirsner, MD, is an Associate Professor in the Department of Dermatology and Cutaneous Surgery and in the Department of Epidemiology and Public Health at the University of Miami School of Medicine.

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