Case Letter

An Unusual Presentation of Calciphylaxis

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The pathogenesis of calciphylaxis is not well understood; however, some researchers suggest that an imbalance in calcium-phosphate homeostasis may lead to calciphylaxis; that is, elevated calcium and phosphate levels exceed their solubility and deposit in the walls of small- and medium-sized arteries, which consequently leads to ischemic necrosis and gangrene of the surrounding tissue.9

Clinically, calciphylaxis has an indolent onset and usually presents as well-demarcated, painful, purplish, mottled lesions that evolve into necrotic gray-black eschars and gangrene in adjacent tissues.1,5,6 The ischemic process may even extend to the muscle layer.5 Other common presentations include mild erythematous patches; livedo reticularis; painful nodules; necrotic ulcerating lesions; and more rarely flaccid, hemorrhagic, or serous bullous lesions followed by ulceration, as was seen in our patient.6,9,10 Lesions usually begin at sites of trauma and seem to be distributed symmetrically.5,6 The most commonly affected locations are the legs, specifically the medial thighs, as well as the abdomen and buttocks, but lesions also can be found at more distal sites such as the breasts, tongue, vulva, penis, fingers, and toes.5,6,10 The head and neck region rarely is affected. Although uncommon, calciphylaxis may affect other organs, including the lungs, stomach, kidneys, and adrenal glands.5 The accompanying systemic symptoms and findings may include muscle weakness, tenderness, or myositis with rhabdomyolysis; calcific cerebral embolism; dementia and infarction of the central nervous system; acute respiratory failure; heart disease; atrioventricular block; and calcification of the cardiac conduction system.6 Unlike other forms of peripheral vascular disease, distal pulses are present in calciphylaxis, as blood flow usually is preserved distal and deep to the areas of necrosis.5,6

A careful history and thorough physical examination are important first steps in the diagnosis of this condition.2,10 Although there are no definitive laboratory tests, elevated serum calcium, phosphorous, and calcium-phosphate product levels, as well as parathyroid hormone level, may be suggestive of calciphylaxis.2,5 Leukocytosis may occur if an infection is present.5

The most accurate method to confirm the diagnosis is a deep incisional biopsy from an erythematous, slightly purpuric area adjacent to the necrotic lesion.2,10,11 The histopathologic features used to make the diagnosis include calcification of medium-sized vessels, particularly the intimal or medial layers, in the deep dermis and subcutaneous fat in addition to lobular capillaries of the subcutaneous fat.5,10 These vessels, including the smaller distal vessels that supply the papillary dermis and epidermis, also may be thrombosed due to calcification, leading to vascular occlusion and subsequently ischemic necrosis of the overlying epidermis.10 Other findings may include pseudoxanthoma elasticum changes, panniculitis, and subcutaneous fat necrosis.4,10

The differential diagnosis for calciphylaxis includes peripheral vascular disease, vasculitis, juvenile dermatomyositis, proteins C and S deficiencies, cryofibrinogenemia, calcinosis cutis, and tumoral calcinosis.2 Polyarteritis nodosa, Sjögren syndrome, atherosclerotic peripheral vascular disease, pyoderma gangrenosum, systemic lupus erythematosus, necrotizing fasciitis, septic embolism, and necrosis secondary to warfarin and heparin may mimic calciphylaxis.5

Treatment of calciphylaxis is multidimensional but primarily is supportive.6,11 Controlling calcium and phosphate levels and secondary hyperparathyroidism through diet and phosphate binders (eg, sevelamer hydrochloride) has been shown to be effective.6 Pamidronate, a bisphosphonate, inhibits arterial calcification in animal models and has been reported to treat calciphylaxis, resulting in marked pain reduction and ulcer healing.4,6 Cinacalcet, which functions as a calcimimetic, has been implicated in the treatment of calciphylaxis. It has been used to treat primary and secondary hyperparathyroidism and to normalize serum calcium levels; it also may be used as an alternative to parathyroidectomy.4,6 Intravenous administration of sodium thiosulfate, a potent antioxidant and chelator of calcium, has been helpful in reversing signs and symptoms of calciphylaxis.6,12 It also has been shown to effectively remove extra calcium during peritoneal dialysis.6 Parathyroidectomy has been useful in patients with markedly elevated parathyroid hormone levels, as it suppresses or eliminates the sensitizing agent causing hypercalcemia, elevated calcium-phosphate product, and hyperparathyroidism.1,2,6,13

Wound care and prevention of sepsis are essential in the treatment of calciphylaxis. Management options include surgical debridement, hydrocolloid and biologic dressings, skin grafts, systemic antibiotics, oral pentoxifylline combined with maggot therapy, nutritional support, hyperbaric oxygen therapy, and revascularization and amputation when other interventions have failed. Pain control with analgesics and correction of thrombosis in the skin and blood vessels via anticoagulation therapy also are important complementary treatments.6

The clinical outcome of calciphylaxis is dependent on early diagnosis, antimicrobial therapy, and wound management,9 but overall, the prognosis usually is poor and has a high mortality rate. The most common causes of death are infection and sepsis.1,9 A study of 7 cases reported 100% mortality,14 but other studies have suggested a mortality rate of 60% to 80%.4,10 Female sex and obesity are poor prognostic indicators.2 A better prognosis has been appreciated in cases in which lesions occur at distal sites (eg, lower legs, hands) compared to more proximal sites (eg, abdomen), where 25% and 75% mortalities have been noted, respectively.10,14,15 In one study, the overall mortality rate was 45% in patients with calciphylaxis at 1 year.6 The rate was 41% in patients with plaques only and 67% in those who presented with ulceration. Patients who survive often experience a high degree of morbidity and prolonged hospitalization; these patients often are severely debilitated, especially in the case of limb amputation.6

Our report of calciphylaxis demonstrates the diversity in clinical presentation and emphasizes the importance of early and accurate diagnosis in reducing morbidity and mortality. In our case, the patient presented with skin pain and tense nonhemorrhagic bullae without underlying ecchymotic or erythematous lesions as the earliest sign of calciphylaxis. Physicians should have a high degree of suspicion in the setting of dialysis-dependent ESRD patients with bullae, extreme pain, and continuous decline. We hope that this case will help increase awareness of the varying presentations of this condition.

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