Case Letter

An Unusual Presentation of Calciphylaxis

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Practice Points

  • Calciphylaxis is a rare microvascular occlusion syndrome characterized by cutaneous ischemia and necrosis secondary to calcification.
  • Clinically, lesions present with severely painful, violaceous, retiform patches and plaques, and less commonly bullae that progress to necrotic ulcers on the buttocks, legs, or abdomen, which is most often associated with end-stage renal disease and hyperparathyroidism.
  • The diagnosis is made through deep wedge or excisional biopsy and shows calcification of medium-sized vessels in the deep dermis and subcutaneous fat. Treatment requires a multidisciplinary approach, but morbidity and mortality remain high.


 

References

To the Editor:

Calciphylaxis (also known as calcific uremic arteriolopathy and calcifying panniculitis) is a rare vasculopathy affecting the small vessels.1 It is characterized by cutaneous ischemia and necrosis secondary to calcification. It is most commonly seen in patients with end-stage renal disease (ESRD) and hyperparathyroidism.1-3 Histopathologic features that are consistent with the diagnosis of calciphylaxis include calcification of medium-sized vessels in the deep dermis or subcutaneous fat as well as smaller distal vessels that supply the papillary dermis and epidermis.4,5 Although it commonly presents as well-demarcated, painful, purplish lesions that evolve into necrotic eschars, calciphylaxis rarely can present with hemorrhagic or serous bullous lesions followed by ulceration, as was seen in our patient.1,5,6 We report this uncommon presentation to highlight the variety in clinical appearance of calciphylaxis and the importance of early diagnosis.

A 43-year-old woman presented to the emergency department for evaluation of chest and abdominal pain that began 1 day prior to presentation. She had a history of systemic lupus erythematosus and ESRD secondary to poststreptococcal glomerulonephritis and was currently on peritoneal dialysis. The patient was admitted for peritonitis and treated with broad-spectrum antibiotics. At the time of admission, the patient also was noted to have several painful bullae on the legs. Her medical history also was remarkable for cerebral infarction, fibromyalgia, cerebral artery occlusion with cerebral infarction, sciatica, hyperlipidemia, deep vein thrombosis, and seizures. She had no history of herpes simplex virus. Surgical history was remarkable for tubal ligation, nephrectomy and kidney transplant, parathyroidectomy, and cholecystectomy. The patient’s medications included sevelamer carbonate, prednisone, epogen, calcium carbonate, esomeprazole, ondansetron, topical gentamicin, and atorvastatin.

Skin examination was performed by the inpatient dermatology service and revealed several tense, 1- to 5-cm, nonhemorrhagic bullae on the thighs and lower legs, some that had ruptured. The lesions were notably tender to palpation. No surrounding erythema, ecchymosis, or warmth was appreciated. The Nikolsky sign was negative. The patient also was noted to have at least grade 2 to 3+ pitting edema of the bilateral legs. The oral and conjunctival mucosae were unremarkable.

Antinuclear antibody, double-stranded DNA, and anti-Smith antibody levels were negative. A punch biopsy of the left lateral thigh revealed intraepidermal vesicular dermatitis with dermal edema suggestive of edema bullae and direct immunofluorescence was negative for immune complex and complement deposition.

Conservative therapy with wound care was recommended. The patient continued to report persistent severe skin pain and developed a subcutaneous nodule on the right inner thigh 1 week later, prompting a second biopsy. Results of the excisional biopsy were nondiagnostic but were suggestive of calciphylaxis, revealing subepidermal bullae with epidermal necrosis, a scant perivascular lymphocytic infiltrate, and extravasated erythrocytes. No evidence of calcification was seen within the vessels. The patient was then started on sodium thiosulfate with hemodialysis for treatment of presumed calciphylaxis.

Despite meticulous wound care and treatment with sodium thiosulfate, the patient developed ulcerations with necrotic eschars on the bilateral buttocks, hips, and thighs 1 month later (Figure 1). She subsequently worsened over the next few weeks. She developed sepsis and was transferred to the intensive care unit. A third biopsy was performed, finally confirming the diagnosis of calciphylaxis. Histopathology revealed small blood vessels with basophilic granular deposits in the walls consistent with calcium in the subcutaneous tissue (highlighted with the von Kossa stain), as well as thrombi in the lumens of some vessels; early fat necrosis; focal epidermal necrosis with underlying congested blood vessels with deposits in their walls; a perivascular infiltrate predominately of lymphocytes and neutrophils with scattered nuclear dust; and thick, hyalinized, closely crowded collagen bundles in the reticular dermis and in a widened subcutaneous septum (Figures 2 and 3).

Figure 1. A and B, Rupture of nonhemorrhagic bullae on the left leg that evolved into ulcerations and necrotic eschars with surrounding purpura.


Figure 2. A–C, A biopsy from the left lateral thigh revealed focal epidermal necrosis with underlying congested blood vessels with fibrin and basophilic granular deposits in the walls. Some of the vessels had thrombi in the lumens. There was a perivascular infiltrate predominantly of lymphocytes and neutrophils with scattered nuclear dust. There was early fat necrosis. In the reticular dermis and in the widened subcutaneous septum, there were thick, hyalinized, closely crowded collagen bundles (H&E; original magnifications ×4, ×10, and ×40, respectively).

Figure 3. Calcium deposits were highlighted in the vessel walls (von Kossa, original magnification ×40).

Supportive care and pain control were continued, but the overall prognosis was determined to be very poor, and the patient eventually was discharged to hospice and died.

Calciphylaxis: Diagnostic and Treatment Pearls

Although calciphylaxis is commonly seen in patients with ESRD and hyperparathyroidism, patients without renal disease also may develop the condition.2,3 Prior epidemiologic studies have shown a prevalence of 1% in patients with chronic kidney disease and up to 4% in those receiving dialysis.2-5 The average age at presentation is 48 years.6,7 Although calciphylaxis has been noted to affect males and females equally, some studies have suggested a female predominance.5-8

The etiology of calciphylaxis is unknown, but ESRD requiring dialysis, primary or secondary hyperparathyroidism, obesity, diabetes mellitus, skin trauma, and/or a hypercoagulable state may put patients at increased risk for developing this disease.2,3 Other risk factors include systemic corticosteroids, liver disease, increased serum aluminum, and increased erythrocyte sedimentation rate. Although high calcium-phosphate product has been noted as a risk factor in prior studies, one retrospective study found that it does not reliably confirm or exclude a diagnosis of calciphylaxis.8

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