Ecchymoses and eschars at sites of injection
Authors: Deborah Pan, Karl Hsu, Stuart C Ray
Journal: The Lancet (1997)

A 54-year-old woman who had had diabetes mellitus for 30 years, complicated by end-stage renal disease and diabetic retinopathy, was admitted to Johns Hopkins Hospital in September, 1995, because of painful lesions on the fronts of her thighs and sides of her buttocks. She began haemodialysis in May, 1995, and 2 months later developed blue, ecchymotic patches on her thighs at the sites of injections of erythropoietin. These patches developed into extensive, painful, black eschars. Her lesions continued to progress despite a course of prednisone for what was presumed to be vasculitis. She had black, necrotic, indurated plaques measuring about 15 cm by 15 cm, over the left and right thighs and buttocks (figure). These areas were exquisitely tender and a malodorous yellowish exudate suggested the presence of infection. Investigation at a previous hospital included testing for antineutrophil cytoplasmic antibodies, antinuclear antibodies, anticardiolipin antibodies, cryoglobulins, and HIV-1 serology which were all negative. On admission to Johns Hopkins Hospital, her laboratory values included: serum calcium 1·82 mmol/L, phosphorus 2·51 mmol/L, alkaline phosphatase of 234 IU/L, and parathyroid hormone of 154 ng/L (intact by immunochemiluminometric assay, normal range 10-65 ng/L). Investigation for a coagulopathy secondary to protein C or protein S deficiency revealed no abnormality. A biopsy specimen of affected skin and fascia showed many vessels within the subcutaneous tissue lobules and septae. There was intravascular thrombosis with neutrophils and some vessels had intramural neutrophil infiltration. Several of the septal vessels had calcification within their walls. Cessation of prednisone, local wound care, and antibiotics resulted in clinical improvement of infection with a decrease in white blood cell count. Since her parathyroid hormone concentration was only slightly elevated, it was felt that parathyroidectomy would not be helpful. She died 5 months later from sepsis, presumably ascribable to her extensive skin lesions. Calciphylaxis, or ischaemic tissue necrosis, was first described by Selye who exposed rats to challenging agents resulting in extensive calcium deposition and dry necrosis.1Selye H Calciphylaxis. The University of Chicago Press, Chicago1962Google Scholar Though this devastating process is rare in human beings, it is more commonly seen in patients with end-stage renal disease on dialysis.2Gipstein RM Coburn JW Adams DA et al.Calciphylaxis in man. A syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure.Arch Intern Med. 1976; 136: 1273-1280Crossref PubMed Scopus (9) Google Scholar Given the rising prevalence of end-stage renal disease, an increase in the incidence of calciphylaxis may be anticipated. Mortality is high, usually secondary to infection and sepsis. The aetiology and pathogenesis are not well understood, but risk factors are thought to include elevated calcium-phosphate product, hyperparathyroidism, trauma, corticosteroids, and immunosuppressive agents. A hypercoagulable state with reduced protein C and protein S activity has also been reported.3Mehta RL Scott G Sloand JA Francis CW Skin necrosis associated with acquired protein C deficiency in patients with renal failure and calciphylaxis.Am J Med. 1990; 88: 252-257Summary Full Text PDF PubMed Scopus (197) Google Scholar In this patient, subcutaneous erythropoietin injections may have triggered calciphylaxis by causing local trauma, seen in many reported cases.4Ruggian JC Maesaka JK Fishbane S Proximal calciphylaxis in four insulin-requiring diabetic hemodialysis patients.Am J Kidney Dis. 1996; 28: 409-414Summary Full Text PDF PubMed Scopus (55) Google Scholar Easily mistaken for vasculitis, the differential diagnosis for calciphylaxis includes polyarteritis nodosa, systemic lupus erythematosus, mixed connective tissue disease, systemic sclerosis, Henoch-Schönlein purpura, metastatic calcification, pancreatic panniculitis, Weber-Christian syndrome, and progressive acral gangrene.4Ruggian JC Maesaka JK Fishbane S Proximal calciphylaxis in four insulin-requiring diabetic hemodialysis patients.Am J Kidney Dis. 1996; 28: 409-414Summary Full Text PDF PubMed Scopus (55) Google Scholar Taking a biopsy specimen helps with the diagnosis, because there are pathological changes which resemble warfarin skin necrosis.3Mehta RL Scott G Sloand JA Francis CW Skin necrosis associated with acquired protein C deficiency in patients with renal failure and calciphylaxis.Am J Med. 1990; 88: 252-257Summary Full Text PDF PubMed Scopus (197) Google Scholar Treatment consists of local wound care and surveillance for infection. Parathyroidectomy is controversial and is warranted only if patients have severe hyperparathyroidism. Lowering of the calcium-phosphate product with phosphate binders may also be beneficial.2Gipstein RM Coburn JW Adams DA et al.Calciphylaxis in man. A syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure.Arch Intern Med. 1976; 136: 1273-1280Crossref PubMed Scopus (9) Google Scholar Patients who undergo early treatment tend to have better outcomes.5Roe SM Graham LD Brock WB Barker DE Calciphylaxis: early recognition and management.Am Surg. 1994; 60: 81-86PubMed Google Scholar Unlike the treatment for vasculitis, corticosteroids may both exacerbate calciphylaxis and mask infection. We thank David Hellman for guidance and assistance.