Postgrad Med J 2001;77:557–561 557 Postgrad Med J: first published as 10.1136/pmj.77.911.557 on 1 September 2001. Downloaded from REVIEWS Calciphylaxis R V Mathur, J R Shortland, A M El Nahas Abstract phosphate diet act as sensitising agents result- The phenomenon of calciphylaxis is rare, ing in a high calcium-phosphate product (Ca × but potentially fatal. It has been recog- P; normal range 4.2–5.6 mmol2/l2) with result- nised for a long time in patients with ant precipitation of Ca-P crystals.14 This results chronic renal failure with secondary hy- in diVuse calcification of the media and perparathyroidism. Disturbed calcium internal elastic lamina of small to medium and phosphate metabolism can result in sized arteries and arterioles with intimal prolif- painful necrosis of skin, subcutaneous tis- eration and rarely arterial occlusion causing sue and acral gangrene. Appearance of the tissue necrosis. This entity was given the term lesions is distinctive but the pathogenesis calcinosis cutis to signify vascular calcification remains uncertain. The beneficial eVects with ischaemic epidermolysis as seen in of parathyroidectomy are controversial. patients with chronic renal failure on However, correction of hyperphosphatae- haemodialysis.15–17 Other triggering events in- mia or occasionally hypercalcaemia is clude intravenous iron dextran and albumin imperative. Fulminant sepsis as a conse- infusion, low serum albumin, corticosteroids, quence of secondary infection of necrotic immunosuppression, trauma, subcutaneous in- and gangrenous tissue is a frequent cause jections in obese patients, and protein C and S of patient morbidity and mortality. deficiencies causing hypercoagulability and 8 12 16 18–25 (Postgrad Med J 2001;77:557–561) subsequent thrombosis. Obesity has recently been established as a risk factor Keywords: calciphylaxis; calcium-phosphate product; primarily due to large deposits of adipose tissue secondary hyperparathyroidism; chronic renal failure that may be associated with reduction of local blood flow.918232526 Diabetics with chronic renal failure are especially prone to develop The syndrome of calciphylaxis is ischaemic acral necrosis partly due to extensive vascular ulceration of skin due to metastatic calcification calcifications.10 Deposition of Ca-P crystals in of subcutaneous tissue and small arteries occur- the interstitium and connective tissue of ring as a consequence of hyperparathyroidism in various organs is designated as systemic uraemic patients (box 1). Bryant and White first calcinosis or metastatic calcifica- http://pmj.bmj.com/ recorded the occurrence of calciphylaxis in tion.4510151618192728 In spite of the high uraemia in 1898 in Guy’s Hospital Reports. Selye incidence of vascular calcification reported in in 1962 coined the term calciphylaxis for acute haemodialysis patients and renal transplant local calcification of various organs and equated recipients, the incidence of tissue necrosis with this to a hypersensitivity reaction. This is 72930 vascular calcification is rare. Levin et al inappropriate, as there is no relation to IgE type have estimated the incidence as approximately 1 mediated allergy. He induced extensive soft one case per hundred haemodialysis patients on September 28, 2021 by guest. Protected copyright. tissue calcification in rats that were previously per year and have suggested a mathematical sensitised by high doses of vitamin D analogues formula (2× [Ca × P−5]×alkaline phosphatase or parathyroid hormone, by local injection of (IU) × parathyroid hormone ratio) to assess the 1–10 irritants designated as challengers. These risk of developing calciphylaxis.31 Gipstein et al experimental conditions were not comparable Northern General are credited for the first compiled series of 11 Hospital, SheYeld, with the clinical situations in the context of the patients with calciphylaxis in 1976.1 An exten- UK: SheYeld Kidney absence of uraemic milieu and ischaemic necro- sive review by Hafner et al found that a total of Institute sis from medial calcification and intimal hyper- 155 cases have been reported from 1936 to R V Mathur plasia of small arteries. Hence the suitability of 1996, including nine of their own.510 Other A M El Nahas 4 5 10–12 the term was doubtful. However, the term sporadic case reports have appeared in the Department of calcinosis fails to distinguish secondary calcifica- literature since then probably owing to a Pathology tion in a necrotic tissue from ischaemic tissue greater awareness of the condition.32–39 Docu- J R Shortland necrosis due to arterial calcification.12 Hafner et mented listing of cases of calciphylaxis in al in 1995 termed this phenomenon as uraemic humans obtained from web site http:// Correspondence to: Dr Rashmi V Mathur, Renal small artery disease to characterise skin necrosis www.ncbi.nlm.nih.gov/PubMed on 4 July Academic OYce, Seminar and acral gangrene consequent to medial calcifi- 2000 has increased to 377 compared with 285 Room 4, Vickers Corridor, cation and intimal hyperplasia in arteries of sub- on 1 July 1999. This database also includes 61 Northern General Hospital, 510 Herries Road, SheYeld cutaneous tissue and those of hands and feet. cases of ocular calciphylaxis in haemodialysis S5 7AU, UK patients and 30 cases of tracheopathia [email protected] Pathogenic factors chondro-osteoplastica—a condition indistin- 13 Submitted 24 July 2000 Pathogenesis remains speculative. Chronic guishable from calciphylaxis because of accu- Accepted 2 October 2000 renal failure, hyperparathyroidism, and a high mulation of calcium salts in the tracheal www.postgradmedj.com 558 Mathur, Shortland, El Nahas Postgrad Med J: first published as 10.1136/pmj.77.911.557 on 1 September 2001. Downloaded from Box 1: Calciphylaxis Box 2: Presentation x Painful necrosis of skin, subcutaneous tis- x Lesions begin as painful, symmetrical, sue and acral gangrene. violaceous discolouration. x Hyperphosphataemia and raised x Lesions evolve into well demarcated, calcium-phosphate product consequent non-healing ulcers that become necrotic to secondary hyperparathyroidism is an and gangrenous. important predisposing factor. x Lesions may have proximal or distal localisation. x Proximal lesions have poorer prognosis. mucosa with no abnormality of calcium and phosphate metabolism. A large number of ani- mal studies and non-syndrome patients have localisation died compared with eight of 25 also been cited.9 Angelis et al have reported a with distal localisation.8 These findings were prevalence of 4.1% in their haemodialysis consistent with Hafner et al’s review. Thirty patients.40 eight of 60 (63%) patients with proximal lesions died as compared with 15/65 (23%) Clinical features with distal localisation or acral gangrene.510 The lesions begin as painful, symmetrical, vio- Duh et al reported that less than 1% of laceous discolouration and evolve into well patients with digital gangrene have calciphy- demarcated non-healing ulcers that become laxis.7 However, it should be suspected in necrotic and gangrenous (fig 1A and B). The patients of uraemia with painful digital gan- lesions on the shoulders (fig 1C), trunk, grene. Calf pain and tenderness are a rare buttocks, and thighs are considered as proxi- presentation. mally localised and have a poorer prognosis On review of the literature no correlation essentially due to the larger bulk of necrotic could be established between age at onset and and infected tissue (fig 1D). Lesions with distal outcome of the disease. Age at onset ranges localisation may involve the calves, forearms, from 6 months to 83 years with a mean age of acral sites (hands, fingers, feet, and toes) and 48 ± 16 years.510 A female preponderance genitalia (box 2).41 42 Facial involvement as seen (61%) is noted due to the tendency to deposit in our patient has not been described so far. fat in subcutaneous sites.5910253343 White Chan et al, in their review of 47 cases, patients were found to be more predisposed to reported that 19 of 22 patients with proximal develop the condition,25 although a few case http://pmj.bmj.com/ on September 28, 2021 by guest. Protected copyright. Figure 1 (A) and (B) Lesions begin as violaceous discolouration and evolve into well demarcated non-healing ulcers. (C) Metastatic calcification presenting as a hard painful subcutaneous lump 4 × 3 cm on the left shoulder. (D) Proximally localised lesions on the right thigh that have become necrotic and gangrenous. www.postgradmedj.com Calciphylaxis 559 Postgrad Med J: first published as 10.1136/pmj.77.911.557 on 1 September 2001. Downloaded from Box 3: Biochemical abnormalities Box 4: Treatment x Hyperphosphataemia >1.7mmol/l (>5 x Essentially supportive involving mg/dl), raised in 68% of cases. multidisciplinary approach. x Ca×P >5.6–12 mmol2/l2 (>70 mg2/dl2), x Early supplementation of vitamin D raised in 33% of cases. analogues—less hypercalcaemic and less x Serum calcium: normal or mildly raised hyperphosphataemic. >2.6 mmol/l (>10.5 mg/dl) in 20% of x Early total parathyroidectomy with cases. autotransplantation (non-compliant x Serum parathyroid hormone: mild to patient) or subtotal parathyroidectomy. moderately raised, >2–3 × upper limit of x Low phosphate diet. normal, raised in 80% of patients. x Open therapy of wounds with judicious x Raised urea/creatinine. use of antibiotics. x Anaemia of chronic renal insuYciency. x Hyperbaric oxygen therapy as in the x Neutrophil leucocytosis due to wound treatment of problem wounds. sepsis. x Low molecular weight heparin—under x Mildly raised serum alkaline