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Calciphylaxis
  1. R V Mathura,
  2. J R Shortlandb,
  3. A M El Nahasa
  1. aNorthern General Hospital, Sheffield, UK: Sheffield Kidney Institute, bDepartment of Pathology
  1. Dr Rashmi V Mathur, Renal Academic Office, Seminar Room 4, Vickers Corridor, Northern General Hospital, Herries Road, Sheffield S5 7AU, UKdmathur{at}aol.com

Abstract

The phenomenon of calciphylaxis is rare, but potentially fatal. It has been recognised for a long time in patients with chronic renal failure with secondary hyperparathyroidism. Disturbed calcium and phosphate metabolism can result in painful necrosis of skin, subcutaneous tissue and acral gangrene. Appearance of the lesions is distinctive but the pathogenesis remains uncertain. The beneficial effects of parathyroidectomy are controversial. However, correction of hyperphosphataemia or occasionally hypercalcaemia is imperative. Fulminant sepsis as a consequence of secondary infection of necrotic and gangrenous tissue is a frequent cause of patient morbidity and mortality.

  • calciphylaxis
  • calcium-phosphate product
  • secondary hyperparathyroidism
  • chronic renal failure

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The syndrome of calciphylaxis is ischaemic ulceration of skin due to metastatic calcification of subcutaneous tissue and small arteries occurring as a consequence of hyperparathyroidism in uraemic patients (box 1). Bryant and White first recorded the occurrence of calciphylaxis in uraemia in 1898 in Guy's Hospital Reports. Selye in 1962 coined the term calciphylaxis for acute local calcification of various organs and equated this to a hypersensitivity reaction. This is inappropriate, as there is no relation to IgE type 1 mediated allergy. He induced extensive soft tissue calcification in rats that were previously sensitised by high doses of vitamin D analogues or parathyroid hormone, by local injection of irritants designated as challengers.1-10 These experimental conditions were not comparable with the clinical situations in the context of the absence of uraemic milieu and ischaemic necrosis from medial calcification and intimal hyperplasia of small arteries. Hence the suitability of the term was doubtful.4 5 10-12 However, the term calcinosis fails to distinguish secondary calcification in a necrotic tissue from ischaemic tissue necrosis due to arterial calcification.12Hafner et al in 1995 termed this phenomenon as uraemic small artery disease to characterise skin necrosis and acral gangrene consequent to medial calcification and intimal hyperplasia in arteries of subcutaneous tissue and those of hands and feet.5 10

Box 1: Calciphylaxis

  • Painful necrosis of skin, subcutaneous tissue and acral gangrene.

  • Hyperphosphataemia and raised calcium-phosphate product consequent to secondary hyperparathyroidism is an important predisposing factor.

Pathogenic factors

Pathogenesis remains speculative.13 Chronic renal failure, hyperparathyroidism, and a high phosphate diet act as sensitising agents resulting in a high calcium-phosphate product (Ca × P; normal range 4.2–5.6 mmol2/l2) with resultant precipitation of Ca-P crystals.14 This results in diffuse calcification of the media and internal elastic lamina of small to medium sized arteries and arterioles with intimal proliferation and rarely arterial occlusion causing tissue necrosis. This entity was given the term calcinosis cutis to signify vascular calcification with ischaemic epidermolysis as seen in patients with chronic renal failure on haemodialysis.15-17 Other triggering events include intravenous iron dextran and albumin infusion, low serum albumin, corticosteroids, immunosuppression, trauma, subcutaneous injections in obese patients, and protein C and S deficiencies causing hypercoagulability and subsequent thrombosis.8 12 16 18-25 Obesity has recently been established as a risk factor primarily due to large deposits of adipose tissue that may be associated with reduction of local blood flow.9 18 23 25 26 Diabetics with chronic renal failure are especially prone to develop acral necrosis partly due to extensive vascular calcifications.10 Deposition of Ca-P crystals in the interstitium and connective tissue of various organs is designated as systemic calcinosis or metastatic calcification.4 5 10 15 16 18 19 27 28 In spite of the high incidence of vascular calcification reported in haemodialysis patients and renal transplant recipients, the incidence of tissue necrosis with vascular calcification is rare.7 29 30Levin et al have estimated the incidence as approximately one case per hundred haemodialysis patients per year and have suggested a mathematical formula (2× [Ca × P − 5]× alkaline phosphatase (IU) × parathyroid hormone ratio) to assess the risk of developing calciphylaxis.31 Gipsteinet al are credited for the first compiled series of 11 patients with calciphylaxis in 1976.1 An extensive review by Hafner et al found that a total of 155 cases have been reported from 1936 to 1996, including nine of their own.5 10 Other sporadic case reports have appeared in the literature since then probably owing to a greater awareness of the condition.32-39 Documented listing of cases of calciphylaxis in humans obtained from web sitehttp://www.ncbi.nlm.nih.gov/PubMed on 4 July 2000 has increased to 377 compared with 285 on 1 July 1999. This database also includes 61 cases of ocular calciphylaxis in haemodialysis patients and 30 cases of tracheopathia chondro-osteoplastica—a condition indistinguishable from calciphylaxis because of accumulation of calcium salts in the tracheal mucosa with no abnormality of calcium and phosphate metabolism. A large number of animal studies and non-syndrome patients have also been cited.9 Angelis et al have reported a prevalence of 4.1% in their haemodialysis patients.40

Clinical features

The lesions begin as painful, symmetrical, violaceous discolouration and evolve into well demarcated non-healing ulcers that become necrotic and gangrenous (fig 1A and B). The lesions on the shoulders (fig 1C), trunk, buttocks, and thighs are considered as proximally localised and have a poorer prognosis essentially due to the larger bulk of necrotic and infected tissue (fig 1D). Lesions with distal localisation may involve the calves, forearms, acral sites (hands, fingers, feet, and toes) and genitalia (box 2).41 42 Facial involvement as seen in our patient has not been described so far.

Box 2: Presentation

  • Lesions begin as painful, symmetrical, violaceous discolouration.

  • Lesions evolve into well demarcated, non-healing ulcers that become necrotic and gangrenous.

  • Lesions may have proximal or distal localisation.

  • Proximal lesions have poorer prognosis.

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.

Chan et al, in their review of 47 cases, reported that 19 of 22 patients with proximal localisation died compared with eight of 25 with distal localisation.8 These findings were consistent with Hafner et al's review. Thirty eight of 60 (63%) patients with proximal lesions died as compared with 15/65 (23%) with distal localisation or acral gangrene.5 10

Duh et al reported that less than 1% of patients with digital gangrene have calciphylaxis.7However, it should be suspected in patients of uraemia with painful digital gangrene. Calf pain and tenderness are a rare presentation.

On review of the literature no correlation could be established between age at onset and outcome of the disease. Age at onset ranges from 6 months to 83 years with a mean age of 48 ± 16 years.5 10 A female preponderance (61%) is noted due to the tendency to deposit fat in subcutaneous sites.5 9 10 25 33 43 White patients were found to be more predisposed to develop the condition,25 although a few case reports of African-Americans have been published.18 26 The role of dialysis, kidney transplantation, and immunosuppression in the development of uraemic small artery disease remains speculative. There was, however, a positive correlation with the duration of azotaemia, which may alter the internal milieu to an extent to intensify vascular calcification. The presence of a proximal ulcer in the absence of neuropathy and peripheral vascular disease is evocative of calciphylaxis as arterial calcification is usually localised to the tunica media. Vascular insufficiency causing tissue necrosis may coexist due to fibrous obliteration of lumen in response to medial calcification.3 7 16 29 44

Diagnosis

The diagnosis of calciphylaxis requires a high index of suspicion in a uraemic patient who presents with characteristic lesions on a background of abnormal biochemistry. Hyperphosphataemia, raised Ca × P (>5.6–12 mmol2/l2), mild to moderately raised serum parathyroid hormone, and a normal or mild increase in serum calcium may frequently but not consistently be seen with this phenomenon (box 3). Roentgenography does not identify patients at risk for developing calciphylaxis, as vascular and soft tissue calcification without skin necrosis is a frequent observation in patients with chronic renal failure on renal replacement therapy. Xeroradiography is the best technique to study soft tissue calcifications.

Box 3: Biochemical abnormalities

  • Hyperphosphataemia >1.7mmol/l (>5 mg/dl), raised in 68% of cases.

  • Ca×P >5.6–12 mmol2/l2 (>70 mg2/dl2), raised in 33% of cases.

  • Serum calcium: normal or mildly raised >2.6 mmol/l (>10.5 mg/dl) in 20% of cases.

  • Serum parathyroid hormone: mild to moderately raised, >2–3 × upper limit of normal, raised in 80% of patients.

  • Raised urea/creatinine.

  • Anaemia of chronic renal insufficiency.

  • Neutrophil leucocytosis due to wound sepsis.

  • Mildly raised serum alkaline phosphatase due to hyperparathyroid bone disease.

Histopathology

Skin biopsy reveals extensive medial calcification of small to medium sized arteries/arterioles with intimal proliferation. The deposition of calcium is either segmental or circumferential and leads to atrophy of the smooth muscle fibres of the media. The arterial lumen is usually preserved (fig 2). These lesions have occasionally been designated as primary. Subcutaneous calcification with ischaemic epidermolysis manifesting as the initial clinical presentation constitutes secondary lesions.9 These lesions are specific but not pathognomonic of calciphylaxis.

Box 4: Treatment

  • Essentially supportive involving multidisciplinary approach.

  • Early supplementation of vitamin D analogues—less hypercalcaemic and less hyperphosphataemic.

  • Early total parathyroidectomy with autotransplantation (non-compliant patient) or subtotal parathyroidectomy.

  • Low phosphate diet.

  • Open therapy of wounds with judicious use of antibiotics.

  • Hyperbaric oxygen therapy as in the treatment of problem wounds.

  • Low molecular weight heparin—under evaluation.

Figure 2

Blood vessels within subcutaneous fat display medial calcification, which is circumferential in an arteriole. There is no significant intimal proliferation and both vessels are patent.

Differential diagnosis

These lesions have to be distinguished from dystrophic calcifications that occur in well defined sites with normal concentration of divalent ions, in an abnormal microenvironment of necrosis. Significant cutaneous calcification is occasionally seen in adult cases of dematomyositis but is not associated with necrosis.45 Negative serologies and the presence of vessel calcification can rule out a vasculitic skin rash. In pancreatic panniculitis necrosis is widespread and frequently pretibial with rapidly normalising serum amylase. Cutaneous infarcts of type 1 (monoclonal) cryoglobulinaemia can be ruled out by the absence of cryogobulin and those associated with disseminated intravascular coagulation are acute in onset with invariable multiorgan failure. Ischaemic changes due to cholesterol emboli manifest more often as livedo reticularis, but can also present as smaller areas of non-healing vascular ulcerations and gangrene of the feet or legs.7 18 33 43 45

Treatment

Therapeutic options are limited, unsatisfactory, and essentially supportive involving multidisciplinary teamwork (see box 4). Prophylaxis with rigorous control of uraemia and prevention of development of secondary hyperparathyroidism is important. To normalise Ca × P in dialysis patients, besides a low phosphate diet, the early supplementation of preferably less hypercalcaemic and less hyperphosphataemic vitamin D products (24,25 dihydroxy cholecalciferol, 22 oxacalcitriol, etc), or use of calcium free (and aluminium free) phosphate binders such as sevelamer hydrochloride (Renagel), should be aimed for.9 11 30 33 46

Local treatment of the ulcers is similar to open therapy for burns with judicious use of antibiotics. The role of wound debridement is controversial.4 7 11 18 30

Until now the effect from parathyroid surgery has been equivocal, although recent series have shown that parathyroidectomised patients have a better outcome with rapid wound healing and drastic reduction of Ca × P. Subtotal parathyroidectomy or total parathyroidectomy with autotransplantation are the preferred options.5 7 9 10 29 33 Survival benefit was statistically non-significant in parathyroidectomised individuals in one review.8 However, Hafner et al stated that 49/70 (70%) of patients who underwent parathyroidectomy survived, compared with 20/47 (43%) of those who did not have parathyroidectomy.5 10

Box 5: Key references

  • Hafner J, Keusch G, Wahl C, et al. Uremic small-artery disease with medial 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.

  • Janigan DT, Hirch DJ, Klassen GA, et al. Calcified subcutaneous arterioles with infarcts of the subcutis and skin (“calciphylaxis”) in chronic renal failure. Am J Kidney Dis 2000;35:588–97.

  • Duh QY, Lim RC, Clark OH. Calciphylaxis in secondary hyperparathyroidism. Diagnosis and parathyroidectomy. Arch Surg 1991;126:1213–19.

  • Llach F. Hyperphosphataemia in end-stage renal disease patients: pathophysiological consequences. Kidney Int 1999;56(suppl 73):S31–7.

  • Vassa N, Twardowski ZJ, Campbell J. Hyperbaric oxygen therapy in calciphylaxis-induced skin necrosis in a peritoneal dialysis patient. Am J Kidney Dis 1994;23:878–81.

Vassa et al recommended treatment of skin ulcers by hyperbaric oxygen therapy.47 They found that transcutaneous oxygen tension in tissues surrounding ulcer craters in calciphylaxis was low and speculated that hypoxic condition existed within the ulcers. Skin lesions healed after 38 treatments in patients who underwent hyperbaric oxygen therapy five times a week, breathing 100% of oxygen while exposed to external pressure of 2.4 A. This resulted in an oxygen pressure of 1000–1700 mm Hg at the wound site. To avoid oxygen toxicity three 30 minute, 100% oxygen inhalations were separated by 10 minute periods of breathing room air. Debridement of the ulcers and skin grafting continued during this period.

Questions (answer true or false; answers on next page)

(1)
Lesions of calciphylaxis usually present as:
  • Painful, symmetrical, well demarcated, non-healing ulcers.

  • Painless, asymmetrical, ill defined, granulating ulcers.

  • Livedo reticularis.

  • Hyperkeratotic papules.

  • Foot ulcers with callosities at the pressure points.

(2)
Calciphylaxis is more likely in the presence of:
  • Peripheral neuropathy.

  • Acute vascular obstructive disease.

  • Chronic degenerative vascular disease.

  • Microvascular calcification.

  • Coagulopathies.

(3)
Soft tissue calcification can be best studied by:
  • Roentgenography.

  • Skin biopsy.

  • Xeroradiography.

  • Fine needle aspiration cytology.

  • x Ray diffraction analysis

(4)
The phenomenon of calciphylaxis may be related to:
  • IgE mediated hypersensitivity reaction.

  • Immune complex mediated response.

  • Delayed hypersensitivity reaction.

  • Previous sensitisation with challengers like parathyroid hormone and vitamin D analogues.

  • Decreased transcutaneous oxygen tension at the site of the lesions.

(5)
Poor prognosis in calciphylaxis is associated with:
  • Uraemia.

  • Wound sepsis.

  • Hyperparathyroidism.

  • Proximal lesions.

  • Distal lesions.

The effect of subcutaneous fractionated heparin in combination with hyperbaric oxygen therapy is currently under study.20 24 48

Prognosis

The outcome of this disease is poor with a mortality of 60%–70%, mainly from uncontrolled sepsis from wound infection.49 Diagnosis is often delayed as the presentation may simulate more common conditions and be due to a lack of pathognomonic investigations. Patients with distal localisation have a better outcome. Parathyroidectomy, though debatable, when performed before the onset of sepsis may be a reasonable step towards preventing fatality.10 The role of hyperbaric oxygen therapy to correct hypoxia within ulcers and the use of subcutaneous fractionated heparin need further evaluation.

Acknowledgments

We are grateful to Dr Timothy Johnson for his assistance with the illustrations.

References

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Footnotes

  • Answers (true (T)/false (F)

  • (1) T, F, T, F, F; (2) F, F, T, T, F; (3) F, F, T, F, T; (4) F, F, F, T, T; (5) F, T, F, T, F.

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