Life-threatening necrosis

An elderly man presents with a non-healing leg ulcer.

CASE STUDY

AN 88-year-old man presents with a two-month history of a non-healing ulcer on his right lower limb.

The lesions started insidiously as multiple red nodules that progressively became ulcerated and painful.

The patient has hypertension and is on warfarin due to his atrial fibrillation.

On examination, he is found to have extensive necrotic ulceration of his shin, covered by black haemorrhagic crust (Figure 1).

Figure 1: Extensive necrotic ulceration of the shin, covered by black haemorrhagic crust.

Laboratory findings demonstrated mildly elevated parathyroid hormone and calcium levels, ALP and inflammatory markers.

His renal function tests showed moderate impairment, and a vasculitic screen was negative.

Subsequent 3 mm punch biopsy of the necrotic lesion demonstrated “benign ulceration”, and an arteriogram of the right lower limb showed calcification of the profunda femoris and superficial femoral arteries.

A provisional diagnosis of calciphylaxis was made.

CALCIPHYLAXIS

Calciphylaxis is a relatively poorly understood syndrome of vascular calcification and skin necrosis.

It is a life-threatening disorder most commonly found in patients with chronic renal disease and secondary hyperpara­thyroidism, who are on haemodialysis or who have received a renal transplant.

Calciphylaxis affects 1%-4% of patients with end-stage renal disease (ESRD), and is thought to be exceedingly rare in the general population.

Mortality rates as high as 60%-80% have been described, with sepsis secondary to infected skin lesions the leading cause of death.

The pathogenesis of calciphylaxis remains elusive, but is likely due to the interplay of various co-morbid factors or events that lead to vascular calcification, in a setting predisposing to thrombosis.

Many molecular and cytochemical factors have been shown to influence the regulation of calcium mineralisation, and recent studies support the idea that the final common endpoint involves the receptor activator of nuclear factor -kB (RANK).

The specific factors that induce calciphylaxis in an individual patient, however, are not known.

Although most commonly seen in ESRD, calciphylaxis can also occur in association with other disease entities, such as diabetes mellitus, obesity, malnutrition, alcoholic liver disease, primary hyperparathyroidism, malignancy and connective tissue disease.

CLINICAL FEATURES

The early lesions of calciphylaxis typically develop suddenly and are intensely painful. They are characterised by non-specific mottling or livedo reticularis, in addition to violaceous, painful subcutaneous purpuric plaques and nodules.

These lesions then rapidly progress to necrotic ulcers with eschars that often become super-infected.

Calciphylactic lesions most often manifest on the lower limbs, or areas of adiposity, such as the trunk and buttocks, and may be singular or multiple.

An intact peripheral pulse helps to distinguish acral calciphylaxis from peripheral vascular disease.

DIFFERENTIAL DIAGNOSIS

The clinical presentation of calciphylaxis is similar to many other disorders, which can confound its diagnosis.

These include atherosclerotic peripheral vascular disease, cholesterol embolisation, warfarin necrosis, cellulitis, vasculitis and cryoglobulinaemia.

DIAGNOSIS

Calciphylaxis should be suspected in patients with ESRD and painful, non-ulcerating subcutaneous nodules, non-healing painful ulcers, or areas of skin necrosis.

There are no specific laboratory findings.

Elevated levels of PTH, phosphorous, calcium and the calcium-phosphorous product may be observed, but are not always present.

Plain x-rays often demonstrate calcification within the dermis and subcutaneous tissue, although this is a common finding in ESRD and not specific to calciphylaxis.

Bone scintigraphy may be utilised to demonstrate calciphylactic lesions, as well as to monitor the progression of disease.

Punch biopsies are usually inadequate, although an incisional biopsy with ample subcutaneous tissue can be diagnostic.

Histopathology will reveal arterial occlusion and calcification, with the most common finding in both early and late stage disease being calcifying septal panniculitis.

Calcification within the media of small- and medium-sized arterioles with microthrombi and necrosis of subcutaneous fat may be observed.

MANAGEMENT

Treatment should include aggressive wound management, judicious use of antibiotics and adequate analgesia. Any conditions of hypercoagulability should be sought and addressed.

Underlying abnormalities in serum concentration of calcium or phosphorus need to be corrected. This can be achieved with the use of non-calcium containing phosphate binders, such as sevelamer.

Calcimimetics, such as cinacalcet, may be beneficial in cases with hyperpara­thyroidism. Some benefit may be attained by increasing the frequency or duration of dialysis sessions.

Recent reports have demonstrated marked improvement in calciphylaxis with the use of intravenous sodium thiosulphate. This potent antioxidant also increases the solubility of calcium deposits.

For patients with refractory hyperparathyroidism, where conservative management has failed, parathyroidectomy should also be considered.

PROGNOSIS

Calciphylaxis is a lethal disease that is associated with a high morbidity and mortality.

The response to any therapeutic regimen is poor, with sepsis and organ failure being common complications.

Currently, the optimal management includes maintaining a high index of suspicion for those patients who are at risk, in order to prevent its development.

Senior author: Professor Dedee F Murrell, MA (Cambridge), BMBCh (Oxford), FAAD (USA), MD (UNSW), Head, Department of Dermatology, St George Hospital; Conjoint Professor, University of New South Wales, Sydney.
Co-author: Dr Laura Baillie, BSc, MBBS (UQ), Resident Medical Officer, Royal Brisbane and Women’s Hospital.

References

1. Arseculeratne G, Evans AT, Morley SM. Calciphylaxis – A Topical Overview. J Eur Acad Dermatol Venereol 2006;20:493-502 
2. Kalajian AH et al. Calciphylaxis With Normal Renal and Parathyroid Function. Arch Dermatol 2009;145(4):451-58
3. Weenig RH. Pathogenesis of Calciphylaxis: Hans Selye to Nuclear Factor k-B. J Am Acad Dermatol 2008; 58(3): 458-71