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Calciphylaxis: emerging concept in vascular patients

European Journal of Dermatology. Volume 17, Number 1, 73-8, January-February 2007, Clinical report

DOI : 10.1684/ejd.2007.0191

Summary

Author(s) : BP Mwipatayi, C Cooke, RH Sinniah, M Abbas, D Angel, K Sieunarine , Department of Vascular Surgery, Royal Perth Hospital, Western Australia, 6000, Department of Pathology, Royal Perth Hospital, Western Australia, 6000.

Summary : Calciphylaxis is a small vessel vasculopathy with medial calcification associated with intimal proliferation, fibrosis and thrombosis. This study discusses the clinical features and treatment of calciphylaxis and assesses the prognosis of patients with calciphylaxis. All patients admitted to vascular or renal wards from January 2003 to December 2004 at Royal Perth Hospital, with diagnosis of calciphylaxis confirmed histologically were included in the study. Five patients were included in the study\; four male and one female. Three patients had end stage renal failure on haemodialysis and two had normal renal function. All three patients with end-stage renal failure had secondary hyperparathyroidism associated with elevated parathormone and corrected ionised calcium. The two patients with normal renal function had normal calcium, phosphate, and parathormone levels. The diagnosis of calciphylaxis was confirmed in all patients. The wounds of four patients healed and one patient died 8 months after the diagnosis of calciphylaxis had been made. Calciphylaxis is a condition mostly present in patients with end-stage renal failure and can occur in patients with normal renal function. It usually carries a poor prognosis, but in this small series the outcome of patients was good with satisfactory healing of wounds.

Keywords : ESRF, end-stage renal failure, PTH, parathormone, N, normal, IDDM, insulin-dependant diabetic mellitus, TIA, transient ischemic attack, IgE, immunoglobin E, CUA, Calcific Uremic Arterio

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ARTICLE

Auteur(s) : BP Mwipatayi¹, C Cooke¹, RH Sinniah², M Abbas¹, D Angel¹, K Sieunarine¹

¹Department of Vascular Surgery, Royal Perth Hospital, Western Australia, 6000
²Department of Pathology, Royal Perth Hospital, Western Australia, 6000

accepté le 7 Septembre 2006

Calciphylaxis is a small vessel vasculopathy involving mural calcification of arterioles with intimal proliferation, fibrosis and thrombosis [1, 2]. It causes a wide spectrum of end organ damage due to ischemia, most commonly manifesting as infarction and necrosis of the skin and underlying subcutaneous fat.There are a number of risk factors associated with the development of calciphylaxis. The typically afflicted patient is female, Caucasian and obese [1-3]. Diabetes mellitus and renal failure often coexist [3-6]. Calciphylaxis occurs predominantly in patients with end stage renal disease; with prevalence in the dialysis population estimated at 1-4% [1, 3] and often occurs within the first year of treatment initiation [4]. Biochemically, a raised calcium and phosphate level, parathormone (PTH) and protein C and S deficiency appear to predispose to development of the syndrome [1, 7, 8]. Warfarin use may also be a significant factor [1, 9].Mortality rates are high and significant morbidity results from pain and superimposed infection. However, the phenomenon is poorly understood and inadequately defined. Clinicians are likely to be confronted with patients with unusual ulcers, for which calciphylaxis is an important differential diagnosis. The aim of this paper is to discuss the clinical features and treatment of calciphylaxis, illustrate that it can occur in the absence of renal failure and assess the prognosis of patients with calciphylaxis.

Patients and methods

All patients admitted to Royal Perth Hospital, from January 2003 to December 2004 with histologically confirmed diagnosis of calciphylaxis were included in the study. Data were collected prospectively on all patients, and included: age, duration of wounds or skin lesion, gender, presence of renal failure, diabetes mellitus (fasting blood ≥ 7 mmol/L or blood sugar 2 hours post glucose load ≥ 11 mmol/L), corrected ionised calcium, inorganic phosphate serum and PTH serum. The patients included in this study were reviewed by the vascular team and a second opinion was obtained from a dermatologist.

All lesions had a punch biopsy performed across the ulcer edge, but if the specimen was insufficient to demonstrate calciphylaxis then a wedged biopsy was performed to confirm the diagnosis. All biopsies were analysed by the same pathologist; the diagnostic criteria used were: medial calcification of dermal small and medium sized arterioles and arteries, intimal fibroblastic and endothelial proliferation associated with ischemic necrosis of subcutaneous adipose tissue, and epidermal ulceration. Medium sized arteries with medial calcific sclerosis (Monckeberg’s medial calcific sclerosis) with no intimal or endothelial proliferation were excluded.

The patient’s wounds were managed by a Clinical Nurse Consultant accordingly. The dry necrotic lesions were kept dry with betadine solution, and covered with an atraumatic dressing (silicone coated, Mepitel^®). After surgical debridement, a conformable hydrogel dressing (IntraSite™ conformable) was applied. IntraSite™ Conformable is a conformable hydrogel dressing which combines the advantages of IntraSite™ Gel with a non-woven dressing to aid in the gentle packing of deep, shallow, open or undermined wounds. The non-woven substrate ensures the gel remains in close contact with the entire wound surface. If the wound was infected, it was treated with a silver-containing hydrofiber dressing (AQUACEL^® Ag). This is an antimicrobial dressing which releases silver at 1 part per million and is microbicidal against aerobic and anaerobic bacteria (including antibiotic-resistant strains), yeasts, and filamentous fungi. Once discharged from the hospital, patients were followed up weekly by the clinical nurse consultant with regular review by the vascular team on a fortnightly basis.

Results

Five patients (median age 52 (33-72)) were included in the study (table 1( Table 1 )), four male and one female. Three patients had end stage renal failure (ESRF) and were on haemodialysis and two had normal renal function. All three patients with ESRF had secondary hyperparathyroidism associated with elevated PTH and corrected ionised calcium. Three patients had Non Insulin-Dependant Diabetic Mellitus (NIDDM). The two patients with normal renal function had normal calcium, phosphate, and PTH levels. Histology confirmed the diagnosis of calciphylaxis in all 5 patients. The wounds of four of the patients healed (median time 5 months), one patient refused further surgical debridement of the wound and died 8 months after the diagnosis of calciphylaxis has been made, from overwhelming sepsis. The history and clinical course of the two patients with normal renal function and calciphylaxis is described below.

Patient 4

A 72 year-old man who presented with a six week history of a painful non-healing ulcer on his right leg ( (figure 1B) ). His medical history included Insulin-Dependant Diabetic Mellitus (IDDM), diagnosed in 1994; associated with profound peripheral neuropathy, retinopathy, refractory hypertension and TIA. Despite the presence of marked albuminuria, his renal function was essentially normal. Blood tests also demonstrated normal calcium, phosphate and PTH levels and a thrombophilia screen was within reference ranges. The histological analysis of punch biopsy tissue demonstrated calciphylaxis with resultant ulceration, necrosis and secondary abscess formation in the surrounding tissue. The wound was treated with AQUACEL^® Ag dressing and healed after six months.
Table 1 Patients details

Patients	Age	Sex	Duration of RF (Years)	DM	Urea / Creatinine	Calcium/Phosphate/PTH	Microbiology	Healing time (months)	Location of ulcer
1	33	M	16	-	21 / 602	2.6 / 2 / 110	C. Fueundii, E. Asburiae, staphylococcus	5	Arm
2	35	F	3	DM	18.8 / 904	2.35 / 2.1 / 118	S. Aureus, S. Epidermidis, D. Bacillus	5	Thigh
3	57	M	2	-	11.3 / 376	2.74 /1.9 / 130	--	^a	Leg
4	72	M	-	DM	8 / 103	1 /1.1 / 6	P. Mirabilis, E. coli	6	Leg
5	72	M	-	DM	4.5 / 83	1.07 / 1 / 6.9	C. Albicans	4- 6	Both legs

^aThis patient’s wound required further debridement but the patient declined further local treatment.

Patient 5

A 72 year-old man who presented with a ten week history of painful, non-healing bilateral leg ulcers. His medical history included IDDM, diagnosed in 1992, and bilateral chronic venous insufficiency. Blood tests revealed normal renal function, calcium, phosphate and PTH levels and a thrombophilia screen was within reference ranges. The histological analysis of punch biopsy tissue of both legs demonstrated calciphylaxis with subcutaneous fat necrosis and dermal fibroblastic proliferation. The wounds were treated with saline compresses initially, and then AQUACEL^® Ag dressing was applied with successful outcome after four months for the right leg wound and six months for the left leg.

Histological features

The defining histological characteristic found in calciphylaxis is a progressive calcification of small and medium sized vessels of the dermis and subcutis layer, leading to calcific thrombogenic microangiopathy. Typically the vessels affected are approximately 100 micrometers in diameter, with a range of 30-600 micrometers [1, 10]. The deposition of calcium in the media is either segmental or circumferential, and is accompanied by intimal hyperplasia, fibrosis and thickening with smooth muscle fibre atrophy. There is intimal proliferation with endovascular fibrosis and calcification and vascular occlusion, although many vessels show the arterial lumen to be preserved. There may be giant cells apposed to the calcifications. There is often associated skin elevation and necrosis with inflammation ( (figure 2) ). There is also severe endovascular fibrosis, thrombosis with calcification most pronounced in the intimal elastic lamina of arteries, and this may reflect early stages of calcification. In the deeper vessels there is also associated panniculitis ( (figure 3) )[1].

Discussion

In 1898, Bryant and White first recorded the occurrence of ‘calciphylaxis’ with uraemia in Guy’s Hospital Report [11]. However, the term calciphylaxis was first used in 1962 by Selye et al to describe a two step ectopic systemic calcification in the experimental animal [12].

By 1973, further papers described a syndrome of peripheral ischemic tissue necrosis, vascular calcification and cutaneous ulceration in uremic patients, using the term calciphylaxis to describe these, in the belief that they were the human equivalent [13, 14].

Tissue calcification in end stage renal disease was first noted in the 1960s when patients receiving dialysis therapy developed panniculitis with calcified subcutaneous nodules. Pathological organ calcification in uremic and non-uremic animals was extensively investigated over the next decade by Selye et al. [12].

This model was later applied to humans [1, 7, 13, 14]. In his experiments, Selye first induced hypercalcemia in rodents with ergocalciferol, dehydrotachysterol or PTH administration. This ‘sensitisation’ phase was followed by a secondary ‘challenge’ with intravenous iron, intraperitoneal egg albumin or direct skin trauma [5, 7, 15-17]. An inflammatory reaction followed over days, with damaged areas becoming necrotic and some calcified. It was thought a similar mechanism of ‘anaphylactoid’ inflammation followed by calcium deposition was the process that occurred in dialysis patients. However, in dialysis patients the tissue calcification is not an immunoglobin E (IgE) mediated process and hence the definition is inaccurate [1]. Furthermore the experimental conditions only remotely resemble the clinical syndrome, and analysis did not demonstrate the associated medial calcification and intimal hyperplasia seen in the uremic human. The recent term ‘Calcific Uremic Arteriopathy’ (CUA) is marginally better than calciphylaxis, but the vasculopathy seen in the syndrome is a rare finding in the clinically uremic patient [6, 15, 18]. Calciphylaxis occurs in both systemic and localized cutaneous forms. The term “vascular calcification-cutaneous necrosis syndrome” used by Dahl et al. [19] will not include the systemic form, which is characterized by calcification of small to medium-sized arteries and arterioles in multiple organ systems (skin, kidneys, skeletal muscles, lungs, heart and gastrointestinal tract).

Pathogenesis remains speculative, but two key elements are seen in the development of the lesions. Chronic renal failure and/or hyperparathyroidism result in high serum levels of calcium and phosphate, with resultant crystallisation and precipitation [4, 16, 18]. Calcium salts accumulate in the media of small arteries and arterioles. Intimal proliferation and endovascular fibrosis with calcification follows and the vessel lumen is narrowed. These primary lesions evolve slowly and are detectable only at biopsy, and their distribution is not uniform. The secondary lesions are what clinically manifest, with ulcer development following infarction and necrosis of the supplied skin and fat.

Typically the skin lesions present with painful areas of skin mottling resembling livedo reticularis, with violaceous discolouration and lumpy induration of the subcutis [18, 20]. As the lesion progresses it becomes haemorrhagic, with the development of subsequent ischemic necrosis and eschar formation. The lesions are almost always superficial, symmetrical and well demarcated. In the majority of cases skin involvement overlies areas of thick adipose tissue, such as the abdominal wall and buttocks, and is classified as central. Calciphylaxis at these sites are more common than the acral variant, where lesions are peripheral, often medial and seem to carry a better prognosis [7]. Calciphylaxis is more frequently reported in women, who, in contrast to men, deposit more of their adipose tissue in the subcutis [1, 3, 13]. In obesity, expansion of the subcutaneous compartment by adipose tissue subjects the tough fibroelastic septa and associated arterioles to angulation and mechanical stress. Large adipose deposits are also associated with reductions in local blood flow [3]. The effect of gravity-dependent blood flow reduction, particularly in the abdominal apron, together with tensile stress about the septa, may be factors in the dystrophic calcification of these structures.

Calcium plays an important role in the skin, where it has a profound effect on keratinocyte proliferation, differentiation and cell to cell adhesion. Despite tight regulation, calcification of cutaneous tissues can occur and is broadly termed ‘Calcinosis cutis’ [20]. Calcinosis, the deposition of calcium salts in non-osseous tissue, may be metastatic, dystrophic, or both [3]. In dystrophic calcification neither hypercalcemia nor hyperphosphatemia are necessary, as deposition is due to the binding of calcium to the phospholipids moieties of injured cell membranes with resultant mineralisation. In contrast, metastatic calcification is dependent on cryptic cell disturbance of normal tissue in response to an elevated serum calcium or phosphate.

Raised serum levels of calcium and phosphorous are most often seen in the context of renal failure, and may explain why the prevalence of the syndrome is highest in this patient population [3-5, 16, 17]. However, dialysis patients with calciphylaxis do not always have statistically significant raised levels at the time of diagnosis [1, 4]. Consistently raised levels are not demonstrable over time either, and although elevated levels have been shown to be associated with increased risk, other aetiological factors must co-exist.

Raised PTH levels have been implicated in the development of calciphylaxis since Selye et al. used PTH as a sensitising agent [3, 4, 12]. In most cases of calciphylaxis in renal dialysis patients, PTH levels are elevated. PTH plays an important role in calcium and phosphorous homeostasis and parathyroidectomy is helpful in normalising levels of these ions.

It is well established that vascular calcification in all forms occurs more frequently in patients with renal disease [1, 17]. This appears to be a regulated biological process; the media is almost always affected and calcification in this area requires alteration to the smooth muscle cell phenotype. Central to the process of calcification is an imbalance between inhibitor and promoter factors. The mineralisation of smooth muscle cell media induces osteocalcin expression, which in turn promotes tissue calcium deposition. Osteopontin can be stimulated by high phosphorous environments, implying a phenotypic shift. It is likely that a disruption in the dynamic equilibrium as opposed to a single agent is central to the development of calciphylaxis related vascular calcification [1, 4, 17].

Calciphylaxis occurs most frequently in patients with renal failure on dialysis. However, a review of literature, demonstrates a number of idiopathic cases [15, 19-21]. Indeed, our limited cases series revealed two such patients with normal creatinine, urea, calcium, phosphate and PTH levels. High levels of PTH have been associated with calciphylaxis in cases of severe primary hyperparathyroidism, advanced liver disease associated with albumin infusion and prednisone therapy, Crohn’s disease and extensive bowel resection [20]. It has been reported in a patient with breast cancer receiving chemotherapy [21] that the occurrence of calciphylaxis was associated with a decline in antigen levels and functional activity of both protein C and its co-factor protein S. High level of PTH, resulting from either hyperparathyroidism secondary to steatorrhea or from severe tertiary hyperparathyroidism [20, 21] and long-term intake of exogenous vitamin D compounds in patients with hepatic dysfunction or renal impairment [19] have been incriminated as well in the development of calciphylaxis. The lack of common features in these cases clearly demonstrates that further investigation into the pathophysiology is essential.

The rarity of the condition and lack of clinical trials makes consensus regarding treatment difficult. Therapeutic options are limited, essentially supportive in nature and almost universally poor. Preventative lifestyle measures such as weight loss, diet modification and reduction of cutaneous tissue trauma are useful and should be tailored individually [1, 5]. In the context of the renal patient, the use of zero-calcium dialysate solution may be of benefit [1, 4, 10].

Parathyroidectomy is advocated in patients with high serum concentrations of calcium and phosphorous; and while the mechanism is poorly understood, dramatic resolutions of secondary lesions have been widely reported [2, 7, 16]. Careful control of calcium and phosphorous levels, with judicious use or substitution of calcium salts as phosphate binders will most likely prove to be the rate limiting step in syndrome progression [3]. Hyperbaric oxygen therapy has been shown to be of benefit in the healing of established cutaneous ulcers of any aetiology [22]. This treatment, though promising, is limited by availability and cost.

Recently, Cicone et al. reported successful treatment of tumoral calcification, a complication of end stage renal disease similar to calciphylaxis, in 9 haemodialysis patients with intravenous (IV) sodium thiosulphate. They went on to treat for the first time a case of calciphylaxis in this way, with apparent remarkable success [8]. Their case report, a 69 year old woman was treated three times weekly for eight months with 25 g iv over 30 months and demonstrated marked reduction in pain and plaque size. These improvements persisted four months after follow up and a technetium scan obtained at this time showed no progression of the lesions.

The outcome of calciphylaxis is poor, with a mortality of 60%-70%, mainly from uncontrolled sepsis from wound infection [23]. Diagnosis is often delayed as the presentation may mimic more common conditions and there is a lack of pathognomonic investigation results to be found. Some authors believe that patients with distal localisation have a better outcome [7]. Parathyroidectomy, though debatable, when performed before the onset of sepsis may be a reasonable step towards preventing fatality [5].

All our patients had their lesions healed, except the patient who refused further debridement and subsequently died of overwhelming sepsis.

Conclusion

Calciphylaxis is an uncommon condition, mostly present in patients with ERSF. A concern exists that the incidence has increased during the last decade because of a number of possible factors, including more widespread use of parenteral vitamin D and iron dextran. It presents typically as ischemic and necrosis of the skin (non-healing ulcer). The diagnosis must be confirmed early by biopsy. It can occur in patients without ERSF, offering a challenge in clinical and histological diagnosis. It carries a poor prognosis as it is difficult to treat; vasculopathy is extensive and most times irreversible.

Acknowledgements

Financial support: None. Conflict of interest: None.

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