Observations  A 58-year-old woman with endometrial carcinoma developed extensive calciphylaxis despite the presence of normal renal and parathyroid function. The disease resolved with rapid diagnosis, supportive therapy, and medical management. Analysis of this case and the 13 previously reported cases of nontraditional calciphylaxis identified the following patient characteristics that highlight clinical situations potentially predisposing to calciphylaxis: hypoalbuminemia, malignant neoplasm, systemic corticosteroid use, anticoagulation with warfarin sodium or phenprocoumon, chemotherapy, systemic inflammation, hepatic cirrhosis, protein C or S deficiency, obesity, rapid weight loss, and infection.

Conclusions  Calciphylaxis is becoming increasingly common in patients with normal renal and parathyroid function. The observations from this study may assist dermatologists in the rapid diagnosis and prompt initiation of therapy for this devastating disease.

Since Selye and coworkers^10-12 originally coined the term in 1962, calciphylaxis has usually been reported in patients with end-stage renal disease and secondary hyperparathyroidism (referred to herein as "traditional" patients).^5-9 Calciphylaxis occurring in patients with both normal renal and parathyroid function (referred to as "nontraditional" patients) is considered extremely rare. Although several single case reports of calciphylaxis occurring in nontraditional patients have recently been reported, the literature does not reflect the increasing prevalence with which calciphylaxis is observed in patients having both normal renal and parathyroid function. In addition, to our knowledge, no report has collectively reviewed these published nontraditional cases in an attempt to identify risk factors for the development of calciphylaxis in this patient population.

We studied a patient with normal renal and parathyroid function who developed extensive calciphylaxis. We evaluated similar reported cases, identifying common characteristics among these patients that may represent risk factors for the development of calciphylaxis. We hope to raise awareness that the development of calciphylaxis in nontraditional patients having both normal renal and parathyroid function is not as rare as previously believed.

REPORT OF A CASE

Physical examination showed an afebrile, hemodynamically stable, obese (body mass index, 53 [calculated as weight in kilograms divided by height in meters squared]) woman in significant pain from a large retiform ulceration on the proximal part of her right thigh covered with a thick eschar surrounded by violaceous, indurated, tender, retiform plaques (Figure 1). The lateral part of the thighs, the hips, and the pannus manifested violaceous indurated plaques. She had no other pertinent cutaneous or mucosal findings. Laboratory investigations are summarized in Table 1.

View larger version (98K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Large retiform ulceration with thick eschar on the proximal part of the right thigh surrounded by violaceous, indurated, tender, retiform plaques.

View this table: [in this window] [in a new window] [as a PowerPoint slide]   Table 1. Results of Laboratory Investigations

Initial clinical differential diagnosis favored a vasculopathic process (calciphylaxis vs warfarin necrosis) over vasculitis, and biopsy specimens were obtained from the center and the periphery of her right thigh ulceration. The patient rapidly developed progressive retiform purpura on her thighs and abdomen despite culture-directed antimicrobial therapy and replacing warfarin with enoxaparin sodium. Initial biopsy specimens showed necrosis of the epidermis and superficial dermis with fibrin microthrombi in the dermal and superficial subcutaneous vasculature with minimal inflammation and no vasculitis. Plain radiographs of her thighs did not identify tissue or vascular calcification. Persistent clinical suspicion of calciphylaxis prompted an incisional wedge biopsy down to fascia, which showed intramural calcium deposition in subcutaneous arterioles with associated intimal hyperplasia and ischemic changes of the surrounding panniculus (Figure 2). These clinical and histopathological findings were consistent with the diagnosis of calciphylaxis.

View larger version (125K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. Cutaneous biopsy specimen showing intramural calcium deposition in subcutaneous arterioles with associated intimal hyperplasia and ischemic changes of the surrounding panniculus (hematoxylin-eosin, original magnification x400).

Enoxaparin treatment was discontinued after 10 days, during which the patient continued to develop new lesions, and ongoing anticoagulation was maintained with warfarin (international normalized ratio ranged from 2.0-6.0 throughout hospitalization). Parathyroid scan failed to show a parathyroid adenoma, and surgical parathyroidectomy was thought unlikely to benefit the patient because her parathyroid hormone level (65 pg/mL; to convert to nanograms per liter, multiply by 1) and calcium-phosphorus product (38 mg²/dL²) were interpreted as normal. However, because of progressive metastatic calcification, oral therapy with cinacalcet hydrochloride (30 mg once daily), sevelamer hydrochloride (1600 mg 3 times daily), and ergocalciferol (50 000 U twice weekly) was initiated promptly after diagnosis to decrease the calcium-phosphorus product in an attempt to improve the calciphylaxis. These medical interventions, in combination with local wound therapy and culture-directed antimicrobial therapy, appeared to stabilize her disease during the next month; however, the lesions did not heal. Sodium thiosulfate (5 g intravenously daily) was then initiated, and within 2 weeks healthy granulation tissue was noted at the borders of the ulcerations.

Oral cinacalcet hydrochloride (30 mg daily), sevelamer hydrochloride (1600 mg 3 times daily), ergocalciferol (50 000 U twice weekly), and intravenous sodium thiosulfate (5 g daily) were continued on transfer to a long-term care facility (at which time her parathyroid hormone level was 33 pg/mL and calcium-phosphorus product was 29 mg²/dL²), where she continued to experience progressive improvement, with decreased pain and size of her ulcerations and no new lesions. Fourteen weeks later, after 4 and 5 months of treatment with sodium thiosulfate and cinacalcet, respectively, the lesions were completely healed (Figure 3). The patient was transferred to a rehabilitation facility for 2 months before returning home, at which time sodium thiosulfate therapy was discontinued. She continued to take cinacalcet, sevelamer, and ergocalciferol and remained in remission from her endometrial carcinoma without further complications from calciphylaxis throughout a posthealing follow-up period of 17 months.

View larger version (87K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 3. Complete healing after 4 and 5 months of treatment with sodium thiosulfate and cinacalcet hydrochloride, respectively.

COMMENT

Vascular calcification and secondary hyperparathyroidism are extremely common in patients undergoing hemodialysis, observed in 80% and 78%, respectively.^13-15 However, Angelis et al¹⁶ noted only a 4% prevalence of calciphylaxis among 242 patients undergoing long-term dialysis. In addition, not all patients with calciphylaxis manifest elevated calcium-phosphorus products, the most commonly cited sensitizer. Budisavljevic et al¹⁷ report only one-third of dialysis recipients with calciphylaxis to have a calcium-phosphorus product greater than 70 mg²/dL². These findings support a more complicated and multifaceted pathogenesis than that originally described by Selye et al. This view is further supported by the sheer volume of risk factors for the development of calciphylaxis reported in traditional cases—and frequently contradicted—in the literature.^5-9,18 This is likely due to the relative rarity of calciphylaxis, limiting analyses to small case series and reviews.¹⁸ A few larger case-control studies have identified several consistent statistically associated risk factors for the development of calciphylaxis in traditional patients. However, findings regarding the relation of other risk factors with calciphylaxis have been less consistent among larger case-control studies. These findings are summarized as follows:

Factors identified as statistically associated with the development of calciphylaxis

• Obesity^{5, 19-20}
  
• Liver disease⁵
  
• Systemic corticosteroid use⁵
  
• Elevated calcium-phosphorus product^{5, 19}
  
• Increased erythrocyte sedimentation rate⁵
  
• White race^19-21
  
• Female sex^19-21
  
• Decreased albumin level^19-21
  
• Elevated phosphorus level^{19, 21}
  
• Elevated alkaline phosphatase level²¹
  

Factors proposed in case reports to be risk factors but not statistically associated with the development of calciphylaxis in case-control studies

• Obesity²¹
  
• Warfarin use⁵
  
• Vitamin D administration⁵
  
• Intact parathyroid hormone level^{5, 19}
  
• Protein C and S levels⁵
  
• Calcium level^{19, 21}
  
• Diabetes mellitus^{5, 20}
  
• Albumin level⁵
  

Recently, several reports of calciphylaxis occurring in nontraditional patients with both normal renal and parathyroid function have been published (Table 2).^22-33 Suspicion of calciphylaxis in nontraditional patients is generally low, as evidenced by the proportion of the reported cases in which accurate diagnosis was delayed.^23-24,28-30 Analysis of these 13 nontraditional cases in addition to the current report showed a mean age of 54.5 years, a preponderance of female patients (female to male ratio, 12:2), and a mortality rate of 43%. The patient characteristics identified as potential risk factors because of their greater than expected incidence among the 14 patients and the proposed mechanism of their contribution to the development of calciphylaxis in nontraditional patients are shown in Table 3.^34-41 Interestingly, many of these patient characteristics are shared by patients with transient acute renal insufficiencies who have calciphylaxis,^{34, 42-43} as well as by patients with chronic renal insufficiency who are not receiving dialysis.⁵ Although our observation that these patient characteristics are overrepresented does not prove causality, it may highlight specific clinical situations in which the diagnosis of calciphylaxis occurring in a nontraditional patient should be considered.

View this table: [in this window] [in a new window] [as a PowerPoint slide]   Table 2. Nontraditional Cases of Calciphylaxis in Patients With Both Normal Renal and Parathyroid Function

View this table: [in this window] [in a new window] [as a PowerPoint slide]   Table 3. Notable Patient Characteristics, Prevalence, and Proposed Mechanism of Action Identified Among Patients With Nontraditional Calciphylaxis With Both Normal Renal and Parathyroid Function

The increasingly common observation of calciphylaxis in patients with normal renal and parathyroid function supports the view of calciphylaxis as a final common end point, reachable via many pathways involving the interplay of various risk factors. Exposure to sensitizers and challengers culminates in an increased susceptibility to vascular calcification and luminally narrowed arterioles, which are subsequently prone to thrombosis if exposed to the proper stimuli. However, only a small proportion of susceptible patients ultimately develop calciphylaxis, suggesting that a specific combination of sensitizing and challenging conditions must surpass a critical threshold in combination with an appropriate thrombogenic stimulus for calciphylaxis-induced ischemic necrosis to develop. The extent and duration of this threshold breach may well correlate with disease severity and clinical outcome. Weenig¹⁸ recently reviewed the interaction of these numerous predisposing factors and provided a comprehensive summary that is invaluable in understanding the complex mechanisms by which the proposed risk factors result in both traditional and nontraditional calciphylaxis. The final common pathway involves nuclear factor B activation leading to vascular calcification, which, when followed by thrombosis, results in the clinical manifestations of calciphylaxis. Thus, in addition to general supportive care and prevention of infection, rapid diagnosis and therapeutic intervention targeted at correction of the specific underlying sensitizers and challengers should improve outcomes in this devastating disease. Our patient's risk factors included female sex, obesity, hypoalbuminemia, hypovitaminosis D, warfarin use, and thrombotic tendency (recent deep venous thrombosis, malignant neoplasm, chemotherapy, and infection).

Paradoxically, although thrombogenesis is clearly involved in the development of calciphylaxis, we identified a relatively high incidence of warfarin or phenprocoumon therapy (43%) in nontraditional patients with calciphylaxis. Price et al³⁹ demonstrated warfarin's ability to promote vascular calcification in rodents likely via inhibition of -carboxylation of matrix -carboxyglutamic acid proteins that normally function to inhibit endogenous calcification. Four of the 6 nontraditional patients with calciphylaxis receiving warfarin or phenprocoumon had simultaneous malignant tumors, the presence of which has been well documented to increase the risk of thrombotic events.³⁵ In addition, our patient and the patient described by Riegert-Johnson et al²⁶ had recent deep venous thromboses, indicative of their hypercoagulable tendencies. Furthermore, acute infection is associated with increased risk of thrombosis, suggesting that our patient's acute and chronic infectious conditions may have contributed to her thrombotic predisposition.⁴¹ In sum, warfarin's ability to promote vascular calcification and the increased risk of thrombosis from comorbid states may outweigh the antithrombotic properties of warfarin.

Recently, promising reports of successful outcomes have been noted after treatment with cinacalcet,^44-45 a calcimimetic shown to lower parathyroid hormone levels and improve calcium-phosphorus metabolism in patients undergoing dialysis, and sodium thiosulfate,^46-47 an inorganic salt that promotes dissolution of calcium deposits via chelating calcium in the form of highly soluble calcium thiosulfate salts. Conversely, systemic corticosteroids, use of which was identified in our review to be overrepresented among nontraditional patients with calciphylaxis, likely have no beneficial role in the treatment of calciphylaxis.

Although our patient's parathyroid status was ultimately interpreted as normal, her endocrine/electrolyte status was difficult to interpret. Her high-normal parathyroid hormone level was attributed to hypovitaminosis D, previously shown to be associated with decreased intestinal calcium absorption with subsequent parathyroid hormone elevation.^{18, 48} However, her fluctuating normal to high serum phosphorus level (range, 4.0-6.2 mg/dL) and mildly decreased 24-hour urine phosphorus levels are difficult to justify considering her high-normal parathyroid hormone level and normal renal function. Spurious hyperphosphatemia has been demonstrated to result from phlebotomy sample contamination by heparin used to maintain the patency of peripheral access lines.⁴⁹ Although we cannot definitively implicate sample contamination in our patient's variable serum phosphorus levels, neither can it be definitively excluded. Nonetheless, despite her normal renal and parathyroid status, she experienced a dramatic improvement and ultimately successful outcome after treatment with cinacalcet and sodium thiosulfate; to our knowledge, this is the first description of a nontraditional patient with calciphylaxis successfully treated with these agents.

We hope that this report will raise awareness of the occurrence of calciphylaxis in nontraditional patients, as well as highlight clinical scenarios in which heightened suspicion of the diagnosis of calciphylaxis may lead to more rapid diagnosis and improved patient outcomes.

AUTHOR INFORMATION

Accepted for Publication: July 6, 2008.

Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kalajian and Parker. Acquisition of data: Kalajian, Malhotra, and Parker. Analysis and interpretation of data: Kalajian, Malhotra, and Callen. Drafting of the manuscript: Kalajian and Malhotra. Critical revision of the manuscript for important intellectual content: Kalajian, Callen, and Parker. Statistical analysis: Not applicable. Obtained funding: Not applicable. Administrative, technical, and material support: Malhotra and Callen. Study supervision: Kalajian and Parker.

Financial Disclosure: Dr Callen has received honoraria from Amgen, Abbott Immunology, Genentech, Centocor, Electrical Optical Sciences, Medicis, and Steifel. He serves on a safety monitoring committee for Genmab.

Disclaimer: Dr Callen is an associate editor of the Archives of Dermatology but was not involved in any of the decisions regarding review of the manuscript or its acceptance.

Additional Contributions: Janine C. Malone, MD, kindly provided dermatopathology assistance.