Customize your JAMA Network experience by selecting one or more topics from the list below.
Copyright 2009 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2009
Calciphylaxis is a life-threatening form of metastatic calcification-induced microvascular occlusion syndrome. Although traditionally observed in patients with end-stage renal disease and/or hyperparathyroidism, the development of calciphylaxis in “nontraditional” patients having both normal renal and parathyroid function has been reported. However, to date there has been no collective analysis identifying common patient characteristics potentially predisposing to the development of calciphylaxis in nontraditional patients.
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.
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.
Calciphylaxis, also known as calcific uremic arteriolopathy, is a metastatic calcification-induced microvascular occlusion syndrome of mural calcification, intimal proliferation, fibrosis, and thrombosis leading to target organ hypoperfusion.1,2 Cutaneous calciphylaxis manifests with noninflammatory retiform purpura, the hallmark of cutaneous microvascular occlusion syndromes, for which the differential diagnosis is broad, including disorders of platelet plugging, cold-related agglutination, vessel invasive organisms, embolization, local or systemic coagulopathies, and miscellaneous conditions (calciphylaxis, Degos disease, and sickle cell anemia).3 Lesions of calciphylaxis are typically very painful, with ulceration, secondary infection, and end-organ hypoperfusion often resulting in gangrene, amputation, and sepsis with associated mortality rates as high as 89%.4,5 Excellent comprehensive reviews of calciphylaxis have been published.5-9
Since Selye and coworkers10-12 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.
A 58-year-old woman had a 4-week history of exquisitely painful ulcerations and violaceous tender plaques on both thighs and her lower abdomen. Seven months earlier she had been diagnosed as having stage IIIc endometrial carcinoma, which was treated with surgery (complicated by a chronic pelvic abscess requiring percutaneous drainage) and chemotherapy. The chemotherapy had been completed (cycle 1 with carboplatin alone and cycles 2 through 5 with carboplatin and paclitaxel) 2 weeks before the development of the cutaneous lesions. The patient's medical history included obesity, hypertension, hypothyroidism, anemia, and venous stasis. Active comorbidities included deep venous thrombosis and Pseudomonas aeruginosa infection of both her lower urinary tract and her right thigh ulceration. Medications included warfarin sodium, amlodipine besylate, levothyroxine sodium, epoetin alfa, paroxetine hydrochloride, furosemide, oxycodone, acetaminophen, simethicone, senna, lorazepam, and 2% mupirocin ointment twice daily. She denied any alterations or interruptions in warfarin dosing. She did not use alcohol, drugs, or tobacco products.
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.
Large retiform ulceration with thick eschar on the proximal part of the right thigh surrounded by violaceous, indurated, tender, retiform plaques.
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.
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 ×400).
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.
Complete healing after 4 and 5 months of treatment with sodium thiosulfate and cinacalcet hydrochloride, respectively.
The pathogenesis of calciphylaxis is unclear. Selye and coworkers10-12 first proposed an underlying mechanism in 1962 after experiments in rodents demonstrated that sensitization with a “sensitizer” followed by exposure to a “challenger” after a latency period could result in extensive tissue calcification. Hyperparathyroidism and hypervitaminosis D were identified as sensitizers, whereas egg albumin, trauma, and iron or aluminum salts were proposed as challengers. However, calciphylaxis in humans differs from the process originally described in rodents because calcification is predominantly of the vasculature in humans and of extravascular tissue in rodents. Nonetheless, Selye and associates' theory of sensitizers and challengers has persisted as the favored mechanism to explain the aberrant calcium-phosphorus metabolism leading to calciphylaxis in humans. This accepted mechanism of calciphylaxis, most commonly observed in patients with end-stage renal disease, is based on secondary hyperparathyroidism-induced elevated calcium-phosphorus product. The elevated calcium-phosphorus product acts as a sensitizer in a patient later exposed to a challenger, resulting in vascular calcification and increased susceptibility to subsequent thrombosis of luminally narrowed vasculature with resultant end-organ hypoperfusion.
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
Systemic corticosteroid use5
Elevated calcium-phosphorus product5,19
Increased erythrocyte sedimentation rate5
Decreased albumin level19-21
Elevated phosphorus level19,21
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
Vitamin D administration5
Intact parathyroid hormone level5,19
Protein C and S levels5
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.
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 κB 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 γ-carboxylation of matrix γ-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.
Correspondence: Andrew H. Kalajian, MD, Division of Dermatology, University of Louisville, 310 E Broadway, Floor 2A, Louisville, KY 40202 (email@example.com).
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.
Kalajian AH, Malhotra PS, Callen JP, Parker LP. Calciphylaxis With Normal Renal and Parathyroid Function: Not as Rare as Previously Believed. Arch Dermatol. 2009;145(4):451–458. doi:10.1001/archdermatol.2008.602
Create a personal account or sign in to: