Copyright 2014 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
Calciphylaxis is a highly morbid disease with a 1-year mortality of approximately 80% that is usually associated with kidney disease.1 We report a case of nonuremic calciphylaxis in the setting of hyperphosphatemia that improved dramatically with phosphate binders and supportive care.
A white woman approximately 60 years old presented with numerous painful subcutaneous plaques and cutaneous necrosis, ulceration, and eschars on her hips, thighs, buttocks, abdomen, and breasts. She had a history of diabetes mellitus, congestive heart failure, tobacco abuse (half-pack of cigarettes daily), and endocarditis with artificial aortic valve replacement 7 years previously, requiring long-term warfarin treatment. Additional medications included aspirin, atorvastatin, furosemide, glimepiride, lisinopril, and metoprolol.
Her physical examination was remarkable for obesity (BMI, 32.3 [calculated as weight in kilograms divided by height in meters squared]) with firm, painful subcutaneous plaques on the lateral hips, thighs, buttocks, breasts, and abdomen. Overlying the plaques were large, angulated ulcerations with firm adherent black eschars and peripheral dusky erythema (Figure 1A and B). Histopathologic analysis confirmed the diagnosis of calciphylaxis (Figure 2).
A and B, On initial clinical presentation, patient had firm, tender subcutaneous plaques on the lateral hips with overlying large, angulated ulcerations with black eschars and peripheral erythema (A, right hip; B, left hip). C and D, After 6 months of multimodality therapy, the ulcerations had shown dramatic improvement in the erythema, pain, and induration (C, right hip; D, left hip) and continued to improve until complete resolution at 15 months with residual scarring.
Within the subcutis, there is concentric and medial calcification in a medium-sized vessel (hematoxylin-eosin, original magnification ×400).
The patient had no history of renal dysfunction, but her serum phosphorus level was elevated, at 5.3 mg/dL (normal, 2.4-4.7 mg/dL). (To convert serum phosphorus to millimoles per liter, multiply by 0.323.) Findings from a complete blood cell count, comprehensive metabolic panel, extended antiphospholipid antibody panel, and assays for parathyroid hormone, vitamin D levels, protein C, and protein S were normal, with the exception of a hemoglobin level of 10.4 g/dL (normal, 12.0-16.0 g/dL). (To convert hemoglobin to grams per liter, multiply by 10.0.) Her prothrombin time and international normalized ratio were appropriate for valvular anticoagulation and had been stable for years. Her hyperphosphatemia in the absence of kidney disease prompted testing for fibroblast growth factor 23 (FGF23) level, which was elevated. Additionally, iron studies demonstrated iron deficiency, at 20 μg/dL (normal range, 28-170 μg/dL). (To convert iron to micromoles per liter, multiply by 0.179.)
Multimodality therapy was instituted, consisting of sevelamer, 800 mg, 3 times daily as a phosphate binder; hyperbaric oxygen, 6 days per week for 10 weeks; oral alendronate, 10 mg/d; and local care with topical collagenase and petrolatum dressings. After 2 months of these therapies, the patient had significant clinical improvement. Warfarin was replaced with dabigatran etexilate owing to reports of warfarin-associated calciphylaxis.2 The patient was counseled about tobacco cessation and quit smoking over 3 months. Surgical debridement was considered but ultimately avoided due to significant, continued clinical improvement (Figure 1C and D).
Calciphylaxis most commonly occurs in the setting of end-stage renal disease and an elevated calcium-phosphate level.1 However, calciphylaxis in the absence of renal impairment has been described in the setting of obesity; liver disease; elevated calcium-phosphorus, phosphorus, and alkaline phosphatase; decreased albumin; diabetes; and treatment with systemic corticosteroids and warfarin. It has most commonly been described in white women.2,3
Our patient’s risk factors for calciphylaxis included smoking, obesity, ethnicity, elevated phosphorus levels, and potentially warfarin treatment. She had substantial clinical improvement with multimodality therapy, with the most specific targeted intervention being treatment with phosphate binders, which normalized her serum phosphorus level. Although smoking cessation and removing warfarin from her drug regimen also may have played a role, she had significant clinical improvement prior to instituting those therapeutic changes.
Notably, our patient also had an increased level of FGF23, which is a bone-derived phosphate and vitamin D–regulating hormone that can be elevated in genetic hypophosphatemic disorders, hyperphosphatemia, and iron deficiency anemia.4- 6 As a counter-regulator of phosphorus homeostasis, elevated FGF23 levels can impact bone homeostasis, leading to elevated phosphorus. Recent data have demonstrated that administration of iron may decrease FGF23 levels and help restore this balance, especially in patients with end-stage renal disease.5 To help decrease FGF23 levels, our patient received intravenous iron, though her clinical lesions had improved prior to this intervention.
Although no definitive treatment of calciphylaxis exists, sodium thiosulfate, surgical debridement, hyperbaric oxygen, cinacalcet, bisphosphonates, and thrombolytic agents have been reported to lead to clinical improvement.2 Because of the significant morbidity and mortality risk, our patient was treated with multiple interventions to help prevent disease progression. We attribute her dramatic clinical improvement primarily to the initial therapy of phosphate binders with normalization of serum phosphate levels, wound care, and hyperbaric oxygen, although all interventions were important to address her risk factors for calciphylaxis. This case highlights the important relationship of nonuremic calciphylaxis, hyperphosphatemia, FGF23, and the importance of multimodality treatment for this debilitating disease.
Corresponding Author: Misha Rosenbach, MD, Department of Dermatology, Hospital of the University of Pennsylvania, 3600 Spruce St, 2 Maloney, Philadelphia, PA 19104 (firstname.lastname@example.org).
Published Online: March 19, 2014. doi:10.1001/jamadermatol.2013.7508.
Conflict of Interest Disclosures: None reported.
Wanat KA, Stewart CL, Negoianu D, Rosenbach M. Severe Nonuremic Calciphylaxis Due to Hyperphosphatemia Resolving With Multimodality Treatment Including Phosphate Binders. JAMA Dermatol. 2014;150(6):671-673. doi:10.1001/jamadermatol.2013.7508