Calciphylaxis with Normal Renal and Parathyroid Function Not As Rare As Previously Believed

OBSERVATION Calciphylaxis With Normal Renal and Parathyroid Function Not as Rare as Previously Believed

Andrew H. Kalajian, MD; Paula S. Malhotra, MD; Jeffrey P. Callen, MD; Lynn P. Parker, MD

Background: Calciphylaxis is a life-threatening form of previously reported cases of nontraditional calciphylaxis metastatic calcification-induced microvascular occlusion identified the following patient characteristics that high- syndrome. Although traditionally observed in patients with light clinical situations potentially predisposing to calci- end-stage renal disease and/or hyperparathyroidism, the phylaxis: hypoalbuminemia, malignant neoplasm, sys- development of calciphylaxis in “nontraditional” pa- temic corticosteroid use, anticoagulation with warfarin tients having both normal renal and parathyroid func- sodium or phenprocoumon, chemotherapy, systemic in- tion has been reported. However, to date there has been flammation, hepatic cirrhosis, protein C or S deficiency, no collective analysis identifying common patient char- obesity, rapid weight loss, and infection. acteristics potentially predisposing to the development of calciphylaxis in nontraditional patients. Conclusions: Calciphylaxis is becoming increasingly common in patients with normal renal and parathyroid Observations: A 58-year-old woman with endometrial function. The observations from this study may assist der- carcinoma developed extensive calciphylaxis despite the matologists in the rapid diagnosis and prompt initiation presence of normal renal and parathyroid function. The of therapy for this devastating disease. disease resolved with rapid diagnosis, supportive therapy, and medical management. Analysis of this case and the 13 Arch Dermatol. 2009;145(4):451-458

ALCIPHYLAXIS, ALSO KNOWN secondary hyperparathyroidism (re- as calcific uremic arterio- ferred to herein as “traditional” patients).5-9 lopathy, is a metastatic Calciphylaxis occurring in patients with calcification-induced mi- both normal renal and parathyroid func- crovascular occlusion syn- tion (referred to as “nontraditional” pa- dromeC of mural calcification, intimal pro- tients) is considered extremely rare. Al- liferation, fibrosis, and thrombosis leading though several single case reports of to target organ hypoperfusion.1,2 Cutane- calciphylaxis occurring in nontraditional ous calciphylaxis manifests with noninflam- patients have recently been reported, the matory retiform purpura, the hallmark of literature does not reflect the increasing cutaneous microvascular occlusion syn- prevalence with which calciphylaxis is ob- dromes, for which the differential diagno- served in patients having both normal re- sis is broad, including disorders of platelet nal and parathyroid function. In addi- plugging, cold-related agglutination, ves- tion, to our knowledge, no report has sel invasive organisms, embolization, local collectively reviewed these published non- or systemic coagulopathies, and miscella- traditional cases in an attempt to identify neous conditions (calciphylaxis, Degos dis- risk factors for the development of calci- ease, and sickle cell anemia).3 Lesions of cal- phylaxis in this patient population. ciphylaxis are typically very painful, with We studied a patient with normal renal ulceration, secondary infection, and end- and parathyroid function who developed organ hypoperfusion often resulting in gan- extensive calciphylaxis. We evaluated simi- Author Affiliations: Division of grene, amputation, and sepsis with associ- lar reported cases, identifying common Dermatology (Drs Kalajian and ated mortality rates as high as 89%.4,5 characteristics among these patients that Callen), Department of Excellent comprehensive reviews of calci- may represent risk factors for the develop- Medicine (Dr Malhotra), and phylaxis have been published.5-9 ment of calciphylaxis. We hope to raise Division of Gynecologic 10-12 Oncology, Department of Since Selye and coworkers origi- awareness that the development of calci- Obstetrics and Gynecology nally coined the term in 1962, calciphy- phylaxis in nontraditional patients having (Dr Parker), University of laxis has usually been reported in pa- both normal renal and parathyroid func- Louisville, Louisville, Kentucky. tients with end-stage renal disease and tion is not as rare as previously believed.

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Initial Range During Reference Laboratory Investigation Value Hospitalization Range Hemoglobin, g/dL 8.9 (↓) 7.3-11.7 11.2-15.7 White blood cells, ϫ103/µL 10.0 5.4-14.0 4.1-10.8 Platelets, ϫ103/µL 438 (↑) 344-639 140-370 Creatinine, mg/dL 0.6 (↓) 0.4-0.8 0.7-1.2 Serum urea nitrogen, 13 5-20 7-20 mg/dL Aspartate aminotransferase, 31 20-54 10-47 U/L Alanine aminotransferase, 25 11-31 10-50 U/L Alkaline phosphatase, U/L 113 88-180 38-126 Albumin, g/dL 2.9 (↓) 2.4-3.1 3.9-5.0 Calcium, mg/dLa 9.1 8.3-10.2 8.8-10.5 Ionized calcium, mg/dL 4.68 4.68-5.08 4.52-5.28 Phosphorus, mg/dL 4.6 (↑) 4.0-6.2 2.5-4.5 Calcium-phosphorus 41.8 33.1-63.4 Ͻ55 product,mg2/dL2a Figure 1. Large retiform ulceration with thick eschar on the proximal part of 25-Hydroxyvitamin D, 7b (↓) NA 20-200 the right thigh surrounded by violaceous, indurated, tender, retiform ng/mL plaques. Parathyroid hormone, 63 33-67 10-65 pg/mL 24-h urine calcium, mg 35.7b (↓) NA 45-353 b REPORT OF A CASE 24-h urine phosphorus, mg 0.37 (↓) NA 0.4-1.3 Protein C, % 106b NA 90-131 Protein S, % 119b (↑) NA 57-88 A 58-year-old woman had a 4-week history of exquis- PT, s 32.5 (↑) 12.8-54.4 9.4-11.6 INR 3.8 (↑) 1.3-6.4 0.9-1.2 itely painful ulcerations and violaceous tender plaques aPTT, s 40.8 (↑) 34.5-64.1 22-30.4 on both thighs and her lower abdomen. Seven months Homocysteine, mg/L 1.41b NA 0.60-1.68 earlier she had been diagnosed as having stage IIIc en- Factor V Leiden mutation Negativeb NA Negative dometrial carcinoma, which was treated with surgery Lupus anticoagulant screen Negativeb NA Negative Anticardiolipin IgG, IgM, All normalb NA IgG and IgM, Ͻ20; (complicated by a chronic pelvic abscess requiring per- IgA antibodies, U/mL IgA, Ͻ12 cutaneous drainage) and chemotherapy. The chemo- ␤2-Glycoprotein-1 IgG, IgG and IgM, NA IgG, Ͻ20; IgM and therapy had been completed (cycle 1 with carboplatin IgM, IgA antibodies, normalb; IgA, Ͻ10 b ↑ alone and cycles 2 through 5 with carboplatin and pac- U/mL IgA, 13 ( ) litaxel) 2 weeks before the development of the cutane- Abbreviations: aPTT, activated partial thromboplastin time; INR, international ous lesions. The patient’s medical history included obe- normalized ratio; NA, not applicable; PT, prothrombin time; ↑, laboratory value sity, hypertension, hypothyroidism, anemia, and venous is above the reference range; ↓, laboratory value is below the reference range. stasis. Active comorbidities included deep venous throm- SI conversion factors: To convert alanine and aspartate aminotransferases and alkaline phosphatase to microkatals per liter, multiply by 0.0167; albumin to bosis and Pseudomonas aeruginosa infection of both her grams per liter, multiply by 10; calcium and ionized calcium to millimoles per lower urinary tract and her right thigh ulceration. Medi- liter, multiply by 0.25; creatinine to micromoles per liter, multiply by 88.4; cations included warfarin sodium, amlodipine besylate, hemoglobin to grams per liter, multiply by 10; homocysteine to micromoles per liter, multiply by 7.397; hydroxyvitamin D to nanomoles per liter, multiply by levothyroxine sodium, epoetin alfa, paroxetine hydro- 2.496; parathyroid hormone to nanograms per liter, multiply by 1; phosphorus chloride, furosemide, oxycodone, acetaminophen, si- to millimoles per liter, multiply by 0.323; platelets to number ϫ109 per liter, methicone, senna, lorazepam, and 2% mupirocin oint- multiply by 1; serum urea nitrogen to millimoles per liter, multiply by 0.357; and ment twice daily. She denied any alterations or white blood cells to number of cells ϫ109 per liter, multiply by 0.001. aCorrected for serum albumin level. interruptions in warfarin dosing. She did not use alco- bMeasured only once during hospital course. hol, drugs, or tobacco products. Physical examination showed an afebrile, hemody- namically stable, obese (body mass index, 53 [calcu- pura on her thighs and abdomen despite culture- lated as weight in kilograms divided by height in meters directed antimicrobial therapy and replacing warfarin with squared]) woman in significant pain from a large reti- enoxaparin sodium. Initial biopsy specimens showed ne- form ulceration on the proximal part of her right thigh crosis of the epidermis and superficial dermis with fi- covered with a thick eschar surrounded by violaceous, brin microthrombi in the dermal and superficial subcu- indurated, tender, retiform plaques (Figure 1). The lat- taneous vasculature with minimal inflammation and no eral part of the thighs, the hips, and the pannus mani- vasculitis. Plain radiographs of her thighs did not iden- fested violaceous indurated plaques. She had no other per- tify tissue or vascular calcification. Persistent clinical sus- tinent cutaneous or mucosal findings. Laboratory picion of calciphylaxis prompted an incisional wedge bi- investigations are summarized in Table 1. opsy down to fascia, which showed intramural calcium Initial clinical differential diagnosis favored a vascu- deposition in subcutaneous arterioles with associated in- lopathic process (calciphylaxis vs warfarin necrosis) over timal hyperplasia and ischemic changes of the surround- vasculitis, and biopsy specimens were obtained from the ing panniculus (Figure 2). These clinical and histo- center and the periphery of her right thigh ulceration. pathological findings were consistent with the diagnosis The patient rapidly developed progressive retiform pur- of calciphylaxis.

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Figure 2. Cutaneous biopsy specimen showing intramural calcium Figure 3. Complete healing after 4 and 5 months of treatment with sodium deposition in subcutaneous arterioles with associated intimal hyperplasia thiosulfate and cinacalcet hydrochloride, respectively. and ischemic changes of the surrounding panniculus (hematoxylin-eosin, original magnification ϫ400).

Enoxaparin treatment was discontinued after 10 days, COMMENT during which the patient continued to develop new lesions, and ongoing anticoagulation was maintained with The pathogenesis of calciphylaxis is unclear. Selye and co- warfarin (international normalized ratio ranged from 2.0- workers10-12 first proposed an underlying mechanism in 6.0 throughout hospitalization). Parathyroid scan failed 1962 after experiments in rodents demonstrated that sen- to show a parathyroid adenoma, and surgical parathy- sitization with a “sensitizer” followed by exposure to a roidectomy was thought unlikely to benefit the patient “challenger” after a latency period could result in exten- because her parathyroid hormone level (65 pg/mL; to con- sive tissue calcification. Hyperparathyroidism and hyper- vert to nanograms per liter, multiply by 1) and calcium- vitaminosis D were identified as sensitizers, whereas egg phosphorus product (38 mg2/dL2) were interpreted as albumin, trauma, and iron or aluminum salts were pro- normal. However, because of progressive metastatic cal- posed as challengers. However, calciphylaxis in humans cification, oral therapy with cinacalcet hydrochloride (30 differs from the process originally described in rodents be- mg once daily), sevelamer hydrochloride (1600 mg 3 times cause calcification is predominantly of the vasculature in daily), and ergocalciferol (50 000 U twice weekly) was humans and of extravascular tissue in rodents. Nonethe- initiated promptly after diagnosis to decrease the calcium- less, Selye and associates’ theory of sensitizers and chal- phosphorus product in an attempt to improve the calci- lengers has persisted as the favored mechanism to ex- phylaxis. These medical interventions, in combination plain the aberrant calcium-phosphorus metabolism leading with local wound therapy and culture-directed antimi- to calciphylaxis in humans. This accepted mechanism of crobial therapy, appeared to stabilize her disease during calciphylaxis, most commonly observed in patients with the next month; however, the lesions did not heal. So- end-stage renal disease, is based on secondary hyperpara- dium thiosulfate (5 g intravenously daily) was then ini- thyroidism-induced elevated calcium-phosphorus prod- tiated, and within 2 weeks healthy granulation tissue was uct. The elevated calcium-phosphorus product acts as a noted at the borders of the ulcerations. sensitizer in a patient later exposed to a challenger, re- Oral cinacalcet hydrochloride (30 mg daily), sevelamer sulting in vascular calcification and increased susceptibil- hydrochloride(1600mg3timesdaily),ergocalciferol(50 000 ity to subsequent thrombosis of luminally narrowed vas- U twice weekly), and intravenous sodium thiosulfate (5 g culature with resultant end-organ hypoperfusion. daily) were continued on transfer to a long-term care facil- Vascular calcification and secondary hyperparathy- ity (at which time her parathyroid hormone level was 33 roidism are extremely common in patients undergoing pg/mL and calcium-phosphorus product was 29 mg2/dL2), hemodialysis, observed in 80% and 78%, respec- where she continued to experience progressive improve- tively.13-15 However, Angelis et al16 noted only a 4% preva- ment, with decreased pain and size of her ulcerations and lence of calciphylaxis among 242 patients undergoing long- no new lesions. Fourteen weeks later, after 4 and 5 months term dialysis. In addition, not all patients with calciphylaxis of treatment with sodium thiosulfate and cinacalcet, respec- manifest elevated calcium-phosphorus products, the most tively, the lesions were completely healed (Figure 3). The commonly cited sensitizer. Budisavljevic et al17 report only patientwastransferredtoarehabilitationfacilityfor2months one-third of dialysis recipients with calciphylaxis to have before returning home, at which time sodium thiosulfate a calcium-phosphorus product greater than 70 mg2/dL2. therapy was discontinued. She continued to take cinacal- These findings support a more complicated and multifac- cet, sevelamer, and ergocalciferol and remained in remis- eted pathogenesis than that originally described by Selye sion from her endometrial carcinoma without further com- et al. This view is further supported by the sheer volume plications from calciphylaxis throughout a posthealing of risk factors for the development of calciphylaxis reported follow-up period of 17 months. in traditional cases—and frequently contradicted—in the

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Table 2. Nontraditional Cases of Calciphylaxis in Patients With Both Normal Renal and Parathyroid Function

Patient Age, y/ Pertinent Proposed Proposed Source Sex Laboratory Valuesa Comorbidities Treatment Sensitizing Agent Challenging Agent Outcome Golitz and 48/F Cr, wnl Osteolytic metastatic breast Inorganic phosphate Hypercalcemia from Transient Death, cause Field,22 SUN, 20 cancer within 1 y; to lower serum Ca; osteolytic metastatic hyperphosphatemia unspecified 1972 PTH, wnl chemotherapy (vincristine systemic breast cancer from inorganic Albumin, NR sulfate, methotrexate, corticosteroids; phosphate therapy; Ca, 9.6b fluorouracil, local wound care systemic Phos, 5.3 (↑) cyclophosphamide) corticosteroids; CaϫPhos, 50.9b elevated CaϫPhos Fader and 58/F Cr, 1.1 Alcoholic cirrhosis with Prednisone taper and Slightly elevated PTH; Albumin infusions; Survived Kang,23 PTH, 70 (↑) history of ascites, ulcer debridement presumed systemic 1996 Albumin, 2.9 (↓) spontaneous bacterial hypercalcemia before corticosteroids Ca, 10.4c peritonitis, and albumin presentation that Phos, 3.4 infusions 5 wk before normalized on CaϫPhos, 35c onset; empirically treated cutaneous deposition with prednisone for vasculitis Mastruserio 49/F Cr, wnl Infiltrating ductal carcinoma Aluminum hydroxide Mildly elevated Systemic Survived et al,24 PTH, wnl with bone metastases 1,25-hydroxyvitamin D corticosteroids 1999 Albumin (↓) diagnosed 4 mo before (no value reported); Ca, 8.6b onset; chemotherapy transient elevation of Phos, 3.3 (mitoxantrone, fluorouracil, free Ca CaϫPhos, 28.4b leucovorin calcium); prednisone initiated for presumptive diagnosis of Sweet syndrome Goyal 64/F Cr, 0.8 Breast cancer 9 mo before Local wound care None suggested Chemotherapy- Death, sepsis et al,25 PTH, 46.1 CUA onset treated with and surgical induced protein C 2000 Albumin, NR chemotherapy debridement and S deficiency Ca, 9.1c (cyclophosphamide, (protein C and S not Phos, 3.6 doxorubicin hydrochloride, measured in CaϫPhos, 32.8c fluorouracil) patient) Riegert- 54/F Cr, 1.6 Deep venous thrombosis LMW heparin; vitamin None suggested Vitamin K Death, sepsis Johnson PTH, 19 diagnosed 1 mo before K supplementation supplementation for et al,26 Albumin, 2.4 (↓) onset and treated with for3d 3 d associated with 2001 Ca, 9.6c warfarin sodium; metastatic worsened Phos, 3.2 cholangiocarcinoma condition; warfarin CaϫPhos, 30.7c diagnosed 4 mo before therapy onset, treated with chemotherapy (gemcitabine hydrochloride, cisplatin); type 2 diabetes mellitus; coagulation evaluation suggested vitamin K deficiency, which was attributed to poor nutritional status Lim et al,27 53/F Cr, wnl Alcoholic liver disease; Local wound care; Elevated CaϫPhos Multiple blood Survived 2003 PTH, 29.1 increased CaϫPhos; pentoxifylline transfusions Albumin, NR multiple blood transfusions Ca, 12.1 (↑)b Phos, 4.64 (↑) CaϫPhos, 56.1 (↑)b CRP,62(↑) Korkmaz 43/M Cr, 1.9 on RA; prednisolone initially Discontinued None suggested Systemic Survived with left et al,28 admission, 0.7 after increased owing to prednisolone; corticosteroids above-knee 2002 rehydration presumptive diagnosis of amputation; ϫ18 y; protein S and 2 finger PTH, 43 rheumatoid vasculitis (CUA sulfasalazine deficiency (values amputations Albumin, 2.0 (↓) worsened with increased (for RA) not reported) Ca, 8.6c dose of corticosteroids) Phos, 3.7 CaϫPhos, 31.8c CRP, 24.6d Banky 68/F Cr, 0.79 Breast cancer 16 y earlier Local wound care; None suggested None suggested Survived with et al,29 PTH, 65 treated with mastectomy hyperbaric oxygen; bilateral 2002 Albumin, NR and radiotherapy; warfarin etidronate disodium above-knee Ca, 9.12b (long term without caused amputations Phos, 3.7 interruption or dosing hyperphosphatemia CaϫPhos, 33.7b change) for atrial fibrillation; (4.6 mg/dL); LMW Proteins C and S, wnl prednisolone therapy heparin initiated for presumptive diagnosis of vasculitis resulted in worsening of CUA

(continued)

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Patient Age, y/ Pertinent Proposed Proposed Source Sex Laboratory Valuesa Comorbidities Treatment Sensitizing Agent Challenging Agent Outcome Kutlu et al,30 15/M Cr, 1.2 Metastatic malignant Calcitonin; etidronate; Malignant None suggested Death, DIC and 2003 PTH, 11 melanoma of soft parts corticosteroids; neoplasm–associated acute renal Albumin, 2.7 (↓) LMW heparin hypercalcemia; failure Ca, 16.5c elevated CaϫPhos Phos, 4.3 CaϫPhos, 71.1 (↑)c Munavalli 28/F Cr, wnl Chronic cirrhosis; rapid Debridement; Rapid weight None suggested Survived et al,31 PTH, NR weight loss via intense hydrotherapy loss–induced MMP; 2003 Albumin, NR dieting; elevated urine MMP-altered vascular Ca, wnl matrix metalloproteinases wall elastin postulated Phos, NR (normal urine does not to provide enhanced CaϫPhos, Ͻ53 contain matrix matrix for Ca Homocysteine, metalloproteinases) deposition 2.49 (↑) Proteins C and S, wnl Bosler 73/F Cr, 1.0-2.0 (↑) Breast cancer with bone Excision; local wound Hypoalbuminemia None suggested Survived et al,32 PTH, 31 metastases originally care; topical 2007 Albumin, 2.7-3.3 (↓) diagnosed 7 y earlier, with corticosteroids Ca, wnl recent recurrence; diabetes Phos, 3.3-5.0 (↑) mellitus; distant history of CaϫPhos, Ͻ52.5 endometrial carcinoma; Obese (BMI not warfarin (long term without reported) interruption or dosing change) for atrial fibrillation Brouns 71/F, Cases 1/2: In both cases, GCA diagnosed Both cases: None suggested Both cases: systemic Case 1: death, et al,33 82/F Cr, 1.09/1.03 and treated with discontinued corticosteroids, sepsis; case 2: 2007 PTH, 0.3/Ͻ 3 methylprednisolone, Ca, corticosteroid, Ca, phenprocoumon; death, cause Albumin, 3.49/4.33 and vitamin D and vitamin D GCA-induced unspecified Ca, 9.58/10.25c approximately 6 mo before therapy; treated vascular Phos, 3.06/3.08 CUA onset; both patients with LMW heparin inflammation or CaϫPhos, 29.3/31.6c taking phenprocoumon for and antibiotics therapy for GCA CRP, 58.9 (↑)/19.1 (↑) atrial fibrillation; patient 2 may have played Protein C, 54% was treated with causative role (↓)/Ͼ150% (↑) alendronate sodium Protein S, NR/64% (↓) Present 58/F Cr, 0.6 Stage IIIc endometrial Local wound care and High-normal PTH; mild Possible Survived report SUN, 13 adenocarcinoma with culture-directed hyperphosphatemia; chemotherapy- PTH, 63 chemotherapy (carboplatin antibiotics; hypoalbuminemia; induced protein C Albumin, 2.9 (↓) and paclitaxel) completed 2 sevelamer malignant neoplasm and S deficiency Ca, 9.08c wk before onset of CUA; hydrochloride; (protein C and S not Phos, 4.6 (↑) warfarin (long term without cinacalcet measured before CaϫPhos, 41.8c interruption or dosing hydrochloride; onset of CUA); Obese (BMI, 53) change) for deep venous sodium thiosulfate warfarin therapy; SeeTable1for thrombosis; morbid obesity; systemic remainder of obesity; pelvic abscess and inflammation; laboratory values urinary tract infection infection

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); Ca, calcium; Cr, creatinine; CRP, C-reactive protein; CUA, calcific uremic arteriolopathy (calciphylaxis); DIC, disseminated intravascular coagulation; GCA, giant cell arteritis; LMW, low-molecular-weight; MMP, matrix metalloproteinase production; NR, not reported; Phos, phosphorus; PTH, parathyroid hormone; RA, rheumatoid arthritis; SUN, serum urea nitrogen; wnl, within normal limits (no value reported); ↑, laboratory value is above the reference range; ↓, laboratory value is below the reference range. SI conversion factors: To convert CRP to nanomoles per liter, multiply by 9.524; (see Table 1 for other conversion factors). aLaboratory evaluation units and reference ranges are as follows: Alb, 3.5 to 4.9 g/dL; BMI, 18.5 to 24.9; Ca, 8.5 to 10.5 mg/dL; CaϫPhos, less than 55 mg2/dL2; Cr, 0.7 to 1.2 mg/dL; CRP, less than 5 mg/L; homocysteine, 1.09 to 1.64 mg/L; Phos, 2.3 to 4.3 mg/dL; protein C, 70% to 149%; protein S, 80% to 120%; PTH, 9 to 69 pg/mL; and SUN, 7 to 20 mg/dL. bCalcium level not corrected for albumin level because of inadequate data. cSerum calcium level corrected for albumin level. dCRP units and reference range, 0 to 5 mg/L.

literature.5-9,18 This is likely due to the relative rarity of cal- v Obesity5,19,20 ciphylaxis,limitinganalysestosmallcaseseriesandreviews.18 v Liver disease5 A few larger case-control studies have identified several v Systemic corticosteroid use5 consistent statistically associated risk factors for the devel- v Elevated calcium-phosphorus product5,19 opment of calciphylaxis in traditional patients. However, v Increased erythrocyte sedimentation rate5 findings regarding the relation of other risk factors with cal- v White race19-21 ciphylaxishavebeenlessconsistentamonglargercase-control v Female sex19-21 studies. These findings are summarized as follows: v Decreased albumin level19-21 Factors identified as statistically associated with the v Elevated phosphorus level19,21 development of calciphylaxis v Elevated alkaline phosphatase level21

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Table 3. Notable Patient Characteristics, Prevalence, and Proposed Mechanism of Action Identified Among Patients With Nontraditional Calciphylaxis With Both Normal Renal and Parathyroid Function

Patient Characteristic Prevalence, No. (%) Suggested Mechanism of Action Hypoalbuminemia 7/9 (78) Increase in free serum calcium34 Malignant neoplasm 8/14 (57) Malignant neoplasm–associated hypercalcemia, hypercoagulability,35 and inflammation; secondary effects of chemotherapy as challenging agent Systemic 7/14 (50) Numerous postulated mechanisms of endothelial damage36; increased bone resorption via corticosteroids upregulation of nuclear factor ␬B ligand (RANKL) and downregulation of osteoprotegerin; RANKL functions to induce osteoclastogenesis; osteoprotegerin is neutralizing receptor for RANKL37,38; may exacerbate calcium and phosphorus abnormalities via induction of adynamic bone disease5 Anticoagulation 6/14 (43) Inhibition of protein C and S; inhibition of ␥-carboxylation of matrix ␥-carboxyglutamic acid proteins, which normally function to inhibit endogenous calcification39 Chemotherapy 5/14 (36) Chemotherapy-induced protein C and/or S deficiencies Systemic inflammation 4/14 (29) Endothelial damage33 Cirrhosis of liver 3/14 (21) Via secondary effects of: impaired production of protein C and/or S; decreased production of albumin leading to increased free serum calcium Protein C or S Identified in 2/14 (14) Mehta et al40 noted similar clinical presentation of warfarin necrosis and identified statistically deficiency Suggested in additional significantly reduced functional protein C level in patients with traditional calciphylaxis vs 2 cases but not tested hemodialysis control patients without calciphylaxis; hypercoagulable state resulting from impaired endothelial production of protein S due to endothelial cell dysfunction from severe vascular calcification28; difficult to interpret protein C and S levels because they are acute-phase reactants; also, level not reported in many cases Obesity 2/14 (14) Sluggish blood flow in large adipose deposits4; likely underreported because body habitus not reported in most cases Rapid weight loss 1/14 (7) Weight loss–induced production of matrix metalloproteinase digestion of vascular elastin, providing enhanced matrix for calcium deposition31 Infection 1/14 (7) Increased thrombosis risk41

Factors proposed in case reports to be risk factors but phylaxis occurring in a nontraditional patient should be not statistically associated with the development of cal- considered. ciphylaxis in case-control studies The increasingly common observation of calciphylaxis in patients with normal renal and parathyroid func- v Obesity21 tion supports the view of calciphylaxis as a final com- v Warfarin use5 mon end point, reachable via many pathways involving v Vitamin D administration5 the interplay of various risk factors. Exposure to sensi- v Intact parathyroid hormone level5,19 tizers and challengers culminates in an increased sus- v Protein C and S levels5 ceptibility to vascular calcification and luminally nar- v Calcium level19,21 rowed arterioles, which are subsequently prone to v Diabetes mellitus5,20 thrombosis if exposed to the proper stimuli. However, v Albumin level5 only a small proportion of susceptible patients ulti- Recently, several reports of calciphylaxis occurring in mately develop calciphylaxis, suggesting that a specific nontraditional patients with both normal renal and para- combination of sensitizing and challenging conditions thyroid function have been published (Table 2).22-33 Sus- must surpass a critical threshold in combination with an picion of calciphylaxis in nontraditional patients is gen- appropriate thrombogenic stimulus for calciphylaxis- erally low, as evidenced by the proportion of the reported induced ischemic necrosis to develop. The extent and du- cases in which accurate diagnosis was delayed.23,24,28-30 ration of this threshold breach may well correlate with Analysis of these 13 nontraditional cases in addition to disease severity and clinical outcome. Weenig18 re- the current report showed a mean age of 54.5 years, a cently reviewed the interaction of these numerous pre- preponderance of female patients (female to male ratio, disposing factors and provided a comprehensive sum- 12:2), and a mortality rate of 43%. The patient charac- mary that is invaluable in understanding the complex teristics identified as potential risk factors because of their mechanisms by which the proposed risk factors result greater than expected incidence among the 14 patients in both traditional and nontraditional calciphylaxis. The and the proposed mechanism of their contribution to the final common pathway involves nuclear factor ␬B acti- development of calciphylaxis in nontraditional patients vation leading to vascular calcification, which, when fol- are shown in Table 3.34-41 Interestingly, many of these lowed by thrombosis, results in the clinical manifesta- patient characteristics are shared by patients with tran- tions of calciphylaxis. Thus, in addition to general sient acute renal insufficiencies who have calciphy- supportive care and prevention of infection, rapid diag- laxis,34,42,43 as well as by patients with chronic renal in- nosis and therapeutic intervention targeted at correc- sufficiency who are not receiving dialysis.5 Although our tion of the specific underlying sensitizers and challeng- observation that these patient characteristics are over- ers should improve outcomes in this devastating disease. represented does not prove causality, it may highlight spe- Our patient’s risk factors included female sex, obesity, cific clinical situations in which the diagnosis of calci- hypoalbuminemia, hypovitaminosis D, warfarin use, and

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 thrombotic tendency (recent deep venous thrombosis, well as highlight clinical scenarios in which heightened malignant neoplasm, chemotherapy, and infection). suspicion of the diagnosis of calciphylaxis may lead to Paradoxically, although thrombogenesis is clearly in- more rapid diagnosis and improved patient outcomes. volved in the development of calciphylaxis, we identified a relatively high incidence of warfarin or phenprocou- Accepted for Publication: July 6, 2008. mon therapy (43%) in nontraditional patients with calci- 39 Correspondence: Andrew H. Kalajian, MD, Division of phylaxis. Price et al demonstrated warfarin’s ability to Dermatology, University of Louisville, 310 E Broadway, promote vascular calcification in rodents likely via inhi- ␥ ␥ Floor 2A, Louisville, KY 40202 (akalajian@yahoo bition of -carboxylation of matrix -carboxyglutamic acid .com). proteins that normally function to inhibit endogenous cal- Author Contributions: All authors had full access to all cification. Four of the 6 nontraditional patients with cal- of the data in the study and take responsibility for the ciphylaxis receiving warfarin or phenprocoumon had si- integrity of the data and the accuracy of the data analy- multaneous malignant tumors, the presence of which has sis. Study concept and design: Kalajian and Parker. Acqui- been well documented to increase the risk of thrombotic sition of data: Kalajian, Malhotra, and Parker. Analysis and events.35 In addition, our patient and the patient de- 26 interpretation of data: Kalajian, Malhotra, and Callen. Draft- scribed by Riegert-Johnson et al had recent deep ve- ing of the manuscript: Kalajian and Malhotra. Critical re- nous thromboses, indicative of their hypercoagulable ten- vision of the manuscript for important intellectual content: dencies. Furthermore, acute infection is associated with Kalajian, Callen, and Parker. Statistical analysis: Not ap- increased risk of thrombosis, suggesting that our pa- plicable. Obtained funding: Not applicable. Administra- tient’s acute and chronic infectious conditions may have 41 tive, technical, and material support: Malhotra and Callen. contributed to her thrombotic predisposition. In sum, Study supervision: Kalajian and Parker. warfarin’s ability to promote vascular calcification and the Financial Disclosure: Dr Callen has received honoraria increased risk of thrombosis from comorbid states may out- from Amgen, Abbott Immunology, Genentech, Cento- weigh the antithrombotic properties of warfarin. cor, Electrical Optical Sciences, Medicis, and Steifel. He Recently, promising reports of successful outcomes 44,45 serves on a safety monitoring committee for Genmab. have been noted after treatment with cinacalcet, a cal- Disclaimer: Dr Callen is an associate editor of the cimimetic shown to lower parathyroid hormone levels Archives of Dermatology but was not involved in any of and improve calcium-phosphorus metabolism in pa- 46,47 the decisions regarding review of the manuscript or its tients undergoing dialysis, and sodium thiosulfate, an acceptance. inorganic salt that promotes dissolution of calcium de- Additional Contributions: Janine C. 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