CALCIPHYLAXIS, ALSO KNOWN

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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 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” pa-tients having both normal renal and parathyroid func-tion has been reported. However, to date there has been no collective analysis identifying common patient char-acteristics potentially predisposing to the development of calciphylaxis in nontraditional patients.

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 high-light clinical situations potentially predisposing to calci-phylaxis: hypoalbuminemia, malignant neoplasm, sys-temic corticosteroid use, anticoagulation with warfarin sodium or phenprocoumon, chemotherapy, systemic in-flammation, 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 der-matologists in the rapid diagnosis and prompt initiation of therapy for this devastating disease.

Arch Dermatol. 2009;145(4):451-458

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ALCIPHYLAXIS,ALSO KNOWN

as calcific uremic arterio-lopathy, is a metastatic calcification-induced mi-crovascular occlusion syn-drome of mural calcification, intimal pro-liferation, fibrosis, and thrombosis leading to target organ hypoperfusion.1,2 Cutane-ous calciphylaxis manifests with noninflam-matory retiform purpura, the hallmark of cutaneous microvascular occlusion syn-dromes, for which the differential diagno-sis is broad, including disorders of platelet plugging, cold-related agglutination, ves-sel invasive organisms, embolization, local or systemic coagulopathies, and miscella-neous conditions (calciphylaxis, Degos dis-ease, and sickle cell anemia).3Lesions of cal-ciphylaxis are typically very painful, with ulceration, secondary infection, and end-organ hypoperfusion often resulting in gan-grene, amputation, and sepsis with associ-ated mortality rates as high as 89%.4,5 Excellent comprehensive reviews of calci-phylaxis have been published.5-9

Since Selye and coworkers10-12 origi-nally coined the term in 1962, calciphy-laxis has usually been reported in pa-tients with end-stage renal disease and

secondary hyperparathyroidism (re-ferred to herein as “traditional” patients).5-9 Calciphylaxis occurring in patients with both normal renal and parathyroid func-tion (referred to as “nontradifunc-tional” pa-tients) is considered extremely rare. Al-though 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 ob-served in patients having both normal re-nal and parathyroid function. In addi-tion, to our knowledge, no report has collectively reviewed these published non-traditional cases in an attempt to identify risk factors for the development of calci-phylaxis in this patient population.

We studied a patient with normal renal and parathyroid function who developed extensive calciphylaxis. We evaluated simi-lar reported cases, identifying common characteristics among these patients that may represent risk factors for the develop-ment of calciphylaxis. We hope to raise awareness that the development of calci-phylaxis in nontraditional patients having both normal renal and parathyroid func-tion is not as rare as previously believed. Author Affiliations: Division of

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REPORT OF A CASE

A 58-year-old woman had a 4-week history of exquis-itely painful ulcerations and violaceous tender plaques on both thighs and her lower abdomen. Seven months earlier she had been diagnosed as having stage IIIc en-dometrial carcinoma, which was treated with surgery (complicated by a chronic pelvic abscess requiring per-cutaneous drainage) and chemotherapy. The chemo-therapy had been completed (cycle 1 with carboplatin alone and cycles 2 through 5 with carboplatin and pac-litaxel) 2 weeks before the development of the cutane-ous lesions. The patient’s medical history included obe-sity, hypertension, hypothyroidism, anemia, and venous stasis. Active comorbidities included deep venous throm-bosis and Pseudomonas aeruginosa infection of both her lower urinary tract and her right thigh ulceration. Medi-cations included warfarin sodium, amlodipine besylate, levothyroxine sodium, epoetin alfa, paroxetine hydro-chloride, furosemide, oxycodone, acetaminophen, si-methicone, senna, lorazepam, and 2% mupirocin oint-ment twice daily. She denied any alterations or interruptions in warfarin dosing. She did not use alco-hol, drugs, or tobacco products.

Physical examination showed an afebrile, hemody-namically stable, obese (body mass index, 53 [calcu-lated as weight in kilograms divided by height in meters squared]) woman in significant pain from a large reti-form ulceration on the proximal part of her right thigh covered with a thick eschar surrounded by violaceous, indurated, tender, retiform plaques (Figure 1). The lat-eral part of the thighs, the hips, and the pannus mani-fested violaceous indurated plaques. She had no other per-tinent cutaneous or mucosal findings. Laboratory investigations are summarized inTable 1.

Initial clinical differential diagnosis favored a vascu-lopathic 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

pur-pura on her thighs and abdomen despite culture-directed antimicrobial therapy and replacing warfarin with enoxaparin sodium. Initial biopsy specimens showed ne-crosis of the epidermis and superficial dermis with fi-brin microthrombi in the dermal and superficial subcu-taneous vasculature with minimal inflammation and no vasculitis. Plain radiographs of her thighs did not iden-tify tissue or vascular calcification. Persistent clinical sus-picion of calciphylaxis prompted an incisional wedge bi-opsy down to fascia, which showed intramural calcium deposition in subcutaneous arterioles with associated in-timal hyperplasia and ischemic changes of the surround-ing panniculus (Figure 2). These clinical and histo-pathological findings were consistent with the diagnosis of calciphylaxis.

Figure 1. Large retiform ulceration with thick eschar on the proximal part of

the right thigh surrounded by violaceous, indurated, tender, retiform plaques.

Table 1. Results of Laboratory Investigations

Laboratory Investigation Initial Value Range During Hospitalization Reference Range Hemoglobin, g/dL 8.9 (↓) 7.3-11.7 11.2-15.7 White blood cells,⫻103/µL 10.0 5.4-14.0 4.1-10.8 Platelets,⫻103/µL 438 (↑) 344-639 140-370 Creatinine, mg/dL 0.6 (↓) 0.4-0.8 0.7-1.2 Serum urea nitrogen,

mg/dL 13 5-20 7-20 Aspartate aminotransferase, U/L 31 20-54 10-47 Alanine aminotransferase, U/L 25 11-31 10-50

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 product,mg2/dL2a 41.8 33.1-63.4 ⬍55 25-Hydroxyvitamin D, ng/mL 7b(↓) NA 20-200 Parathyroid hormone, pg/mL 63 33-67 10-65 24-h urine calcium, mg 35.7b(↓) NA 45-353 24-h urine phosphorus, mg 0.37b(↓) NA 0.4-1.3 Protein C, % 106b NA 90-131 Protein S, % 119b(↑) NA 57-88 PT, s 32.5 (↑) 12.8-54.4 9.4-11.6 INR 3.8 (↑) 1.3-6.4 0.9-1.2 aPTT, s 40.8 (↑) 34.5-64.1 22-30.4 Homocysteine, mg/L 1.41b NA 0.60-1.68 Factor V Leiden mutation Negativeb NA Negative Lupus anticoagulant screen Negativeb NA Negative Anticardiolipin IgG, IgM,

IgA antibodies, U/mL

All normalb NA IgG and IgM,⬍20; IgA,⬍12 ␤2-Glycoprotein-1 IgG,

IgM, IgA antibodies, U/mL

IgG and IgM, normalb; IgA, 13b(↑)

NA IgG,⬍20; IgM and IgA,⬍10

Abbreviations: aPTT, activated partial thromboplastin time; INR, international normalized ratio; NA, not applicable; PT, prothrombin time;↑, laboratory value is above the reference range;↓, laboratory value is below the reference range. SI conversion factors: To convert alanine and aspartate aminotransferases and alkaline phosphatase to microkatals per liter, multiply by 0.0167; albumin to grams per liter, multiply by 10; calcium and ionized calcium to millimoles per liter, multiply by 0.25; creatinine to micromoles per liter, multiply by 88.4; 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 2.496; parathyroid hormone to nanograms per liter, multiply by 1; phosphorus to millimoles per liter, multiply by 0.323; platelets to number⫻109per liter,

multiply by 1; serum urea nitrogen to millimoles per liter, multiply by 0.357; and white blood cells to number of cells⫻109per liter, multiply by 0.001.

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Enoxaparin treatment was discontinued after 10 days, during which the patient continued to develop new le-sions, 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 parathy-roidectomy was thought unlikely to benefit the patient because her parathyroid hormone level (65 pg/mL; to con-vert to nanograms per liter, multiply by 1) and calcium-phosphorus product (38 mg2/dL2) were interpreted as normal. However, because of progressive metastatic cal-cification, 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 calci-phylaxis. These medical interventions, in combination with local wound therapy and culture-directed antimi-crobial therapy, appeared to stabilize her disease during the next month; however, the lesions did not heal. So-dium thiosulfate (5 g intravenously daily) was then ini-tiated, and within 2 weeks healthy granulation tissue was noted at the borders of the ulcerations.

Oral cinacalcet hydrochloride (30 mg daily), sevelamer hydrochloride(1600mg3timesdaily),ergocalciferol(50 000 U twice weekly), and intravenous sodium thiosulfate (5 g daily) were continued on transfer to a long-term care facil-ity (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 improve-ment, 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, respec-tively, the lesions were completely healed (Figure 3). The patientwastransferredtoarehabilitationfacilityfor2months before returning home, at which time sodium thiosulfate therapy was discontinued. She continued to take cinacal-cet, sevelamer, and ergocalciferol and remained in remis-sion from her endometrial carcinoma without further com-plications from calciphylaxis throughout a posthealing follow-up period of 17 months.

COMMENT

The pathogenesis of calciphylaxis is unclear. Selye and co-workers10-12first proposed an underlying mechanism in 1962 after experiments in rodents demonstrated that sen-sitization with a “sensitizer” followed by exposure to a “challenger” after a latency period could result in exten-sive tissue calcification. Hyperparathyroidism and hyper-vitaminosis D were identified as sensitizers, whereas egg albumin, trauma, and iron or aluminum salts were pro-posed as challengers. However, calciphylaxis in humans differs from the process originally described in rodents be-cause calcification is predominantly of the vasculature in humans and of extravascular tissue in rodents. Nonethe-less, Selye and associates’ theory of sensitizers and chal-lengers has persisted as the favored mechanism to ex-plain 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 hyperpara-thyroidism-induced elevated calcium-phosphorus prod-uct. The elevated calcium-phosphorus product acts as a sensitizer in a patient later exposed to a challenger, re-sulting in vascular calcification and increased susceptibil-ity to subsequent thrombosis of luminally narrowed vas-culature with resultant end-organ hypoperfusion.

Vascular calcification and secondary hyperparathy-roidism are extremely common in patients undergoing hemodialysis, observed in 80% and 78%, respec-tively.13-15However, Angelis et al16noted only a 4% preva-lence 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 al17report 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 multifac-eted 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

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⫻400).

Figure 3. Complete healing after 4 and 5 months of treatment with sodium

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Table 2. Nontraditional Cases of Calciphylaxis in Patients With Both Normal Renal and Parathyroid Function Source Patient Age, y/ Sex Pertinent

Laboratory Valuesa Comorbidities Treatment Sensitizing AgentProposed Challenging AgentProposed Outcome Golitz and Field,22 1972 48/F Cr, wnl SUN, 20 PTH, wnl Albumin, NR Ca, 9.6b Phos, 5.3 (↑) Ca⫻Phos, 50.9b

Osteolytic metastatic breast cancer within 1 y; chemotherapy (vincristine sulfate, methotrexate, fluorouracil, cyclophosphamide) Inorganic phosphate to lower serum Ca; systemic corticosteroids; local wound care

Hypercalcemia from osteolytic metastatic breast cancer Transient hyperphosphatemia from inorganic phosphate therapy; systemic corticosteroids; elevated Ca⫻Phos Death, cause unspecified Fader and Kang,23 1996 58/F Cr, 1.1 PTH, 70 (↑) Albumin, 2.9 (↓) Ca, 10.4c Phos, 3.4 Ca⫻Phos, 35c

Alcoholic cirrhosis with history of ascites, spontaneous bacterial peritonitis, and albumin infusions 5 wk before onset; empirically treated with prednisone for vasculitis

Prednisone taper and ulcer debridement Slightly elevated PTH; presumed hypercalcemia before presentation that normalized on cutaneous deposition Albumin infusions; systemic corticosteroids Survived Mastruserio et al,24 1999 49/F Cr, wnl PTH, wnl Albumin (↓) Ca, 8.6b Phos, 3.3 Ca⫻Phos, 28.4b

Infiltrating ductal carcinoma with bone metastases diagnosed 4 mo before onset; chemotherapy (mitoxantrone, fluorouracil, leucovorin calcium); prednisone initiated for presumptive diagnosis of Sweet syndrome

Aluminum hydroxide Mildly elevated 1,25-hydroxyvitamin D (no value reported); transient elevation of free Ca Systemic corticosteroids Survived Goyal et al,25 2000 64/F Cr, 0.8 PTH, 46.1 Albumin, NR Ca, 9.1c Phos, 3.6 Ca⫻Phos, 32.8c

Breast cancer 9 mo before CUA onset treated with chemotherapy (cyclophosphamide, doxorubicin hydrochloride, fluorouracil)

Local wound care and surgical debridement

None suggested Chemotherapy-induced protein C and S deficiency (protein C and S not measured in patient) Death, sepsis Riegert-Johnson et al,26 2001 54/F Cr, 1.6 PTH, 19 Albumin, 2.4 (↓) Ca, 9.6c Phos, 3.2 Ca⫻Phos, 30.7c

Deep venous thrombosis diagnosed 1 mo before onset and treated with warfarin sodium; metastatic cholangiocarcinoma diagnosed 4 mo before onset, treated with chemotherapy (gemcitabine hydrochloride, cisplatin); type 2 diabetes mellitus; coagulation evaluation suggested vitamin K deficiency, which was attributed to poor nutritional status

LMW heparin; vitamin K supplementation for 3 d

None suggested Vitamin K supplementation for 3 d associated with worsened condition; warfarin therapy Death, sepsis Lim et al,27 2003 53/F Cr, wnl PTH, 29.1 Albumin, NR Ca, 12.1 (↑)b Phos, 4.64 (↑) Ca⫻Phos, 56.1 (↑)b CRP, 62 (↑)

Alcoholic liver disease; increased Ca⫻Phos; multiple blood transfusions

Local wound care; pentoxifylline

Elevated Ca⫻Phos Multiple blood transfusions Survived Korkmaz et al,28 2002 43/M Cr, 1.9 on admission, 0.7 after rehydration PTH, 43 Albumin, 2.0 (↓) Ca, 8.6c Phos, 3.7 Ca⫻Phos, 31.8c CRP, 24.6d

RA; prednisolone initially increased owing to presumptive diagnosis of rheumatoid vasculitis (CUA worsened with increased dose of corticosteroids) Discontinued prednisolone; amputation; sulfasalazine (for RA)

None suggested Systemic corticosteroids ⫻18 y; protein S deficiency (values not reported)

Survived with left above-knee and 2 finger amputations Banky et al,29 2002 68/F Cr, 0.79 PTH, 65 Albumin, NR Ca, 9.12b Phos, 3.7 Ca⫻Phos, 33.7b Proteins C and S, wnl

Breast cancer 16 y earlier treated with mastectomy and radiotherapy; warfarin (long term without interruption or dosing change) for atrial fibrillation; prednisolone therapy initiated for presumptive diagnosis of vasculitis resulted in worsening of CUA

Local wound care; hyperbaric oxygen; etidronate disodium caused hyperphosphatemia (4.6 mg/dL); LMW heparin

None suggested None suggested Survived with bilateral above-knee amputations

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literature.5-9,18This is likely due to the relative rarity of cal-ciphylaxis,limitinganalysestosmallcaseseriesandreviews.18 A few larger case-control studies have identified several consistent statistically associated risk factors for the devel-opment of calciphylaxis in traditional patients. However, findings regarding the relation of other risk factors with cal-ciphylaxishavebeenlessconsistentamonglargercase-control studies. These findings are summarized as follows:

Factors identified as statistically associated with the development of calciphylaxis

v Obesity5,19,20 v Liver disease5

v Systemic corticosteroid use5

v Elevated calcium-phosphorus product5,19 v Increased erythrocyte sedimentation rate5 v White race19-21

v Female sex19-21

v Decreased albumin level19-21 v Elevated phosphorus level19,21 v Elevated alkaline phosphatase level21 Table 2. Nontraditional Cases of Calciphylaxis in Patients With Both Normal Renal and Parathyroid Function (continued)

Source

Patient Age, y/ Sex

Pertinent

Laboratory Valuesa Comorbidities Treatment Sensitizing AgentProposed Challenging AgentProposed Outcome Kutlu et al,30 2003 15/M Cr, 1.2 PTH, 11 Albumin, 2.7 (↓) Ca, 16.5c Phos, 4.3 Ca⫻Phos, 71.1 (↑)c Metastatic malignant melanoma of soft parts

Calcitonin; etidronate; corticosteroids; LMW heparin Malignant neoplasm–associated hypercalcemia; elevated Ca⫻Phos

None suggested Death, DIC and acute renal failure Munavalli et al,31 2003 28/F Cr, wnl PTH, NR Albumin, NR Ca, wnl Phos, NR Ca⫻Phos, ⬍53 Homocysteine, 2.49 (↑) Proteins C and S, wnl

Chronic cirrhosis; rapid weight loss via intense dieting; elevated urine matrix metalloproteinases (normal urine does not contain matrix metalloproteinases) Debridement; hydrotherapy Rapid weight loss–induced MMP; MMP-altered vascular wall elastin postulated to provide enhanced matrix for Ca deposition

None suggested Survived

Bosler et al,32 2007 73/F Cr, 1.0-2.0 (↑) PTH, 31 Albumin, 2.7-3.3 (↓) Ca, wnl Phos, 3.3-5.0 (↑) Ca⫻Phos, ⬍52.5 Obese (BMI not

reported)

Breast cancer with bone metastases originally diagnosed 7 y earlier, with recent recurrence; diabetes mellitus; distant history of endometrial carcinoma; warfarin (long term without interruption or dosing change) for atrial fibrillation

Excision; local wound care; topical corticosteroids

Hypoalbuminemia None suggested Survived

Brouns et al,33 2007 71/F, 82/F Cases 1/2: Cr, 1.09/1.03 PTH, 0.3/⬍ 3 Albumin, 3.49/4.33 Ca, 9.58/10.25c Phos, 3.06/3.08 Ca⫻Phos, 29.3/31.6c CRP, 58.9 (↑)/19.1 (↑) Protein C, 54% (↓)/⬎150% (↑) Protein S, NR/64% (↓)

In both cases, GCA diagnosed and treated with methylprednisolone, Ca, and vitamin D

approximately 6 mo before CUA onset; both patients taking phenprocoumon for atrial fibrillation; patient 2 was treated with alendronate sodium Both cases: discontinued corticosteroid, Ca, and vitamin D therapy; treated with LMW heparin and antibiotics

None suggested Both cases: systemic corticosteroids, phenprocoumon; GCA-induced vascular inflammation or therapy for GCA may have played causative role Case 1: death, sepsis; case 2: death, cause unspecified Present report 58/F Cr, 0.6 SUN, 13 PTH, 63 Albumin, 2.9 (↓) Ca, 9.08c Phos, 4.6 (↑) Ca⫻Phos, 41.8c Obese (BMI, 53) See Table 1 for

remainder of laboratory values

Stage IIIc endometrial adenocarcinoma with chemotherapy (carboplatin and paclitaxel) completed 2 wk before onset of CUA; warfarin (long term without interruption or dosing change) for deep venous thrombosis; morbid obesity; pelvic abscess and urinary tract infection

Local wound care and culture-directed antibiotics; sevelamer hydrochloride; cinacalcet hydrochloride; sodium thiosulfate High-normal PTH; mild hyperphosphatemia; hypoalbuminemia; malignant neoplasm Possible chemotherapy-induced protein C and S deficiency (protein C and S not measured before onset of CUA); warfarin therapy; obesity; systemic inflammation; infection Survived

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; Ca⫻Phos, 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.

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

v Obesity21 v Warfarin use5

v Vitamin D administration5

v Intact parathyroid hormone level5,19 v Protein C and S levels5

v Calcium level19,21 v Diabetes mellitus5,20 v Albumin level5

Recently, several reports of calciphylaxis occurring in nontraditional patients with both normal renal and para-thyroid function have been published (Table 2).22-33 Sus-picion of calciphylaxis in nontraditional patients is gen-erally 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 charac-teristics 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 inTable 3.34-41Interestingly, many of these patient characteristics are shared by patients with tran-sient acute renal insufficiencies who have calciphy-laxis,34,42,43as well as by patients with chronic renal in-sufficiency who are not receiving dialysis.5Although our observation that these patient characteristics are over-represented does not prove causality, it may highlight spe-cific clinical situations in which the diagnosis of

calci-phylaxis occurring in a nontraditional patient should be considered.

The increasingly common observation of calciphy-laxis in patients with normal renal and parathyroid func-tion supports the view of calciphylaxis as a final com-mon end point, reachable via many pathways involving the interplay of various risk factors. Exposure to sensi-tizers and challengers culminates in an increased sus-ceptibility to vascular calcification and luminally nar-rowed arterioles, which are subsequently prone to thrombosis if exposed to the proper stimuli. However, only a small proportion of susceptible patients ulti-mately 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 du-ration of this threshold breach may well correlate with disease severity and clinical outcome. Weenig18 re-cently reviewed the interaction of these numerous pre-disposing factors and provided a comprehensive sum-mary 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 acti-vation leading to vascular calcification, which, when fol-lowed by thrombosis, results in the clinical manifesta-tions of calciphylaxis. Thus, in addition to general supportive care and prevention of infection, rapid diag-nosis and therapeutic intervention targeted at correc-tion of the specific underlying sensitizers and challeng-ers should improve outcomes in this devastating disease. Our patient’s risk factors included female sex, obesity, hypoalbuminemia, hypovitaminosis D, warfarin use, and 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,35and inflammation; secondary

effects of chemotherapy as challenging agent Systemic

corticosteroids

7/14 (50) Numerous postulated mechanisms of endothelial damage36; increased bone resorption via

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 deficiency

Identified in 2/14 (14) Suggested in additional

2 cases but not tested

Mehta et al40noted similar clinical presentation of warfarin necrosis and identified statistically

significantly reduced functional protein C level in patients with traditional calciphylaxis vs 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

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thrombotic tendency (recent deep venous thrombosis, malignant neoplasm, chemotherapy, and infection).

Paradoxically, although thrombogenesis is clearly in-volved in the development of calciphylaxis, we identified a relatively high incidence of warfarin or phenprocou-mon therapy (43%) in nontraditional patients with calci-phylaxis. Price et al39demonstrated warfarin’s ability to promote vascular calcification in rodents likely via inhi-bition of␥-carboxylation of matrix ␥-carboxyglutamic acid proteins that normally function to inhibit endogenous cification. Four of the 6 nontraditional patients with cal-ciphylaxis receiving warfarin or phenprocoumon had si-multaneous malignant tumors, the presence of which has been well documented to increase the risk of thrombotic events.35In addition, our patient and the patient de-scribed by Riegert-Johnson et al26had recent deep ve-nous thromboses, indicative of their hypercoagulable ten-dencies. Furthermore, acute infection is associated with increased risk of thrombosis, suggesting that our pa-tient’s acute and chronic infectious conditions may have contributed to her thrombotic predisposition.41In sum, warfarin’s ability to promote vascular calcification and the increased risk of thrombosis from comorbid states may out-weigh the antithrombotic properties of warfarin.

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

Although our patient’s parathyroid status was ulti-mately interpreted as normal, her endocrine/electrolyte status was difficult to interpret. Her high-normal para-thyroid hormone level was attributed to hypovitamino-sis D, previously shown to be associated with decreased intestinal calcium absorption with subsequent parathy-roid hormone elevation.18,48However, her fluctuating normal to high serum phosphorus level (range, 4.0-6.2 mg/dL) and mildly decreased 24-hour urine phospho-rus levels are difficult to justify considering her high-normal parathyroid hormone level and high-normal renal function. Spurious hyperphosphatemia has been dem-onstrated to result from phlebotomy sample contami-nation by heparin used to maintain the patency of pe-ripheral access lines.49Although we cannot definitively implicate sample contamination in our patient’s vari-able serum phosphorus levels, neither can it be defini-tively excluded. Nonetheless, despite her normal renal and parathyroid status, she experienced a dramatic im-provement and ultimately successful outcome after treatment with cinacalcet and sodium thiosulfate; to our knowledge, this is the first description of a nontra-ditional 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.

Accepted for Publication: July 6, 2008.

Correspondence: Andrew H. Kalajian, MD, Division of

Dermatology, University of Louisville, 310 E Broadway, Floor 2A, Louisville, KY 40202 (akalajian@yahoo .com).

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 analy-sis. Study concept and design: Kalajian and Parker. Acqui-sition of data: Kalajian, Malhotra, and Parker. Analysis and interpretation of data: Kalajian, Malhotra, and Callen. Draft-ing of the manuscript: Kalajian and Malhotra. Critical re-vision of the manuscript for important intellectual content: Kalajian, Callen, and Parker. Statistical analysis: Not ap-plicable. Obtained funding: Not apap-plicable. Administra-tive, technical, and material support: Malhotra and Callen. Study supervision: Kalajian and Parker.

Financial Disclosure: Dr Callen has received honoraria

from Amgen, Abbott Immunology, Genentech, Cento-cor, 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.

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