BRIEF REPORT
Calciphylaxis: A Pseudo-Vasculitis Syndrome Vasileios C. Kyttaris, MD,* Sukran Timbil, MD,† Dimitrios Kalliabakos, MD,‡ George Vaiopoulos, MD,§ and Arthur Weinstein, MD¶
Objectives: To report a case of fatal calciphylaxis, an uncommon condition affecting patients with chronic renal disease and calcium metabolism abnormalities, that can mimic vasculitis. Methods: We reviewed the English literature using the Medline and Embase databases and keywords “calciphylaxis” and “calcific uremic arteriolopathy.” Results: A patient with end-stage renal disease and no known calcium metabolism abnormalities presented with intractable lower extremity ulcers and skin findings suggestive of small-vessel disease of the upper extremities. Biopsy of the lesions showed classic calciphylaxis without evidence of vasculitis. The patient died shortly after an above-the-knee amputation. Conclusion: Calciphylaxis needs to be considered in the differential diagnosis of vasculitis. Skin biopsy soon after presentation is imperative for diagnosis and to avoid potentially harmful treatments such as corticosteroids and immunosuppressive medications. © 2007 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 36:264-267 Keywords: calciphylaxis, kidney failure, hyperparathyroidism, vasculitis
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nd-stage renal disease is characterized by a number of metabolic abnormalities that may lead to calcium deposition in various tissues. When calcium deposits in the wall of cutaneous vessels, a condition called calciphylaxis, the vessels become thrombosed leading to skin ischemia and necrosis. Herein we present a case of calciphylaxis that mimicked cutaneous vasculitis in its presentation. METHODS We searched the English language literature from 1966 to date using Medline and Embase and the keywords: “calciphylaxis” and “uremic calcific arteriolopathy.” We discuss the results of this search in reference to our own case report focusing on articles that propose novel treatments for this syndrome.
*Section of Rheumatology, Washington Hospital Center, Washington, DC, and Division of Rheumatology, Beth Israel Deaconess Medical Center, Boston, MA. †Section of Rheumatology, University of Pittsburgh Medical Center, Pittsburgh, PA. ‡Department of Medicine, 401 General Army Hospital, Athens, Greece. §First Department of Internal Medicine, Laikon General Hospital, Athens University Medical School, Athens, Greece. ¶Section of Rheumatology, Washington Hospital Center, Washington, DC. Reprint requests to: Vasileios Kyttaris, Harvard Institutes of Medicine, 4 Blackfan Circle, HIM-238, Boston, MA 02115. E-mail:
[email protected].
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CASE REPORT A 53-year-old hemodialysis-dependent black woman was admitted in the vascular surgery service with mental status changes and intractable right leg pain. Two months before admission she developed leg ulcers on the lower extremities. Conservative treatment with broad-spectrum antibiotics was ineffective at reducing the pain and drainage of the ulcers. The patient was admitted to the hospital with fever up to 39°C, low blood pressure, confusion, and progressively worsening (right more than left) leg ulcers with superficial necrosis and purulent drainage. Cultures of the draining fluid were positive for methicillin-resistant staphylococcus but blood cultures were repeatedly negative. Imaging studies of the lower extremities disclosed no arterial or venous disease. Despite repeated debridements of the ulcers and combination antibiotics (vancomycingentamicin), she continued to have fever, confusion, and worsening ulcers. Small round lesions on the forearms and cyanotic fingers on both hands also developed. A rheumatology consult was called. Her past medical history included end-stage renal disease (ESRD) presumed to be secondary to diabetes mellitus, hypertension, coronary artery disease, gout, depression, and sarcoidosis (hilar adenopathy only; chronic prednisone dose: 10 mg/d). She had no history of smoking, alcohol, or intravenous substance abuse. She was allergic to sulfa-containing drugs. Her past surgical history
0049-0172/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2006.10.002
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Figure 1 (A) Necrosis of the fingertips and splinter hemorrhages. (B) A papule with central necrotic eschar similar to the one that was biopsied.
was significant for a hysterectomy 18 years before admission and hemodialysis catheter placement 1 year before admission. Her family history included diabetes mellitus and hypertension but not autoimmune diseases. Her medications were vancomycin, gentamicin, insulin, prednisone, enoxaparin, buspirone, clonazepam, oxycodone, megestrol, vitamin C, sevelamer, and omeprazole. She denied alopecia, oral ulcers, decreased visual acuity, dyspnea, chest pain on exertion, or abdominal pain, but complained of arthralgias of both hands without Raynaud’s symptoms. Physical examination revealed a cachectic woman in moderate pain with intermittent fever (39.5°C), a labile blood pressure (97/57 mm Hg at the time of evaluation), and tachycardia (94/min). Cardiopulmonary and abdominal exams were essentially normal without evidence of murmurs or bruits. Skin examination disclosed multiple confluent ulcers with black eschars in the lower extremities. The second and third digits of the left and right hand, respectively, showed impending acral gangrene and splinter hemorrhages (Fig. 1A). On the forearms and the thighs multiple small nonpainful, nonpruritic papules with black eschars were present (Fig. 1B). Further laboratory evaluation showed that calcium levels were between 7.9 and 10.4 mg/dL and phosphorus levels were between 1.5 to 5.4 mg/dL; the calcium-phosphorus product was less than 50 on repeated measurements during and before this admission. She has been on dialysis for 1 year before hospitalization and was compliant with her dialysis treatments. Parathyroid hormone (PTH), angiotension-converting enzyme levels, lupus anticoagulant, anticardiolipin antibody, protein C activity, antineutrophil cytoplasmic antibodies, antinuclear antibodies, rheumatoid factor, sedimentation rate, and C-reactive protein were all within normal limits. A radiograph of the hands showed osteomyelitis of the second left finger. Angiography of the upper extremities revealed normal filling of the radial, ulnar, and interosseous arteries
with very poor filling of the digital arteries; challenge with nitroglycerine did not lead to vasodilatation of the small digital arteries. The brachial arteries had multiple areas of stenosis due to atherosclerosis. A transesophageal echocardiogram was normal. The patient underwent biopsy of a papule from the left thigh (Fig. 2) that was consistent with calciphylaxis. In this figure the pathological presentation of calciphylaxis is exemplified: calcification of the medial layer of a subcutaneous blood vessel wall, intimal hyperplasia and thrombosis without evidence of vasculitis, and widespread epidermal and subcutaneous necrosis. Nifedipine was prescribed in an attempt to increase the blood supply to the extremities, but the patient continued to have fever, leukocytosis, and severe limb pain. She underwent an above-the-knee amputation of the right leg. However on the fourth postoperative day she suffered cardiopulmonary arrest with asystole and although initially resuscitated, she died following anoxic brain injury. DISCUSSION Calciphylaxis, also called uremic calcific arteriolopathy, is a syndrome of unknown etiology, associated with uremia and characterized by calcification and thrombosis of cutaneous vessels, leading to ulceration and necrosis of the skin. Hans Selye first used the term calciphylaxis in the 1960s (1) to describe an experimental phenomenon in normal rats of tissue calcification as a response to appropriate stimuli. He initially “sensitized” the animals with substances such as vitamin D, PTH, or dihydrotachysterol (systemic calcifiers). After a few days he “challenged” the animals by injecting them intravenously or intradermally with a chemical compound (such as iron salts, dextran, egg yolk) or by inflicting minor skin trauma. The result was local (skin) or systemic tissue calcification. Animal calciphylaxis resembled anaphylaxis in its time
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Figure 2 Thrombus (arrowhead) is seen within a cutaneous vessel. The vessel wall contains calcium deposits (thin arrow) and shows profound intimal hyperplasia (thick arrow) (hematoxylin– eosin, Von Kossa’s calcium staining method).
course (sensitization followed by a reaction after challenging), but there was no evidence of antibody production or classic immunologic hypersensitivity. In some of the forms of this experimental condition, mast cells seemed to play a role. A few years later a condition of skin calcification was described in uremic patients and, since this resembled Selye’s model, it was called calciphylaxis. Although the term calciphylaxis in humans mainly refers to vascular calcification, Selye’s animal models developed calcification of the cutaneous tissues. Calciphylaxis in humans is an uncommon disorder, mainly described in association with ESRD. It is estimated to affect 1 to 4% of uremic patients on dialysis a year (2-4). Predisposing factors are poorly controlled hyperphosphatemia, increased calcium-phosphate product, and increased PTH levels (5,6). Less concrete associations have been made between low-protein C and S levels (7), immunosuppressive medications and corticosteroid treatment (8), and the development of calciphylaxis. On a pathophysiologic level, there is a clear association of calciphylaxis with abnormalities in calcium-phosphate regulation but the exact mechanisms that lead to the deposition of calcium in the subcutaneous vessels remain elusive. Interestingly, patients with calciphylaxis had in-
V.C. Kyttaris et al.
creased expression of osteopontin in their skin biopsies when compared with the ESRD patients without history of calciphylaxis (9). Osteopontin is a chemoattractant that is secreted among other matrix proteins by smooth muscle cells that dedifferentiate into osteoblast-like cells. However, evidence of a significant contribution of the immune system to the pathophysiology of calciphylaxis is still lacking. Pathologically, calciphylaxis is characterized by calcification of the walls of small subcutaneous vessels accompanied by intimal proliferation and fibrosis. Thrombi form inside the lumen of affected venules, arterioles, and capillaries resulting in skin ischemia, necrosis, and formation of skin ulcerations. Unlike vasculitis, there are very few if any inflammatory cells in and around the blood vessels unless the skin is secondarily infected. Clinically, the patients present with painful skin nodules or papules, often in a livedo reticularis pattern, which in time ulcerate and become necrotic. The lesions usually involve the lower extremities (3), although lesions on the breast (10), tongue (11), and penis (11) have also been reported. Generally, areas of fat deposition such as the thighs, buttocks, and abdomen are affected. Although the typical patient has ESRD and calcium metabolism abnormalities such as elevated calcium or phosphorus, not infrequently systemic laboratory abnormalities are not found. The diagnosis is made by skin biopsy that shows calcification of the medial walls of cutaneous vessels without inflammation. Radiological studies are rarely helpful (12,13). Treatment of calciphylaxis can be challenging. Prompt treatment of skin infections with surgical debridement and appropriate antibiotics is imperative. Underlying calcium metabolism abnormalities should be corrected with the use of low calcium baths for hemodialysis, phosphatebinding resins, and/or parathyroidectomy (14,15). Successful treatment has also been reported with the use of cinacalcet in lieu of parathyroidectomy (16). Potentially harmful exogenous substances such as vitamin D or corticosteroids should be stopped if possible. Anticoagulation may be helpful in cases of protein C and S deficiency. A relatively new antioxidant, sodium thiosulfate (infused 3 times weekly), has been used successfully for the treatment of calciphylaxis in a limited number of case reports (17). Finally local treatment with medical maggots (18) or hyperbaric oxygen (19,20) may prove helpful in treating calciphylaxis-associated ulcers. Overall, the prognosis of patients with calciphylaxis remains poor (21). A multidisciplinary approach to optimize renal replacement therapy, control of underlying conditions such as diabetes, hypertension, hyperparathyroidism, and treat superimposed infections may prove fruitful (6,22). In conclusion, we present a case of a patient with ESRD and classic calciphylaxis. Despite aggressive antibiotic treatment and surgical debridement, she died. Treatment of underlying metabolic abnormalities in patients with
Calciphylaxis
ESRD may help avert such complications. The skin lesions of calciphylaxis can be confused with vasculitis, especially if the patient has an autoimmune disease that was the underlying cause of renal failure. These patients may therefore be started on immunosuppressive treatment that could deteriorate their condition. Early skin biopsy of noninfected skin, aggressive wound care, antibiotic treatment, and correction of calcium metabolism abnormalities may be lifesaving. REFERENCES 1. Selye H. Calciphylaxis. Chicago, IL, University of Chicago Press, 1962. 2. Naik BJ, Lynch DJ, Slavcheva EG, Beissner RS. Calciphylaxis: medical and surgical management of chronic extensive wounds in a renal dialysis population. Plast Reconstr Surg 2004;113:304-12. 3. Dosanjh A, Kebebew E. Calciphylaxis: rare but fatal. Curr Surg 2005;62:455-8. 4. McAuley K, Devereux F, Walker R. Calciphylaxis in two noncompliant patients with end-stage renal failure. Nephrol Dial Transplant 1997;12:1061-3. 5. Kent RB, 3rd, Lyerly RT. Systemic calciphylaxis. South Med J 1994;87:278-81. 6. Duh QY, Lim RC, Clark OH. Calciphylaxis in secondary hyperparathyroidism. Diagnosis and parathyroidectomy. Arch Surg 1991;126:1213-8; discussion 1218-9. 7. Goli AK, Goli SA, Shah LS, Byrd RP Jr, Roy TM. Calciphylaxis: a rare association with alcoholic cirrhosis. Are deficiencies in protein C and S the cause? South Med J 2005;98:736-9. 8. Ozbalkan Z, Calguneri M, Onat AM, Ozturk MA. Development of calciphylaxis after long-term steroid and methotroxate use in a patient with rheumatoid arthritis. Intern Med 2005;44:1178-81. 9. Ahmed S, O’Neill KD, Hood AF, Evan AP, Moe SM. Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells. 2001;37: 1267-76.
267 10. Thang OHD, Jaspars EH, Wee PMt. Necrotizing mastitis caused by calciphylaxis. Nephrol Dial Transplant 2006:gfl135. 11. Bedoya RM, Gutierrez JL, Mayorga F. Calciphylaxis causing localized tongue necrosis: a case report. J Oral Maxillofac Surg 1997;55:193-6. 12. Goldsmith D, Nogueira P, Cochat P. Calcifying panniculitis or ‘simple’ inflammation? Biopsy is better than a bone scan. Nephrol Dial Transplant 1997;12:2463-4. 13. Cosmin A, Soudry G. A case of severe calciphylaxis seen on threephase bone scan. Clin Nucl Med 2005;30:765-6. 14. Wang HY, Yu CC, Huang CC. Successful treatment of severe calciphylaxis in a hemodialysis patient using low-calcium dialysate and medical parathyroidectomy: case report and literature review. Ren Fail 2004;26:77-82. 15. Russell R, Brookshire MA, Zekonis M, Moe SM. Distal calcific uremic arteriolopathy in a hemodialysis patient responds to lowering of Ca x P product and aggressive wound care. Clin Nephrol 2002;58:238-43. 16. Velasco N, MacGregor MS, Innes A, MacKay IG. Successful treatment of calciphylaxis with cinacalcet—an alternative to parathyroidectomy? Nephrol Dial Transplant 2006;21:114. 17. Cicone JS, Petronis JB, Embert CD, Spector DA. Successful treatment of calciphylaxis with intravenous sodium thiosulfate. Am J Kidney Dis 2004;43:1104-8. 18. Tittelbach J, Graefe T, Wollina U. Painful ulcers in calciphylaxis— combined treatment with maggot therapy and oral pentoxyfillin. J Dermatolog Treat 2001;12:211-4. 19. Dwyer KM, Francis DMA, Hill PA, Murphy BF. Calcific uraemic arteriolopathy: local treatment and hyperbaric oxygen therapy. Nephrol Dial Transplant 2002;17:1148-9. 20. Basile C, Montanaro A, Masi M, Pati G, De Maio P, Gismondi A. Hyperbaric oxygen therapy for calcific uremic arteriolopathy: a case series. J Nephrol 2002;15:676-80. 21. Duffy A, Schurr M, Warner T, Chen H. Long-term outcomes in patients with calciphylaxis from hyperparathyroidism. Ann Surg Oncol 2006;13:96-102. 22. Milas M, Weber CJ. Near-total parathyroidectomy is beneficial for patients with secondary and tertiary hyperparathyroidism. Surgery 2004;136:1252-60.
