Clinical Review & Education
JAMA Surgery Clinical Challenge
Progressive Soft-Tissue Necrosis Jane H. Kim, PhD; Stephen Somach, MD; Christopher R. McHenry, MD
A
B
D
E
C
Figure 1. Photographs of necrosis and eschar formation involving fingers (A), right (B) and left (C) toes, left posterior medial calf (D), and violaceous skin with central eschar on the posterior medial aspect of the right leg (E).
A 52-year-old man with type 2 diabetes mellitus and end-stage renal disease presented with painful and progressive cutaneous necrosis of his fingers, toes, and calves and generalized muscle weakness with difficulty getting out of bed and walking. He had undergone hemodialysis for the past year and had a brachiocephalic fistula in his left arm. His medical history was also significant for peripheral vascular disease, hypertension, and antiphospholipid antibody syndrome for which he was receiving warfarin sodium since 2010. His other medications were epoetin alpha, ferrous gluconate, cinacalcet hydrochloride, paricalcitol, sevelamer carbonate, amlodipine besylate, labetalol hydrochloride, lisinopril, simvastatin, pentoxifylline, and Humalog and Lantus insulin. He did not smoke. The patient had a temperature of 37.6°C and a grade II/VI systolic ejection murmur. He had necrosis and eschar formation involving his fingers (Figure 1A), toes (Figure 1B and C), and left posterior medial calf (Figure 1D). He had violaceous skin with central eschar on the posterior medial aspect of his right leg (Figure 1E) that was exquisitely tender with gangrenous change. He had normal femoral pulses with no distal pulses palpable. Both feet were warm with good DopQuiz at jamasurgery.com pler signals in the dorsalis pedis and posterior tibial arteries. He had a palpable pulse and thrill in the brachiocephalic fistula in his left upper arm. There was also a weak distal radial pulse. He had good Doppler signals over the radial, ulnar, and palmar arch arteries bilaterally. Laboratory studies revealed a white blood cell count of 13 900/μL (to convert to ×109 per liter, multiply by 0.001), a hemoglobin level of 7.7 g/dL (to convert to grams per liter, multiply by 10.0), a platelet count of 309 × 103/μL (to convert to ×109 per liter, multiply by 1.0), an international normalized ratio of 2.4, a blood urea nitrogen level of 88 mg/dL (to convert to millimoles per liter, multiply by 0.357), a creatinine level of 9.9 mg/dL (to convert to micromoles per liter, multiply by 88.4), a calcium level of 7.5 mg/dL (to convert to millimoles per liter, multiply by 0.25), an albumin level of 2.4 g/dL (to convert to grams per liter, multiply by 10), and an intact parathyroid hormone level of 349.7 pg/mL (to convert to nanograms per liter, multiply by 1.0). A skin biopsy specimen of the calf showed epidermal necrosis, dermal hemorrhage, focal dermal intravascular thrombi, and subcutaneous intravascular and extravascular calcifications.
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WHAT IS THE DIAGNOSIS?
A. Subacute bacterial endocarditis B. Warfarin-induced skin necrosis C. Calcific uremic arteriolopathy D. Buerger disease
JAMA Surgery February 2014 Volume 149, Number 2
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Clinical Review & Education JAMA Surgery Clinical Challenge
Diagnosis C. Calcific uremic arteriolopathy
Discussion Calcific uremic arteriolopathy, also known as calciphylaxis, is a rare disorder of unknown etiology characterized by medial calcification, intimal proliferation, and fibrosis of the walls of small subcutaneous vessels (Figure 2), which leads to thrombosis, ulceration, and necrosis of the dermis, subcutaneous tissue, and, less often, the muscle. It occurs most commonly in patients with end-stage renal disease and secondary hyperparathyroidism with a mortality rate of 60%.1 It may rarely occur in patients with primary hyperparathyroidism. The exact mechanism that leads to the deposition of calcium in the subcutaneous vessels is unknown. Factors that have been implicated in the pathogenesis of calcific uremic arteriolopathy include poorly controlled hyperphosphatemia, increased levels of calcium-phosphate product, increased serum parathyroid hormone levels, and low protein C and S levels.2 Our patient’s skin lesions progressed despite administration of a noncalcium phosphate binder (sevelamer) to reduce hyperphosphatemia and cinacalcet therapy to control the serum parathyroid hormone level. Owing to his refractory hyperparathyroidism, a total parathyroidectomy with bilateral transcervical thymectomy was performed. The final pathology confirmed parathyroid hyperplasia. The 2 inferior glands were in the thymus and weighed 110 and 670 mg, respectively. The 2 superior parathyroid glands weighed 440 and 580 mg, respectively. Parathyroidectomy has been reported to be associated with the best chance of cure and prolonged survival.3 Given the high mortality rate associated with calcific uremic arteriolopathy, and the potential for progression after subtotal parathyroidectomy, total parathyroidectomy with transcervical thymectomy is advocated.4,5 Transcervical thymectomy is important because 10% to 15% of patients have 5 or more parathyroid glands,
Author Affiliations: Department of Surgery, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio (Kim, McHenry); Departments of Dermatology and Pathology, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio (Somach). Corresponding Author: Christopher R. McHenry, MD, Department of Surgery, MetroHealth Medical Center, Case Western Reserve University of Medicine, 2500 MetroHealth Dr, H-917, Cleveland, OH 44109-1998 ([email protected]). Section Editor: Carl E. Bredenberg, MD. Accepted for Publication: August 20, 2012.
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and the most common location for a supernumerary parathyroid gland is in the thymus. Patients with calcific uremic arteriolopathy present with painful cutaneous necrosis, often in a livedo reticularis pattern that may progress to deep soft-tissue necrosis, secondary infection, limb loss, and death.6,7 Although it most often occurs in patients with endstage renal disease being treated with hemodialysis, it has also been reported in patients with primary hyperparathyroidism.8 The clinical presentation may resemble vasculitis, warfarin-induced skin necrosis, or peripheral embolization. The diagnosis should be suspected for patients with characteristic skin lesions and a skin biopsy that shows vascular and extravascular calcification in the absence of vasculitis.
Conflict of Interest Disclosures: None reported.
ARTICLE INFORMATION
Published Online: January 1, 2014. doi:10.1001/2013.jamasurg.356.
Figure 2. Photomicrograph of punch biopsy of the skin from left posterior medial calf demonstrating epidermal necrosis, dermal hemorrhage, focal dermal intravascular thrombi, and subcutaneous intravascular (white arrowhead) and extravascular (black arrowhead) calcifications; there were no features of vasculitis (hematoxylin-eosin, original magnification ×400).
REFERENCES 1. Chan MR, Yevzlin AS, Hinshaw M, Jaffery JB. Calciphylaxis responsive to lanthanum carbonate (FOSRENOL) therapy. WMJ. 2008;107(7):335-338.
5. Duh QY, Lim RC, Clark OH. Calciphylaxis in secondary hyperparathyroidism: diagnosis and parathyroidectomy. Arch Surg. 1991;126(10):1213-1218, discussion 1218-1219. 6. Ng AT, Peng DH. Calciphylaxis. Dermatol Ther. 2011;24(2):256-262.
2. Nazarian RM, Van Cott EM, Zembowicz A, Duncan LM. Warfarin-induced skin necrosis. J Am Acad Dermatol. 2009;61(2):325-332.
7. Sulková SD, Válek M. Skin wounds associated with calciphylaxis in end-stage renal disease patients on dialysis. Nutrition. 2010;26(9):910-914.
3. Girotto JA, Harmon JW, Ratner LE, Nicol TL, Wong L, Chen H. Parathyroidectomy promotes wound healing and prolongs survival in patients with calciphylaxis from secondary hyperparathyroidism. Surgery. 2001;130(4):645-650, discussion 650-651.
8. Nigwekar SU, Wolf M, Sterns RH, Hix JK. Calciphylaxis from nonuremic causes: a systematic review. Clin J Am Soc Nephrol. 2008;3(4):1139-1143.
4. McHenry CR, Wilhelm SM, Ricanati E. Refractory renal hyperparathyroidism: clinical features and outcome of surgical therapy. Am Surg. 2001;67(4):310-316, discussion 316-317.
JAMA Surgery February 2014 Volume 149, Number 2
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archsurg.jamanetwork.com/ by a University of Manitoba User on 06/10/2015
jamasurgery.com
JAMA Surgery Clinical Challenge
Progressive Soft-Tissue Necrosis Jane H. Kim, PhD; Stephen Somach, MD; Christopher R. McHenry, MD
A
B
D
E
C
Figure 1. Photographs of necrosis and eschar formation involving fingers (A), right (B) and left (C) toes, left posterior medial calf (D), and violaceous skin with central eschar on the posterior medial aspect of the right leg (E).
A 52-year-old man with type 2 diabetes mellitus and end-stage renal disease presented with painful and progressive cutaneous necrosis of his fingers, toes, and calves and generalized muscle weakness with difficulty getting out of bed and walking. He had undergone hemodialysis for the past year and had a brachiocephalic fistula in his left arm. His medical history was also significant for peripheral vascular disease, hypertension, and antiphospholipid antibody syndrome for which he was receiving warfarin sodium since 2010. His other medications were epoetin alpha, ferrous gluconate, cinacalcet hydrochloride, paricalcitol, sevelamer carbonate, amlodipine besylate, labetalol hydrochloride, lisinopril, simvastatin, pentoxifylline, and Humalog and Lantus insulin. He did not smoke. The patient had a temperature of 37.6°C and a grade II/VI systolic ejection murmur. He had necrosis and eschar formation involving his fingers (Figure 1A), toes (Figure 1B and C), and left posterior medial calf (Figure 1D). He had violaceous skin with central eschar on the posterior medial aspect of his right leg (Figure 1E) that was exquisitely tender with gangrenous change. He had normal femoral pulses with no distal pulses palpable. Both feet were warm with good DopQuiz at jamasurgery.com pler signals in the dorsalis pedis and posterior tibial arteries. He had a palpable pulse and thrill in the brachiocephalic fistula in his left upper arm. There was also a weak distal radial pulse. He had good Doppler signals over the radial, ulnar, and palmar arch arteries bilaterally. Laboratory studies revealed a white blood cell count of 13 900/μL (to convert to ×109 per liter, multiply by 0.001), a hemoglobin level of 7.7 g/dL (to convert to grams per liter, multiply by 10.0), a platelet count of 309 × 103/μL (to convert to ×109 per liter, multiply by 1.0), an international normalized ratio of 2.4, a blood urea nitrogen level of 88 mg/dL (to convert to millimoles per liter, multiply by 0.357), a creatinine level of 9.9 mg/dL (to convert to micromoles per liter, multiply by 88.4), a calcium level of 7.5 mg/dL (to convert to millimoles per liter, multiply by 0.25), an albumin level of 2.4 g/dL (to convert to grams per liter, multiply by 10), and an intact parathyroid hormone level of 349.7 pg/mL (to convert to nanograms per liter, multiply by 1.0). A skin biopsy specimen of the calf showed epidermal necrosis, dermal hemorrhage, focal dermal intravascular thrombi, and subcutaneous intravascular and extravascular calcifications.
jamasurgery.com
WHAT IS THE DIAGNOSIS?
A. Subacute bacterial endocarditis B. Warfarin-induced skin necrosis C. Calcific uremic arteriolopathy D. Buerger disease
JAMA Surgery February 2014 Volume 149, Number 2
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archsurg.jamanetwork.com/ by a University of Manitoba User on 06/10/2015
211
Clinical Review & Education JAMA Surgery Clinical Challenge
Diagnosis C. Calcific uremic arteriolopathy
Discussion Calcific uremic arteriolopathy, also known as calciphylaxis, is a rare disorder of unknown etiology characterized by medial calcification, intimal proliferation, and fibrosis of the walls of small subcutaneous vessels (Figure 2), which leads to thrombosis, ulceration, and necrosis of the dermis, subcutaneous tissue, and, less often, the muscle. It occurs most commonly in patients with end-stage renal disease and secondary hyperparathyroidism with a mortality rate of 60%.1 It may rarely occur in patients with primary hyperparathyroidism. The exact mechanism that leads to the deposition of calcium in the subcutaneous vessels is unknown. Factors that have been implicated in the pathogenesis of calcific uremic arteriolopathy include poorly controlled hyperphosphatemia, increased levels of calcium-phosphate product, increased serum parathyroid hormone levels, and low protein C and S levels.2 Our patient’s skin lesions progressed despite administration of a noncalcium phosphate binder (sevelamer) to reduce hyperphosphatemia and cinacalcet therapy to control the serum parathyroid hormone level. Owing to his refractory hyperparathyroidism, a total parathyroidectomy with bilateral transcervical thymectomy was performed. The final pathology confirmed parathyroid hyperplasia. The 2 inferior glands were in the thymus and weighed 110 and 670 mg, respectively. The 2 superior parathyroid glands weighed 440 and 580 mg, respectively. Parathyroidectomy has been reported to be associated with the best chance of cure and prolonged survival.3 Given the high mortality rate associated with calcific uremic arteriolopathy, and the potential for progression after subtotal parathyroidectomy, total parathyroidectomy with transcervical thymectomy is advocated.4,5 Transcervical thymectomy is important because 10% to 15% of patients have 5 or more parathyroid glands,
Author Affiliations: Department of Surgery, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio (Kim, McHenry); Departments of Dermatology and Pathology, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio (Somach). Corresponding Author: Christopher R. McHenry, MD, Department of Surgery, MetroHealth Medical Center, Case Western Reserve University of Medicine, 2500 MetroHealth Dr, H-917, Cleveland, OH 44109-1998 ([email protected]). Section Editor: Carl E. Bredenberg, MD. Accepted for Publication: August 20, 2012.
212
and the most common location for a supernumerary parathyroid gland is in the thymus. Patients with calcific uremic arteriolopathy present with painful cutaneous necrosis, often in a livedo reticularis pattern that may progress to deep soft-tissue necrosis, secondary infection, limb loss, and death.6,7 Although it most often occurs in patients with endstage renal disease being treated with hemodialysis, it has also been reported in patients with primary hyperparathyroidism.8 The clinical presentation may resemble vasculitis, warfarin-induced skin necrosis, or peripheral embolization. The diagnosis should be suspected for patients with characteristic skin lesions and a skin biopsy that shows vascular and extravascular calcification in the absence of vasculitis.
Conflict of Interest Disclosures: None reported.
ARTICLE INFORMATION
Published Online: January 1, 2014. doi:10.1001/2013.jamasurg.356.
Figure 2. Photomicrograph of punch biopsy of the skin from left posterior medial calf demonstrating epidermal necrosis, dermal hemorrhage, focal dermal intravascular thrombi, and subcutaneous intravascular (white arrowhead) and extravascular (black arrowhead) calcifications; there were no features of vasculitis (hematoxylin-eosin, original magnification ×400).
REFERENCES 1. Chan MR, Yevzlin AS, Hinshaw M, Jaffery JB. Calciphylaxis responsive to lanthanum carbonate (FOSRENOL) therapy. WMJ. 2008;107(7):335-338.
5. Duh QY, Lim RC, Clark OH. Calciphylaxis in secondary hyperparathyroidism: diagnosis and parathyroidectomy. Arch Surg. 1991;126(10):1213-1218, discussion 1218-1219. 6. Ng AT, Peng DH. Calciphylaxis. Dermatol Ther. 2011;24(2):256-262.
2. Nazarian RM, Van Cott EM, Zembowicz A, Duncan LM. Warfarin-induced skin necrosis. J Am Acad Dermatol. 2009;61(2):325-332.
7. Sulková SD, Válek M. Skin wounds associated with calciphylaxis in end-stage renal disease patients on dialysis. Nutrition. 2010;26(9):910-914.
3. Girotto JA, Harmon JW, Ratner LE, Nicol TL, Wong L, Chen H. Parathyroidectomy promotes wound healing and prolongs survival in patients with calciphylaxis from secondary hyperparathyroidism. Surgery. 2001;130(4):645-650, discussion 650-651.
8. Nigwekar SU, Wolf M, Sterns RH, Hix JK. Calciphylaxis from nonuremic causes: a systematic review. Clin J Am Soc Nephrol. 2008;3(4):1139-1143.
4. McHenry CR, Wilhelm SM, Ricanati E. Refractory renal hyperparathyroidism: clinical features and outcome of surgical therapy. Am Surg. 2001;67(4):310-316, discussion 316-317.
JAMA Surgery February 2014 Volume 149, Number 2
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archsurg.jamanetwork.com/ by a University of Manitoba User on 06/10/2015
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