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A Surfeit of Possibilities: Nonhealing Ulcers
DIAGNOSTIC DILEMMA Aimee K. Zaas, MD, Section Editor
A Surfeit of Possibilities: Nonhealing Ulcers Janelle Gooden, MD, Elfriede Agyemang, MD, Jason Post, MD Department of Medicine, Mayo Clinic, Rochester, Minn.
PRESENTATION Precise diagnosis of lower-extremity ulcerations is essential. Management differs so extensively between etiologies that misdiagnosis can lead to fatal outcomes. This was brought to mind when an 89-year-old woman was admitted directly to the hospital for treatment of worsening bilateral lower-extremity ulcerations. She had been transferred from another institution after a 2-week hospitalization due to concerns for calciphylaxis. Her symptoms started with edema of the distal bilateral lower-extremities 6 weeks earlier. Edema was followed by erythema and ulceration of the lateral aspect of her legs. These ulcers were bilateral but more pronounced on her right side. They were exquisitely painful, continued to enlarge, and occasionally discharged serosanguineous material; the exudate was never pustular. When first evaluated at her local hospital, the patient received antibiotics with no improvement in her ulcers. Two biopsies were unrevealing. She had a history of atrial fibrillation requiring warfarin for 3 years, but the drug had been discontinued a few days prior to transfer in case she was developing warfarin-induced skin necrosis. Her past medical history also was significant for chronic obstructive pulmonary disease, dilated cardiomyopathy with an ejection fraction of 30%, hypothyroidism, and hypertension. She had no history of vascular or kidney disease, tobacco use, or autoimmune disorders. Her other medications were carvedilol, enalapril, furosemide, metolazone, and levothyroxine. On arrival at our institution, the patient was afebrile and normotensive. Her physical exam was remarkable for irregularly irregular heart rhythm with a 2/6 systolic ejection murmur best heard parasternally. She had no jugular venous distention, and her pulses were palpable throughout. An examination of the lower extremities revealed several stel-
Funding: Funded provided by the Mayo Clinic. Conflict of Interest: None. Authorship: All authors were involved in the revision and compilation of this manuscript. Requests for reprints should be addressed to Jason Post, MD, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905. E-mail address: [email protected]
0002-9343/$ -see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2013.02.007
late areas of purplish purpuric discoloration with associated necrosis and ulcerations distal to the knee and most notably, on the dorsolateral aspects of her right leg (Figure 1). Some mild erythema around the ulcers coexisted with the purplish discoloration. Her toes were normal.
ASSESSMENT Our differential diagnoses included vasculitis, calciphylaxis, warfarin-induced skin necrosis, peripheral vascular disease, and pyoderma gangrenosum. The patient’s laboratory results were remarkable for hemoglobin, 13 g/dL; white blood cells, 11 ⫻ 103/L; platelets, 329 ⫻ 103/L; creatinine, 2.3 mg/dL; blood urea nitrogen, 75 mg/dL; C-reactive protein, 160.1 mg/dL; and thyroid stimulating hormone, 3.8 mIU/L. A coagulation panel in the setting of warfarin use suggested possible lupus anticoagulant but was otherwise negative for protein C/S deficiency, factor V Leiden, or prothrombin gene mutation. Elevated fibrinogen and d dimer levels indicated ongoing fibrinolysis. Complement measurements, including C3, C4, and total levels, were normal. Serum protein electrophoresis, cryoglobulins, urinalysis, and an autoimmune panel investigating for systemic lupus erythematosus, mixed connective tissue disease, Sjögren’s syndrome, granulomatosis with polyangiitis, and polymyositis were obtained, and all results were normal. Doppler ultrasound of the lower extremities was remarkable for atherosclerotic disease of unclear severity. The patient’s ankle-brachial index was 1.6 and 1.1 using the posterior tibial and dorsalis pedis vessels on the right, respectively, and 1.1 in both vessels on the left. She had no history of peripheral vascular disease and the distribution of her ulcers was not consistent with a venous stasis pattern. No evidence of current or previous venous thrombosis was found. Punch biopsies were performed and significant for superficial dermal angioplasia, microvascular occlusion, dermal hemorrhage, and focal fibrinoid microvascular necrosis, signs suggesting small-vessel vasculopathy. One sample also had subcutaneous vascular calcifications.
492
The American Journal of Medicine, Vol 126, No 6, June 2013 rowing diminishes distal blood flow and leads to local ischemia and skin necrosis despite a lack of significant arterial disease. Local ischemia also explains the etiology of pain that patients experience.
MANAGEMENT
Figure 1 The patient had posterolateral stellate ulcerations with purple purpuric and erythematous borders, centrally necrotic tissue, and eschar formation.
DIAGNOSIS Based on the patient’s presentation, history of hypertension, distal dorsolateral distribution of ulcers, and biopsy and test results, we diagnosed Martorell’s or hypertensive ischemic leg ulcers. Lack of longstanding kidney disease made calciphylaxis less likely. In addition, her calcium and phosphorus levels were normal. Warfarin-induced skin necrosis is similar to severe protein C deficiency and usually occurs within the first few weeks of therapy. Our patient had used warfarin for more than 3 years and had normal protein C levels. Her autoimmune panel was negative, making vasculitis unlikely. Fernando Martorell Otzet was a Spanish cardiologist who first described hypertensive ischemic ulcers in a 1945 case series of 4 women.1,2 Martorell’s ulcers typically occur on the distal dorsolateral aspects of the legs in patients with poorly controlled hypertension.3 The ulcers are painful and usually appear with central necrosis and surrounding purple discoloration, which is followed by circumferential erythematous skin changes (Figure 1). There is often symmetry on presentation, as well as a lack of significant large artery disease.4 Patients usually do not have chronic kidney disease. A biopsy at the border of the healthy skin and the necrotic lesion usually illustrates occlusive arteriolosclerosis and possibly, calcium deposits in the subcutaneous tissue (Figure 2).3 Patients with end-stage renal disease, similar biopsy results, and comparable physical examination findings would be diagnosed with calciphylaxis. Pyoderma gangrenosum may have a similar presentation, including painful violet ulcers with satellite pustules and surrounding erythema, perhaps accompanied by pathergy. Histopathology would show neutrophilic or lymphocytic infiltration without bacteria and the absence of vasculopathy.5 The etiology of skin necrosis is thought to be secondary to hypertension-mediated small-vessel ischemia in the dermis. Hypertension causes intima hyperplasia, which results in arteriolar narrowing and occlusion. Such arteriolar nar-
The mainstay of management for Martorell’s ulcers usually includes surgical debridement of necrotic tissue and skingrafting for wound closure.1 Basic wound care techniques also are indicated. Unlike the treatment for pyoderma gangrenosum, steroid therapy is not advised and can lead to episodes of sepsis and death.3 Hypertension control also is thought to aid in management, although the literature does not support its use as sole therapy. One randomized controlled trial from 1995 sought to investigate the utility of nifedipine, 10 mg, 3 times daily, vs placebo for management of hypertensive leg ulcers. Thirty patients were treated for 2 months, and after that time, a significant reduction in ulcer surface area was noted in the nifedipine group (26.9% vs 8.6% with placebo).6 Another study of 10 patients with Martorell’s ulcers found that daily sustained prostaglandin E1 elastomer administration significantly shortened ulcer duration and decreased pain in as few as 2 days when compared to standard therapy with a calcium channel blocker or an angiotensin-converting enzyme inhibitor.7 Overall, vasodilation and blood pressure control are believed to have a favorable effect on this disease. Beta blockers are not recommended, as administration can lead to peripheral vasoconstriction and impaired wound healing. In particular, use of nonselective beta blockers are not advised in patients with Martorell’s ulcer because they decrease cardiac output and skin perfusion pressure.1 Because our patient had cardiomyopathy with an ejection fraction of 30% and chronic obstructive lung disease, she was not an optimal surgical candidate. Instead, she was managed conservatively with dressing changes and sulfur-
Figure 2 A biopsy of an ulcer showed pannicular intravascular calcification that may be present on histopathology in cases of calciphylaxis or Martorell’s ischemic ulcers.
Gooden et al
Bilateral Nonhealing Ulcerations
based creams, as suggested by our colleagues in plastic surgery. She remained normotensive, and her creatinine returned to the normal baseline within 4 days of admission. Her pain was well-controlled with low-dose narcotics as needed. After a year of conservative management with wound care and topical sulfur-based creams, her ulcers healed.
References 1. Vuerstaek JD, Reeder SW, Henquet CJ, Neumann HA. Arteriolosclerotic ulcer of Martorell. J Eur Acad Dermatol Venereol. 2010;24:867874.
493 2. Shutler SD, Baragwanath P, Harding KG. Martorell’s ulcer. Postgrad Med J. 1995;71:717-719. 3. Hafner J, Nobbe S, Partsch H, et al. Martorell hypertensive ischemic leg ulcer: a model of ischemic subcutaneous arteriolosclerosis. Arch Dermatol. 2010;146:961-968. 4. Graves JW, Morris JC, Sheps SG. Martorell’s hypertensive leg ulcer: case report and concise review of the literature. J Hum Hypertens. 2001;15:279-283. 5. Brooklyn T, Dunnill G, Probert C. Diagnosis and treatment of pyoderma gangrenosum. BMJ. 2006;333:181-184. 6. Nikolova K. Treatment of hypertensive venous leg ulcers with nifedipine. Methods Find Exp Clin Pharmacol. 1995;17:545-549. 7. Pacifico F, Acernese CA, Di Giacomo A. PGE(1) therapy for Martorell’s ulcer. Int Wound J. 2011;8:140-144.
A Surfeit of Possibilities: Nonhealing Ulcers Janelle Gooden, MD, Elfriede Agyemang, MD, Jason Post, MD Department of Medicine, Mayo Clinic, Rochester, Minn.
PRESENTATION Precise diagnosis of lower-extremity ulcerations is essential. Management differs so extensively between etiologies that misdiagnosis can lead to fatal outcomes. This was brought to mind when an 89-year-old woman was admitted directly to the hospital for treatment of worsening bilateral lower-extremity ulcerations. She had been transferred from another institution after a 2-week hospitalization due to concerns for calciphylaxis. Her symptoms started with edema of the distal bilateral lower-extremities 6 weeks earlier. Edema was followed by erythema and ulceration of the lateral aspect of her legs. These ulcers were bilateral but more pronounced on her right side. They were exquisitely painful, continued to enlarge, and occasionally discharged serosanguineous material; the exudate was never pustular. When first evaluated at her local hospital, the patient received antibiotics with no improvement in her ulcers. Two biopsies were unrevealing. She had a history of atrial fibrillation requiring warfarin for 3 years, but the drug had been discontinued a few days prior to transfer in case she was developing warfarin-induced skin necrosis. Her past medical history also was significant for chronic obstructive pulmonary disease, dilated cardiomyopathy with an ejection fraction of 30%, hypothyroidism, and hypertension. She had no history of vascular or kidney disease, tobacco use, or autoimmune disorders. Her other medications were carvedilol, enalapril, furosemide, metolazone, and levothyroxine. On arrival at our institution, the patient was afebrile and normotensive. Her physical exam was remarkable for irregularly irregular heart rhythm with a 2/6 systolic ejection murmur best heard parasternally. She had no jugular venous distention, and her pulses were palpable throughout. An examination of the lower extremities revealed several stel-
Funding: Funded provided by the Mayo Clinic. Conflict of Interest: None. Authorship: All authors were involved in the revision and compilation of this manuscript. Requests for reprints should be addressed to Jason Post, MD, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905. E-mail address: [email protected]
0002-9343/$ -see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2013.02.007
late areas of purplish purpuric discoloration with associated necrosis and ulcerations distal to the knee and most notably, on the dorsolateral aspects of her right leg (Figure 1). Some mild erythema around the ulcers coexisted with the purplish discoloration. Her toes were normal.
ASSESSMENT Our differential diagnoses included vasculitis, calciphylaxis, warfarin-induced skin necrosis, peripheral vascular disease, and pyoderma gangrenosum. The patient’s laboratory results were remarkable for hemoglobin, 13 g/dL; white blood cells, 11 ⫻ 103/L; platelets, 329 ⫻ 103/L; creatinine, 2.3 mg/dL; blood urea nitrogen, 75 mg/dL; C-reactive protein, 160.1 mg/dL; and thyroid stimulating hormone, 3.8 mIU/L. A coagulation panel in the setting of warfarin use suggested possible lupus anticoagulant but was otherwise negative for protein C/S deficiency, factor V Leiden, or prothrombin gene mutation. Elevated fibrinogen and d dimer levels indicated ongoing fibrinolysis. Complement measurements, including C3, C4, and total levels, were normal. Serum protein electrophoresis, cryoglobulins, urinalysis, and an autoimmune panel investigating for systemic lupus erythematosus, mixed connective tissue disease, Sjögren’s syndrome, granulomatosis with polyangiitis, and polymyositis were obtained, and all results were normal. Doppler ultrasound of the lower extremities was remarkable for atherosclerotic disease of unclear severity. The patient’s ankle-brachial index was 1.6 and 1.1 using the posterior tibial and dorsalis pedis vessels on the right, respectively, and 1.1 in both vessels on the left. She had no history of peripheral vascular disease and the distribution of her ulcers was not consistent with a venous stasis pattern. No evidence of current or previous venous thrombosis was found. Punch biopsies were performed and significant for superficial dermal angioplasia, microvascular occlusion, dermal hemorrhage, and focal fibrinoid microvascular necrosis, signs suggesting small-vessel vasculopathy. One sample also had subcutaneous vascular calcifications.
492
The American Journal of Medicine, Vol 126, No 6, June 2013 rowing diminishes distal blood flow and leads to local ischemia and skin necrosis despite a lack of significant arterial disease. Local ischemia also explains the etiology of pain that patients experience.
MANAGEMENT
Figure 1 The patient had posterolateral stellate ulcerations with purple purpuric and erythematous borders, centrally necrotic tissue, and eschar formation.
DIAGNOSIS Based on the patient’s presentation, history of hypertension, distal dorsolateral distribution of ulcers, and biopsy and test results, we diagnosed Martorell’s or hypertensive ischemic leg ulcers. Lack of longstanding kidney disease made calciphylaxis less likely. In addition, her calcium and phosphorus levels were normal. Warfarin-induced skin necrosis is similar to severe protein C deficiency and usually occurs within the first few weeks of therapy. Our patient had used warfarin for more than 3 years and had normal protein C levels. Her autoimmune panel was negative, making vasculitis unlikely. Fernando Martorell Otzet was a Spanish cardiologist who first described hypertensive ischemic ulcers in a 1945 case series of 4 women.1,2 Martorell’s ulcers typically occur on the distal dorsolateral aspects of the legs in patients with poorly controlled hypertension.3 The ulcers are painful and usually appear with central necrosis and surrounding purple discoloration, which is followed by circumferential erythematous skin changes (Figure 1). There is often symmetry on presentation, as well as a lack of significant large artery disease.4 Patients usually do not have chronic kidney disease. A biopsy at the border of the healthy skin and the necrotic lesion usually illustrates occlusive arteriolosclerosis and possibly, calcium deposits in the subcutaneous tissue (Figure 2).3 Patients with end-stage renal disease, similar biopsy results, and comparable physical examination findings would be diagnosed with calciphylaxis. Pyoderma gangrenosum may have a similar presentation, including painful violet ulcers with satellite pustules and surrounding erythema, perhaps accompanied by pathergy. Histopathology would show neutrophilic or lymphocytic infiltration without bacteria and the absence of vasculopathy.5 The etiology of skin necrosis is thought to be secondary to hypertension-mediated small-vessel ischemia in the dermis. Hypertension causes intima hyperplasia, which results in arteriolar narrowing and occlusion. Such arteriolar nar-
The mainstay of management for Martorell’s ulcers usually includes surgical debridement of necrotic tissue and skingrafting for wound closure.1 Basic wound care techniques also are indicated. Unlike the treatment for pyoderma gangrenosum, steroid therapy is not advised and can lead to episodes of sepsis and death.3 Hypertension control also is thought to aid in management, although the literature does not support its use as sole therapy. One randomized controlled trial from 1995 sought to investigate the utility of nifedipine, 10 mg, 3 times daily, vs placebo for management of hypertensive leg ulcers. Thirty patients were treated for 2 months, and after that time, a significant reduction in ulcer surface area was noted in the nifedipine group (26.9% vs 8.6% with placebo).6 Another study of 10 patients with Martorell’s ulcers found that daily sustained prostaglandin E1 elastomer administration significantly shortened ulcer duration and decreased pain in as few as 2 days when compared to standard therapy with a calcium channel blocker or an angiotensin-converting enzyme inhibitor.7 Overall, vasodilation and blood pressure control are believed to have a favorable effect on this disease. Beta blockers are not recommended, as administration can lead to peripheral vasoconstriction and impaired wound healing. In particular, use of nonselective beta blockers are not advised in patients with Martorell’s ulcer because they decrease cardiac output and skin perfusion pressure.1 Because our patient had cardiomyopathy with an ejection fraction of 30% and chronic obstructive lung disease, she was not an optimal surgical candidate. Instead, she was managed conservatively with dressing changes and sulfur-
Figure 2 A biopsy of an ulcer showed pannicular intravascular calcification that may be present on histopathology in cases of calciphylaxis or Martorell’s ischemic ulcers.
Gooden et al
Bilateral Nonhealing Ulcerations
based creams, as suggested by our colleagues in plastic surgery. She remained normotensive, and her creatinine returned to the normal baseline within 4 days of admission. Her pain was well-controlled with low-dose narcotics as needed. After a year of conservative management with wound care and topical sulfur-based creams, her ulcers healed.
References 1. Vuerstaek JD, Reeder SW, Henquet CJ, Neumann HA. Arteriolosclerotic ulcer of Martorell. J Eur Acad Dermatol Venereol. 2010;24:867874.
493 2. Shutler SD, Baragwanath P, Harding KG. Martorell’s ulcer. Postgrad Med J. 1995;71:717-719. 3. Hafner J, Nobbe S, Partsch H, et al. Martorell hypertensive ischemic leg ulcer: a model of ischemic subcutaneous arteriolosclerosis. Arch Dermatol. 2010;146:961-968. 4. Graves JW, Morris JC, Sheps SG. Martorell’s hypertensive leg ulcer: case report and concise review of the literature. J Hum Hypertens. 2001;15:279-283. 5. Brooklyn T, Dunnill G, Probert C. Diagnosis and treatment of pyoderma gangrenosum. BMJ. 2006;333:181-184. 6. Nikolova K. Treatment of hypertensive venous leg ulcers with nifedipine. Methods Find Exp Clin Pharmacol. 1995;17:545-549. 7. Pacifico F, Acernese CA, Di Giacomo A. PGE(1) therapy for Martorell’s ulcer. Int Wound J. 2011;8:140-144.