Morphology Blackwell International IJD Oxford, UK 0011-9059 XXX Publishing Journal Ltd, Ltd of Dermatology 2007 Hypozincemia and hyperzincuria associated with necrolytic acral erythema Zinc Najarian Morphology deficiency et al. associated with necrolytic acral erythema David James Najarian, MD, James Stephen Najarian, MD, Babar K. Rao, MD, and Amy S. Pappert, MD From the Department of Dermatology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 1 World’s Fair Drive, Somerset, NJ 08879, and Randolph Medical and Renal Associates, Randolph, NJ 07869 Correspondence David James Najarian, MD Department of Dermatology University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School 1 World’s Fair Drive Somerset, NJ 08879 E-mail: najaridj@umdnj.edu Statement of financial disclosures and conflicts of interest: The authors report no financial or other conflicts of interest related to this case. Case Report In March 2006, a 65-year-old African American retired nurse presented to us for a chronic dermatitis. Her internist had been treating her for atopic dermatitis for 18 years. Routine laboratory tests ordered in 1999, which included liver function tests, were normal. The patient had tried a variety of topical medicaments, including 0.1% triamcinalone cream, without success. She was also taking amlodipine for hypertension. Physical examination revealed hyperkeratotic and eroded papules and plaques, many of which were surrounded by a distinctive rim of erythema (Fig. 1). Lesions were primarily on acral sites. Overall, physical examination suggested the diagnosis of necrolytic acral erythema (NAE). There were no other signs, symptoms, or laboratory evidence of other necrolytic erythemas (Table 1). Histological findings from a skin biopsy of an arm lesion revealed mild hyperkeratosis, acanthosis, and spongiosis, Table 1 The necrolytic erythemas have similar clinical and histological features and are associated with metabolic deficiencies Necrolytic erythema Associated systemic diseases Associated metabolic deficiencies Necrolytic acral erythema Acrodermatitis enteropathica Hepatitis C Crohn’s disease, AIDS, malnutrition, and other disorders Glucagonoma, bronchial carcinoma, and hepatocellular dysfunction Malnutrition, carcinoid syndrome, and other disorders Malnutrition and malabsorption Malnutrition and malabsorption Zinc deficiency Zinc deficiency and free fatty acid deficiency Necrolytic migratory erythema Pellagra Unnamed Unnamed Zinc deficiency, essential fatty acid deficiency, vitamin deficiency, and amino acid deficiency Niacin deficiency Essential fatty acid deficiency Biotin deficiency 709 © 2008 The International Society of Dermatology International Journal of Dermatology 2008, 47, 709–711 710 Morphology Zinc deficiency associated with necrolytic acral erythema Najarian et al. Discussion Figure 1 Plaques on the hands of a patient with necrolytic acral erythema (a). After 5 weeks of oral zinc therapy the plaques had markedly improved (b) a few necrotic keratinocytes, and a superficial perivascular lymphocytic infiltrate. These findings were also suggestive of NAE.1 Laboratory studies revealed antibodies to the hepatitis C type 1a virus (HCV-1a) and a viral load of 4,380,000 IU/ml, confirming a diagnosis of NAE. Evidence of an association between NAE and zinc deficiency has been reported by us and another group, and we have postulated that NAE may result from zinc deficiency driven by chronic HCV infection.2,3 For this reason, we ordered a work up for zinc deficiency, which revealed a serum zinc level of 27 µg/dl (normal, 60–120 µg/dl). A 24 h urine collection also demonstrated 1736.8 µg zinc per gram of creatinine (NL 10–938), suggesting her kidneys were wasting zinc into her urine. We prescribed 220 mg zinc sulfate once a day, and at 1 month follow up signs and symptoms had markedly resolved (Fig. 1). The serum zinc level had risen to 61 µg/dl. International Journal of Dermatology 2008, 47, 709–711 NAE is a rare diagnostic cutaneous sign of HCV infection, first reported in Egypt.4 Histological and clinical features of NAE have led to its classification within a group of diseases called necrolytic erythemas, which are linked to systemic diseases and nutrient deficiencies (Table 1).4 The reason NAE presents in patients with HCV is uncertain. However, we have recently reported the case of a patient with NAE and serological evidence of zinc deficiency, and our patient’s skin responded to oral zinc therapy, suggesting NAE may sometimes result from zinc deficiency driven by chronic HCV infection.2 In addition, urine zinc studies of our patient suggested her kidneys were wasting zinc into her urine, a finding that had not been reported in other NAE patients. We now report the case of another patient with NAE and serological evidence of hypozincemia and hyperzincuria. The detection of hypozincemia in our patient and the response of her condition to zinc suggest a physiological link between zinc deficiency and NAE. The association of zinc deficiency with NAE further suggests a physiological basis for classifying NAE among the necrolytic erythemas (Table 1). The mechanism by which patients with NAE may develop zinc deficiency is unknown. However, HCV infections have been associated with hepatic zinc deficiency and hypozincemia.5–8 Acute viral hepatitis has also been associated with hepatic zinc deficiency, hypozincemia, and hyperzincuria.5,9 Hypozincemia and hyperzincuria have also been seen in patients with chronic liver diseases from other etiologies.10 In conclusion, we present a case suggesting NAE may result from zinc deficiency driven by chronic HCV infection and perhaps urine zinc losses. Routine measurements of zinc levels of the skin, serum, urine, and other tissues may be warranted to characterize the bio-distribution of zinc in patients with NAE. Acknowledgments We are grateful to Vincent J. McAuliffe, md at the Robert Wood Johnson University Hospital for kindly referring his patient to our service. References 1 Abdallah MA, Ghozzi MY, Monib HA, et al. Histological study of necrolytic acral erythema. J Ark Med Soc 2004; 100: 354 –355. 2 Najarian DJ, Lefkowitz I, Balfour E, et al. Zinc deficiency associated with necrolytic acral erythema. J Am Acad Dermatol 2006; 55: S108 –S110. 3 Nofal AA, Nofal E, Attwa E, et al. Necrolytic acral erythema: a variant of necrolytic migratory erythema or a distinct entity? Int J Dermatol 2005; 44: 916 –921. © 2008 The International Society of Dermatology Najarian et al. 4 el Darouti M, Abu el Ela M. Necrolytic acral erythema: a cutaneous marker of viral hepatitis C. Int J Dermatol 1996; 35: 252 –256. 5 Stehbens WE. Oxidative stress in viral hepatitis and AIDS. Exp Mol Pathol 2004; 77: 121–132. 6 Ko WS, Guo CH, Hsu GS, et al. The effect of zinc supplementation on the treatment of chronic hepatitis C patients with interferon and ribavirin. Clin Biochem 2005; 38: 614–620. 7 Nagamine T, Takagi H, Hashimoto Y, et al. The possible role of zinc and metallothionein in the liver on the © 2008 The International Society of Dermatology Zinc deficiency associated with necrolytic acral erythema Morphology therapeutic effect of IFN-α to hepatitis C patients. Biol Trace Elem Res 1997; 58: 65–76. 8 Loguercio C, De Girolamo V, Federico A, et al. Trace elements and chronic liver diseases. J Trace Elem Med Biol 1997; 11: 158–161. 9 Beisel WR. Trace elements in infectious processes. Med Clin North Am 1976; 60: 831–846. 10 Gusau KA, Elegbede JA, Idoko JA, et al. Zinc status in chronic liver disease; studies in Nigerian patients. West Afr J Med 1990; 9: 245–251. 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