Necrolytic Acral Erythema

Updated: Oct 04, 2019
  • Author: Fnu Nutan, MD, FACP; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

Necrolytic acral erythema (NAE) was first described in Egyptian patients in 1996 by El Darouti and Abu El Ela. [1] NAE has been referred to as a cutaneous marker of hepatitis C infection owing to its strong association with the infection. [2, 3] Most of the cases described in literature have been in Egypt, although there have been reports of necrolytic acral erythema around the world. The prevalence of hepatitis C infection is high in Egypt, at 15-20%, owing in part to parenteral antischistosomal therapy. [4] Necrolytic acral erythema manifests as well-circumscribed, dusky erythematous plaques with adherent scale. Lesions classically have an acral distribution. While the plaques are psoriasiform, they do not manifest an Auspitz sign as would be seen with psoriasis. Burning or pruritus may occur with active disease. Several cases of necrolytic acral erythema have occurred in patients without hepatitis C. [5, 6, 7] This suggests hepatitis C infection is not the sole causation for necrolytic acral erythema. Some sources support zinc deficiency as a cause of necrolytic acral erythema. Indeed, oral zinc supplementation has been an effective treatment for necrolytic acral erythema in some cases. [8, 9] While zinc deficiency is reported in Egyptian populations of stunted children and pregnant women, why Egypt is the epicenter of necrolytic acral erythema is not clear. It is hoped that the prevalence of necrolytic acral erythema will decrease worldwide with effective treatments available for hepatitis C. [10]

Authors debate whether necrolytic acral erythema is a distinct entity or a subtype of necrolytic migratory erythema. However, the distinct appearance and association with hepatitis C infections suggests that it is a unique entity. It has been speculated that viral load and viral genotype might play a role in necrolytic acral erythema. [11] This has been underlined by a study in the Journal of the American Academy of Dermatology. [12] It seems that one reason for the underdiagnosis of necrolytic acral erythema is that it has a range of histology and clinical findings and thus is more of a reaction pattern (eg, a spectrum), rather than a sharply defined entity. [13]

Another debate has arisen regarding cases of necrolytic acral erythema that are seronegative for hepatitis C and whether these cases constitute a distinct and separate clinical subset of necrolytic acral erythema. [14, 15]

It should be kept in mind that hepatitis C has many other associated clinical conditions that include not only necrolytic acral erythema but also autoimmune thyroiditis, diabetic nephropathy, renal membranoproliferative glomerulonephritis, insulin resistance, mixed cryoglobulinemia, immune complex deposition, non-Hodgkin lymphoma, sialadenitis, and sicca syndrome. These are related to (1) chronic inflammation, (2) immune complex deposition, and (3) immunoproliferative phenomenon. [16]

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Pathophysiology

The pathophysiology of necrolytic acral erythema (NAE) is uncertain. Proposed theories for the cause of necrolytic acral erythema describe alterations in some metabolic factor, many of which are seen in other necrolytic erythemas, including necrolytic migratory erythema, pellagra, essential fatty acid and biotin deficiency, and acrodermatitis enteropathica. The hypothesized causes for the metabolic alteration include hypoalbuminemia, hypoaminoacidemia, low zinc level, increased glucagon, liver dysfunction, or diabetes. 

An odd finding is that no cases of necrolytic acral erythema have been reported in Japan, where prevalence of hepatitis C infection is high.

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Etiology

The cause of necrolytic acral erythema (NAE) is uncertain, but a metabolic alteration due to hepatocellular degeneration from hepatitis C infection is proposed. Many hypotheses describe deficiencies similar to those of the other necrolytic erythemas; histological features are similar among necrolytic acral erythema and other nutrient deficiencies.

Zinc deficiency has been proposed to play a role in the pathogenesis of necrolytic acral erythema. Moneib et al studied zinc levels in the serum, lesional skin, and perilesional skin of 15 necrolytic acral erythema patients and found that all three were significantly decreased compared with levels in healthy subjects. [17] Zinc is a cofactor involved in the differentiation and proliferation of keratinocytes and is required in wound repair. [18] It is still unknown what causes zinc deficiency in necrolytic acral erythema patients. One theory attributes low serum zinc levels to its role as a cofactor in hepatitis C viral proteins; another theory is that lipopolysaccharides build up in hepatic patients, causing a cytokine-induced redistribution of zinc in the body. [17] Patient responses to zinc supplementation have been mixed, suggesting that the etiology of necrolytic acral erythema is multifactorial.

High glucagon levels may contribute to its pathogenesis. In hepatic patients, increased glucagon levels allow "potentiation" of arachidonic acid after trauma, which may induce inflammatory changes and necrosis in the epidermis. [1]

Low amino acid levels may lead to epidermal protein depletion and necrolysis.

Low albumin levels have also been postulated as causative. Albumin sequesters fatty acids and helps regulate prostaglandin levels. High levels of prostaglandins as a result of low levels of albumin may induce inflammation. Because albumin is the main carrier of zinc in plasma, these two may be interrelated.

Diabetic microangiopathy also may play a role; four of five necrolytic acral erythema patients described by Nofal et al [19] also had diabetes.

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Epidemiology

Frequency

United States

Twenty-three cases of necrolytic acral erythema (NAE) have been described in the United States to date. All except for one [7] of these cases were in individuals positive for hepatitis C virus. In the United States, necrolytic acral erythema has been most frequently reported in African American patients with hepatitis C virus genotype 1. In a study by Raphael et al of 300 patients in Philadelphia with chronic hepatitis C, only 5 of 300 individuals were found to have necrolytic acral erythema, putting the prevalence of necrolytic acral erythema at 1.7%. [12] Thus, necrolytic acral erythema is still an uncommon entity in hepatitis C infection.

International

Between 1996 and 2019, 145 cases of necrolytic acral erythema have been described internationally. One-hundred and nineteen of these 145 cases were in Egypt. Cases have also been reported in India, Taiwan, Brazil, France, Pakistan, and others. El-Ghandour et al [20] in Egypt described a series of 23 patients (mean age, 41.7 ±11.5 y; male-to-female ratio, 10:13) with clinical features consistent with necrolytic acral erythema examined over a 3-year period. Most necrolytic acral erythema patients were adults (91.3%), and the skin lesions were predominantly chronic (78.3%), with the dorsa of the toes and/or feet affected in all cases.

Race

Most cases of necrolytic acral erythema have been reported in Egyptians. A dark-skinned woman aged 56 years with hepatitis C who had the disease for 10 years was reported at a case conference at the department of dermatology of New York University. [21] Although most of the reported cases are in individuals with darker skin, there have been a few instances of necrolytic acral erythema in patients with lighter skin. [8]

Sex

To date, no sex predisposition is reported for necrolytic acral erythema.

Age

Necrolytic acral erythema has been reported in patients ranging in age from 9-76 years, with the typical age of onset at age 35-55 years.

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Prognosis

With therapy, prognosis is fair. Some patients have a relapsing course. Necrolytic acral erythema (NAE) has no known directly associated morbidly or mortality. Rather, the morbidity and mortality are related to the primary illness, hepatitis C.

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