Necrolytic Acral Erythema

Updated: Nov 05, 2018
  • Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

Necrolytic acral erythema (NAE) was first described in 1996 by physicians in Egypt, M. El Darouti and M. Abu El Ela. [1] Reports have continued to link hepatitis C with necrolytic acral erythema. [2] Hepatitis C virus (HCV) infection is widespread in Egypt, owing to parenteral antischistosomal therapy, leading to a prevalence rate of HCV infection in Egypt of 15-20%. [3] Necrolytic acral erythema manifests as well-circumscribed, dusky erythematous plaques with adherent scale. While the plaques are psoriasiform, they do not manifest an Auspitz sign as would be seen with psoriasis. Patients with active necrolytic acral erythema report burning or pruritus. It is limited to an acral distribution and, in most cases, is associated with hepatitis C infection. [4, 5] Several cases of necrolytic acral erythema have occurred in patients without hepatitis C. [6] This suggests that necrolytic acral erythema might be a result of zinc dysregulation, rather than a result of hepatitis C infection itself. Other sources support zinc deficiency as a cause of necrolytic acral erythema. [7, 8] 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 now that effective treatments are available of hepatitis C, this will decrease the prevalence of the disease worldwide. [9]

Authors debate whether necrolytic acral erythema is a distinct entity or a subtype of necrolytic migratory erythema. However, the distinct appearance and usual coincidence 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. [10] This has been underlined by a study in the Journal of the American Academy of Dermatology. [11] 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. [12]

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. [13, 14] In 2017, another case of a patient with necrolytic acral erythema who was seronegative for hepatitis C was published. [15]

It should be kept in mild that hepatitis C has many related finding that include 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. They are related to (1) chronic inflammation, (2) immune complex deposition, and (3) immunoproliferative diseases. [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. Only hepatitis C is universally present in all persons with necrolytic acral erythema.

An odd fact is that no cases of necrolytic acral erythema have been reported in Japan, which has a high seroprevalence rate of hepatitis C.

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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.

el Darouti and Abu El Ela [1] suggested that the increased levels of glucagon seen in persons with liver disease allow for "potentiation" of arachidonic acid after trauma.

High glucagon levels alone may allow for greater arachidonic acid potentiation, which may induce inflammatory changes and necrosis in the epidermis.

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.

Low zinc levels have also been proposed as a cause. Because albumin is the main carrier of zinc in plasma, these two may be interrelated.

Diabetic microangiopathy also may play a role; 4 of 5 necrolytic acral erythema patients described by Nofal et al [17] also had diabetes.

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Epidemiology

Frequency

United States

Only two cases of necrolytic acral erythema (NAE) have been described in the United States to date, but the condition is likely more common than the case reports suggest. Still, in a series of 300 patients with chronic hepatitis C in Philadelphia, only 1.7% had necrolytic acral erythema (all African American with HCV genotype 1, a viral load >200,000 IU/mL, which is considered to be high). [11] While cases of necrolytic acral erythema continue to be reported, [18] the actual prevalence of one series of 300 patients suffering from chronic hepatitis C infection was only 5 individuals, for a prevalence of 1.7%. [19] Thus, while necrolytic acral erythema is a real entity in a not uncommon disease, is uncommon and might become even less common as more new treatments for HCV are approved and used.

International

Forty-two cases of necrolytic acral erythema have been described internationally, mostly in Egypt. 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. No cases have been reported in whites. A dark-skinned woman aged 56 years with hepatitis C who had the disease for 10 years was reported at a case conference at department of dermatology of New York University. [21]

Sex

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

Age

The ages of the patients with necrolytic acral erythema have ranged from 11-60 years, but the onset typically occurs between 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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