Necrolytic acral erythema

Dermatology Online Journal
Volume 16 Number 11
November 2010

Utpal Patel MD PhD, Aaron Loyd MD, Rishi Patel MD, Shane Meehan MD, Roopal Kundu MD
Dermatology Online Journal 16 (11): 15
Department of Dermatology, New York University, New York, New York

Abstract

Necrolytic acral erythema (NAE) is a recently recognized dermatosis almost exclusively associated with hepatitis C virus (HCV) infection and closely related to a group of necrolytic erythemas and metabolic syndromes. NAE is characterized by pruritic, symmetric, well-demarcated, hyperkeratotic, erythematous-to-violaceous, lichenified plaques with a rim of dusky erythema on the dorsal aspects of the feet and extending to the toes. Based on morphology and histopathologic features, NAE can be difficult to distinguish from certain groups of necrolytic erythemas, which include necrolytic migratory erythema, acrodermatitis enteropathica, biotin deficiency, niacin deficiency, and essential fatty acid deficiencies. The condition is particularly important for clinicians to diagnose because the majority of the patients present to dermatologists without a known history of HCV infection. Thus, NAE can serve as a cutaneous marker for underlying HCV infection. Resolution of NAE can be achieved by treatment of the underlying HCV infection and the use of oral zinc therapy.

History

Figure 1

Figure 2

A 53-year-old woman presented to the Charles C. Harris Skin and Cancer Pavilion with a scaly, lichenified, pruritic eruption over the dorsal aspects of the feet and ankles for approximately one year. A diagnosis of eczematous dermatitis initially was made, and she was treated with triamcinolone 0.1 percent ointment and urea cream. This treatment led to resolution of the pruritus; however, there was minimal improvement of the cutaneous lesions. A biopsy was performed, and patch tests to the North American Standard Series and shoe series were negative. Review of systems was not contributory.

Past medical history included dermatomyositis that was treated with intravenous immunoglobin, hepatitis C virus infection treated with ribavarin and INF-α, cataracts, and iron-deficiency anemia. The patient was treated with zinc sulfate 220 mg twice daily. There was partial resolution of the plaques over three months of treatment.

Physical examination

Symmetric, sharply-demarcated, hyperkeratotic, violaceous, hyperpigmented, lichenified plaques were present on the dorsal aspects of the feet and extended to the toes and over the Achilles tendons.

Laboratory data

A comprehensive metabolic profile, complete blood count, thyroid function tests, amylase, lipase, and zinc levels were normal. Hepatitis C virus RNA count was measured at 11.5 x 106 IU/mL, and the genotype was determined to be type IA. Ultrasound and a computed tomography scan of the abdomen showed no evidence of cirrhosis, portal hypertension, or hepatocellular carcinoma.

Histopathology

There is a superficial, perivascular inflammatory infiltrate comprised predominantly of lymphocytes. Some lymphocytes extend to a hyperplastic epidermis where there are spongiosis and foci of sharply demarcated parakeratosis. There is slight pallor of the superficial epidermis.

Comment

Necrolytic acral erythema (NAE) is a recently recognized dermatosis, which is almost exclusively associated with hepatitis C virus infection and is closely related to a group of necrolytic erythemas and metabolic syndromes. It was first described in 1996 in Egyptian patients with hepatitis C virus (HCV) infection [1]. NAE is characterized by pruritic, symmetric, well-demarcated, hyperkeratotic, erythematous-to-violaceous, lichenified plaques with a rim of dusky erythema on the dorsal aspects of the feet and extending to the toes. The average patient age is 40 years (range from 11 to 76 years) and there is no sex predilection [2]. Since the initial report, over 70 cases have been described worldwide, including Pakistan, India, United States, and Taiwan, but the vast majority of reports have come from Egypt [3-18]. The disproportionate regional distribution is likely due to several factors: 1. The worldwide prevalence of HCV infection is 3 percent, whereas in Egypt it is estimated to be 15 to 20 percent. 2. There are differences in the HCV genotype. 3. There is likely a lack of clinical awareness of the condition among physicians [12, 14, 19]. NAE is particularly important for clinicians to diagnose because the majority of patients present to dermatologists without a known history of HCV infection [12, 14] Thus, NAE can serve as a cutaneous marker for underlying HCV infection.

Based on a longitudinal study, NAE develops in three stages, with variable degrees of pruritus and/or burning [14]. The initial stage is characterized by scaly, dusky papules with an erythematous rim. The lesion then progresses to the fully-developed, erythematous-to-violaceous, lichenified, scaly plaque. In the third stage, the lesion progressively thins and exhibits increased hyperpigmentation. The most common sites of involvement are the dorsal aspects of the feet, over the Achilles tendons, malleoli, legs, and knees. Less frequent sites of involvement include the elbows, hands, buttocks, and genitalia. There is sparing of the palms, soles, face, and mucous membranes [12]. Histopathologic features include a non-specific psoriasiform pattern [5, 14, 17], acanthosis, papillomatosis, and hyper- and parakeratosis, with necrotic keratinocytes in the superficial epidermis. NAE can be difficult to distinguish from certain groups of necrolytic erythemas, which include necrolytic migratory erythema, acrodermatitis enteropathica, biotin deficiency, niacin deficiency, and essential fatty acid deficiencies. However, these entities can be distinguished based on clinical and laboratory evaluation [8].

Although a number of mechanisms have been proposed for NAE, there is insufficient evidence to support a precise pathogenesis. The most consistent finding associated with NAE is HCV infection. In fact, there are only four reported cases of NAE without associated HCV infection [3, 4, 8]. Furthermore, two of three studies have observed a correlation between the severity of HCV infection (based on liver enzymes) and the severity of NAE [1, 13, 14]. Additional support comes from cases in which treatment of HCV with ribavarin and INF-α has lead to resolution of NAE [1, 14, 16]. The mechanism by which HCV infection causes NAE is not clear. Attempts to demonstrate HCV viral particles in the involved skin with electron microscopy (for viral particles) or with real time polymerase chain reaction (for HCV RNA) have been unsuccessful [12]. NAE may arise secondary to HCV viral antigen-induced humoral and/or cell-mediated autoimmune responses to viral and/or endogenous cutaneous antigens. Yet another possibility is the development of metabolic abnormalities secondary to hepatocellular dysfunction from HCV infection, which leads to cutaneous manifestations [20, 21].

The next most consistent finding associated with NAE is zinc deficiency, which may result from HCV infection. There are a number of studies that demonstrate decreased zinc levels in patients with NAE [11, 13]. When patients with laboratory evidence of zinc deficiency are treated with zinc (at doses ranging from 60 mg to 440 mg per day), clinical improvement has been noted that ranges from mild to complete resolution [1, 7, 9, 11, 12, 13, 18]. The most consistent improvement is noted at the dose of 440 mg per day. Even in patients with normal serum zinc levels, zinc supplementation has lead to clinical improvement of NAE. It is thought that zinc deficiency may occur in the skin prior to the development of clinical zinc deficiency as assessed by serum zinc levels [22].

Other metabolic conditions that are less clearly associated with NAE are hypoalbuminemia, which is possibly due to the role of albumin as a carrier for essential nutrients that include zinc; hypoaminoacidemia, which is secondary to depletion of epidermal protein and which may increase susceptibility of keratinocytes to necrolysis; and elevated glucagon levels, which are thought to cause elevated levels of pro-inflammatory arachidonic acid and its metabolites [1, 13, 16, 18, 23, 24]. Some authors argue that NAE is a variant of necrolytic migratory erythema (NME) based on the similarity of the clinical and histopathologic features and the proposed pathologic mechanisms, such as hypoalbuminemia and zinc deficiency [13]. The main features that differentiate NAE from NME are the strong association of NAE with HCV infection and the typical localization of NAE to the dorsal aspects of the feet.

Treatment for NAE is not well defined. Because the majority of patients with NAE present without a prior diagnosis of HCV infection, it is imperative to determine HCV infection status in any patient suspected to have NAE. If an infection is identified, the HCV disease severity should be assessed and a treatment plan devised with a hepatologist. An evaluation should be carried out to identify and treat the underlying metabolic deficiency. Zinc therapy (440 mg per day) should be attempted, even in patients with normal serum zinc levels because the probability of benefit outweighs the minimal risk of therapy. There is a single case report that shows improvement with the use of tacrolimus ointment, which may be attempted [6].

References

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