Necrolytic Acral Erythema

Are You Confident of the Diagnosis?

What you should be alert for in the history

Necrolytic acral erythema (NAE) is a cutaneous marker of Hepatitis C viral infection (HCV). In the absence of HCV, one should consider other diagnoses in the differential. The diagnosis of NAE often precedes that of HCV, and presence of NAE should prompt the clinician to test for HC. It is recommended to first do an antibody test (EIA-2 and 3) and if positive perform a confirmatory HCV RNA molecular assay. RIBA testing may be used to distinguish between HCV RNA negative patients to determine false positive antibody tests and recovered HCV infection.

Characteristic findings on physical examination

Clinical appearance depends on the stage of NAE at presentation. Classically, early/acute presentation reveals scaly, erythematous papules or plaques with dusky centers on the dorsal hands and feet (Figure 1, Figure 2). Erosions and blisters can be seen in the acute stage. In long-standing/chronic stage NAE, the papules become confluent with increasing scale and diminished erythema. A hyperpigmented, velvety, acanthosis nigricans-like appearance develops. Hyperkeratotic, well-demarcated borders are also characteristic.

Classically, NAE involves the dorsal feet, but can affect the hands, ankles, legs, and knees; less common sites include the elbows, genitalia, and buttocks. Palms, soles, and nails typically are spared, but rare cases have been reported. Lesions can be painful and most patients describe pruritus and burning, which are useful clues in the history.

Expected results of diagnostic studies

Laboratory work-up should focus on evaluating for underlying liver disease, especially for HCV infection. Hepatitis serologies and liver function tests (including aspartate aminotransferase, alanine aminotransferase, total bilirubin, Lactate dehydrogenase, and alkaline phosphatase) should be performed. Transaminitis due to HCV may be seen.

A glucagon and zinc level should be performed to distinguish NAE from necrolytic migratory erythema and acrodermatitis enteropathica, respectively. Serum albumin and amino acids levels should be evaluated as these may be low with NAE. A check of biotin, free fatty acids, and Vitamin B3 should be performed to rule out other similar conditions that mimic NAE, due to deficiencies in these nutrients.

A skin biopsy of NAE will vary depending on the stage of disease (Figure 3, Figure 4). Early lesions show epidermal thickening and spongiosis with inflammation around the superficial vessels of the dermis. Later stages reveal distinctive epidermal pallor, psoriasiform hyperplasia leading to clubbing of the rete pegs, prominent papillae elevating the skin’s surface, retention of nuclei in the corneal layer, subcorneal pustules, and necrotic keratinocytes.

These findings are nonspecific for NAE and are commonly seen in other nutritional deficiencies, and thus must be correlated clinically. However, the focal nature of epidermal dyskeratosis and pallor, along with basal cell vacuolar degeneration can be useful in distinguishing NAE from other clinical mimickers, such as psoriasis. Skin biopsy is useful when the previously mentioned laboratory values are not helpful.

There is little value in other imaging studies.

Diagnosis confirmation

The differential diagnosis for NAE includes necrolytic migratory erythema (NME), classically associated with elevated glucagon levels and glucagonoma, acrodermatitis enteropathica (distinguished by low zinc levels and typical involvement of the groin and perioral skin), biotin and fatty acid deficiencies, vitamin B3 deficiency/pellegra (niacin deficiency, characterized by diarrhea, dementia and dermatitis of the neck area), acrokeratosis paraneoplastica (Bazex syndrome, showing hyperkeratotic erythematous lesions on the acral skin, nose, and ears), hypertrophic lichen planus (thick lichenified plaques often on the lower legs), and acral psoriasis (silvery scaly patches and plaques).

Characteristic findings that distinguish NAE from other similar conditions listed above include:

• Flaccid blisters, dusky rim, and acral distribution in acute lesions.

• Consistent association with HCV infection

• Though the focal keratinocyte degeneration and basal layer vacuolar degeneration can be seen in other nutritional deficiency states, in the proper clinical setting (such as with documented HCV infection), one can differentiate among these diagnoses in most cases.

The question of whether NAE is simply a variant of NME linked with HCV is an area of debate in the literature.

Who is at Risk for Developing this Disease?

NAE is a rare disease, with fewer than 100 cases reported in the literature (although some feel the disease is underreported). Males and females are affected equally and the mean age of those affected is 41.7 years.

NAE was first described in the 1990s in Egypt, and subsequent reports suggest that the incidence of NAE in Egypt and the surrounding region is high – presumably due to higher rates of HCV infection.

The biggest risk factor for NAE is HCV and any patient presenting with a condition suspicious for NAE should be tested for HCV. In one study, 4 out of 5 patients with NAE were found to be diabetic, though this could be secondary to complications from HCV. No cases of NAE have been reported with Hepatitis A or B. Necrolytic migratory erythema has been associated with Hepatitis B.

What is the Cause of the Disease?

Etiology

The cause of NAE is unknown, though the metabolic derangements from an HCV-infected liver are believed to play a role. Of interest, the level of liver damage as assessed by liver enzymes has not been consistently correlated with disease activity.

Several theories have been proposed regarding the etiology and pathophysiology of NAE including hypoaminoacidemia, hyperglucagonemia, hypoalbuminemia, and low serum zinc levels.

Pathophysiology

Low amino acid levels in the setting of high glucagon levels, both results of liver damage, may impact the levels of anabolic proteins in the epidermal layer leading to decreased synthesis of new keratinocytes and necrolysis from imbalanced protein metabolism. However, low levels of amino acids are not consistently found in NAE and amino acid infusions have not been consistently useful in treating NAE.

Trauma to the acral areas may release acrachidonic acid, and in the presence of high glucagon levels may lead to the characteristic distribution of NAE. However, koebnerization is not characteristic of NAE and glucagon is not consistently elevated.

Low albumin could lead to elevated prostaglandins, causing inflammation. Albumin is a carrier of zinc and essential fatty acids; therefore, low albumin levels cause decreased amounts of these molecules. Hypoalbuminemia has been found in a few patients, but not in the majority.

Subclinical zinc deficiency may lead to apoptosis of cells as zinc has antiapoptotic properties. One study showed decreased zinc levels in the epidermal layer as well as in the serum, though this is not always the case. Low zinc is thought to play a role as replacement leads to improvement in the skin.

Systemic Implications and Complications

The importance of recognizing NAE is in making sure that HCV has been diagnosed and appropriate treatment initiated. There are no direct systemic effects of NAE per se, but it serves as a cutaneous marker of HCV.

Treatment Options

Treatment options are summarized in Table I.

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