Necrolytic Acral Erythema

Etiology

Necrolytic acral erythema is primarily associated with HCV infection, which is central to its pathogenesis. The exact mechanism by which HCV leads to necrolytic acral erythema is not fully elucidated but involves several key factors. The virus may induce skin changes through direct viral effects, immune-mediated mechanisms, or metabolic disturbances related to liver dysfunction.[4]

Epidemiology

Necrolytic acral erythema was initially reported among patients in areas with highly prevalent and untreated HCV infection, such as Egypt. Subsequent studies have reported cases from various regions worldwide, including the Middle East, Asia, Europe, and North America. However, the prevalence and incidence of necrolytic acral erythema remain poorly defined due to its rarity and underreporting in clinical practice.[5] Although initially considered a rare dermatosis, its association with chronic HCV infection has led to increased recognition in regions with a high prevalence of HCV. Necrolytic acral erythema predominantly affects adults, with the majority of reported cases occurring in individuals between the ages of 40 and 60, and does not appear to have a gender predilection.[6] Chronic HCV infection is considered the primary associated factor in the pathogenesis of necrolytic acral erythema. Infection is common in patients with necrolytic acral erythema; however, viral loads are not necessarily elevated.[7]

Pathophysiology

Zinc deficiency is a well-recognized factor in the development of necrolytic acral erythema.[7] Zinc is an essential cofactor in numerous enzymatic processes, including skin integrity and repair.[8] Experts have also hypothesized that HCV infection exacerbates zinc deficiency by altering zinc metabolism or through the systemic inflammatory response it provokes. In addition, the infection can lead to liver dysfunction, affecting metabolic processes and nutritional status. 

Acrodermatitis enteropathica, a condition caused by zinc deficiency, provides a pertinent example of this pathophysiology. This autosomal recessive disorder is characterized by mutations in SLC39A4, which encodes a zinc transporter protein essential for zinc uptake in the intestine. The resulting impaired zinc absorption manifests as acral and periorificial dermatitis, alopecia, and diarrhea. Both necrolytic acral erythema and acrodermatitis enteropathica highlight zinc's critical role in maintaining skin health and the systemic consequences of its deficiency. Understanding the pathophysiology of zinc deficiency in necrolytic acral erythema, including its impact on enzymatic processes and skin integrity, underscores the importance of addressing zinc levels in affected patients.[9] In addition, malabsorption of essential nutrients, including amino acids and vitamins, can contribute to skin manifestations. The resultant hypoaminoacidemia may impair protein synthesis and skin barrier function, exacerbating the symptoms of necrolytic acral erythema.[10]

Histopathology

The histology of necrolytic acral erythema depends on the disease's location and stage at the time of biopsy. In the early stages, the outer layer of the epidermis exhibits necrosis, leading to blister formation as the epidermis detaches from the underlying tissue. Histologically, the epidermis shows thickening (acanthosis) and intercellular edema (spongiosis), accompanied by superficial dermal inflammatory infiltrate resembling nummular dermatitis. The accumulation of necrotic keratinocytes can lead to the formation of clefts in the upper epidermis (see Image. Necrolytic Acral Erythema Histopathology). In addition, areas of dyskeratosis (abnormal keratinization) and epidermal pallor help differentiate necrolytic acral erythema from psoriasis. The characteristic necrosis of keratinocytes and vacuolar degeneration of some basal cells are critical diagnostic features of necrolytic acral erythema.[11]

History and Physical

Patients with necrolytic acral erythema may be unaware of their HCV status. Moreover, given the different stages and durations of necrolytic acral erythema, history may be variable, with lesions presenting intermittently.[6] Necrolytic acral erythema is characterized by painful, erythematous, eroded, and occasionally bullous plaques primarily affecting the acral areas, such as the hands and feet.[1] 

Physical examination findings may show lesions in 3 distinct stages—initial, well-developed, and late. The initial stage presents with lesions that begin as small, erythematous macules or plaques that gradually enlarge and develop central necrosis and crusting. In the well-developed stages, the lesions merge to form distinct, thick, dark plaques with attached scales. As the condition progresses to the late stage, the lesions become more circumscribed, thinner, and hyperpigmented.[1]

Evaluation

The evaluation of necrolytic acral erythema involves a thorough investigation to identify underlying causes and metabolic disturbances. Early recognition of necrolytic acral erythema is crucial for diagnosing and treating any underlying conditions, particularly HCV infection. In more than 75% of necrolytic acral erythema cases, HCV is diagnosed for the first time, highlighting the importance of HCV serology in all patients with necrolytic acral erythema.[1]

Although no specific diagnostic laboratory tests exist for necrolytic acral erythema, a comprehensive biochemical evaluation is essential. Serum zinc levels are typically normal, though isolated reports indicate occasional low levels.[12][13] In addition, measuring amino acid and albumin levels is important, as these may be abnormal in some patients. Normal glucagon levels can help to differentiate necrolytic acral erythema from necrolytic migratory erythema. Liver function tests, including transaminase levels and total serum bilirubin, are crucial, particularly for HCV patients. Abnormal liver function tests and ultrasonography findings are common, reported in 84.3% and 76.9% of cases, respectively.[6] Furthermore, investigations should be conducted to rule out other differential diagnoses based on the clinical presentation of necrolytic acral erythema. This diagnostic approach results in more accurate identification and appropriate management of the condition.

Treatment / Management

The management of necrolytic acral erythema focuses on treating both the underlying cause and the skin manifestations. In patients with HCV infection, antiviral treatments such as ribavirin and interferon-alpha have been shown to improve the condition, even if the viral load remains high. Interferon-alpha monotherapy has also been effective. Oral zinc therapy is recognized as the most effective treatment for necrolytic acral erythema, even in patients without a deficiency. Interestingly, zinc therapy has also been noted to enhance the efficacy of interferon treatment in HCV patients with necrolytic acral erythema. A 220 mg oral zinc regimen taken twice daily for up to 8 weeks has been shown to clear skin findings.[14] Other treatments have been explored with varied results. Mid- to high-potency topical and systemic corticosteroids and topical tacrolimus have been tried with mixed results.[15] Phototherapy methods, including psoralen plus ultraviolet A therapy and narrowband ultraviolet B therapy, have also been tested but have not shown benefit.[16]

Differential Diagnosis

Necrolytic acral erythema can be misdiagnosed as several other dermatological conditions with similar clinical features, including erythema, scaling, and psoriasiform plaques. Accurate differentiation is crucial for appropriate diagnosis and treatment. Conditions presenting with acral erythemas include acrodermatitis enteropathica, the dermatitis of niacin deficiency, and deficiencies such as biotin and fatty acid. These conditions typically have a distinctive acral distribution and lack systemic symptoms, which helps distinguish them from necrolytic acral erythema.[17][18] 

Psoriasis often presents with well-demarcated, erythematous plaques covered with silvery scales commonly located on the elbows, knees, scalp, and lower back. Necrolytic acral erythema can be differentiated from psoriasis by its dark and verrucous scales and the absence of central clearing in the lesions. Histopathological examination may sometimes be required to confirm the diagnosis and exclude psoriasis.[19] Lichen simplex chronicus is another skin disorder characterized by thickened, scaly patches resulting from chronic rubbing or scratching. The lesions are typically well-defined, lichenified plaques that are intensely pruritic. Unlike necrolytic acral erythema, lichen simplex chronicus lacks necrotic features and systemic associations with HCV. However, late stages of necrolytic acral erythema may appear lichenified. Differentiation is based on a clinical history of chronic itching and physical examination, though a biopsy may be used to confirm the diagnosis if necessary.[20]

Erythrokeratoderma manifests as hyperkeratotic, erythematous plaques, often in a geographic or linear pattern, and typically appears in infancy or childhood. Unlike necrolytic acral erythema, erythrokeratoderma typically shows symmetrical distribution and has a genetic basis.[21] Nummular eczema is characterized by coin-shaped, erythematous, and scaly plaques, often associated with itching and discomfort. The absence of well-defined lesions and verrucous scales observed in necrolytic acral erythema helps differentiate these conditions.[22] In addition, dermatophytosis presents with erythematous plaques with central clearing and peripheral scaling, typically caused by fungal infections. The absence of central clearing and the distinct histopathological features of necrolytic acral erythema assist in distinguishing it from dermatophytosis.[17][10][14] 

Prognosis

The prognosis of necrolytic acral erythema varies and largely depends on recognizing the underlying cause, the effectiveness of the treatment administered, and a timely diagnosis. As necrolytic acral erythema is commonly associated with HCV infection, successful management of the underlying HCV can significantly improve skin lesions and overall outcomes.[23] Nonetheless, some reports indicate that necrolytic acral erythema lesions can reappear after stopping interferon treatment, and instances of necrolytic acral erythema recurrence might align with the return of liver disease symptoms and the recovery of HCV viral load. Moreover, mixed findings regarding the association between hepatic disease and skin burden have been reported.[24] The delay in diagnosing necrolytic acral erythema can negatively impact the prognosis due to its wide range of possible diagnoses and rarity.[24]

Complications

The complications of necrolytic acral erythema primarily arise from its persistent and recurrent lesions, which can be chronic, particularly if the underlying HCV infection is not adequately controlled.[6] These lesions can be painful, causing significant discomfort and impacting the patient's quality of life. Moreover, they are prone to secondary infections, especially if the skin barrier is compromised due to ulceration or scratching.

Chronic or recurrent necrolytic acral erythema lesions often lead to scarring and postinflammatory hyperpigmentation, which can be cosmetically concerning for patients. As necrolytic acral erythema typically affects the hands and feet, severe cases can impair the patient's mobility and ambulation, further diminishing their quality of life.[25] 

Necrolytic acral erythema is closely linked to chronic HCV, a condition that can lead to severe complications, including cirrhosis, liver failure, and hepatocellular carcinoma, if not adequately managed. This association underscores the importance of addressing the underlying infection in treating necrolytic acral erythema.[26] However, treatment challenges arise when HCV therapy is discontinued or proves ineffective, as this can lead to relapses of necrolytic acral erythema, complicating overall disease management.[10]