Necrolytic Acral Erythema

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 been reported in patients without hepatitis C, suggesting that hepatitis C may not be the sole cause.[5, 6, 7] Some sources support zinc deficiency as a cause of necrolytic acral erythema. Indeed, oral zinc supplementation has been an effective treatment for in some cases.[8, 9] While zinc deficiency is reported in Egyptian populations of children and pregnant women, why Egypt is the epicenter of necrolytic acral erythema is not clear. It is speculated 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 infection suggest 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, 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 the condition.[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]

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

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.[18] Zinc is a cofactor involved in the differentiation and proliferation of keratinocytes and is required in wound repair.[19] 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.[18] Patient responses to zinc supplementation have been mixed, suggesting that the etiology of necrolytic acral erythema is multifactorial.

High glucagon levels may contribute to necrolytic acral erythema pathogenesis. In hepatic patients, increased glucagon levels allow for "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 may also be 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.

Necrolytic acral erythema after hepatitis B vaccination was noted in 2014.[20]

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, five of 300 individuals were found to have necrolytic acral erythema, putting the prevalence at 1.7%.[12]

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[21] 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.

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

Race

Most cases of necrolytic acral erythema have been reported in Egyptians. A dark-skinned Caucasian female with hepatitis C and necrolytic acral erythema was reported at New York University.[22] 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. Most necrolytic acral erythema patients were adults (91.3%).

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.

Patients with necrolytic acral erythema (NAE) present with a 1-month to 2-year history of a rash, usually on the dorsum of the feet or the hands. In many cases, it has been unresponsive to topical steroids. Itching can precede the development of the rash.

Patients do not necessarily give a history of hepatitis C. Necrolytic acral erythema may be the presenting sign. Patients may report a burning sensation, especially when walking or standing. Sometimes, necrolytic acral erythema lesions are pruritic or express purulent drainage. The most common area of origin of the rash is the dorsal aspect of the great toe. It also occurs on the shins. In 43 of 44 reported cases, necrolytic acral erythema did not affect the palms or soles, nail bed, nail plate, or mucous membranes.

Williams[23] reported a case of necrolytic acral erythema in an adolescent boy with a history of infection with hepatitis C virus; he had hepatic fibrosis, hypertension, and thrombocytopenia. The patient developed a pruritic eruption on his face, trunk, genitals, and extremities, and the eruption had a predilection for bony prominences. This patient did not respond to topical steroids, antihistamines, topical barrier repair creams, narrow-band UV-B therapy, or tar baths. A skin biopsy specimen demonstrated a nonspecific psoriasiform dermatitis consistent with necrolytic acral erythema. Hepatitis C virus RNA polymerase chain reaction studies showed 974,000 IU/mL (< 50) and hepatitis C virus RNA genotype 1b.

Dusky, red erythematous plaques are present bilaterally on the dorsum of the feet and toes. In 2018, an image gallery of pictures of necrolytic acral erythema (NAE) was published.[24] Lesions may extend around to the skin overlying the Achilles tendon and up the lower leg, as depicted in the image below.

Plaque of necrolytic acral erythema on the ankle of a male.

A key finding of necrolytic acral erythema is that while the plaques have a psoriatic morphology, they do not show the psoriasis Auspitz sign (ie, if you pick at the scale, it does not bleed).[25] Active necrolytic acral erythema has different symptoms from psoriasis. The plaques of psoriasis itch, and the plaques of necrolytic acral erythema can express burning or pruritus. Usually, lesions do not occur on the trunk as in psoriasis. Necrolytic acral erythema is an all-acral disease. Some necrolytic acral erythema patients have zinc dysregulation and not hepatitis C infection, showing the complexity of the disease.

The dorsum of the hands may or may not be involved. The lesions are clearly demarcated from uninvolved skin by a dark red border. The surface may be scaly, eroded, or velvety. Thick hyperkeratosis is sometimes present. Active lesions often include flaccid blisters. Edema may or may not be present.

Abdallah et al[26] describe the following stages of the lesions:

1. Initial stage: Erythematous papules or plaque with scale are present and have a dusky or eroded center.

2. Fully developed stage: A confluence of papules and plaques with sharply defined margins and adherent scale develops. Increased hyperpigmentation and decreased redness may be present. Lesions may be lichenified. Pustules also may occur at this stage.

3. Late stage: Thinning of lesions occurs, with continued hyperpigmentation. Demarcation continues, followed by spontaneous relapse and remission.

As a general rule, necrolytic acral erythema does not affect the palms or soles, the nail bed, nail plate, or mucous membranes. Hivnor et al[27] reported a single case in which the plaques extended proximally to the thighs. This patient also had hyperkeratosis of the palms and soles and involvement of the face. While multiple biopsy specimens confirmed necrolytic acral erythema histologically, it is not clear whether these biopsy specimens were taken from the typical locations of necrolytic acral erythema or if the palms and soles were also included in the biopsy specimen.

Other disorders that can be seen in persons with hepatitis C should be considered as possible epiphenomena. These include the following:

• Lichen planus

• Porphyria cutanea tarda

• Palpable purpura/leukocytoclastic vasculitis

• Spider telangiectasias

• Vitiligo

• Polyarteritis nodosa

• Erythema multiforme

• Urticaria

• Erythema nodosum

The complications of necrolytic acral erythema (NAE) are cosmetic. Resolution of the active lesions often leaves postinflammatory pigmentary alteration.

Hepatitis A, B, and C serologies are the most important tests because necrolytic acral erythema (NAE) has a high association with hepatitis C. Abdallah et al found that in 26 (87%) of 30 necrolytic acral erythema patients, recognition of the skin disease led to the initial diagnosis of hepatitis C virus infection.[3]

Assess liver function, including aspartate aminotransferase, alanine aminotransferase, bilirubin, protein, albumin, and alkaline phosphatase values. Some authors believe the lesions are most active during the active stage of hepatitis. The severity of the lesions does not correlate with the severity of the hepatitis.

Serum zinc, serum glucagon, and serum amino acid levels are low in some reported cases. Zinc deficiency and hyperzincuria was noted by Najarian et al.[29, 30]

Consider performing serum glucose and hemoglobin A1C tests because necrolytic acral erythema may be more common in persons with diabetes and hepatitis C.

CT scanning or MRI of the liver and pancreas can be considered as an ancillary assessment. In some reported cases, the pancreas was imaged, most likely because some believe necrolytic acral erythema (NAE) is a subset of necrolytic migratory erythema, a condition indicative of pancreatic glucagonoma. No pancreatic masses were found any of the patients imaged.

Consider skin biopsy to substantiate the diagnosis of necrolytic acral erythema (NAE).

Necrolytic acral erythema (NAE) is perhaps best defined clinically rather than histologically. Bentley et al noted a case of necrolytic acral erythema without classic histology findings, which responded to oral zinc therapy.[31]

In 2004, Abdallah et al[26] noted the histopathological features described below.

Early stage - Nummular dermatitis–like moderate and regular acanthosis, as follows:

• Variable spongiosis

• Inflammatory infiltrate

• Pigment incontinence

Fully evolved stage - Psoriasiform epidermal hyperplasia, as follows:

• Marked papillomatosis

• Parakeratosis

• Focal hypergranulosis

• Pigment incontinence

• Occasional subcorneal pustules

• Epidermal pallor

• Vascular ectasia

• Infiltrate of inflammatory cells in the papillary dermis

• Necrotic keratinocytes - Sometimes become confluent in the upper epidermis, sometimes tracking along the acrosyringium

Late stage samples - Minimal-to-moderate acanthosis, as follows:

• Minimal-to-moderate inflammatory cell infiltrate

• Pigment incontinence

Others have noted epidermal necrosis with or without blister formation; vacuolar degeneration of the basal layer; and psoriatic changes with acanthosis, papillomatosis, hyperkeratosis, and parakeratosis. All of these are commonly found in persons in deficient nutritional states. Dermal findings have included a nonspecific superficial perivascular and interstitial lymphocytic dermatitis.

El-Ghandour et al[21] noted that electron microscope examination of patients with necrolytic acral erythema demonstrated clumped tonofilaments in the keratinocytes, yet hepatitis C virus RNA could not be detected in the plaques of necrolytic acral erythema.

Some have attempted to stage necrolytic acral erythema (NAE) with the following[32] :

• Stage 1: Erythematous papules or plaque without with scale; dusky or eroded center; histological findings of nummular eczema–range of spongiosis, variable inflammatory infiltrate, and pigmentary incontinence

• Stage 2: Papular or plaque confluence, sharp borders, thick adherent scale, less redness, more pigmentation; lichenification and pustules are variants; histological findings of parakeratosis, marked papillomatosis, pigment incontinence, rare subcorneal pustules, focal hypergranulosis, vascular ectasia, papillary dermis, variable inflammatory cell infiltrate, epidermal pallor, occasional acrosyringium tracking, necrotic keratinocytes, and a confluence of findings

• Stage 3: Plaques usually thin, hyperpigmentation remains demarcated, chronic clearing and reoccurrence; histological findings of pigmentary incontinence and moderate-to-mild inflammatory cell infiltrate

The optimal treatment for necrolytic acral erythema (NAE) is the optimal treatment of hepatitis C—combination therapy with interferon and ribavirin. In one patient, ribavirin in addition to the interferon-alfa therapy improved the necrolytic acral erythema despite the presence of a continued high viral load.[27] In a study by El-Ghandour et al, interferon-alfa combined with ribavirin given to four patients caused regression of the plaques of necrolytic acral erythema in three patients and complete clearance in one patient.[21] Interferon-alfa monotherapy has been reported to be effective treatment.[33] A 2017 review of the literature noted a case report describing treatment of hepatitis C with sofosbuvir and ledipasvir that resulted in clearance of necrolytic acral erythema from the skin.[34] This report has not yet been noted by others, yet it is promising.

Patients have been responsive to oral zinc supplementation in several cases.[9, 29, 35, 36] Oral zinc supplements can be effective in patients with normal serum zinc levels.[6, 9, 35] In two cases, the combination of oral zinc and interferon-alfa therapy resulted in total clearance.[1, 33] Zinc supplementation has been shown to enhance the effects of hepatitis C treatment.[37]

Amino acid replacement therapy, both orally and parenterally, has yielded some improvement.[8, 13]

One report noted the use of cetirizine, oral zinc, topical tacrolimus, and salicylic acid with success.[32]

Disease response to corticosteroid therapy (ie, topical, intralesional, and systemic) has been poor. No benefit has been seen with topical tar or tetracycline.

A surgical approach has not been shown to be therapeutically beneficial.

Consultation with an infectious disease specialist, gastroenterologist, or hepatologist may be helpful for management of the hepatitis C. Consultation with a dermatologist may be helpful for diagnosis and management of cutaneous findings.

Supplementation with zinc and amino acids has shown benefit.

No restrictions on activity are needed for persons with this condition.

Preventing hepatitis C is the primary prevention for necrolytic acral erythema (NAE).

The goal of treatment is to decrease the burning and pruritus and improve the appearance of the lesions of necrolytic acral erythema. Zinc sulfate,[36] amino acid supplementation, and interferon alfa have been successful in treating necrolytic acral erythema (NAE). Topical tacrolimus has been reported as an effective treatment for necrolytic acral erythema.[38]

Class Summary

Minerals act as enzyme cofactors and are required in metabolic processing.

Zinc

Use sulfate or gluconate zinc salt. Zinc sulfate 4.4 mg = 1 mg of elemental zinc. Zinc gluconate 7.1 mg = 1 mg of elemental zinc.

Class Summary

Interferons are naturally occurring compounds that have both antiviral and immunomodulatory effects.

Peginterferon alfa-2a (Pegasys)

Peginterferon alfa-2a is used in combination with ribavirin to treat patients with chronic hepatitis C who have compensated liver disease and have not previously received interferon alfa. It consists of interferon alfa-2a attached to a 40-kd branched PEG molecule. Peginterferon alfa-2a is predominantly metabolized by the liver.

Peginterferon alfa-2b (PEG Intron)

Peginterferon alfa-2b is an Escherichia coli recombinant product. It is used to treat chronic hepatitis C in patients not previously treated with interferon alfa who have compensated liver disease. Peginterferon alfa-2b exerts cellular activities by binding to specific membrane receptors on cell surface, which, in turn, may suppress cell proliferation and may enhance phagocytic activity of macrophages. It may also increase the cytotoxicity of lymphocytes for target cells and inhibit virus replication in virus-infected cells.

Class Summary

Nucleoside analogs are drugs that interfere with the production of DNA and RNA.

Ribavirin (Virazole)

Ribavirin is an antiviral nucleoside analog. The chemical name is D -ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. Given alone, ribavirin has little effect on the course of hepatitis C. When given with interferon, it significantly augments rate of sustained virologic response.