AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Necrolytic acral erythema (NAE) was first described in 1996 by physicians in Egypt, M. El Darouti and M. Abu El Ela.¹ NAE 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 NAE report burning or pruritus. It is limited to an acral distribution and, in all cases, is associated with hepatitis C infection.^{2, 3}

Authors debate whether NAE is a distinct entity or a subtype of necrolytic migratory erythema. However, the distinct appearance and constant coincidence with hepatitis C infections suggests that it is a unique entity.

Pathophysiology

The pathophysiology of this condition is uncertain. Proposed theories for the cause of NAE 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 NAE.

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

Frequency

United States

Only 2 cases have been described in the United States to date, but the condition is likely more common than the case reports suggest.

International

Forty-two cases have been described internationally, mostly in Egypt. El-Ghandour et al⁴ 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 NAE examined over a 3-year period. Most NAE 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.

Mortality/Morbidity

NAE has no known directly associated morbidly or mortality. Rather, the morbidity and mortality are related to the primary illness, hepatitis C.

Race

Most cases have been reported in Egyptians. No cases have been reported in whites.

Sex

To date, no sex predisposition is reported.

Age

The ages of the patients with this condition have ranged from 11-60 years, but the onset typically occurs between 35-55 years.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Patients present with a 1-month to 2-year history of a rash on the dorsum of the feet, which may or may not also involve the hands. In many cases, it has been unresponsive to topical steroids.
• Patients do not necessarily give a history of hepatitis C. NAE may be the presenting sign.
• Patients may report a burning sensation, especially when walking or standing. Sometimes, NAE lesions are pruritic.
• The most common area of origination of the rash is the dorsal aspect of the great toe. It also occurs on the shins.
• In 43 of 44 reported cases, NAE did not affect the palms or soles, the nail bed, nail plate, or mucous membranes.
• Williams⁵ reported a case of NAE 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 NAE. Hepatitis C virus RNA polymerase chain reaction studies showed 974,000 IU/mL (<50) and hepatitis C virus RNA genotype 1b.
• Janjua⁶ noted a 45-year-old man who developed well-defined erythematous hyperpigmented keratotic pruritic plaques on the dorsa of his feet and the lateral aspect of his ankles; he was determined to have NAE.

Physical

• Dusky, red erythematous plaques are present bilaterally on the dorsum of the feet and toes. These may extend around to the skin overlying the Achilles tendon and up the lower leg.
• 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 al⁷ describe 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, NAE does not affect the palms or soles, the nail bed, nail plate, or mucous membranes. Hivnor et al⁸ 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 NAE histologically, it is not clear whether these biopsy specimens were taken from the typical locations of NAE 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

Causes

The cause 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 NAE and other nutrient deficiencies.

• el Darouti and Abu El Ela¹ 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 2 may be interrelated.
• Diabetic microangiopathy also may play a role; 4 of 5 NAE patients described by Nofal et al⁹ also had diabetes.

DIFFERENTIALS

Section 4 of 11  

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• Clinical
• Differentials
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• Follow-up
• Miscellaneous
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• References

Other Problems to be Considered

Necrolytic migratory erythema
Erythrokeratoderma
Eczematous dermatitis

WORKUP

Section 5 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Hepatitis A, B, and C serologies: These are the most important tests because NAE has 100% association with hepatitis C.
• Assessment of 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: These values have been reduced in some reported cases. Zinc deficiency associated with NAE was noted by Najarian et al.¹⁰
• Serum glucose and hemoglobin A1C levels: Consider performing these tests because NAE may be more common in persons with diabetes and hepatitis C.

Imaging Studies

• CT scanning 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 NAE is a subset of necrolytic migratory erythema, a condition indicative of pancreatic glucagonoma. No pancreatic masses were found any of the patients imaged.

Procedures

• Consider skin biopsy to substantiate the diagnosis of NAE.
• Consider liver biopsy to assess the status of hepatitis and before the institution of hepatitis C treatment.

Histologic Findings

In 2004, Abdallah et al⁷ noted the following histopathological features:

• Early stage - Nummular dermatitis–like moderate and regular acanthosis
• • Variable spongiosis
  • Inflammatory infiltrate
  • Pigment incontinence
• Fully evolved stage - Psoriasiform epidermal hyperplasia
• • 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
• • 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 al⁴ noted that electron microscope examination of patients with NAE demonstrated clumped tonofilaments in the keratinocytes, yet hepatitis C virus RNA could not be detected in the plaques of NAE.

TREATMENT

Section 6 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• The optimal treatment for 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 NAE despite the presence of a continued high viral load.
• Oral zinc replacement has been successful in some cases.^{3, 11} Interferon alfa monotherapy has been reported to be effective treatment.³
• Amino acid replacement therapy, both orally and parenterally, has yielded some improvement.
• Disease response to corticosteroid therapy (ie, topical, intralesional, and systemic) has been poor.
• No benefit has been seen with topical tar or tetracycline.
• El-Ghandour et al⁴ noted in their series of 23 Egyptian patients that interferon alfa combined with ribavirin caused regression of the plaques of NAE in 3 patients and complete clearance in 1 patient. Oral zinc administration induced some improvement in the appearance of the skin in some patients.

Surgical Care

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

Consultations

• 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.

Diet

Supplementation with zinc and amino acids has shown benefit.

Activity

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

MEDICATION

Section 7 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

The goal of treatment is to decrease the burning and pruritus and improve the appearance of the lesions of NAE. Zinc sulfate, amino acid supplementation, and interferon alfa have been successful in treating this condition.

Drug Category: Minerals

Act as enzyme cofactors and are required in metabolic processing.

Drug Category: Interferons

Naturally occurring compounds that have both antiviral and immunomodulatory effects.

Drug Category: Nucleoside analogs

Drugs that interfere with the production of DNA and RNA.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Deterrence/Prevention

• Preventing hepatitis C is the primary prevention for NAE.

Complications

• The complications of NAE are cosmetic. Resolution of the active lesions often leaves postinflammatory pigmentary alteration.

Prognosis

• With therapy, prognosis is fair. Some patients have a relapsing course.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Test for hepatitis C in patients with clinical conditions that suggest NAE.
• Ensure the condition is not another inflammatory condition.
• Ensure the condition is not a fungal or bacterial infection.

MULTIMEDIA

Section 10 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
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• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Plaque of necrolytic acral erythema on the ankle of a male.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
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• Differentials
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• Follow-up
• Miscellaneous
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• References

1. el Darouti M, Abu el Ela M. Necrolytic acral erythema: a cutaneous marker of viral hepatitis C. Int J Dermatol. Apr 1996;35(4):252-6. [Medline].
2. Abdallah MA, Ghozzi MY, Monib HA, Hafez AM, Hiatt KM, Smoller BR, et al. Necrolytic acral erythema: a cutaneous sign of hepatitis C virus infection. J Am Acad Dermatol. Aug 2005;53(2):247-51. [Medline].
3. Khanna VJ, Shieh S, Benjamin J, Somach S, Zaim MT, Dorner W Jr, et al. Necrolytic acral erythema associated with hepatitis C: effective treatment with interferon alfa and zinc. Arch Dermatol. Jun 2000;136(6):755-7. [Medline].
4. El-Ghandour TM, Sakr MA, El-Sebai H, El-Gammal TF, El-Sayed MH. Necrolytic acral erythema in Egyptian patients with hepatitis C virus infection. J Gastroenterol Hepatol. 2006 Jul;21(7):1200-6.:[Medline].
5. Williams J. Necrolytic acral erythema. DermAtlas. Available at http://dermatlas.med.jhmi.edu/derm/result.cfm?Diagnosis=178630456. Accessed January 25, 2007.
6. Janjua SA. Necrolytic acral erythema. DermAtlas. Available at http://dermatlas.med.jhmi.edu/derm/result.cfm?Diagnosis=178630456. Accessed January 25, 2007.
7. Abdallah MA, Ghozzi MY, Monib HA, Hafez AM, Hiatt KM, Smoller BR, et al. Histological study of necrolytic acral erythema. J Ark Med Soc. Apr 2004;100(10):354-5. [Medline].
8. Hivnor CM, Yan AC, Junkins-Hopkins JM, Honig PJ. Necrolytic acral erythema: response to combination therapy with interferon and ribavirin. J Am Acad Dermatol. May 2004;50(5 Suppl):S121-4. [Medline].
9. Nofal AA, Nofal E, Attwa E, El-Assar O, Assaf M. Necrolytic acral erythema: a variant of necrolytic migratory erythema or a distinct entity?. Int J Dermatol. Nov 2005;44(11):916-21. [Medline].
10. Najarian DJ, Lefkowitz I, Balfour E, Pappert AS, Rao BK. Zinc deficiency associated with necrolytic acral erythema. J Am Acad Dermatol. 2006 Nov;55(5 Suppl):S108-10.:[Medline].
11. Abdallah MA, Hull C, Horn TD. Necrolytic acral erythema: a patient from the United States successfully treated with oral zinc. Arch Dermatol. Jan 2005;141(1):85-7. [Medline].
12. Marinkovich MP, Botella R, Datloff J, Sangueza OP. Necrolytic migratory erythema without glucagonoma in patients with liver disease. J Am Acad Dermatol. Apr 1995;32(4):604-9. [Medline].
13. Pujol RM, Wang CY, el-Azhary RA, Su WP, Gibson LE, Schroeter AL. Necrolytic migratory erythema: clinicopathologic study of 13 cases. Int J Dermatol. Jan 2004;43(1):12-8. [Medline].
14. van Beek AP, de Haas ER, van Vloten WA, Lips CJ, Roijers JF, Canninga-van Dijk MR. The glucagonoma syndrome and necrolytic migratory erythema: a clinical review. Eur J Endocrinol. Nov 2004;151(5):531-7. [Medline].

Article Last Updated: Feb 18, 2008