ISSN: 2476-2415

Case Report International Journal of Clinical & Experimental Dermatology

Necrolytic Acral Erythema
Aulia Rahman1*, Nurrachmat Mulianto1, Indah Julianto1, Oyong2, Prasetyadi Mawardi1 and Suci Widhiati1

Corresponding author
*

Aulia Rahman, Dermato-venereology Department, Clinic Microbiology

Dermato-venereology Department
1
Department, Faculty of Medical Sebelas Maret University, Dr. Moewardi
General Hospital Surakarta, Pathology Department, Faculty of Medical
Pathology Department
2
Hasanuddin University Makassar. E-mail: auliarahman.dr@gmail.com.

Submitted: 23 Aug 2017; Accepted: 28 Aug 2017; Published: 02 Sep 2017

Abstract
Background: Necrolytic acral erythema (NAE) is a rare dermatosis which has been regarded as an early cutaneous
marker of hepatitis C virus infection. The clinical manifestasion of NAE is similar to necrolytic migratory erythema,
psoriasis and tinea corporis. The difference is that the patients with NAE also suffer from hepatitis C virus infection.

Case: A 59 year old woman came and complained about itchy erythematous-violaceous plaques since a year ago. The
patient has a history of hepatitis C infection since 2 years ago. On the superior and inferior extremities region, there
were erythematous-violaceous plaques witch is partially hyperpigmentation with well-demarcated border, multiple
discretes with thin scales and lichenification. Histopathological examination of the lesion obtained psoriasiform,
hyperkeratosis, neutophylic microabscess, epidermal necrosis, spongiosis and infiltration of inflammatory cells in
the epidermis.

Discussion: Necrolytic acral erythema has been reported exclusively in patients with hepatitis C and is thought to
be pathognomonic of this infection. Acute lesions often show erythema with vesicles and flaccid bullae. Chronic
lesions appear as erythematous to violaceous plaques with thick scales, erosions and crust. Acral sites are
predominantly involved. The histopathological examination shows psoriasiform hyperplasia epidermal, neutrophylic
microabscesses, dilatation of small vessels, parakeratosis and infiltration of inflammatory cells. In this case, the
physical and histopathological examination support the diagnosis of NAE.

Keywords: Hepatitis c, necrolytic acral erythema. In most cases, the mechanisms which triggers or worsens the skin
manifestations of HCV infection are still unknown and further
Introduction examination is needed [4]. Some of the dermatological features of
Hepatitis C virus (HCV) is a type of ribonucleic acid (RNA) virus HCV infection are: mixed cryglobulinemia, polyarteritis nodusa
with 6 major genotypes. This virus is responsible for acute and (PAN), necrolytic acral erythema (NAE), red finger syndrome,
chronic hepatitis, cirrhosis, and liver cancer [1]. The World Health porfiria cutanea tarda, puritus, and planus lichen [5]. Beside that,
Organization (WHO) estimated that around 170 million people in other dermatological features caused by HCV are: urticaria,
the world is infected with hepatitis C. This virus is considered a vasculitis urticaria, and multiform erythema [6].
global health problem, because of its prevalence of intra and extra
hepatic features. About 85% of the cases developed into chronic Necrolytic acral erythema (NAE) was first described by el Darouti
hepatitis. Chronic hepatitis C viral infection often shows varied et al in 1996 [7-12]. Necrolytic acral erythema (NAE) is a rare
difference of clinical spectrum, from asymptomatic with normal skin condition in hepatitis C patients and is thought to be related to
enzyme level to severe active chronic hepatitis. Therefore, early zinc deficiency, although the mechanism is unclear. This problem
diagnosis is mandatory [2]. A recent study showed that around 70- has been reported in around the world, such as Pakistan, India, and
74% cases manifest to extra hepatic features [3]. the United States with the majority of cases was found in Egypt.
It may be related to the higher prevalence of hepatitis C in Egypt
Extra hepatic manifestations of HCV infection include abnormalities (more than 20%) than other places in the world (3%). One cohort
of the blood, skin, and kidney, autoimmune manifestation, and study showed that the prevalence of NAE in hepatitis C patients is
abnormalities of the nervous system, endocrine, cardiovascular and around 1.7% [13].
respiratory [1]. Skin is the main target of extra hepatic feature of
HCV infection. There are some factors causing the HCV-related The etiology of NAE is multi factorial and liver dysfunction is
skin abnormalities, such as viral, genetic, and environmental factors. known to be related to the development of the disease. Very little

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information has been provided about the history, prevalence, and
clinical features of NAE [14].

Case
A 59 years old woman came to the Dermatovenereology Outpatient
Clinic of Moewardi General Hospital Surakarta Indonesia and
complained about painless, itchy, erythematous-violaceous plaques
on her hands and legs since 1 year ago. At first, she complained about
vesicles filled with fluid and erythematous plaques, but then the
vesicles ruptured. Then the plaques became violaceous accompanied
with thin scales. The symptoms occurred after the patient was infected
with hepatitis C virus 2 years ago. The patient also suffered from
diabetes since 5 months ago and she already got the medications for
her diabetes from Internal Medicine Clinic of Moewardi General
Hospital. The physical examination revealed normal range, on the Figure 2: (A) Histopathology examination using HE staining with 10x
superior and inferior extremities we found erythematous-violaceous magnification shows psoriasiform image, neutrophilic microabscess,
plaques with hyperpigmentation and well-demarcated border, discrete, epidermal necrosis, and inflammatory cells infiltration. (B) With 40x
and lichenified with thin scales (Figure. 1). magnification we found hyperkeratosis and spongiosis.

From the Internal Medicine Department, this patient has given

therapies which are 200 mg Curcuma® once daily, 300 mg UDCA®
twice daily, B complex vitamin once daily, and Novorapid® injection
10-10-8. From the Dermato-venereology Clinic she was given
Methylprednisolone 20 mg daily, Cetirizine 10 mg daily, Zinc tablets
twice daily and Inerson® zalf twice daily.

Discussion
Hepatitis C is an inflammation of the liver caused by HCV infection.
The disease transmission is from direct contact with contaminated
blood. This inflammation occurs in most of the infected people,
but it depends on the intensity and duration. Unlike other hepatitis
viruses, HCV does not induce adequate immune response so the
acute manifestations are often subtle and most of the infected people
become carrier of chronic hepatitis with long term consequences. The
disease is also reported transmitted via secrete (breast milk, saliva,
urine, and sperm). This virus can survive in the outside for 16 hours to
4 days. There are several genotypes (variant) of this virus. We order to
establish the diagnosis of hepatitis C we need to identify the anti-HCV
antibody using ELISA [2].

Autoimmune manifestations in chronic HCV infection is related to

the epitopes cross reactions detected in viral and human polyprotein.
Figure 1: (A-F) Superior and inferior extremities showed erythematous- For example, the presence of the same homolog sequence in
violaceous plaques with hyperpigmentation, multiple, discrete, cytochrome P4502E1 and protein HCV-NS5b is responsible for
lichenified with thin scales. autoantibody production which targeted our own protein product.
Other case of molecular similarity is the homolog of NS5 region and
From the laboratory findings we found that increased of AST level was 3 human proteins, which are nitrogen oxide synthase, tyrosin kinase-
164 U/L (normal range: 5-40 U/L), ALT level was 120 U/L (normal Lck, proto-oncogen and liver growth factor activator. Thus, epitopes
range: 5-41 U/L), total bilirubin level was 4.00 (normal range: <1.1 similarity between HCV and human autoantigen triggers autoantibody
mg/dl) and direct bilirubin level was 3.00 (normal range: < 0.3 mg/ non-specific production, which causes tissue destruction and produce
dl). We also found antibody anti-HCV reactivity with enzyme-linked inflammatory reaction [15].
immunosorbent assay (ELISA) technique. Abdominalcontrasted
MSCT scan demonstrated liver enlargement. The skin scraping Dermatologic manifestations related to VHC infection are caused by
examination with 10% KOH was negative. The histopathological three different viral actions. The direct action occurs in keratinocytes,
examination using hematoxylin eosin (HE) staining showed lymphocytes, antigen presenting cells, dendritic cells, and blood
psoriasiform, hyperkeratosis, neutrophilic microabscess, epidermal vessels. The indirect action is related to immune complex development
and spongiosum necrosis, with inflammatory cell infiltration, or autoimmune process. The third viral action is caused by the organic
supporting the diagnosis of NAE (Figure 2). functional disturbance, which includes the dermatologic manifestations
caused by organs that are not directly related to HCV viral infection [2].

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Necrolytic acral erythema (NAE) is related to the necrolytic erythema is rare and only 400 cases have been recorded in literatures. There
group and metabolic syndrome. The clinical manifestation of NAE is no gender differences in glucagonoma incidence and the highest
is shown as erythematous-violaceous plaques with well-demarcated glucagonoma incidence occur in the sixth decades of life. The clinical
border, hyperpigmentation, with scales, hyperkeratosis, and manifestations of glucagonoma are commonly related to excessive
lichenification. These findings are often associated with itch or burning glucagon. The amino acid level decreases due to glucagon stimulation
feeling. Necrolytic acral erythema may occur in patients who are 11-60 to consume amino acid substrate for gluconeogenesis and to increase
years of age, but the highest incidence occur in people of 35-55 years amino acid oxidation. The decreasing of amino acid (histidine and
of age, and gender does not differ the incidence of NAE. Necrolytic triptophane) induces pain, erythema, and intertriginosa erosion.
acral erythema is often found in the dorsal part of feet, around Achilles Glucagon also increases skin arachidonat acid level, which also
tendon, and the knee [8]. Hepatitis C viral infection is considered increases inflammatory mediators (prostaglandine and leukotrien),
pathognomonic for NAE. Skin findings may be vary, depend on the The skin lesion of NME is polymorphic, but erosion and crusts often
stage of the lesion. Acute lesions show vesicles and flaccid bullaes occur. Erythematous plaques are the primary lesion of NME. It can
around the plaques. Chronic lesions show erythematous-violaceous develop into bullae and progressive erosion may occur. Itch and pain
plaques with thin scale, erosion, crusts, and usually dark red-colored. may also be complained by the patient. The predilection location is the
From the histopathology examination of the punch biopsy specimen intertriginosa area (inguinal, perineum, buttock, and lower abdomen),
we can find psoriasisform hyperplasia with prominent confluence the center part of the face (perioral), and distal extremities. If the
parakeratosis, hypergranulosis, and suprapapillary plates depletion. lesion extend to the mucosa, chielitis angular, glossitis atrophic, and
In the parakeratosis layer we can find a lot of neutrophiles with stomatitis may occur. Histopathological of NME lesion, we can find
neutrophilic microabscess. Hair follicle infundibular plugging with upper epidermal necrosis from the spinosum layer and neutrophilia in
parakeratosis and neutrophils. Small vessels dilatation in dermal acute lesions. In chronic lesion, dermatitis psoriasiform, parakeratosis,
papilla and superficial perivascular lymphocytic and neutrophile and hyperkeratosis can be found in our patient, we did not find either
infiltration in dermis [9]. mucosal lesion or pancreas glucagonoma, thus the diagnosis of NME
can be excluded [17].
Based on a longitudinal observation, the evolution of NAE can be
categorized into 3 stages. In the early stage, skin changes consist of The other differential diagnosis is psoriasis. Psoriasis is a chronic
erythematous papules which are 2-3 mm in diameter. Growth and the papulosquamosa inflammatory disease with the characteristic of
thickening of the papules extend and also accompanied by scales. multiple remission and relapse [18]. The most common lesion of
Hyperpigmented papules or plaques is the early sign of erosion. psoriasis is well-demarcated erythematous plaques with thick scales,
Thus, the primary lesion is the papules or the erytematous-violaceous but rarely sterile pustules can be found. The most common predilections
plaques with erythematous macules around it. In the development of psoriasis are the scalp, the elbows, knees, nails, legs, and the trunk
stage, the diameter and the thickness of the papules continue to grow, (including intergluteal fold). From the histopathological examination
so does the scales and lichenification. Then, the erythema is replaced revealed acanthosis with elongated rete ridges, hypogranulosis, hyper
by hyperpigmentation and the scale production reduces. Necrosis of and parakeratosis, dilated vessels, and lymphocytes and neutrophils
superficial epidermis is showed by the production of hyperpigmented perivascular infiltrate in the epidermis. Psoriasis can be found in
crust. Pustules may develop, but not very often. In this stage, the people of all ages. External factors (Koebner phenomenon) and
border and the distribution of the lesion is the pathognomonic, so systemic factors (infection, HIV, endocrine, psychogenic stress,
that we can establish the diagnosis of NAE. The plaques may persist drugs, alcohol consumption, smoking, and obesity) may trigger the
for several months and may cause itchy feeling. In the late stage, exacerbation of psoriasis [19]. In our patient, we found thin scales
the lesion become thinner and hyperpigmentation is prominent. The on the superior and inferior extremities but we did not find Koebner
crust and erosion may persist in some cases. The distribution and phenomenon as one of the triggering factors, so that the diagnosis of
well-demarcated border is more prominent in chronic lesion. The psoriasis can be excluded.
remission and exacerbation of this disease may happen spontaneously
[16]. Several cases are successfully treated with 3 million units of Other differential diagnosis is tinea corporis. Tinea corporis is a
subcutaneous interferon alpha, with zinc sulfate and amino acids kind of dermatophytosis that occur in glabrous skin, except the
orally [12]. palmar, plantar, and the inguinal. Tinea corporis is transmitted
directly from the infected human or animal via fomites, or it can
In this case, the original lesions are flaccid bullae and erythematous arise from autoinoculation of dermatophytes reservoir colonies of
plaques which then, developed hyperpigmentation, crusts, scales and the feet. Children are more prone to zoophilic pathogens, especially
lichenification. Skin scraping examination with 10% KOH solution Microsporum canis which is carried by dogs and cats. Occlusive
shows negative result. The histopathological examination revealed clothes and damp climate increase the progression of the disease.
psoriasiform, hyperkeratosis, neutrophilic microabscess, epidermal Wearing occlusive clothes, skin to skin contact, and mild trauma may
necrosis, spongiosis, and epidermal inflammatory cells infiltrations. cause development of dermatophytes. Tinea corporis gladiatorum is
From the serologic anti-HCV obtained reactivity and increased level often caused by Trichopyton tonsurans. The main predilection areas
of AST/ALT. are the head, neck, and upper arm. The most common etiology of
tinea corporis is Trichophyton rubrum. The clinical manifestations of
The differential diagnoses of this case is necrolytic migratory tinea corporis are annular plaques (ringworm-like) or serpiginosa with
erythema (NME), psoriasis, and corporal tinea. Necrolytic migratory scales on the active edges of the lesion, hyphae is also seen in KOH
erythema (NME) is pathognomonic for pancreas glucagonoma and 10% examination [20, 21].
more than two third of the patients are diagnosed with tumor. If NME
occurs without underlying characteristic pancreas malignancy, this In our patient hyphae was not obtained in KOH 10% examination,
condition is called pseudoglucagonoma syndrome. Glucagonoma therefore we ruled out diagnosis of tinea corporis can be excluded.
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APPENDIX 8. Hayat W, Zahra K, Malik LM, Azfar NA, Jahangir M (2012)
Necrolyticacral erythema: An unsual cutaneouspresentation of
hepatitis c virus infection. J Pak Assoc Dermatol 22: 66-69.
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classichistology should not prevent diagnosis of necrolytic acral
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10. Panda S, Lahiri K (2010) Seronegativenecolyticacral erythema:
A distinct clinical subset? Indian J Dermatol 55: 259-261.
11. Khanna VJ, Shieh S, Benjamin J, Somach S, Zaim MT. et
al (2000) Necrolyticacral erythema with hepatitis c effective
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757.
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Necrolyticacral erythema: Response to combination therapy with
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13. Iyengar S, Chang S, Ho B, Fung M, Konia TH, et al (2014)
Necrolyticacral erythema masquerading as cellulitis. Dermatol
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Figure: (A) The facial region is normal (B-E) The upper and lower 962-968.
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ago has been reported. The patient has experienced this complain since 17. De Witt CA, Buescher LS, Stone SP (2012) Cutaneous manifestation
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