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Year : 2015  |  Volume : 60  |  Issue : 2  |  Page : 136-141
Zinc-responsive acral hyperkeratotic dermatosis-A novel entity or a subset of some well-known dermatosis?

Department of Dermatology, Institute of Post Graduate Medical Education and Research (IPGMER), Kolkata, West Bengal, India

Date of Web Publication3-Mar-2015

Correspondence Address:
Ishad Aggarwal
Department of Dermatology, Institute of Post Graduate Medical Education and Research (IPGMER), 244 AJC Bose Road, Kolkata - 700 020, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-5154.152507

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Background: We are reporting a series of interesting cases, which presented to us with psoriasiform lesions distributed over the acral regions of the body. The cases are unusual because they were resistant to conventional treatment modalities like topical corticosteroids, tacrolimus and oral methotrexate but showed significant improvement on oral zinc therapy. Materials and Methods: Ten patients with characteristic clinical features of distinctive hyperkeratotic plaque in the acral areas, who were resistant to treatment by different modalities including potent topical steroids and oral methotrexate, were included for detailed investigations. A proper history was taken and relevant laboratory investigations were done which included blood count, urine, liver function, renal function, hepatitis-C virus serology and serum zinc levels. Patients were followed up every 2 weeks. Histopathological examinations of the lesional tissue were done at baseline and after 6 weeks of therapy. Patients were given oral zinc daily and no other treatment during the 6 weeks course. Results: All our patients were non-reactive to hepatitis-C. Of the ten patients only one patient (10%) showed low titer of serum zinc, another (10%) showed higher zinc level, while the rest of the patients had normal zinc level. Five of our patients had chronic renal failure, one had Grave's disease and the remaining had no associated systemic illness. Histopathology mostly showed hyperkeratosis, acanthosis, prominent granular layer, spongiosis and dermal infiltrate. After 6 weeks of follow up, all patients showed rapid and remarkable therapeutic response with zinc. Conclusions: We here report a series of patients, discernible because of their uniform clinical presentation of acral hypekeratotic plaques and in showing a noticeable response to zinc. Clinical, histopathological and laboratory investigations were done to rule out diseases of similar morphology including psoriasis, acral necrolytic erythema and lichen simplex chronicus. Authors understand that further studies with greater number cases and more detailed investigations are required to establish exact etio-pathogenesis and nomenclature of this distinct subset of patients.

Keywords: Acral hyperkeratosis, hyperkeratosis, necrolytic acral erythema, zinc

How to cite this article:
Ghosh A, Aggarwal I, De A, Samanta A, Chatterjee G, Bala S, Biswas P, Chowdhary N. Zinc-responsive acral hyperkeratotic dermatosis-A novel entity or a subset of some well-known dermatosis?. Indian J Dermatol 2015;60:136-41

How to cite this URL:
Ghosh A, Aggarwal I, De A, Samanta A, Chatterjee G, Bala S, Biswas P, Chowdhary N. Zinc-responsive acral hyperkeratotic dermatosis-A novel entity or a subset of some well-known dermatosis?. Indian J Dermatol [serial online] 2015 [cited 2022 May 23];60:136-41. Available from:

What was known?

  1. Acral hyperkeratosis is seen in lichen simplex chronicus, psoriasis and necrolytic acral erythema (NAE).
  2. NAE is unique because of it′s dramatic response to oral zinc.
  3. However, NAE is a considered a cutaneous marker for Hepatitis-C infection with typical histopathological findings.

   Introduction Top

While working in a tertiary referral center of eastern India, the authors started taking note of a group of cases, which were being treated by different dermatologists with potent topical steroids, immunomodulators, and methotrexate for prolonged duration without much success. The patients presented to us typically with persistent well-defined hyperpigmented, psoriasiform plaques, with occasional rim of erythema, distributed symmetrically over the acral regions of the body mostly over dorsum of feet extending on to the toes. Our differential diagnoses at the time of presentation included psoriasis, lichen simplex chronicus and acral necrolytic erythema. However, these cases were distinctive in their complete lack of response to all modalities of treatment including topical steroids, tacrolimus, and oral methotrexate.

Thus, the authors felt the need to investigate this particular group of treatment resistant cases to attain a scientific and logical conclusion. Here, we are reporting a series of interesting cases, which were distinctive in their clinical and histopathological features and remarkable in showing a significant response to zinc.

   Materials and Methods Top

All the cases that had this distinctive morphology of chronic hyperkeratotic acral plaques were included to investigate further over the past 2 years. The clinical features of the cases were quite characteristic and uniform.

Patients were thoroughly investigated for a possible etiology which included routine blood investigations, urine routine, chest X-ray, liver and renal functions test, hepatitis B and C serology, HIV ELISA, serum zinc level and histopathology examinations. Patients' detailed clinical features and associations were noted in case record forms after duly signing informed consent. Patient's improvement was noted based on reduction of size and thickness of lesions. Standard Physician Global Assessment scores were used to note the improvement. We have given a score of 0 for no improvement, 1 for mild (<25%) improvement, 2 for moderate (25-50%) improvement, 3 for good (50-75%) improvement and 4 for excellent (>75%) improvement. Treatment failure was defined as a score of 0 or 1 at end of 6 weeks of therapy and treatment success was defined as score of 2, 3, 4 at 6 weeks.

As the patients were already treated exhaustively with immune-modulators and immune-suppressants without any response, we decided to give the patients a trial of oral zinc sulfate therapy with a dose of 200 mg three times daily for 6 weeks. We followed up the patients every 2 weeks and did a repeat biopsy at 2 weeks.

   Results Top

Out of 10 patients in our study 3 were females and 7 were males. The age at presentation varied from 9 years to 47 years. The duration of these lesions varied considerably, while in one patient the lesions were present for as long as 20 years with recent exacerbations, others mostly had the lesions from time spanning from few months to few years.

All of the patients had involvement of the dorsa of the feet including toes with two patients also having associated involvement of dorsum of the hand. Lesions were well-defined, pigmented, psoriasiform plaques, with dusky hue, with occasional rim of erythema, and were distributed symmetrically [Figure 1], [Figure 2], [Figure 3] and [Figure 4]. Most of the patients were asymptomatic except for few cases that complained of burning sensation. While the disease was non-progressive in most of the patients, one of them gave history of increase in size of lesions over time. No changes in hair, nail or mucosa were seen. Lesions were particularly non-scaly and Auspitz's sign could not be elicited in any of these patients.
Figure 1: (a) Hyperkeratotic plaques on feet of a patient before therapy. (b) Lesions after 6 weeks of therapy in same patient

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Figure 2: (a) Hyperkeratotic plaques on feet of a patient before therapy. (b) Lesions after 6 weeks of therapy in same patient

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Figure 3: (a) Hyperkeratotic plaques on feet of a patient before therapy. (b) Lesions after 6 weeks of therapy in same patient

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Figure 4: (a) Hyperkeratotic plaques on feet of a patient before therapy. (b) Lesions after 6 weeks of therapy in same patient

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Six out of the 10 (60%) patients were having some form of systemic associations. Five patients had renal disease, out of which four had chronic renal failure (CRF) while the other had nephrotic syndrome. Of the patients with CRF, one each had SLE (lupus nephritis grade IV), diabetes mellitus, hypertensive nephropathy, and focal segmental glomerular nephritis. Two out of them had undergone renal allograft transplantation. Most of these patients were being treated with systemic corticosteroid and immunomodulators like systemic tacrolimus and mycophenolate mofetil at the time of presentation. The sixth patient with systemic involvement had thyrotoxicosis due to Grave's disease for which he was on treatment with propylthiouracil and radioactive iodine. No history of any significant systemic disorder could be obtained from other four patients.

Before presenting to us most of our patients had been treated with topical corticosteroids of different potencies, topical vitamin D3 analogues, tacrolimus, oral methotrexate and anti-histamines, but to no relief. Even systemic tacrolimus prescribed to the renal allograft recipients did not have any favorable effect on their cutaneous manifestations.

A summary of clinical features and history has been given in [Table 1].
Table 1: Summary of clinical features

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Routine investigations were mostly found normal except for five patients who were found to be mild to moderately anemic. Three patients showed hypoproteinemia with reversal of albumin and globulin ratio. Four patients were found to have elevated serum urea and creatinine levels; these patients were the known cases of CRF. Serum zinc levels were normal in most of the patients except for one each where it was less and more than the normal values. All were negative for the viral serological markers.

We also obtained tissue samples from the lesional skin by a punch biopsy for histopathological examination (HPE) using H and E (Hematoxylin and Eosin) stain. HPE revealed hyperkeratosis and parakeratosis [Figure 5], [Figure 6] and [Figure 7] uniformly in all the cases. The pattern of parakeratosis varied; focal parakeratosis being the commonest one. The stratum granulosum was conspicuous in its presence in most of the biopsy samples, in fact showing hyperplasia in a few of them. The above finding was also seen in two specimens, which showed suprapapillary thinning. Acanthosis [Figure 5], [Figure 6] and [Figure 7] was present in all the cases and the keratinocytes looked paler in comparison to rest of the cells in a number of specimens [Figure 7]. The epidermis showed spongiosis to a varied extent in four of the slides. Basal cell layer was intact. The rete ridges showed hyperplasia and there was sparse infiltrate of lymphocytes and histiocytes in upper dermis and around the blood vessels. The histopathological findings are summarized in [Table 2]. We started the patients on oral zinc sulfate 200 mg three times daily. The patients started showing improvement both in the size of the lesions and the symptoms, within 2 weeks of therapy. They were sequentially followed up at every 2 weeks interval.
Figure 5: Photomicrograph showing hyperkeratosis, parakeratosis, prominent stratum granulosum, acanthosis, spongiosis and mild upper dermal infiltrate. (H and E, ×40)

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Figure 6: Photomicrograph showing hyperkeratosis, prominent stratum granulosum, acanthosis, necrotic keratinocyte, epidermal pallor, spongiosis and upper dermal infiltrate. (H and E, ×400)

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Figure 7: Photomicrograph showing hyperkeratosis, parakeratosis, prominent stratum granulosum, acanthosis, epidermal pallor, spongiosis and upper dermal infiltrate. (H and E, ×400)

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Table 2: Summary of histopathological findings

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At the end of the therapy 5 out of 10 (50%) patients showed >75% improvement, whereas 4 out of 10 (40%) showed more than 50% reduction and only one patient (10%) showed less than 50% reduction in size of the lesions at end of 6 weeks of oral zinc supplementation. So, we had seen a clinical response with zinc in all of our patients, which varied from moderate to excellent.

   Discussion Top

We here report a series of patients, uniform in their clinical presentation of acral hyperkeratotic plaques and distinctive in their noticeable response to zinc. These patients were refractory to different modalities of treatment. As discussed earlier our differential diagnoses included psoriasis, lichen simplex chronicus and necrolytic acral erythema (NAE).

The persistent non-scaly lesions confined only to dorsal acral areas with non-elicitation of Auspitz's sign and also, a complete lack of response to oral and topical immune-modulators, made these cases untenable with a clinical diagnosis of psoriasis. HPE findings including the absence of hypogranulosis in epidermis and dilated blood vessels in papillary dermis almost ruled out the possibility of psoriasis.

The presence of spongiosis in few of our cases suggests possible eczematous origin. However, lack of pruritus in many of our cases, absence of lichenification, absence of finger like projections of the rete ridges and absolute lack of response to topical steroids nulls out the possibility of lichen simplex chronicus and dermatitis group of disorders.

Since NAE has been noted to be associated with hepatitis-C, we took history of repeated blood transfusions, intravenous drug abuse and unprotected sexual intercourse in our patients, and all of them gave a negative history. We also did hepatitis-B and -C serological profiles along with HIV-I and -II. All the patients were found to be non-reactive. We also evaluated the patients' serum samples for zinc levels. Serum zinc levels were within normal range in 8 out of 10 patients (80%). One patient showed higher levels, while another showed lower than normal levels although none of the patients had any other features of zinc deficiency.

Histopathology of the patients was not classical of NAE; as though there was parakeratosis, necrolysis was conspicuous in its absence in all of the specimens. However, pallor of keratinocytes suggests possibility of a nutritional deficiency.

However, the very rapid response to zinc in all of our patients in spite of near normal zinc level in serum makes NAE the closest differential of our cases. We tried to critically analyze the similarities and dissimilarities of our cases with NAE.

First described in Egypt in 1996, [1] NAE still continues to be an enigma. It is closely related to a group of necrolytic erythema and metabolic syndromes. NAE usually manifests as well circumscribed, dusky to violaceous plaques with or without scales, with a rim of erythema around them, distributed symmetrically and exclusively over the acral areas, confined mainly to dorsal surfaces of feet and hands. However, there have been reports of its occurrence over Achilles tendons, malleoli, legs, and knees. Less frequent sites of involvement include the elbows, hands, buttocks, and genitalia. [2],[3] The mucous membranes, hair and nails are spared. Pain and pruritus are predominant symptoms although as reported by one of our patients, burning sensation may also be seen.

Our patients had lesions clinically consistent with many of these findings. Though the lesions tend to mimic psoriasis, clinically Auspitz's sign is characteristically absent and can serve as a guide for the clinician to clinch the diagnosis. Clinically our cases resemble advanced NAE; however none of our cases gave history of vesiculation or pustulation at any point during the course. Erythema, except for an occasional rim, was significantly absent in our cases.

The etiopathogenesis of NAE is still a matter of much speculation. Abnormality in metabolic factors that are also seen in other necrolytic erythemas (like necrolytic migratory erythema, pellagra, essential fatty acid and biotin deficiency, and acrodermatitis enteropathica) has been proposed by many to be a cause. Metabolic alterations like hypoalbuminemia, hypoaminoacidemia, increased glucagon levels, [1] hyperglycemia [4],[5] and deranged liver function have been hypothesized to play a role.

Four of our patients showed hypoalbuminemia of whom one patient had long-standing diabetes mellitus, but the remaining patients did not have any metabolic abnormality. Of special importance is the dysregulation of zinc metabolism, [6],[7] which has gained much attention recently, because of dramatic response of this dermatosis to oral zinc therapy. Serum zinc levels in our study were found to be within normal range in 8 of 10 patients, one of them showed higher than normal levels, while the other had low levels. None of our patients had any clinical features of zinc deficiency but responded remarkably to zinc supplementation.

Ever since in their original description of the disorder in 1996, el Darouti M and Abu el Ela M of Egypt, reported an exclusive occurrence of this entity in patients of Hepatitis-C, [1],[2],[8],[9] NAE has been considered to be a cutaneous marker of hepatitis-C infection. Of particular interest is the fact that many abnormalities hypothesized of causing NAE also co-occur in patients suffering from chronic hepatitis-C (like hypoalbuminemia, liver dysfunction). Hence, it could be proposed that like other cutaneous manifestations of hepatitis-C, immune complex deposition and chronic inflammation may have an important role to play in etiopathogenesis of NAE, [10] although much work still needs to be done to support this hypothesis. Some workers also speculated that viral load and viral genotype [11] may have implications on development of this entity. However, recently cases have been reported all over the world in people who were seronegative to hepatitis-C virus (HCV). [8],[9],[12],[13],[14],[15] In our study too, none of the patients were found to be positive for the sero markers of HCV infection.

Association of NAE has rarely been reported with patients of chronic renal disease. Four of our patients had CRF while one had nephrotic syndrome prior to onset of lesions in them. Two of them were renal allograft recipients. Causes of renal failure differed in all of them, while one had grade IV lupus nephritis, other two had hypertensive and diabetic nephropathy. All of them had been treated with immune suppressants like prednisolone, systemic tacrolimus and mycophenolate mofetil.

Histopathological correlation was done in 36 patients of NAE associated with HCV by Abdallah et al. [16] in Egypt by double blinding and they found out that in early disease the picture resembles that of nummular eczema showing, acanthosis with moderate spongiosis and inflammatory infiltrate along with pigmentary incontinence. Fully developed lesions show psoriasiform hyperplasia, hyperkeratosis, parakeratosis, papillomatosis, focal hypergranulosis, pigment incontinence, inflammatory cells in papillary dermis and necrotic keratinocytes, while only mild acanthosis and inflammation is seen in late stage of the disease. Our cases differ from NAE in consistent presence of granular cell layer and consistent absence of necrolysis. Our cases also showed marked hyperkeratosis, uniform parakeratosis, spongiosis in some and epidermal pallor in others.

el Darouti and Abu el Ela proposed that metabolic abnormalities mentioned before may lead to epidermal protein depletion, resulting in necrolysis of epidermal cells, [1] while Abdallah et al. proposed that zinc has anti-apoptotic properties and its deficiency may contribute to NAE, and it's the levels of epidermal zinc which may be decreased even in presence of normal serum zinc levels. [9]

Our patients responded very well to oral zinc therapy. Most of them showed rapid diminution of size of the lesions at follow up in the second week. One of them showed complete resolution of the lesions in the fourth week of treatment. Oral zinc therapy has been reported for its efficacy in NAE throughout the world. [17],[18],[19] This is where our cases resembled NAE although they differed to some extent clinically and markedly in HPE.

We report these cases, which have a unique presentation of treatment refractory hyperkeratotic acral plaques and significant response to oral zinc, because of their stark dissimilarity to most known dermatological conditions. We urge practicing dermatologists to take note of this condition, as these are chronic, refractory and resistant to conventional treatments. However, we understand that further research with larger number of cases is required to confirm whether this is a novel entity or a different subset of a previously known condition.

   References Top

el Darouti M, Abu el Ela M. Necrolytic acral erythema: A cutaneous marker of viral hepatitis C. Int J Dermatol 1996;35:252-6.  Back to cited text no. 1
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;21:1200-6.  Back to cited text no. 2
Janjua SA. Necrolytic Acral Erythema. Derm Atlas. Available from: Diagnosis=178630456. [Last accessed on 2014 Feb 7].  Back to cited text no. 3
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 2005;44:916-21.  Back to cited text no. 4
Mason AL, Lau JY, Hoang N, Qian K, Alexander GJ, Xu L, et al. Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology 1999;29:328-33.  Back to cited text no. 5
Najarian DJ, Lefkowitz I, Balfour E, Pappert AS, Rao BK. Zinc deficiency associated with necrolytic acral erythema. J Am Acad Dermatol 2006;55(Suppl 5):S108-10.  Back to cited text no. 6
Najarian DJ, Najarian JS, Rao BK, Pappert AS. Hypozincemia and hyperzincuria associated with necrolytic acral erythema. Int J Dermatol 2008;47:709-11.  Back to cited text no. 7
Tabibian JH, Gerstenblith MR, Tedford RJ, Junkins-Hopkins JM, Abuav R. Necrolytic acral erythema as a cutaneous marker of hepatitis C: Report of two cases and review. Dig Dis Sci 2010;55:2735-43.  Back to cited text no. 8
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 2005;53:247-51.  Back to cited text no. 9
Ko HM, Hernandez-Prera JC, Zhu H, Dikman SH, Sidhu HK, Ward SC, et al. Morphologic features of extrahepatic manifestations of hepatitis C virus infection. Clin Dev Immunol 2012;2012:740138.  Back to cited text no. 10
Panda S, Lahiri K. Seronegative necrolytic acral erythema: A distinct clinical subset? Indian J Dermatol 2010;55:259-61.  Back to cited text no. 11
[PUBMED]  Medknow Journal  
Wu YH, Tu ME, Lee CS, Lin YC. Necrolytic acral erythema without hepatitis C infection. J Cutan Pathol 2009;36:355-8.  Back to cited text no. 12
Nikam BP. Necrolytic acral erythema seronegative for hepatitis C virus - two cases from India treated with oral zinc. Int J Dermatol 2009;48:1096-9.  Back to cited text no. 13
Liu A, Erickson CP, Cockerell CJ, Hsu S. Necrolytic acral erythema: A case not associated with hepatitis C infection. Dermatol Online J 2008;14:10.  Back to cited text no. 14
El-Darouti MA, Mashaly HM, El-Nabarawy E, Eissa AM, Abdel-Halim MR, Fawzi MM, et al. Leukocytoclastic vasculitis and necrolytic acral erythema in patients with hepatitis C infection: Do viral load and viral genotype play a role? J Am Acad Dermatol 2010;63:259-65.  Back to cited text no. 15
Abdallah MA, Ghozzi MY, Monib HA, Hafez AM, Hiatt KM, Smoller BR, et al. Histological study of necrolytic acral erythema. J Ark Med Soc 2004;100:354-5.  Back to cited text no. 16
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 2000;136:755-7.  Back to cited text no. 17
Abdallah MA, Hull C, Horn TD. Necrolytic acral erythema: A patient from the United States successfully treated with oral zinc. Arch Dermatol 2005;141:85-7.  Back to cited text no. 18
de Carvalho Fantini B, Matsumoto FY, Arnone M, Sotto MN, Júnior WB. Necrolytic acral erythema successfully treated with oral zinc. Int J Dermatol 2008;47:872-3.  Back to cited text no. 19

What is new?

  1. These group of cases have distinctive clinical and histopathological features, and non-responsive to most standard immunomodulators.
  2. However most of these cases showed unique and dramatic response to oral zinc sulfate.


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]

  [Table 1], [Table 2]


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