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Necrolytic acral erythema: response to combination therapy with interferon and ribavirin
Necrolytic acral erythema: Response to combination therapy with interferon and ribavirin Chad M. Hivnor, MD,a Albert C. Yan, MD,b Jacqueline M. Junkins-Hopkins, MD,a and Paul J. Honig, MDb Philadelphia, Pennsylvania Necrolytic acral erythema is a papulosquamous and sometimes vesiculobullous eruption bearing clinical and histologic similarity to other necrolytic erythemas such as necrolytic migratory erythema, pseudoglucagonoma, and nutritional deficiency syndromes. Necrolytic acral erythema is distinguished by its association with hepatitis C infection and its predominantly acral distribution. We describe a pediatric patient with necrolytic acral erythema whose eruption resolved with hyperalimentation and combination interferon and ribavirin therapy, despite the persistence of detectable viral load and continued hepatic and renal insufficiency. (J Am Acad Dermatol 2004;50:S121-4.)
I
n 1996 El Darouti and Abu el Ela1 described 7 patients, aged 12 to 55 years, with papulosquamous or vesiculobullous eruptions localized to acral surfaces. The clinical morphology and histology of the cutaneous eruption were strikingly similar to those of other previously described necrolytic erythemas. In contrast to these other reports, all 7 patients were distinguished by the acral localization of their skin condition, the lack of periorificial involvement, and the universal coexistence of hepatitis C infection. Treatments previously have included amino acid and zinc supplements, hyperalimentation, and interferon alfa2 with varied success. We describe an 11-year-old girl with a history of chronic hepatitis C infection who developed findings characteristic of necrolytic acral erythema (NAE). Her eruption appeared responsive to combination therapy with interferon and ribavirin, but not to interferon alone.
CASE REPORT An 11-year-old African American girl with chronic hepatitis C and associated nephrotic syndrome presented with a diffuse, bilateral, pruritic eruption on dorsal acral surfaces. The cutaneous eruption began several weeks after restarting interferon therapy for hepatitis C infection. Although she had previously received 2 courses of interferon alfa for her hepatitis and nephrotic syndrome without complication, her nephrologist discontinued the interferon after the onset of this skin condition because of concerns about a possible evolving drug reaction. On physical examination, large, annular, hyperkeratotic, and This supplement is made possible through an unrestricted educational grant from Stiefel Laboratories to the American Academy of Dermatology. From the Department of Dermatology, University of Pennsylvania School of Medicine,a and Section of Dermatology, Department of Pediatrics, Children’s Hospital of Philadelphia.b Funding sources: None. Conflicts of interest: None identified. Reprint requests: Albert C. Yan, MD, Section of Dermatology, Children’s Hospital of Philadelphia, 34th and Civic Center Blvd, First Floor Wood Bldg, Philadelphia, PA 19104. E-mail: [email protected]. 0190-9622/$30.00 © 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2003.09.017
violaceous plaques with raised, erythematous, scaly borders were observed on the arms and legs. Her palms, soles, and the back surfaces of the feet and hands were markedly hyperkeratotic and scaly with small fissures and erosions within the inflammatory plaques (Fig 1). The eruption progressed to involve the upper aspect of her thighs (Fig 2) with small lesions on her face and trunk. However, periorificial, periauricular, and oral mucosal lesions were never observed. Functional limitations in her ability to perform basic daily tasks were noted; she had difficulty walking and even manipulating a pencil. Her continued systemic disease symptoms prompted treatment with combination therapy using ribavirin and interferon. Initial laboratory studies revealed a normal complete blood cell count, electrolytes, creatinine, glucagon, and zinc levels. Liver enzymes, fatty acid levels, and amino acids were all elevated and protein levels (total protein and albumin) were decreased, reflecting active liver disease. The urinalysis confirmed ongoing nephritic syndrome. Several skin biopsy specimens were obtained at different stages of her course. All showed evidence of psoriasiform hyperplasia, parakeratotic scale, papillary dermal edema, and variable reticular degeneration of the superficial keratinocytes with dyskeratosis (Fig 3). Clinicopathologic correlation indicated a diagnosis of NAE associated with hepatitis C infection. The patient’s lesions did not respond to high-potency topical steroids. Initial hyperalimentation with protein and zinc improved the albumin and total protein to 3.0 and 9.1, respectively. This resulted in a modest clinical improvement limited to proximal areas. Within 8 weeks, marked clinical improvement was noted with decreased scale of the back of her foot and no evidence of residual proximal disease. The patient was then lost to dermatologic follow-up for 6 months, although she continued to be seen by both her nephrologist and gastroenterologist. Because the patient’s liver disease did not respond to combination antiviral therapy, treatment with interferon and ribavirin was discontinued after 1 year. On re-evaluation 4 years later, her acral involvement had nearly completely resolved. Only minimal velvety lichenification with postinflammatory hyperpigmentation remained on the back of her foot. During her course of antiviral therapy, her viral load of hepatitis C never diminished below 5 million copies/mL (the highest detectable limit). Despite the lack of a serum response in viral load, her skin remains essentially clear 4 years later.
S121
S122 Hivnor et al
J AM ACAD DERMATOL MAY 2004
Fig 3. Biopsy specimen demonstrating psoriasiform hyperplasia, broad parakeratotic scale, hypogranulosis, papillary dermal edema, and reticular degeneration of superficial keratinocytes with dyskeratosis. (Hematoxylin-eosin stain; original magnification ⫻20.)
Fig 1. Back of hand with markedly hyperkeratotic, scaly plaques, with serpiginous active border of papules and incipient vesicles.
Fig 2. Hyperkeratotic, scaly plaques in annular and serpiginous configurations on legs.
DISCUSSION NAE is an uncommon, chronic, papulosquamous, and occasionally vesiculobullous eruption. This cutaneous manifestation of hepatitis C infection was first described in 7 patients by El Darouti and Abu el Ela,1 and later by Khanna et al,2 who characterized an eighth case (Table I). Lesions of NAE appear
acrally located as well-defined dusky or erythematous plaques with a hyperkeratotic surface. Flaccid blisters may manifest initially at the periphery of the plaques with associated tenderness. NAE can be distinguished from the other necrolytic erythemas in its predilection for acral localization, lack of periorificial involvement, universal association with hepatitis C infection, and normal glucagon and zinc levels. Amino acid levels may be low or normal. Histologically, necrosis in the upper part of the epidermis with occasional blister formation separating the necrotic and healthy epidermis is typical. Individual necrotic keratinocytes may be present with vacuolar alteration of the dermoepidermal junction. Some lesions may show hyperkeratosis or psoriasisform epidermal hyperplasia. Reported cases have been treated with interferon alfa, zinc sulfate, and amino acids with varied success.1,2 Although the various necrolytic erythemas share some clinical and histologic similarities, the various entities can be distinguished on the basis of cutaneous distribution and underlying biochemical abnormalities. Necrolytic migratory erythema manifests with elevated glucagon levels,3,4 acrodermatitis enteropathica with depressed zinc levels,5 and pellagra with low levels of niacin, whereas other necrolytic processes demonstrate deficiencies of biotin, amino acids, and essential fatty acids. Several of the necrolytic erythemas have been associated with biochemical deficiencies of fatty acids, amino acids, vitamins, and minerals. Indeed, patients with necrolytic migratory erythema associated with glucagonoma syndrome may demonstrate clinical improvement on supplementation with amino acids and zinc despite the lack of detectable deficiencies.5 In our patient, hepatitis C infection and nephrotic syndrome resulted in a hypoproteinemic state associated with decreased fatty acid levels. Partial correction of these deficiencies may have contributed to her clinical improvement after hyperalimentation, suggesting some role for these biochemical factors in the pathogenesis of this disorder. Concomitant therapy with interferon alone had little impact on her clinical course. However, the addition of ribavirin appeared to coincide with clinical improvement in the cutaneous findings of NAE even though her viral load remained elevated. Ribavirin is an antiviral agent with activity against a variety of viruses including hepatitis C virus. Its metabolite, ribavirin monophosphate, is a substrate mimic of inosine 5’-monophosphate (IMP) for its enzyme, IMP dehydrogenase. IMP dehydrogenase acts as a key step in the synthesis of purine nucleotides within lymphocytes and inhibition of this enzyme results in immunosuppression. In experimental models, similar substrate
Hivnor et al S123
J AM ACAD DERMATOL VOLUME 50, NUMBER 5
Table I. A review of published cases describing necrolytic acral erythema
Source
Case No./ Sex/Age (y)
El Darouti 1/F/55 et al, 19961
2/F/12
3/M/45
4/M/38
5/M/50
Clinical findings
Well-defined, tender, dusky erythematous lesions with flaccid blisters
Location
Back of feet
Associated findings
HCV positive, normal zinc levels, amino acid levels low
Not reported HCV positive, liver Well-defined biopsy specimen erythematous revealed chronic plaques with active hepatitis, velvety surface, normal zinc levels dusky erythematous borders, flat blisters Well-defined, thick, Back of feet, lower HCV positive, normal aspect of legs, zinc levels dusky, knees erythematous lesions; hyperkeratotic surface, flat, cyanotic border Back of feet HCV positive Dusky, red psoriasiform lesions, velvety surface, dark red rim
6/F/40
“Unusual erythematous lesions” “Typical lesions”
7/F/35
“Typical lesions”
Khanna et 8/F/43 al, 20002
Dusky, erythematous papules, eroded violaceous patches, edema
Hivnor et 9/F/11 al (current case)
Dusky, erythematous, hyperkeratotic papules with peripheral bullous lesions
F, Female; HCV, hepatitis C virus; M, male.
Hands, feet, knees
HCV positive
Lower aspect of HCV positive, normal legs, back of feet zinc levels, amino acid levels low Back of feet HCV positive
Treatment
Oral zinc, intravenous Marked improvement and later oral amino initially with zinc acids and amino acids, then partial relapse with only amino acids Oral zinc and oral Partial response amino acids
Oral zinc and oral amino acids
Very little improvement
Oral zinc and amino acids; then interferon alfa (3 million U subcutaneously 3 times/wk) “Liver supplements”
Little improvement with combination, but marked response at 12 weeks with interferon No response
Oral zinc and oral amino acids
Partial response
Interferon alfa
Almost complete response at 12 wk Partial improvement with zinc at 5 wk; complete clearance at 6 mo with interferon
Oral zinc (220 mg HCV positive, liver twice a day) biopsy specimen followed by revealed mild interferon alfa-2b fibrosis and chronic (3 million U hepatitis; normal subcutaneously 3 zinc, normal times/wk) glucagon levels HCV positive (highest Hyperalimentation Back of feet and with amino acid detectable viral hands, proximal and zinc loads), normal zinc, extremities, supplementation, amino acid, and minimal interferon alfa-2b glucagon levels involvement of (3 million U neck and face subcutaneous 3 times/wk)
Back of feet
Response
Partial response to hyperalimentation. No response to interferon alone. Marked clinical improvement with combination ribavirin and interferon at 8 wk with eventual resolution at 6 mo (historic as patient was subsequently lost to follow-up)
S124 Hivnor et al mimics of IMP act as successful IMP dehydrogenase inhibitors in the treatment of psoriasis and hepatitis C. Given the papulosquamous nature of NAE, ribavirin may act not through direct effects on the hepatitis C viral load itself, but may do so through an alternate mechanism. Although purely speculative, ribavirin may affect skin-trafficking lymphocytes in the skin of patients with papulosquamous lesions of NAE as it may in experimental models of psoriasis.6 These effects may counteract the well-known effects of interferon on activating psoriasis in patients who are susceptible. Summary Patients with hepatitis C infection who manifest acrally located papulosquamous or vesiculobullous lesions may have NAE. Conversely, patients with an acrodermatitis resembling NAE may benefit from hepatitis C screening. In those given the diagnosis of this condition, a hepatitis panel; liver function tests; and serum albumin, total protein, amino acids, zinc, biotin, and glucagon levels should help to clarify the diagnosis. Use of interferon in combination with ribavirin and supplementation
J AM ACAD DERMATOL MAY 2004
with zinc and deficient amino acids may prove useful in the treatment of this otherwise recalcitrant cutaneous disorder. Despite the association of NAE with hepatitis C, it should be noted that the response of NAE to therapy might not directly correlate with the hepatitis C viral load. REFERENCES 1. El Darouti M, Abu el Ela M. Necrolytic acral erythema: a cutaneous marker of viral hepatitis C. Int J Dermatol 1996;35:252-6. 2. Khanna VJ, Shieh S, Benjamin J, Somach S, Zaim MT, Dorner W, et al. Necrolytic acral erythema associated with hepatitis C: effective treatment with interferon alpha and zinc. Arch Dermatol 2000;136:755-7. 3. Chastain MA. The glucagonoma syndrome: a review of its features and discussion of new perspectives. Am J Med Sci 2001;321:306-20. 4. Swartz RA. Glucagonoma and pseudoglucagonoma syndromes. Int J Dermatol 1997;36:81-9. 5. Sinclair SA, Reynolds NJ. Necrolytic migratory erythema and zinc deficiency. Br J Dermatol 1997;136:783-5. 6. Sintchak MD, Nimmesgern E. The structure of inosine 5’-monophosphate dehydrogenase and the design of novel inhibitors. Immunopharmacology 2000;47:163-84.
I
n 1996 El Darouti and Abu el Ela1 described 7 patients, aged 12 to 55 years, with papulosquamous or vesiculobullous eruptions localized to acral surfaces. The clinical morphology and histology of the cutaneous eruption were strikingly similar to those of other previously described necrolytic erythemas. In contrast to these other reports, all 7 patients were distinguished by the acral localization of their skin condition, the lack of periorificial involvement, and the universal coexistence of hepatitis C infection. Treatments previously have included amino acid and zinc supplements, hyperalimentation, and interferon alfa2 with varied success. We describe an 11-year-old girl with a history of chronic hepatitis C infection who developed findings characteristic of necrolytic acral erythema (NAE). Her eruption appeared responsive to combination therapy with interferon and ribavirin, but not to interferon alone.
CASE REPORT An 11-year-old African American girl with chronic hepatitis C and associated nephrotic syndrome presented with a diffuse, bilateral, pruritic eruption on dorsal acral surfaces. The cutaneous eruption began several weeks after restarting interferon therapy for hepatitis C infection. Although she had previously received 2 courses of interferon alfa for her hepatitis and nephrotic syndrome without complication, her nephrologist discontinued the interferon after the onset of this skin condition because of concerns about a possible evolving drug reaction. On physical examination, large, annular, hyperkeratotic, and This supplement is made possible through an unrestricted educational grant from Stiefel Laboratories to the American Academy of Dermatology. From the Department of Dermatology, University of Pennsylvania School of Medicine,a and Section of Dermatology, Department of Pediatrics, Children’s Hospital of Philadelphia.b Funding sources: None. Conflicts of interest: None identified. Reprint requests: Albert C. Yan, MD, Section of Dermatology, Children’s Hospital of Philadelphia, 34th and Civic Center Blvd, First Floor Wood Bldg, Philadelphia, PA 19104. E-mail: [email protected]. 0190-9622/$30.00 © 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2003.09.017
violaceous plaques with raised, erythematous, scaly borders were observed on the arms and legs. Her palms, soles, and the back surfaces of the feet and hands were markedly hyperkeratotic and scaly with small fissures and erosions within the inflammatory plaques (Fig 1). The eruption progressed to involve the upper aspect of her thighs (Fig 2) with small lesions on her face and trunk. However, periorificial, periauricular, and oral mucosal lesions were never observed. Functional limitations in her ability to perform basic daily tasks were noted; she had difficulty walking and even manipulating a pencil. Her continued systemic disease symptoms prompted treatment with combination therapy using ribavirin and interferon. Initial laboratory studies revealed a normal complete blood cell count, electrolytes, creatinine, glucagon, and zinc levels. Liver enzymes, fatty acid levels, and amino acids were all elevated and protein levels (total protein and albumin) were decreased, reflecting active liver disease. The urinalysis confirmed ongoing nephritic syndrome. Several skin biopsy specimens were obtained at different stages of her course. All showed evidence of psoriasiform hyperplasia, parakeratotic scale, papillary dermal edema, and variable reticular degeneration of the superficial keratinocytes with dyskeratosis (Fig 3). Clinicopathologic correlation indicated a diagnosis of NAE associated with hepatitis C infection. The patient’s lesions did not respond to high-potency topical steroids. Initial hyperalimentation with protein and zinc improved the albumin and total protein to 3.0 and 9.1, respectively. This resulted in a modest clinical improvement limited to proximal areas. Within 8 weeks, marked clinical improvement was noted with decreased scale of the back of her foot and no evidence of residual proximal disease. The patient was then lost to dermatologic follow-up for 6 months, although she continued to be seen by both her nephrologist and gastroenterologist. Because the patient’s liver disease did not respond to combination antiviral therapy, treatment with interferon and ribavirin was discontinued after 1 year. On re-evaluation 4 years later, her acral involvement had nearly completely resolved. Only minimal velvety lichenification with postinflammatory hyperpigmentation remained on the back of her foot. During her course of antiviral therapy, her viral load of hepatitis C never diminished below 5 million copies/mL (the highest detectable limit). Despite the lack of a serum response in viral load, her skin remains essentially clear 4 years later.
S121
S122 Hivnor et al
J AM ACAD DERMATOL MAY 2004
Fig 3. Biopsy specimen demonstrating psoriasiform hyperplasia, broad parakeratotic scale, hypogranulosis, papillary dermal edema, and reticular degeneration of superficial keratinocytes with dyskeratosis. (Hematoxylin-eosin stain; original magnification ⫻20.)
Fig 1. Back of hand with markedly hyperkeratotic, scaly plaques, with serpiginous active border of papules and incipient vesicles.
Fig 2. Hyperkeratotic, scaly plaques in annular and serpiginous configurations on legs.
DISCUSSION NAE is an uncommon, chronic, papulosquamous, and occasionally vesiculobullous eruption. This cutaneous manifestation of hepatitis C infection was first described in 7 patients by El Darouti and Abu el Ela,1 and later by Khanna et al,2 who characterized an eighth case (Table I). Lesions of NAE appear
acrally located as well-defined dusky or erythematous plaques with a hyperkeratotic surface. Flaccid blisters may manifest initially at the periphery of the plaques with associated tenderness. NAE can be distinguished from the other necrolytic erythemas in its predilection for acral localization, lack of periorificial involvement, universal association with hepatitis C infection, and normal glucagon and zinc levels. Amino acid levels may be low or normal. Histologically, necrosis in the upper part of the epidermis with occasional blister formation separating the necrotic and healthy epidermis is typical. Individual necrotic keratinocytes may be present with vacuolar alteration of the dermoepidermal junction. Some lesions may show hyperkeratosis or psoriasisform epidermal hyperplasia. Reported cases have been treated with interferon alfa, zinc sulfate, and amino acids with varied success.1,2 Although the various necrolytic erythemas share some clinical and histologic similarities, the various entities can be distinguished on the basis of cutaneous distribution and underlying biochemical abnormalities. Necrolytic migratory erythema manifests with elevated glucagon levels,3,4 acrodermatitis enteropathica with depressed zinc levels,5 and pellagra with low levels of niacin, whereas other necrolytic processes demonstrate deficiencies of biotin, amino acids, and essential fatty acids. Several of the necrolytic erythemas have been associated with biochemical deficiencies of fatty acids, amino acids, vitamins, and minerals. Indeed, patients with necrolytic migratory erythema associated with glucagonoma syndrome may demonstrate clinical improvement on supplementation with amino acids and zinc despite the lack of detectable deficiencies.5 In our patient, hepatitis C infection and nephrotic syndrome resulted in a hypoproteinemic state associated with decreased fatty acid levels. Partial correction of these deficiencies may have contributed to her clinical improvement after hyperalimentation, suggesting some role for these biochemical factors in the pathogenesis of this disorder. Concomitant therapy with interferon alone had little impact on her clinical course. However, the addition of ribavirin appeared to coincide with clinical improvement in the cutaneous findings of NAE even though her viral load remained elevated. Ribavirin is an antiviral agent with activity against a variety of viruses including hepatitis C virus. Its metabolite, ribavirin monophosphate, is a substrate mimic of inosine 5’-monophosphate (IMP) for its enzyme, IMP dehydrogenase. IMP dehydrogenase acts as a key step in the synthesis of purine nucleotides within lymphocytes and inhibition of this enzyme results in immunosuppression. In experimental models, similar substrate
Hivnor et al S123
J AM ACAD DERMATOL VOLUME 50, NUMBER 5
Table I. A review of published cases describing necrolytic acral erythema
Source
Case No./ Sex/Age (y)
El Darouti 1/F/55 et al, 19961
2/F/12
3/M/45
4/M/38
5/M/50
Clinical findings
Well-defined, tender, dusky erythematous lesions with flaccid blisters
Location
Back of feet
Associated findings
HCV positive, normal zinc levels, amino acid levels low
Not reported HCV positive, liver Well-defined biopsy specimen erythematous revealed chronic plaques with active hepatitis, velvety surface, normal zinc levels dusky erythematous borders, flat blisters Well-defined, thick, Back of feet, lower HCV positive, normal aspect of legs, zinc levels dusky, knees erythematous lesions; hyperkeratotic surface, flat, cyanotic border Back of feet HCV positive Dusky, red psoriasiform lesions, velvety surface, dark red rim
6/F/40
“Unusual erythematous lesions” “Typical lesions”
7/F/35
“Typical lesions”
Khanna et 8/F/43 al, 20002
Dusky, erythematous papules, eroded violaceous patches, edema
Hivnor et 9/F/11 al (current case)
Dusky, erythematous, hyperkeratotic papules with peripheral bullous lesions
F, Female; HCV, hepatitis C virus; M, male.
Hands, feet, knees
HCV positive
Lower aspect of HCV positive, normal legs, back of feet zinc levels, amino acid levels low Back of feet HCV positive
Treatment
Oral zinc, intravenous Marked improvement and later oral amino initially with zinc acids and amino acids, then partial relapse with only amino acids Oral zinc and oral Partial response amino acids
Oral zinc and oral amino acids
Very little improvement
Oral zinc and amino acids; then interferon alfa (3 million U subcutaneously 3 times/wk) “Liver supplements”
Little improvement with combination, but marked response at 12 weeks with interferon No response
Oral zinc and oral amino acids
Partial response
Interferon alfa
Almost complete response at 12 wk Partial improvement with zinc at 5 wk; complete clearance at 6 mo with interferon
Oral zinc (220 mg HCV positive, liver twice a day) biopsy specimen followed by revealed mild interferon alfa-2b fibrosis and chronic (3 million U hepatitis; normal subcutaneously 3 zinc, normal times/wk) glucagon levels HCV positive (highest Hyperalimentation Back of feet and with amino acid detectable viral hands, proximal and zinc loads), normal zinc, extremities, supplementation, amino acid, and minimal interferon alfa-2b glucagon levels involvement of (3 million U neck and face subcutaneous 3 times/wk)
Back of feet
Response
Partial response to hyperalimentation. No response to interferon alone. Marked clinical improvement with combination ribavirin and interferon at 8 wk with eventual resolution at 6 mo (historic as patient was subsequently lost to follow-up)
S124 Hivnor et al mimics of IMP act as successful IMP dehydrogenase inhibitors in the treatment of psoriasis and hepatitis C. Given the papulosquamous nature of NAE, ribavirin may act not through direct effects on the hepatitis C viral load itself, but may do so through an alternate mechanism. Although purely speculative, ribavirin may affect skin-trafficking lymphocytes in the skin of patients with papulosquamous lesions of NAE as it may in experimental models of psoriasis.6 These effects may counteract the well-known effects of interferon on activating psoriasis in patients who are susceptible. Summary Patients with hepatitis C infection who manifest acrally located papulosquamous or vesiculobullous lesions may have NAE. Conversely, patients with an acrodermatitis resembling NAE may benefit from hepatitis C screening. In those given the diagnosis of this condition, a hepatitis panel; liver function tests; and serum albumin, total protein, amino acids, zinc, biotin, and glucagon levels should help to clarify the diagnosis. Use of interferon in combination with ribavirin and supplementation
J AM ACAD DERMATOL MAY 2004
with zinc and deficient amino acids may prove useful in the treatment of this otherwise recalcitrant cutaneous disorder. Despite the association of NAE with hepatitis C, it should be noted that the response of NAE to therapy might not directly correlate with the hepatitis C viral load. REFERENCES 1. El Darouti M, Abu el Ela M. Necrolytic acral erythema: a cutaneous marker of viral hepatitis C. Int J Dermatol 1996;35:252-6. 2. Khanna VJ, Shieh S, Benjamin J, Somach S, Zaim MT, Dorner W, et al. Necrolytic acral erythema associated with hepatitis C: effective treatment with interferon alpha and zinc. Arch Dermatol 2000;136:755-7. 3. Chastain MA. The glucagonoma syndrome: a review of its features and discussion of new perspectives. Am J Med Sci 2001;321:306-20. 4. Swartz RA. Glucagonoma and pseudoglucagonoma syndromes. Int J Dermatol 1997;36:81-9. 5. Sinclair SA, Reynolds NJ. Necrolytic migratory erythema and zinc deficiency. Br J Dermatol 1997;136:783-5. 6. Sintchak MD, Nimmesgern E. The structure of inosine 5’-monophosphate dehydrogenase and the design of novel inhibitors. Immunopharmacology 2000;47:163-84.