Abstract and Introduction
Context: Necrolytic migratory erythema (NME) is a characteristic skin condition seen in the presence of a pancreatic glucagonoma. The presence of NME in the absence of a pancreatic tumor has been termed the pseudoglucagonoma syndrome. In such cases, NME is commonly associated with conditions, such as liver disease, inflammatory bowel disease, pancreatitis, malabsorption disorders (ie, celiac sprue), and other malignancies. There are many theories on the pathogenesis of NME, which include the direct action of glucagon in inducing skin necrolysis, hypoaminoacidemia-inducing epidermal protein deficiency and necrolysis, a nutritional or metabolic deficiency of zinc or essential fatty acids, liver disease, glucagon induction of inflammatory mediators, a substance secreted from pancreatic and other visceral tumors associated with NME, and generalized malabsorption.
Objective: To present a review of the literature on the clinical presentation, etiology, pathogenesis, and treatment of NME.
Design: Review of the literature on NME occurring in patients both with and without a pancreatic glucagonoma.
Methods: We performed a PubMed review of the literature on the etiology and pathogenesis of NME to identify case reports and reviews published in both the internal medicine and dermatology literature.
Results: Our literature review encompassed 17 primary case reports and literature reviews published in the dermatologic and internal medicine literature on NME in patients both with and without a pancreatic glucagonoma. Although we found no clear consensus among the investigators of a universally accepted pathogenesis for NME, we did identify 4 main categories of etiologic/pathogenetic mechanisms for NME (glucagon excess, nutritional deficiencies, inflammatory mediators, and liver disease) that were discussed by many of the investigators and validated by both clinical and scientific evidence.
Conclusion: The exact pathogenesis and treatment of NME remain ill-defined despite many case reports and studies on NME in the literature. The many systemic diseases and nutritional deficiencies that have been found to be associated with NME suggest a multifactorial model for the pathogenesis of the disease. The most comprehensive, postulated mechanism for NME involves a combination of zinc, amino acid, and fatty acid deficiencies (arising from a wide variety of causes, such as dietary insufficiency, malabsorption syndromes, liver disease, elevated glucagon levels, and disorders of metabolism) that contributes to increased inflammation in the epidermis in response to trauma and to the necrolysis observed in NME. The importance of gaining an understanding of the etiology and pathogenesis of NME lies in the fact that there is no universally accepted mechanism of pathogenesis for NME, and that the only treatment reported to resolve the rash in these patients is to adequately identify and treat the underlying associated systemic condition or nutritional deficiency.
Necrolytic migratory erythema (NME) was first described by Becker and colleagues in 1942 in a woman with an alpha-cell tumor of the pancreas with an elevated serum glucagon and significant hypoaminoacidemia. Subsequently, in 1966 the hyperglycemic potential of the neoplasm was identified and glucagon was discovered at high levels within the neoplasm. In 1979, Mallinson and associates coined the term glucagonoma syndrome to describe this alpha-cell pancreatic tumor with its characteristically associated rash, NME. This characteristic rash is diagnosed both clinically, as a painful scaly erythematous patch, and histologically, by parakeratosis with the loss of the granular layer, necrosis, and separation of the upper epidermis with vacuolization of the keratinocytes, dyskeratotic keratinocytes, and neutrophils in the upper epidermis (see Figure 1) Originally only described in association with glucagonomas, the clinical and histologic features of NME have also been seen in the absence of the pancreatic tumor, which has been described as the pseudoglucagonoma syndrome. Pseudoglucagonoma is typically seen in association with intestinal malabsorption disorders (ie, celiac sprue), cirrhosis, inflammatory bowel disease, pancreatitis. and malignancies (other than pancreatic). Of interest, glucagon levels in these patients are also commonly elevated. In one study, 48% of patients with pseudoglucagonoma syndrome were reported to have elevated serum glucagon levels, ranging from 247 to 1300 pg/mL, in which normal serum glucagon levels range from 50 to 150 pg/mL. However, glucagon levels in pseudoglucagonoma syndrome are not typically elevated at the same proportion as that seen in glucagonomas. The rash of NME in pseudoglucagonoma syndrome is clinically and histologically identical to that in patients with glucagonomas. Pseudoglucagonoma syndrome is often seen in patients with nutritional deficiencies and/or liver disease. In a study of 21 patients with pseudoglucagonoma syndrome, the serum zinc levels were low in 37% and liver function tests were elevated in 38% of patients. Thus, there may be a similar pathogenic origin of skin lesions in both pseudoglucagonoma and glucagonoma syndromes in terms of elevated glucagon levels and/or a nutritional deficiency/malabsorption disorder.
Histology of necrolytic migratory erythema (NME) revealing parakeratosis, the loss of the granular layer, necrosis, and separation of the upper epidermis with vacuolization of the keratinocytes, dyskeratotic keratinocytes, and neutrophils in the upper epidermis. Reprinted with permission from Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz S, eds. Fitzpatrick's Dermatology in General Medicine. Vol II. 6th ed. New York: McGraw-Hill; 2003:1972. Fig 184-8 A and B.
The clinical features of NME include waves of irregular erythema in which a central bulla develops, subsequently erodes, and becomes crusted. The lesions typically wax and wane for approximately 10 days, beginning with an erythematous patch that blisters centrally, erodes, and then crusts and heals with hyperpigmentation. The lesions are typically highly pruritic with painful annular plaques that demonstrate confluence, and there is a predilection for areas subject to greater pressure and friction, ie, the perineum, buttocks, groin, lower abdomen, and lower extremities (see Figures 2 and 3). Lesions also commonly follow a periorificial distribution. Angular cheilitis, glossitis, and stomatitis are commonly also found in NME.
NME with annular erythematous plaques, vesicles, and erosions involving the whole perineal area. Reprinted with permission from Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz S, eds. Fitzpatrick's Dermatology in General Medicine. Vol II. 6th ed. New York: McGraw-Hill; 2003:1972. Fig 184-8 A and B.
Close-up view of an annular plaque showing NME. Reprinted with permission from Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz S, eds. Fitzpatrick's Dermatology in General Medicine. Vol II. 6th ed. New York: McGraw-Hill; 2003:1972. Fig 184-8 A and B.
Since 1942, less than 200 cases of NME have been reported worldwide in the literature. The prevalence is equal in women and men, and the most common age group is 50-59. In patients with associated glucagonomas, at least 50% of the tumors are metastatic at the time of diagnosis. One study of 21 patients with glucagonoma syndrome reported tumor-related death in 9 of 21 patients, an average of 4.9 years after diagnosis. The associated clinical features of glucagonoma syndrome include an alpha-cell tumor of the pancreas, hyperglucagonemia, glucose intolerance, normochromic/normocytic anemia, diarrhea, malaise, weight loss, venous thrombosis, and neuropsychiatric features.
There are many theories on the pathogenesis of NME that explain the associations with glucagonomas as well as with the diseases commonly associated with pseudoglucagonoma syndrome, such as various nutritional deficiencies, malabsorption syndromes, autoimmune conditions, and liver disease. Some of these hypotheses include the direct action of glucagon in inducing skin necrolysis, hypoaminoacidemia-inducing epidermal protein deficiency and necrolysis, a nutritional or metabolic deficiency of zinc or essential fatty acids, liver disease, glucagon induction of inflammatory mediators (which are derivatives of arachidonic acid), a substance secreted from pancreatic and other visceral tumors associated with NME (in addition to glucagon), and generalized malabsorption.
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Cite this: Etiology and Pathogenesis of Necrolytic Migratory Erythema: Review of the Literature - Medscape - Sep 10, 2004.