eMedicine Specialties > Endocrinology > Multiple Endocrine Disease and Miscellaneous Endocrine Disease
Glucagonoma
Updated: Nov 20, 2008
Introduction
Background
A glucagonoma is a rare neuroendocrine tumor with nearly exclusive pancreatic localization. Malignant glucagonomas are islet cell pancreatic tumors that are discovered because of glucagonoma syndrome (in which the glucagonoma autonomously secretes glucagon), because of local mass effects, or incidentally. Glucagonomas originate from the alpha-2 cells of the pancreas.
In 1942, Becker and colleagues first described glucagonomas. Fewer than 250 cases of glucagonomas have been described in the literature. Unregulated production (overproduction) of peptide hormones and growth factors, which are not normally expressed in the tissue of origin, is characteristic of neuroendocrine tumors. Abnormal production of these bioactive peptides can lead to significant systemic toxic consequences and to the promotion of further tumor growth. The origin of this pathology remained unknown until 1966, when McGavran and colleagues assessed the radioimmunoassay (RIA) technique for glucagon.1
In 75-80% of cases, the glucagonoma starts in malignant form, and in 50% of these cases, metastasis exists at diagnosis. The tumor's presence is characterized by glucagon overproduction, weight loss, diabetes mellitus, hypoaminoacidemia, normochromic and normocytic anemia, and necrolytic migratory erythema (NME), which is the most characteristic clinical sign (as opposed to symptom) of this pathology. NME presents as phlogistic damage to tissues in areas exposed to friction and pressure.
Another noteworthy feature of glucagonoma syndrome is a high rate of thromboembolic complications and consequent pulmonary embolisms; this is dangerous for many patients who can succumb to it. The correct recognition of NME is very important, because it may allow early detection either of glucagonoma or of extrapancreatic, glucagon-secreting tumors.2,3
Glucagonomas that are not associated with glucagonoma syndrome are diagnosed in various ways. The tumor may appear as a malignant pancreatic tumor discovered because of local growth, with or without metastases, or the tumor may be associated with insulinoma or gastrinoma. Glucagonoma may also occur as a single microadenoma found incidentally at autopsy in elderly patients. Glucagonoma very rarely is part of multiple endocrine neoplasia (MEN) type 1 syndrome (also called Wermer syndrome), and in such cases, the glucagonoma appears as a single, biologically inactive lesion. Similar to other islet cell tumors, the primary and metastatic lesions are slow growing.
However, it is noteworthy that some cases of NME without glucagonoma have been reported.4,5 It has been suggested that in such patients, hyponutrition, especially that resulting from a lack of vitamins and minerals, causes differentiation/proliferation modifications of keratinocytes.
Related eMedicine topics:
Glucagonoma Syndrome
Diabetes Mellitus, Type 2 [Endocrinology]
Diabetes Mellitus, Type 2 [Pediatrics: General Medicine]
Diabetes Mellitus, Type 2 - A Review
Multiple Endocrine Neoplasia
Multiple Endocrine Neoplasia Type 1
Multiple Endocrine Neoplasia, Type 2
Neoplasms of the Endocrine Pancreas
Pancreas, Islet Cell Tumors
Pathophysiology
Although the relationship between hyperglucagonemia and necrolytic migratory erythema (NME) is not clear, elevated glucagon serum levels can be found at the same time as this cutaneous manifestation of the disease. Glucagon is a peptidic hormone mostly produced from alpha-2 cells of the pancreas and, in smaller amounts, from amine precursor uptake and decarboxylation (APUD) cells in gastric and duodenal mucosa. Three known forms of this hormone exist. The pancreatic form contains 29 amino acids and has a molecular weight of 3485 daltons, the gastric form contains 29 amino acids and has a molecular weight of 3500 daltons, and the enteric form, or enteroglucagon, contains a polypeptidic chain, has a high molecular weight, and is biologically and chemically different from other hormones, although it cross-reacts with them.
Glucagon is secreted under the influence of various factors. The most important of these is the reduced blood concentration of glucose. Acetylcholine and catecholamines elevate serum levels of glucagon and somatostatin; serotonin reduces these levels. Physiologic glucagon activity includes the following:
- Glycogenolysis activation with contemporary glycolysis inhibition and activation of the gluconeogenesis
- Stimulation of lipolysis and catecholamine secretion
- Inhibition of gastric secreting activity, pancreatic secreting activity, and GI motility
- Stimulation of urinary excretion of water and phosphates, as well as of sodium, calcium, and magnesium ions
Hyperglycemia linked to glucagonoma is a consequence of the glycogenolytic and gluconeogenic effects of glucagon. Similarly, glucagon excess (or relative glucagon excess) can be observed in diabetes mellitus and its complication, diabetic ketoacidosis.
When glucagon is secreted by a tumor, it becomes independent and is no longer influenced by feedback control mechanisms; the subsequent increase in glucagon concentration in the blood produces characteristic symptoms. Diabetes mellitus occurs in patients with glucagonoma because of the lack of equilibrium between insulin production and glucagon production (which occurs when high serum levels of glucagon and normal levels of insulin exist or when insulin production is reduced and a normal glucagon level is present). However, glucagon may not induce hyperglycemia directly unless the metabolism of glucose by the liver is directly compromised.
Another factor affecting glucagon secretion may be variation in the molecular species of glucagon that is present in each case, and the biologic potency of these molecular species of glucagon. Weight loss is due to the action of glucagon on lipid and protein metabolism; increased caloric expenditure, as determined by the proteic catabolism; and the consequent increase of gluconeogenesis and ureagenesis. This mechanism is probably also responsible for the cases of anemia and hypoaminoacidemia observed in patients with glucagonoma. Thromboembolism, occasionally observed in patients, is attributable to the production of a molecule similar to coagulative factor X from tumoral cells.
Although many theories about the pathogenesis of NME exist, the process of pathogenesis is not explained with certainty. According to one theory, NME can be caused by a tryptophan loss in cutaneous tissues because of the excess circulating glucagon. The amino acid tryptophan is responsible for niacin (pellagra prevention vitamin) function, which regulates cell turnover, capillary tone, and the maturation of the epidermis and mucosal epithelia.
According to another theory, NME is related to the hypoalbuminemia due to glucagon excess; in fact, albumin acts as a carrier for zinc and essential fatty acids. Zinc carries out a fundamental role in the maintenance of cutaneous trophism. The mineral is also responsible for the linoleic acid desaturation and is therefore involved in prostaglandin synthesis, which could determine phlogistic damage to tissues in areas exposed to friction and pressure if it occurs in excess. NME may also occur in areas of cutaneous trauma.
Frequency
United States
A study by Yao and colleagues, based on an analysis of the Surveillance, Epidemiology, and End Results (SEER) program database, reported the occurrence of a total of 2705 cases of endocrine pancreatic tumors in the United States over a period of 28 years, ending Jan 1, 2003.6 According to these authors, the incidence of glucagonoma is very low, with islet cell neoplasms accounting for 1.3% of pancreatic cancers.
International
A rare pathology, glucagonoma probably accounts for 1% of all neuroendocrine tumors. Between 1942 and the beginning of the 21st century, approximately 250 cases were described in the literature. Incidence of this pathology is estimated on an annual basis, with 1 case occurring in every 20 million people. This number is probably an underestimation of the actual occurrence because of the relative lack of specificity of the symptoms. The fact that the tumors are, for a time, clinically silent also contributes to this underestimation.
Mortality/Morbidity
Glucagonomas have a slow rate of growth. Most cases start with nonspecific symptoms. In a report on patients with functional pancreatic tumors, the average delay in diagnosis was 3 years. Approximately 50% of cases have metastases at diagnosis; for patients in whom metastasis has occurred, the prognosis is poor.
Because of the small number of cases of glucagonoma, the rate of survival after 5 years has not been determined. However, one study reported an average survival time of 3.7 years in a group of 12 patients and an average survival period of 4.9 years in another group, consisting of 9 patients.
Like other islet cell neoplasms, glucagonomas may overproduce multiple hormones, each of which can have clinical manifestations. Insulin is the second-most common hormone secreted by these tumors. Others include (in order of frequency) adrenocorticotropic hormone (ACTH), pancreatic polypeptide, and parathyroid hormone (PTH) or substances with activity similar to PTH, such as gastrin, serotonin, vasoactive intestinal polypeptide (VIP), and melanocyte-stimulating hormone (MSH).
Race
No race prevalence is known for glucagonoma.
Sex
The frequency of glucagonoma in males and females is nearly equal, although a greater incidence has been reported in females.
Age
Most patients with glucagonoma are in the sixth decade of life, with a mean age of 55 years and an age range of 19-84 years.
Clinical
History
- Glucagonoma initially manifests with a nonspecific clinical scenario characterized, in most cases, by weight loss, diabetes mellitus, diarrhea, and stomatitis.
- The cutaneous lesions in this phase of the disease can easily be confused with nonspecific dermatitis, which occurs more often in patients with diabetes mellitus.
- Poorly defined symptoms of this condition sometimes make it difficult to establish a correct differential diagnosis (eg, with a pancreatic adenocarcinoma that causes weight loss, the early stages of dyspepsia, and the later stages of jaundice).
- The so-called 4D syndrome consists of diabetes, dermatitis, DVT (deep vein thrombosis), and depression.
Physical
- The most frequent clinical sign observed in patients with glucagonoma is necrolytic migratory erythema (NME), which is present in 80% of cases and is characterized by an erythematous and swollen area of skin.
- The symptoms that appear on the skin include (in order of appearance) maculopapular, ringed lesions and blisters that breach after a few days, as well as, possibly, pustular evolution due to bacterial superinfection. The lesions are often confluent, evolve in a period of 1-2 weeks, and are strongly pruritic and painful. They heal with hyperpigmentation.
- NME initially occurs in areas of the skin that are subject to friction and pressure, such as the feet and legs, the hands and forearms, and the buttocks, pubic area, groin area, and perineal area. Mucocutaneous lesions are frequently observed as atrophic glossitis, commissural cheilitis, stomatitis, balanoposthitis or vulvovaginitis, and ungual and hair dystrophies.
- Aside from NME, symptoms often observed in glucagonoma are diabetes or glucose intolerance (in 80-90% of cases) and a weight loss of 5-15 kg (in most patients).
- Symptoms that occur less frequently are venous thromboses, in particular DVT (in approximately 40% of cases); intestinal motility alterations with diarrhea and abdominal pains (in approximately 20% of cases); cachexia; anemia; scotomata and other optical disturbances; and psychical disturbances, such as insomnia, depression, disorientation, lethargy, and bradylalia.
Causes
The causes of this pathology remain unknown, although some genetic factors could play an important role, especially in patients who have a family history of multiple endocrine neoplasia type 1 syndrome.
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References
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Further Reading
Keywords
glucagonoma, glucagon, glucagonoma syndrome, alpha-cell tumor, alpha-cell adenoma, alpha cell, alpha cells, alpha-2 cell, alpha-2 cells, diabetes, diabetes mellitus, diabetes mellitus type 2, pancreas, hyperglycemia, hyperglycemic, neuroendocrine, 4D syndrome, neuroendocrine tumor, islet cell, islet cells, islet cell pancreatic tumor, pancreatic tumor, pancreas tumor, insulin, insulinoma, glucagon overproduction, hypoaminoacidemia, weight loss, normochromic and normocytic anemia, necrolytic migratory erythema, NME, hyperglucagonemia, pancreas, octreotide, Sandostatin, peptide hormone, bioactive peptide, tumor of the pancreas, multiple endocrine neoplasia type1, MEN I, islet celltumor
