Glucagonoma

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Glucagonoma
Specialty Oncology

Glucagonoma is a very rare tumor of the pancreatic alpha cells that results in the overproduction of the hormone , glucagon. Typically associated with a rash called necrolytic migratory erythema, weight loss, and mild diabetes mellitus, most people with glucagonoma contract it spontaneously. [1] However, about 10% of cases are associated with multiple endocrine neoplasia type 1 (MEN-1) syndrome. [1]

Contents

Causes

Although the cause of glucagonoma is unknown, some genetic factors may lead to the condition. A family history of multiple endocrine neoplasia type 1 (MEN1) is a risk factor. [1] Additionally, those with Mahvash disease have an increased risk for glucagonoma, as the glucagon receptor gene (GCGR) is mutated. [2]

Mechanism

Glucagonoma results from the overproduction of glucagon, a peptide hormone located in the pancreatic alpha cells. [3] Classic symptoms include, but are not limited to, necrolytic migratory erythema (NME), diabetes mellitus, and weight loss. [3] NME presents in about 70% of cases of glucagonoma, [4] and is characterized by erythematous lesions over the distal extremities and the groin area. [3] NME has occasionally been observed in people who do not have glucagonoma. [2] People who develop glucagonoma from Mahvash disease also do not develop NME, implying that working glucagon receptors are needed in order for NME to be present in a person. [3] Weight loss, the most commonly associated effect with glucagonoma, results from the glucagon hormone, which prevents the uptake of glucose by somatic cells. [3] Diabetes is not present in all cases of glucagonoma, [3] but does frequently result from the insulin and glucagon imbalance. [5]

Diagnosis

The presence of glucagonoma syndrome, the symptoms that accompany the pancreatic tumor, as well as elevated levels of glucagon in the blood, are what is used to diagnose glucagonoma. [6] When a person presents with a blood glucagon concentration greater than 500 mg/mL along with the glucagonoma syndrome, a diagnosis can be established. [3] It is important to note that not all cases of hyperglucagonemia will lead to a diagnosis of glucagonoma. [3] Elevated blood levels of glucagon are associated with other disorders like pancreatitis and kidney failure. [3]

About 60% of people diagnosed with glucagonoma are women. [7] Most of those that are diagnosed are between 45–60 years of age. [7]

Treatment

People who are diagnosed with sporadic glucagonoma often have an increased mortality rate compared to those with MEN1, as the latter group will go to the doctor for periodic visits. [4] People whose tumor have metastasized cannot easily be treated as the tumor is resistant to chemotherapy. [4] The only curative therapy for glucagonoma is surgery, and even this is not always successful. [6] [4]

Heightened glucagon secretion can be treated with the administration of octreotide, a somatostatin analog, which inhibits the release of glucagon. [8] Doxorubicin and streptozotocin have also been used successfully to selectively damage alpha cells of the pancreatic islets. These do not destroy the tumor, but help to minimize progression of symptoms. [9]

History

Fewer than 251 cases of glucagonoma have been described in the literature since their first description by Becker in 1942. Because of its rarity (fewer than one in 20 million worldwide), long-term survival rates remain unknown. Glucagonoma accounts for approximately 1% of neuroendocrine tumors, although this may be an underestimate given that glucagonoma is associated with non-specific symptoms. [2]

Related Research Articles

<span class="mw-page-title-main">Endocrine system</span> Hormone-producing glands of a body

The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neural control center for all endocrine systems. In humans, the major endocrine glands are the thyroid gland and the adrenal glands. The study of the endocrine system and its disorders is known as endocrinology.

<span class="mw-page-title-main">Pancreas</span> Organ of the digestive system and endocrine system of vertebrates

The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an endocrine and a digestive exocrine function. 99% of the pancreas is exocrine and 1% is endocrine. As an endocrine gland, it functions mostly to regulate blood sugar levels, secreting the hormones insulin, glucagon, somatostatin, and pancreatic polypeptide. As a part of the digestive system, it functions as an exocrine gland secreting pancreatic juice into the duodenum through the pancreatic duct. This juice contains bicarbonate, which neutralizes acid entering the duodenum from the stomach; and digestive enzymes, which break down carbohydrates, proteins, and fats in food entering the duodenum from the stomach.

<span class="mw-page-title-main">Pancreatic islets</span> Regions of the pancreas

The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% of the pancreas volume and receive 10–15% of its blood flow. The pancreatic islets are arranged in density routes throughout the human pancreas, and are important in the metabolism of glucose.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Multiple endocrine neoplasia</span> Medical condition

Multiple endocrine neoplasia is a condition which encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign. Benign or malignant tumors of nonendocrine tissues occur as components of some of these tumor syndromes.

<span class="mw-page-title-main">Zollinger–Ellison syndrome</span> Condition in which tumours stimulate excessive gastric acid production

Zollinger–Ellison syndrome is a disease in which tumors cause the stomach to produce too much acid, resulting in peptic ulcers. Symptoms include abdominal pain and diarrhea.

<span class="mw-page-title-main">Alpha cell</span>

Alpha cells(α cells) are endocrine cells that are found in the Islets of Langerhans in the pancreas. Alpha cells secrete the peptide hormone glucagon in order to increase glucose levels in the blood stream.

<span class="mw-page-title-main">Insulinoma</span> Medical condition

An insulinoma is a tumour of the pancreas that is derived from beta cells and secretes insulin. It is a rare form of a neuroendocrine tumour. Most insulinomas are benign in that they grow exclusively at their origin within the pancreas, but a minority metastasize. Insulinomas are one of the functional pancreatic neuroendocrine tumour (PNET) group. In the Medical Subject Headings classification, insulinoma is the only subtype of "islet cell adenoma".

<span class="mw-page-title-main">Octreotide</span> Octapeptide that mimics natural somatostatin pharmacologically

Octreotide, sold under the brand name Sandostatin among others, is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. It was first synthesized in 1979 by the chemist Wilfried Bauer, and binds predominantly to the somatostatin receptors SSTR2 and SSTR5.

<span class="mw-page-title-main">Multiple endocrine neoplasia type 1</span> Medical condition

Multiple endocrine neoplasia type 1 (MEN-1) is one of a group of disorders, the multiple endocrine neoplasias, that affect the endocrine system through development of neoplastic lesions in pituitary, parathyroid gland and pancreas. It was first described by Paul Wermer in 1954.

A VIPoma or vipoma is a rare endocrine tumor that overproduces vasoactive intestinal peptide. The incidence is about 1 per 10,000,000 per year. VIPomas usually originate from the non-β islet cells of the pancreas. They are sometimes associated with multiple endocrine neoplasia type 1. Roughly 50–75% of VIPomas are malignant, but even when they are benign, they are problematic because they tend to cause a specific syndrome: the massive amounts of VIP cause a syndrome of profound and chronic watery diarrhea and resultant dehydration, hypokalemia, achlorhydria, acidosis, flushing and hypotension, hypercalcemia, and hyperglycemia. This syndrome is called Verner–Morrison syndrome (VMS), WDHA syndrome, or pancreatic cholera syndrome (PCS). The eponym reflects the physicians who first described the syndrome.

Pancreatic diseases are diseases that affect the pancreas, an organ in most vertebrates and in humans and other mammals located in the abdomen. The pancreas plays a role in the digestive and endocrine system, producing enzymes which aid the digestion process and the hormone insulin, which regulates blood sugar levels. The most common pancreatic disease is pancreatitis, an inflammation of the pancreas which could come in acute or chronic form. Other pancreatic diseases include diabetes mellitus, exocrine pancreatic insufficiency, cystic fibrosis, pseudocysts, cysts, congenital malformations, tumors including pancreatic cancer, and hemosuccus pancreaticus.

<span class="mw-page-title-main">Necrolytic migratory erythema</span> Medical condition

Necrolytic migratory erythema is a red, blistering rash that spreads across the skin. It particularly affects the skin around the mouth and distal extremities; but may also be found on the lower abdomen, buttocks, perineum, and groin. It is strongly associated with glucagonoma, a glucagon-producing tumor of the pancreas, but is also seen in a number of other conditions including liver disease and intestinal malabsorption.

Somatostatinomas are a tumor of the delta cells of the endocrine pancreas that produces somatostatin. Increased levels of somatostatin inhibit pancreatic hormones and gastrointestinal hormones. Thus, somatostatinomas are associated with mild diabetes mellitus, steatorrhoea and gallstones, and achlorhydria. Somatostatinomas are commonly found in the head of pancreas. Only ten percent of somatostatinomas are functional tumours [9], and 60–70% of tumours are malignant. Nearly two-thirds of patients with malignant somatostatinomas will present with metastatic disease.

<span class="mw-page-title-main">Enteroendocrine cell</span>

Enteroendocrine cells are specialized cells of the gastrointestinal tract and pancreas with endocrine function. They produce gastrointestinal hormones or peptides in response to various stimuli and release them into the bloodstream for systemic effect, diffuse them as local messengers, or transmit them to the enteric nervous system to activate nervous responses. Enteroendocrine cells of the intestine are the most numerous endocrine cells of the body. They constitute an enteric endocrine system as a subset of the endocrine system just as the enteric nervous system is a subset of the nervous system. In a sense they are known to act as chemoreceptors, initiating digestive actions and detecting harmful substances and initiating protective responses. Enteroendocrine cells are located in the stomach, in the intestine and in the pancreas. Microbiota plays key roles in the intestinal immune and metabolic responses in these enteroendocrine cells via their fermentation product, acetate.

<span class="mw-page-title-main">PDX1</span> A protein involved in the pancreas and duodenum differentiation

PDX1, also known as insulin promoter factor 1, is a transcription factor in the ParaHox gene cluster. In vertebrates, Pdx1 is necessary for pancreatic development, including β-cell maturation, and duodenal differentiation. In humans this protein is encoded by the PDX1 gene, which was formerly known as IPF1. The gene was originally identified in the clawed frog Xenopus laevis and is present widely across the evolutionary diversity of bilaterian animals, although it has been lost in evolution in arthropods and nematodes. Despite the gene name being Pdx1, there is no Pdx2 gene in most animals; single-copy Pdx1 orthologs have been identified in all mammals. Coelacanth and cartilaginous fish are, so far, the only vertebrates shown to have two Pdx genes, Pdx1 and Pdx2.

<span class="mw-page-title-main">Pancreatic neuroendocrine tumor</span> Medical condition

Pancreatic neuroendocrine tumours, often referred to as "islet cell tumours", or "pancreatic endocrine tumours" are neuroendocrine neoplasms that arise from cells of the endocrine (hormonal) and nervous system within the pancreas.

<span class="mw-page-title-main">Brockmann body</span> Endocrine organ in some teleost fish

Brockmann body is an endocrine organ in some teleost fish, and is composed of a collection of islet tissues. The islet tissues are in turn composed of endocrine cells which are the principal sites of insulin synthesis. They are distributed around the spleen and the large intestine. They also secrete other hormones such as glucagon and somatostatin. Hence, Brochmann body is the centre of control of blood glucose level in these fishes. Glucagon is also produced from the intestine, but Brockmann body is the major source. Increased level of glucose stimulate the Brockmann body to release insulin, while inhibiting glucagon. Somatostatin released from Brockmann body inhibits cells to produce insulin and glucagon. In addition it inhibits release of growth hormone from the pituitary. It is named after a German physician Heinrich Brochmann who discovered it in 1848.

<span class="mw-page-title-main">Mahvash disease</span> Medical condition

Mahvash disease is an autosomal recessive, hereditary pancreatic neuroendocrine tumor syndrome. The genetic defect that causes Mahvash disease is biallelic inactivating mutations of the glucagon receptor gene (GCGR). Mahvash disease was discovered by American physician Run Yu and his colleagues in 2008. Mahvash disease is very rare. There have been over 10 cases of Mahvash disease described by the end of 2018. Mahvash disease occurs in both females and males. Mahvash disease is also called “glucagon cell hyperplasia and neoplasia” or “glucagon cell adenomatosis” by some authors but Mahvash disease is a distinct disease entity while the two alternative terms are mostly histological descriptions. Some patients with “glucagon cell hyperplasia and neoplasia” do not have glucagon receptor mutations.

Alpha cell hyperplasia is defined as a specific, diffuse, and overwhelming (many-fold) increase of the number of pancreatic alpha cells. The pancreatic islets normally contain 4 types of cells; the alpha cells produce and release glucagon, a hormone that regulates the metabolism of glucose and amino acids. Although first described in early 1990s, alpha cell hyperplasia had remained an esoteric topic until the mid-2010s. Based on the pathogenesis and clinical presentation, alpha cell hyperplasia can be divided into 3 types: reactive, nonfunctional, and functional.

References

  1. 1 2 3 Vinik, Aaron; Pacak, Karel; Feliberti, Eric; Perry, Roger R. (2000), Feingold, Kenneth R.; Anawalt, Bradley; Boyce, Alison; Chrousos, George (eds.), "Glucagonoma Syndrome", Endotext, MDText.com, Inc., PMID   25905270 , retrieved 2019-09-24
  2. 1 2 3 "Glucagonoma: Practice Essentials, Pathophysiology, Epidemiology". 2019-02-01.{{cite journal}}: Cite journal requires |journal= (help)
  3. 1 2 3 4 5 6 7 8 9 Albrechtsen, Nicolai Jacob Wewer; Challis, Benjamin; Damjanov, Ivan; Holst, Jens Juul (2016-02-01). "Do glucagonomas always produce glucagon?". Bosnian Journal of Basic Medical Sciences. 16 (1): 1–7. doi:10.17305/bjbms.2015.794. ISSN   1840-4812. PMC   4765933 . PMID   26773171.
  4. 1 2 3 4 van Beek AP, de Haas ER, van Vloten WA, Lips CJ, Roijers JF, Canninga-van Dijk MR (November 2004). "The glucagonoma syndrome and necrolytic migratory erythema: a clinical review". Eur. J. Endocrinol. 151 (5): 531–7. doi: 10.1530/eje.0.1510531 . PMID   15538929.
  5. ↑ Koike N, Hatori T, Imaizumi T, Harada N, Fukuda A, Takasaki K, Iwamoto Y (2003). "Malignant glucagonoma of the pancreas diagnoses through anemia and diabetes mellitus". Journal of Hepato-Biliary-Pancreatic Surgery. 10 (1): 101–5. doi:10.1007/s10534-002-0791-y. PMID   12918465.
  6. 1 2 Song, Xujun; Zheng, Suli; Yang, Gang; Xiong, Guangbing; Cao, Zhe; Feng, Mengyu; Zhang, Taiping; Zhao, Yupei (March 2018). "Glucagonoma and the glucagonoma syndrome". Oncology Letters. 15 (3): 2749–2755. doi:10.3892/ol.2017.7703. ISSN   1792-1074. PMC   5778850 . PMID   29435000.
  7. 1 2 Adams, David R.; Miller, Jeffrey J.; Seraphin, Kathryn E. (2005-10-01). "Glucagonoma syndrome". Journal of the American Academy of Dermatology. 53 (4): 690–691. doi:10.1016/j.jaad.2005.04.071. ISSN   0190-9622. PMID   16198793.
  8. ↑ Moattari AR, Cho K, Vinik AI (1990). "Somatostatin analogue in treatment of coexisting glucagonoma and pancreatic pseudocyst: dissociation of responses". Surgery. 108 (3): 581–7. PMID   2168587.
  9. ↑ "Glucagonoma". The Lecturio Medical Concept Library. Retrieved 23 July 2021.
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