Mahvash disease

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Mahvash disease
Other namesGlucagon cell hyperplasia and neoplasia
Mahvash disease.tif
Photographic image of the numerous islets of various sizes in the pancreas of a patient with Mahvash disease

Mahvash disease is an autosomal recessive, hereditary pancreatic neuroendocrine tumor syndrome. [1] [2] The genetic defect that causes Mahvash disease is biallelic inactivating mutations of the glucagon receptor gene (GCGR). [3] Mahvash disease was discovered by American physician Run Yu and his colleagues in 2008. [4] Mahvash disease is very rare. There have been approximately 15 cases of Mahvash disease described in detail by the end of 2023. [3] [4] [5] [6] [7] [8] [9] [10] [11] 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. [12] Some patients with “glucagon cell hyperplasia and neoplasia” do not have glucagon receptor mutations.

Contents

Signs and symptoms

Most patients with Mahvash disease are diagnosed in adulthood. Patients with Mahvash disease usually present with vague abdominal discomfort. Imaging with CT or MRI identifies a very large pancreas with one or more tumors. Biochemical testing shows marked hyperglucagonemia (hundreds-fold elevated). If the tumors are resected, they are found to be neuroendocrine tumors that usually express glucagon. In the tumor margin, pancreatic alpha cell hyperplasia is pervasive, numerous large islets composed of mostly alpha cells are evident, and multiple microadenomas and small neuroendocrine tumors often are present. The pancreatic neuroendocrine tumors are the main health concern for patients with Mahvash disease. Although the tumors commonly are indolent, death due to liver metastasis has been reported. [3] In patients with complete loss of glucagon receptor function, Mahvash disease can present at younger age with portal hypertension and hepatic encephalopathy. [11]

Pathogenesis

Mahvash disease is a form of reactive pancreatic alpha cell hyperplasia. [12] The loss of normal glucagon signaling (particularly in the liver) due to inactive glucagon receptor results in enzymatic changes in the liver so that the liver releases abnormally large quantities of amino acids into the circulation. [13] High concentration of amino acids in the circulation (hyperaminoacidemia) stimulates the pancreatic alpha cells (the cells that normally produce glucagon) to proliferate and to produce and release much more glucagon. The enormous proliferative activity of the pancreatic alpha cells predisposes them to tumor formation. [14] All patients with Mahvash disease have hyperaminoacidemia, hyperglucagonemia (high concentration of glucagon in the circulation), and pancreatic alpha cell hyperplasia, and develop pancreatic neuroendocrine tumors in adulthood. [3] The pathogenesis of portal hypertension and hepatic encephalopathy is not clear yet. [11]

Diagnosis

A large pancreas with marked hyperglucagonemia in an adult makes the diagnosis of Mahvash disease very likely. The existence of pancreatic tumors makes the diagnosis even more likely. Histologically, pancreatic alpha cell hyperplasia and microadenomas suggest the diagnosis of Mahvash disease. The final diagnosis of Mahvash disease requires mutational analysis of the glucagon receptor gene. [3]

Treatment

The treatment of Mahvash disease currently focuses on managing the pancreatic neuroendocrine tumors. Small tumors can be monitored but large ones need to be resected. As patients with Mahvash disease have life-long risk of developing pancreatic neuroendocrine tumors, they need to undergo periodic biochemical testing and imaging. [3] Liver transplant is a safe and effective treatment for patients with portal hypertension and hepatic encephalopathy. [11]

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 in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypothalamus is the neural control center for all endocrine systems.

<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 the 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 rare 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">Pancreatic cancer</span> Type of endocrine gland cancer

Pancreatic cancer arises when cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a mass. These cancerous cells have the ability to invade other parts of the body. A number of types of pancreatic cancer are known.

<span class="mw-page-title-main">Glucokinase</span> Enzyme participating to the regulation of carbohydrate metabolism

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

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

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.

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. However, about 10% of cases are associated with multiple endocrine neoplasia type 1 (MEN-1) syndrome.

<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. Individuals suffering from this disorder are prone to developing multiple endocrine and nonendocrine tumors. It was first described by Paul Wermer in 1954.

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

Gastrinomas are neuroendocrine tumors (NETs), usually located in the duodenum or pancreas, that secrete gastrin and cause a clinical syndrome known as Zollinger–Ellison syndrome (ZES). A large number of gastrinomas develop in the pancreas or duodenum, with near-equal frequency, and approximately 10% arise as primary neoplasms in lymph nodes of the pancreaticoduodenal region.

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

Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lung, and the rest of the body.

<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.

<span class="mw-page-title-main">Glucagon receptor</span> Protein-coding gene in the species Homo sapiens

The glucagon receptor is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors, coupled to G alpha i, Gs and to a lesser extent G alpha q. Stimulation of the receptor results in the activation of adenylate cyclase and phospholipase C and in increased levels of the secondary messengers intracellular cAMP and calcium. In humans, the glucagon receptor is encoded by the GCGR gene.

<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 play key roles in the intestinal immune and metabolic responses in these enteroendocrine cells via their fermentation product, acetate.

<span class="mw-page-title-main">Glucagon-like peptide-1 receptor</span> Receptor activated by peptide hormone GLP-1

The glucagon-like peptide-1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of GPCRs. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.

<span class="mw-page-title-main">MEN1</span> Protein

Menin is a protein that in humans is encoded by the MEN1 gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1 and has autosomal dominant inheritance. Variations in the MEN1 gene can cause pituitary adenomas, hyperparathyroidism, pancreatic neuroendocrine tumors, gastrinoma, and adrenocortical cancers.

<span class="mw-page-title-main">Somatostatin receptor 2</span> Protein-coding gene in the species Homo sapiens

Somatostatin receptor type 2 is a protein that in humans is encoded by the SSTR2 gene.

<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.

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. ↑ "Mahvash disease, Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. National Institutes of Health . Retrieved 2018-12-08.
  2. ↑ "MAHVASH DISEASE; MVAH, Online Mendelian Inheritance in Man (OMIM)". www.omim.org. Johns Hopkins University . Retrieved 2023-11-23.
  3. 1 2 3 4 5 6 Yu R (2018). "Mahvash Disease: 10 Years After Discovery". Pancreas. 47 (5): 511–515. doi:10.1097/MPA.0000000000001044. PMID   29702528. S2CID   13871451.
  4. 1 2 Zhou C, Dhall D, Nissen NN, Chen CR, Yu R (November 2009). "Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor". Pancreas. 38 (8): 941–6. doi:10.1097/MPA.0b013e3181b2bb03. PMC   2767399 . PMID   19657311.
  5. ↑ Sipos B, Sperveslage J, Anlauf M, Hoffmeister M, Henopp T, Buch S, Hampe J, Weber A, Hammel P, Couvelard A, Höbling W, Lieb W, Boehm BO, Klöppel G (May 2015). "Glucagon cell hyperplasia and neoplasia with and without glucagon receptor mutations". The Journal of Clinical Endocrinology and Metabolism. 100 (5): E783-8. doi: 10.1210/jc.2014-4405 . PMID   25695890.
  6. ↑ Larger E, Wewer Albrechtsen NJ, Hansen LH, Gelling RW, Capeau J, Deacon CF, Madsen OD, Yakushiji F, De Meyts P, Holst JJ, Nishimura E (2016). "Pancreatic α-cell hyperplasia and hyperglucagonemia due to a glucagon receptor splice mutation". Endocrinology, Diabetes & Metabolism Case Reports. 2016: 0081. doi:10.1530/EDM-16-0081. PMC   5118975 . PMID   27933176.
  7. ↑ Gild ML, Tsang V, Samra J, Clifton-Bligh RJ, Tacon L, Gill AJ (September 2018). "Hypercalcemia in Glucagon Cell Hyperplasia and Neoplasia (Mahvash Syndrome): A New Association". The Journal of Clinical Endocrinology and Metabolism. 103 (9): 3119–3123. doi: 10.1210/jc.2018-01074 . PMID   30032256.
  8. ↑ Li H, Zhao L, Singh R, Ham JN, Fadoju DO, Bean LJ, Zhang Y, Xu Y, Xu HE, Gambello MJ (December 2018). "GCGR is identified by newborn screening of elevated arginine". Molecular Genetics and Metabolism Reports. 17: 46–52. doi:10.1016/j.ymgmr.2018.09.006. PMC   6171159 . PMID   30294546.
  9. ↑ Amano S, Suenaga S, Hamamoto K, Yada S, Tsuyama T, Shinoda S, Tanaka Y, Takemoto Y, Harada E, Tanabe K, Asahara S, Hoshii K, Takami T (March 2023). "A case of multiple glucagonomas with no clinical manifestations of excess glucagon despite hyperglucagonemia". DEN Open. 3 (1): e230. doi: 10.1002/deo2.230 . PMC   10043567 . PMID   36998346.
  10. ↑ Deng W, He M, Wang W, Xue H (August 2023). "Gastrointestinal: Pancreatic NETs with GCGR heterozygous mutation: Mahvash disease". J Gastroenterol Hepatol. 38 (8): 1243. doi: 10.1111/jgh.16104 . PMID   36698259.
  11. 1 2 3 4 Robbins J, Halegoua-DeMarzio D, Basu Mallick A, Vijayvergia N, Ganetzky R, Lavu H, Giri VN, Miller J, Maley W, Shah AP, DiMeglio M, Ambelil M, Yu R, Sato T, Lefler DS (November 2023). "Liver transplantation in a woman with Mahvash disease". New England Journal of Medicine. 389 (21): 1972–8. doi: 10.1056/NEJMoa2303226 . PMID   37991855.
  12. 1 2 Yu R (March 2014). "Pancreatic α-cell hyperplasia: facts and myths". The Journal of Clinical Endocrinology and Metabolism. 99 (3): 748–56. doi: 10.1210/jc.2013-2952 . PMID   24285676.
  13. ↑ Solloway MJ, Madjidi A, Gu C, Eastham-Anderson J, Clarke HJ, Kljavin N, et al. (July 2015). "Glucagon Couples Hepatic Amino Acid Catabolism to mTOR-Dependent Regulation of α-Cell Mass". Cell Reports. 12 (3): 495–510. doi: 10.1016/j.celrep.2015.06.034 . PMID   26166562.
  14. ↑ Yu R, Dhall D, Nissen NN, Zhou C, Ren SG (2011). "Pancreatic neuroendocrine tumors in glucagon receptor-deficient mice". PLOS ONE. 6 (8): e23397. Bibcode:2011PLoSO...623397Y. doi: 10.1371/journal.pone.0023397 . PMC   3154424 . PMID   21853126.
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