:Intrinsic factor

{{Short description|Glycoprotein produced in the stomach which binds to vitamin B12}}

Intrinsic factor (IF), also known as cobalamin binding intrinsic factor, or gastric intrinsic factor (GIF), is a glycoprotein produced by the parietal cells (in humans) or chief cells (in rodents) of the stomach. It is necessary for the absorption of vitamin B₁₂ later on in the distal ileum of the small intestine.{{cite book | vauthors = Pocock G, Richards C | title = Human Physiology: The Basis of Medicine | isbn = 978-019-856878-0 | pages = 230 | date = 2006 | publisher = Oxford University Press | edition = 3rd }} In humans, the gastric intrinsic factor protein is encoded by the CBLIF gene.{{cite web | title = CBLIF - Cobalamin binding intrinsic factor precursor - Homo sapiens (Human) - CBLIF gene & protein | url = https://www.uniprot.org/uniprot/P27352 | website = www.uniprot.org | access-date = 15 March 2022 | language = en }} Haptocorrin (transcobalamin I) is another glycoprotein secreted by the salivary glands which binds to vitamin B₁₂. Vitamin B₁₂ is acid-sensitive and in binding to haptocorrin it can safely pass through the acidic stomach to the duodenum.

In the less acidic environment of the small intestine, pancreatic enzymes digest the glycoprotein carrier and vitamin B₁₂ can then bind to intrinsic factor. This new complex is then absorbed by the epithelial cells (enterocytes) of the ileum.{{cite book | vauthors = Fedosov SN | chapter = Physiological and Molecular Aspects of Cobalamin Transport | title = Water Soluble Vitamins | volume = 56 | pages = 347–367 | year = 2012 | pmid = 22116708 | doi = 10.1007/978-94-007-2199-9_18 | department = (review) | series = Subcellular Biochemistry | isbn = 978-94-007-2198-2 }} Inside the cells, vitamin B₁₂ dissociates once again and binds to another protein, transcobalamin II; the new complex can then exit the epithelial cells to be carried to the liver.{{cite journal | vauthors = Alpers DH, Russell-Jones G | title = Gastric intrinsic factor: the gastric and small intestinal stages of cobalamin absorption. A personal journey | journal = Biochimie | volume = 95 | issue = 5 | pages = 989–994 | date = May 2013 | pmid = 23274574 | doi = 10.1016/j.biochi.2012.12.006 | department = (review) }}

Site of secretion

Intrinsic factor is secreted by parietal cells within the stomach, and so is present in the gastric juice as well as in the gastric mucous membrane.{{cite book | vauthors = Sharma K | chapter = Gastrointestinal System | title = Textbook Of Biochemistry, Biotechnology, Allied And Molecular Medicine | pages = 632 | date = 2016 | veditors = Talwar G, Hasnain SE, Sarin SK | publisher = PHI Learning Private Limited | isbn = 978-81-203-5125-7 | edition = 4th | chapter-url = https://books.google.com/books?id=mVuNCwAAQBAJ&q=gastric+intrinsic+factor+secreted++parietal+cells&pg=PA632 | department = (secondary) }} The optimum pH for its action is approximately 7.{{cite journal | vauthors = Shum HY, O'Neill BJ, Streeter AM | title = Effect of pH changes on the binding of vitamin B12 by intrinsic factor | journal = Journal of Clinical Pathology | volume = 24 | issue = 3 | pages = 239–243 | date = Apr 1971 | pmid = 5103294 | pmc = 476962 | doi = 10.1136/jcp.24.3.239 }} Its concentration does not correlate with the amount of HCl or pepsin in the gastric juice, e.g., intrinsic factor may be present even when pepsin is largely absent.{{cite journal | vauthors = Poliner IJ, Spiro HM, Pask BA, Trocchio N | title = The independent secretion of acid, pepsin, and intrinsic factor by the human stomach | journal = Gastroenterology | volume = 34 | issue = 2 | pages = 196–209 | date = Feb 1958 | pmid = 13512593 | doi = 10.1016/S0016-5085(58)80102-X | department = (primary) }} The site of formation of the intrinsic factor varies in different species. In pigs it is obtained from the pylorus and beginning of the duodenum;{{cite journal | vauthors = Heatley NG, Florey H, Turnbull A, Jennings MA, Watson GM, Wakisaka G, Witts LJ | title = Intrinsic factor in the pyloric and duodenal secretions of the pig | journal = Lancet | location = London, England | volume = 267 | issue = 6838 | pages = 578–580 | date = Sep 1954 | pmid = 13193076 | doi = 10.1016/S0140-6736(54)90355-4 | department = (primary) }} in human beings it is present in the fundus and body of the stomach.{{cite journal | vauthors = Howard TA, Misra DN, Grove M, Becich MJ, Shao JS, Gordon M, Alpers DH | title = Human gastric intrinsic factor expression is not restricted to parietal cells | journal = Journal of Anatomy | volume = 189 | issue = Pt 2 | pages = 303–313 | date = Oct 1996 | pmid = 8886952 | pmc = 1167747 | department = (primary) }}

The limited amount of normal human gastric intrinsic factor limits normal efficient absorption of B₁₂ to about 2 μg per meal, a nominally adequate intake of B₁₂.{{cite journal | vauthors = Watanabe F | title = Vitamin B12 sources and bioavailability | journal = Experimental Biology and Medicine | location = Maywood, N.J. | volume = 232 | issue = 10 | pages = 1266–1274 | date = Nov 2007 | pmid = 17959839 | doi = 10.3181/0703-MR-67 | s2cid = 14732788 | department = (review) }}

Insufficiency

In pernicious anemia, which is usually an autoimmune disease, autoantibodies directed against intrinsic factor or parietal cells themselves lead to an intrinsic factor deficiency, malabsorption of vitamin B₁₂, and subsequent megaloblastic anemia.{{cite journal | vauthors = Osborne D, Sobczyńska-Malefora A | title = Autoimmune mechanisms in pernicious anaemia & thyroid disease | journal = Autoimmunity Reviews | volume = 14 | issue = 9 | pages = 763–768 | date = Sep 2015 | pmid = 25936607 | doi = 10.1016/j.autrev.2015.04.011 | department = (review) }} Atrophic gastritis can also cause intrinsic factor deficiency and anemia through damage to the parietal cells of the stomach wall.{{cite journal | vauthors = Neumann WL, Coss E, Rugge M, Genta RM | title = Autoimmune atrophic gastritis--pathogenesis, pathology and management | journal = Nature Reviews. Gastroenterology & Hepatology | volume = 10 | issue = 9 | pages = 529–541 | date = Sep 2013 | pmid = 23774773 | doi = 10.1038/nrgastro.2013.101 | s2cid = 205487577 | department = (review) }} Pancreatic exocrine insufficiency can interfere with normal dissociation of vitamin B₁₂ from its binding proteins in the small intestine, preventing its absorption via the intrinsic factor complex.{{cite journal | vauthors = Guéant JL, Champigneulle B, Gaucher P, Nicolas JP | title = Malabsorption of vitamin B12 in pancreatic insufficiency of the adult and of the child | journal = Pancreas | volume = 5 | issue = 5 | pages = 559–567 | date = Sep 1990 | pmid = 2235967 | doi = 10.1097/00006676-199009000-00011 | s2cid = 9077477 | department = (review) }} Other risk factors contributing to pernicious anemia are anything that damages or removes a portion of the stomach's parietal cells, including bariatric surgery, gastric tumors, gastric ulcers, and excessive consumption of alcohol.{{cn|date=November 2021}}

Mutations in the GIF gene are responsible for a rare inheritable disease called intrinsic factor deficiency{{cite web | title = Intrinsic factor deficiency {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program|url=https://rarediseases.info.nih.gov/diseases/3024/intrinsic-factor-deficiency|website=rarediseases.info.nih.gov|access-date=2022-03-15|archive-date=2022-05-27|archive-url=https://web.archive.org/web/20220527032557/https://rarediseases.info.nih.gov/diseases/3024/intrinsic-factor-deficiency/|url-status=dead}} which results in malabsorption of vitamin B₁₂.{{cite journal | vauthors = Kozyraki R, Cases O | title = Vitamin B12 absorption: mammalian physiology and acquired and inherited disorders | journal = Biochimie | volume = 95 | issue = 5 | pages = 1002–1007 | date = May 2013 | pmid = 23178706 | doi = 10.1016/j.biochi.2012.11.004 | department = (review) }}

= Treatment =

In most countries, intramuscular injections of vitamin B₁₂ are used to treat pernicious anemia. Orally administered vitamin B₁₂ is absorbed without intrinsic factor, but at levels of less than one percent than if intrinsic factor is present.{{cite journal | vauthors = Alpers DH | title = What is new in vitamin B(12)? | journal = Current Opinion in Gastroenterology | volume = 21 | issue = 2 | pages = 183–186 | date = Mar 2005 | pmid = 15711210 | doi = 10.1097/01.mog.0000148331.96932.44 | department = (review) }} Despite the low amounts absorbed, oral vitamin B₁₂ therapy is effective at reducing symptoms of pernicious anemia.{{cite journal | vauthors = Andrès E, Fothergill H, Mecili M | title = Efficacy of oral cobalamin (vitamin B12) therapy | journal = Expert Opinion on Pharmacotherapy | volume = 11 | issue = 2 | pages = 249–256 | date = Feb 2010 | pmid = 20088746 | doi = 10.1517/14656560903456053 | s2cid = 37088496 | department = (review) }}

Vitamin B₁₂ can also be given sublingually, but there is no evidence that this route of administration is superior to the oral route,{{cite journal | vauthors = Sharabi A, Cohen E, Sulkes J, Garty M | title = Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route | journal = British Journal of Clinical Pharmacology | volume = 56 | issue = 6 | pages = 635–638 | date = Dec 2003 | pmid = 14616423 | pmc = 1884303 | doi = 10.1046/j.1365-2125.2003.01907.x | department = (primary) }} and only Canada and Sweden routinely prescribe this route of administration.{{cite journal | vauthors = Shipton MJ, Thachil J | title = Vitamin B12 deficiency - A 21st century perspective | journal = Clinical Medicine | location = London, England | volume = 15 | issue = 2 | pages = 145–150 | date = Apr 2015 | pmid = 25824066 | pmc = 4953733 | doi = 10.7861/clinmedicine.15-2-145 | department = (review) }}

Because vitamin B₁₂ absorption is a multistep process that involves the stomach, pancreas and small intestine, and is mediated by two carriers: Haptocorrin and intrinsic factor, and because Haptocorrin (transcobalamin I) binds to vitamin B₁₂, and Vitamin B₁₂ is acid-sensitive, when vitamin B₁₂ binds to Haptocorrin it can safely pass through the acidic stomach to the duodenum, given time in the mouth.

References

External links

{{MeshName|Intrinsic+factor}}
{{MedlinePlusEncyclopedia|002381}}
{{PDBe-KB2|P27352|Cobalamin binding intrinsic factor}}

Category:Hematology

Category:Gastroenterology

Category:Genes mutated in mice

Category:Stomach