Editing Intrinsic factor

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

'''Intrinsic factor''' ('''IF'''), also known as  '''cobalamin binding intrinsic factor''',<ref name="uniprot" /> or '''gastric intrinsic factor''' ('''GIF'''), is a [[glycoprotein]] produced by the [[parietal cell]]s (in humans) or chief cells (in rodents) of the [[stomach]]. It is necessary for the absorption of [[vitamin B12|vitamin B<sub>12</sub>]] later on in the distal [[ileum]] of the [[small intestine]].<ref name="Pocock_2006">{{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 }}</ref> In humans, the gastric intrinsic factor [[protein]] is encoded by the ''CBLIF'' [[gene]].<ref name="uniprot">{{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 }}</ref> [[Haptocorrin]] ([[Transcobalamin|transcobalamin I]]) is another glycoprotein secreted by the [[salivary gland]]s which binds to  vitamin B<sub>12</sub>. Vitamin B<sub>12</sub> is acid-sensitive and in binding to haptocorrin it can safely pass through the acidic stomach to the duodenum.<ref name="Fedosov_2012" />

In the less acidic environment of the [[small intestine]], pancreatic enzymes digest the glycoprotein carrier and vitamin B<sub>12</sub> can then bind to intrinsic factor.<ref name="Fedosov_2012" /> This new complex is then absorbed by the epithelial cells ([[enterocyte]]s) of the [[ileum]].<ref name="Fedosov_2012">{{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 }}</ref> Inside the cells, vitamin B<sub>12</sub> dissociates once again and binds to another protein, [[transcobalamin|transcobalamin II]]; the new complex can then exit the epithelial cells to be carried to the liver.<ref name="Alpers_2013">{{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) }}</ref>

== Site of secretion ==
Intrinsic factor is secreted by [[parietal cell]]s within the stomach, and so is present in the gastric juice as well as in the [[Gastric mucosa|gastric mucous membrane]].<ref name="Sharma_2016">{{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) }}</ref> The optimum pH for its action is approximately 7.<ref name="Shum_1971">{{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 }}</ref> Its concentration does not correlate with the amount of [[hydrochloric acid|HCl]] or [[pepsin]] in the gastric juice, e.g., intrinsic factor may be present even when pepsin is largely absent.<ref name="Poliner_1958">{{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) }}</ref> 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]];<ref name="Heatley_1954">{{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) }}</ref>  in human beings it is present in the [[Fundus (stomach)|fundus]] and body of the [[stomach]].<ref name="Howard_1996">{{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) }}</ref>

The limited amount of normal human gastric intrinsic factor limits normal efficient absorption of B<sub>12</sub> to about 2&nbsp;μg per meal, a nominally adequate intake of B<sub>12</sub>.<ref>{{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) }}</ref>

== Insufficiency ==
In [[pernicious anemia]], which is usually an [[autoimmune disease]], [[autoantibody|autoantibodies]] directed against intrinsic factor or parietal cells themselves lead to an intrinsic factor deficiency, [[malabsorption]] of vitamin B<sub>12</sub>, and subsequent [[megaloblastic anemia]].<ref name="Osborne_2015">{{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) }}</ref> [[Atrophic gastritis]] can also cause intrinsic factor deficiency and anemia through damage to the parietal cells of the stomach wall.<ref name="Neumann_2013">{{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) }}</ref> [[Exocrine pancreatic insufficiency|Pancreatic exocrine insufficiency]] can interfere with normal dissociation of vitamin B<sub>12</sub> from its binding proteins in the small intestine, preventing its absorption via the intrinsic factor complex.<ref name="Gueant_1990">{{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) }}</ref> 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.{{citation needed|date=November 2021}}

Mutations in the ''GIF'' gene are responsible for a rare inheritable disease called ''intrinsic factor deficiency''<ref name="gard">{{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}}</ref> which results in malabsorption of vitamin B<sub>12</sub>.<ref name="Kozyraki_2013">{{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) }}</ref>

=== Treatment ===

In most countries, [[intramuscular injection]]s of vitamin B<sub>12</sub> are used to treat [[pernicious anemia]].<ref name="Shipton_2015" /> Orally administered vitamin B<sub>12</sub> is absorbed without intrinsic factor, but at levels of less than one percent than if intrinsic factor is present.<ref>{{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) }}</ref>  Despite the low amounts absorbed, oral vitamin B<sub>12</sub> therapy is effective at reducing symptoms of pernicious anemia.<ref name="Andres_2010">{{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) }}</ref>

Vitamin B<sub>12</sub> can also be given [[sublingual administration|sublingually]], but there is no evidence that this route of administration is superior to the oral route,<ref name="Sharabi_2003">{{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) }}</ref> and only Canada and Sweden routinely prescribe this route of administration.<ref name="Shipton_2015">{{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) }}</ref>

Because vitamin B<sub>12</sub> 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|transcobalamin I]]) binds to vitamin B<sub>12</sub>, and  Vitamin B<sub>12</sub> is acid-sensitive, when vitamin B<sub>12</sub> binds to [[Haptocorrin]] it can safely pass through the acidic stomach to the duodenum, given time in the mouth.<ref name="Fedosov_2012" />

== References ==
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== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Devalia V, Hamilton MS, Molloy AM | title = Guidelines for the diagnosis and treatment of cobalamin and folate disorders | journal = British Journal of Haematology | volume = 166 | issue = 4 | pages = 496–513 | date = Aug 2014 | pmid = 24942828 | doi = 10.1111/bjh.12959 | s2cid = 5772424 | department = (review) | doi-access = free }}
* {{cite journal | vauthors = Coati I, Fassan M, Farinati F, Graham DY, Genta RM, Rugge M | title = Autoimmune gastritis: Pathologist's viewpoint | journal = World Journal of Gastroenterology | volume = 21 | issue = 42 | pages = 12179–12189 | date = Nov 2015 | pmid = 26576102 | pmc = 4641135 | doi = 10.3748/wjg.v21.i42.12179 | department = (review) | doi-access = free }}
* {{cite journal | vauthors = Quadros EV | title = Advances in the understanding of cobalamin assimilation and metabolism | journal = British Journal of Haematology | volume = 148 | issue = 2 | pages = 195–204 | date = Jan 2010 | pmid = 19832808 | pmc = 2809139 | doi = 10.1111/j.1365-2141.2009.07937.x | department = (review) }}
* {{cite journal | vauthors = Christensen EI, Nielsen R, Birn H | title = From bowel to kidneys: the role of cubilin in physiology and disease | journal = Nephrology, Dialysis, Transplantation| volume = 28 | issue = 2 | pages = 274–281 | date = Feb 2013 | pmid = 23291372 | doi = 10.1093/ndt/gfs565 | department = (review) }}

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

{{Gastrointestinal physiology}}
{{Mucoproteins}}

[[Category:Hematology]]
[[Category:Gastroenterology]]
[[Category:Genes mutated in mice]]
[[Category:Stomach]]