Medicine:Intrinsic factor

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Short description: Glycoprotein produced in the stomach which binds to vitamin B12


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Intrinsic factor (IF), cobalamin binding intrinsic factor,[1] also known as 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.[2] In humans, the gastric intrinsic factor protein is encoded by the CBLIF gene.[1] 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.[3]

In the less acidic environment of the small intestine, pancreatic enzymes digest the glycoprotein carrier and vitamin B12 can then bind to intrinsic factor.[3] This new complex is then absorbed by the epithelial cells (enterocytes) of the ileum.[3] 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.[4]

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.[5] The optimum pH for its action is approximately 7.[6] 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.[7] 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;[8] in human beings it is present in the fundus and body of the stomach.[9]

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.[10]

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.[11] Atrophic gastritis can also cause intrinsic factor deficiency and anemia through damage to the parietal cells of the stomach wall.[12] 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.[13] 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]

Mutations in the GIF gene are responsible for a rare inheritable disease called intrinsic factor deficiency[14] which results in malabsorption of vitamin B12.[15]

Treatment

In most countries, intramuscular injections of vitamin B12 are used to treat pernicious anemia.[16] Orally administered vitamin B12 is absorbed without intrinsic factor, but at levels of less than one percent than if intrinsic factor is present.[17] Despite the low amounts absorbed, oral vitamin B12 therapy is effective at reducing symptoms of pernicious anemia.[18]

Vitamin B12 can also be given sublingually, but there is no evidence that this route of administration is superior to the oral route,[19] and only Canada and Sweden routinely prescribe this route of administration.[16]

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.[3]

References

  1. ↑ 1.0 1.1 "CBLIF - Cobalamin binding intrinsic factor precursor - Homo sapiens (Human) - CBLIF gene & protein" (in en). https://www.uniprot.org/uniprot/P27352. 
  2. ↑ Human Physiology: The Basis of Medicine (3rd ed.). Oxford University Press. 2006. p. 230. ISBN 978-019-856878-0. 
  3. ↑ 3.0 3.1 3.2 3.3 "Physiological and Molecular Aspects of Cobalamin Transport". Water Soluble Vitamins. Subcellular Biochemistry. 56. 2012. pp. 347–67. doi:10.1007/978-94-007-2199-9_18. ISBN 978-94-007-2198-2. 
  4. ↑ "Gastric intrinsic factor: the gastric and small intestinal stages of cobalamin absorption. A personal journey". Biochimie 95 (5): 989–94. May 2013. doi:10.1016/j.biochi.2012.12.006. PMID 23274574. 
  5. ↑ Sharma, K.N. (2016). "Gastrointestinal System". Textbook Of Biochemistry, Biotechnology, Allied And Molecular Medicine (4th ed.). PHI Learning Private Limited. p. 632. ISBN 978-81-203-5125-7. https://books.google.com/books?id=mVuNCwAAQBAJ&q=gastric+intrinsic+factor+secreted++parietal+cells&pg=PA632. 
  6. ↑ "Effect of pH changes on the binding of vitamin B12 by intrinsic factor". Journal of Clinical Pathology 24 (3): 239–43. 1971. doi:10.1136/jcp.24.3.239. PMID 5103294. 
  7. ↑ "The independent secretion of acid, pepsin, and intrinsic factor by the human stomach". Gastroenterology 34 (2): 196–209. 1958. doi:10.1016/S0016-5085(58)80102-X. PMID 13512593. 
  8. ↑ "Intrinsic factor in the pyloric and duodenal secretions of the pig". Lancet 267 (6838): 578–80. 1954. doi:10.1016/S0140-6736(54)90355-4. PMID 13193076. 
  9. ↑ "Human gastric intrinsic factor expression is not restricted to parietal cells". Journal of Anatomy 189 (Pt 2): 303–13. 1996. PMID 8886952. 
  10. ↑ "Vitamin B12 sources and bioavailability". Experimental Biology and Medicine 232 (10): 1266–74. Nov 2007. doi:10.3181/0703-MR-67. PMID 17959839. 
  11. ↑ "Autoimmune mechanisms in pernicious anaemia & thyroid disease". Autoimmunity Reviews 14 (9): 763–8. 2015. doi:10.1016/j.autrev.2015.04.011. PMID 25936607. 
  12. ↑ "Autoimmune atrophic gastritis--pathogenesis, pathology and management". Nature Reviews. Gastroenterology & Hepatology 10 (9): 529–41. 2013. doi:10.1038/nrgastro.2013.101. PMID 23774773. 
  13. ↑ "Malabsorption of vitamin B12 in pancreatic insufficiency of the adult and of the child". Pancreas 5 (5): 559–67. 1990. doi:10.1097/00006676-199009000-00011. PMID 2235967. 
  14. ↑ "Intrinsic factor deficiency | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". https://rarediseases.info.nih.gov/diseases/3024/intrinsic-factor-deficiency. 
  15. ↑ "Vitamin B12 absorption: mammalian physiology and acquired and inherited disorders". Biochimie 95 (5): 1002–7. 2013. doi:10.1016/j.biochi.2012.11.004. PMID 23178706. 
  16. ↑ 16.0 16.1 "Vitamin B12 deficiency - A 21st century perspective". Clinical Medicine 15 (2): 145–50. 2015. doi:10.7861/clinmedicine.15-2-145. PMID 25824066. 
  17. ↑ "What is new in vitamin B(12)?". Current Opinion in Gastroenterology 21 (2): 183–6. Mar 2005. doi:10.1097/01.mog.0000148331.96932.44. PMID 15711210. 
  18. ↑ "Efficacy of oral cobalamin (vitamin B12) therapy". Expert Opinion on Pharmacotherapy 11 (2): 249–56. 2010. doi:10.1517/14656560903456053. PMID 20088746. 
  19. ↑ "Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route". British Journal of Clinical Pharmacology 56 (6): 635–8. 2003. doi:10.1046/j.1365-2125.2003.01907.x. PMID 14616423. 

Further reading

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