|Gastric intrinsic factor (vitamin B synthesis)|
Rendering based on PDB
Intrinsic factor (IF), also known as gastric intrinsic factor (GIF), is a glycoprotein produced by the parietal cells of the stomach. It is necessary for the absorption of vitamin B12 (cobalamin) later on in the small intestine. In humans, the gastric intrinsic factor protein is encoded by the GIF gene.
Upon entry into the stomach, vitamin B12 becomes bound to haptocorrin (aka HC, R factor, transcobalamin I, TCN1), a glycoprotein. The resulting complex enters the duodenum, where pancreatic enzymes digest haptocorrin. In the less acidic environment of the small intestine, B12 can then bind to intrinsic factor. This new complex travels to the ileum, where special epithelial cells endocytose them. Inside the cell, B12 dissociates once again and binds to another protein, transcobalamin II (TCN2). The new complex can exit the epithelial cells to enter the liver.
Site of secretion
The intrinsic factor is secreted by the stomach. It is present in the gastric juice as well as in the gastric mucous membrane. The optimum pH for its action is 7 and it is inactivated at temperatures above 45 °C. It does not necessarily run parallel with the amount of HCl or pepsin in the gastric juice. So in some cases, the intrinsic factor may be present even if there is no HCl or pepsin or vice versa. 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. In human beings it is present in the fundus and body of the stomach.
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. Atrophic gastritis can also cause intrinsic factor deficiency and anemia through damage to the parietal cells of the stomach wall. 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.
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.
Patients experiencing an insufficiency in their intrinsic factor levels cannot benefit from a low dose oral vitamin B12 supplement, because it will not absorb through the wall of the small intestine. Historically, the disease was thought untreatable before the discovery that it could be managed with daily uptake of 300 g raw liver pulp (Nobel Prize in Physiology or Medicine 1934 to Whipple, Minot & Murphy). Unlike other water soluble vitamins, vitamin B12 is stored in the liver. The high dose of vitamin B12 thus ingested allowed enough of it to be taken up passively. As more and more potent liver extracts became available this repugnant treatment became unnecessary, improving the life quality of the patients. Today synthetic vitamin B12 is injected monthly, thus bypassing the digestive tract altogether. More recently, Swedish researchers discovered that sufficiently large doses of B12 can also be absorbed sublingually, removing the necessity for injectable B12. However, no standards have been set for treatment by the sublingual route yet, and injections of B12 are the only reliable method of treatment.
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Model organisms have been used in the study of intrinsic factor function. A conditional knockout mouse line, called Giftm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty-seven tests were carried out on mutant mice and four significant abnormalities were observed. Homozygous mutant males displayed increased aggression towards their pups and therefore had reduced fecundity. Mutants of both sex had increased susceptibility to infection with both Citrobacter and Salmonella.
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- Intrinsic factor at the US National Library of Medicine Medical Subject Headings (MeSH)
- MedlinePlus Encyclopedia 002381
- Overview at colostate.edu