Intrinsic factor

Intrinsic factor (IF), also known as gastric intrinsic factor (GIF), is a is_associated_with::glycoprotein produced by the is_associated_with::parietal cells of the is_associated_with::stomach. It is necessary for the absorption of vitamin B12 (cobalamin) later on in the small intestine. In humans, the gastric intrinsic factor is_associated_with::protein is encoded by the GIF is_associated_with::gene.

is_associated_with::Haptocorrin (also known as HC, R protein, and transcobalamin I, TCN1), is a glycoprotein secreted by the is_associated_with::salivary glands which binds to vitamin B12. Vitamin B12 is acid sensitive and in binding to transcobalamin I it can safely pass through the acidic stomach to the duodenum. Here in the less acidic environment of the small intestine, pancreatic enzymes digest the glycoprotein carrier and vitaminB12 can then bind to intrinsic factor. This new complex is then absorbed by the epithelial cells (is_associated_with::enterocytes) of the ileum. Inside the cells, B12 dissociates once again and binds to another protein, transcobalamin II (TCN2). The new complex can then exit the epithelial cells to be carried to 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 is_associated_with::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 is_associated_with::duodenum. In human beings it is present in the fundus and body of the is_associated_with::stomach.

The limited amount of normal human gastric intrinsic factor limits normal efficient absorption of B12 to about 2 mcg per meal, a nominally adequate intake of B12. (Watanabe F. Vitamin B12 sources and bioavailability. Exp Biol Med (Maywood) 2007;232:1266–74. )

Clinical significance
In is_associated_with::pernicious anemia, which is usually an is_associated_with::autoimmune disease, autoantibodies directed against intrinsic factor or parietal cells themselves lead to an intrinsic factor deficiency, is_associated_with::malabsorption of vitamin B12, and subsequent is_associated_with::megaloblastic anemia. is_associated_with::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 is_associated_with::bariatric surgery, gastric tumors, gastric ulcers, and excessive consumption of alcohol.

Treatment
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 allows 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 can be injected monthly, thus bypassing the digestive tract altogether.

Although IF is necessary for efficient absorption of B12, even without IF the intestines can directly absorb about 1% of ingested B12. Oral supplement of 500-1000 mcg (readily available OTC) per day provides adequate direct absorption without functioning IF. (Eussen SJ, de Groot LC, Clarke R, Schneede J, Ueland PM, Hoefnagels WH, van Staveren WA. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial. Arch Intern Med. 2005 May 23;165(10):1167-72. )