Intrinsic factor

Gastric intrinsic factor (vitamin B synthesis)
250px Rendering based on PDB 2CKT
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2CKT, 2PMV, 3KQ4
Identifiers
Symbols	GIF ; IF; IFMH; INF; TCN3
External IDs	OMIM: 609342 MGI: 1202394 HomoloGene: 3773 GeneCards: GIF Gene
Gene ontology Molecular function • cobalamin binding Cellular component • extracellular region • extracellular space • endosome • microvillus • apical plasma membrane • lysosomal lumen Biological process • vitamin metabolic process • water-soluble vitamin metabolic process • cobalt ion transport • cobalamin metabolic process • cobalamin transport • small molecule metabolic process Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	2694	14603
Ensembl	ENSG00000134812	ENSMUSG00000024682
UniProt	P27352	P52787
RefSeq (mRNA)	NM_005142	NM_008118
RefSeq (protein)	NP_005133	NP_032144
Location (UCSC)	Chr 11: 59.83 – 59.85 Mb	Chr 19: 11.75 – 11.76 Mb
PubMed search	[1]	[2]

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.

Haptocorrin (also known as HC, R protein, and transcobalamin I, TCN1), is a glycoprotein secreted by the 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 vitamin B₁₂ can then bind to intrinsic factor. This new complex is then absorbed by the epithelial cells (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 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.

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.

Clinical significance

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.

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.

However, sublingual B₁₂ supplements overcome this problem. Historically, the disease was thought untreatable before the discovery that it could be managed with daily uptake of 300g raw liver pulp.

Unlike other water-soluble vitamins, vitamin B₁₂ is stored in the liver. 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 intrinsic factor 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 intrinsic factor.

External links

• Intrinsic factor at the US National Library of Medicine Medical Subject Headings (MeSH)
• MedlinePlus Encyclopedia 002381
• Overview at colostate.edu