Intrinsic factor
Encyclopedia
Intrinsic factor also known as gastric intrinsic factor (GIF) is a glycoprotein
produced by the parietal cell
s of the stomach
. It is necessary for the absorption of vitamin B12
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
(R factor), 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. The new complex can exit the epithelial cells to enter the liver.
. In human beings it is present in the fundus
and body of the stomach
.
, 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.
Bariatric surgery
is a known risk factor in the development of pernicious anemia. Other risk factors contributing to this condition are stomach tumors, gastric ulcers, and excessive consumption of alcohol.
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 regular injections of vitamin B12, thus bypassing the digestive tract. More recently, Swedish researchers discovered that sufficiently large doses of B12 can also be absorbed sublingual
ly, removing the necessity for injectable B12. However, as of yet, no standards have been set for treatment by the sublingual route and injections of B12 are the only reliable method of treatment.
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
produced by the parietal cell
Parietal cell
Parietal cells, or oxyntic cells, are the stomach epithelium cells that secrete gastric acid and intrinsic factor.Acetylcholine and gastrin . The histamine receptors act by increasing intracellular cAMP, whereas the muscarinic and gastrin receptors increase intracellular Ca2+ levels...
s of the stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
. It is necessary for the absorption of vitamin B12
Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
later on in the small intestine. In humans, the gastric intrinsic factor protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
is encoded by the GIF gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Upon entry into the stomach, vitamin B12 becomes bound to haptocorrin
Haptocorrin
Haptocorrin also known as transcobalamin-1 is a protein that in humans is encoded by the TCN1 gene. The essential function of haptocorrin is protection of the acid-sensitive vitamin B12 while it moves through the stomach.- Function :...
(R factor), 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. The new complex can exit the epithelial cells to enter the liver.
Site of secretion
The intrinsic factor is an enzyme-like unidentified substance 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 45oC. 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 duodenumDuodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
. In human beings it is present in the fundus
Fundus (stomach)
The fundus of the stomach is the left portion of the stomach's body, and is marked off from the remainder of the body by a plane passing horizontally through the cardiac orifice....
and body of the stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
.
Clinical significance
In pernicious anemiaPernicious anemia
Pernicious anemia is one of many types of the larger family of megaloblastic anemias...
, an autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
, autoantibodies
Autoantibody
An autoantibody is an antibody manufactured by the immune system that is directed against one or more of the individual's own proteins. It is derived from the Greek "auto" which means "self", "anti" which means "against" and "body"...
directed against intrinsic factor or parietal cells themselves lead to an intrinsic factor deficiency, malabsorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
of vitamin B12, and subsequent megaloblastic anemia
Megaloblastic anemia
Megaloblastic anemia is an anemia that results from inhibition of DNA synthesis in red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis stage...
. Atrophic gastritis
Atrophic gastritis
Atrophic gastritis is a process of chronic inflammation of the stomach mucosa, leading to loss of gastric glandular cells and their eventual replacement by intestinal and fibrous tissues...
can also cause intrinsic factor deficiency and anemia through damage to the parietal cells of the stomach wall. Pancreatic exocrine insufficiency
Exocrine pancreatic insufficiency
Exocrine pancreatic insufficiency is the inability to properly digest food due to a lack of digestive enzymes made by the pancreas. This disease is found frequently in dogs. EPI is also found in humans afflicted with cystic fibrosis and Shwachman-Diamond Syndrome. EPI is caused by a progressive...
can interfere with normal dissociation of vitamin B12 from its binding proteins in the small intestine, preventing its absorption via the intrinsic factor complex.
Bariatric surgery
Bariatric surgery
Bariatric surgery includes a variety of procedures performed on people who are obese. Weight loss is achieved by reducing the size of the stomach with an implanted medical device or through removal of a portion of the stomach or by resecting and re-routing the small intestines...
is a known risk factor in the development of pernicious anemia. Other risk factors contributing to this condition are stomach 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 B12Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
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 regular injections of vitamin B12, thus bypassing the digestive tract. More recently, Swedish researchers discovered that sufficiently large doses of B12 can also be absorbed sublingual
Sublingual
Sublingual, literally 'under the tongue', from Latin, refers to the pharmacological route of administration by which drugs diffuse into the blood through tissues under the tongue...
ly, removing the necessity for injectable B12. However, as of yet, no standards have been set for treatment by the sublingual route and injections of B12 are the only reliable method of treatment.