Intrinsic factor deficiency

In contrast to other water-soluble vitamins, significant amounts (4 to 5 mg) of vitamin B-i2 are stored in the body. As a result, it may fete several years tor the clinical symptoms of B12 deficiency to develop in individuals who have had a partial or total gastrectomy (/vhq therefore, become intrinsic factor-deficient) and can no longer absorb the vitamin. 

Commonly, achlorhydria may not be accompanied by other diseases, but in some cases theie is a connection. F01 example, achloihydiia is an abnormality that sometimes occurs with severe iron deficiency. Histalog-fast achlorhydria, resulting from intrinsic factor deficiency in gastric juice, may be an indication of pernicious anemia. Hyperplastic polyps are often found in association with achlorhydria. 

K2. Katz, J. H., diMase, J., and Donaldson, R. M., Simultaneous administration of gastric juice bound and free radioactive cyanocobalamins rapid procedure for differentiating between intrinsic factor deficiency and other causes of vitamin B12 malabsorption. J. Lab. Clin. Med. 61, 266-271 (1963). 

Absorption of vitamin B12 can be investigated in several ways after oral delivery of radioactive vitamin B12 (e.g. containing Co) and subsequent measurement of radioactivity in faecal excretion, whole body counting or liver uptake, plasma radioactivity or the popular Schilling test. For the Schilling test, urinary excretion of radioactive vitamin B12 is measured 24 h following oral delivery, and impaired absorption may indicate intrinsic factor deficiency bacterial colonization of the small intestine (stagnant gut syndrome) or ileal disease. 

DEFICIENCY Pernicious anemia. Conceivably, one could get Bi2 deficiency on a purely vegetarian diet, but this is rare. Deficiency is more likely with diseases of the intestine that impede absorption (e.g., tropical sprue, regional enteritis). The tapeworm Diphyllobothrium latum may deplete Bi2 stores. A deficiency of gastric intrinsic factor (a glycoprotein) may result in Bj2 deficiency, as intrinsic factor is important in facilitating Bj2 absorption in the bowel. Intrinsic factor deficiency may occur following gastrectomy or as an entity in itself, in pernicious anemia. Intrinsic factor deficiency sometimes results from an autoimmune disease. 

Vitamin Bn can be deficient due to a lack of intrinsic factor, which is a glycoprotein secreted by gastric parietal cells. A lack of intrinsic factor or a dietary deficiency of cobalamin can cause pernicious anemia and neuropsychiatric symptoms. The only known treatment lor intrinsic factor deficiency (vitamin Bn deficiency) is intramuscular injection of cyanocobalamin throughout the patient s life. 

Isolated deficiencies of methylcobalamin or of 5 -deoxyadenosylcobalamin result in homocystinuria or methylmalonic aciduria respectively, whereas deficiencies in the earlier reductase steps result in combined disorders. Intrinsic factor deficiency also leads to combined methylmalonic aciduria and homocystinuria because of the low serum vitamin B12 levels, but the urinary concentrations recorded are only moderately increased in comparison to those encountered in methylmalonic aciduria due to primary enzyme deficiencies. Defects in vitamin B12 transport, TCI and TCII deficiency do not appear to produce abnormal organic or amino acidurias. Deficiencies of intrinsic factor or of ileal absorption of vitamin B12 respond clinically and biochemically to physiological doses (1-5 fig day ) of vitamin B12 given intravenously or intramuscularly, whereas deficiencies in transport proteins require pharmacological doses (>500 pg day ). The involvement of 5 -deoxyadenosylcobalamin in methylmalonate metabolism also suggests the possibility of vitamin Bi2-responsive primary methylmalonic aciduria, and this is discussed further below. 

Intrinsic Factor. Vitamin B 2 deficiency commonly is caused by inadequate absorption resulting from a lack or insufficient intrinsic factor (IF) (153). 

Clinical manifestation of vitamin B 2 deficiency is usually a result of absence of the gastric absorptive (intrinsic) factor. Dietary deficiency of vitamin B 2 is uncommon and may take 20 to 30 years to develop, even in healthy adults who foUow a strict vegetarian regimen. An effective enterohepatic recycling of the vitamin plus small amounts from bacterial sources and other contaminants greatly minimizes the risk of a complete dietary deficiency. Individuals who have a defect in vitamin B 2 absorption, however, may develop a deficiency within three to seven years. 

Vitamin B12 is essential to growth, cell reproduction, the manufacture of myelin (which surrounds some nerve fibers), and blood cell manufacture. The intrinsic factor, which is produced by cells in the stomach, is necessary for the absorption of vitamin B12 in the intestine A deficiency of the intrinsic factor results in abnormal formation of erythrocytes because of the body s failure to absorb vitamin B12, a necessary component for blood cell formation. The resulting anemia is a type of megaloblastic anemia called pernicious anemia. 

Pernicious anemia arises when vitamin B,2 deficiency blocks the metabohsm of folic acid, leading to functional folate deficiency. This impairs erythropoiesis, causing immature precursors of erythrocytes to be released into the circulation (megaloblastic anemia). The commonest cause of pernicious anemia is failure of the absorption of vitamin B,2 rather than dietary deficiency. This can be due to failure of intrinsic factor secretion caused by autoimmune disease of parietal cells or to generation of anti-intrinsic factor antibodies. 

Megaloblastic anemias Deficiency of vitamin 6,2 Decreased absorption of 6,2, often due to a deficiency of intrinsic factor, normally secreted by gastric parietal cells... 

Vitamin B12 (cyanocobalmin) administered both orally and parenterally is equally effective in treating anemia from vitamin B12 deficiency. However, use of parenteral cyanacobalamin is the most common method of vitamin B12 replacement because it may be more reliable and practical. Subcutaneous or intramuscular administration is appropriate. Vitamin B12 is absorbed completely following parenteral administration, whereas oral vitamin B12 is absorbed poorly via the GI tract. Furthermore, use of parenteral vitamin B12 to treat megaloblastic anemia may circumvent the need to perform a Schilling test to diagnose lack of intrinsic factor. 

Very small amounts of cobalamin are required each day (<5 i.g) and the diet normally provides plenty more than the minimum, so dietary B12 deficiency is uncommon, except in very strict vegetarians. Pernicious anaemia arises when a defect in the stomach results in too little secretion of a protein called intrinsic factor, without which, cobalamin cannot be absorbed in the ileum of the small intestine. 

The most likely reason for cobalamin deficiency is pernicious anemia (failure to absorb vitamin B 2 in the absence of intrinsic factor from parietal cells). Vitamin Bjj absorption also decreases with aging and in individuals with chronic pancreatitis. Less common reasons for Bjj deficiency include a long-term completely vegetarian diet (plants don t contain vitamin Bjj) and infection with Diphyllobothrium latum, a parasite found in raw fish. Excess vitamin B,2 is stored in the body, so deficiencies develop slowly. 

Nutritional Deficiency-Related Dementias. We have already mentioned that chronic alcoholics are subject to thiamine deficiency that can cause dementia. It usually occurs only after heavy, prolonged abuse of alcohol. In developed countries, the other key nutritional concern is vitamin deficiency. Vitamin deficiency can surprisingly strike even those with a healthy diet. Such people are missing a vital protein, intrinsic factor, which would enable them to absorb it from their digestive tract. 

Vitamin Bn deficiency Deficiency, although rare, results in two serious problems megaloblastic anaemia (which is identical to that caused by folate deficiency) and a specific neuropathy called Bi2-associated neuropathy or cobalamin-deficiency-associated neuropathy (previously called, subacute combined degeneration of the cord). A normal healthy adult can survive more than a decade without dietary vitamin B12 without any signs of deficiency since it is synthesised by microorganisms in the colon and then absorbed. However, pernicious anaemia develops fairly rapidly in patients who have a defective vitamin B12 absorption system due to a lack of intrinsic factor. It results in death in 3 days. Minot and Murphy discovered that giving patients liver, which contains the intrinsic factor, and which is lightly cooked to avoid denaturation, cured the anaemia. For this discovery they were awarded the Nobel Prize in Medicine in 1934. 

A frequent cause of vitamin B12 deficiency is atrophic gastritis leading to a lack of intrinsic factor. Besides megaloblastic anemia, damage to mucosal linings and degeneration of myelin sheaths with neurological sequelae will occur (pernicious anemia). 

Cobalamine can only be resorbed in the small intestine when the gastric mucosa secretes what is known as intrinsic factor—a glycoprotein that binds cobalamine (the extrinsic factor) and thereby protects it from degradation. In the blood, the vitamin is bound to a special protein known as trans-cobalamin. The liver is able to store vitamin Bi2 in amounts suf cient to last for several months. Vitamin B12 deficiency is usually due to an absence of intrinsic factor and the resulting resorption disturbance. This leads to a disturbance in blood formation known as pernicious anemia. 

Dietary forms of vitamin B12 are converted to active forms in the body. Vitamin B12, mainly from liver, eggs and dairy products, is absorbed in terminal ileum. Intrinsic factor from parietal cells is required for absorption. Vitamin B12 is transported in the blood by transcobalamin II and stored in the liver. These stores are such that generally a patient does not become symptomatic until some years after the onset of vitamin B12 deficiency. 

The main causes for vitamin B12 deficiency are impaired absorption due to a lack of gastric intrinsic factor (e.g. pernicious anemia), ileal abnormalities, or it can be the result of a strictly vegetarian diet. 

Cyanocobalamin and the derivative hydroxo-cobalamin, given IM or deep subcutaneously, are indicated for treating vitamin B12 deficiency. Only in strict vegetarians oral preparations may be effective. Oral preparations with added intrinsic factor mostly are not reliably in patients with pernicious anemia. More than half the dose of cyanocobalamin injected is excreted in the urine within 48 hours and the therapeutic advantages of doses higher than 100 pg are questionable because of this rapid eiimination. As... 

Severe cyanocobalamin (vitamin B12) deficiency results in pernicious anemia that is characterized by megaloblastic anemia and neuropathies. The symptoms of this deficiency can be masked by high intake of folate. Vitamin B12 is recycled by an effective enterohep-atic circulation and thus has a very long half-hfe. Absorption of vitamin B12 from the gastrointestinal tract requires the presence of gastric intrinsic factor. This factor binds to the vitamin, forming a complex that... 

Cobento Biotech A/S Denmark Human intrinsic factor, for vitamin B12 deficiency Arabidopsis... 

Bi2 are only about 2 meg, it would take about 5 years for all of the stored vitamin B12 to be exhausted and for megaloblastic anemia to develop if Bi2 absorption were stopped. Vitamin B12 in physiologic amounts is absorbed only after it complexes with intrinsic factor, a glycoprotein secreted by the parietal cells of the gastric mucosa. Intrinsic factor combines with the vitamin Bi2 that is liberated from dietary sources in the stomach and duodenum, and the intrinsic factor-vitamin Bi2 complex is subsequently absorbed in the distal ileum by a highly selective receptor-mediated transport system. Vitamin Bi2 deficiency in humans most often results from malabsorption of vitamin B12 due either to lack of intrinsic factor or to loss or malfunction of the specific absorptive mechanism in the distal ileum. Nutritional deficiency is rare but may be seen in strict vegetarians after many years without meat, eggs, or dairy products. 

Vitamin B12 deficiency also occurs when the region of the distal ileum that absorbs the vitamin B12-intrinsic factor... 

Maintenance therapy consists of 100-1000 meg intramuscularly once a month for life. If neurologic abnormalities are present, maintenance therapy injections should be given every 1-2 weeks for 6 months before switching to monthly injections. Oral vitamin B12-intrinsic factor mixtures and liver extracts should not be used to treat vitamin B12 deficiency ... 

This vitamin is not synthesized in animals, but rather it results from the bacterial or fungal fermentation in the rumen, after which it is absorbed and concentrated during metabolism. Among the known vitamins, this exclusive microbial synthesis is of great interest. One of the major results of vitamin Bn deficiency is pernicious anemia. This disease, however, usually does not result from a dietary deficiency of the vitamin, but rather by an absence of a glycoprotein ( gastric intrinsic factor ) in the gastric juices that facilitates absorption of the vitamin in the intestine. Control of the diseases hence is either by injection of Bn or by oral administration of the intrinsic factor, with or without the vitamin injection. 

Factors which tend to decrease the availability of this vitamin include (1) cooking losses, since the vitamin is heat labile (2) cobalt deficiency in ruminants (3) intestinal malabsorption or parasites (4) lack of intrinsic factor (5) intestinal disease (6) aging (7) vegetarian diet (8) excretion... 

Unusual features of vitamin Bn observed by some investigators include (1) the cyanide group is an artifact of preparation (2) the only vitamin synthesized in appreciable amounts only by microorganisms (possible in tumors) (3) only vitamin with a metal ion (4) works with glutathione (5) glutathione content decreased on B12 deficiency (6) mitosis retarded in B12 deficiency (7) requires intrinsic factor (enzyme) for oral activity (8) increases tumor size (Rous sarcoma) (9) diamagnetic properties (10) no acidic or basic groups revealed on titration (no pKa). 

This case prompted a report of 10 metformin- associated patients with cobalamin deficiency among 162 patients with vitamin Bi2 concentrations below 200 pg/ml (91). They had taken a mean dose of metformin of 2015 mg/ day for an average of 8.9 years. The mean vitamin B12 concentration was 140 pg/ml. All had normal serum folate and creatinine concentrations and no antibodies to intrinsic factor. In one patient there was malabsorption. 

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