Vitamin B12 intrinsic factor

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 ... 

Facilitated transport is essentially the same as carrier-mediated transport, except that besides a carrier molecule, another transport facilitator is essential. For example, vitamin B12 attaches to the intrinsic factor, and the vitamin B12-intrinsic factor complex then attaches to the carrier molecule and is transported. This transport process does not require energy and does not proceed against a concentration gradient (Figure 1.3). 

Vitamin B12 deficiency also occurs when the region of the distal ileum that absorbs the vitamin B12-intrinsic factor complex is damaged, as when the ileum is involved with inflammatory bowel disease, or when the ileum is surgically resected. In these situations, radioactively labeled vitamin B12 is not absorbed in the Schilling test, even when intrinsic factor is added. Other rare causes of vitamin B,2 deficiency include bacterial overgrowth of the small bowel, chronic pancreatitis, and thyroid disease. Rare cases of vitamin B12 deficiency in children have been found to be secondary to congenital deficiency of intrinsic factor and congenital selective vitamin Bi2 malabsorption due to defects of the receptor sites in the distal ileum. 

Vitamin B12 can be absorbed when present in physiological amounts only if it is first bound to a specific protein—the so-called intrinsic factor—that tightly binds to the vitamin. The complex then passes through the jejunum to the ileum, which contains receptor sites for the vitamin B12/intrinsic factor complex. Calcium ions are required for the reaction between ileal receptors and the intrinsic factor/vitamin B12 complex. The reaction is inhibited by EDTA and reduced by a pH below 5.4. The vitamin appears to be separated from intrinsic factor at the ileal receptor sites and is then bound to another protein carrier, transcobalamin II, which transports the vitamin and permits its uptake by a number of tissues. The subject has been well reviewed by Jacob and her colleagues (Jl). Removal of 60 cm of ileum may impair vitamin B12 absorption and with the loss of 180 cm absorption is almost always affected. 

Vitamin B12 is special in as far as its absorption depends on the availability of several secretory proteins, the most important being the so-called intrinsic factor (IF). IF is produced by the parietal cells of the fundic mucosa in man and is secreted simultaneously with HC1. In the small intestine, vitamin B12 (extrinsic factor) binds to the alkali-stable gastric glycoprotein IF. The molecules form a complex that resists intestinal proteolysis. In the ileum, the IF-vitamin B 12-complex attaches to specific mucosal receptors of the microvilli as soon as the chymus reaches a neutral pH. Then either cobalamin alone or the complex as a whole enters the mucosal cell. 

Because dietary vitamin B12 is protein bound, the first step in absorption is its release in the stomach. Release is enhanced by gastric pH and pancreatic proteases. The freed vitamin is bound immediately to a glycoprotein, the intrinsic factor, secreted by parietal cells of the gastric mucosa. The vitamin Bi -intrinsic factor complex is carried to the intestines, where it binds with receptors in the ileum. Absorption is mainly by an active proccs.s, which can be saturated by 1.3 to 3 /eg of vitamin B, Excess amounts may be absorbed passively. 

Vitamin B12 deficiency results more commonly from a stomach defect than from a dietary deficiency. Before it can be absorbed the vitamin B12 (extrinsic factor) that is released from associated peptides and proteins in the stomach must combine with the intrinsic factor, a small glycoprotein secreted by the parietal cells. Subjects who suffer from pernicious anaemia fail to produce intrinsic factor with the result that the vitamin is not absorbed and must be given by injection. Vitamin B]2 produced by microbes in the lower reaches of the intestine is of no use to the body. 

A mucoprotein, secreted by the parietal cells of the stomach, which binds with vitamin B12 (extrinsic factor) to form a complex. This complex binds to the intestinal cell and enables the vitamin to be absorbed. Lack of intrinsic factor can occur in various conditions leading to vitamin B12 deficiency and pernicious anaemia. Intrinsic factor secretion can be investigated by the Schilling test. 

Also, the outcome covers a large spectrum. Autoantibodies can specifically block an important protein (such as the gastric intrinsic factor required for the uptake of orally taken vitamin B12), or the receptor for —> acetylcholine (as in myasthenia gravis), but also can... 

The treatment of an autoimmune disease very much depends on the nature of the clinical outcome it causes. Although the formation of autoantibodies causes the inactivation of the gastric intrinsic factor, the subsequent shortage of vitamin B12 can be easily overcome by supplying it via an parenteral route. Lifelong immunosuppression (with all its side effects) thus is inappropriate. When, however, as in sympathetic ophtalmia, after damage of the first eye the second eye is endangered, an even drastic immunosuppression is mandatory. 

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. 

VITAMIN S12. Fhtients with pernicious anemia are treated with vitamin B12 by tiie parenteral route (IM) weekly stabilized. The parenteral route is used because tiie vitamin is ineffective orally due to the absence of tiie intrinsic factor in tiie stomach, which is necessary for utilization of vitamin B12. After stabilization, maintenance (usually monthly) injections are necessary for life... 

A person with pernicious anemia lacks intrinsic factor, a compound required for the absorption of vitamin B12 and its storage in the liver. The diagnosis is confirmed... 

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. 

Intrinsic factor is produced by the parietal cells. Within the stomach, it combines with vitamin Bu to form a complex necessary for absorption of this vitamin in the ileum of the small intestine. Vitamin B12 is an essential factor in the formation of red blood cells. Individuals unable to produce intrinsic factor cannot absorb vitamin B12 and red blood cell production is impaired. This condition, referred to as Pernicious anemia, occurs as a result of an autoimmune disorder involving destruction of parietal cells. 

Oral vitamin B12 supplementation appears to be as effective as parenteral, even in patients with pernicious anemia, because the alternate vitamin B12 absorption pathway is independent of intrinsic factor. Oral cobalamin is initiated at 1 to 2 mg daily for 1 to 2 weeks, followed by 1 mg daily. 

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. 

Vitamin B12 (cyanocobalamin) is produced by bacteria B12 generated in the colon, however, is unavailable for absorption (see below). liver, meat, fish, and milk products are rich sources of the vitamin. The minimal requirement is about 1 pg/d. Enteral absorption of vitamin B 2 requires so-called intrinsic factor from parietal cells of the stomach. The complex formed with this glycoprotein undergoes endocytosis in the ileum. Bound to its transport protein, transcobalamin, vitamin B12 is destined for storage in the liver or uptake into tissues. 

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. 

Pharmacokinetics The parietal cells of the stomach secrete intrinsic factor, which regulates the amount of vitamin B-12 absorbed in the terminal ileum. Bioavailability of oral preparations is approximately 25%. Vitamin B12 is primarily stored in the liver. Enterohepatic circulation plays a key role in recycling vitamin B-12 from mainly bile. If plasma-binding proteins are saturated, excess free vitamin B- 2 will be excreted in the kidney. 

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... 

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