Cobalamin absorption

Strict vegetarian diet or after diseases affecting cobalamin absorption. The main effects of vitamin deficiency are pernicious anemia, macrocytosis, and neurological problems. A particularity of this vitamin is that it can be stored especially in the liver and kidneys. 

Herbert, V., Fong, W, Guile, V, and Stopler, T. (1990. Low holotranscobalamin II is the earliest serum marker for subnormal vitamin Bn (cobalamin) absorption in patients with AIDE. Am. ]. Hematol. 34,132-139. 

Watkins D, Rosenblatt DS. Cobalamin and inborn errors of cobalamin absorption and metabolism. Endocrinologist 2001 11 98-104. 

TCI has a high affinity for and is about 90% saturated with cobalamin, while TCIII binds less strongly and is largely unsaturated. However, TCII binds newly absorbed cobalamins, and the TCII-cobalamin complex appears to deliver cobalamin to peripheral tissues (Figure 38-18). TCII accounts for most of the unsaturated vitamin B12 binding capacity of serum. Therefore, cobalophilins (except TCII see below) probably have a minimal role in cobalamin absorption, transport, and metabolism. Thus, members of the family with congenital cobalophilin deficiency showed no symptoms of vitamin B12 deficiency despite a very low serum concentration of the vitamin secondary to the absence of TCI. 

Dietary cobalamin is absorbed from animal food sources by a multistage process shown in Figure 42-2. Cobalamin absorption requires the presence of a protein (the intrinsic factor, IF) secreted from the parietal cells of the stomach to bind cobalamin and aid in its absorption in the ileum. The protein is released into the ileum while the cobalamin is transported to the blood stream where it binds specialized serum proteins, the transcobalamins (TC), which transport it to other tissues such as liver where cobalamin can be stored (usually several milligrams are present in liver). In the absence of the intrinsic factor... 

Cobalamin absorption from the gastrointestinal tract requires the presence of a protein (the intrinsic factor, IF) secreted from the parietal cells of the stomach to bind cobalamin and aid in its absorption in the ileum. 

Elderly people 40 subjects (19M) frequently suffering from vitamin B12 deficiency (>20%), often neither identified nor investigated because of its subclinical manifestations, or mainly caused by reduced production or lack of intrinsic factor (15-20%), or altered cobalamin absorption, or possibly associated with insufficient dietary intake. 

Chen, X., Remacha, A.F., Sarda, M.P., and Carmel, R., 2005. Influence of cobalamin deficiency compared with that of cobalamin absorption on serum holo-transcobalamin II. The American Journal of Clinical Nutrition. 81 110-114. 

Efficient absorption of cobalamin requires that the vitamin form a macromolecular complex with the glycoprotein secreted by the stomach. In patients with pancreatic insufficiency, cobalamin absorption is poor, suggesting that pancreatic proteases are necessary for this process, although the mechanism responsible has not yet been identified. For efficient absorption, the distal small bowel must be intact, and in its absence, the absorption of cobalamin is... 

Festen H, Klinkenberg-Knol E, Kuipers E et al (1993) Cobalamin absorption during omeprazole treatment short and long-term studies. Gastroenterology 104 A77... 

Dietary deficiency in the absence of absorption defects can be effectively reversed with oral supplementation of 1 p.m of vitamin B 2 daily. If deficiency is related to a defect in vitamin absorption, daily doses of 1 pg adininistered subcutaneously or intramuscularly are effective (33). However, a single intramuscular dose of 100 pg of cobalamin once per month is adequate in patients with chronic gastric or ileal damage. Larger doses are generally rapidly cleared from the plasma into the urine and are not effective unless the patient demonstrates poor vitamin retention. 

Radioisotope dilution assays are based on the principle of competition between radioactive labeled ( Co) vitamin B 2 and cobalamins extracted from matrices for binding sites on the intrinsic factor (a glycoprotein). Binding is in proportion to the concentration of the radioactive and nonradio active B 2 with the concentration of intrinsic factor as the limiting factor. Free cobalamins are separated from those bound on the intrinsic factor by absorption... 

Spectrophotometric deterrnination at 550 nm is relatively insensitive and is useful for the deterrnination of vitamin B 2 in high potency products such as premixes. Thin-layer chromatography and open-column chromatography have been appHed to both the direct assay of cobalamins and to the fractionation and removal of interfering substances from sample extracts prior to microbiological or radioassay. Atomic absorption spectrophotometry of cobalt has been proposed for the deterrnination of vitamin B 2 in dry feeds. Chemical methods based on the estimation of cyanide or the presence of 5,6-dimethylben2irnida2ole in the vitamin B 2 molecule have not been widely used. 

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. 

As Co-containing organometallic compounds, cobalamins are unique in nature, and they have a genetic history of more than four billion years. Their biosynthesis, absorption, transport, and metabolism have been well documented in organisms of both marine and terrestrial origin.1110-1112... 

Mammalian intestinal absorption requires the presence of two receptors and two transporters, which is itself a unique feature. Specific transporters such as intrinsic factor, transcobalamin, and haptocorrin have been characterized,1113 as well as a number of receptors for passage across cell membranes. A number of biochemical studies on cell uptake1114 and receptors1115,1116 of cobala-mins have been reported. Genetic disorders that impair the synthesis, transport, or transmembrane passage of cobalamins and their consequences have been reviewed.1117,1118... 

The nitroxalkylcorrinoids are easy to characterize since they are basically alkyl corrinoids. The u.v.-visible absorption spectra of the nitroxalkylcorrinoids are quite similar to other alkylcorrinoids. The nitroxalkyl cobalamin has a spectrum with Amax at 525,357, and 329nm with relative extinctions of 1.1, 1.2, and 0.65 respectively. Spectra for a number of typical alkylcobalamins have been reported by Firth et al. (121). The corresponding cobinamide has absorption maxima at 455, 428, 360, and 325 nm with relative extinctions of 1.4, 1.0, 0.61, and 0.62 respectively. Aerobic photolysis of these compounds leaves the corresponding aquocobalamin or aquocobinamide. Likewise, addition of cyanide to the nitroxalkylcobinamide in base leaves dicyano cobinamide. 

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. 

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. 

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. 

The answer is D. Several vitamin deficiencies can cause anemia due to reduced DNA synthesis in the erythropoietic cells of the bone marrow, especially folic acid and vitamin Bj2 (cobalamin), which are particularly prevalent among elderly patients due to poor diet and reduced absorption. In addition, deficiencies of either folic acid or vitamin Bj2 could produce the megaloblastic anemia seen in this patient. However, the absence of neurologic symptoms, a hallmark of vitamin Bj2 deficiency, makes that diagnosis less likely than folic acid deficiency. 

Cobalt must be supplied in the diet in its physiologically active form, vitamin B12. GI absorption of cobalt is about 25%, with wide individual variation excretion occurs mainly via the urine. The major part is excreted within days and the rest has a biological half-life of about two years. Originally, the therapy for pernicious anemia was to have patients eat large amounts of liver. The most reliable treatment now is monthly injections of cobalamin. 

Alsenz, J., Russell-Jones, G. J., Westwood, S., et al. Oral absorption of peptides through the cobalamin (vatamin B12) pathway in the rat intestine. Pharm. Res. 17 825-832, 2000. 

B21. Brugge, W. R., Goff, J. S., Allen, N. C., Podell, E. R., and Allen, R. H., Development of a dual label Schilling test for pancreatic exocrine function based on the differential absorption of cobalamin bound to intrinsic factor and R protein. Gastroenterology 78, 937-949 (1980). 

Role of Cobalamin in Amino Acid Catabolism Pernicious anemia is caused by impaired absorption of vitamin Bi2. What is the effect of this impairment on the catabolism of amino acids Are all amino acids equally affected (Hint see Box 17-2.)... 

Oral vitamin Bj2 supplementation appears to be as effective as parenteral, even in patients with pernicious anemia, because the alternate vitamin Bj2 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 daUy. Parenteral therapy is more rapid acting than oral therapy and should be used if neurologic symptoms are present. A popular regimen is cyanocobalamin 1,000 meg daily for 1 week, then weekly for 1 month, and then monthly. When symptoms resolve, daily oral administration can be initiated. 

Considerably more intrinsic factor is secreted than is needed for the binding and absorption of dietary vitamin B12, which requires only about 1 % of the total intrinsic factor available. There is a considerable enterohepatic circulation of vitamin B12, variously estimated as between 1 to 9 /rg per day, about the same as the dietary intake. Like dietary vitamin B12 bound to salivary cobalophilin, the biliary cobalophUins are hydrolyzed in the duodenum, and the vitamin released binds to intrinsic factor, thus permitting reabsorption in the Ueum. Whereas cobalophUins and transcorrin III have low specificity, and wUl bind a variety of corrinoids, intrinsic factor orUy binds cobalamins, and only the biologicaUy active vitamin wiU be reabsorbed to any significant extent. 

The human Bu-binder intrinsic factor is a glycoprotein of ca. 44kDa, with a high binding constant (in 1 1 complexes) for vitamin B12 (1) and other cobalamins. The intrinsic factor is secreted by cells of the gastric mucosa and specifically binds cobalamins and carries them to the ileum. There the ileum receptor protein accepts the corrinoid from the intrinsic factor complex and transports it further across the intestinal epithelial absorptive cell. The cobalamins then appear to be bound to transcobalamin II and transported in the blood in this way to membrane-bound transcobalamin/corrin receptor proteins of the specific cells. ... 

The daily requirement of cobalamin is about 3.0 micrograms. Absorption takes place mainly in the terminal ileum, and it is carried in plasma bound to proteins. Some 90% of recently absorbed or administered cobalamin is carried on transco-balamin II an important transport protein which is rapidly cleared from the circulation 6-9 minutes). Hereditary deficiency of transcobalamin II causes severe cobalamin deficiency. About 80% of all circulating cobalamin is bound to transcobalamin I (t) 9-12 days) which is possibly a plasma storage form (hereditary deficiency of which is of no consequence). Cobalamin in its reduced form... 

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