Vitamin B12

how to assess status of vitamin b12:

Status assessed using several indices 1. Serum B12 concentration (bound to TC-II) < 200 pg/mL is considered deficient Serum B12 concentration is maintained at the expense of tissues, so an individual may exhibit normal serum concentration but have low tissue level 2. Urinary methylmalonic acid excretion Normally, little or no methylmalonic acid is lost Urinary excretion > 300 mg/d is indicative of deficiency 3. The Schilling test Used to determine problems with B12/IF insufficiency Oral radioactive Vit B12 appearance of isotope in urine

Intestinal processing and transport

Vitamin B12 in enterocyte, binds to transcobalamin II (TC-II) and is released into the blood stream Transcobalamins (R-protein) & transport B12 in a 1:1 ratio TC-II is the major binding protein for B12 > assess status ~ 60 - 80% of circulating B12 is methylcobalamin ~ 20% of circulating B12 adenosylcobalamin All tissues have receptors for TC-II TC-II/cobalamin complex binds to TC-II receptors on the cell surface and is taken into cells by endocytosis Receptor/TC-II/cobalamin complex fuses with the lysosomes that degrade the TC-II and release the vitamin (same as B12 -IF complex)

name for vitamin b12:

cobalamin

susceptibility to vitamin B12 deficiency?

1. Decreased secretion of pancreatic proteases (cystic fibrosis); major problems absorbing vitamin B12 Remains bound to R-binders and is eliminated in feces TRX: B12 injections 2. Failure to produce IF; only absorb vitamin B12 by passive diffusion Primary cause; reduces absorption 50-fold Autosomal dominant trait; increases the rate of pernicious anemia to 25 per 1000 TRX: B12 injections or large oral doses (1000 g/d) 3. Atrophic gastritis or gastrectomy TRX: B12 injections or large oral doses (1000 g/d) 4. Parasitic infections (tapeworms) 5. Infants and children on strict vegetarian diets TRX: oral B12 (1-3 g)

what percentage of vitamin b12 is absorbed?

11-65%

digestion and absorption:

Dietary vitamin B12 (only found in animal products/bacteria) is primarily bound to proteins HCl and pepsin release vitamin B12 from protein In plants as a contamination (manure, nitrogen fixing bacteria) R-proteins (B12 binding proteins) Also called cobalophilins or hapatocorrins High affinity for cobalamins in the stomach In the stomach; free vitamin B12 binds to R-proteins that are secreted by the stomach (protects vitamin B12 from damage by HCl) In the duodenum; pancreatic proteases (trypsin, chymotrypsin etc.) digest the R-proteins and release free vitamin B12

enterohepatic circulation:

Enterohepatic circulation: ~1.4 µg cobalamin/d is thought to be secreted in bile Majority of cobalamin in bile binds to IF and is reabsorbed in the ileum Malabsorptive syndromes decrease the absorption of ingested B12, and decrease enterohepatic circulation

B12 deficiency: neurological features

Greater risk & severity of neurological & psychiatric manifestations in B12 deficiency are the major clinical difference between it and folate deficiency Myelopathy and Neuropathy are typical and severe Related to methionine/SAM availability Myelin loss; axonal degeneration, gliosis "Subacute combined degeneration" of the spinal cord Ataxia, spasticity, and incontinence will occur as the myelopathy progresses Cerebral changes may range from diminished memory to psychosis and delirium Neurological and mental conditions can become permanently debilitating if not treated promptly

vitamin b12 deficiency:

In vitamin B12 deficiency: 5-methyl THF ↑ because methionine synthase (enzyme that converts 5-methyl THF THF), is non-functional Accumulation of 5-methyl THF which cannot be utilized; clinical consequences of B12 deficiency closely resemble those of folate deficiency Referred to as a methyl trap; thus, an individual who is vitamin B12 deficient is functionally folate deficient; macrocytic anemia is produced due to the secondary folate deficiency TREATMENT Either folate or vitamin B12 (folate can "mask" the B12 deficiency) However, the other symptoms of vitamin B12 deficiency are so severe that only vitamin B12 should be used

digestion and absorption continued:

Intrinsic Factor (IF) Secreted by parietal cells (stomach); low pH in stomach causes it to mis-fold and interfere with B12 binding At higher pH (in SI) IF refolds so that it binds B12 (any form of cobalamin) → B12 -IF complex travels to ileum where special receptors (cubilins) recognize the B12-IF complex and internalize it Endocytosis: endocytotic vesicles fuses with a lysosome → secondary lysosome; degrades the B12 -IF complex and releases vitamin B12 into the cytosol

about vitamin b12:

Last vitamin to be discovered Dorothy Hodgkin discovered the structure Carbon-metal bond Corrin nucleus (Corrinoids group of compounds) Fairly stable and resistant to light, heat and oxidation

vitamin b12 def continued

Manifestations of vitamin B12 deficiency occur in stages: 1st: serum concentration diminishes; indicated by holo-TC-II 2nd: cellular concentration diminishes 3rd: biochemical functions become compromised; decreased DNA synthesis / elevated homocysteine and methylmalonic acid concentrations are observed 4th: macrocytic, megaloblastic anemia develops 5th: neurological symptoms Signs and symptoms: Skin pallor, fatigue, shortness of breath, palpitations, insomnia & neurological problems

b12 deficiency: anemia

Megaloblastic anemia appears ~1 year before the neurological symptoms When the anemia is cured by treatment with vitamin B12 the neurological symptoms do not appear But, high folate intake and folate therapy can "mask" the B12 deficiency Folate therapy can cure the anemia Delays the recognition of the B12 deficiency Neurological symptoms persist because the individual is still B12 deficient, despite normal blood cells

functions and mechanisms of action:

Vitamin B12 is stored for long periods of time (~12 y) Unlike other water-soluble vitamins Two enzymatic reactions require vitamin B12 One requires methylcobalamin One requires adenosylcobalamin Conversion of homocysteine → methionine requires methylcobalamin - Cobalamin picks up a methyl group from 5-methyl THF to form methylcobalamin & binds to methionine synthase 2. Conversion of L-methylmalonyl CoA succinyl CoA requires adenosylcobalamin (catalyzed by methylmalonyl CoA mutase in mitochondria) Conversion of propionyl CoA to L-methylmalonyl CoA (2-steps) is biotin, ATP & Mg dependent Vitamin B12 deficiency will lead to a build-up of methylmalonyl CoA and methylmalonic acid in body fluids > assess status