Vitamin B12

BACKGROUND

Vitamin B 12 is the generic descriptor for those corrinoid compounds exhibiting qualitatively the biological activity of cyanocobalamin. The main cobalamins with physiological action are hydroxycobalamin, methylcobalamin and deoxyadenosylcobalamin. Vitamin B 12 is required for the synthesis of fatty acids in myelin and, in conjunction with folate, for DNA synthesis. Adequate intake of vitamin B 12 is essential for normal blood function and neurological function. It can be stored in the liver for many years.

Vitamin B 12 can be converted to either of the two cobalamin coenzymes that are active in humans; methylcobalamin and 5-deoxyadenosylcobalamin. Vitamin B 12 is a cofactor for the enzymes methionine synthase and L-methylmalonyl-CoA mutase and is involved in the conversion of homocysteine to methionine and of L-methylmalonyl-coenzyme A (CoA) to succinyl-CoA. In vitamin B 12 deficiency, folate may accumulate in serum as a result of slowing of the vitamin B 12 -dependent methyltransferase.

Whilst there are some plant-based sources of vitamin B 12 , such as certain algae and plants exposed to bacterial action or contaminated by soil or insects, humans obtain almost all of their vitamin B 12 from animal foods. About 25% of vitamin B 12 comes from red meats (Baghurst et al 2000). For adults and children, about 30% and 50%, respectively, is from milk and dairy products (Cobiac et al 1999).

Absorption of vitamin B 12 is now known to be more complex than was once thought. In foods, methyl-, deoxyadenosyl-, or hydroxocobalamin are bound to enzymes in meat and other animal foods. The cobalamin is released by the action of acid and pepsin that digest the binding protein in the (normal) stomach. The freed cobalamin forms a stable complex with R binder, a glycoprotein secreted in saliva or by the stomach. Meanwhile, intrinsic factor (IF), a 50 kDa glycoprotein that binds cobalamin, is secreted after a meal by the parietal cells of the stomach. However, the binding of cobalamin to IF does not take place in the stomach as was once thought because its affinity is very low at acid pH.

The R binders are partly degraded in the duodenum by pancreatic proteases. The cobalamin then binds IF with high affinity in the more alkaline environment. Unlike R binders, IF is not digested by pancreatic enzymes. Vitamin B 12 from the bile duct can also combine with IF, forming an enterohepatic cycle. The vitamin B 12 -IF complex then passes unchanged down the small intestine and is absorbed in the terminal ileum by endocytosis after attachment to a specific 460 kDa IF membrane receptor. The receptor only binds vitamin B 12 that is attached to IF and does not bind vitamin B 12 analogues.

Vitamin B 12 absorption increases with increasing intake (Adams et al 1971, Chanarin 1979). It is absorbed at varying rates from different foods ranging from 11% from liver, 24–40% from eggs and trout, to more than 60% from mutton and chicken (Doscherholmen et al 1975, 1978, 1981, Heyssel et al 1966). The low absorption rate from liver probably relates to the liver's very high content of B 12 . No studies have been reported on red meat, pork or dairy foods or fish other than trout, so a conservative adjustment for bioavailability of 50% for healthy adults with normal gastric function was assumed in developing the intake requirements. If people consumed large amounts of foods naturally rich in vitamin B 12 , the absorption rate would be lower.

Vitamin B 12 added to foods (eg beverages, meat analogues or soy milks) in crystalline form has a similar absorption rate if added in low amounts (<5 µg per dose), but very low absorption (1% or less) if added at 500 µg per dose or above (Berlin et al 1968, Heyssel et al 1996). Excretion of vitamin B 12 is generally through the faeces and is proportional to body stores (Adams 1970, Heinrich 1964, Mollin & Ross 1952). Other losses occur through the skin and through metabolic reactions.

Requirements for vitamin B 12 can be affected by age, although not all studies confirm this (van Asselt et al 1996). The age effect may act through the influence of increasing levels of atrophic gastritis (Krasinski et al1986) or reduced gastric acidity (Scarlett et al 1992). Rates of atrophic gastritis in the elderly ranging from 10-30% have been reported in Australia (Andrews et al 1967), the US (Hurwitz et al 1997, Krasinski et al 1986) and Scandinavia (Johnsen et al 1991).

Under utilisation of vitamin B 12 may occur in those with genetic defects including deletions or defects in MMA-CoA mutase, transcobalamin II or enzymes in the cobalamin adenosylation pathway.

Vitamin B 12 deficiency can produce haematological, neurological or gut symptoms. The haematological effects are indistinguishable from folate deficiency. They include a range of effects generally associated with anaemia such as skin pallor, lowered energy and exercise tolerance, fatigue, shortness of breath and palpitations. The underlying problem is interference with DNA synthesis leading to production of abnormally large erythrocytes.

Neurological complications are present in about 75–90% of people with frank deficiency. These complications appear to be inversely related to the occurrence of the haematological symptoms (Healton et al 1991, Savage et al 1994). They include sensory disturbances in the extremities, motor disturbance and cognitive changes from memory loss to dementia, with or without mood change. There may also be visual disturbances, impotency and impaired bowel and bladder control. A study by Louwman et al (2000) indicated that cobalamin deficiency in the absence of haematological signs may also affect cognitive function in adolescence.

The indicators that are available for estimating requirements for vitamin B 12 include haematological response as well as measures of serum or plasma vitamin B 12 , MMA, homocysteine, formiminoglutamic acid, propionate and methylcitrate and holo-transcobalamin II.

Haematological responses that have been assessed include increases in haemoglobin, haematocrit and erythrocyte count or decreases in MCV or an optimal rise in reticulocyte numbers. Of these, MCV has limited use because of the 120 days needed to see change, and whilst erythrocyte, haemoglobin and haematocrit are robust they are slow to change. However, reticulocyte count is useful as increases in response to diet are apparent within 48 hours and reach a peak in 5–8 days.

Serum or plasma vitamin B 12 reflects both intake and stores but acceptable levels can be maintained for some time after deficiency occurs because of compensatory release of vitamin B 12 from tissues. Low levels would, however, represent long-term deficiency or chronic low intakes. MMA exhibits a four-fold range in the normal population but rises when the supply of vitamin B 12 is low or when absorption is affected (Joosten et al 1996). Elevated MMA levels can be reduced by vitamin B 12 administration (Joosten et al 1993, Naurath et al 1995, Norman & Morrison 1993, Pennypacker et al 1992).

As the presence of elevated MMA represents a vitamin B 12 -specific change, MMA is the preferred indicator of vitamin B 12 status. However, there are not sufficient data available to use MMA levels to set dietary recommendations. Homocysteine concentration does change in response to vitamin B 12 status but it is not specific to vitamin B 12 , responding also to folate or vitamin B 6 status or both, and formiminoglutamic acid also changes with folate status. Proprionate and methylcitrate both respond to changes in vitamin B 12 status (Allen et al 1993), however they offer no advantages over MMA. Measures of holotranscobalamin II are insufficiently robust to allow the assessment of requirements.