Intrinsic Factor: The Key to Absorbing Vitamin B12

For vitamin B12 absorption to be possible, a special transport molecule produced by the parietal cells is required. This molecule is called intrinsic factor (IF).

Vitamin B12 is mostly bound to proteins in food and is separated by specific enzymes in the stomach. It is then transported to the small intestine by a different transport protein called haptocorrin, where it binds to IF. Following this, IF transports the B12 to receptors in the intestinal mucosa, where the vitamin can then gain access to the mucosal cells.

There is a limited number of intrinsic factor receptors, meaning that only around 1.5 to 2 µg of B12 per dose or meal can be absorbed in this way.

A further 1% of the dosage is absorbed via passive diffusion, bypassing the need for IF. Because it is only 1% that is absorbed, this method is only effective when high vitamin B12 doses are consumed (1, 2). 

Intrinsic Factor – Limiting the Vitamin B12 Intake

Because foods tend to contain very small amounts of vitamin B12, it is vitally important that as much as possible is exposed to IF in the digestive system, to allow for adequate B12 absorption from the diet. Without IF it is very difficult to cover the body’s B12 requirement – and therefore reap the many benefits of this essential vitamin – through food alone. 

Intrinsic factor even affects how vitamin B12 supplements should be taken: small doses of between 3 – 10 µg should be administered at intervals throughout the day, to optimise B12’s uptake via IF. 

High Dose Vitamin B12 Bypasses the Need for Intrinsic Factor

Since this is likely quite inconvenient for most people and potentially unreliable, most supplements are dosed highly enough to allow for sufficient absorption via passive diffusion. This has been calculated at around 200 µg in most cases, however doses between 500 and 1000 µg per day are still safe. 

The Production of Intrinsic Factor

In the human body, IF is produced by the parietal cells in the stomach. If this secretion is disturbed in anyway and there is an IF shortage, vitamin B12 deficiency is likely to arise.

 The most common cause of B12 malabsorption is atrophic gastritis (type A gastritis), a chronic gastritis and autoimmune disorder in which the body produces antibodies that attack and destroy the parietal cells that produce IF.

A shortage of IF can also be the result of surgery that involves the removal of parts of the stomach (gastric resection, gastrectomy). Alcoholism is also known to affect the production of IF, as the stomach lining becomes inflamed.

Antibodies

There are other autoimmune disorders that impair the uptake of vitamin B12 by IF. In the case of these disorders, the body’s own antibodies attack the intrinsic factor. Two types of antibodies are distinguishable here:

IF blocking antibodies: prevent B12 from binding to IF.

IF binding antibodies: bind to the B12 and intrinsic factor complex, preventing it from attaching to receptors at the binding site in the small intestine. 

Both can be detected using special tests. 

The Impact of Intrinsic Factor Deficiency

As a consequence of IF deficiency, all vitamin B12 deficiency symptoms can occur. The most severe include pernicious anaemia and funicular myelosis (subacute combined degeneration of the spinal cord). 

Intrinsic Factor and Calcium

For IF to bind to the receptors in the intestines, calcium is required. If the mineral is not present, B12 cannot be absorbed – even when there is a sufficient amount of IF. 

This is very relevant for diabetic patients, for example, who are taking the medication Metformin. This has a negative effect on intestinal calcium levels, which is why many Metformin patients develop B12 deficiency over time. This can be prevented by administering high doses of vitamin B12 (300-1000 μg), which are absorbed directly via passive diffusion. It can also be compensated by taking an additional high dose of calcium – as studies have shown (3). 

Some vitamin B12 supplements therefore contain calcium to optimise absorption.

Intrinsic Factor Test

Today, IF deficiency is usually detected indirectly through a test for IF antibodies.

For a long time, the so-called Schilling test was used for this purpose, but it is no longer available today. Here patients were administered radioactively labelled B12, before the uptake was measured.

Intrinsic Factor for Vegetarians and Vegans

The highest concentrations of vitamin B12 are found in meat. From offal through lean meat, to milk and lastly eggs; the concentration of B12 decreases. The lower the concentration of B12 in the diet, the more important the active intake via IF.

If this intake pathway is impaired, a B12 deficiency can also occur in vegetarians who consume a lot of dairy – here B12 supplements are recommended. In any case, vegans usually always require B12 supplements. 

Sources

1. Abels, J., Vegter, J. J. M., Woldring, M. G., Jans, J. H. and Nieweg, H. O. (1959), The Physiologic Mechanism of Vitamin B12 Absorption. Acta Medica Scandinavica, 165: 105–113. doi: 10.1111/j.0954-6820.1959.tb14477.x
2. Berlin, H., Berlin, R. and Brante, G. (1968), Oral Treatrment Of Pernicious Anemia With High Doses Of Vitamin B12 Without Intrinsic Factor. Acta Medica Scandinavica, 184: 247–258. doi: 10.1111/j.0954-6820.1968.tb02452.x
3. Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000 Sep;23(9):1227-31. PubMed PMID: 10977010.