Entero-hepatic circulation of B12 – or Why don’t vegetarians get B12 deficiency?

When you stop eating B12 in your diet (for example by becoming a vegetarian), you may not notice if it on your B12 level for 10 years or more.

Conversely, when you develop a condition like pernicious anaemia, the effects can be devastating and very fast. We wondered why this was?

B12 stores in the body

The body stores 2-5mg Vitamin B12, of which around 80% is in the liver[1, 2]. B12 in the blood circulates either bound to Transcobalamin I or III, (the inactive forms), or transcobalamin II (active B12, or holotranscobalamin). Active B12 is 7%-20% of total blood B12, but this percentage varies [3-7].

Inactive B12 can't be converted to active B12, either in the blood, or in the liver.
The Recommended Dietary Allowance/Recommended Dietary Intake (RDA/RDI) of vitamin B12 is around 2.4 µg per day[7], though it should be higher for people older than 51 years old.

Circulation via the liver, bile duct and small intestine

To get the active form, the body takes inactive forms from the liver (and the liver can take it from the blood), and pumps it out into the top of the small intestine through the bile duct

 B12 in the gut then combines with Intrinsic Factor from the stomach and can be absorbed by the villi of the small intestine to combine with TC-II and form holotranscobalamin.

This this enterohepatic circulation is also used for, for example: fatty acids and phospholipids [8-10], so it may be the most efficient way of converting stores for use in the body.

The Car Oil Sump analogy

The body doesn’t show signs of B12 deficiency until the level of active B12 drops below a certain level (probably around 50 pmol/L = 67ng/L). This means that the level of B12 in the blood can vary enormously, from over 2000µg/L down to the threshold (see discussions and Signs & Symptoms)

The level of B12 may be dropping, but the problem won’t be detected until it falls below a threshold causing symptoms.

This is exactly what happens in a motor car engine. Oil is pumped into the top of the engine and trickles down, lubricating all parts, until it gathers in the oil sump at the bottom of the engine. There is usually plenty of oil in the engine, and the oil pump will continue circulating oil even when the level drops a very long way below normal, as might occur perhaps with an oil leak (faulty seal, crack in the sump, etc). Checking the dip stick might reveal that levels are at the low end of normal, and need topping up, but we don’t check B12 levels in people (perhaps we should?).

Once the level of oil in the engine falls to the point where the oil pump can’t pump enough back up to the top to keep the engine lubricated, then you have a disaster on your hands – things will start to seize up; con rods will stick themselves to prop shafts, cam shafts will grind out of shape against tappets, the engine could become a wreck in a matter of minutes. Most engines have a warning light which informs us that the oil is running low, well before there is a problem. Sadly, humans don’t have this warning light for B12 shortage.

How long does it take to use up B12 stores?

So we know that the level of B12 in the body is usually large (Chanarin calculated, for example, that it should take 7 years to use up the body’s supply of B12 at 2µg/day (2 µg/5 mg = 2,500 days =approx. 6.8 ys) [11] – forgetting that B12 is water soluble and will therefore eliminate from the body via the urine if not kept topped up.

In our experience the circulation of B12 appears to be remarkably efficient; you can eliminate B12 from your diet by becoming a vegetarian and you may not suffer from B12 deficiency for up to 15 years (Hugo Minney – personal experience; Kevin Byrne – personal experience). On the other hand, if you have a problem with absorbing B12 from the gut, then not only do you have a problem absorbing B12 from your diet, but the entero-hepatic circulation system (“entero” – within or through; “hepatic” – the liver (dative form for to, within, through) ie circulation via the liver, bile duct and small intestine) also breaks down – B12 is secreted into the small intestine but then can’t be re-absorbed so the body’s levels of stored B12 will continue to drop dramatically

Once B12 runs out, the level of active or available B12 in the blood will fall suddenly and dramatically In Dr Chandy’s practice, we observe people with Serum B12 above the threshold (180µg/L at present) who exhibit signs and symptoms of deficiency (qv … ) but we are not allowed to commence treatment. We know from experience that once they exhibit signs and symptoms their serum B12 is already falling and it is no longer than 6 months and often considerably less before their serum B12 falls to a level where we can commence treatment.

It is absolutely vital at this stage to commence treatment as quickly as possible. Apart from the obvious discomfort to the patient caused by symptoms, we believe that there is a limited “window of opportunity” before the symptoms change from reversible to permanent[12].

What this means for treatment

Those at risk of B12 deficiency, ie vegetarians, the elderly, people taking PPIs (antacids for example), anyone who has had Gastro-intestinal surgery (eg gastric band, any ileal resections), and people with B12 absorption difficulties (eg presence of Intrinsic Factor antibodies) should consider taking oral B12 prophylactically (just in case)[7, 13]. Harrison’s ‘Principles of Internal Medicine’ 16th edition (2005) also indicates that people with diabetes and renal imbalance should also consider taking B12 prophylactically.

Those whose levels of serum B12 are falling should be monitored. We believe that the UK and USA should recognise both severe deficiency (200 µg/L), and preclinical, or interim deficiency (serum B12 less than 350 ng/L and raised MMA) [7, 14, 15]

At treatment initiation, patients need a ‘loading dose’ of very large quantities of B12 over an extended period to replenish the body’s stores – this is the recommendation of the British National Formulary but is often not adhered to[16, 17]. Once B12 treatment has commenced, we should assume that the B12 circulation “has a leak”, and that treatment should continue for life. We observe that some patients reverse all of their symptoms including problems absorbing B12, but this should be assumed to be the exception rather than the rule.

Documents referred to

1. Vegetarian Society. Information Sheet: Vitamin B12. 2009 [cited 2010 4 August 2010]; Available from: http://www.vegsoc.org/info/b12.html.

2. Chanarin, I., The megaloblastic anaemias. 1969, Oxford,: Blackwell Scientific. vii, 1000 p., 23 plates.

3. Nexo, E., et al., Quantification of holo-transcobalamin, a marker of vitamin B12 deficiency. Clin Chem, 2002. 48(3): p. 561-2.

4. Nexo, E., et al., Holo-transcobalamin is an early marker of changes in cobalamin homeostasis. A randomized placebo-controlled study. Clin Chem, 2002. 48(10): p. 1768-71.

5. Wickramasinghe, S.N., Diagnosis of Megaloblastic anaemias. Blood Reviews, 2006. 20(6): p. 299-318.

6. McCaddon, A., et al., Analogues, ageing and aberrant assimilation of vitamin B12 in Alzheimer's disease. Dement Geriatr Cogn Disord, 2001. 12(2): p. 133-7.

7. Park, S. and M.A. Johnson, What is an Adequate Dose of Oral Vitamin B12 in Older People with Poor Vitamin B12 Status? Nutrition Reviews, 2006. 64(8): p. 373-378.

8. Vazquez, C.M., F.J. Muriana, and V. Ruiz-Gutierrez, Changes in fatty acid desaturation in hepatic and intestinal tissues induced by intestinal resection. Lipids, 1993. 28(5): p. 471-3.

9. Hendel, J. and H. Brodthagen, Entero-hepatic cycling of methotrexate estimated by use of the D-isomer as a reference marker. Eur J Clin Pharmacol, 1984. 26(1): p. 103-7.

10. Ejiri, K., [Studies on entero hepatic circulation of urea nitrogen in pregnant rat (author's transl)]. Nippon Sanka Fujinka Gakkai Zasshi, 1980. 32(5): p. 601-10.

11. Chanarin, I., The Megaloblastic Anaemias. 3rd ed. 1986, Oxford: Blackwell Scientific Publications.

12. Chandy (Kayalackakom), J., A forgotten illness - Vitamin B12 Deficiency with Neuro Psychiatric signs and symptoms with or without Anaemia or Macrocytosis. 2006: Durham, UK. p. 26.

13. Baboir, B.M. and H.F. Bunn, Pernicious Anaemia, in Harrison's Principles of Internal Medicine. 2005. p. 601-607.

14. McBride, J. B12 Deficiency May Be More Widespread Than Thought. Agricultural Research Service 2000 2 Aug [cited 2009 2 Oct]; Available from: http://www.ars.usda.gov/is/pr/2000/000802.htm.

15. Mitsuyama, Y. and H. Kogoh, Serum and cerebrospinal fluid vitamin B12 levels in demented patients with CH3-B12 treatment--preliminary study. Jpn J Psychiatry Neurol, 1988. 42(1): p. 65-71.

16. BNFC, British National Formulary for Children. 2008, Paediatric Formulary Committee, BMJ Publishing, RPS Publishing and RCPCH Publications.

17. BNF, British National Formulary. 2009, Joint Formulary Committee, British Medical Association & Royal Pharmaceutical Society of Great Britain, JFC.