Symptoms of B12 deficiency are generally non-specific, that is, they could be caused by a number of different things.  It's only when you have a number of different symptoms, occurring at the same time, that it makes sense to look for a common cause such as B12 deficiency.

And of course your GP (General Practitioner, Family Practitioner, Primary Care Doctor) is always where you should start.  You may know your symptoms better than anyone, but your GP knows what to do about them - as long as you are prepared to discuss them openly and honestly.

Your doctor should ask about your symptoms, your family history, and some other information (such as whether you are vegetarian, drink or smoke a lot, take Nitrous Oxide - yes people die because NO2 stops the B12 working), and will usually then take blood for a blood test for, amongst other things, MCV, U&E, Folic Acid, B12.  MCV (Mean Cell Volume) tells if you have undersized cells (a sign of anaemia/anemia or iron deficiency) or oversized cells (macrocytosis - a sign of problems in the folic acid pathway exacerbated by B12 deficiency and used to diagnose Pernicious Anaemia/PA/Pernicious Anemia), and the rest highlight what other conditions may be causing problem.  For example, protein in the blood tells the doctor a whole lot of things.

Laboratory results

Sometimes the GP will rely on the lab to say whether someone has B12 deficiency or not - but labs all use different thresholds and really it is up to the GP, who has you in front of them, to include the B12 level in their assessment of what is the cause of your symptoms.  Many labs in UK use a threshold of 180ng/L or 200ng/L - above this you are fine, below this you are deficient.  But other countries use different thresholds and there's a growing body of evidence that even if the threshold were twice this (400ng/L or 300pmol/L - these are the same amount in different units), it would still miss some people.  We believe that doctors should use signs and symptoms to diagnose B12 deficiency, and that blood serum B12 level is useful information but not the only information to take into account.

Therapeutic trial

Ultimately, the best way to tell if B12 deficiency is the problem, is a therapeutic trial of B12 injections (hydroxocobalamin, methylcobalamin, but preferably not cyanocobalamin).  This should be in the form of a “loading dose”, ie 2 weeks’ of alternate day injections 1mg (1000mcg).  If the symptoms remain then they were caused by something else (this isn’t always the case; for example if you have severe MS then you may need other things eg Vit D, thyroxine, cortisol to kick start your body again for a short period whilst the B12 stabilises everything and restores the hormones to their normal balance and gets you out of doors to get your Vit D performing); if you get relief then B12 is of value. 

 B12 isn’t the answer to everything, and your GP will make a differential diagnosis to exclude other conditions which could need urgent treatment.  But many of the “difficult” conditions such as Chronic Fatigue Syndrome, loss of power in a limb, pins and needles, difficulty swallowing, difficulty controlling the eyeball (especially where this is one-sided), neuroses, dementia (well, that’s the main neurological ones + fatigue – there are also symptoms related to hormones eg unexplained hair falling out, digestive problems, gynaecological problems including heavy periods, etc) all seem to get a whole lot better with lots of B12 intake.

Is B12 safe?

Your doctor has a duty of care - he or she must take care that the treatment they are offering isn't worse than the disease it is supposed to cure. So they have to ask "is B12 safe?".

In 2004, the European Union published a report of studies they had done on a whole range of nutritional supplements (B12 isn't a medicine it is a nutritional supplement) which showed the upper safe limits that people could consume of things like black cohosh, vitamin C and so on.  Vitamin B12 was declared 'completely safe at any level' (well the EU report used a lot more words and wasn't so exciting, but it was definite).

Since then, scientists in Japan and USA have started testing B12 as a cure for cancer.  They use very high levels, using B12's feature that it helps DNA transcription.  This is currently being done in mice, not yet in humans (although a dear friend has a neck tumour which is inoperable because a slip during the operation would leave him paralysed and quadraplegic, and he's using high doses of B12 and the consultant has told him that it seems to be working - the tumour is smaller and our friend is back on his feet and back to racing all over the place being busy).  So the scientists have tested B12 levels in the mice at 100million times the pharmacological dose, with no signs of toxicity.

B12 doesn't interact with any medication that you may be taking.  I think it is fair to say that B12 is completely safe, and your doctor can run a therapeutic trial without any worries about safety.

Does B12 deficiency cause folate deficiency?  Is it the other way around?  Can you tell if you are folate-deficient or B12 deficient?  can one cure a deficiency of the other?

B12 AND FOLATE: The evidence is still unclear.  We know that folate is a methyl-donor, but appears not to be able to donate where it is needed.  We know that B12 is a methyl-donor (at least for its interaction on DNA transcription), so it's our opinion (without evidence) that B12 supplements may not have their full impact if the folate is deficient.  Our view of how it works is that if folate is deficient, then B12 can't give up its methyl group to the DNA to control which genes are read. 

DNA reading is best described like using a cookbook.  You bounce into the kitchen with a pile of ingredients (the cell has a vast number of amino acids and needs to make proteins).  You work out that you need a cake (the cell needs some more cell membrane gates to let in ions which allow it to react to the world outside).  The cookbook lies open so you start making the recipe, only it isn't at the right page so you make the wrong thing and "waste" a whole lot of ingredients (DNA requires methyl groups to switch genes on and off, by covering up the start sequence of each gene.  If there isn't enough material to switch genes off (or shut all of the other pages so you are only looking at the cake recipe), then the body could make the wrong proteins resulting in no ingredients to make the right proteins - and at worst, cancer).

B12 is vital to this process by donating its methyl group, but it appears that it needs folate to back it up to do this effectively.

Up until now I've thought that this was just a minor part of B12's vital activities, perhaps the slowest to react.  I'm now beginning to think that it plays a more important and immediate role.

The other things B12 does are:

* remove toxins (it binds with them and passes out in the urine, which means it sacrifices itself.  So if you smoke, for example, you will probably be B12 deficient because the B12 has been sacrificing itself to remove toxins)

* the energy cycle and mood (B12 plays a part in the Krebbs cycle - technically not a very important part but the body appears to need it to produce energy.  In this role, it takes homocysteine, a low-mood chemical, and converts it so people's mood rises)

* lipid metabolism.  This appears to be its most important role, though see above we're having a re-think.  This applies to:

 - nerve cell membranes, ie deficiency causes neural degeneration both CNS and PNS, including pins and needles, paralysis, cognitive and memory problems when the Swann cells which cover nerve axons break down.  Depriving mice of B12 causes both the symptoms and the characteristic plaques of MS, and restoring the B12 causes healing

 - immune system relies on proteins embedded in the cell membrane.  If the membrane goes wrong then the immune system usually stops working, resulting in lots of autoimmune conditions and inability to stave off minor illness

 - endocrine system similarly relies on lots of proteins in the cell membrane (see example of DNA reading above), and if the proteins can't detect the hormones eg if they are on their side or upside down, then the whole endocrine system goes to pot.  This results most visibly in infertility and abnormal uterine bleeding, but also hyper/ hypo thyroidism etc

So our view isn't that B12 causes folate deficiency nor that folate can cure B12 deficiency, but that both are needed at the same time.  The key difference is that folate can be not so good for you in overdose, but there is no such thing as an overdose for B12.  So take the right amount of folate to push your folate level towards the top of the normal range, but take any amount of B12.

We have little experience of the Active B12 test.  We suspect it is a red herring until there is a lot more work done to find the variation in active B12 levels in normal people and in people with symptoms.

A dear friend sent me this article to comment on http://www.livestrong.com/article/333971-the-side-effects-of-excessive-vitamin-b12-on-the-liver/.

Is it possible that excessive levels of B12 could be dangerous?  The pharma companies certainly want us to think so.

Let's examine the facts:

1. there is a lot of B12 in the liver.  B12 used to be produced from Liver Extract, and anyway, there is so much blood in the liver that it will always contain a lot of B12.  There's some suggestion that the way the body converts stored B12 (mostly floating around in the blood in an inactive form, we think) into active B12 is by removing it to the gut and re-absorbing (entero-hepatic circulation).  So that's TRUE
2. excess B12 is excreted by the kidneys. B12 attached to toxins is also excreted by the kidneys.  In fact the main loss of B12 from the body is probably B12 attached to toxins such as alcohol, tobacco products, heavy metals (such as lead, caesium, arsenic, etc), cyanide (from smoke), and so on, which is likely to be one of the main reasons why taking poisons damages your health - because it reduces the body's supply of B12.  So far so good - the article has a couple of TRUE bits.
3. what level of B12 do they consider excessive?  One of the commentators points out that  humans have been dosed with very high levels of B12 (54000pmol is the same as 73,000ng/L) for medicinal purposes, and even children hav been dosed with 10,000ng/L for medicinal purposes.  That's a lot higher than the normal range of around 500-1100ng/L in a healthy adult.  These levels are considered safe, and not just save in strong adults, but safe in weak, sick people too.  I've heard that B12 is being tested as a cure for cancer, and high levels around 1000 times this have been tested in mice with no ill effects. So B12 is NOT toxic at any level so far tested - it is completely safe.
4. many of the symptoms they talk about could be expected in someone with B12 supplements.  That's because you only take supplements if you have been deficient, and if you have been deficient then you are quite likely to get these symptoms of deficiency.  It's like saying that because so many people with plaster casts on their arms have broken bones, the plaster casts cause the broken bones.  Or that having a car forces you to work further away from your house.
5. Primary biliary cirrhosis - the article talks about damage and scarring of the liver, usually caused by an autoimmune condition.  Severe B12 deficiency often causes autoimmune diseases such as Pernicious anaemia (intrinsic factor antibodies or parietal cell antibodies attacking the parietal cells), Hashimoto's, and of course this rather rare liver damage.  They often occur together with CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) which is thought to be an autoimmune symptom. If a person has this form of liver damage, then they are likely to take B12 supplements to stop the deficiency.  The important question is "which came first?"  I could look at the number of people with broken bones who are wearing a plaster cast.  It would be "natural to conclude" that wearing a plaster cast breaks the bones beneath it - is that what this author is getting at?
6. side effects - I went looking on Drugs.com.  They describe side effects that we have already referred to on our own web site - people starting on B12 supplement after severe deficiency often find that they are "reversing" back out of the symptoms on their way to wellness.  So we would expect that.  They also write about headaches, but are quick to point out that these headaches occur with cyanocobalamin, which is our observation too - for patients who can use cyanocobalamin, they release cyanide into the blood stream which for many people causes headaches (don't worry, at this concentration it's annoying rather than fatal).  That's why we always say "don't get cyanocobalamin"

Which brings us on to the next question - who pays for "research" like this?  Who stands to gain?  People who want you to buy expensive medication perhaps?  

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.

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.

 Please note: a variety of sources of evidence is given here. Some are from peer-reviewed sources (medical journals) and some are more popular. The scientific community gives little credibility to non peer-reviewed sources; however they are often easier to read.

DNA and genes

Each and every working cell in the human/every living thing body contains a nucleus and the nucleus basically consists of DNA and its protective proteins. The DNA contains the blueprints to every protein the body makes, and the proteins then make everything else happen including consuming food, growing, moving, thinking, fighting off disease, hormones etc).

B12 seems to mainly affect which genes are read when – but this in turn affects

• how DNA is copied (which could affect whether mutations get passed on to daughter cells and the next generation of children)(Piyathilake, Johanning et al. 2000; Elias, Peeters et al. 2005),
• when a particular gene switches on and off (many long-term conditions such as obesity, diabetes, heart disease are affected by whether a gene is left switched on too long. Cancer is a particularly clear example of a gene not being switched off in time)(Piyathilake, Johanning et al. 2000; Elias, Peeters et al. 2005)

Mood chemicals

A low mood or depression chemical, homocysteine, are converted to chemicals important to the body by a process involving B12. This is so sensitive that high levels of homocysteine have been used as an indicator to decide if someone has B12 deficiency, though other things can cause high homocysteine so this may not be a particularly specific test for B12 deficiency (Nilsson, Gustafson et al. 1994).

The result of low B12 (or B12 lower than the body needs) is that this low mood chemical accumulate and the sufferer feels a non-specific depression or sadness, which combined with many of the other symptoms such as tiredness can lead to a spiral downwards in mood.

Excess of homocysteine may also lead to dementia (loss of cognitive function which means the inability to think or remember)(Diaz-Arrastia 1998; Diaz-Arrastia 2000; Hultberg, Isaksson et al. 2001). B12 deficient patients notice this because dementia or poor memory and thinking may come and go (similar to the relapsing/ remitting nature of multiple-sclerosis). The problems may be solved by B12 in isolation, or may require a combination – for example B12 and folic acid work together on many pathways including the homocysteine pathway (Nilsson, Gustafson et al. 2001).

Energy production

Once foodstuffs get into the cell they are transported to organelles (literally “little organs”) called mitochondria, which produce energy. Basically they take sugars, fats, any carbohydrates they can lay their bits on, and turn them into energy (not sparks of electricity, the body’s universal fuel ATP – which you can’t buy in shops because it is too powerful and unstable).

The mitochondria have different transport proteins to get the B12 in(Coelho, Suormala et al. 2008), and then B12 is absolutely vital for the production of energy in the mitochondria. People suffering from B12 deficiency often find they lack energy, can be extremely tired and at the same time not have the energy to get to sleep at night(Coelho, Suormala et al. 2008; Miousse, Watkins et al. 2009; Myhill, Booth et al. 2009).

If left untreated, this results in the wasting disease reported by Combe (1824), Addison (1859), Russell (1900) and many others reported in (Chanarin 1969) in the 19th C and throughout the 20th C as ME, Post Viral Chronic Fatigue Syndrome, Fibromyalgia

Lipid processing in particular Cell membrane manufacture and maintenance

Cell membranes are vital for all sorts of things. Examples include nerve cell conduction (next), endocrine system (all of the hormones), digestive function, immune function

Nerve Maintenance – the nerve signal is transmitted along an axon (the wire) surrounded by a myelin sheath (the insulation). The myelin sheath is essentially a special cell which wraps itself around the axon many times forming many layers of cell membrane – and as the cell membrane is made up of lipids this is an insulating layer allowing the signal to travel down the nerve.

The myelin needs B12 to build itself and repair (most cells go through a natural cycle of break down and repair, and if the repair doesn’t work then the natural cycle continues to break down the sheath). Without the myelin sheath, the nerve can’t transmit a signal. Eventually the nerve gives up and dies. (Scalabrino 2009)(Scalabrino, Veber et al. 2007)

People suffering from B12 deficiency experience this damage in a number of ways – for example shooting pains, pins and needles, numbness, paralysis and/or loss of power or grip; if left untreated it can result in Multiple Sclerosis(Scalabrino 2005; van Rensburg, Kotze et al. 2006; Ascherio and Munger 2007; Solomon 2007; Kocer, Engur et al. 2009; Scalabrino 2009; Stewart 2009; Turner and Talbot 2009). In particular, the nerves in hands and feet which are unmyelinated, for detecting temperature and vibration, may be particularly sensitive to B12 deficiency and may lead to the numbness and pins and needles which people report as early symptoms (Smith, Ali et al. 1991)
Demyelination can also show up as ‘the fogs’, a feeling of confusion and not being able to think. Of course there are bundles of nerves to the eye, the tongue, the throat, so a shortage of B12 can cause blindness (especially in one eye), inability to swallow and so on (see http://b12d.org/content/B12-signs-symptoms-assessment-form).

One characteristic of B12 deficiency is a loss of balance – there’s a particular sideways walk called ataxia which is characteristic of B12 deficiency.(McBride 2000)

Scalabrino in Italy showed that when a mouse is deprived of B12, it first develops symptoms like Multiple Sclerosis (MS), and eventually develops the characteristic plaques that define MS (Scalabrino 2005). What more proof do you need of a connection?

Immune system – also uses the cell membrane; special cells can detect ‘foreign’ and ‘self’ proteins in the body or on the surface of organisms like bacteria. Sometimes it breaks down and doesn’t recognise ‘self’; antibodies (the signals that call the phagocytes or cleanup cells to an infection) are produced and the immune system will start to destroy your body from the inside – a condition called an Autoimmune disease.

Autoimmune diseases can attack any part of the body (they usually attack a single type of cell). For example, one form of the condition produces antibodies to cells in the stomach, the parietal cells (Qureshi, Rosenblatt et al. 1994; Oh and Brown 2003).

Correspondence on the WD thread suggests that established autoimmune conditions seldom exist alone; Hashimoto's Thyroiditis seems to be a particularly common companion to PA. It's not an area that I have personal experience of, so I'm no expert. One writer, though (unfortunately no longer posting), was particularly good on the subject; he said that there's actually a kind of autoimmune quintet. If you develop one, then wait (or live) long enough, you'll eventually stand a chance of collecting the whole set - PA, Hashimoto's, Alopecia, Vitiligo, Coeliac.

He seemed to know what he was talking about, and he had the lot. He had gone looking for coeliac disease when he had realised that he had the other four, and had been persistent enough - via his GP and referrals - to have its presence diagnosed. I could find nothing on the Net connecting all five. There is, however, plenty of stuff connecting any two or three. (these last two paragraphs from Kevin Byrne) 

These will either show up as Parietal Cell antibodies or Intrinsic Factor (IF) antibodies, though they both have the same effect – it means the body starts to attack cells which produce all of the digestive chemicals in the stomach including hydrochloric acid, the proteases and intrinsic factor. Without intrinsic factor you can’t absorb B12, which means the autoimmune disease is likely to get worse. Your stomach may atrophy, which essentially means that it has died and doesn’t work.

There are a number of other autoimmune diseases; they can affect nerve cells, organs and so on. We believe that if your B12 is low then you could develop an autoimmune disease, though which one could depend on a variety of other factors.

With a mal-functioning immune system you will probably be prone to all sorts of other things like colds, cracked skin, fungal infections, infections and sores, etc.

Endocrine system – hormones control all the things that you don’t stop to think about: how you feel from moment to moment (angry, alert, relaxed, happy, ready for action); how you grow, the menstrual cycle, how you age, everything that isn’t controlled by nerves. 

The endocrine system also relies on cell membranes and special glands in the membrane to secrete the hormones. Lack of B12 can upset the cell membranes and the special glands, meaning hormones start to go wrong, in particular the thyroid hormones (Nilsson-Ehle 1998).

Mostly this shows up when a woman has irregular periods and can’t conceive (Menachem, Cohen et al. 1994; Elias, van Noord et al. 2005). But it can also show when you’re prone to disease, weepy or irritable all of the time (snappy), tired, depressed. But for long-term deficiency, you might see problems with growing and puberty. The sad thing is that if B12 deficiency goes on this long, the patient is probably very near death for other reasons.

Documents Relied On

Ascherio, A. and K. L. Munger (2007). "Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors." Ann Neurol 61(6): 504-513. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17492755 

Chanarin, I. (1969). The megaloblastic anaemias. Oxford,, Blackwell Scientific.
Coelho, D., T. Suormala, et al. (2008). "Gene identification for the cblD defect of vitamin B12 metabolism." N Engl J Med 358(14): 1454-1464. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18385497

Diaz-Arrastia, R. (1998). "Hyperhomocysteinemia: A New Risk Factor for Alzheimer Disease?" Arch Neurol 55(11): 1407-1408. http://archneur.ama-assn.org

Diaz-Arrastia, R. (2000). "Homocysteine and Neurologic Disease." Arch Neurol 57(10): 1422-1427. http://archneur.ama-assn.org/cgi/content/abstract/57/10/1422

Elias, S. G., P. H. Peeters, et al. (2005). "The 1944-1945 Dutch famine and subsequent overall cancer incidence." Cancer Epidemiol Biomarkers Prev 14(8): 1981-1985. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16103448
http://cebp.aacrjournals.org/cgi/reprint/14/8/1981.pdf

Elias, S. G., P. A. van Noord, et al. (2005). "Childhood exposure to the 1944-1945 Dutch famine and subsequent female reproductive function." Hum Reprod 20(9): 2483-2488. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15932913
http://humrep.oxfordjournals.org/cgi/reprint/20/9/2483.pdf

Hultberg, B., A. Isaksson, et al. (2001). "Markers for the functional availability of cobalamin/folate and their association with neuropsychiatric symptoms in the elderly." Int J Geriatr Psychiatry 16(9): 873-878. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11571767

Kocer, B., S. Engur, et al. (2009). "Serum vitamin B12, folate, and homocysteine levels and their association with clinical and electrophysiological parameters in multiple sclerosis." J Clin Neurosci 16(3): 399-403. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19153046

McBride, J. (2000, 2 Aug). "B12 Deficiency May Be More Widespread Than Thought." Agricultural Research Service Retrieved 2 Oct, 2009, from http://www.ars.usda.gov/is/pr/2000/000802.htm.

Menachem, Y., A. M. Cohen, et al. (1994). "Cobalamin deficiency and infertility." Am J Hematol 46(2): 152. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8172185

Miousse, I. R., D. Watkins, et al. (2009). "Clinical and molecular heterogeneity in patients with the cblD inborn error of cobalamin metabolism." J Pediatr 154(4): 551-556. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19058814
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WKR-4V2X6WG-2&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=7e9f3f06b65ad87a51774a739d3ed2d5

Myhill, S., N. E. Booth, et al. (2009). "Chronic fatigue syndrome and mitochondrial dysfunction." Int J Clin Exp Med 2(1): 1-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19436827

Nilsson-Ehle, H. (1998). "Age-related changes in cobalamin (vitamin B12) handling. Implications for therapy." Drugs Aging 12(4): 277-292. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9571392

Nilsson, K., L. Gustafson, et al. (1994). "Plasma homocysteine in relation to serum cobalamin and blood folate in a psychogeriatric population." Eur J Clin Invest 24(9): 600-606. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7828631

Nilsson, K., L. Gustafson, et al. (2001). "Improvement of cognitive functions after cobalamin/folate supplementation in elderly patients with dementia and elevated plasma homocysteine." Int J Geriatr Psychiatry 16(6): 609-614. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11424170

Oh, R. and D. L. Brown (2003). "Vitamin B12 deficiency." Am Fam Physician 67(5): 979-986. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12643357
http://www.aafp.org/afp/20030301/979.pdf

Piyathilake, C. J., G. L. Johanning, et al. (2000). "Localized folate and vitamin B-12 deficiency in squamous cell lung cancer is associated with global DNA hypomethylation." Nutr Cancer 37(1): 99-107. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10965526

Qureshi, A. A., D. S. Rosenblatt, et al. (1994). "Inherited disorders of cobalamin metabolism." Crit Rev Oncol Hematol 17(2): 133-151. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7818787
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T5S-4BWYMB2-25&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=332d6ca737fa1cbcaca09a77b64dfa86

Scalabrino, G. (2005). "Cobalamin (vitamin B(12)) in subacute combined degeneration and beyond: traditional interpretations and novel theories." Exp Neurol 192(2): 463-479. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15755562
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WFG-4FDJ6VP-1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=f5c81433d09be8ac1e3b28208b1e3913

Scalabrino, G. (2009). "The multi-faceted basis of vitamin B12 (cobalamin) neurotrophism in adult central nervous system: Lessons learned from its deficiency." Prog Neurobiol 88(3): 203-220. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19394404

Scalabrino, G., D. Veber, et al. (2007). "New pathogenesis of the cobalamin-deficient neuropathy." Med Secoli 19(1): 9-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18447164

Smith, S. J. M., Z. Ali, et al. (1991). "Cutaneous thermal thresholds in patients with painful burning feet." Journal of Neurology, Neurosurgery, and Psychiatry 54: 877-881. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1014571/pdf/jnnpsyc00508-0025.pdf

Solomon, L. R. (2007). "Disorders of cobalamin (vitamin B12) metabolism: emerging concepts in pathophysiology, diagnosis and treatment." Blood Rev 21(3): 113-130. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16814909

Stewart, G. (2009). "Multiple sclerosis and vitamin D: don't (yet) blame it on the sunshine." Brain 132(Pt 5): 1126-1127. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19372268
http://brain.oxfordjournals.org/cgi/content/full/132/5/1126

Turner, M. R. and K. Talbot (2009). "Functional vitamin B12 deficiency." Pract Neurol 9(1): 37-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19151237

van Rensburg, S. J., M. J. Kotze, et al. (2006). "Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis." Metab Brain Dis 21(2-3): 121-137. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16729250

No animals can digest the cellulose that makes up plants.  Some animals such as cattle and sheep (ruminants) get around this by filling their stomach with bacteria, fungi and yeasts.  These microbes can digest cellulose and manufacture a whole range of nutrients (including B₁₂) which the cattle and sheep can then absorb.  The microbes get a safe place to live and the cattle and sheep can use the grass and leaves they eat. The microbes produce a lot of B₁₂  and all of that extra vitamin B₁₂ gets stored in the muscle and meat for us to eat. 
However we know that modern farming methods require farmers to inject B₁₂  (90% of the world’s production of Vitamin B₁₂  is for farm animals).  It could be because of the speed animals are grown, or pesticides/ fertilisers on the grass, or antibiotics fed to keep the animals free from disease.

Natural cattle and sheep probably have very high levels of B₁₂ in their meat.  If a farmer injects B₁₂, he or she will only do so if it’s really needed, and will only inject enough to grow the animal fast.  Therefore we’re probably getting less than we used to from our food.

Microwave ovens

B₁₂ is a robust molecule and survives cooking.  One of the few things that can break it is a microwave oven.  Even if you don’t use a microwave yourself, it’s possible that foods containing B₁₂ have been irradiated to stop microbes growing, which might break down B₁₂.

I have a theory.  Now I must tell you that I’m not a doctor and have no medical qualifications so I can’t advise you; but I can share my experience.  In the past, Caucasians (white Europeans and colonists) got our B12 from meat.  People living nearer the equator had more vegetables in their diet, so if they weren’t really efficient at “scavenging” B12 – recycling it very efficiently, they died and were out of the gene pool, but Caucasians were under less pressure (if they didn’t have enough meat, starvation was a more important problem than the lack of B12) so now around 40% of the population has less efficient B12 recycling.  This means that we need B12 in the diet probably every day.

B12 is manufactured by bacteria in the guts of ruminant animals (cows, sheep) and in the guts of some other animals (eg rabbits and rats get their B12 by coprophagy – actually humans have the same bacteria but we don’t eat our own stools – see Gruesome facts on our web site!).  So we get our B12 by eating meat.  But cattle used to be slaughtered for the table at 36 months, after they had had plenty of time to get B12 into the muscle, whereas they are now slaughtered at more like 13 months.  The food they eat may not have enough Cobalt – without cobalt the bacteria can’t manufacture B12.  The result is, 90% of the world’s manufactured B12 is injected into farm animals to help them grow, and profit-conscious farmers are only going to inject enough to ensure the animal grows, not a whole lot extra so it can be stored in the meat for the human consumer.

Added to this, the meat is passed through microwaves on the way through the abattoir so that it keeps better.  B12 is a very strong molecule but about the only things that destroy it are microwaves and UV light; when you warm your food in a microwave you can say goodbye to the B12, but it was probably already destroyed well before it got to your freezer.

We go a whole stage further in our efforts to be sick.  We diet.  We take antacids and PPIs which prevent the stomach digesting the food, so B12 from meat sources isn’t freed up to be absorbed.  We add gastric bands and GI surgery.This means that more people than ever before have less B12 in their diet.  The 60% who are still highly efficient with B12 can probably manage on this small amount, but the rest of us need additional supplies; some of us have developed real difficulties absorbing B12 (probably as a result of B12 deficiency which can cause autoimmune diseases such as the development of parietal cell antibodies and IF antibodies) so we need it by injection.  Once you find out that injections solve your problems, you might want to try experimenting using oral treatment – methylcobalamin tablets for instance in case this is sufficient for you.  I function much better with injections, but if I set my sights low (ie was prepared to put up with poor memory and tiredness) then I’m sure I could get by on tablets

Vitamin B12 is manufactured by microorganisms in the gut of many animals.  Mostly in our diet, humans get it from ruminants, that is, cattle and sheep.  They have special stomachs called "rumen" which are pots of microorganisms busily digesting grass and turning it into organic chemicals that animals can use, and one of these is B12.

But if you aren't getting your B12 from the cow (for example, you are vegetarian, or you can't absorb, or the cow isn't manufacturing B12 because it can't get cobalt or it is eating corn instead of grass) - what then?

Manufactured B12

Humans do manufacture B12 artificially.  It isn't very artificial - basically we set up a big jar with the microorganisms from a cow's stomach, and filter off the good stuff and separate out the B12 from this - but it is  artificial.  

Most of this B12 is manufactured as cyanocobalamin.  That means that cyanide is attached to the space called "R".  Cyanide binds very strongly to molecules, so this form of B12 can survive heat, cold, sunlight, and various other things that punish B12.  Unfortnuately it is also so strong that many humans can't make use of it - they can't free up the cyanide to release the B12.

Also (this is also a bit unfortunate) your kidneys are on the lookout for cyanocobalamin, the same way that they are on the look out for cobalamin attached to any other poisons (heavy metals, etc).  They flush it into your urine, which isn't the best use of the money you spent getting your B12.

So we recommend methylcobalamin or adenosylcobalamin.  They are exactly the same, only they are versions of B12 that you would find in your own body - methylcobalamin is the usual one that floats around in your blood and goes into your cells, and adenosylcobalamin is used in the mitochondria in your cells which make energy.

if you take B12 in one or other of these forms, your  body can use it most quickly.  Another popular form for injection is hydroxocobalamin, but this has to be convereted into methylcobalamin before it can be used by your body.

Injection or tablet?

in theory, you can absorb B12 from tablets, even if your intrinsic factor isn't working.  Also in theory, you can use sublinguals (tablets you place under your tongue) which will absorb much more quickly into the blood stream.

So why don't tablets seem to work?

In our experience, people get better from their symptoms with injections, even if tablets can stop their symptoms getting worse.  So we recommend injections if possible, and if you really need a lot of B12 (and some people do), then have both.

Mixture?

different organisations have developed different mixtures in the same tablet.  For example, with modern diets in a developed country, you can be just about sure that the processing that happens to your food means you will be short of something.  I'd always recommend taking a low cost multi-vitamin multi-mineral tablet each day.  It won't give you much B12, but it will make sure you aren't suffering badly from something else.

Recently one manufacturer (No Shot) has started manufacturing B12/ B6/ folic acid tablets.  This particular combination is shown to be especially effective at stopping dementia, and if it works on dementia then it is probably good for any form of B12 deficiency (note again - tablets stop symptoms getting worse, they don't get you better).  So we wondered why?

It is probably that vitamins work together.  For example, B12 needs to change form from methyl to adenosyl and so on.  Folic acid is a very good methyl donor.  That means that it can both accept and give a methyl group to B12, which means the B12 can change more easily - a bit like holding my coat when I'm changing.  Very useful, thank-you!

Keep the questions coming!

The section on B12 deficiency starts around 13:38 and includes an interview with Martyn Hooper and Prof John Hunter

http://www.bbc.co.uk/radio/player/b01mdfc0

Martyn Hooper was diagnosed after he felt tired and unable to work, but did not originally suspect Pernicious anaemia

Prof Hunter speaks about how B12 deficiency comes about, including the impact of many drugs and on gut flora and fauna.  He also highlights that the current blood test is failiing and the threshold limits should be raised at least to 300ng/L.

Dr Mark Porter then says that his patients say the B12 injections don't last long enough.  So need to bring forward the time of the injections.  The book and local labs say only treat every 3 months, but Prof Hunter confirms that patients should receive injections when they need it, which may be much more frequently than in the "book".

The lack of flexibility from GPs results in patients self-medicating and even going for expensive infusions.