Some Thoughts on the Subject of Vitamin B12
Vitamin B12, also known as Cobalamin, is a critical and very complex essential vitamin within the human body. It has to be absorbed from food, as we cannot manufacture it ourselves.
I became interested in B12, as it seems to affect many thyroid patients. Thyroid disease seems to make low B12 more likely. This might be due to the fact that low B12, makes T4 to T3 conversion worse. Low thyroid hormone may also make the absorption of B12 from food or supplements less effective. Thyroid disease is often cause my autoimmune disease (Hashimoto's thyroiditis), and we know that where there is one autoimmune disease, others can be present also. Anyway, let me discuss B12 in more detail and why it is so important to investigate it properly.
B12 is used in the process of making good quality red blood cells. If B12 is too low, we cannot make the quality of red blood cells needed to carry oxygen around in the body. Sometimes, it affects the number of red blood cells produced and it can cause the ones that are made to die off early. Red blood cells are cycled within the body every 3-4 months, but they can die off and be recycled far sooner if B12 is low.
Low B12 results in a condition known as anaemia. Anaemia, is the most common disorder of the blood. It is caused by either a low or below average number of red blood cells in the blood, or less than the normal amount of haemoglobin in the blood. If a patient has the normal number of red blood cells but they have lower than normal haemoglobin, then the patient is usually diagnosed as having 'iron deficiency anaemia', as iron is used to make the haemoglobin (and it is usually low iron levels that have caused the problem). Low iron can therefore impact the ability to carry the oxygen around, because the oxygen is carried in the haemoglobin. Iron deficiency anaemia is often detected by low Haemoglobin in a Full Blood Count (FBC).
However, I am going to restrict myself here to the topic of B12. As mentioned above, low B12 can impact the quality and the number of red blood cells, as it is needed to make them in the bone marrow. Low B12 may be present with, or without Pernicious Anaemia, which is an autoimmune condition where the body attacks itself and cannot make enough Intrinsic Factor in the stomach. The Intrinsic factor is essential so that the B12 is absorbed in the small intestine (in the ileum - the last stage of the small intestine).There are at least two types of autoantibodies that can cause pernicious anaemia. One type, anti-intrinsic factor antibodies, attacks the intrinsic factor itself. The other, parietal cell antibodies, attack the parietal cells in the stomach that make the intrinsic factor (and parietal cells also make our stomach acid). Anything that disrupts the parietal cells can also reduce the level of intrinsic factor, e.g. helicobacter pylori bacteria.
When B12 deficiency is severe this can reduce the number of red blood cells in the body and someone could have a low RBC (red blood cell count). Very low B12 can also cause the red blood cells to enlarge and be less effective in carrying oxygen. This can be measured by the MCV (mean corpuscular volume). Both RBC and MCV are also present in a FBC, but there are problems with detecting low B12 that I will discuss in this article.
I have just been reading Martyn Hooper's excellent book: 'What you Need to Know about Pernicious Anaemia and Vitamin B12 Deficiency'. I was prompted to write this as I have just read that research has shown that there is an approximately 40% prevalence of B12 deficiency in hypothyroid patients! Staggeringly high. Whether this is because many hypothyroid patients have the autoimmune condition Hashimoto's thyroiditis and pernicious anaemia is another autoimmune condition I don't know.
However, I do know that the diagnosis and treatment of low B12 in all its forms is far from straightforward.
Let me give a brief summary of some of the numerous symptoms of B12 deficiency:
- Tiredness / fatigue.
- Shortness of breath.
- Inability to do exercise like you once did.
- Brain fog / confusion / memory problems.
- Pins & needles / numbness (esp. legs/feet) / nerve damage (can be permanent).
- Worst case with pernicious anaemia and very low B12 - spinal cord damage, brain lesions and serious nerve damage.
- Balance / coordination / clumsiness.
- Hair loss.
- Mood changes / irritability.
- Almost any neurological problem from anxiety, panic to depression because low B12 affects the red blood cells and the nervous system.
- and more.
Low B12 might be detected by Total Serum B12, or possibly Active B12 (if you can get the test). However, both tests have drawbacks.
Total Serum B12 tests what the name implies, i.e. all circulating B12. This includes a large portion, which is bound to protein and unavailable to the cells. There is a new test called the Holotranscobalamin test (the Active B12 test), that measures only the Active B12 but that is only available currently in a limited number of hospitals in the UK. There are many other issues though.
In the UK the reference range for Total Serum B12 is typically about 180 - 1000 pg/ml. With results below this considered low, 180-350 pg/ml is considered borderline, and more than 350 pg/ml considered normal. However, there is huge controversy over this. In other countries the low end of the range is higher. In Japan for instance, a patient would be put on routine B12 injections if their levels were below 500 pg/ml. Many B12 medical researchers and doctors who focus on the B12 issue consider that 550 pg/ml should be the low-end cut-off point. It is also possible for some patients to have faults of their cell receptors and have high B12 results but still be clinically B12 deficient. There are pressure groups & charities working at the present to get the low-threshold of the B12 reference range, raised to at least 300 pg/ml and hopefully higher.
Active B12 has its own issues and researchers and doctors are still not entirely sure whether it is going to give more reliable diagnosis than the Total Serum B12. This test still measures a blood level of B12 also - it does not reflect B12 that is actually active within the cells (as the name might imply to some readers).
Pernicious Anaemia (severe anaemia brought about by the inability to produce enough Intrinsic Factor needed to absorb the B12 in the gut) has additional tests that can be done. These are the Parietal Cell Antibody test and the Intrinsic Factor Blocking Antibody test. But there are issues with these tests too. People with Pernicious Anaemia caused by either destruction of the Paretal Cells (which produce intrinsic factor and stomach acid), or destruction of Intrinsic Factor, invariably need B12 intramuscular injections to maintain their B12 levels. The frequency of these needs to be determined based on symptoms. Unfortunately, some countries have poor guidelines for how often these ought to be (the UK is currently one of these).
Two important research papers appeared in the New England Journal of Medicine in 2012. One showed clearly that the presence of Intrinsic Factor Antibodies cause false positive levels of B12 in the blood, and causes clinicians to rule out B12 deficiency. A second paper in the same journal showed that the current machines that are used to test for B12, yield false positive results in up to 35% of patients - again causing misdiagnosis. It is also known that Intrinsic Factor Antibodies only show positive in 40-60% of cases, and often have false negative results! On top of all of this, any test of blood-based B12 does not necessarily show how well the B12 is being effective within the cells. No such test is possible - yet. On top of all of this, the tests for Intrinsic Factor Antibodies and Parietal Cell Antibodies are known to be unreliable and misleading. The British Society for Haematology have guidelines on Intrinsic Factor Ab testing: 'Patients negative for intrinsic factor antibody with no other causes of deficiency, may still have pernicious anaemia and should be treated as anti-intrinsic factor antibody negative pernicious anaemia. Lifelong therapy should be continued in the presence of an objective clinical response'.
Furthermore, it is now known from research that 1) Low B12 levels can be present in the absence of enlarged red cells in over 60% of cases, and 2) neuro-psychiatric abnormalities due to low B12 can be present in a significant number of patients with normal haemoglobin and normal red blood cell count.
If low B12 is present and you have a balanced diet it is likely that you do have low B12 and so proper treatment is important. This may well involve B12 injections.
To complicate things further, low folic acid can also have an impact; if it is low, you also cannot produce enough healthy red blood cells. So, testing Serum Folate is also important.
All in all, the current diagnosis methods for low B12 are flawed. The campaigners and doctors who specialise in B12 are aware of this and are pushing for major changes.
So, almost all the tests may show that everything is OK, yet the person might still have low B12 and be struggling with the myriad of symptoms that can come from it, e.g. depression, fatigue, headaches, shortness of breath, diarrhoea, pins and needles, other neurological issues including paranoia and even psychosis to name but a few. Left untreated, low B12 can result in permanent nerve damage!
What if you've been on B12 supplements and then test B12?
To make matters even worse, if someone has been on any form of supplement containing B12, it can leave the serum levels of B12 elevated for a long time afterwards - in some cases 4 - 6 months! This latter point makes the testing of B12 in the blood relatively futile once any treatment is started and is therefore, not likely to result in any clear diagnosis. If someone has been supplementing with B12 tablets or patches or sublingual tablets, their blood level of B12 is likely to be high, yet they may have inadequate cellular levels of B12. In many cases the B12 taken this way is bound to protein and just continues to circulate in the bloodstream, i.e. it doesn't get cleaved from protein and very little of it reaches the cells where it is needed. Hence, for someone with symptoms of low B12 it would be better to do the testing before any supplemental B12 is ever used. I have highlighted this last point as thyroid patients often take a lot of supplements in an attempt to ensure that they 'have enough of everything'. Whilst for most of the other things they might want to test, this won't cause much of an issue if the supplement is stopped first for a week or two prior to the testing, for B12 it makes a massive difference.
I cannot stress the last point enough, so please read this paragraph. If you have not had a B12 test prior to taking any supplement containing B12, you will probably not have true serum B12 result (with all of its faults). If you are on some form of B12, your results are likely to be high. If they are high due to any supplementation your doctor may say you should stop the B12, but this is just serum B12 and not representative of the actual effectiveness of B12 (as there is no test for this). You could drink a bath-full of B12 and not have any problems - it is one of the safest supplements that we know of.
Also be aware that if you've been on oral supplementation of B12 and your results now look good or high, they could still be dangerously low. So, supplementation ought to be avoided for many months if you plan to test B12. You have to be off ALL B12 supplements for 4-6 months to get a valid B12 test result. Oral B12 supplements just end up circulating around the body in some individuals and they do not make it to the cells. The B12 can in some patients just remain bound to protein with nothing to release the B12 for use. Some patients have been known to appear to have good B12 levels due to supplementation but their cells were starved of B12 and they suffered permanet neurological damage.
Also see the following document by the Dutch Research group, an official government group, the only one specifically mandated to research B12 in the world:
Once on B12 injections, serum levels remain high, which is needed to repair neurological damage. And there is no toxicity as stated by World Health Organisation. The injections are very high dosage, and they bypass the stage where it attaches to one protein and is blocked there. It gets cleaved. When you take a tablet, the gut attaches a protein which needs being cleaved along the way, and it does not happen if the circuit is broken somewhere. Additionally, there's a 1% passive absorption in all forms of B12, but nowhere enough to repair damage.
What does this all imply?
So, what does all this mean? It means it is a very complex situation, and it can be extremely difficult to get a clear diagnosis of B12 deficiency or Pernicious Anaemia.
Some people have methylation issues which affect their ability to convert some forms of B12 to active form, methyl B12. Hydroxy or cyano cobalamin products can be less efficient for these people, and they may do better with methyl-cobalamin. This issue might possibly be detected these days by some of the genetic testing that can be done through companies like Ancestry.com or 23andMe.com. However, interpretation of the results can be difficult.
I do worry that a lot of thyroid patients who are not responding to thyroid treatment may well have undiagnosed B12 issues. Note also: simply taking B12 supplements (even if sublingual or patches) may simply not provide enough B12 for some people to keep the cellular levels high. However, the supplements could mask diagnosis. Many B12 deficient patients struggle for years to get a proper diagnosis. If they do achieve this, they often fail to get the treatment that they need to keep the effects of low B12 at bay, i.e. the required frequency of intramuscular B12 injections. Many of them find that within a few weeks of a B12 injection, their symptoms are starting to return. For these people, injections every 3-4 weeks are necessary but this is hard to get within the UK, unless the patient has a good haematologist or doctor. Some of the most affected pernicious anaemia patients need much more frequent injections, or even regular intravenous B12, in order to saturate their cells with B12. In most cases of seriously low B12, loading doses of frequent B12 are needed for a couple of weeks in order to get the levels up quickly - this involves B12 injections three times per week in the first two weeks of treatment.
All in all, the entire situation is a bit of a shambles. The Pernicious Anaemia Society charity in the UK, chaired by Martyn Hooper, is trying to work with the medical profession and other groups to create awareness and bring about change. There is still a long way to go though.
It now seems clear to me that if someone has symptoms that fit extremely well with B12 deficiency or Pernicious Anaemia and there is any doubt about the blood tests at all, it is worth seeking a referral to a good Haematologist. They ought to know that the clinical presentation is the most important thing and that sometimes a therapeutical trial and assessment of the person's response to regular B12 injections might be the only way to reach a correct diagnosis.
I recommend reading these excellent books by Martyn Hooper: 'What you Need to Know about Pernicious Anaemia and Vitamin B12 Deficiency', and 'Pernicious Anaemia: The Forgotten Disease'. Both books cover both B12 deficiency and Pernicious Anaemia (the autoimmune version of low B12).
A less easy, but also excellent read is 'Could it be B12?' by Pacholok and Stuart.
For more information, please see the post script to this blog.
I also attach a link to the 2014 guidelines on B12 and folate treatment from the British Society of Haematologists, and the summary of that from the Pernicious Anaemia Society (PAS), which is a little more digestible.
Summary for the diagnosis and treatment of cobalamin and folate disorders (from the British Society of Haematologists - for medical professionals) See: https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.12959
Here is the summary of this report from Martyn Hooper of the Pernicious Anaemia Society:
In June 2014 the British Committee for Standards in Haematology issued new; revised Guidelines on Vitamin B12 and Folate. The new guidelines acknowledge the failings of the current assay used to determine B12 status in patients. Below are the main recommendations of the committee:
1. The clinical picture is the most important factor in assessing the significance of test results assessing cobalamin status because there is no 'gold standard' test to define deficiency.
2. Definitive cut-off points to define clinical and subclinical deficiency states are not possible, given the variety of methodologies used and technical issues.
3. In the presence of discordance between the test result and strong clinical features of deficiency, treatment should not be delayed to avoid neurological impairment.
4. The absence of a raised MCV cannot be used to exclude the need for cobalamin testing because neurological impairment occurs with a normal MCV in 25% of cases.
5. Some assays may give false normal results in sera with high titre anti-intrinsic factor antibodies.
6. It is not entirely clear what should be regarded as a clinically normal serum cobalamin level.
7. It is even less clear what levels of serum cobalamin represent 'subclinical' deficiency.
8. Neurological symptoms due to cobalamin deficiency may occur in the presence of a normal MCV.
9. IFAB is positive in only 40-60% of cases, i.e. low sensitivity, and the finding of a negative IFAB assay does not therefore rule out pernicious anaemia (hereafter referred to as AbNegPA).
10. Standard initial therapy for patients without neurological involvement is 1000ug intramuscularly ['i.m.'] three times a week for 2 weeks. The BNF advises that patients presenting with neurological symptoms should receive 1000ug i.m. on alternate days until there is no further improvement.
11. Care must be taken if low dose supplements are prescribed, as such an approach risks the suboptimal treatment of latent and emerging pernicious anaemia with possible inadequate treatment of neurological features.
12. There are arguments against the use of oral cobalamin in initiation of cobalamin therapy in severely deficient individuals who have poor absorption, especially due to pernicious anaemia.
13. Patients with pernicious anaemia need treatment for life regardless of serum cobalamin levels.