Vitamin B12 deficiency: testing and treatment

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Vitamin B12 deficiency has been recognised as a medical problem for over a century. It's one which is now being increasingly appreciated as a cause of multiple problems. A decent proportion of our population is vitamin B12 deficient, and it can cause a broad array of different clinical problems. Yeah, there's quite a bit of nuance to navigate in terms of causality and testing, and management continues to develop. How do we find a way through all of this?

Well, fear not because there's an excellent article in the Australian Prescriber, and the senior author of that article joins me today. Dr Cecily Forsyth is a haematologist on the Central Coast, and she's brought us an excellent overview of how to manage a vitamin B12 deficiency in practice.

Cecily, welcome to the Australian Prescriber Podcast.

Pleasure to be here again. Thank you very much.

It's great to have you back. So, tell me a little bit about vitamin B12 deficiency, and how that's evolved as a problem in our practice and in our society.

I think the incidence is increasing for a number of reasons, but I think that a couple of the groups that I would regularly see [are] the increasing use of bariatric surgery, so that really puts people at risk of B12 deficiency, the use of medications that decrease B12 absorption. So metformin, very commonly, we're now seeing that in widespread use for diabetes and some other associated diseases. And I think, vegan and vegetarian diets. Those 3 factors are the main reasons that we are seeing an increase in B12 deficiency. But I also do have to flag that we do know that B12 deficiency is more common in refugees, and certainly from places in the Middle East have a high instance of B12 deficiency. We really want to make sure we diagnose B12 and treat them appropriately, because the symptoms patients have can be so nonspecific, so variable, and may not be in any shape or form linked to something like B12 deficiency.

Let's talk about that first. It does strike me that a lot of different things seem to get pinned on vitamin B12 deficiency nowadays. Can you talk me through that and how real some of these are? Because it does seem like a really broad spectrum of problem.

Look, it is. I'm a haematologist. I'm late career. When I was training, B12 deficiency had megaloblastic anaemia, very characteristic blood count abnormalities, large red cells, hypersegmented neutrophils, eventually pancytopenia. So, that's what we thought was B12 deficiency. It's taken time to realise that it's not all megaloblastic anaemia and subacute combined degeneration of the cord. There are much more subtle manifestations. And probably, our colleagues who are geriatricians showed us that initially, when they say some people with cognitive dysfunction, it's all B12-related, and started incorporating B12 screening into assessment of cognitive dysfunction. And there are many cognitive, psychiatric abnormalities that we now realise can occur with B12 deficiency. So, fatigue, weakness, weight loss, anorexia. These things do occur with B12 deficiency. That doesn't mean that every tired person is going to be B12 deficient, but we do need to think about it.

The other emerging area is the psychiatric manifestations; irritability, personality change, cognitive dysfunction, even depression can be a clinical manifestation of B12 deficiency. I think we all have our little biases, and B12 deficiency might be diagnosed by a neurologist, a geriatrician, a haematologist. I would say, by the time I see anybody, they've got a blood count abnormality and they may have those symptoms. But the geriatricians will say, 'No, actually we see people whose blood count is normal and still have B12 deficiency.' The neurologists will say, 'Yes, sometimes we see neuropathy, but they haven't got blood count abnormality.' So, all of us have our own biases from what we see in practice.

The other area which, is a bit more niche, is vitamin B12 deficiency in women who are pregnant and in mothers. Can you tell me a little bit about that?

I think the problem is testing in pregnancy. What we find is that in pregnancy, patients will often have low B12 binder. The main one, haptocorrin, is low in pregnancy related to high oestrogen levels. We also see that in patients on the oral contraceptive pill. So, these 2 groups of patients will have low haptocorrin levels, which is the major binding for B12. Their total B12 level will be low, but actually their active B12, the part of the B12 that is available for metabolic usage, may be normal. And so, screening for B12 deficiency in pregnancy and in patients using the oral contraceptive pill is going to be much more effective if we measure the active B12 level. Most pathology labs will measure active B12 levels in pregnancy, and we use that in pregnancy to guide and inform us if our patients are truly B12 deficient.

Of course, the B12 deficiency, though in utero, is so impactful, isn't it?

Absolutely, because of the neural tube defects. So, it is something that we do not want to miss. We don't want to give people folate supplement who are truly B12 deficient. And we know that yes, some of our pregnant women have had bariatric surgery in the past, may have been on metformin as well for a number of different reasons, and maybe vegetarian or vegan. So, there is B12 deficiency in that population, and we certainly don't want to miss it for consequences to the baby and also, of course, consequences to mum.

That makes absolute sense. So we've talked a little bit about gastric surgery, gastrectomy, talked about metformin, and about dietary intake. Are there other people we should be worried about? What are the other risk factors that we should be concerned about?

So, inadequate dietary intake. That might be people older, cognitive dysfunction, living alone, tea-and-toast type of patients, people who drink excessive amounts of alcohol, and their caloric intake is alcohol, breastfed babies of mothers that are vegetarian, people with eating disorders. And again, some of those groups, as we've mentioned, have increased over time. We need to think about the group of patients who have decreased intrinsic factor. So, if you've got no intrinsic factor from your stomach, then you cannot absorb B12. So, the atrophic gastritis, pernicious anaemia group of patients, they're the characteristic ones that we learned about even when I was at medical school. But Helicobacter pylori–associated gastritis, the bariatric surgery we mentioned, and the standard gastrectomy will all impact on intrinsic factor. Then of course, the B12 and intrinsic factor bound together is absorbed in your ileum. So if you've got a problem in your terminal ileum, you're not going to absorb that B12.

So inflammatory bowel disease, coeliac disease, patients who've had surgery, or patients who've had small bowel radiotherapy. And some evidence also that that bacterial overgrowth of the small intestine in some patients, like patients with diabetes, may also lead to B12 malabsorption, along with a number of other vitamins that may be malabsorbed. We did cover metformin, and metformin is really the most characteristic one. Not trying to encourage people to test unnecessarily, but I do think when people are on metformin, you do need to be thinking, could you have B12 deficiency? Could any of your symptoms be due to B12? And certainly in my population, if I start thinking, 'Are you a bit tired? Are you a bit moody? Are you a bit irritable?' and you're on metformin, I think I'm going to be testing that group of patients, thinking about it at least on a 1- or 2-year type basis.

There are other drugs as well, and obviously proton pump inhibitors, long-term H2 blockers. But there's also some funny other ones [for example]; the antiepileptic group of drugs. So pregabalin, particularly, may also be another factor why B12 deficiency is a little bit more common. We see a lot of that. And as a haematologist, I cause a lot of people some painful neuropathy with some of my drugs, and a lot of them end up on pregabalin. And there's colchicine as well. So, some of those drugs we may see contributing to the increase in B12 deficiency. I don't think everybody on pregabalin needs to have a B12 every year, but I do think it is important to look at the blood count. Is their MCV [mean corpuscular volume] higher than expected? Is there something else on that blood count that should make me decide to do a B12 level? The other one is the recreational nitrous oxide use.

Clearly, the overall population of potentially at-risk people is growing. As you've mentioned, things like colchicine being used for secondary management of established cardiovascular disease. Those kind of things mean that a lot of people are at risk. But it's perhaps understandable in that context that the Medicare rebate now is only once every 11 months, is that correct?

That's right. It's been a tricky situation, because for a couple of years, most of the laboratories were looking at the B12 level. And if it was in the lower third of their normal range, they would often automatically do an active B12 level. When the Medicare rebate changed, it was really price matched at a level of somewhere under $30, is the Medicare rebates. Whereas the cost of an active B12, for the companies, they maintain that's really somewhere between $50 and $75. So, active B12 is really not now routinely done for the patients who are in that bottom third of the total B12. And that is a lot of patients in that area where they potentially could have deficiency of active B12, a functional deficiency, but a high total. And that is where it's really tricky. A lot of guidelines will say, 'Yes, look at the homocysteine.' But homocysteine levels are increased in so many of our patients anyway that will often have B12 level that is in the lower end of the normal range and a homocysteine level that is elevated.

We have our chronic kidney disease, our thyroid, the really obvious causes of high homocysteine. But there's mildly increased homocysteine with ageing, with inflammation, with other deficiencies. There are a number of reasons why the homocysteine level is slightly increased. Yes, it's there for completeness, but a high homocysteine level and a low-ish B12 does not necessarily mean you've got B12 deficiency. I think further testing needs to be done or needs to be carefully considered, whether you really feel this person is at risk and has some clinical manifestations that are consistent with that diagnosis. Most labs don't rush into methylmalonic acid testing. It's a bit slower to come back. I think it's a little bit more expensive. Not every lab does it. So, that is also problematic in these patients.

And I think that's why we put in the article that very soft reason that sometimes if you're not sure, it is better to treat these patients than to miss B12 deficiency, because B12 replacement isn't particularly expensive and it isn't dangerous. So, we do put that there as a soft guideline. We would like not to have put it there, but sometimes we really just don't know. And $75 for an active B12 test is out of the financial range of many of my patients on the Central Coast, and many of all of our patients in this cost-of-living crisis. So, it is tricky.

Let's try and navigate that a little bit. How would you approach testing vitamin B12?

I think when I see a patient, especially now B12 will only be paid once a year, I may not know that it's been done, but trying to find out if the patient has had a B12 level ,and what that showed, is really a very early step when we're looking at how we test and who we test. So, to me, often, it will be because their blood count is abnormal. But just for example, when we're looking at investigating an elevated MCV, of course we all remember that B12 and folate causes that, but so does thyroid disease, so does drinking too much alcohol, so does chronic liver disease. Smokers tend to have mildly increased MCV.

So, there's a whole lot of reasons that the patient sitting opposite you might have an elevated MCV. So, trying to see if they've had a B12 level is really important. And then if they haven't, think about are they at risk for all the reasons that we've looked at, and then really, the first test that we all do is a total B12 or cobalamin test. And it's difficult because each lab has a slightly different range. We said in this article, greater than just over 250 picomoles per litre for your total B12 makes deficiency unlikely. So, we try and give some guidelines [about when] deficiency [is] likely, when it's clearly low and then the grey area in the middle.

When you get this result back, often you will also get back a homocysteine because the lab will just run that automatically, and your homocysteine level is often elevated. So then at that time, that is where further investigation of this group is really important. And it is important to be, again, mindful of, is there a reason for this to be low and what might you do. Is there another reason for the homocysteine level to be elevated? Is this somewhere where I really feel an active B12 level is going to be needed? Trying to use that active B12 if it really is important, if that patient has got risk factors, is in that indeterminate area. But what we want to try and do is have people who have got proven B12 deficiency with a low B12, [and] nothing further needs to be done except treat them.

Those who are unlikely, don't further investigate those. And it's that grey area where, yes, have a look at the homocysteine. If that is up but they've got a bit of kidney disease or there's a reason for that being up, think about a methylmalonic, but you may find the same problem with that. And then think about, 'What problem am I blaming? Yes, they have got a risk factor. I'm going to treat this because they are on metformin. It is indeterminate, but that's a good reason to be B12 deficient, or their B12 may be precarious and be deficient in 12 months' time.' So in that case, I would, yes, jump in and treat their B12 deficiency. It is hard to be as dogmatic as people would like with a guideline, but we do try and say, 'This is safe. These ones are a problem.' And that area in the middle is the one that people do need to carefully consider.

So once we take that, we've made a decision as to whether we need to treat or not. Obviously, intramuscular replacement has been the cornerstone for quite a while. Can you talk me through when that's mandatory, and then as well this idea that oral replacement might be appropriate for some?

I think that anybody with subacute combined [degeneration of the spinal cord], anybody with neurological, and probably also with any cognitive or psychosis, anybody with any major B12 complication. And I also put in there haematological. If you have got megaloblastic anaemia and pancytopenia, you've got neurological issues, psychiatric issues, I actually think the safest way to make those patients replete rapidly is to give a good dose of B12 intramuscularly. And I would certainly do that at the beginning to be 100% sure that they cannot progress with their neurological issues, their cognitive issues, their psychosis, or their blood count abnormalities. So, I would often do that to begin with right away while we're still waiting for their intrinsic factor antibodies to come back to work out the cause. So severe B12 deficiency, I think, deserves intramuscular therapy.

And then when you've sorted out the cause, it depends if there's a reversible cause. So, if you have no stomach, you've had a gastrectomy or you've got no ileal area, so your ileum and absorption is compromised, I just don't think you can give someone oral replacement and think that's going to work. I think that group of patients should predominantly be on intramuscular replacement indefinitely. Maybe that will change, and maybe there will be bigger randomised studies being a hundred percent sure that sublingual is good enough, but it's just too precarious. If it is something that you can reverse, the patient is on a drug that you can stop, you can use a different drug, or their diet is going to improve. One of the miracles of modern time, they're going to stop drinking and they're going to eat a better diet. If there's going to be something reversible, then I certainly think that you can put them on oral B12 supplementation.

Make sure they're compliant with it, because it is, in my experience, something that people get sick of and it drops off. So, if you're giving someone oral replacement long term and the cause for their B12 deficiency has not been reversed, you do need to make sure they are compliant with it and they keep taking it. Because you don't write a prescription for it, patients buy it over the counter, and you might have told them you need to stay on it for life, and they've gone somewhere else and they've had a B12 measured and it's high, and someone said, 'Oh, you don't need that B12. Why do you want it?' And it gets stopped, or the patient runs out of motivation.

So, it is very important if you're using oral B12 for someone... Like the metformin group of patients where it will work well, that you actually make sure they stay on that for the life of their metformin exposure, pregabalin exposure, or whatever it is. Certainly, dietary as well. That's, obviously, very easy to correct orally. Where there is a grey area might be celiac disease and the patient's on a gluten-free diet, and therefore they should be able to absorb nice and normally. Crohn's disease, or if they've had partial gastrectomy or bit of a gastric sleeve, will they be able to absorb enough orally? And there are studies that have looked at B12 orally, and that can be done sublingually or high-dose oral, and that has shown, in certain circumstances, that it is as effective as intramuscular replacement.

I guess, intramuscular replacement often is a very easy option. And it really is fairly low risk, isn't it?

Absolutely. And in fact, some chemists now do B12 injections, so it's very easy for patients to access. It is relatively cheap. If there's any doubt about it, if the patient's not compliant and the risk factor is still ongoing, it is much easier for that patient to be having 3 monthly B12 replacement. They often see their GP every 3 months. They can see the nurse, get 3 B12 shots on a script and it really, I think, is easy and safe way to be sure that our patients are being replaced when it is incredibly important.

So, how do we follow these patients? When do we expect to see recovery? And I guess, when do we retest them?

I think if you're giving intramuscular B12 replacement, you should not have to retest that group of patients. You should be making sure that you give adequate B12 to get their stores right up, and then a 3 monthly schedule should be absolutely fine. The biggest warning is that when patients have had pernicious anaemia, that is a lifelong problem. If you have no stomach, that is a lifelong problem. So, patients who have irreversible causes must be told their B12 cannot be stopped. We see it all of the time that it was stopped by a well-meaning doctor who missed that bit of the history and who said, 'Your B12 level is really sky-high.' So, we must remember to inform our patients when we take their stomach out or we diagnose their pernicious anaemia, that you are on this for life. Don't have the B12 level measured. Don't let anyone stop it.

So, in that circumstance, where it is intramuscular [and an] irreversible cause, I don't believe there's any role for measuring levels. In patients who are doing B12 orally, it is really important to follow those patients and make sure that their clinical manifestations of the B12 deficiency correct. So, you will see a reticulocytosis occurring in megaloblastic anaemia very quickly once you replace that B12 deficiency, within a very short period of time, in a week or 2. The neurological problems will certainly improve in a much slower rate, but patients will actually tell you that it does start to improve quicker than you would think. But 6 to 12 weeks, and the patients will say, 'Yes, this is getting better,' but the neurological improvement may not be complete. Clearly, that group of patients, with neurological problems and significant megaloblastic anaemia, I will be giving them intramuscular B12. But if it's at a lower level for patients on oral B12, I would reassess after 2 to 3 months, see what their symptoms are, because we all know that fatigue and depression and irritability may not all be B12. There may just be other factors in our life that's contributing to those.

If there's doubt about adherence to the B12, then it is something that you may need to retest . You would hope that by 3 to 6 months of oral treatment that the homocysteine level is down, that the methylmalonic acid is down, and the B12 level is all up and corrected. So I think in that group of patients, there is a Medicare rebate for people who've been shown to be low and you're assessing the efficacy of replacement. And I think that is reasonable to do if patients, 3 months down the track, the problem you're trying to correct has not got any better. And if that problem hasn't got any better and the B12 level is now replete, then it means that something else is driving that symptom. And that's very common because many of these symptoms are so nonspecific.

Nevertheless, it does seem that it's relatively straightforward to take a sensible approach here that improve the lives of a lot of different people.

Cecily, thank you so much once again for joining us.

It's a pleasure.

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Cecily Forsyth has been on advisory boards for Novartis and GSK, and has received fees from AstraZeneca, Janssen, Novartis, and Aviva to speak or attend educational meetings. And I am a member of the Drug Utilisation Sub Committee of the PBAC [Pharmaceutical Benefits Advisory Committee]. I'm David Liew and thank you once again for joining us on the Australian Prescriber Podcast.

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