Vitamin B12 deficiency is incredibly common in the population, yet often undiagnosed and can lead to all types of health issues. In medical school I was taught that B12 deficiency is often called “the great masquerader” since it can mimic a whole range of different medical conditions.
Patients often undergo expensive work-ups or are given incorrect diagnoses like dementia or chronic fatigue, when B12 deficiency may have been the underlying culprit or at least a major contributor to symptoms all along.
In this post we will discuss the critical role of B12, common symptoms and associated conditions, and how we can effectively diagnose and treat B12 deficiency. I want to warn you that I am going to get a little “geeky” when describing some of the key roles of B12 because it is a vitamin that deserves some deeper knowledge.
If you absolutely do not want to understand some of the intricacies of B12 deficiency (please give it a try!), then don't give up on this post. Just scroll past the discussion of methionine and the MTHFR gene straight to symptoms, diagnosis and treatment.
I also discuss “special populations” at the end including pregnancy, children, seniors and those of South Asian ancestry where B12 deficiency is common and can have dire consequences on the health of youth and seniors.
This includes more challenging and complex conditions like autism spectrum disorders in children and dementia in seniors.
Why Is B12 Important?
Vitamin B12 (aka Cobalamin) is a water-soluble vitamin like the other B vitamins, and I think of it as a “builder vitamin” since B12 helps us build a healthier brain, nerves, red blood cells, DNA and so much more. This is why there is a wide array of different symptoms that can occur (discussed later) with B12 deficiency.
I want to spend the next two sections talking about B12's specific role with a key process called methylation in addition to detoxification since many chronic health conditions like cancer and “mystery” conditions like autism spectrum disorders (ASDs) in children may have a link to this pathway.
Before we jump into the basic science, I want to use some abbreviations and terms to make this content more easily understandable:
B12: may be used interchangeably at times with cobalamin
Folate: same as vitamin B-9. B12 and Folate are co-workers that collaborate to produce some vital chemical reactions we'll discuss in a moment.
Methionine: This is an essential amino acid and a KEY precursor to other vital compounds like SAM and glutathione (see below) that help the body carryout critical processes like methylation and detoxification which are key to preventing a wide range of diseases (cancer, heart disease, Alzheimer's disease, autism, etc.).
Methyl group: in chemistry, this is a single carbon atom attached to 3 hydrogens, aka “CH3“
Methylation: The act of donating a methyl group (above) to a molecule and is an essential step in switching genes and proteins on or off. Methionine (mentioned above) is involved in methylation (donation of CH3s)
S-adenosylmethionine: Nicknamed “SAM” is derived from methionine and is a generous methylator, donating methyl groups to all types of genes and proteins so they can carry out essential functions
Glutathione: Like SAM above, this molecule is also born from methionine and is often referred to as the MASTER ANTIOXIDANT since it is incredibly powerful at removing damaging free radicals and toxins and also enhances the effects of other antioxidants in your body that come from nutrients in your diet.
Homocysteine: will abbreviate as HC. Can be measured in the blood and when elevated indicates a problem with producing methionine and as I mentioned, problems making methionine lead to all types of health issues.
Genes & DNA: Genes are the chemical structures we inherit from our parents, made up of subunits called DNA. Genes and DNA are often used interchangeably and a key function of genes is to provide the blueprint to produce proteins essential for life. When DNA becomes damaged, chronic diseases like cancer, heart disease, neurodegenerative and developmental disorders can occur, in addition to premature aging. To live long and thrive, we want our genes to be pristine!
If all these terms are making your head spin, just focus your attention on methionine in particular and 2 of it's essential roles:
Methionine as a Methylator: Methionine donates methyl groups (CH3) to genes and proteins to turn them on or off so they can carry out their functions. Methylation is absolutely key for genes and cells to do what they are designed to do
Methionine as a Mother molecule: I also call methionine a “mother molecule” since it is an essential amino acid that “gives birth” to key compounds like SAM (a master methylator) and Glutathione (a master antioxidant).
Hopefully I've convinced you what a key compound methionine is. Now this “methylating-mother-of-a-molecule” can't be formed without the help of vitamin B12 and folate which convert homocysteine (HC) into methionine.
Let's add some visuals to help you grasp all this. See the image below and start at the bottom left. Notice how HC is converted to methionine by the addition of a methyl group (CH3). Now who enabled this key conversion to occur? Our vitamin co-workers, Folate and B12 (labeled in red below)!
The reason HC is labeled as “bad” is not because HC itself is necessarily toxic, but rather when levels are increased it's a marker that methionine production is impaired possibly due to deficiency in vitamin B12, folate or vitamin B-6 (another B vitamin we won't cover now).
Methionine is labeled “good” because as we discussed it's the “mother” giving rise to key compounds like SAM and glutathione.
Notice how methionine is converted to SAM by the addition of a chemical called adenosine and then the addition of another CH3 (methyl group) turns SAM into SAH which then gets recycled back into HC after adenosine is removed.
These reactions are actually far more complex, but the above image simplifies it, so keep coming back to this image if you get lost. Basically HC–>Methionine–>SAM–>SAH–>back to Methionine and so on.
The way these cycles work is that if any particular step is impaired, you get a back-up/elevation of the preceding step. For example, if you are deficient in vitamin B12, HC can't be converted to methionine, so HC accumulates in the blood and you would get an elevated level on your blood test.
Let's come back to the critical process of methylation which helps to turn your genes on and off. Imagine having a device like a smartphone and not being able to turn it on or off. How useful would that be? The same applies to your genes.
Without proper methylation, your genes become damaged and dysfunctional.
Methionine and Sam are examples of methylators, or what I call philanthropic chemical compounds that donate methyl groups to genes and proteins (aka methylation) so they can carry out their essential function.
See the methyl group (CH3) attached below in red. Methionine and Sam “tag” genes, proteins and other compounds like you would tag a friend's photo on Facebook by adding the CH3 (methyl) group to it.
Now Sam has deeper pockets and tends to be a more generous philanthropic methyl donor than methionine, but keep in mind that Sam wouldn't exist without methionine since methionine is its mom (aka “precursor”).
Again, the importance of all of this is that when methylation is impaired, you cannot turn on or off key genes or you may turn key genes on or off at the wrong time, leading to damaged genes and cells which in turn can cause cancer, heart disease, Alzheimer's disease, autism, premature aging, etc.
When people have trouble with methylation, we nickname them “poor methylators.” There are a host of different reasons why you might be a poor methylator and vitamin B12 deficiency is one of them.
You can't effectively make our key molecule methionine without sufficient vitamin B12, the topic of today's post. You can also be a poor methylator if you have a defective gene called MTHFR which we'll discuss next.
The MTHFR Gene
I hope you have stuck with me so far. If I lost you, just think to your self that B12 works with its friend Folate (B9) to produce our all-star chemical methionine, the methylating-mother-of-a-molecule that gives birth to gifted offspring like SAM (prolific methylator) and glutathione (master antioxidant).
Now let's briefly introduce the MTHFR gene which you may have heard of, especially if you've had gene testing done through a company like 23&me. MTHFR codes for an enzyme, methylenetetrahydrofolate reductase, that enables methylation and in particular conversion of HC (homocysteine) into methionine (refer back to our prior image).
MTHFR has also earned the unfortunate nickname of the “MoTHer F***eR” (fill in the blanks) gene, which despite being a bit crude, is one way to make this complex gene name absolutely unforgettable.
Depending on what type of MTHFR gene you inherit determines how good of a methylator you are.
By the way, we all want to be great methylators (aka methyl group donors) since that drives healthy gene function and powerful detoxification and antioxidant activity.
However, even if you have the best type of MTHFR gene but are eating a diet deficient in key nutrients (like vitamin B12 and Folate), you will be a poor methylator.
On the other hand if based on your MTHFR gene status you are genetically a weak methylator, then eating an optimum diet with possibly some supplementation may boost your ability to methylate.
If you are interested in learning about your methylation status and what foods may help power optimal methylation along with a host of other nutrition and lifestyle recommendations based on your gut and genes, check out our personalized weight loss program here and diabetes program here (Disclosure: I am an advisor to this company).
B12 Deficiency Symptoms and Related Conditions
Now that you are an expert on methionine, methylation and MTHFR, we can move onto some practical matters like identifying symptoms and conditions connected to B12 deficiency.
Vitamin B12 is necessary to make not only DNA, but also red blood cells and key components of nerves like the myelin sheath that surrounds it (see image below). The nerves in your brain and all over your body are essentially electrical circuits, and myelin is the insulation that protects nerve cells and allows them to fire faster. This means quicker movements and thought processes when B12 is within range.
Now you can imagine that if B12 is key to genes, red blood cells and your nervous system, diminished levels can produce a wide range of symptoms like the following:
Nerve symptoms: numbness, tingling or strange sensations in hands, arms, legs and/or feet
Brain symptoms: memory loss, weakness, trouble focusing, thinking or reasoning (aka “brain fog”)
Fatigue and overall weakness
Problems walking (balance, disorientation, etc.)
Mood disorders like depression
Swollen, inflamed tongue
Now I also mentioned that B12 deficiency is the “Great Masquerader” since it can mimic the signs of symptoms of multiple other conditions such as the following:
Dementia (Alzheimer's, senile, etc.)
Other neurological conditions like MS (multiple sclerosis)
Autism spectrum disorder and other learning and developmental disorders in kids
The key here is if you or a loved one has signs of B12 deficiency like dementia, then you must think of the common causes along with B12 deficiency. In addition, if you've been diagnosed with B12 deficiency don't just chalk up all your symptoms to B12 deficiency alone. Be sure to rule out other conditions that may also cause similar symptoms (cancer, neurological disease, etc.).
Who's At Risk?
Those at risk for B12 deficiency can be split into 2 broad categories consisting of poor intake of B12 and poor absorption of B12 into the body from the digestive tract.
1.Poor B12 Intake: Vitamin B12 is obtained almost exclusively from animal sources like meat, eggs and dairy, so vegans are almost universally B12 deficient based on diet alone, as are a significant percent of vegetarians.
Vitamin B12 from plant sources like algae are not true B12, but instead a form known as cobamides, which are not biologically active
The problem with cobamides is they actually interfere with the action of true B12 and can also falsely elevate levels tested in the blood, masking a true deficiency. I briefly discuss options for vegetarians later in this post.
2.Poor B12 Absorption: Even if you are getting B12 from foods, the next step is the B12 needs to travel from inside your intestine to the cells in your body.
The vitamin B12 we get from animal foods is bound to protein and must be released by stomach acid in order to become active.
This means anything that interferes with stomach acid production will inhibit B12 absorption.
Other intestinal diseases and competing nutrients can also impair B12 absorption. See below for common conditions that block B12 absorption:
Low stomach acid: this can be due to long-term use of acid blockers like PPIs (proton pump inhibitors), low stomach acid is common in the elderly where acid production naturally diminishes with age, and even conditions like chronic stress can significantly lower stomach acid production. Be sure to read my prior post on low stomach acid which highlights the risks of low stomach acid and what you can do.
Intestinal diseases: Crohn's disease, ulcerative colitis, celiac disease, SIBO (small intestinal bacterial overgrowth) or IBS
Pernicious anemia (PA): this is a form of anemia due to an autoimmune attack on a protein called intrinsic factor (IF) which normally allows B12 to be absorbed from the small intestine. The autoimmune attack can also cause inflammation of the stomach lining, a condition called atrophic gastritis. PA can also occur with other autoimmune conditions like thyroid disease and vitiligo (skin depigmentation disorder). Keep in mind that anemia is a later stage manifestation of B12 deficiency, so other symptoms (nerve, brain, etc.) may occur long before anemia develops.
Metformin: There is a small, but significant risk of B12 deficiency with long term Metformin use. Read more here.
Be sure to read my “Special Populations” section at the end where I discuss groups who are especially at risk and vulnerable to the effects of B12 deficiency.
Diagnosing B12 Deficiency
If there is a suspicion of B12 deficiency based on the factors we have discussed such as vegan/vegetarian diet, chronic use of acid-blocking medications, and the symptoms described in prior sections, then blood testing for B12 deficiency should be requested.
Some blood tests that are typically ordered when looking for B12 deficiency include the following:
Serum vitamin B12 level: This is an easily obtained test. The primary issue is that the cutoff point in the US tends to be set somewhere between 200-300 pg/mL which means if you have a level of 310, you are considered normal in the US. In Japan and other parts of the world, the cutoff is set closer to 500 pg/mL which means more individuals get diagnosed and supplemented.
Serum folate level: Recall how folate is a close co-partner to vitamin B12 in metabolic processes like the production of methionine. It's typically ordered along with vitamin B12.
Homocysteine and MMA levels: These are metabolic precursors that can become elevated in B12 and/or Folate deficiency. For B12 deficiency both homocysteine and MMA (methylmalonic acid) levels are typically elevated , while with folate deficiency only homocysteine increases. If my clinical suspicion is high enough for B12 deficiency based on risk factors and/or symptoms, I often check B12 along with homocysteine and MMA at the same time.
A Blood Count: Anemia (low blood count) with larger red blood cell size (indicated by test called MCV which is part of blood count) is a clue to vitamin B12 and/or folate deficiency. Recall how I said anemia is a LATE stage occurrence so you can still be B12 deficient with symptoms long before your blood tests show anemia
Elevated homocysteine is associated with an increased risk of heart disease, stroke and blood clots in veins, but most studies find that lowering homocysteine with B vitamin supplements does not prevent or reduce the risk of these conditions. It appears homocysteine is more of a risk marker for suboptimal underlying metabolic processes rather than it being a direct toxin.
Remember, abnormalities in the above lab tests indicate that you are likely a poor methylator. Even if your genetic tests for MTHFR are normal, but these tests are not, you have impaired methylation. On the other hand if your MTHFR genetic results indicate you have the weaker methylation gene, but the above tests are normal, it's unlikely you need to supplement.
Genetic tests alone for most conditions only indicate potential risk and should be combined with appropriate lab tests and a thorough clinical evaluation to determine true functional status.
Treating B12 Deficiency
B12 deficiency can be treated with diet and/or supplements. The standard daily dietary requirements are for 2.4 micrograms (mcg) of vitamin B12 daily, but this level can vary depending on individual needs.
B12 rich foods are listed below:
Organ Meats: liver in particular is a rich source of B12 as are kidneys.
Shellfish: clams are top of the list as a source of B12 with a whopping 84 mcg of B12 per serving
Fish: sardines, salmon, tuna and trout are all good sources, but not as superior as clams
Dairy: eggs, milk, cheese and yogurt
Animal meat: such as beef and chicken, with beef having considerably more B12 than chicken
Fortified foods such as cereals: keep in mind that many junk foods are fortified with B vitamins like B12, so don't use unhealthy foods as a vehicle for getting B12. Stick to natural sources like the ones listed above. This study also suggests that the most common form of B12 used to fortify foods, cyanocobalamin, appears to be less bioavailable in our body's tissues and may potentially lead to the accumulation of the toxin cyanide over many years.
As a reminder, vegetarian sources of B12 like algae, fermented soy, brewer's yeast and spirulina are not nearly as bioavailable as the B12 from animals and seafood.
Now I'm not telling vegans and vegetarians to become meat-eaters due to a lack of natural, bioavailable B12 sources. I would just encourage them to get blood levels checked and if low, be sure to supplement.
I have read some literature vehemently suggesting that vegan sources of B12 are adequate and perhaps this is true for some, but on blood testing some of my vegan and vegetarian patients consuming plant sources of B12, I have diagnosed fairly significant B12 deficiency.
In terms of supplementation for low vitamin B12, typical oral doses are between 1000 to 2000 mcg daily or B12 injections are often administered as well. Studies show that either route is effective for raising vitamin B12.
If taking oral B12 does not raise your vitamin levels or if you clearly have a condition that would impair B12 absorption from your intestinal tract, then injectable B12 is an option.
In terms of the preferred form of oral vitamin B12, I favor using methylcobalamin since theoretically the methylated form should be better absorbed by our tissues and especially if there is any evidence that you are a poor methylator. Recall the study mentioned earlier in the post finds pretty comparable bioavailability between different forms other than the cheaper cyanocobalamin used commonly to fortify foods.
For children, talk to your pediatrician about appropriate formulation and dosing.
Pregnancy is an absolutely critical time to ensure that mothers are not deficient in vitamin B12. Ideally you would identify and replenish vitamin B12 levels if deficient, before pregnancy but this is not routinely the case.
If mom is B12 deficient during pregnancy, then not only is baby deficient during the fetal stage, but also during the newborn and infancy stage. The fetus' B12 status is dependent on mom.
Recall how I said earlier in the post that vitamin B12 is absolutely critical as a “Builder vitamin” that builds key components for the brain and nervous system, red blood cells, and genes. Imagine how vital these functions are for a developing fetus.
This explains the wide range of symptoms in B12 deficient infants such as failure-to-thrive, irritability, developmental delay, apathy, refusal of solid foods, etc. An inability to properly methylate and detoxify may also be linked to a whole range of behavioral and neurodevelopmental disorders given the impact it would have on brain and nervous system development.
For parents caring for children who may have neurological or behavioral conditions, please do not feel guilty if you were not eating a B12-rich diet or if you were not regularly taking your prenatal vitamins or supplements to fortify your B12 and folate levels.
There is so much uncertainty when it comes to neurodevelopmental conditions with a wide range of factors playing a role, so it's unlikely that a single factor played a causative role. For women who are planning to get pregnant, it makes sense based on existing evidence to optimize B12 and overall nutritional and lifestyle factors to try to maximize the chance of the healthiest pregnancy outcome.
Eating a clean and diverse diet to ensure you are getting all essential nutrients, combined with regular exercise and sleep/stress management are cornerstones not just for individual health, but also during pregnancy to ensure optimal health for future generations.
As a continuation of the fetal risks of vitamin B12 deficiency just mentioned, there are ongoing risks to children and teens with low B12 with a long list of potential symptoms that include delayed speech, language and social development, in addition to behavioral and cognitive issues, and problems with fine and gross motor movement.
As mentioned, signs and symptoms of B12 deficiency in kids can mimic autism spectrum disorders which is why it's important to get screening tests done. For infants and children, more subtle signs may be a dull or apathetic baby or infants who are “late walkers” or “late talkers” due to lack of adequate nervous system development.
Just like in adults, causes can be due to decreased B12 intake which may have originated during mother's pregnancy, reduced absorption in the small intestine (Crohn's disease, celiac disease, etc.), or less commonly congenital disorders in transport or metabolism.
Treatment principles in children are similar to what we discussed already, but dosing will vary. You must address the underlying cause of the B12 deficiency whether it's increasing dietary intake with or without supplements or eliminating gluten if celiac disease is present.
The modern diet for today's children is extremely nutrient deficient and full of sugar and processed foods that put kids at risk for deficient B12 and other essential nutrients. Even if B12 levels return normal, I talked about the key process of methylation which is dependent on a whole host of different nutrients.
A growing body of research is showing that improper methylation from an unhealthy diet and lifestyle leads to toxin accumulation in a child's brain, which is linked to a growing list of neurodevelopmental disorders.
Be sure to work with a pediatrician or health care provider who is familiar with diagnosing and treating B12 deficiency appropriately.
There are also a growing number of certified integrative and functional medicine pediatricians who are especially skilled in looking for B12 deficiency along with other nutrient gaps and toxin exposures that can be linked to neurodevelopmental conditions in kids.
We discussed how vitamin B12 is critical for early stage neurological development in kids. In seniors sufficient B12 is essential for preservation of brain function. If we want to maintain our mood and cognitive abilities (memory, focus, ability to learn, etc.), nutrients like B12 must be within normal range.
Seniors are especially vulnerable to multiple risk factors for B12 deficiency. Recall how I mentioned that stomach acid is a key factor for enabling vitamin B12 absorption. Aging already leads to a reduction in stomach acid production and many seniors are also taking additional acid blocking medications in addition to other classes of medications that can lead to low B12.
Many seniors also naturally reduce their overall dietary intake due to a lower appetite and may develop intestinal conditions that also impair B12 absorption.
Typical B12 deficiency symptoms in seniors can mimic dementia and include trouble walking, trouble thinking and remembering, and overall weakness.
As discussed you can also develop numbness, tingling or strange sensations in hands, legs and/or feet. Later stage symptoms like anemia may make all of these symptoms even worse.
If you or a loved one is experiencing any of the above symptoms, be sure to pay very close attention to the risk factors for B12 deficiency we discussed and make sure appropriate diagnostic testing is done. Again, don't have unrealistic expectations that normalizing B12 levels will lead to reversal in all symptoms experienced in seniors.
Dementia, weakness and frailty are complex issues often due to multiple factors including inactivity and muscle wasting (aka sarcopenia), mood disorders unrelated to B12 and/or underlying cardiovascular or neurodegenerative conditions. Vitamin B12 deficiency may be one of many factors that needs to be addressed.
4. SOUTH ASIANS
In my clinic I see quite a few South Asian who are vegetarian or vegan with all types of digestive issues prompting them to take acid-blocking medications. Their B12 deficiency is often due to a combination of low intake because of their diet and poor absorption from limited stomach acid and or intestinal inflammation from conditions like celiac disease or SIBO (small intestinal bacterial overgrowth).
Even my South Asians who state they are non-vegetarians may still eat very limited amounts of B12-containing foods like eggs or meat since they have a spouse or other family member at home who is vegetarian.
In addition, although South Asians may think they are getting adequate B12 by drinking milk, the common practice of heating milk actually destroys the B12.
This is an excellent study examining B12 deficiency in South Asians living in New Zealand and summarizes cultural risk factors for low B12 status.
Hopefully you stuck with me through this lengthy and comprehensive post on B12 deficiency. I hope you have a deeper understanding of the pervasive impact B12 deficiency can have on every major system in our body, especially the brain and nervous system.
I also hope you appreciate the multigenerational impact of B12 deficiency since it can lead to serious disease and disability that impacts every member of the family. For anyone caring for a child or senior with a chronic health condition, you know firsthand the physical, emotional and financial impact these disorders can have.
This post is not just making a case for the importance of B12 as an essential nutrient, but instead for the critical role that overall nutrient deficiencies from an unhealthy diet and lifestyle play in triggering most chronic health conditions.
Taking a vitamin B12 supplement alone in the context of a poor diet and unhealthy overall lifestyle is unlikely to produce any perceptible improvements in physical and mental health.
As our fast paced modern lives keep pushing healthy eating further aside, we need to reprioritize and refocus our energies on eating the right foods to preserve and promote optimal health for ourselves and those we care for.