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The causes of B12 deficiency and how it’s related to MTHFR

The causes of B12 deficiency and how it’s related to MTHFR

The causes of B12 deficiency and how it’s related to MTHFR

Vitamin B12 deficiency is one of the most overlooked deficiencies in Australia, and probably worldwide.  It is widely underdiagnosed and can cause a myriad of health problems. 

Once diagnosed with and treated for a B12 deficiency, many of my patients have an extremely positive change in mood and energy, making a speedy return overall wellness. Low B12 levels impact many systems in the body that addressing a deficiency can have life-changing effects. 

The causes of B12 deficiency and the relationship between this deficiency and MTHFR mutations is complex. Let’s look at just why we need B12, symptoms of B12 deficiency and how it relates to genetic disorders.

What is vitamin B12?

…also known as cobalamin, is an important water-soluble vitamin. It is a nutrient that helps keep the body’s nerve and blood cells healthy and helps make DNA, the genetic material in all cells. “It’s…involved in the production of the myelin sheath around the nerves and the conduction of nerve impulses. If you can think of the brain and the nervous system as a big tangle of wires. Myelin is the insulation that protects those wires and helps them to conduct messages.” 1

Vitamin B12 also helps prevent a type of anaemia called pernicious anaemia that makes people tired and weak.


B12 cannot be manufactured in human beings. It must be regularly obtained from animal proteins or fortified food products. Plant foods have no vitamin B12 unless they are fortified. 

You can get recommended amounts of vitamin B12 by eating a variety of foods including the following:

  • Beef liver and clams, which are the best sources of vitamin B12
  • Fish, meat, poultry, eggs, milk, and other dairy products, which also contain vitamin B12
  • Some breakfast cereals, nutritional yeasts, and other food products that are fortified with vitamin B12.

To find out if vitamin B12 has been added to a food product, check the product labels

What causes B12 deficiency?

The main causes of B12 deficiency include inadequate dietary intake and malabsorption issues yet genetic predisposition to vitamin B12 deficiency has been demonstrated in various studies. 

“For instance, mutations and polymorphisms in transport proteins such as transcobalamin TCN, gastric intrinsic factor GIF and metabolic enzymes such as methylenetetrahydrofolate reductase MTHFR have been associated with vitamin B12 deficiency.” 2

Vitamin B12 deficiency may also occur if you have certain conditions, such as:

  • Pernicious anaemia, which makes it hard for your body to absorb vitamin B12 (characterized by a lack of intrinsic factor – individuals cannot properly absorb vitamin B12 in the gastrointestinal tract)
  • Atrophic gastritis or inadequate production of stomach acid (occurs in 10-30% of older adults!)
  • Helicobacter pylori infection in the stomach
  • Surgery that removes part of your stomach or small intestine which can result in a loss of cells that secrete hydrochloric acid and intrinsic factor
    • Bariatric surgery
    • Gastrointestinal tract or weight loss surgery
  • Conditions that affect the small bowel 
    • Crohn’s disease
    • Celiac disease (11-41% of patients with celiac will have B12 deficiency)
    • Small intestinal bacterial overgrowth (SIBO)
    • Parasite infections (Giardia and tapeworm)
    • Chronic pancreatitis
  • Heavy alcohol use or advanced liver disease
  • Autoimmune conditions
    • Grave’s disease
    • Lupus
  • Malnutrition or eating disorders
  • Long term use of medications 
    • Proton pump inhibitors
    • H2 blockers
    • Metformin
    • Certain antibiotics 3

How does your body absorb vitamin B12?

Vitamin B12 absorption relies almost solely on your gut and stomach acid breaking down the protein to get the B12 from your food. You need to have an intrinsic factor, a protein made by cells in your gut lining to bring B12 into circulation, transcobalamin proteins to move it around the body and finally, pancreatic enzymes for absorption.

B12’s role in your genetic pathways and as a methyl donor

Vitamin B12 has an important role in some of your key genetic pathways.  B12 needs to be converted into its active form, methylcobalamin to be usable in the cells of your body.  This process takes place through the MTRR enzyme. Up to 30% of the population has a down-regulated MTRR SNP (single-nucleotide polymorphism) potentially impairing this vital process.  

Methylcobalamin intersects with methylfolate at the MTR enzyme, where both nutrients are required to stimulate the methionine pathway.  

The methionine pathway is one of the most crucial in the body as it involves the production of SAMe, the body’s major methyl donor.  Methylation and the methionine pathway is upstream of many functions in the body, including detoxification and the clearance of hormone and neurotransmitters.

MTHFR is an enzyme that participates in your body’s folate and methylation cycle. It is needed to produce methylfolate, which recycles homocysteine, produces SAMe and recycles biopterin, all extremely important nutrients in the body. 


Methylation is an essential biochemical process that is part of our metabolism. The methyl group acts like an on/off switch for major metabolic processes. These processes include liver detoxification pathways, estrogen metabolism, DNA replication, energy production and the production and clearance of neurotransmitters. 

Find out more about the methylfolate pathway here.

If you have an MTHFR polymorphism, enzymatic reactions can slow down by 40-70%. This leads to elevated homocysteine levels which diminish your ability to eliminate toxins. When you can’t eliminate toxins efficiently, your body can accumulate heavy metals and suffer imbalances, resulting in other health issues. 

B12 is the most important nutrient for you to absorb folate.

“When you have MTHFR gene mutations you lack the enzymes responsible for the conversion of folate that you eat into the active form 5-Methyltetrahydrofolate. However, this important reaction is then directly involved in the utilization of vitamin B12…(this) is vitally important in the processing of homocysteine. So, if your vitamin B12 is not working properly because your folate metabolism isn’t working properly this causes homocysteine imbalances which are considered a serious health problem for anyone especially for those with MTHFR gene mutations.” 4

Reactions to Methylfolate supplementation

Individuals that cannot tolerate Methylfolate often have low B12 levels in their cells.  This can cause “methyl trapping”, where the excess methylfolate is unable to be utilised in the methionine cycle (through the MTR enzyme) as usable B12 levels are too low.  Supplementation of B12 for a number of weeks prior to supplementing methylfolate, will avoid reactions to methylfolate.

MTHFR gene mutations negatively impact the methylation pathway and vitamin B12 levels.

“This happens because certain MTHFR mutations (C667T and A129C) lower the amount of active folate being produced in the body, and the use of vitamin B12 requires the active form of folate. Vitamin B12 deficiency can be occurring while vitamin B12 levels are at levels not typically associated with deficiency due to the presence of deleterious MTHFR mutations.” 5

If you have one or more MTHFR, MTRR or MTR gene mutations, you will be less able to methylate B12 or convert your B12 to methylcobalamin. The more mutations you have, the less likely you are to make this conversion. 6

How do you know if you have a vitamin B12 deficiency?

There are many B12 deficiency signs and symptoms, including:

  • Numbness
  • Tingling, pins and needles
  • Weakness, dizziness
  • High homocysteine, low methionine
  • Megaloblastic macrocytic anaemia
  • Mild or moderate leukopenia (low white blood cells)
  • Mild or moderate thrombocytopenia (low platelets)
  • Enlarged red blood cells (macrocytosis)
  • Abnormal white cell (neutrophils)
  • Chronic fatigue or tiredness
  • General weakness or lethargy

General Signs and Symptoms:

  • Ataxia, (unsteady walking)
  • Paresthesia (prickling sensation) and weakness in peripheral nerves
  • Confusion
  • Infertility
  • Vision loss
  • Leg pains
  • Shortness of breath
  • Loss of appetite/weight loss
  • Epigastric pain
  • Osteoporosis
  • Increased susceptibility to infection
  • Failure to thrive in infants
  • Vitiligo
  • Premature greying of hair
  • Burning feet

Mental Changes

  • Depression (including postpartum depression)
  • Irritability
  • Apathy
  • Psychosis
  • Sleepiness
  • Suspiciousness (paranoia)
  • Personality changes
  • Memory loss
  • Dementia, intellectual deterioration
  • Hallucinations
  • Violent behaviour
  • Developmental delay and/or autistic behaviour in children

Neurological signs and symptoms

  • Abnormal sensations ie: pain, tingling, numbness of legs, arms, trunk
  • A diminished sense of touch, pain and/or temperature
  • Loss of position sense (awareness of body position)
  • Weakness of limbs
  • Clumsiness
  • Tremor
  • Symptoms mimicking Parkinson’s disease or MS
  • Spasticity of muscles
  • Incontinence (urine or stool)
  • Paralysis
  • Vision changes
  • Damage to the optic nerve –neuritis, inflammation, atrophy

Vascular Problems

  • Transient ischemic attacks (TIAs)
  • Cerebral vascular accident
  • Coronary artery disease
  • Myocardial infarction
  • Congestive heart failure
  • Palpitations
  • Orthostatic hypotension
  • Deep vein thrombosis
  • Pulmonary embolism 7

Why is B12 deficiency often underdiagnosed?

A healthy vitamin B12 level is between 500-800+ µmol.

There are two reasons B12 deficiency is often undiagnosed. Firstly, it is not routinely tested, and secondly, low levels are often labeled as ‘normal’ e.g. sometimes as low as 200 µmol. 8

Just relying on testing B12 in the blood is not always as simple as it sounds.  Some patients have adequate levels of blood B12 but are lacking in the cells.  Testing Active B12, also known as holotranscobalamin, provides a clearer indication of the utilisation of B12. 

Testing the organic acid, methylmalonic acid, provides a more accurate level of actual usable B12 in patients.  

How can you treat B12 deficiency?

  • Optimise your nutrition
  • Fix any gut issues
  • Check MTHFR, MTRR, MTR and other associated genes for mutations and supplement if necessary

Consult your Functional Medicine health practitioner about which form of B12 supplement is best for your condition.

Forms of B12

B12 has many forms, these are cyanocobalamin, hydroxocobalamin, adenosylcobalamin and methylcobalamin (methyl-B12). 

In order for our bodies to use B12, the form of cobalamin must be converted into methylcobalamin through the MTRR enzyme.

People often wonder what form of B12 they should supplement with, as a basic rule, 

  • Methylcobalamin (active form of B12) – can be utilised by the body without requiring conversion, the best form to supplement with as long as it is well tolerated. Those with MTRR SNPs commonly do well with this form. A great B12 form for those with mental health issues. Individuals with excess methylation often do not do well with this form.
  • Hydroxycobalamin (nitric oxide scavenger) – An excellent form to start supplementation with, well-tolerated, those patients that cannot tolerate methyl well do better on this form. Excellent with low blood pressure, dizziness and with smokers as it detoxifies cyanide.
  • Adenosylcobalamin (energy production) 9 – works well with patients with low energy, often given in combination with hydroxocobalamin. 
  • Cyanocobalamin – a synthetic form of B12 in many cheap supplements, the body has to work much harder to be able to convert this form into the usable methylB12. We don’t recommend this for supplementation and the other forms are much better.

How Advanced Functional Medicine can help you

B12 is just one important factor in a complex relationship in the biochemical pathways of your body.

There are many key factors to understand when balancing methylation, the interaction of B12 and understanding how other body systems interact with these pathways. 

B12 and methylation can impact many biochemical pathways and affects your DNA replication, the rate at which we age, energy production, detoxification, mental health, and hormones.

At our Perth Clinic, we believe there are many reasons to consider B12 vitamins in the proper treatment of MTHFR and related conditions. 

Our treatment method

Genetic testing in conjunction with comprehensive blood chemistry, gut health assessment, and organic acid testing can provide a comprehensive picture of your health.

At Advanced Functional Medicine, we utilise advanced testing to take the guesswork out of diagnosis. Our focus is on balancing your biochemistry, rather than chasing symptoms and, consequently, providing “band-aid” solutions.  By adopting this focus and balancing the biochemistry of the body, symptoms begin to fall away. The body can, therefore, begin to heal itself rather than masking symptoms with drugs or unnecessary supplements.

If you would like more information on how to start the process of testing or to find out more, please contact us at 1800 11 22 36 or complete the form below.

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The above information is intended to be general, educational advice only, on topics which are of interest to us. It is not intended to represent specific or individual health or medical advice and is not specific to your situation. The below information is educative and is not intended to advertise any service.

Before making any decisions in relation to your health, you should always discuss your individual situation with your own health practitioners to ensure that any advice you have read is right for you.

Jarrod Cooper – ND

Jarrod Cooper – ND

Jarrod Cooper - ND is the founder of Advanced Functional Medicine Australia. He is a Naturopathic Doctor with extensive functional medicine training from leading practitioners in the USA and worldwide.

He is leading the way with advancements of functional medicine, clinically implementing worldwide best practices in Functional Medicine throughout Australia.

Jarrod consults in person from Perth, Western Australia and also online via Telehealth throughout Australia and worldwide.

If you are looking for personalised treatment, we highly recommend contacting Jarrod Cooper’s Advanced Functional Medicine clinic in Australia.

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