Vitamin B-12 Sample

Why could it be low?

  • Common deficiency in vegans and vegetarians, since B12 is mostly found in animal products.
    • One study of almost 500 vegans and vegetarians found that 52% of vegans and 7% of vegetarians were B-12 deficient (1).
  • Early in life, the most common cause of deficiency is inadequate intake (usually lack of animal protein). In the US & UK only 6% prevalence in people under 60 years old (213).
  • In older adults (over 60), the biggest cause is malabsorption due to atrophic gastritis (inflammation of the stomach leading to atrophy of the tissue) and the increasing prevalence of pernicious anemia (when your immune system attacks your parietal cells in the stomach and reduces the secretion of intrinsic factor, which is needed for B-12 absorption) or even an autoimmune attack against intrinsic factor itself. 20% of older adults are deficient (213).
    • H. pylori infections may be a root cause of atrophic gastritis, but not always (3).
  • Low stomach acid, because there is not enough acid to activate intrinsic factor & absorb B12 (6).
  • Pernicious anemia (4).
    • Signs of pernicious anemia – low hemoglobin or hematocrit, and large red blood cells (mean corpuscular volume).
    • Can also do a test for serum intrinsic factor levels and/or parietal cell antibodies.
  • Zollinger-Ellison syndrome – when a pancreatic tumor causes excess production of stomach acid and ulcers. These people are usually put on a PPI (13).
  • Active gut infections like SIBO or giardia or tapeworms – the pathogens consume the B12 in your gut, so there is not much left for you (715).
  • Surgical removal of the terminal ileum or ileal resection (since this is where B12 is absorbed) (14).
  • Gastric bypass surgery – bypassing the stomach leads to not enough intrinsic factor for proper B12 absorption (8)
  • Genetic mutations that affect B12 absorption or metabolism (8).
    • CUBN – gene that codes for the absorptive sites for IF/B12 in the terminal ileum
    • AMN – gene that codes for the part of the B12 receptor that brings B12 across the intestinal border
    • MMAA – gene that codes for cobalamin A, a protein that makes sure that cobalamin remains in the adenosylcobalamin form in order to be used inside the mitochondria
    • MMAB – gene that codes for cobalamin B, a protein that catalyzes the adenosylation of B12 in the mitochondria
    • MMACHC – gene that codes for cobalamin C, a protein that catalyzes the removal of cyano and alkyl from B12
    • MMADHC – gene that codes for cobalamin D, a protein that binds to B12 inside the cell and shuttles it to the mitochondria or reactions in the cytosol
    • MTRR – gene that codes for cobalamin E, a protein that catalyzes the methylation of B12 in the cytosol
    • MTR – gene that encodes for methionine synthase, an enzyme that converts homocysteine to methionine (if this is not working, could have trouble with folate, which is needed for B12 to become methylcobalamin and convert to adenosylcobalamin)
    • TCN-1 – gene that codes for transcobalamin, a transport protein for B12, helps bring B12 into cells.
    • GIF (TCN-3) – gene that code for intrinsic factor
    • MUT – gene that encodes for methylmalonyl CoA mutase enzyme, which transforms methylmalonyl-CoA to succinyl-CoA. If they have MUT mutation, adenosylcobalamin may be a better supplement choice, especially if not responsive to methylcobalamin.
  • Celiac disease or Crohn’s disease – both cause small intestine damage that interferes with absorption (8).
  • Pancreatic insufficiency or chronic pancreatitis – without enough pancreatic juices, B12 can’t be released from haptocorrin/transcobalamin I (a protein that binds with B12 in the stomach to protect it from the acid), and then can’t be absorbed in the small intestine (8)
  • HIV/AIDS – they have a higher need for B12, so it’s easier to become deficient (11)
  • Excessive alcohol intake (17)
  • Certain medications:
    • Long term use of antacids (3)
    • PPI use for more than 2 years (12)
    • H2 antagonists (used to treat peptic ulcers) for more than 2 years (12)
    • Cholestyramine (used to treat high cholesterol) (16)
    • Nitric oxide (18)
    • Neomycin & Ciprofloxacin (antibiotics) (19)
    • Colchicine (gout medicine) (19)
    • Potassium chloride (Slow K) (19)
    • Metformin (35, 910)
    • Oral contraceptives (19)
  • If you did Spectracell, may also want to check serum B12 to get more info (and other better markers like MMA or homocysteine).
    • If serum is high, but intracellular B12 is low, then we know there is an issue with it getting into the cells.
    • Could be related to low lithium levels.

What does B12 do in the body?

  • A cofactor for:
    • Forming blood cells and white blood cells
    • Energy metabolism in the mitochondria (need B-12 to convert methylmalonyl-CoA to succinyl-CoA, which goes into the Kreb’s cycle to create NADH, FADH, and ATP)
    • Transformation of homocysteine to methionine
    • Neurotransmitter synthesis
    • Protein and fat metabolism (breakdown of proteins into amino acids and fatty acids into fats)
    • Metabolism of odd-chain fatty acids and branched amino acids
    • Maintenance of the myelin sheath around nerves (because SAM, which is made from methionine, is needed for methylating myelin sheath phospholipids)
  • Prevents folate derivatives from being trapped in unused states.
  • Modulates melatonin secretion for normal circadian rhythms
  • Key role in methylation & synthesis of DNA

What are common symptoms of deficiency? (13)

  • Shortness of breath
  • Fatigue
  • Weakness
  • Unsteady gait
  • Cardiomyopathy
  • Irritability
  • Depression
  • Impaired cognition / brain fog
  • Psychosis/delusions
  • Osteoporosis
  • Sore/inflamed tongue
  • Changes in taste sensation
  • Loss of appetite
  • Constipation
  • Tingling in the extremities
  • Myelopathy (disease of the spinal cord)
  • Infertility
  • Macrocytosis (enlarged red blood cells)
  • Pancytopenia (deficiency in red blood cells, white blood cells, and platelets)
  • Hypersegmentation of neutrophils
  • Progressive neuropathy, can be permanent without repletion
  • Elevated homocysteine levels (increases heart disease risk)
  • If you have malabsorption, it can take 2-5 years for symptoms of a deficiency to appear, or 10 years on a vegan diet, due to large body stores.

How common is deficiency?

  • Vitamin B12 deficiency has a prevalence of anywhere between 1.5-15% of the general United States population (21).
  • Common deficiency in vegans and vegetarians, since B12 is mostly found in animal products.
    • One study of almost 500 vegans and vegetarians found that 52% of vegans and 7% of vegetarians were B-12 deficient (1).
  • Early in life, the most common cause of deficiency is inadequate intake (usually lack of animal protein). In the US & UK only 6% prevalence in people under 60 years old (213).
  • 20% of older adults are deficient (213).
  • Individuals who take supplements or consume fortified cereal products at least four times per week are significantly less likely to develop a deficiency (22).

Best Food Sources (from USDA database):

  • Seafood – especially clams, octopus, oysters, mussels, caviar, mackerel, herring, salmon, crab, tuna, cod, sardines, trout, beluga, bluefish, cuttlefish, conch, bass, pollock, snapper, crayfish, eel, sturgeon, catfish, turbot, cod, lobster, tilapia, scallops, swordfish, homemade fish stock
  • Organ meats – especially liver, kidneys, brain, pancreas, heart, testes, tongue, spleen, lungs
  • Game meats – especially emu, beaver, muskrat, opossum, rabbit, raccoon, caribou, squirrel, ostrich, deer, moose, goose, horse, elk, bison, bear
  • Animal proteins – beef, lamb, salami, turkey, pork, eggs, chicken thighs
  • Fortified cereals or beverages
  • Whey protein powder
  • Dairy – especially swiss cheese, mozzarella, feta, Parmesan, fontina, queso fresco, muenster, provolone, cheddar, and yogurt
  • Vegans must take supplements or consume fortified foods (cereals, fortified nutritional yeast, fortified soy, etc.)

How much B-12 do people need each day?

  • The RDA for B-12 is:
    • 0.4 mcg for 0-6 months old
    • 0.5 mcg for 7-12 months old
    • 0.9 mcg for 1-3 years old
    • 1.2 mcg for 4-8 years old
    • 1.8 mcg for 9-13 years old
    • 2.4 mcg for 14 years and up
    • 2.6 mcg for pregnancy
    • 2.8 mcg for breast feeding
  • If you have GI disturbances or low stomach acid, you may need injections or sublingual forms. (Usually monthly injections).
  • According to NHANES data from the year 2000, the average American consumes roughly 3.4 mcg per day, surpassing the RDA (20).

What type of B12 is best for supplementation?

It really depends! Hard to say without some trial and error and/or genetic information.

There are 4 types of B-12 supplements:

  1. Cyanocobalamin
  2. Hydroxycobalamin
  3. Methylcobalamin
  4. Adenosylcobalamin

Let’s review each type!

1. Cyanocobalamin:

  • This is the worst option for supplementation, but also the cheapest, so it gets used often in drug-store quality vitamins.
  • It is an artificial version of B12, made by bacterial fermentation.
  • It is not an active form of B12, and has to be converted before it can be used by the body.
  • First, the cyano group that is attached to the cobalamin has to be removed.
    • This requires NADPH, FAD, and GSH.
  • Once the cyano is removed, you now have hydroxycobalamin.

2. Hydroxycobalamin:

  • Hydroxycobalamin is a natural form of B12 that is created by bacteria.
  • It is active in the body, but not in the same way as methylcobalamin or adenosylcobalamin.
    • It is good at combating cyanide poisoning, because it can strongly bind to cyanide and render it harmless/ready for excretion.
    • It can also lower nitric oxide levels, which can be useful if NO is chronically elevated (can occur sometimes in people with fibromyalgia or chronic fatigue or autoimmune issues).
  • In order to become methylcobalamin or adenosylcobalamin, the hydroxy has to be removed, which creates an intermediate form of B12 known as cob(II)alamin.
    • This process requires NADH and FAD or FMN.

3. Methylcobalamin

  • Cob(II)alamin can be directly converted to methylcobalamin, which is one of the highly active forms of B12.
    • This conversion process requires SAM as a methyl donor.
  • Or, it can be indirectly converted to methylcobalamin.
    • In this process, cob(II)alamin can be first converted to cob(I)alamin, and THEN converted to methylcobalamin (so 1 extra step basically).
    • This requires 5-MTHF (L-methylfolate), so folate levels have to be normal in order for B12 to work optimally.

4. Adenosylcobalamin

  • This is the other highly active form of folate, and is the form used in the conversion of methylmalonyl-CoA to succinyl-CoA (which then enters the Kreb’s cycle for energy).
  • It can be created indirectly from methylcobalamin or directly from cob(I)alamin.
    • To be made from methylcobalamin, the methyl group must be removed first (which happens as homocysteine is converted to methionine). Once the methyl group is removed, you have cob(I)alamin.
  • Cob(I)alamin can then be converted to adenosylcobalamin.
    • This requires ATP.

Which form is the best?

Most practitioners recommend methylcobalamin, adenosylcobalamin, or hydroxycobalamin for supplementation, and do NOT recommend cyanocobalamin, since it requires extra conversion steps in order to be a usable form of B12.

Which of the other 3 forms is best for you depends on your overall health/nutrient status and genetics. It may require some experimenting and tweaking based on how you respond.

Most practitioners jump right into recommending methylcobalamin, since it is an active form of B12, but it is not always the best option for everyone.

Adenosylcobalamin can be a good option for people who feel that they are very fatigued and have poor exercise tolerance.

It is possible that they have issues converting methylmalonyl-CoA to succinyl-CoA (which requires adenosylcobalamin), and thus are not able to create enough energy via the Krebs cycle. Adenosylcobalamin supplementation might be a good choice for this type of person, since they may have trouble converting methylcobalamin to adenosylcobalamin.

If MMA levels are high, that means adenosylcobalamin levels are low. (But it is still unclear whether this is something going wrong w. adenosylcobalamin function, OR because something is going on further upstream, like poor intake or poor absorption).

Other things to consider:

  • Glutathione levels – glutathione is needed for methylcobalamin to bind to its transfer protein (transcobalamin) in the blood. So if someone is deficient in glutathione and is taking supplemental methylcobalamin, they might not feel much better until they get their glutathione levels back up so that methylcobalamin can be shuttled around the body properly.

How much B-12 is needed to replete a deficiency?

A 500 mcg daily supplement (oral or sublingual) has been shown to be enough to correct a deficiency in 1 month (24).

However, most practitioners recommend 1g daily, to account for differences in absorption (25).

Intrinsic factor gets maxed out with a dose of 1-2 mcg, so only about 1% of large oral dosages will be absorbed by passive diffusion (26).

Absorbed 2x better on an empty stomach than when taken with meals (26).

If someone is having neurological symptoms, they should start to improve within 1 week of supplementation, but may take 6 weeks to 3 months for optimal improvement (25).


What are some reputable supplement brands?

Oral:

  • Pure Encapsulations – Adenosyl/Hydroxycobalamin (2g capsules, 1g each form of B12) Made from corn dextrose fermentation
    • Inactive ingredients: hypoallergenic plant fiber (cellulose), vegetarian capsule (cellulose, water)
  • Pure Encapsulations – Methylcobalamin (1g capsules) Made from corn dextrose fermentation
    • Inactive ingredients: hypoallergenic plant fiber (cellulose), vegetarian capsule (cellulose, water)
  • Thorne – Methylcobalamin (1g capsules)
    • Inactive ingredients: Microcrystalline Cellulose, Hypromellose (derived from cellulose) capsule, Leucine, Silicon Dioxide.

Sublingual/lozenges/liquid:

  • Life Extension – Methylcobalamin Lozenges (1g daily).
    • Inactive ingredients: sucrose, vanilla, mannitol, sorbitol, stearic acid, croscarmellose sodium, tapioca, and vegetable stearate.
  • Pure Encapsulations – Liquid Methylcobalamin (1g per dropper) (from corn dextrose fermentation)
    • Inactive ingredients: purified water, natural glycerin, citric acid, potassium sorbate, stevia leaf extract
  • Pure Encapsulations – Liquid Adenosyl/Hydroxycobalamin (1g per dropper, 50% each type) (from corn dextrose fermentation)
    • Inactive ingredients: purified water, natural glycerin, citric acid, potassium sorbate

What is the best way to measure B-12 status?

The best way is MMA (methylmalonic acid, an organic acid measured in urine or blood) (23).

Normally, B-12 is needed in oder to convert methylmalonyl-CoA to succinyl-CoA (which would then go into the Krebs cycle for energy).

If there is NOT ENOUGH B-12 to do this, methylmalonyl-CoA gets converted to MMA instead, and that is excreted in the urine.

Serum B-12 is the last place to show a deficiency, so it is not a very good measure of B-12 status.

If MMA levels are above 350 nmol/L, that indicates a B12 deficiency.

MMA can be requested by dietitians & is available on most organic acid tests (OATs). It was also recently added to the DUTCH hormone test.


Nutrients that impact MMA status:

  • If you are deficient in biotin, then even if you ARE deficient in B-12, MMA may not be elevated (so you could falsely think your B-12 levels are fine, when really they are being masked by the biotin deficiency).
  • This is because biotin is needed for the conversion of Propionyl-CoA —> methylmalonyl-CoA.
    • Without enough biotin, you can’t make methylmalonyl-CoA, so then you can’t make MMA.

How can you help someone with high MMA (and therefore low B-12 levels)?

First, try to figure out WHY the B-12 became low in the first place (see the extensive list above), and work on addressing that.

Regardless of whether you know the cause yet, you should start a supplement in order to replete levels. This can be a bandaid to help them feel better while you work on finding and addressing the root cause.


Why might someone be LOW in B-12 on a test like Spectracell (intracellular levels) if they are taking a B-12 supplement or multivitamin with plenty of B-12?

This means that the B-12 is not getting into the cells properly.

They could have a genetic defect that affects B-12 transport proteins (like transcobalamin II). TCIIG>C gentoype is the mutation that can negatively impact B-12 transport.

Since the B-12 is not getting into the cells to be used, you would expect MMA to be high as well.

Another possibility is that they are not properly absorbing the B-12 they are taking, or if the supplement contains low-quality cyanocobalamin, they might be having trouble converting it to an active form.

Essentially, they are getting enough B-12, but their bodies can’t use it properly.


Vitamin B-12 and homocysteine levels:

Methylcobalamin (and zinc) are required in order to convert homocysteine to methionine.

Once methionine is made, it can go on to form SAM, which is an important methyl donor in the body, especially for DNA methylation.

So, if B-12 is low, homocysteine may be high.

But genetics also matter. The MTR and MTRR enzymes are required to convert homocysteine to methionine, and these are made by the MTR and MTRR genes. Some people have mutations that reduce the functioning of these enzymes (see above).

Also, even if you are deficient in B-12, technically there is another way your body can convert homocysteine to methionine – the BHMT pathway.

The BHMT pathway is a shortcut from homosysteine to methionine that does NOT require vitamin B-12 (methylcobalamin).

BUT, it does require other vitamins – choline, betaine, and zinc. So you still need good nutrition for this pathway to function.


How does B-12 status (as measured with MMA) relate to hormones and other organic acids?

If B-12 is low, methionine (and therefore SAM) may be low (because B-12 is needed as a cofactor to make methionine).

Without enough SAM, estrogen may not be methylated rapidly enough to be properly detoxified in the liver, so estrogen levels may be elevated .

Not having enough methionine may also slow the activity of the COMT and PNMT methylation enzymes.

COMT is required to breakdown dopamine into HVA (homovanillic acid – an organic acid that can be measured in the urine). So if B-12 (and methionine) are low, HVA may be low on an OAT test too.

COMT is also needed to break down norepinephrine and epinephrine into VMA (vanilmandelate – an organic acid that can be measured in the urine). So if B-12 (and methionine) are low, VMA may be low on an OAT test too.

PNMT is needed to convert norepinephrine to epinephrine, so if B-12 is low (and methionine), then norepinephrine may be elevated, and epinephrine may be low.