VITAMIN B12

B12 - OVERVIEW

Vitamin B12 is required to form blood and immune cells, and support a healthy nervous system. A series of closely related compounds known collectively as cobalamins or vitamin b12 are converted into active forms methylcobalamin or 5-deoxyadenosylcobolamain. Methylcobolamin interacts with folate metabolism, preventing folate derivatives from being trapped in unusable states. Adenosylcobalamin is involved in the metabolism of odd fatty chain acids and branched chain amino acids.

B12 also plays important roles in energy production from fats and proteins, methylation, synthesis of hemoglobin & RBS’s, and maintenance of nerve cells, DNA, and RNA. Vitamin B12 is an important coenzyme when in its active form of methylcobalamin. B12 facilitates the metabolism of folic acid as a methyl donor and requires intrinsic factor for absorption, which is calcium dependent. B12 is also required in the production of some neurotransmitters. [1,2,8]

B12 overlaps with folate, but has one role in energy metabolism which makes B12 indirectly responsible supporting the antioxidant system to recycle homocysteine to methionine. B12 is more directly responsible for providing the ATP that is needed to activate methionine to SAMe. Thus, B12 is necessary to prevent accumulation of homocysteine. B12 is also required to prevent macrocytic, megaloblastic anemia (too few , and too large red blood cells).

B12 deficiency causes the same macrocytic, megaloblastic anemia that folate deficiency causes. B12 can cause folate to remain un processed and cause anemia. High folate intake, from foods or supplements, can mask a B12 deficiency. Anemia testing is easier to see than nervous system symptomology. Folate prevents anemia but not the nervous system degeneration. Folate supplementation can cause nervous system degeneration in people with B12 deficiency. [1,2,8]

Deficiency Symptoms

Deficiency symptoms of vitamin b12 are hematological (pernicious anemia) and neurological. A megaloblastic anemia may occur because the effects of the vitamin b12 deficiency on folate metabolism. Shortness of breath, fatigue, weakness, irritability, sore tounge, decrease in blood cell counts (red, white, and platelets) are signs of a b12 deficiency. Neurological symptoms are neuropathy with loss of position and sense and ataxia. If vitamin b12 repletion is not initiated, permanent neurological damage, including degeneration of nerves and spinal cord can result. Mental symptoms of depression and fatigue are detectable before anemia develops.[1,2,8]

Pernicious anemia usually develops due to lack of intrinsic factor. Another form of anemia associated with B12 deficiency is megoblastic anemia, when folate is in excess and insufficient B12 is present, which creates a ‘folate trap.’ Another symptom of B12 deficiency is dementia due to degeneration of myelin. In B12 deficiency, methylmalonyl CoA will be metabolized to methylmalonic acid (MMA) - making MMA the ideal functional marker for B12 deficiency. Achlorhydria (insufficient stomach acid) can lead to B12 deficiency because HCl is required to cleave B12 from intrinsic factor.

Vitamin B12 is synthesized by bacteria and exists in all animal foods, however, the B12 synthesized by gut bacteria may not be a significant source for humans, as it is not absorbed in the colon.

Low B12 may result from alcoholism, malabsorption, hypochlorhydria (e.g. from atrophic gastritis, H. Pylori infection, pernicious anemia, H2 blockers, PPI’s, vegan diets, diabetic meds, cholestyramine, chloramphenicol, neomycin, or colchicine). [6]

B12 deficiency can lead to anemia, fatigue, neurological symptoms (e.g. paresthesias, memory loss, depression, dementia) methylation defects or chromosome breaks. Hypochlorhydria and gastrointestinal disturbances are frequently associated with vitamin b12 deficiency.

Age is a risk factor for deficiency of B12 due to a natural decline in intrinsic factor. Chronic use of PPIs may reduce HCl and lead to sub-clinical deficiencies. Some genetic SNPs (such as MTHFR, see more below) may lead to deficiencies in active B12 (methylcobalamin).

B12 deficiency can cause nervous system degeneration and is needed to maintain the integrity of the myelin sheath therefore, is important in nerve impulse propagation. This results from the combination of functional B5 deficiency, the toxicity of amino acid breakdown products and methylation issues. Biotin prepares breakdown products for B12 to bind them and put them into the krebs cycle. If this does not occur they bind to B5 and cause B5 deficiency, and can cause neurological dysfunction.

Many of b12 deficiency features are mental, such as memory loss, changes in personality or mood, delirium or psychosis.[1] Other changes generally begin at the feet and work their way up. They can include [1,2]:

• Incorrect sense of position

• Tingling, numbness, or the feeling of something crawling on your skin

• Loss of full control over your movements

• Being unable to relax your muscles

• Walking strangely

• Optic neuritis, which can cause pain and temporary loss of vision in your eyes

• Visual disturbances

• Dizziness or faintness upon standing from sudden changes in blood pressure

• Exercise intolerance from your heart not adjusting properly to accommodate your exertion

B12 is the one case where the overwhelmingly most probable reason for deficiency is poor absorption rather than poor intake. Pernicious anemia occurs in 0.1% of the general population and 2% of the elderly. This is an autoimmune condition where the body attacks its own cells, specifically destroying the stomach cells required to absorb B12. [5,6,9]

H. pylori infections can cause inflammation, known as gastritis, and impedes B12 absorption. Putting age aside, over 70% of all vegetarians and over 90% of all vegans have evidence in their bloodwork of early B12 deficiency. [5,6,9]

Other cause of b12 deficiency include: digestive disorders (SIBO, candida, oxalates, parasites, etc), stomach surgery, alcoholism, AIDS, and antacids hurt absorption. Finally, there are rare defects in the absorption or utilization of B12 – look for the genes below. [5,6]

Vitamin B12 is found almost exclusively in animal products. The exceptions appear to be a very specific subsets of mushrooms and algae. For mushrooms: black trumpet, chanterelle, and shiitake. Vegan sources of B12 also contain B12 antagonists. [4]

Your liver houses up to a 30 year storage supply of b12 – things like Liver, clams, oysters, and nori allow you to build this and, deficiency may not show up until mid life given the storage we start out with from birth. Foods like meat, milk, cheese, chanterelle, are net neutral basically. Vegetarians and vegans are high-risk and should get tested, or supplement, while elderly and chronically ill, or folks with gut issues are at risk given absorption issues. High-dose supplements are safe and usually effective even in cases of poor absorption. Lozenge, sublingual forms appear best.

Vitamin B12 is required to produce tetrahydrobiopterin (BH4), which is involved in the production of the neurotransmitters serotonin, melatonin, dopamine, norepinephrine, and epinephrine.

B12 deficiency can cause negativism, confusion, disorientation, amnesia, impaired concentration and attention, and insomnia; while psychiatric disorders that may be diagnosed in patients having vitamin B12 deficiency include depression, bipolar disorder, panic disorder, psychosis, phobias, and dementia. [1,2,8]

Amount of B12 Needed / RDA

The RDA for B12 is 6 mcg/day. Vitamin B12 is extremely safe. No toxicity from high doses of vitamin B12 has ever been reported. Intramuscular injections are used, to bypass intrinsic factor issues. We store large amounts of B12 in the liver so larger doses can be given at 6 month intervals. It can take years to deplete the body of B12. Vitamin B12 supplementation may help manage anemia, asthma, fatigue, hepatitis, dementia, epilepsy, depression, psychosis, irritability, ataxia, numbness, tingling, neuropathy, AIDS, multiple sclerosis, tinnitus, and infertility. You can only absorb one day's worth of B12 at a time. Many foods like liver, oysters, and clams have many days worth of B12 in one serving, but your body cannot store this excess, but only a days worth at each meal. [5]

Food Sources of B12

Eggs are not a good source of B12. If you don't eat liver, oysters, or clams, you have to eat at least 12 ounces of meat, poultry, fish, or dairy just to meet the RDA.

Clams 3 ounces (84mcg); Beef liver 2 ounces (70mcg); Mussels 3 ounces (20mcg); Mackerel 3 ounces (16mcg); Crab 3 ounces (10mcg); Trout, wild 3 ounces (5.4 mcg); Trout, farmed 3 ounces (3.5mcg); Salmon, farmed 3 ounces (2.4mcg); Beef 3 ounces (2.1 mcg); Egg 1 large (0.6mcg). Others: shellfish, red meat, poultry, fish, eggs, milk, cheese, black trumpet, chanterelle, or shiitake mushrooms. [3]

B12 STATUS AND TESTING

Vegetarian based diets and anyone over the age of 65 should test vitamin B12 status and annually if deficient. B12 levels do not tell you that the B12 is necessarily getting into your cells. MMA is a good functional marker for b12 status (see below), available on some micronutrient panels (Vibrant) and most Organic Acids Tests (Great Plains, Vibrant, Genova).

SUMMARY

If you have signs of undermethylation, macrocytic anemia, or B12-deficiency nervous system degeneration, you may need more B12.

B12 has all the benefits of folate in methylation and the prevention of anemia AND it prevents irreversible nervous system degeneration. High intakes of folate can mask B12 deficiency and possibly even provoke its neurological problems.

B12 SUPPLEMENTS AND FORMS

B12 supplements exist in various forms, including injection. Supplementation is generally absorbed a little at a time even with large dosing. And there is no evidence of toxicity at high doses. High-dose oral B12 supplements at doses of 2000-5000 mcg per day are usually effective at treating deficiencies. Supplemental B12 is commonly given in 1000 to 5000 mcg doses.

HYDROXYCOBALAMIN: This is the most common form of B12 in foods. It helps detoxify d-lactate from the blood in addition to vitamin B1, a common issue in leaky gut from lactic acid producing bacteria that leak into the blood stream. Can be converted efficiently by the body into other forms of b12 as needed. Hydroxocobalamin is recommended for patients with autoimmune diseases and elevated nitric oxide levels or excess d-lactate in the blood. Hydroxycobalamin is the preferred default supplement, which detoxes d-lactate from the blood

METHYLCOBALAMIN: Found in milk. Helps support methylation, but can cause reactions in people with significant COMT mutations – watch for these effects. Consider MTHFR genetic, and methyl cobalamin supplementation, particularly with hyperhomocysteinemia. Methylcobalamin is the recommended form of supplementation, but may be poorly absorbed in people taking antacids or those with very poor absorption (celiac, intestinal permeability, etc). Glutathione is also required for methylcobalamin to be bound for transport adequately. while methylcobalamin can be used to support methylation if needed.

ADENOSYL-COBALAMIN: Found in meat, and a cofactor in reactions with B7- biotin to process amino acids.

CYANOCOBALAMIN: Not found in natural foods, a common cheap form of b12, not recommended. We make cyanocobalamin, excreted in the urine mostly, and less effective at improving B12 status. Cyanocobalamin is not recommended for patients with MTHFR mutations.

Some of my favorite B12 supplements:

Methylcobalamin: Jarrow Methyl Folate and B12 lozenges (1,000mcg)

Natural grocers methyl folate 667mcg and methyl b12 2,500 mcg lozenges

Now – methylcobolmain lozenges (1,000, 2500, 5000, 10000 mcg)

Source Naturals – hydroxycobolamin lozenges

Swanson Hydroxy b12 lozenges

Seeking Health – Hydroxy b12 lozenges

Key Genes To Inspect Related to B12:

Primarily: TCN1, TCN2, TCN3 (GIF3), FUT2

Secondarily: MTR, MTRR, MAT1A, GAMT, AHCY

GIF (gastric intrinsic factor) reduces the absorption of B12, while TCN1 and TCN2 limit the transport of B12. Higher demand, less absorption and transport may limit functions dependent on B12. Peripheral neuropathy is weakness, numbness, and pain in the hands and feet from nerve damage. Variants in the FUT2 genes may decrease the absorption of B12. [9,10,11,12,13]

MMA

MMA (Methylmalonic Acid) is a metabolite (or metabolic byproduct) of methylmalonyl CoA, which normally converts to succinyl CoA during reactions in the krebs cycle (one of the main body cycles to produce ATP). When there is B12 deficiency, methylmalonic acid accumulates in the blood and produces MMA as a byproduct. MMA is a toxic compound so the higher the level of MMA circulating in the blood the greater the risk. Because the accumulation of MMA is CAUSED by Vitamin B12 deficiency, MMA is considered a FUNCTIONAL measure of B12 deficiency. It is helpful to use MMA in conjunction with B12 to establish a person’s B12 status. MMA can also be elevated with certain anemias, renal insufficiency, and celiac disease.

Methylmalonyl-CoA is converted into succinyl-CoA in a reaction that requires B12 as a cofactor; succinyl-CoA then enters the Krebs cycle where it functions to produce energy.

MMA does not get depleted, as it is a marker of B12 status, however, B12 can be depleted through either inadequate dietary consumption, or reduced methylation of cyanocobalamin to methylcobalamin.

Levels of MMA are elevated in 90-98% of patients with B12 deficiency. It is not recommended to test MMA levels in the elderly, as they can be elevated in the absence of a B12 deficiency in this population.

[1] Mood disorder with mixed, psychotic features due to vitamin b12 deficiency in an adolescent: case report. Ali Evren Tufan, Rabia Bilici, Genco Usta, and Ayten Erdoğan. Child Adolesc Psychiatry Ment Health ; v.6; 2012 ; PMC3404901; Child Adolesc Psychiatry Ment Health. 2012; 6: 25. Published online 2012 Jun 22. doi: 10.1186/1753-2000-6-25. PMCID: PMC3404901. PMID: 22726236

[2] Mood disorder with mixed, psychotic features due to vitamin b12 deficiency in an adolescent: case report Ali Evren Tufan, Rabia Bilici,Genco Usta, and Ayten Erdoğan. Child Adolesc Psychiatry Ment Health . v.6; 2012. PMC3404901. Child Adolesc Psychiatry Ment Health. 2012; 6: 25. Published online 2012 Jun 22. doi: 10.1186/1753-2000-6-25. PMCID: PMC3404901. PMID: 22726236

[3] Dietary sources of B12: https://nutritiondata.self.com/foods-000116000000000000000-2w.html?

[4] Vitamin B12 and folate status in Spanish lacto-ovo vegetarians and vegans. Angélica Gallego-Narbón,1 Belén Zapatera, Laura Barrios, and M. Pilar Vaquero. J Nutr Sci. v.8; 2019. PMC6391582. J Nutr Sci. 2019; 8: e7. Published online 2019 Feb 26. doi: 10.1017/jns.2019.2. PMCID: PMC6391582. PMID: 30828450

[5] NIH: Vitamin B12 Deficiency. Alex Ankar; Anil Kumar. Last Update: October 22, 2022.

[6] Vitamin B12 absorption and malabsorption. Jean-Louis Guéant, Rosa-Maria Guéant-Rodriguez, David H Alpers.. Vitam Horm . 2022;119:241-274. doi: 10.1016/bs.vh.2022.01.016. Epub 2022 Mar 1. PMID: 35337622 DOI: 10.1016/bs.vh.2022.01.016

[7] Neurological disorders in vitamin B12 deficiency. Ch Pavlov, I V Damulin, Yu hulpekova, Ter Arkh. 2019 May 16;91(4):122-129.doi:10.26442/00403660.2019.04.000116. PMID: 31094486. DOI: 10.26442/00403660.2019.04.000116

[8] Hereditary partial transcobalamin II deficiency with neurologic, mental and hematologic abnormalities in children and adults. Valery Teplitsky, David Huminer, Joseph Zoldan, Silvio Pitlik, Mordechai Shohat, Moshe Mittelman. Isr Med Assoc J. . 2003 Dec;5(12):868-72. PMID: 14689755

[9] Functional vitamin B12 deficiency and determination of holotranscobalamin in populations at risk. Wolfgang Herrmann 1, Rima Obeid, Heike Schorr, Jürgen Geisel. Clin Chem Lab Med. . 2003 Nov;41(11):1478-88. doi: 10.1515/CCLM.2003.227. PMID: 14656029 DOI: 10.1515/CCLM.2003.227

[10] The FUT2 secretor variant p.Trp154Ter influences serum vitamin B12 concentration via holo-haptocorrin, but not holo-transcobalamin, and is associated with haptocorrin glycosylation. Aneliya Velkova, et al. Journal List . Hum Mol . Genet . PMC5886113. Hum Mol Genet. 2017 Dec 15; 26(24): 4975–4988. Published online 2017 Oct 12. doi: 10.1093/hmg/ddx369. PMCID: PMC5886113. PMID: 29040465

[11] Single nucleotide polymorphisms related to vitamin B12 serum levels in autoimmune gastritis patients with or without pernicious anaemia {TCN2}. Edith Lahner. Et al. PMID: 25681243. DOI: 10.1016/j.dld.2015.01.147. Dig Liver Dis. 2015 Apr;47(4):285-90. doi: 10.1016/j.dld.2015.01.147. Epub 2015 Jan 22.

[12] Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway {TCN1}. Aditi Hazra. Et al. Hum Mol Genet . PMC2773275. Hum Mol Genet. 2009 Dec 1; 18(23): 4677–4687.Published online 2009 Sep 10. doi: 10.1093/hmg/ddp428. PMCID: PMC2773275. PMID: 19744961

[13] Associations of MTHFR C677T and MTRR A66G Gene Polymorphisms with Metabolic Syndrome: A Case-Control Study in Northern China {MTRR}. Boyi Yang Int J Mol Sci . PMC4284672. Int J Mol Sci. 2014 Dec; 15(12): 21687–21702. Published online 2014 Nov 25. doi: 10.3390/ijms151221687. PMCID: PMC4284672. PMID: 25429430