B Vitamins - For the nerves

Vitamin B12

Vitamin B₁₂ (Cobalamin) - "The energy vitamin"

Introduction to B₁₂

B₁₂ is the largest molecule of all the vitamins. Also has a complex structure. B12 is unique among the vitamins containing a metal ion (cobalt). Explaining its name

In mammals, B₁₂ is a cofactor for 2 enzymes:

Methione synthase. Required for synthesis of amino acid methionine from homocysteine (elevated levels involved in CVD), which is itself needed for synthesis of SAME ( methyl group donor for methylation reactions, including methylation of DNA)
L.methylmalonyl- CoA mutase. Instrumental in producing energy from fats and proteins, and in synthesis of hemoglobin (carries oxygen in RBCs)

B₁₂ found in significant amounts in animal foods, but neglible amounts in plant food

B₁₂ absorption "journey" in the body

Stomach acid and the protease enzyme pepsin frees B₁₂ from food. The free B₁₂ then binds to an R protein (haptocorrin), a glycoprotein released from the salivary glands and gastric mucosa.
Pancreatic enzymes again release the B₁₂ from R protein in the less acidic small intestine (duodenum). Allowing the free- again B₁₂ to bind to intrinsic factor (IF), which was secreted by parietal cells of the stomach lining (gastric mucosa)
After traveling to the ileum, intestinal lining receptors take up B₁₂-IF complex. There its B₁₂ is endocytosed by epithelial cells bound to transcobalamin to enter the liver, but only if calcium is present (supplied by the pancreas)
Alternatively, B₁₂ can be absorbed via the intestinal lining of the terminal ileum. By passive diffusion into the mesenteric veins, but this route has a very inefficient 1% absorption rate

Carmel R. Cobalamin (Vitamin B₁₂). In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease. Philadelphia: Lippincott Williams & Wilkins; 2006:482497.

B₁₂ is stored in the liver for about 1 - 5 years. Depends on amount consumed, amount absorbed and hepatic function B₁₂

This antioxidant vitamin has many functions in the body

B₁₂ has benefical functional roles in:

Maintaining energy levels involved in metabolizing carbohydrate and fats
Neurological function /mental alertness/Stress
Homocysteine levels for healthy cardiac function
Insomnia
Cell growth / repair
Immune function

B₁₂ health benefits - include:

Help folic acid form red blood cells
Helps body utilize iron
Aids neural function/ communication; helps maintain neural sheath protecting nerves
Involved in adrenal hormone production
Required for MELATONIN production

B₁₂ deficiency is not uncommon and often goes unrecognized

Some misdiagnosed diseases may simply be a B₁₂deficiency which has been referred to as a "silent epidemic". Symptoms of B12deficiency can parallel those of several diseases, misleading doctors to misdiagnosis of M.S., Alzheimer's, dementia, early Parkinson's disease, diabetic neuropathy, chronic fatigue syndrome and more.

Sally M Pacholok, Jeffrey J Stuart, Could it be B12? An Epidemic of Diagnoses 2^nd Edition Feb 2011

A B₁₂ deficiency needs to be timely addressed, since it can result in permanent damage due to neuronal demyelination and axonal degeneration (called Wallerian degeneration results from insult to peripheral nerve fibers),which if left untreated will result in neuronal death.

Serum levels of B₁₂ below 221 pmol/L (300 pg/mL) is the generally accepted level suggesting a tissue level deficiency

Rajan S, Wallace JI, Beresford SA, et al. Screening for cobalamin deficiency in geriatric outpatients: prevalence and influence of synthetic cobalamin intake. J Am Geriatr Soc, 2002;50:624630.

B₁₂ deficiency is commonly related to:

Food. Cobalamin malabsorption syndrome (MOST COMMON REASON) - occurs when the stomach lining loses the ability to produce intrinsic factor, a protein that binds to B12 to enable its absorption whenit reaches the lower end of the small intestine;
- You can be consuming B₁₂ in animal products and still not be absorbing enough of it
- Those over the age of 50 have limited ability to absorb B₁₂
Pernicious Anemia. Progressive automimmune destruction ofstomach lining cells:

(1) Reduces secretion of B₁₂- releasing gastric acid and enzymes

AND

(2) Antibodies bind to intrinsic factor preventing formation of B₁₂- IF complex and consequently B₁₂ absorption.

Intramuscular B₁₂ shots are a common treatment, although high dose oral B₁₂ delivers similar amounts (E.g. 1000mg supplies 1 mg B₁₂ by passive absorption) .

Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 1998;92(4):11911198. (PubMed)

Lederle FA. Oral cobalamin for pernicious anemia. Medicine's best kept secret? JAMA. 1991;265(1):94-95.

Hathcock JN, Troendle GJ. Oral cobalamin for treatment of pernicious anemia? JAMA. 1991;265(1):96-97.

Food-bound vitamin B₁₂ malabsorption. More common in those over 60 commonly resulting from atrophic gastritis, in which atrophy of stomach glands results in stomach inflammation (possibly associated with H. Pylori)and decreased stomach acid production, and thus nonrelease of B₁₂ from food. This is different to pernicious anemia because intrinsic factor is still available, which means that crystalline-form B₁₂ in supplements or fortified food, which is not bound to protein, can still be absorbed.
Aging. Typically because of dietary insufficiency or malabsorption. Hydrochloric acid (HCl) is needed to release B₁₂ from food, but HCl production decreases with age and HCl levels are decreased by long-term use of antacids or anti-ulcer drugs.

20- 50% of those over 50 are unable to absorb natural (protein-bound) B₁₂

Institute of Medicine. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B₁₂, pantothenic acid, biotin and choline. Washington, DC: National Academy Press 1998.

AIDS. Increases risk of B₁₂ deficiency, possibly due to failure of IF-B₁₂ receptors to take up IF-B₁₂ complex

Shane B. Folic acid, vitamin B₁₂, and vitamin B6. In: Stipanuk M, ed. Biochemical and Physiological Aspects of Human Nutrition. Philadelphia: W.B. Saunders Co.; 2000:483518.

Vegan diet. Animal products are the prime B₁₂ source; predominantly vegetarian cultures (E.g. India) have high B₁₂ deficiency rates.
Surgical resection of ileal intestine containing IF- B₁₂ receptors
Pancreatic insufficiencies of enzymes or calcium
Those taking Metformin. May interfere with absorption of calcium, required for small intestine receptors to take up B₁₂

Herbert V. Vitamin B₁₂. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington D.C.: ILSI Press; 1996:191205.

Symptoms of B₁₂ deficiency include:

Megaloblastic anemia. Diminished folate production, even in the presence of folate; a symptom of pernicious anemia; produces large, immature, hemoglobin-poor RBCs
Neurological. Numbness/tingling in arms, or legs, difficulty walking, memory loss, disorientation, dementia, possibly due to megaloblastic anemia or nerve sheath damage
GI-related symptoms - sore tongue, loss of appetite, constipation

Some diseases associated with B₁₂ deficiency

Reference: Linus Pauling Institute

Cardiovascular Disease (CVD) related to elevated homocysteine levels
Cancer related to deficiency of folate and its connection to DNA synthesis
Neural tube defects - possibly connected to folates role in reducing homocysteine, since increased risk of NTD is associated with elevated levels of homocysteine
Alzheimer's disease / Dementia - possibly connected to B₁₂'s role in myelin sheath integrity
Depression

RDA for adult men and women is 2.4 mcgB₁₂ /day

Absorption or retention rate is related to the dose provided

Institute of Medicine. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid,biotin and choline. Washington, DC: National Academy Press 1998.

Dose Synthetic B₁₂	Delivery Method	Absorption Rate
(i.e. Non- protein bound)
< 5 μg	Oral (w/ non- deficiency)	50-60%
>500μg	Oral (w/ non- deficiency)	1%
<40 μg	IM	93-100%
1000 μg	IM	15%

Natural B₁₂ Sources

Only bacteria can make B₁₂ - such that B₁₂ is naturally present bound to protein in fish, animals and their products, but not significantly in plants (unless they still have dirt on them). In this form, B₁₂ must first be cleaved from protein via stomach acidand pepsin to be available for absorption.

Food	Serving	Vitamin B₁₂ (mcg)
Clams (steamed)*	3 ounces	84.0
Mussels (steamed)*	3 ounces	20.4
Crab (steamed)*	3 ounces	8.8
Salmon (baked)	3 ounces	2.4
Beef (cooked)	3 ounces	2.1
Nutritional yeast	1 T flakes	2.1
Milk (whole, 3.25%)	1 Cup	1.1
Yogurt (Plain, lowfat)	4 ounces	0.75
Egg (poached)	1 large	0.6
Brie (cheese)	1 ounce	0.5
Chicken (roasted)	3 ounces	0.3
Turkey (roasted)	3 ounces	0.3

*There's a reason for the high B₁₂ values in shellfish i.e. a high bacterial load!

Who needs to supplement B₁₂?

Non-vegan diet for healthy people should provide sufficient B_12. However, the following persons should definitely supplement B₁₂

Strict vegetarians
Women intending to get pregnant

It is prudent for those with conditions related to B12 malabsorption to empirically supplement B12 (especially given the lack of reliable diagnostic tests together with the low risk of B12supplementation)

The "Over 50's"
Those who have had:
- Bariactric surgery
- Ileal resection of >20cm
- Partial or total gastrectomy may damage/remove parietal cells responsible for gastric acid production
Those with:
- Low stomach acid. Usually due to atrophic gastritis caused by H. Pylori infection, common in over 50's). Need B12 in supplemental (non-protein bound) form since they can not depend on hydrochloric acid to cleave B12 from food.
- Pernicious anema. Due to lack of gastric acid and intrinsic factor; those with pernicious anemia need a high dose B12 supplement that relies on the 1% B12 absorption by passive diffusion at the terminal ileum (where the small intestine meets the colon). E.g. Crohn's disease, Celiac's disease
- People with chronic alcoholism. Due to atrophy of the villi in the small intestines. Lambert D, Benhayoun S, Adjalla C, et al. Alcoholic cirrhosis and cobalamin metabolism. Digestion, 1997;58:64- 71.
- Whipples Disease. Causes malabsorption
- Chronic pancreatitis. Insufficient pancreatic secretions impedes cleavage of B₁₂ from B₁₂Rprotein complex, and therefore formation of the B₁₂IF complex. Andres E, VidalAlaball J, Federici L, et al. Clinical aspects of cobalamin deficiency in elderly patients. Epidemiology, causes,clinical manifestations, and treatment with special focus on oral cobalamin therapy. Eur J Intern Med, 2007;18:456- 462.
- Small intestine bacterial overgrowth. Bacteria bind B₁₂ for their own use; at risk are those with hypochlorhydria, intestinal dysmotility, intestinal obstructions or adhesions, intestinal diverticuli, blind loops of bowel due to past surgery, and those without an intact ileocecal valve.
People taking meds that interfere with B₁₂ absorption:
- Gastric acid suppressive agents. i.e. proton pump inhibitors (E.g. omeprazole, lansoprazole), H2inhibitor antagonists (E.g. Tagamet, Pepsid, Zantac);
- Cholestyramine (anti-cholesterol)
- Neomycin (antibiotic)
- Colchine (anti- gout)
- Metformin (diabetic med) (ties up needed calcium)
- Nitrous oxide (laughing gas) (anaesthetic) inhibits B₁₂-dependent enzymes
Also those with cirrhosis. Diminishes liver's storage capacity of B₁₂; Paradoxically, a degrading liver causes high serum B₁₂ as it releases its stores, although despite raised serum levels, the tissues remain depleted.

Ermens AAM, Vlasveld LT. Significance of elevated cobalamin (vitamin B₁₂) levels in blood. Clin Biochem, 2003;36:585590.

Supplementing B₁₂

Which is the best form of B₁₂ supplement?

There are 3 forms of B₁₂ to choose from found in supplements and fortified foods:

Hydroxycobalamin
Cyanocobalamin (popular form in supplements). Produced from hydroxocobalamin, the form produced by bacteria;
Methycobalamin (BEST, "Ready- to- go", physiological form). Natural form produced in the body from bacterial hydroxycobalamin;

Delivery methods

There are 3 main delivery methods for B₁₂ i.e. Injection (IM), oral tablets or sublingual tablets or drops. Study showed that all 3 methods have an equal affect at correcting B₁₂ deficiency (study participants'average serum B₁₂ was 100 pmol /L)

Delpre G, Stark P, Niv Y. Sublingual therapy for cobalamin deficiency as an alternative to oral and parenteral cobalamin supplementation. Lancet. 1999;354:740741. PubMed

Sharabi, A., Cohen, E., Sulkes, J. and Garty, M. (2003), Replacement therapy for vitamin B₁₂ deficiency: comparison between the sublingual and oral route. British Journal of Clinical Pharmacology, 56:635638. doi:10.1046/j.13652₁₂5.2003.01907.x BJCP

B₁₂ also available as a nasal spray (www.nascobal.com),skin patch or mouth spray

B₁₂ in a multivitamin may be counterproductive. The late renowned B₁₂ researcher Victor Herbert determined that many multivitamin supplements also contain B₁₂ analogs (meaning they prevent B₁₂ absorption by interacting with them)

Herbert V. Vitamin B₁₂. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington D.C.: ILSI Press; 1996:191205.

Some good product choices:

Vegan B₁₂ Sublingual Each melt-under-the-tongue tablet contains 1000mcg B₁₂, also contains folic acid (400mcg) and B6 (2mg), all needed for MELATONIN production.

<$10 + s/h for 90 tablets (3 month supply). Also tastes good!

How much B12 to take?

B₁₂ Deficiency Replacement Doses
Oral or Sublingual (synthetic)	1000 μg/day for 1- 4 weeks
B₁₂ Maintenance Dose
	Food- cobalamin malabsorption	Perniceous anemia or No ileal receptors
Oral or Sublingual (synthetic)	125-500 μg/day	1000 μg/day
Intramuscular (IM)	1000 μg / month

VidalAlaball J, Butler CC, CanningsJohn R, et al. Oral vitamin B₁₂versus intramuscular vitamin B₁₂for vitamin B₁₂deficiency. Cochrane Database Syst Rev, 2005;20;(3): CD004655.

Andres E, Loukili NH, Noel E, et al. Vitamin B₁₂(cobalamin) deficiency in elderly patients. Can Med Assoc J, 2004;171(3):251259.

Oh RC, Brown DL. Vitamin B₁₂deficiency. Am Fam Physician, 2003;1;67(5):979986

B₁₂ doses to counter drug- induced malabsorption are undetermined

Since B₁₂ is stored in the liver, it does not have to be supplemented every day. E.g. 1000 ug tablets can be taken every other day or every third day for lower dose requirements. In figuring your dose you will need to somewhat compensate for the finding that a singular higher dose is not as well absorbed as when split into smaller doses. The exact compensation has not been determined for all doses and conditions so you will need to experiment for your specific case. Unused B12 is eliminated from the body

Pernicious anemia and lack of ileal receptors requires the high 1000 μg dose that relies on the 1% passive diffusion of B₁₂ at the terminal ileum a dose of 1000 μg would provide 100 μg B₁₂ by this route without the need for gastric acid or intrinsic factor.

Painful IM B₁₂ shots can be effectively replaced with HIGH oral doses that also rely on the 1% passive diffusion at the terminal ileum

B₁₂ Toxicity?

No upper Intake Limit (UL) has been set for B₁₂ - as there is little evidence of toxicity

Excess B₁₂ is harmlessly eliminated

References

Liz da Silva Stacey McCray Vitamin B₁₂: No One Should Be Without It. PRACTICAL GASTROENTEROLOGY ▪JANUARY 2009 Online Link

Linus Pauling Institute Online Link

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