Vitamin B12

Vitamin B12, known as cobalamin, is an indispensable water-soluble nutrient pivotal for overall health and wellness. Its significance lies in its many functions including the synthesis of red blood cells essential for oxygen transportation, maintenance of nerve cell integrity, and its contribution to DNA synthesis. 

Unlike some vitamins, the human body lacks the ability to synthesize Vitamin B12 endogenously.  Thus, dietary choices play a critical role in maintaining optimal B12 levels.  Supplementation may also be recommended for some individuals.

In this article we will explore the structure and function, and various forms of vitamin B12 including those available for supplementation; its crucial role in the methylation pathway; testing options for assessing B12 levels; and natural therapies aimed at supporting healthy Vitamin B12 levels and optimizing its physiological functions.

Overview of B Vitamin Family

The B vitamin family comprises a group of water-soluble vitamins that play critical roles in numerous physiological processes essential for human health. 

Comprising eight distinct vitamins, it includes riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folate (B9), and cobalamin (B12), these vitamins are intricately related and often function as coenzymes in various metabolic pathways. 

VItamin B12 is the only B vitamin that can be stored in the body, in the liver.  All other B vitamins are quickly excreted through the urine, therefore they require daily repletion.  

Individually, the B vitamins contribute to energy production, DNA synthesis, nervous system function, and red blood cell formation, among other vital functions. Collectively, the B vitamins are indispensable for maintaining overall health and well-being, underscoring their importance in supporting various physiological systems within the human body.

Definition of Vitamin B12

What is Vitamin B12?

Vitamin B12, also known as cobalamin, is a water-soluble vitamin that plays a critical role in various physiological processes in the human body.  It is essential for the synthesis of DNA, the maintenance of neurological function, and the formation of red blood cells.

Structurally, vitamin B12 contains a cobalt ion coordinated with a corrin ring, which resembles the structure of heme and chlorophyll.  While cobalamin carries cobalt, a heme ring carries iron and a chlorophyll ring carries magnesium.  [18.] 

Humans are unable to synthesize vitamin B12 endogenously, hence we rely on dietary sources such as meat, fish, dairy products, and fortified cereals for its intake. Once consumed, B12 undergoes a complex process of absorption in the gastrointestinal tract, requiring intrinsic factor (IF) secreted by gastric parietal cells for efficient uptake in the ileum.  Excess vitamin B12 is stored in the liver.  

Any disruption in this process can lead to vitamin B12 deficiency, which manifests as hematological, neurological, and gastrointestinal abnormalities.

Recommended Daily Intake (RDI) of Vitamin B12

The RDI of vitamin B12 is 2.4 mcg for adult males and females; that number rises to 2.6 mcg in pregnancy, and 2.8 mcg in lactation.  [17.]

Functions of Vitamin B12: What Does Vitamin B12 Do in the Body?

Vitamin B12 is essential for many processes essential for human health, including:

• Essential for the synthesis of DNA and RNA, contributing to cellular growth and division
• Facilitates the conversion of homocysteine to methionine, crucial for methylation reactions
• Aids in the metabolism of fatty acids and amino acids
• Supports the production of red blood cells by assisting in the maturation of red blood cell precursors
• Necessary for the maintenance of myelin sheaths around nerves, promoting proper nerve function  [12.]
• Plays a role in the synthesis of neurotransmitters such as serotonin and dopamine  [24.]
• Contributes to homocysteine metabolism by converting homocysteine to methionine, which is important for cardiovascular health
• Supports energy metabolism by participating in the citric acid cycle  [21.]
• Facilitates the conversion of methylmalonyl-CoA to succinyl-CoA, which is essential for energy production and metabolism

Importance and Prevalence of Vitamin B12 Deficiency

Vitamin B12 deficiency can lead to a variety of symptoms affecting multiple systems in the body.  Once liver stores of vitamin B12 are depleted, it takes 6-12 months to become vitamin B12-deficient.  [21.]

Symptoms of vitamin B12 deficiency include:

• Anemia
• Fatigue
• Weakness
• Shortness of breath
• Numbness or tingling sensation in the hands and feet
• Difficulty walking
• Glossitis (inflammation of the tongue)
• Palpitations
• Difficulty concentrating
• Memory problems
• Depression

Severe or prolonged deficiency can result in irreversible neurological damage and cognitive impairment. It is crucial to address and treat vitamin B12 deficiency promptly to prevent long-term complications.

Vitamin B12 deficiency is relatively common.  [9.]  Frank vitamin B12 deficiency affects about 6% of the US and UK population below the age of 60, but that number rises to over 20% in the population older than 60.  Additionally, levels tend to drop in pregnancy, but rise after delivery.  [16., 17.]

Forms and Functions of Vitamin B12

Adenosylcobalamin

Adenosylcobalamin, one of the active forms of vitamin B12, holds a distinct role in energy metabolism as a cofactor for the enzyme methylmalonyl-CoA mutase. This enzyme facilitates the conversion of methylmalonyl-CoA to succinyl-CoA; this is a critical step in the Krebs cycle, which produces energy within mitochondria. 

Adenosylcobalamin's utilization in mitochondria underscores its indispensable function in cellular energy production, highlighting its unique importance in maintaining metabolic vitality and overall physiological well-being.

Adenosylcobalamin is commonly available as a supplement, and is available in foods, commonly in meat, eggs, and dairy products.  

Methylcobalamin

Methylcobalamin, another active form of vitamin B12, plays a pivotal role in methylation reactions as a cofactor for the enzyme methionine synthase. 

This enzyme facilitates the conversion of homocysteine to methionine, a crucial step in the methylation cycle that is vital for DNA synthesis, neurotransmitter metabolism, and epigenetic regulation. 

Methylcobalamin's involvement in these processes distinguishes it as a key player in maintaining optimal neurological function, supporting cardiovascular health, and regulating gene expression. 

Methylcobalamin is also available as a supplement, as well as in foods, commonly in meat, eggs, and dairy products.  

Hydroxocobalamin

Hydroxocobalamin is a natural form of vitamin B12.  As a precursor form of vitamin B12, it is converted into active B12 as methylcobalamin or adenosylcobalamin in the body.  Hydroxocobalamin is the preferred form of vitamin B12 supplementation in Europe, whereas in the US cyanocobalamin is generally preferred.  [19.] 

Hydroxocobalamin is primarily known for its role in detoxifying cyanide by converting it into cyanocobalamin, which is less toxic and easily excreted from the body via urine.  [19.]  In this setting it is administered intravenously.  

Cyanocobalamin

Cyanocobalamin is a synthetic form of B12 commonly used in supplements and fortified foods. It contains a cyanide molecule attached to the cobalamin, which is converted into its active forms, methylcobalamin and adenosylcobalamin, within the body.  Conversion of cyanocobalamin to methyl- or adenosylcobalamin requires a methyl or adenosyl group. 

These active forms are necessary for various biochemical processes including energy metabolism and methylation reactions, ensuring the proper functioning of cells and tissues throughout the body.

Vitamin B12 and the Methylation Pathway

Methylation has been increasingly studied in recent years, due to its importance in cellular health and function, and its implications for overall health and wellness.  

Overview of Methylation Reactions

Methylation reactions are vital biochemical processes involved in various cellular functions including DNA synthesis, gene regulation, protein synthesis, and neurotransmitter metabolism.

In these reactions, a methyl group (-CH3) is transferred from one molecule to another, facilitated by methyltransferase enzymes. Methylation plays a crucial role in regulating gene expression, cell differentiation, and cellular metabolism, making it essential for health at a cellular level.

Vitamin B12’s Role as a Cofactor in Methylation

As methylcobalamin, vitamin B12 is a crucial cofactor in methylation reactions by acting as a methyl carrier.  Methylcobalamin participates in the transfer of methyl groups to substrates like homocysteine, generating methionine. 

Methionine then serves as a precursor for the synthesis of S-adenosylmethionine (SAMe), a universal methyl donor required for numerous methylation reactions throughout the body. 

Vitamin B12 deficiency can have profound consequences for methylation processes in the body. Without sufficient vitamin B12, the methylation cycle is disrupted which causes elevated levels of homocysteine. 

Elevated homocysteine levels are associated with various health issues including cardiovascular disease, neurological disorders, hip fracture, mood disturbances, cancer, and hypothyroidism.  [9., 22.]

Vitamin B12 deficiency can significantly impair methylation processes with far-reaching consequences for cellular function, health, and disease susceptibility.

Vitamin B12’s Impact on DNA Regulation and Neurotransmitter Synthesis

Through the methylation pathway, vitamin B12 plays a significant role in DNA regulation and neurotransmitter synthesis. 

Methylation of DNA is crucial for gene expression and silencing, or “turning genes on and off,” which affect cellular differentiation and development. 

Additionally, vitamin B12-mediated methylation reactions contribute to the synthesis of neurotransmitters such as serotonin and dopamine, which are essential for mood regulation, cognitive function, and overall neurological health.  [24.]

Therefore, adequate levels of vitamin B12 are essential for supporting these vital processes and maintaining optimal physiological function.

Testing Options for Vitamin B12 Deficiency

Blood Tests: Serum B12 Levels, Methylmalonic Acid (MMA) and Homocysteine Levels

Vitamin B12 levels can be assessed through various blood testing options.  

Serum B12 levels can be measured to assess the concentration of vitamin B12 in the bloodstream, providing insight into the individual's B12 status. 

Additionally, methylmalonic acid (MMA) and homocysteine can be measured to offer complementary information. 

Elevated levels of MMA and homocysteine are indicative of vitamin B12 deficiency, as these compounds accumulate when B12 is insufficient for their metabolism. 

Vitamin B12 plays a crucial role in the conversion of MMA to succinyl-CoA and homocysteine to methionine. In the absence of sufficient vitamin B12, these metabolic pathways are disrupted, leading to the accumulation of MMA and homocysteine. 

Test Procedure and Preparation Guidelines

Fasting before the blood draw is preferred to obtain accurate results. Additionally, patients should be advised to stop all supplements containing biotin for at least 72 hours prior to the blood draw.

Consulting with a healthcare professional is advisable to ensure proper test procedure and preparation for accurate diagnosis and interpretation of results.

Reference Ranges for Vitamin B12 Testing

Typical reference ranges for vitamin B12 levels may be between 232−1245 pg/mL.  [1.]

Typical reference ranges for methylmalonic acid (MMA) may be between 0−378 nmol/L, with elevated levels indicating a vitamin B12 deficiency.  [2.] 

Typical reference ranges for homocysteine vary by age, with increasing levels typically seen with increasing age.  The reference ranges provided by one lab company are between 0.0-21.3 in populations above 80 years of age.  [3.]  As with MMA, increasing levels of homocysteine correlate with vitamin B12 deficiency.

It is important to consult individual lab companies regarding specific reference ranges for these biomarkers.  

Clinical Significance of Low Vitamin B12 [15.]

Several factors can contribute to vitamin B12 deficiency.  Vitamin B12 deficiency is more common in vegan and vegetarian populations than in people eating meat.  Outside of dietary choices, other possible causes of vitamin B12 deficiency may include:

• Low levels of intrinsic factor, a protein produced in the stomach essential for B12 absorption, occurs in pernicious anemia, which is more prevalent among those of northern European or African descent. 
• Decreased stomach acid can also cause vitamin B12 deficiency.  
• Aging often leads to digestive issues that hinder B12 absorption. 
• Lifestyle habits, such as excessive alcohol consumption, can interfere with B12 absorption, as can certain medications like heartburn medications and metformin for diabetes treatment. 
• Various medical conditions including autoimmune diseases like celiac disease and thyroid disease, genetic conditions like Imerslund-Gräsbeck syndrome, and digestive disorders like Crohn's disease, can also elevate the risk of B12 deficiency. 
• Stomach or intestinal surgeries, such as weight-loss surgery or gastrectomy, can disrupt B12 absorption pathways.

Medications That Lower Vitamin B Levels in the Body

Individuals taking the following medications may want to discuss their B vitamin needs with their healthcare provider:

• Metformin: Used to treat type 2 diabetes, metformin can reduce vitamin B12 absorption and increase the risk of deficiency over time.  [13.]
• Proton pump inhibitors (PPIs): These medications, such as omeprazole and esomeprazole, are commonly used to treat acid reflux and peptic ulcers. Long-term use of PPIs can interfere with the absorption of vitamin B12.  [13.]
• Histamine H2-receptor antagonists: Drugs like ranitidine and cimetidine, used to reduce stomach acid production, may also impair vitamin B12 absorption.  [13.]
• Anticonvulsants: Some antiepileptic drugs like phenytoin, phenobarbital, and primidone can lower levels of folate and vitamin B12 in the body.  [20.]
• Chemotherapy drugs: Chemotherapy medications can affect the body's ability to absorb and utilize B vitamins, leading to deficiencies.  [7.]
• Oral contraceptives: Some birth control pills can deplete levels of B vitamins, particularly folate and vitamin B6.  [26.]
• Diuretics: Certain diuretic medications, including loop and thiazide diuretics, can increase urinary excretion of B vitamins, particularly vitamin B1 (thiamine) and folate.  [14., 23.]

It's important to consult with a healthcare professional if you're taking any of these medications to discuss potential nutrient deficiencies and appropriate supplementation, if needed.

Clinical Significance of High Vitamin B12 Levels

High vitamin B12 levels are often seen with excessive supplementation of vitamin B12.  However, other conditions associated with high vitamin B12 levels include liver disease, myeloproliferative disorders, and certain cancers such as leukemia or myeloid neoplasms.  [5., 8.]

It's essential to investigate the cause of elevated B12 levels thoroughly, as they can serve as indicators of serious underlying medical conditions. Monitoring and proper evaluation are crucial to determine appropriate management strategies and address any associated health concerns.

Natural Therapies to Support Healthy Vitamin B12 Levels and Function

Dietary Sources Rich in Vitamin B12  [25.]

Beef liver: one of the richest sources of B12, providing well over 1000% of the daily value (DV) per 100 grams.

Shellfish: clams, oysters, and mussels are excellent sources, with high B12 content.

‍Fish: salmon, trout, tuna, and other fatty fish contain significant amounts of vitamin B12.

‍Meat: beef, lamb, and poultry are good sources, particularly organ meats like kidney and heart.

‍Eggs and dairy: eggs, milk, cheese, and yogurt contain moderate levels of vitamin B12.

Fortified foods: many breakfast cereals, plant-based milk alternatives (e.g., soy, almond, oat), and nutritional yeast are fortified with vitamin B12 for vegetarians and vegans.

Lifestyle Strategies to Enhance Vitamin B12 Absorption and Utilization

Limit alcohol intake: excessive alcohol consumption can impair B12 absorption. Moderation is key.

Avoid long-term use of acid-suppressing medications: proton pump inhibitors (PPIs) and H2-receptor antagonists can reduce stomach acid, hindering B12 absorption.  [13.]

Consider supplementation: individuals at risk of deficiency may benefit from B12 supplements or fortified foods, especially older adults, vegetarians, and those with digestive disorders.

Balance diet diversity: consume a varied diet rich in whole foods to ensure adequate B12 intake and overall nutrient absorption.

Seek medical advice: consult a healthcare professional if experiencing symptoms of B12 deficiency or if unsure about dietary or supplementation needs.

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