B vitamins are a group of water-soluble micronutrients. They are vital to cell function and act as coenzymes in several metabolic activities, including energy generation, methylation, red and white blood cell development, antioxidant activity, DNA metabolism and repair, cell signaling, and the processing of carbohydrates, protein, and fat (Kennedy 2016).
B vitamin status can be evaluated clinically using laboratory assessment along with a nutrition-based physical assessment to identify signs of deficiency.
| B Vitamin & Active Form (Raymond 2021) |
Basic B Vitamin Functions (Lykstad 2023) |
Direct Laboratory Assessment |
Thiamine (B1)
Thiamine pyrophosphate
Benfotiamine |
Cofactor for enzymes involved in glucose metabolism. Depletion affects energy production, especially in the heart, brain, and nerves. Deficiency results in heart failure, edema, shortness of breath, polyneuritis, muscle wasting, and cognitive changes. |
Can be measured directly in blood. However, serum thiamine levels don’t reflect storage levels, and evaluation of the active form RBC thiamine pyrophosphate (TPP) and transketolase activity may be a more reliable assessment of status. Magnesium is instrumental in converting thiamine to TPP (Hanna 2022). |
Riboflavin (B2)Riboflavin-5’-phosphate |
Cofactor in redox reactions Deficiency leads to oral inflammation and corneal vascularization. |
Can be measured directly in blood. However, measuring erythrocyte glutathione reductase activity coefficient (EGRAC) is considered a more sensitive test of riboflavin status. Riboflavin is effective at reducing elevated homocysteine (Hanna 2022). |
Niacin (B3)Niacinamide, NAD, NADP |
Deficiency leads to the 3 “Ds” diarrhea, dermatitis, and dementia. Cofactor in redox reactions.
|
Can be measured directly in blood. The RBC nicotinamide adenine dinucleotide to nicotinamide adenine dinucleotide phosphate ratio may provide a more accurate assessment. |
Pantothenic acid (B5)
Pantothenate |
Essential to energy production and hormone synthesis as a component of coenzyme A and fatty acid synthase. Deficiency leads to dermatitis, GI inflammation, hair loss, and adrenal insufficiency. |
Can be measured directly in blood, though levels don’t correlate with status until deficient at a level below 50 ug/mL (Hanna 2022). Brain levels are 50 times higher than blood levels (Kennedy 2016). |
Pyridoxine (B6)
|
Participates in glycogen metabolism, decarboxylation, transamination, and red blood cell production. Deficiency leads to sideroblastic anemia, peripheral neuropathy, and confusion, |
Can be measured directly in blood. However, B6 function is best assessed using RBC transaminase activity and pyridoxal 5’-phosphate (Hanna 2022). |
Biotin (B7) |
Required for carbohydrate, protein, fat, and keratin metabolism.
Deficiency leads to muscle pain, cardiac complications, anemia, and depression.
|
Can be measured directly in blood, but levels may not reflect intake or sufficiency. Urinary excretion of 3- hydroxyisovaleric acid is considered superior to blood level testing (Hanna 2022). Biotin works closely with B12 in carbohydrate, protein, and fat metabolism. High doses can interfere with clinical testing, including thyroid hormone and vitamin D assays (Hanna 2022). |
Folate (B9)
5-MTHF, 5-formyltetrahydrofolate, folinic acid
|
Vital to RNA and DNA synthesis.
Deficiency leads to neural tube defects and macrocytic megaloblastic anemia.
|
Can be measured directly in blood, which reflects recent intake. However, measuring RBC folate is the best way to evaluate long-term status as well as storage in the liver (Chen 2019). Transport of folate into the cell requires vitamin B12. Therefore, serum folate can be elevated with a B12 deficiency, while intracellular folate will be low. It is important to evaluate folate and B12 together (Pagana 2022). |
Cobalamin (B12)Methyl-cobalaminAdenosyl-cobalamin Hydroxo-cobalamin |
Essential for red blood cell formation and nervous system maintenance and development Deficiency leads to pernicious anemia, spinal cord degeneration, and macrocytic megaloblastic anemia, which can be differentiated from folate-deficiency anemia by an increase in methylmalonic acid and the presence of neurological symptoms. |
Can be measured directly in blood, though levels won’t reflect intracellular status. Vitamin B12 is required for the transport of folate into the cell, and B12 insufficiency can lead to elevated serum folate (Pagana 2022). A combined deficiency of vitamins B6, B12, and folate is associated with increased osteoclast activity and bone degradation (Herrmann 2007). |
Direct measurement of B vitamins in the blood or in red blood cells provides information about the amount immediately available to cells. However, testing of compounds that utilize or affect B vitamins provides more information about the metabolism and cellular utilization of B vitamins.
An increased anion gap may be associated with an insufficiency of thiamine, which can lead to a buildup of lactic acid (Hammond 2013, O’Donnell 2017).
It is important to evaluate the risk of thiamine deficiency, including intake of excess carbohydrates and insufficient thiamine intake. Since thiamine plays such an important role in glucose metabolism, an increase in dietary carbohydrates increases the relative need for thiamine (Dhir 2019).
A low-histamine diet can provide relief from histamine intolerance symptoms and may even increase serum levels of DAO. Consuming adequate cofactors for DAO production may also improve HIT symptoms, these include vitamin B6, vitamin C, and copper (Hrubisko 2021).
Low GGT levels may be associated with vitamin B6 insufficiency (Thomas 1998).
Approximately 20-25% of circulating B12 (cobalamin) is bound to transcobalamin in a complex called holotranscobalamin (holoTC). The holoTC is biologically active and readily taken up by the cell. It is considered the most direct measurement of vitamin B12 status (Nexo 2011).
The most common cause of elevated homocysteine is insufficient vitamins B6, B12, or folate (Pagana 2022). However, riboflavin is also important to maintaining healthy homocysteine levels (Elias 2022, Hanna 2022). Elevated homocysteine is also associated with elevated red cell distribution width (Peng 2017).
Methylmalonic acid (MMA) is considered an early indicator of B12 insufficiency but also serves as a biomarker of mitochondrial dysfunction and oxidative stress (Polytarchou 2020).
MMA is formed when a lack of vitamin B12 leads to the impairment of methylmalonyl-CoA mutase, the enzyme that converts methylmalonyl-CoA to succinyl-CoA in the citric acid/tricarboxylic acid cycle (Harrington 2017).
Methylmalonyl-CoA is a byproduct of the metabolism of propionic acid, which is produced by the breakdown of branch-chain amino acids, odd-chain fatty acids, and cholesterol sidechains and by bacterial fermentation in the colon. Accumulating methylmalonyl-CoA and intermediary propionyl-CoA is toxic to the cell and contributes to impaired gluconeogenesis, fatty acid oxidation, pyruvate oxidation, and ureagenesis (Riphagen 2020).
A decreased MCV can be associated with B6 insufficiency (Maner 2021), while an elevated MCV can be associated with megaloblastic anemia and B12 or folate insufficiency (Pagana 2022).
The MPV can be increased with a B12 or folate deficiency (Pagana 2022).
An increase in RDW is seen with folate and B12 deficiencies (Fava 2019).
Reticulocytes are also low in the presence of certain anemias, including aplastic anemia, megaloblastic anemia (e.g., pernicious anemia, vitamin B12 and/or folate deficiency); hypochromic anemias (e.g., iron deficiency, sideroblastic, and anemia of chronic disease) (Pagana 2022, Riley 2001),
A vitamin B12/cobalamin deficiency can mask iron deficiency and interfere with the accurate assessment of UIBC. In a study of 75 patients with cobalamin deficiency, serum iron, ferritin, and transferrin saturation levels were increased while UIBC was decreased, suggesting iron sufficiency. After cobalamin therapy, serum iron, ferritin, and transferrin saturation decreased significantly while the UIBC increased significantly, revealing a likely iron insufficiency (Solmaz 2015).
B12 works with other B vitamins and supports several physiological activities, including mitochondrial energy generation, protein metabolism, DNA synthesis, red blood cell production, folate metabolism, and the conversion of homocysteine to methionine. Insufficiency of B12 will disrupt these functions and contribute to anemia, fatigue, neuropathy, cognitive impairment (especially with the ApoE4 genotype), and reproductive impairment (Allen 2018).
Vitamin B12 also appears to function as an antioxidant. It may help scavenge superoxide, preserve glutathione, protect against the oxidative stress associated with homocysteine and advanced glycosylation end products, and modulate the oxidation and inflammation associated with the immune response (van de Lagemaat 2019). Oxidative stress and glutathione insufficiency, in turn, contribute to intracellular functional B12 deficiency (Vollbracht 2020).
A B12 deficiency can lead to cellular accumulation of 5-MTHF (the “methyl-folate trap”) as well as homocysteine despite adequate folate availability (Ohrvik 2011).
The adverse effects of unmetabolized folic acid may be magnified with compromised vitamin B12 status, resulting in elevated homocysteine and methylmalonic acid and decreased holotranscobalamin (active B12). A combination of elevated folate and insufficient B12 in mothers may contribute to the incidence of insulin resistance and stunted growth in their offspring. Vitamin B12 status should be evaluated along with folate, especially if folate levels in the blood are elevated, which may reflect insufficient B12. The combination of folate and B12 deficiency is associated with neuropathy, cognitive decline, and depression (Sobczyńska-Malefora 2018).
RBC folate, serum folate, and homocysteine levels should be part of a comprehensive assessment of folate status (Ohrvik 2011). Folate interacts closely with vitamins B2 and B6 as well, and these vitamins should be assessed along with folate (Bailey 2015).
Folate supplementation should always be combined with vitamin B12 to avoid masking a B12 deficiency (Pizzorno 2016).
Niacin can be produced in the body from the amino acid tryptophan, a process that requires riboflavin, another example of the interdependent nature of B vitamins (Hanna 2022).
A comprehensive evaluation is needed to assess B6 status in order to overcome potential confounding variables that can affect levels, including inflammation, alcohol intake, renal function, low albumin (albumin transports PLP), inorganic phosphate (elevations of which increase plasma PLP), and alkaline phosphatase activity.
Research suggests an inverse association between PLP and acute-phase reactants, CRP, and other inflammatory markers (Ueland 2015).
Thiamine is essential to energy generation, amino acid metabolism, synthesis of nucleic acids, antioxidant systems, cell membrane stability, myelin sheath maintenance, nerve conduction, and synthesis of glutamate and gamma-aminobutyric acid (GABA) (Hammond 2013).
Thiamine deficiency and insufficiency of active thiamine pyrophosphate can lead to increased glutamate and decreased production of acetylcholine and myelin, leading to delirium (Hanna 2022).
Research suggests that thiamine deficiency may be also be associated with vascular inflammation, myocardial infarction, heart failure, diabetes, obesity, conduction deficits, and depression (Eshak 2018).
Source: Kennedy, David O. “B Vitamins and the Brain: Mechanisms, Dose and Efficacy--A Review.” Nutrients vol. 8,2 68. 27 Jan. 2016, doi:10.3390/nu8020068 This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
| Vitamin |
Good Dietary Sources |
Symptoms of Deficiency |
Brain-Specific Symptoms of Deficiency |
Specific Risk Factors for Deficiency |
| B1 Thiamine |
Cereals (esp. whole grain), brown rice, green vegetables, potatoes, pasta, liver, pork, eggs |
Mild deficiency: general fatigue/weakness gastro-intestinal symptoms. |
Mild deficiency: irritability, emotional disturbances, confusion, disturbed sleep, memory loss. |
Alcohol abuse, obesity |
| B2 Riboflavin |
Dairy products, leafy vegetables, legumes, liver, kidneys, yeast, mushrooms |
Weakness, oral pain/tenderness, burning/itching of the eyes, dermatitis, anemia |
Fatigue, personality change, brain dysfunction |
inherited riboflavin malabsorption/utilisation (10%–15% prevalence) |
| B3 Niacin |
Meat, fish, whole grain cereal, legumes, mushrooms, nuts |
Pellagra: dermatitis/photo dermatitis, alopecia, muscle weakness, twitching/burning in the extremities, altered gait, diarrhea |
Depression, anxiety, progressing to vertigo, memory loss, paranoia, psychotic symptoms, aggression (Pellagrous insanity) |
Alcohol abuse |
| B5 Pantothenic acid |
Meat, whole grain cereals, broccoli |
Numbness/burning sensations in extremities, dermatitis, diarrhoea |
Encephalopathy, behaviour change, demyelination |
|
| B6 pyridoxal, pyridoxamine, pyridoxine |
Meat, fish, legumes, nuts, bananas, potatoes |
Anemia |
Irritability, impaired alertness, depression, cognitive decline, dementia, autonomic dysfunction, convulsions |
Alcohol abuse, age-related malabsorption, contraceptive medications |
| B7 Biotin |
Eggs, liver, pork, leafy vegetables |
Seborrheic eczematous rash, tingling/burning of the extremities |
Depression, lethargy, hallucinations, seizures |
Type II diabetes, poor gluco-regulation |
| B9 Folate |
Leafy vegetables, legumes, citrus fruits |
megaloblastic anemia, peripheral neuropathy, spinal cord lesions, metabolic abnormalities
|
Affective disorders, behaviour changes, psychosis, cognitive impairment/decline, dementia (inc Alzheimer’s disease and vascular dementia) |
Common genetic polymorphisms (inc. MTHFR C667T) Low Riboflavin and B12 |
| B12 Cobalamin |
Meat, fish and other animal products |
age-related malabsorption, vegetarians, vegans. Genetic polymorphisms. |
Source: Kennedy, David O. “B Vitamins and the Brain: Mechanisms, Dose and Efficacy--A Review.” Nutrients vol. 8,2 68. 27 Jan. 2016, doi:10.3390/nu8020068 This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
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