Vitamin Biomarkers: Vitamin B6

Optimal Takeaways

Vitamin B6 occurs in several forms, although pyridoxal 5’ phosphate is the primary bioactive coenzyme that participates in more than 100 metabolic functions. B6 is especially important for the metabolism of protein, carbohydrates, lipids, homocysteine, and neurotransmitters and has antioxidant and anti-inflammatory properties. Insufficiency of B6 can contribute to altered mental status and mood, diabetes and its complications, neuropathy, skin issues, seizures, and pregnancy complications. Excess B6 can also cause neuropathy, pain, loss of balance, ataxia, nausea, and heartburn.

Standard Range: 2.10 – 21.70 ng/mL (8.5 – 87.80 nmol/mL)

The ODX Range: 12.36 – 21.70 ng/mL (50.01 – 87.80 nmol/L)

Low vitamin B6 is associated with microcytic anemia, peripheral neuropathy, seborrheic dermatitis, glossitis, dental decay, depression, confusion, convulsions, EEG abnormalities, elevated homocysteine, and compromised immunity. Deficiency may be due to poor intake, alcohol intake, autoimmune disease, compromised renal function, genetic factors, and use of certain medications including isoniazid, cycloserine, valproic acid, phenytoin, carbamazepine, hydralazine, and theophylline (Abosamak 2022).

Low B6 levels may also be associated with diabetes, diabetic complications (Mascolo 2020), low serum ALT (Ramati 2015), low serum AST (Pagana 2021), normocytic anemia, protein-energy malnutrition, obesity, bariatric surgery, malabsorption, hepatic dysfunction, pruritic rash, stomatitis, cheilitis, glossitis, irritability, altered mental status, abnormal tryptophan metabolism, preeclampsia, eclampsia (Brown 2022), hypertension (Houston 2010), pregnancy, lactation (Morris 2008), immune dysregulation, excess Th2 immune response, allergy, stroke, high-risk atherosclerosis, thrombosis (Stach 2021), inflammation, diabetes, CVD, cancer, celiac disease, IBD, rheumatoid arthritis, decreased transaminase activity, and hypophosphatemic rickets with elevated alkaline phosphatase (Ueland 2015).

High vitamin B6 is associated with testicular atrophy, decreased sperm motility, sensory neuropathy, extremity pain, ataxia, loss of balance (Abosamak 2022), hypophosphatasia, and low serum alkaline phosphatase (Ueland 2015). Signs of toxicity may include nausea, heartburn, skin eruptions, photosensitivity, decreased coordination, and decreased sensations of touch, vibration, and temperature. Intake above 250 mg/day may induce toxicity symptoms. Excess B6 can also interfere with seizure medicines and levodopa (Brown 2022).

Overview

Vitamin B6 is an essential water-soluble micronutrient that occurs in various forms, including pyridoxine, pyridoxal, pyridoxamine, pyridoxamine 5’ phosphate (PMP), and pyridoxal 5’ phosphate (PLP). The latter two are bioavailable coenzyme esters found primarily in meat or produced within the body. Inactive pyridoxine, found primarily in plant-based foods and many supplements, must be converted to its bioactive ester to function (Brown 2022).

Inactive B6 is converted to its bioactive coenzyme form pyridoxal 5-phosphate (PLP or P5P) in the intestine and liver. PLP is a cofactor in metabolizing amino acids, proteins, carbohydrates, and lipids. It also participates in neurotransmitter synthesis, gluconeogenesis, and glycogenolysis. Pyridoxine may be used therapeutically in mushroom poisoning, ethylene glycol toxicity, and other toxic exposures (Abosamak 2022). Plasma PLP is the most commonly evaluated biomarker of B6 status (Ueland 2015, Morris 2018).

Vitamin B6 is also essential to one-carbon metabolism, transsulfuration (e.g., conversion of homocysteine to cysteine and glutathione metabolism), glycine and serine metabolism, and aminotransferase synthesis. A comprehensive evaluation is needed to assess B6 status 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. Alkaline phosphatase can dephosphorylate free unbound PLP to inactive pyridoxal and decrease serum PLP. Research suggests an inverse association between PLP and acute-phase reactants, CRP, and other inflammatory markers (Ueland 2015).

An inverse association is observed between vitamin B6 status and diabetes, with B6 insufficiency considered a potential cause and effect of type 2 diabetes. Mechanisms behind this association include increased B6 demands during obesity, pregnancy, and inflammation; the impact of B6 insufficiency on insulin secretion and biological action; enhanced tryptophan catabolism, impaired lipid, and adipose metabolism; loss of vitamin B6-related antioxidant activity; and increased susceptibility to advanced glycation production formation (Mascolo 2020).

Low levels of plasma PLP have been observed in inflammatory conditions even when dietary intake of B6 is adequate, and no apparent cause of low PLP or catabolism is present. Researchers suggest that PLP may be shunted to areas of inflammation to support immune function (Paul 2013, Ueland 2017, Sakakeeny 2012).

A review of NHANES data found that PLP was significantly lower in women of childbearing age and those who took oral contraceptives, with levels falling below 4.9 ng/mL (20 nmol/L). Low plasma PLP also persisted with a B6 intake of 2-2.9 mg/day in all subgroups studied and remained low despite an intake of 3-4.9 mg/day in the elderly, smokers, non-Hispanic blacks, and former oral contraceptive users. The higher intake helped maintain plasma PLP in most groups and protected against hyperhomocysteinemia. A plasma PLP of 4.9 ng/mL (20 nmol/L) and above was associated with a significant reduction in plasma homocysteine. Ironically, the RDA for vitamin B6 is 2 mg per day or less and likely inadequate for many individuals (Morris 2008).

While plasma PLP levels reflect B6 intake and tissue stores, changes in plasma patterns of organic acids and amino acids influenced by B6 can provide further insight into B6 sufficiency. This includes metabolites involving the kynurenine pathway, one-carbon metabolism, transsulfuration, and glycine decarboxylation. A plasma PLP below 12.36 ng/mL (50 nmol/L) may be considered inadequate as it can interfere with vital metabolic processes (Bjørke-Monsen 2023).

Active B6 also participates in regulating blood pressure and blood clotting, antioxidant activity, protection from oxidative stress, decreased formation of advanced glycation end products (Stach 2021), and synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Inborn errors of metabolism that interfere with vitamin B6 activation are associated with seizures that respond to B6 supplementation. Inactivation of PLP can also contribute to acquired epilepsy (Wilson 2019).

It is important to note that excess intake of inactive B6 (e.g., pyridoxine in supplement form) may interfere with the active PLP form. Adverse effects may include mild neurological symptoms with a pyridoxine intake above 100 mg/day and more severe neurological symptoms, including ataxia, neuropathy, and decreased muscle tone with doses of 500 mg/day or more. Although B6 deficiency can contribute to bone loss and osteoporosis, excess B6 may also interfere with bone metabolism and increase fracture risk. Researchers suggest the link between excess B6 and fracture risk may be associated with neurological symptoms that increase the risk of a fall, as well as interference with estrogen metabolism (Li 2021).

References

Abosamak, NourEldin R. and Vikas Gupta. “Vitamin B6 (Pyridoxine).” StatPearls, StatPearls Publishing, 23 May 2022.

Bjørke-Monsen, Anne-Lise, and Per Magne Ueland. “Vitamin B6: a scoping review for Nordic Nutrition Recommendations 2023.” Food & nutrition research vol. 67 10.29219/fnr.v67.10259. 19 Dec. 2023, doi:10.29219/fnr.v67.10259

Brown, Mary J., et al. “Vitamin B6 Deficiency.” StatPearls, StatPearls Publishing, 18 July 2022.

Houston, Mark C. “Nutrition and nutraceutical supplements in the treatment of hypertension.” Expert review of cardiovascular therapy vol. 8,6 (2010): 821-33. doi:10.1586/erc.10.63

Li, Zhihao et al. “Vitamin B6 as a novel risk biomarker of fractured ankles.” Medicine vol. 100,40 (2021): e27442. doi:10.1097/MD.0000000000027442

Mascolo, Elisa, and Fiammetta Vernì. “Vitamin B6 and Diabetes: Relationship and Molecular Mechanisms.” International journal of molecular sciences vol. 21,10 3669. 23 May. 2020, doi:10.3390/ijms21103669

Morris, Martha Savaria et al. “Plasma pyridoxal 5'-phosphate in the US population: the National Health and Nutrition Examination Survey, 2003-2004.” The American journal of clinical nutrition vol. 87,5 (2008): 1446-54. doi:10.1093/ajcn/87.5.1446

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Paul, Ligi et al. “Mechanistic perspective on the relationship between pyridoxal 5'-phosphate and inflammation.” Nutrition reviews vol. 71,4 (2013): 239-44. doi:10.1111/nure.12014

Ramati, Erez, et al. "Low ALT activity amongst patients hospitalized in internal medicine wards is a widespread phenomenon associated with low vitamin B6 levels in their blood." Harefuah 154.2 (2015): 89-93.

Sakakeeny, Lydia et al. “Plasma pyridoxal-5-phosphate is inversely associated with systemic markers of inflammation in a population of U.S. adults.” The Journal of nutrition vol. 142,7 (2012): 1280-5. doi:10.3945/jn.111.153056

Stach, Kamilla et al. “Vitamin B6 in Health and Disease.” Nutrients vol. 13,9 3229. 17 Sep. 2021, doi:10.3390/nu13093229

Ueland, Per Magne et al. “Direct and Functional Biomarkers of Vitamin B6 Status.” Annual review of nutrition vol. 35 (2015): 33-70. doi:10.1146/annurev-nutr-071714-034330

Ueland, Per Magne et al. “Inflammation, vitamin B6 and related pathways.” Molecular aspects of medicine vol. 53 (2017): 10-27. doi:10.1016/j.mam.2016.08.001

Wilson, Matthew P et al. “Disorders affecting vitamin B6 metabolism.” Journal of inherited metabolic disease vol. 42,4 (2019): 629-646. doi:10.1002/jimd.12060