Reference from the joint report of FAO/WHO expert consultation of Human Vitamins and Minerals verbatim. (Chapter 3)
Vitamin B6
Background with requisite function in human metabolic processes
Deficiency
72. McCormick, D.B. 1988. Vitamin B6. In: Modern Nutrition in Health and Disease, 6th edition. Shils, M.E., Young, V.R., eds. Philadelphia: Lea & Febiger, p. 376-82.
A deficiency of vitamin B6 alone is uncommon because it usually occurs in association with a deficit in other B-complex vitamins (72). Early biochemical changes include decreased levels of plasma PLP and urinary 4-pyridoxic acid. These are followed by decreases in synthesis of transaminases (aminotransferases) and other enzymes of amino acid metabolism such that there is an increased urinary xanthurenate and a decreased glutamate conversion to the antineurotransmitter γ-aminobutyrate.
9. McCormick, D.B & Greene, H.L. 1994. Vitamins. In: Tietz Textbook of Clin Chem., 2nd edition. Burtis, V.A., Ashwood, E.R., eds. Philadelphia: W.B. Saunders, p. 1275-1316.
Hypovitaminosis B6 may often occur with riboflavin deficiency, because riboflavin is needed for the formation of the co-enzyme PLP. Infants are especially susceptible to insufficient intakes, which can lead to epileptiform convulsions. Skin changes include dermatitis with cheilosis and glossitis. There is usually a decrease in circulating lymphocytes and possibly a normocytic, microcytic, or sideroblastic anaemia (9).
The sensitivity of such systems as sulphur amino acid metabolism to vitamin B6 availability is reflected in homo-cysteinemia. A decrease in the metabolism of glutamate in the brain, which is found in vitamin B6 insufficiency, reflects a nervous system dysfunction. As is the case with other micronutrient deficiencies, vitamin B6 deficiency results in an impairment of the immune system.
A current concern is for the rather pandemic occurrence of somewhat low vitamin B6 intakes in many people who eat poorly (e.g., people with eating disorders). Vitamin B6 deficiency has also been observed in Russian schoolchildren (Moscow), Southeast Asian schoolchildren (infected with hookworm), elderly Europeans (Dutch), and in some individuals with hyperhomo-cysteinemia or on chronic hemodialysis. Several medical conditions can also affect vitamin B6 metabolism and lead to deficiency symptoms.
Toxicity
6. Food and Nutrition Board, Institute of Medicine/National Academy of Sciences- National Research Council. 1998. Dietary Reference Intake: Folate, Other B Vitamins, and Choline. Washington, D.C., National Academy Press.
Use of high doses of pyridoxine for dubious treatment of pre-menstrual syndrome, carpal tunnel syndrome, and some neurologic diseases has resulted in neurotoxicity. A UL of 100 mg/day as proposed by the US Food and Nutrition Board (6) was adopted by this consultation.
Functions
10. McCormick, D.B. 1996. Co-enzymes, Biochemistry of. In: Encyclopedia of Molecular Biology and Molecular Medicine, Vol. 1. Meyers, R.A., ed. Weinheim: VCH, p. 396-406.
11. McCormick, D.B. 1997. Co-enzymes, Biochemistry. In: Encyclopedia of Human Biology 2nd edition. Dulbecco, R., ed.-in-chief. San Diego: Academic Press, p. 847-64.
There are three natural vitamers (different forms of the vitamin) of vitamin B6, namely pyridoxine, pyridoxamine, and pyridoxal. These must be phosphorylated and the 5'-phosphates of the first two oxidized to the functional PLP, which serves as a carbonyl-reactive co-enzyme to diverse enzymes involved in the metabolism of amino acids. Such enzymes include aminotransferases, decarboxylases, and dehydratases, δ-aminolevulinate synthase in heme biosynthesis, phosphorylase in glycogen breakdown, and sphingoid base biosynthesis, etc. (10, 11).
Biochemical indicators
Indicators used to estimate vitamin B6 requirements are PLP, urinary excretion, erythrocyte aminotransferases activity coefficients, tryptophan catabolites, erythrocyte and whole blood PLP, and plasma homo-cysteine. PLP is the major vitamin B6 form in tissue and reflects liver PLP; it changes fairly slowly in response to vitamin intake. The excretion rate of vitamin and particularly 4-pyridoxate reflects intake. Erythrocyte aminotransferases for aspartate and alanine reflect PLP levels and show large variations in activity coefficients. The urinary excretion of xanthurenate, a tryptophan catabolite, is used especially after a tryptophan loadtest.
9. McCormick, D.B & Greene, H.L. 1994. Vitamins. In: Tietz Textbook of Clin Chem., 2nd edition. Burtis, V.A., Ashwood, E.R., eds. Philadelphia: W.B. Saunders, p. 1275-1316.
73. Liu, A., Lumeng, L., Aronoff, G.R. & Li, T.-K. 1985. Relationship between body store of vitamin B6 and plasma pyridoxal-P clearance: metabolic balance studies in Humans. J. Lab. Clin. Med., 106: 491-7.
74. Kretsch, M.J., Sauberlich, H.E. & Newbrun, E. 1991. Electroencephalographic changes and periodontal status during short-term vitamin B6 depletion of young, nonpregnant women. Am. J. Clin. Nutr., 53: 1266-74.
Vitamin B6 status is most appropriately evaluated by using a combination of indicators, including those considered direct (e.g., vitamer concentration in cells or fluids) and indirect or functional indicators (e.g., erythrocyte aminotransferase saturation by PLP or tryptophan metabolites) (9). Plasma PLP may be the best single indicator because it appears to reflect tissue stores (73). Kretsch et al. (74) found that diets containing less than 0.05 mg vitamin B6 given to 11 young women led to abnormal electroencephalograph patterns in 2 of the women and a plasma PLP of approximately 9 nmol.
6. Food and Nutrition Board, Institute of Medicine/National Academy of Sciences-National Research Council. 1998. Dietary Reference Intake: Folate, Other B Vitamins, and Choline. Washington, D.C., National Academy Press.
73. Liu, A., Lumeng, L., Aronoff, G.R. & Li, T.-K. 1985. Relationship between body store of vitamin B6 and plasma pyridoxal-P clearance: metabolic balance studies in Humans. J. Lab. Clin. Med., 106: 491-7.
75. Bailey, A.L., Wright, A.J.A. & Southon, S. 1999. Pyridoxal-5-phosphate determination in Human plasma by high performance liquid chromatography: How appropriate are cutoff values for vitamin B6 deficiency? Eur. J. Clin. Nutr., 53(6): 448-55.
76. Hamfelt, A. & Tuvemo, T. 1972. Pyridoxal phosphate and folic acid concentration in blood and erythrocyte aspartate aminotransferase activity during pregnancy. Clinica Chimica Acta, 41: 287-98.
77. Lekem, J.E. 1990. Vitamin B6: a status report. J. Nutr., 120(11): 1503-7.
Hence, a level of about 10 nmol is considered suboptimal. A cut-off for plasma PLP of 20 nmol has been proposed as an index of adequacy (6) based on recent findings (73, 75). Plasma PLP levels have been reported to fall with age (76). Urinary 4-pyridoxic acid level changes promptly with changes in vitamin B6 intake (73) and is therefore of questionable value in assessing status. However, a value higher than 3 μmol/day , achieved with an intake of ~1 mg/d, has been suggested to reflect adequate intake (77).
Erythrocyte aminotransferases for aspartate and alanine are commonly measured before and after addition of PLP to ascertain amounts of apoenzymes, the proportion of which increases with vitamin B6 depletion. Values of 1.5–1.6 for the aspartate aminotransferase and approximately 1.2 for the alanine aminotransferase have been suggested as being adequate (9, 77). Catabolites from tryptophan and methionine have also been used to assess vitamin B6 status. In a review of such literature, Leklem (77) suggested that a 24-hour urinary excretion less than 65 μmol xanthurenate after a 2-g oral dose of tryptophan indicates normal vitamin B6 status.
Factors affecting requirements
78. Gregory, J.F. III. 1997. Bio-availability of vitamin B6. Eur. J. Clin. Nutr., 51(1): S43-8.
79. Tarr, J.B., Tamura, T. & Stokstad, E.L. 1981. Availability of vitamin B6 and pantothenate in an average American diet in man. Am. J. Clin. Nutr., 34: 1328-37.
80. Wozenski, J.R., Leklen, J.E. & Miller, L.T. 1980. The metabolism of small doses of vitamin B6 in men. J. Nutr., 110: 275-85.
A recent review by Gregory (78) shows that bio-availability of vitamin B6 in a mixed diet is about 75 percent (79), with approximately 8 percent of this total contributed by pyridoxine β- D-glucoside, which is about half as effectively utilised (78) as free B vitamers or their phosphates. The amine and aldehyde forms of vitamin B6 may be about 10 percent less effective than pyridoxine (80).
81. Pannemans, D.L.E., van den Berg, H. & Westerterp, K.R. 1994. The influence of protein intake on vitamin B6 metabolism differs in young and elderly Humans. J. Nutr., 124: 1207-14.
82. Shane, B. & Contractor, S.F. 1975. Assessment of vitamin B6 status. Studies on pregnant women and oral contraceptive users. Am. J. Clin. Nutr., 28: 739-47.
83. Rose, D.P. 1978. Oral contraceptives and vitamin B6. In: Human Vitamin B6 Requirements (Proceedings of a Workshop). P. 193-201. Washington, D.C., National Academy Press.
84. Brophy, M.H. & Siiteri, P.K. 1975. Pyridoxal phosphate and hypertensive disorders of pregnancy. Am. J. Obstet. Gynecol., 121: 1075-9.
85. Shane, B. & Contractor, S.F. 1980.Vitamin B6 Status and metabolism in pregnancy. In: Vitamin B6 metabolism and role in growth. Tryfiates, G.P., ed. Westport, Connecticut:
Food & Nutrition Press, p. 137-71.
Despite the involvement of PLP with many enzymes affecting amino acid metabolism, there seems to be only a slight effect of dietary proteins on vitamin B6 status (81). Studies reported decreases in indicators of vitamin B6 status in women receiving oral contraceptives (82, 83), but this probably reflects hormonal stimulation of tryptophan catabolism rather than any deficiency of vitamin B6 per se. Subjects with pre-eclampsia or eclampsia have lowered plasma PLP levels than do healthy pregnant women (84, 85).
86. West, K.D. & Kirksey, A. 1976. Influence of vitamin B6 intake on the content of the
vitamin in Human milk. Am. J. Clin. Nutr., 29: 961-9.
87. Andon, M.B., Reynolds, R.D., Moser-Veillon, P.B. & Howard, M.P. 1989. Dietary intake of total and glycosylated vitamin B6 and the vitamin B6 nutritional status of
unsupplemented lactating women and their infants. Am. J. Clin. Nutr., 50: 1050-8.
88. Heiskanen, K., Kallio, M., Salmenperä, L., Siimes, M.A., Roukonen, I. & Perkeentupa, J. 1995. Vitamin B6 status during childhood: tracking from 2 months to 11 years of age. J. Nutr., 125: 2985-92.
6. Food and Nutrition Board, Institute of Medicine/National Academy of Sciences- National Research Council. 1998. Dietary Reference Intake: Folate, Other B Vitamins, and Choline. Washington, D.C., National Academy Press.
89. Linkswiler, H.M. 1978. Vitamin B6 requirements of men. In: Human Vitamin B6 Requirements (Proceedings of a workshop). p. 279-90. Washington, D.C., National Academy Press.
90. Miller, L.T., Leklem, J.E. & Shultz, T.D. 1985. The effect of dietary protein on the metabolism of vitamin B6 in Humans. J. Nutr., 115: 1663-72.
Findings by age and life stage The average intake for infants, based on human-milk content, is 0.13 mg/l (86) or 0.1 mg/0.75 l/day. With an average maternal dietary intake of vitamin B6 of 1.4 mg/day, human milk was found to contain 0.12 mg/l, and plasma PLP of nursing infants averaged 54 nmol (87). Extrapolation on the basis of metabolic body size, weight, and growth suggests 0.3 mg/day as an adequate intake for infants 6–12 months of age (6). Information on vitamin B6 requirements for children is limited, but Heiskanen et al. (88) found an age-related decrease in erythrocyte PLP and an increase in the aspartate aminotransferase activation.
In a review of earlier studies of men with various protein intakes, Linkswiler (89) concluded that normalisation of a tryptophan load test required 1–1.5 mg vitamin B6. Miller et al. (90) found that 1.6 mg vitamin B6 led to plasma PLP levels above 30 nmol/l for young men with various protein intakes.
91. Brown R.R., Rose, D.P., Leklem, J. E., Linkswiler, H. & Anand, R. 1975. Urinary 4-pyridoxic acid, plasma pyridoxal phosphate, and erythrocyte aminotransferase levels in oral contraceptive users receiving controlled intakes of vitamin B6. Am. J. Clin. Nutr., 28: 10-19.
92. Kretsch, M.J., Sauberlich, H.E., Skala, J.H. & Johnson, H.L. 1995. Vitamin B6 requirement and status assessment: young women fed a depletion diet followed by a plantor animal- protein diet with graded amounts of vitamin B6. Am. J. Clin. Nutr., 61: 1091-101.
93. Hansen, C.M., Leklem, J.E. & Miller, L.T. 1996. Vitamin B6 status of women with a constant intake of vitamin B6 changes with three levels of dietary protein. J. Nutr., 126: 1891-901.
94. Hansen, C.M., Leklem, J.E. & Miller, L.T. 1997. Changes in vitamin B6 status indicators of women fed a constant protein diet with varying levels of vitamin B-6. Am. J. Clin. Nutr., 66: 1379-87.
95. Ribaya-Mercado, J.D., Russell, R.M., Sahyoun, N., Morrow, F.D. & Gershoff, S.N. 1991. Vitamin B6 requirements of elderly men and women. J. Nutr., 121: 1062-74.
96. Selhub, J., Jacques, P.F., Wilson, P.W.F., Rush, D. & Rosenherg, I.H. 1993. Vitamin status and intake as primary determinants of homo-cysteinemia in an elderly population. JAMA, 270: 2693-8.
From several investigations of young women (91-94), a requirement closer to 1–1.2 mg vitamin B6 could be estimated. Limited studies of the elderly indicate that requirements may be somewhat higher, at least to maintain plasma PLP above a 20-nmolar cut-off level (95, 96).
85. Shane, B. & Contractor, S.F. 1980.Vitamin B6 Status and metabolism in pregnancy. In: Vitamin B6 metabolism and role in growth. Tryfiates, G.P., ed. Westport, Connecticut: Food & Nutrition Press, p. 137-71.
97. Cleary, R.E., Lumeng, L. & Li, T.-K. 1975. Maternal and foetal plasma levels of pyridoxal phosphate at term: adequacy of vitamin B6 supplementation during pregnancy. Am. J. Obstet. Gynecol., 121: 25-8.
98. Lumeng, L., Cleary, R.E., Wagner, R., Yu, P.-L. & Li, T.-K. 1976. Adequacy of vitamin B6 supplementation during pregnancy: a prospective study. Am. J. Clin. Nutr., 29:1376-83.
6. Food and Nutrition Board, Institute of Medicine/National Academy of Sciences- National Research Council. 1998. Dietary Reference Intake: Folate, Other B Vitamins, and Choline. Washington, D.C., National Academy Press.
For pregnancy it was confirmed that indicators of vitamin B6 status decrease, especially in the third trimester (85, 97, 98). It is not clear, however, whether this is a normal physiologic phenomenon. For a maternal body store of 169 mg and foetal plus placental accumulation of 25 mg vitamin B6, about 0.1 mg/day is needed on average over gestation (6).
99. Borschel, M.W. 1995. Vitamin B6 in infancy: requirements and current feeding practices. In: Vitamin B6 Metabolism in Pregnancy, Lactation and Infancy. Raiten, D.J., ed. Boca Raton, Florida: CRC Press, Inc., p. 109-24.
With additional allowances for the increased metabolic need and weight of the mother and about 75 percent of bio-availability, an additional average requirement in pregnancy of 0.25 mg can be assumed. Because most of this need is in the latter stages of pregnancy and vitamin B6 is not stored to any significant extent, an extra 0.5 mg/day of vitamin B6 may be justified to err on the side of safety. For lactation, it may be prudent to add 0.6 mg vitamin B6 to the base requirement for women because low maternal intakes could lead to a compromised vitamin B6 status in the infant (99).
Recommendations
The recommendations for vitamin B6 are given in Table 9.
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