Reference from the joint report of FAO/WHO expert consultation on Human Vitamins and Minerals verbatim. (Chapter 3)
Niacin
Background with requisite function in human metabolic processes
Deficiency
8. McCormick, D.B. 1997. Vitamin, Structure and Function of. In: Encyclopedia of Molecular Biology and Molecular Medicine, Vol. 6. Meyers, R.A., ed. Weinheim: VCH, p. 244-52.
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.
61. McCormick, D.B. 1988. Niacin. In: Modern Nutrition in Health and Disease, 6th edition. Shils, M.E., Young, V.R., eds. Philadelphia: Lea & Febiger, 370-5.
Niacin (nicotinic acid) deficiency classically results in pellagra, which is a chronic wasting disease associated with a characteristic erythematous dermatitis that is bilateral an symmetrical, a dementia after mental changes including insomnia and apathy preceding an overt encephalopathy, and diarrhoea resulting from inflammation of the intestinal mucous surfaces (8, 9, 61).
62. Carpenter, K.J. & Lewin, W.J. 1985. A reexamination of the composition of diets associated with pellagra. J. Nutr., 115: 543-52.
At present, pellagra occurs endemically in poorer areas of India, China, and Africa. Its cause has been mainly attributed to a deficiency of niacin; however, its biochemical inter-relationship to riboflavin and vitamin B6, which are needed for the conversion of L-tryptophan to niacin equivalents (NEs), suggests that insufficiencies of these vitamins may also contribute to pellagra (62).
61. McCormick, D.B. 1988. Niacin. In: Modern Nutrition in Health and Disease, 6th edition. Shils, M.E., Young, V.R., eds. Philadelphia: Lea & Febiger, 370-5
Pellagra-like syndromes occurring in the absence of a dietary niacin deficiency are also attributable to disturbances in tryptophan metabolism (e.g., Hartnup disease with impaired absorption of the amino acid and carcinoid syndrome where the major catabolic pathway routes to 5-hydroxytryptophan) (61). Pellagra also occurs in people with chronic alcoholism (61). Cases of niacin deficiency have been found in people suffering from Crohn’s disease (61).
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.
Although therapeutically useful in lowering serum cholesterol, administration of chronic high oral doses of nicotinic acid can lead to hepatotoxicity as well as dermatologic manifestations. An upper limit (UL) of 35 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.
Niacin is chemically synonymous with nicotinic acid although the term is also used for its amide (nicotinamide). Nicotinamide is the other form of the vitamin, which does not have the pharmacologic action of the acid that is administered at high doses to lower blood lipids. It is the amide form that exists within the redox-active co-enzymes, nicotinamide adenine dinucleotide (NAD) and its phosphate (NADP), which function in dehydrogenase-reductase systems requiring transfer of a hydride ion (10, 11).
63. Berger, N.A. 1985. Poly(ADP-ribose) in the cellular response to DNA damage. Radiat. Res., 101: 4-15.
NAD is also required for non-redox adenosine diphosphate–ribose transfer reactions involved in DNA repair (63) and calcium mobilisation. NAD functions in intracellular respiration and with enzymes involved in the oxidation of fuel substrates such as glyceraldehyde 3-phosphate, lactate, alcohol, 3- hydroxybutyrate, and pyruvate. NADP functions in reductive biosyntheses such as fatty acid and steroid syntheses and in the oxidation of glucose-6-phosphate to ribose-5-phosphate in the pentose phosphate pathway.
Biochemical indicators
Indicators used to estimate niacin requirements are urinary excretion, plasma concentrations of metabolites, and erythrocyte pyridine nucleotides. The excretion rate of metabolites, mainly N'-methyl-nicotinamide and its 2- and 4-pyridones, reflects intake and is usually expressed as a ratio of the pyridones to N'-methyl-nicotinamide. Concentrations of metabolites, especially 2-pyridone, are measured in plasma after a load test. Erythrocyte pyridine nucleotides measure NAD concentration changes.
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.
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.
65. Jacob, R.A., Swendseid, M.E., McKee, R.W., Fu, C.S. & Clemens, R.A. 1989. Biochemical markers for assessment of niacin status in young men: urinary and blood levels of niacin metabolites. J. Nutr., 119: 591-8.
Niacin status has been monitored by daily urinary excretion of methylated metabolites, especially the ratio of the 2-pyridone to N'-methyl-nicotinamide; erythrocyte pyridine nucleotides; oral dose uptake tests; erythrocyte NAD; and plasma 2-pyridone (6, 9). Shibata and Matsuo (64) found that the ratio of urinary 2-pyridone to N'-methyl-nicotinamide was asmuch a measure of protein adequacy as it was a measure of niacin status. Jacob et al. (65) found this ratio too insensitive to marginal niacin intake.
66. Dillon, J.C., Malfait, P., Demaux, G. & Foldi-Hope, C. 1992. The urinary metabolites of niacin during the course of pellagra. Ann. Nutr. Metab., 36: 181-5.
65. Jacob, R.A., Swendseid, M.E., McKee, R.W., Fu, C.S. & Clemens, R.A. 1989. Biochemical markers for assessment of niacin status in young men: urinary and blood levels of niacin metabolites. J. Nutr., 119: 591-8.
67. Fu, C.S., Swendseid, M.E., Jacob, R.A. & McKee, R.W. 1989. Biochemical markers for assessment of niacin status in young men: levels of erythrocyte niacin co-enzymes and plasma tryptophan. J. Nutr., 119: 1949-55.
68. Ribaya-Mercado. J.D., Russell, R.M., Rasmussen, H.M., Crim, M.C., Perrone-Petty, G. & Gershoff, S.N. 1997. Effect of niacin status on gastrointestinal function and serum lipids. FASEB J., 11: A179 abstract.
The ratio of the 2-pyridone to N'- methyl-nicotinamide also appears to be associated with the clinical symptoms of pellagra, principally the dermatitic condition (66). In plasma, 2-pyridone levels change in reasonable proportion to niacin intake (65). Similarly to the situation for erythrocyte pyridine nucleotide (nicotinamide co-enzymes), NAD concentration decreased 70 percent whereas NADP remained unchanged in adult males fed diets with only 6 or 10 mg NEs/day (67). Erythrocyte NAD provided a marker at least as sensitive as urinary metabolites of niacin in this study (67) and in a niacin depletion study of elderly subjects (68).
Factors affecting requirements
61. McCormick, D.B. 1988. Niacin. In: Modern Nutrition in Health and Disease, 6th edition. Shils, M.E., Young, V.R., eds. Philadelphia: Lea & Febiger, 370-5.
69. Rose, D.P. & Braidman, I.P. 1971. Excretion of tryptophan metabolites as affected by
pregnancy, contraceptive steroids, and steroid hormones. Am. J. Clin. Nutr., 24: 673-83.
70. Patterson, J.I., Brown, R.R., Linkswiler, H. & Harper, A.E. 1980. Excretion of tryptophan-niacin metabolites by young men: effects of tryptophan, leucine, and vitamin B6 intakes. Am. J. Clin. Nutr., 33: 2157-67.
71. Horwitt, M.K., Harper, A.E. & Henderson, L.M. 1981. Niacin-tryptophan relationships for evaluating for evaluating niacin equivalents. Am. J. Clin. Nutr., 34: 423-7.
The biosynthesis of niacin derivatives on the pathway to nicotinamide co-enzymes stems from tryptophan, an essential amino acid found in protein, and as such this source of NEs increases niacin intake. There are several dietary, drug, and disease factors that reduce the conversion of tryptophan to niacin (61) (e.g. the use of oral contraceptives [69]). Although a 60-to-1 conversion factor represents the average for human utilisation of tryptophan as NEs, there are substantial individual differences (70, 71).
49. McCormick, D.B. 1989. Two interconnected B vitamins: riboflavin and pyridoxine. Physiol. Revs., 69: 1170-98.
There is also an interdependence of enzymes within the tryptophan-to-niacin pathway where vitamin B6 (as pyridoxal phosphate) and riboflavin (as FAD) are functional. Further, riboflavin (as FMN) is required for the oxidase that forms coenzymic PLP from the alcohol and amine forms of phosphorylated vitamin B6 (49).
Findings by age and life stage
64. Shibata, K. & Matsuo, H. 1989. Effect of supplementing low protein diets with the limiting amino acids on the excretion of N1-methylnicotinamide and its pyridones in rat. J. Nutr., 119: 896-901.
Niacin content of human milk is approximately 1.5 mg (12.3 μmol) /l and the tryptophan content is 210 mg (1.0mmol) /l (21). Hence, the total content is approximately 5 mg NEs/l or 4 mg NEs/ 0.75 l secreted daily in human milk. Recent studies (64, 70) together with those reported in the 1950s suggest that 12.5 mg NEs, which corresponds to 5.6 mg NEs/4184 kJ, is minimally sufficient for niacin intake in adults.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 pregnant women, where 230 MJ is the estimated energy cost of pregnancy, calculated needs above those of non-pregnant women are 5.6 mg NEs/ 4186 kjoule (1,000 kcal) × 230,000 kjoule (55,000 kcal), or 308 mg NEs for the entire pregnancy or 1.7 mg NEs/day (308 mg NEs/180 days) for the second and third trimester, which is about a 10 percent increase. Also about 2 mg NEs/day is required for growth in maternal and foetal compartments (6).
For lactating women, an estimated 1.4 mg preformed niacin is secreted daily, and an additional requirement of less than 1 mg is needed to support the energy expenditure of lactation. Hence, 2.4 mg NEs/day is the added need attributable to lactation.
Recommendations
The recommendations for niacin are given in Table 8.
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