2.2 POLITICAS COMUNITARIAS 40
2.2.1 Sostenibilidad: antecedentes y marco internacional 41
Anticarcinogenic effects of vitamin K have been reported in animal and cell studies, and an observational study has suggested an association between menaquinone intake and reduced risk of cancer (33). In addition, a role for vitamin K against insulin resistance has been proposed, but human data are still limited (34, 35). Vitamin K is also suggested to reduce inflam- mation (3, 11).
Requirement and recommended intake
Clinical deficiency is normally not detected after the first few months of life in otherwise healthy individuals. Deficiency has been seen in connection with malabsorption, antibiotic treatment, and parenteral nutrition without vitamin K supplementation.
Determination of the requirement for vitamin K has been difficult be- cause it is not possible to induce clinical deficiency symptoms with a vita- min K depletion diet. Bacterial synthesis in the intestine is not sufficient, however, to maintain normal serum levels of vitamin K. The traditional, insensitive method to evaluate vitamin K status has been to determine the concentration of coagulation factors, most often measured with the pro- thrombin time test. Newer biomarkers of vitamin K status include serum concentrations of phylloquinone, the degree of carboxylation of vitamin K-dependent proteins, and urinary vitamin K metabolites (1, 11, 36). The U.S. Institute of Medicine (37) determined, however, that these methods could not be used in the assessment of requirements because of uncertainty surrounding their true physiological significance and the lack of sufficient dose-response data. Therefore, the U.S. Institute of Medicine set an ad- equate intake (AI) of 120 and 90 µg/d for men and women, respectively, based on self-reported median vitamin K dietary intakes in apparently healthy population groups (37).
A depletion-repletion study on 10 young men showed that a reduction of phylloquinone in the diet from the normal level of 80 µg/d to about half that level for 3 weeks resulted in reduced plasma phylloquinone, an increase in undercarboxylated prothrombin in plasma, and reduced uri- nary excretion of Gla (38). Supplementation with 50 µg/d reversed these changes. However, in another study a similar supplementation did not bring the plasma phylloquinone levels back to original levels after the depletion diet (39). Healthy young individuals with intakes of about 60 to
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80 µg/d (corresponding a daily intake of 1 µg/kg) have shown no signs of clinical deficiency, indicating that this intake is adequate for the majority of individuals based on our current understanding of vitamin K’s function in blood coagulation (38, 40–42). However, studies indicate that this amount might be insufficient to support adequate carboxylation of extrahepatic vitamin K-dependent proteins (43–48). However, available data to base recommendations are not sufficient.
In NNR 2004 a provisional recommended intake of 1 µg/kg body weight per day was given for both children and adults. This level is maintained in NNR 2012, since no strong scientific evidence for change has emerged.
Breastfed new-borns are at risk of haemorrhage. Vitamin K concen- trations in human breast milk have ranged from 0.85 µg/L to 9.2 µg/L with a mean of 2.5 µg/L (37). Using the average concentration as a basis, and average intake of milk, the U.S. Institute of Medicine set an AI at 2 µg/d for infants 0–6 months of age. It is recommended that all new-borns should routinely be given vitamin K (as a 1 mg intramuscular dose or as weekly oral doses) to avoid haemorrhage during the neonatal period, and oral prophylaxis should be continued for the first three months (49, 50).
Upper intake levels and toxicity
No evidence of toxicity associated with high intakes of any form of natural vitamin K has been reported. The Scientific Committee on Food of the European Commission concludes in their report that there is no evidence of adverse effects associated with supplementary intakes of vitamin K in the form of phylloquinone of up to 10 mg/d for limited periods of time (51). This is supported by Cheung and co-workers (19) who reported no increased adverse effects in women receiving 5 mg phylloquinone daily for 4 years. Synthetic analogues such as menadione have been associ- ated with liver damage and haemolytic anaemia and should not be used therapeutically.
References
1. Booth SL, Suttie JW. Dietary intake and adequacy of vitamin K. J Nutr. 1998 May;128(5):785–8. 2. Koivu‑Tikkanen T. Determination of phylloquinone and menaquinones in foods. [PhD thesis]. Helsinki:
University of Helsinki; 2001.
3. Shearer MJ, Newman P. Metabolism and cell biology of vitamin K. Thromb Haemost. 2008 Oct;100(4):530–47.
NORDIC NUTRITION RECOMMENDATIONS 2012
4. Becker W, Staffas A, Abbasi H. K‑vitamin i livsmedel. Resultat från Livsmedelsverkets analyser 1996–97 samt litteraturdata (Vitamin K in Swedish foods. English summary). Uppsala: Livsmedelsverket1998 Report No.: 4/98.
5. Piironen V, Koivu T, Tammisalo O, Mattila P. Determination of phylloquinone in oils, margarines and butter by high‑perfomance liquid chromatography with electro¬chemi¬cal detection. Food Chemistry. 1997;59(3):8.
6. Paturi M, Tapanainen H, Reinivuo H, Pietinen P. The national FINDIET 2007 survey. Helsinki: National Public Health Insitute2008.
7. Apalset E, Gjesdal CG, Eide GE, Johansen A‑MW, Drevon CA, Tell GS. Dietary vitamins K1, K2 and bone mineral density: the Hordaland Health Study. Arch Osteoporos. 2010(5):73–81.
8. Rejnmark L, Vestergaard P, Charles P, Hermann AP, Brot C, Eiken P, et al. No effect of vitamin K1 intake on bone mineral density and fracture risk in perimenopausal women. Osteoporos Int. 2006;17(8):1122–32. 9. Suttie JW. Synthesis of vitamin K‑dependent proteins. Faseb J. 1993 Mar;7(5):445–52.
10. Cranenburg EC, Schurgers LJ, Vermeer C. Vitamin K: the coagulation vitamin that became omnipotent. Thromb Haemost. 2007 Jul;98(1):120–5.
11. Booth SL. Roles for vitamin K beyond coagulation. Annu Rev Nutr. 2009;29:89–110.
12. Shearer MJ, McBurney A, Barkhan P. Studies on the absorption and metabolism of phylloquinone (vitamin K1) in man. Vitam Horm. 1974;32:513–42.
13. Gijsbers BL, Jie KS, Vermeer C. Effect of food composition on vitamin K absorption in human volunteers. Br J Nutr. 1996 Aug;76(2):223–9.
14. Garber AK, Binkley NC, Krueger DC, Suttie JW. Comparison of phylloquinone bioavailability from food sources or a supplement in human subjects. J Nutr. 1999 Jun;129(6):1201–3.
15. Novotny JA, Kurilich AC, Britz SJ, Baer DJ, Clevidence BA. Vitamin K absorption and kinetics in human subjects after consumption of 13C‑labelled phylloquinone from kale. Br J Nutr. 2010 Sep;104(6):858–62.
16. Shea MK, Booth SL, Gundberg CM, Peterson JW, Waddell C, Dawson‑Hughes B, et al. Adulthood obesity is positively associated with adipose tissue concentrations of vitamin K and inversely associated with circulating indicators of vitamin K status in men and women. J Nutr. 2010 May;140(5):1029–34. 17. Bolton‑Smith C, McMurdo ME, Paterson CR, Mole PA, Harvey JM, Fenton ST, et al. Two‑year randomized
controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women. J Bone Miner Res. 2007 Apr;22(4):509–19.
18. Binkley N, Harke J, Krueger D, Engelke J, Vallarta‑Ast N, Gemar D, et al. Vitamin K treatment reduces undercarboxylated osteocalcin but does not alter bone turnover, density, or geometry in healthy postmenopausal North American women. J Bone Miner Res. 2009 Jun;24(6):983–91. 19. Cheung AM, Tile L, Lee Y, Tomlinson G, Hawker G, Scher J, et al. Vitamin K supplementation in
postmenopausal women with osteopenia (ECKO trial): a randomized controlled trial. PLoS Med. 2008 Oct 14;5(10):e196.
20. Braam LA, Knapen MH, Geusens P, Brouns F, Hamulyak K, Gerichhausen MJ, et al. Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age. Calcif Tissue Int. 2003 Jul;73(1):21–6.
21. Kanellakis S, Moschonis G, Tenta R, Schaafsma A, van den Heuvel EG, Papaioannou N, et al. Changes in parameters of bone metabolism in postmenopausal women following a 12‑month intervention period using dairy products enriched with calcium, vitamin D, and phylloquinone (vitamin K(1)) or menaquinone‑7 (vitamin K (2)): the Postmenopausal Health Study II. Calcif Tissue Int. 2012 Apr;90(4):251–62.
22. Cockayne S, Adamson J, Lanham‑New S, Shearer MJ, Gilbody S, Torgerson DJ. Vitamin K and the prevention of fractures: systematic review and meta‑analysis of randomized controlled trials. Arch Intern Med. 2006 Jun 26;166(12):1256–61.
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23. Knapen MH, Schurgers LJ, Vermeer C. Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int. 2007 Jul;18(7):963–72. 24. Emaus N, Gjesdal CG, Almas B, Christensen M, Grimsgaard AS, Berntsen GK, et al. Vitamin K2
supplementation does not influence bone loss in early menopausal women: a randomised double‑blind placebo‑controlled trial. Osteoporos Int. 2010 Oct;21(10):1731–40.
25. Caraballo PJ, Gabriel SE, Castro MR, Atkinson EJ, Melton LJ, 3rd. Changes in bone density after exposure to oral anticoagulants: a meta‑analysis. Osteoporos Int. 1999;9(5):441–8.
26. Woo C, Chang LL, Ewing SK, Bauer DC. Single‑point assessment of warfarin use and risk of osteoporosis in elderly men. J Am Geriatr Soc. 2008 Jul;56(7):1171–6.
27. Erkkila AT, Booth SL. Vitamin K intake and atherosclerosis. Curr Opin Lipidol. 2008 Feb;19(1):39–42. 28. Rees K, Guraewal S, Wong YL, Majanbu DL, Mavrodaris A, Stranges S, et al. Is vitamin K consumption
associated with cardio‑metabolic disorders? A systematic review. Maturitas. 2010 Oct;67(2):121–8. 29. Shea MK, O’Donnell CJ, Hoffmann U, Dallal GE, Dawson‑Hughes B, Ordovas JM, et al. Vitamin K
supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr. 2009 Jun;89(6):1799–807.
30. Braam LA, Hoeks AP, Brouns F, Hamulyak K, Gerichhausen MJ, Vermeer C. Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow‑up study. Thromb Haemost. 2004 Feb;91(2):373–80.
31. Gast GC, de Roos NM, Sluijs I, Bots ML, Beulens JW, Geleijnse JM, et al. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis. 2009 Sep;19(7):504–10. 32. Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van der Meer IM, et al. Dietary intake
of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004 Nov;134(11):3100–5.
33. Nimptsch K, Rohrmann S, Kaaks R, Linseisen J. Dietary vitamin K intake in relation to cancer incidence and mortality: results from the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC‑Heidelberg). Am J Clin Nutr. 2010 May;91(5):1348–58.
34. Yoshida M, Jacques PF, Meigs JB, Saltzman E, Shea MK, Gundberg C, et al. Effect of vitamin K
supplementation on insulin resistance in older men and women. Diabetes Care. 2008 Nov;31(11):2092–6. 35. Beulens JW, van der AD, Grobbee DE, Sluijs I, Spijkerman AM, van der Schouw YT. Dietary phylloquinone
and menaquinones intakes and risk of type 2 diabetes. Diabetes Care. 2010 Aug;33(8):1699–705. 36. Harrington DJ, Booth SL, Card DJ, Shearer MJ. Excretion of the urinary 5C‑ and 7C‑aglycone metabolites
of vitamin K by young adults responds to changes in dietary phylloquinone and dihydrophylloquinone intakes. J Nutr. 2007 Jul;137(7):1763–8.
37. Dietary reference intakes for vitamin A, Vitamin K, Arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium and zinc. Washington D.C: Institute of Medicine, Food and Nutrition Board;2001.
38. Suttie JW, Mummah‑Schendel LL, Shah DV, Lyle BJ, Greger JL. Vitamin K deficiency from dietary vitamin K restriction in humans. Am J Clin Nutr. 1988 Mar;47(3):475–80.
39. Ferland G, Sadowski JA, O’Brien ME. Dietary induced subclinical vitamin K deficiency in normal human subjects. J Clin Invest. 1993 Apr;91(4):1761–8.
40. Jones DY, Koonsvitsky BP, Ebert ML, Jones MB, Lin PY, Will BH, et al. Vitamin K status of free‑living subjects consuming olestra. Am J Clin Nutr. 1991 Apr;53(4):943–6.
41. Bach AU, Anderson SA, Foley AL, Williams EC, Suttie JW. Assessment of vitamin K status in human subjects administered “minidose” warfarin. Am J Clin Nutr. 1996 Dec;64(6):894–902.
42. Recommended dietary allowances. Tenth edition. 10 ed. Washington, D.C.: National Academy Press; 1989.
43. Binkley NC, Krueger DC, Kawahara TN, Engelke JA, Chappell RJ, Suttie JW. A high phylloquinone intake is required to achieve maximal osteocalcin gamma‑carboxylation. Am J Clin Nutr. 2002 Nov;76(5):1055–60.
NORDIC NUTRITION RECOMMENDATIONS 2012
44. Booth SL, Lichtenstein AH, O’Brien‑Morse M, McKeown NM, Wood RJ, Saltzman E, et al. Effects of a hydrogenated form of vitamin K on bone formation and resorption. Am J Clin Nutr. 2001 Dec;74(6):783–90.
45. Booth SL, Martini L, Peterson JW, Saltzman E, Dallal GE, Wood RJ. Dietary phylloquinone depletion and repletion in older women. J Nutr. 2003 Aug;133(8):2565–9.
46. Bugel S, Sorensen AD, Hels O, Kristensen M, Vermeer C, Jakobsen J, et al. Effect of phylloquinone supplementation on biochemical markers of vitamin K status and bone turnover in postmenopausal women. Br J Nutr. 2007 Feb;97(2):373–80.
47. Schurgers LJ, Teunissen KJ, Hamulyak K, Knapen MH, Vik H, Vermeer C. Vitamin K‑containing dietary supplements: comparison of synthetic vitamin K1 and natto‑derived menaquinone‑7. Blood. 2007 Apr 15;109(8):3279–83.
48. McCann JC, Ames BN. Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? Am J Clin Nutr. 2009 Oct;90(4):889–907.
49. Hansen KN, Minousis M, Ebbesen F. Weekly oral vitamin K prophylaxis in Denmark. Acta Paediatr. 2003 Jul;92(7):802–5.
50. Van Winckel M, De Bruyne R, Van De Velde S, Van Biervliet S. Vitamin K, an update for the paediatrician. Eur J Pediatr. 2009 Feb;168(2):127–34.
51. Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Vitamin K (expressed on 4 April 2003). Brussels: European Commission, Health and Consumer Protection Directorate‑General, Scientific Committee on Food;2003.
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Thiamin
Thiamin
mg/d Women Men Children
2–5 y 6–9 y 10–13 y girls/boys Recommended intake
Average requirement Lower intake level Upper intake level
RI AR LI UL 1.1 0.9 0.5* – ** 1.4 1.2 0.6* – ** 0.6 0.9 1.0/1.2
* 0.8 mg at energy intakes <8 mJ/d and 1.0 mg/d for elderly. ** not established.
Introduction
Thiamin (vitamin B1) is essential for the utilisation of carbohydrates and
branched-chain amino acids in the body. Thiamin participates in metabo- lism in the form of thiamin pyrophosphate (TPP, also known as thiamine diphosphate) as a coenzyme for pyruvate dehydrogenase, transketolase,
and α-ketoglutarate dehydrogenase in the oxidative decarboxylation of
α-keto acids to aldehydes and in the utilisation of pentoses (1, 2). TPP is also a coenzyme for keto acid dehydrogenase in the metabolism of branched chain amino acids (1). Thiamin triphosphate is involved in nerve and possibly muscle function (1).
Dietary sources and intakes
Major food sources of thiamin in the Nordic diet are cereals and cereal products, meat and meat products, and milk and dairy products. The di- etary supply of thiamin in the Nordic countries is 1.4–1.7 mg/10 MJ (see chapter on intake of vitamin and minerals in the Nordic countries).
NORDIC NUTRITION RECOMMENDATIONS 2012
Physiology and metabolism
In vegetable foods, thiamin occurs mainly in the free form and in animal foods mainly in phosphorylated forms that are converted to free thiamin prior to absorption (3, 4). Absorption takes place in the small intestine, generally via an active, carrier-mediated system involving phosphoryla- tion. At high intakes, passive diffusion also takes place (5, 6). Thiamin is also obtained from the normal bacterial microflora of the large intestine and it is absorbed in that region of the gut (4), but the quantitative im-
portance of this source is uncertain. Studies with 14C-labelled thiamin in
young men (7) showed that more than 95% of the vitamin was absorbed at intakes of 1–2 mg/d. At intakes above 5 mg/d, the relative absorption rapidly decreases.
After absorption, thiamin is transported to the liver where it is converted to its biologically active form, TPP (2). The total body pool of thiamin in an adult is about 30 mg and most of this is found in the muscles and liver (2, 7). The metabolism of thiamin in the body is relatively fast, and the half-life of 14C-labelled thiamin is estimated to be 9–18 days (7).
Thiamin deficiency causes beriberi. In adults, symptoms include dis- turbances in the peripheral nervous system and heart function. Early de- ficiency symptoms can include anorexia, weight loss, mental changes, and muscle weakness. In alcoholics, conditions such as Wernicke’s en- cephalopathy and Korsakoff’s psychosis can occur and these are strongly related to insufficient thiamin intake and/or malabsorption (8). Among children, symptoms appear more quickly and are generally more severe and can lead to heart failure.
Commonly used indicators of thiamin status include the enzymatic activ-
ity of transketolase in the erythrocytes (ETKAC). The NNR reference values
for thiamin consider urinary excretion relative to ETKAC and to thiamin
intake. The activity coefficient represents the degree of enzyme activity stim- ulation in vitro, and the activity of this enzyme depends not only on TPP availability but also on glucose phosphate availability. An activity coefficient below 1.15 is regarded as an indicator of sufficient status, and an activity coefficient of 1.15–1.25 indicates marginal status (9). The concentration of free thiamin and its phosphate esters in blood or erythrocytes has been shown to be a good indicator of thiamin status (10), especially among sub- jects at risk for thiamin deficiency (10, 11). The usefulness of the activity coefficient as an indicator of thiamin status in population surveys has been questioned, mainly due to its low correlation with erythrocyte thiamin (12).
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