Homocysteine as a novel risk factor for atherosclerosis

Current Opinion in Cardiology

Volumn 14, Issue 4, 1999, Pages 283-291

  Guthikonda, Sasidhar ^a   Haynes, William G ^a  

^a UNIVERSITY OF IOWA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID; CYANOCOBALAMIN; FOLIC ACID; HOMOCYSTEINE; METHIONINE; PYRIDOXINE; THIOL DERIVATIVE;

ARTERY DISEASE; ARTERY ENDOTHELIUM; ATHEROSCLEROSIS; CEREBROVASCULAR DISEASE; HUMAN; HYPERHOMOCYSTEINEMIA; ISCHEMIC HEART DISEASE; METABOLISM; MUSCLE GROWTH; OXIDATIVE STRESS; PRIMARY PREVENTION; PRIORITY JOURNAL; REVIEW; RISK FACTOR; SCREENING; VASCULAR ENDOTHELIUM; VASCULAR SMOOTH MUSCLE;

ARTERIOSCLEROSIS; HUMANS; HYPERHOMOCYSTEINEMIA; RISK FACTORS;

EID: 0032809626     PISSN: 02684705     EISSN: None     Source Type: Journal    
DOI: 10.1097/00001573-199907000-00002     Document Type: Review

References (95)

1. 1 Mudd SH, Levy HL, Scovby F: Disorders of transulfuration. In The Metabolic Basis of Inherited Disease, edn 6. Edited by Scriver CR, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 1989:693-734.
2. 2 McCully KS: Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969, 56:111-128.
3. 3 Rosenblatt DS: Inherited disorders of folate transport and metabolism. In The Metabolic Basis of Inherited Disease, edn 6. Edited by Scriver CR, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 1989:2049-2064.
4. 4 Finkelstein JD: The metabolism of homocysteine: pathways and regulation. Eur J Pediatr 1998, 157(suppl):40-44.
5. 5 Miner SE, Evrovski J, Cole DE: Clinical chemistry and molecular biology of homocysteine metabolism: an update. Clin Biochem 1997, 30:189-201.
6. 6 Boers GHJ: State of the art. In Homocystinuria: A Risk Factor of Premature Vascular Disease, edn 1. Edited by Boers GHJ. Amsterdam: Foris; 1986:7-10.
7. 7 Stampfer MJ, Malinow MR, Willett MC, Mewcomer LM, Upson B, Ullman D, et al.: A prospective study of plasma homocysteine and risk of myocardial infarction in US physicians. JAMA 1992, 268:877-881.
8. 8 Jacques PF, Rosenberg IH, Rogers G, Selhub J, Bowman BA, Gunter EW, et al.: Serum total homocysteine concentrations in adolescent and adult Americans: results from the third national health and nutrition examination survey. Am J Clin Nutr 1999, 69:482-489.
9. 9 Rossi E, Beilby JP, McQuillan BM, Hung J: Biological variability and reference intervals for total plasma homocysteine. Ann Clin Biochem 1999, 36:56-61.
10. 10 Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE, et al.: Total plasma homocysteine and cardiovascular risk profile: The Hordaland Homocysteine Study. JAMA 1995, 274:1526-1533.
11. 11 Ubbink JB, Vermaak WJ, Delport R, van der Merwe A, Becker PJ, Potgieter H: Effective homocysteine metabolism may protect South African blacks against coronary heart disease. Am J Clin Nutr 1995, 62:802-808.
12. 12 Stolzenberg-Solomon RZ, Miller ER III, Maguire MG, Selhub J, Appel LJ: Association of dietary protein intake and coffee consumption with serum homocysteine concentrations in an older population. Am J Clin Nutr 1999, 69:467-475. The study assesses the effects of protein and coffee intake on plasma homocyst(e)ine.
13. 13 Nygard O, Refsum H, Ueland PM, Vollset SE: Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study. Am J Clin Nutr 1998, 67:263-270. The effects of lifestyle factors on plasma homocyst(e)ine are demonstrated in this study.
14. 14 Tucker KL, Selhub J, Wilson PW, Rosenberg IH: Dietary intake pattern relates to plasma folate and homocysteine concentrations in the Framingham Heart Study. J Nutr 1996, 126:3025-3031.
15. 15 Rozen R: Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost 1997, 78:523-526.
16. 16 Morita H, Kurihara H, Tsubaki S, Sugiyama T, Hamada C, Kurihara Y, et al.: Methylenetetrahydrofolate reductase gene polymorphism and ischemic stroke in Japanese. Arterioscler Thromb Vasc Biol 1998, 18:1465-1469.
17. 17 Verhoeł P, Kok FJ, Kluijtmans LA, Blom HJ, Refsum H, Ueland PM, Kruyssen A: The 677C >T mutation in the methylenetetrahydrofolate reductase gene: associations with plasma total homocysteine levels and risk of coronary atherosclerotic disease. Atherosclerosis 1997, 132:105-113.
18. 18 Dunn J, Title LM, Bata I, Johnstone DE, Kirkland SA, O'Neill BJ, et al.: Relation of a common mutation in methylenetetrahydrofolate reductase to plasma homocysteine and early onset coronary artery disease. Clin Biochem 1998, 31:95-100.
19. 19 Markus HS, Ali N, Swaminathan R, Sankaralingam A, Molloy J, Powell J: A common polymorphism in the methylenetetrahydrofolate reductase gene, homocysteine, and ischemic cerebrovascular disease. Stroke 1997, 28:1739-1743.
20. 20 Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, et al.: Relation between folate status, a common mutation in methylenetetrahydrofolate reductase and plasma homocysteine concentrations. Circulation 1996, 93:7-9.
21. 21 Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg IH: Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993, 270:2693-2698.
22. 6 supplements in elderly people with normal serum vitamin concentrations. Lancet 1995, 346:85-89.
23. 23 Engbersen AMT, Franken DG, Boers GHJ, Stevens EMB, Trijbels FJM, Blom HJ: Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet 1995, 56:142-150.
24. 24 Selhub J, Jacques PF, Bostom AG, D'Agostino RB, Wilson PW, Belanger AJ, et al.: Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995, 332:286-291.
25. 25 Chong SW, Ting AC, Wong J: Fasting total plasma homocysteine and atherosclerotic peripheral vascular disease. Ann Vasc Surg 1997, 11:217-223.
26. 26 Aronow WS, Ahn C: Association between plasma homocysteine and peripheral arterial disease in older persons. Coron Artery Dis 1998, 9:49-50.
27. 27 Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, et al.: Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997, 277:1775-1781.
28. 6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. Circulation 1998, 97:421-424.
29. 29 Valentine RJ, Kaplan HS, Green R, Jacobsen DW, Myers SI, Clagett GP: Lipoprotein (a), homocysteine, and hypercoagulable states in young men with premature peripheral atherosclerosis: a prospective, controlled analysis. J Vasc Surg 1996, 23:53-61.
30. 30 Amundsen T, Ueland PM, Waage A: Plasma homocysteine levels in patients with deep venous thrombosis. Arterioscler Thromb Vasc Biol 1995, 15:1321-1323.
31. 31 Taylor LM Jr, Moneta GL, Sexton GJ, Schuff RA, Porter JM: Prospective blinded study of the relationship between plasma homocysteine and progression of symptomatic peripheral arterial disease. J Vasc Surg 1999, 29:8-19. This excellent prospective study tries to establish the risk for symptomatic arterial occlusive diseases and mortality by homocyst(e)ine.
32. 32 Boushey CJ, Beresford SAA, Omenn GS, Molutsky AG: A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. JAMA 1995, 274:1049-1057.
33. 33 Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG: Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995, 346:1395-1398.
34. 34 Stehouwer CD, Weijenberg MP, van den Berg M, Jakobs C, Feskens EJ, Kromhout D: Serum homocysteine and risk of coronary heart disease and cerebrovascular disease in elderly men: a 10-year follow-up. Arterioscler Thromb Vasc Biol 1998, 18:1895-1901. This prospective epidemiologic study assesses the relationship between plasma homocyst(e)ine and IHD and cerebrovascular disease.
35. 35 Voutilainen S, Alfthan G, Nyyssonen K, Salonen R, Salonen JT: Association between elevated plasma total homocysteine and increased common carotid artery wall thickness. Ann Med 1998, 30:300-306.
36. 36 Aronow WS, Ahn C: Association between plasma homocysteine and coronary artery disease in older persons. Am J Cardiol 1997, 80:1216-1218.
37. 37 Montalescot G, Ankri A, Chadefaux-Vekemans B, Blacher J, Philippe F, Drobinski G, et al.: Plasma homocysteine and the extent of atherosclerosis in patients with coronary artery disease. Int J Cardiol 1997, 60:295-300.
38. 38 Donner MG, Schwandt P, Richter WO: Homocysteine and coronary heart disease: is slight or moderate homocysteinemia related to increased risk of coronary heart disease? Fortschr Med 1997, 115:24-30.
39. 39 Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, et al.: A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992, 268:877-881.
40. 40 Wald NJ, Watt HC, Law MR, Weir DG, McPartlin J, Scott JM: Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention. Arch Intern Med 1998, 158:862-867. This important study strengthens the association between homocyst(e)ine and IHD.
41. 41 Evans RW, Shaten BJ, Hempel JD, Cutler JA, Kuller LH: Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscler Thromb Vasc Biol 1997, 17:1947-1953.
42. 42 Alfthan G, Pekkanen J, Jauhiainen M, Pitkaniemi J, Karvonen M, Tuomilehto J, et al.: Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis 1994, 106:9-19.
43. 43 Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE: Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997, 337:230-236.
44. 44 Folsom AR, Nieto FJ, McGovern PG, Tsai MY, Malinow MR, Eckfeldt JH, et al.: Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the atherosclerosis Risk in Communities (ARIC) study. Circulation 1998, 98:204-210.
45. 45 Ray JG: Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med 1998, 158:2101-2106. In this comprehensive meta-analysis, the role of homocyst(e)ine on venous thromboembolic diseases is studied.
46. 46 Rodgers GM, Fryer RH, Wilson BD, Gubler DB, Fitzgerald LA: Homocysteine, a risk factor for vascular disease and thrombosis, induces tissue factor activity in endothelial cells [abstract]. Clin Res 1993, 41:19.
47. 47 Rodgers GM, Kane WH: Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 1986, 77:1909-1916.
48. 48 Lentz SR, Sadler JE: Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest 1991, 88:1906-1914.
49. 49 Harpel PC, Chang VT, Borth W: Homocysteine and other sulfhydryl compounds enhance the binding of lipoprotein(a) to fibrin: a potential biochemical link between thrombosis, atherogenesis and sulfhydryl compound metabolism. Proc Natl Acad Sci U S A 1992, 89:10193-10197.
50. 50 Kottke-Marchant K, Green R, Jacobsen D, Dicorleto P: Sub-cytotoxic homocysteine increases monocyte adhesion to human aortic endothelial cells [abstract]. Blood 1990, 76:511.
51. 51 Graeber JE, Slott JH, Ulane RE, Schulman JD, Stuart MJ: Effect of homocysteine and homocystine on platelet and vascular arachidonic acid metabolism. Pediatr Res 1982, 16:490-493.
52. 52 Hajjar KA, Mauri L, Jacovina AT, Zhong F, Mirza UA, Padovan JC, Chait BT: Tissue plasminogen activator binding to the annexin II tail domain: direct modulation by homocysteine. J Biol Chem 1998, 273:9987-9993. In this interesting study, the prothrombogenioc role of homocyst(e)ine is examined through its actions on tissue plasminogen activator.
53. 53 Durand P, Lussier-Cacan S, Blache D: Acute methionine load-induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats. FASEB J 1997, 11:1157-1168.
54. 54 Durand P, Prost M, Blache D: Pro-thrombotic effects of a folic acid deficient diet in rat platelets and macrophages related to elevated homocysteine and decreased n-3 polyunsaturated fatty acids. Atherosclerosis 1996, 121:231-243.
55. 55 De Groot PG, Willems C, Boers GHJ, Gonsalves MD, Van Aken WG, Van Mourik JA: Endothelial cell dysfunction in homocystinuria. Eur J Clin Invest 1983, 13:405-410.
56. 56 Wall RT, Harlan JM, Harker LA, Striker GE: Homocysteine-induced endothelial cell injury in vivo: a model for the study of vascular injury. Thromb Res 1980, 18:113-121.
57. 57 Wang H, Yoshizumi M, Lai K, Tsai JC, Perrella MA, Haber E, Lee ME: Inhibition of growth and p21ras methylation in vascular endothelial cells by homocysteine but not cysteine. J Biol Chem 1997, 272:25380-25385.
58. 58 Stamler JS, Osborne JA, Jaraki O, Rabbani LE, Mullins M, Singel D, Loscalzo J: Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest 1993, 91:308-318.
59. 59 Lentz SR, Sobey CG, Piegors DJ, Bhopatkar MY, Faraci FM, Malinow MR, Heistad DD: Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia. J Clin Invest 1996, 98:24-29.
60. 60 Lentz SR, Malinow MR, Piegors DJ, Teredesai MB, Faraci FM, Heistad DD: Consequences of hyperhomocyst(e)inemia on vascular function in atherosclerotic monkeys. Arterioscler Thromb Vasc Biol 1997, 17:2930-2934.
61. 61 Van den Berg M, Boers GH, Franken DG, Blom HJ, Van Kamp GJ, Jakobs C, et al.: Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease. Eur J Clin Invest 1995, 25:176-181.
62. 62 Celermajer DS, Sorensen K, Ryalls M, Robinson J, Thomas O, Leonard JV, Deanfield JE: Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents. J Am Coll Cardiol 1993, 22:854-858.
63. 63 Takawol A, Omland T, Gerhard M, Wu JT, Creager MA: Hyperhomocyst(e)inemia is associated with impaired endothelium dependent vasodilatation in humans. Circulation 1997, 95:1119-1121.
64. 64 Izzo MR, Feldman MD, Wu CC, Jafar MZ, Jacobs K, Husan S, et al.: Lowering plasma homocysteine improves brachial artery vasoreactivity in patients with coronary artery disease [abstract]. Circulation 1995, 92(suppl 1):708.
65. 65 Haynes WG, Sinkey CA, Kanani P: Acute methionine loading produces endothelial dysfunction in humans [abstract]. J Invest Med 1997, 45:210.
66. 66 Bellamy MF, McDowell IF, Ramsey MW, Brownlee M, Bones C, Newcombe RG, Lewis MJ: Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. Circulation 1998, 98:1848-1852. This study determines the role of experimental hyperhomocyst(e)inemia on endothelial dysfunction in humans.
67. 67 Chambers JC, McGregor A, Jean-Marie J, Kooner JS: Acute hyperhomocysteinaemia and endothelial dysfunction. Lancet 1998, 351:36-37.
68. 68 Usui M, Matsuoka H, Miyazaki H, Ueda S, Okuda S, Imaizumi T: Endothelial dysfunction by acute hyperhomocyst(e)inemia: restoration by folic acid. Clin Sci 1999, 96:235-239.
69. 69 Haynes WG, Sinkey CA, Knapp HR, Kanani PM: Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans [abstract]. J Hypertens 1998, 16(suppl):12.
70. 70 Starkebaum G, Harlan JM: Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 1993, 77:1370-1376.
71. 71 Heinecke JW, Rosen H, Suzuki LA, Chait A: The role of sulfur-containing amino acids in superoxide production and modification of low density lipoprotein by arterial smooth muscle cells. J Biol Chem 1987, 262:10098-10103.
72. 72 Zhang F, Slungaard A, Vercellotti GM, Iadecola C: Superoxide-dependent cerebrovascular effects of homocysteine. Am J Physiol 1998, 274: R1704-R1711.
73. 73 Emsley AM, Jeremy JY, Gomes GN, Angelini GD, Plane F: Investigation of the inhibitory effects of homocysteine and copper on nitric oxide-mediated relaxation of rat isolated aorta. Br J Pharmacol 1999, 126:1034-1040.
74. 74 Upchurch GR Jr, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keaney JF Jr, Loscalzo J: Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 1997, 272:17012-17017.
75. 75 Outinen PA, Sood SK, Liaw PC, Sarge KD, Maeda N, Hirsh J, et al.: Characterization of the stress-inducing effects of homocysteine. Biochem J 1998, 332:213-221.
76. 76 Austin RC, Sood SK, Dorward AM, Singh G, Shaughnessy SG, Pamidi S, et al.: Homocysteine-dependent alterations in mitochondrial gene expression, function and structure. Homocysteine and H2O2 act synergistically to enhance mitochondrial damage. J Biol Chem 1998, 273:30808-30817.
77. 77 Hultberg B, Andersson A, Isaksson A: The cell-damaging effects of low amounts of homocysteine and copper ions in human cell line cultures are caused by oxidative stress. Toxicology 1997, 123:33-40.
78. 78 Megnien JL, Gariepy J, Saudubray JM, Nuoffer JM, Denarie N, Levenson J, Simon A: Evidence of carotid artery wall hypertrophy in homozygous homocystinuria. Circulation 1998, 98:2276-2281. This article demonstrates an association between homocyst(e)ine and carotid atheroma.
79. 79 Brown JC, Rosenquist TH, Monaghan DT: ERK2 activation by homocysteine in vascular smooth muscle cells. Biochem Biophys Res Commun 1998, 251:669-676.
80. 80 Majors A, Ehrhart LA, Pezacka EH: Homocysteine as a risk factor for vascular disease: enhanced collagen production and accumulation by smooth muscle cells. Arterioscler Thromb Vasc Biol 1997, 17:2074-2081.
81. 81 Tang L, Mamotte CD, Van Bockxmeer FM, Taylor RR: The effect of homocysteine on DNA synthesis in cultured human vascular smooth muscle. Atherosclerosis 1998, 136:169-173.
82. 82 Nishio E, Watanabe Y: Homocysteine as a modulator of platelet-derived growth factor action in vascular smooth muscle cells: a possible role for hydrogen peroxide. Br J Pharmacol 1997, 122:269-274.
83. 83 Dalton ML, Gadson PF Jr, Wrenn RW, Rosenquist TH: Homocysteine signal cascade: production of phospholipids, activation of protein kinase C, and the induction of c-fos and c-myb in smooth muscle cells. FASEB J 1997, 11:703-711.
84. 84 Lubec B, Labudova O, Hoeger H, Muehl A, Fang-Kircher S, Marx M, et al.: Homocysteine increases cyclin-dependent kinase in aortic rat tissue. Circulation 1996, 94:2620-2625.
85. 85 Fritzer-Szekeres M, Blom HJ, Boers GH, Szekeres T, Lubec B: Growth promotion by homocysteine but not by homocysteic acid: a role for excessive growth in homocystinuria or proliferation in hyperhomocysteinemia? Biochim Biophys Acta 1998, 1407:1-6.
86. 86 Sutton-Tyrrell K, Bostom A, Selhub J, Zeigler-Johnson C: High homocysteine levels are independently related to isolated systolic hypertension in older adults. Circulation 1997, 96:1745-1749.
87. 87 Rolland PH, Friggi A, Barlatier A, Piquet P, Latrille V, Faye MM, et al.: Hyperhomocysteinemia-induced vascular damage in the minipig: captopril-hydrochlorothiazide combination prevents elastic alterations. Circulation 1995, 91:1161-1174.
88. 88 Peterson JC, Spence JD: Vitamins and progression of atherosclerosis in hyperhomocyst(e)inaemia. Lancet 1998, 351:263.
89. 89 Goodman SI, Elsas LJ, Rosenblatt DS: ASHG/ACMG Statement: Measurement and use of total plasma homocysteine. Am J Hum Genet 1998, 63:1541-1543.
90. 90 van der Griend R, Haas FJ, Duran M, Biesma DH, Meuwissen OJ, Banga JD: Methionine loading test is necessary for detection of hyperhomocysteinemia. J Lab Clin Med 1998, 132:67-72. This study emphasizes the importance of postmethionine load plasma homocyst(e)ine levels in detection of hyperhomocyst(e)inemia.
91. 91 Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ 1998, 316:894-898. This excellent meta-analysis examines the efficacy of various treatments for hyperhomocyst(e)inemia.
92. 92 Bronstrup A, Hages M, Prinz-Langenohl R, Pietrzik K: Effects of folic acid and combination of folic acid and vitamin B-12 on plasma homocyst(e)ine concentrations in healthy, young women. Am J Clin Nutr 1998, 68:1104-1110.
93. 93 Bostom AG, Gohh RY, Beaulieu AJ, Nadeau MR, Hume AL, Jacques PF, et al.: Treatment of hyperhomocysteinemia in renal transplant recipients: a randomized, placebo-controlled trial. Ann Intern Med 1997, 127:1089-1092.
94. 94 Malinow MR, Duell PB, Hess DL, Anderson PH, Kruger WD, Phillipson BE, et al.: Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med 1998, 338:1009-1015. This important study suggests the importance of food fortification with folic acid in lowering plasma homocyst(e)ine.
95. 95 Tucker KL, Mahnken B, Wilson PW, Jacques P, Selhub J: Folic acid fortification of the food supply: potential benefits and risks for the elderly population. JAMA 1996, 276:1879-1885.