Biological and Environmental Determinants of Plasma Homocysteine

JØR. N. SCHNEEDE; H. E. L. G. A. REFSUM; P. E. R. M. A. G. N. E. UELAND

doi:10.1055/s-2000-8471

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2000; Volume 26(Number 03): 263-280
DOI: 10.1055/s-2000-8471

Biological and Environmental Determinants of Plasma Homocysteine

JØRN. SCHNEEDE, HELGA. REFSUM, PER. MAGNE. UELAND

Department of Pharmacology, University of Bergen, Norway

Abstract

ABSTRACT

This article gives an overview over common physiological, lifestyle, and pathological conditions that may modulate the homocysteine status. The interplay of several environmental factors, including age, gender, nutrition, smoking, and coffee consumption and physical activity with commonly used drugs and prevalent diseases are described. In most cases, an abnormal homocysteine status is not caused by a single factor alone but often is the result of combined effects. We address these frequently found ``clusters'' of homocysteine-modulating factors. Finally, we give an overview of likely causes of hyperhomocysteinemia found in an authentic material. This material is based on 2462 routine measurements of plasma total homocysteine carried out at the Haukeland University Hospital. The data represent the total number of combined homocysteine and methylmalonic acid determinations, requested by general practitioners in Norway during February 1998.

KEYWORD

Homocysteine - hyperhomocysteinemia - environmental factors - methylmalonic acid - lifestyle

Volltext

Referenzen

REFERENCES

1 Refsum H, Ueland P M, Nygård O, Vollset S E. Homocysteine and cardiovascular disease. Annu Rev Med . 1998; 49 31-62
2 Tonstad S, Refsum H, Sivertsen M. Relation of total homocysteine and lipid levels in children to premature cardiovascular death in male relatives. Pediatr Res . 1996; 40 47-52
3 Nygård O, Vollset S E, Refsum H. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA . 1995; 274 1526-1533
4 Tonstad S, Refsum H, Ueland P M. Association between plasma total homocysteine and parental history of cardiovascular disease in children with familial hypercholesterolemia. Circulation . 1997; 96 1803-1808
5 Bjorke-Monsen A L, Vollset S E, Ueland P M, Refsum H. Plasma total homocysteine, vitamin status and the 5,10-methylenetetrahydrofolate reductase polymorphism in children. Neth J Med . 1998; 51 S50
6 Andersson A, Brattström L, Israelsson B. Plasma homocysteine before and after methionine loading with regard to age, gender, and menopausal status. Eur J Clin Invest . 1992; 22 79-87
7 Anker G, Lonning P E, Ueland P M, Refsum H, Lien E A. Plasma levels of the atherogenic amino acid homocysteine in post-menopausal women with breast cancer treated with tamoxifen. Int J Cancer . 1995; 60 365-368
8 Wouters M G, Moorrees M T, van der Mooren M J. Plasma homocysteine and menopausal status. Eur J Clin Invest . 1995; 25 801-805
9 Zmuda J M, Bausserman L L, Maceroni D, Thompson P D. The effect of supraphysiologic doses of testosterone on fasting total homocysteine levels in normal men. Atherosclerosis . 1997; 130 199-202
10 van der Mooren M J, Mijatovic V, van Baal W M, Stehouwer C D. Hormone replacement therapy in postmenopausal women with specific risk factors for coronary artery disease. Maturitas . 1998; 30 27-36
11 Mudd S H, Levy H L, Skovby F. Disorders of transsulfuration. in: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease New York: McGraw-Hill, 1995: 1279-1327
12 Norlund L, Grubb A, Fex G. The increase of plasma homocysteine concentrations with age is partly due to the deterioration of renal function as determined by plasma cystatin C. Clin Chem Lab Med . 1998; 36 175-178
13 Andersson A, Brattstrom L, Israelsson B. Plasma homocysteine before and after methionine loading with regard to age, gender, and menopausal status. Eur J Clin Invest . 1992; 22 79-87
14 Kang S S, Wong P W, Zhou J M, Cook H Y. Total homocyst(e)ine in plasma and amniotic fluid of pregnant women. Metabolism . 1986; 35 889-891
15 Andersson A, Hultberg B, Brattstrom L, Isaksson A. Decreased serum homocysteine in pregnancy. Eur J Clin Chem Clin Biochem . 1992; 30 377-379
16 Walker M C, Smith G N, Perkins S L, Keely E J, Garner P R. Changes in homocysteine levels during normal pregnancy. Am J Obstet Gynecol . 1999; 180 660-664
17 Bonnette R E, Caudill M A, Boddie A M. Plasma homocyst(e)ine concentrations in pregnant and nonpregnant women with controlled folate intake. Obstet Gynecol . 1998; 92 167-170
18 Andersson A, Hultberg B, Brattström L, Isaksson A. Decreased serum homocysteine in pregnancy. Eur J Clin Chem Clin Biochem . 1992; 30 377-379
19 Malinow M R, Rajkovic A, Duell P B, Hess D L, Upson B M. The relationship between maternal and neonatal umbilical cord plasma homocyst(e)ine suggests a potential role for maternal homocyst(e)ine in fetal metabolism. Am J Obstet Gynecol . 1998; 178 228-233
20 Hermann W, Quast S, Ullrich M. Hyperhomocysteinemia in high-aged subjects: Relation of B-vitamins, folic acid, renal function and the methylenetetrahydrofolate reductase mutation. Atherosclerosis . 1999; 144 91-101
21 Arnadottir M, Hultberg B, Nilsson-Ehle P, Thysell H. The effect of reduced glomerular filtration rate on plasma total homocysteine concentration. Scand J Clin Lab Invest . 1996; 56 41-46
22 Tucker K L, Selhub J, Wilson P W, Rosenberg I H. Dietary pattern relates to plasma folate and homocysteine concentrations in the Framingham Heart Study. J Nutr . 1996; 126 3025-3031
23 Koehler K M, Pareo-Tubbeh S L, Romero L J, Baumgartner R N, Garry P J. Folate nutrition and older adults: Challenges and opportunities. J Am Diet Assoc . 1997; 97 167-173
24 Pennypacker L C, Allen R H, Kelly J P. High prevalence of cobalamin deficiency in elderly outpatients. J Am Geriatr Soc . 1992; 40 1197-1204
25 Lindenbaum J, Rosenberg I H, Wilson P W, Stabler S P, Allen R H. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr . 1994; 60 2-11
26 Allen R H, Lindenbaum J, Stabler S P. High prevalence of cobalamin deficiency in the elderly. Trans Am Clin Climatol Assoc . 1995; 107 37-45
27 Nilsson-Ehle H. Age-related changes in cobalamin (vitamin B₁₂) handling. Implications for therapy. Drugs Aging . 1998; 12 277-292
28 van Asselt D Z, de Groot L C, van Staveren W A. Role of cobalamin intake and atrophic gastritis in mild cobalamin deficiency in older Dutch subjects. Am J Clin Nutr . 1998; 68 328-334
29 Saltzman J R, Russell R M. The aging gut. Nutritional issues. Gastroenterol Clin North Am . 1998; 27 309-324
30 Ubbink J B. Should all elderly people receive folate supplements?. Drugs Aging . 1998; 13 415-420
31 Wilcken D E, Wilcken B. B vitamins and homocysteine in cardiovascular disease and aging. Ann NY Acad Sci . 1998; 854 361-370
32 Carmel R. Cobalamin, the stomach, and aging. Am J Clin Nutr . 1997; 66 750-759
33 Mudd S H, Skovby F, Levy H L. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet . 1985; 37 1-31
34 Brenton D P, Cusworth D C, Dent C E, Jones E E. Homocystinuria. Clinical and dietary studies. QJM . 1966; 35 325-346
35 Tsai M Y, Garg U, Key N S. Molecular and biochemical approaches in the identification of heterozygotes for homocystinuria. Atherosclerosis . 1996; 122 69-77
36 Ubbink J B, van der Merwe A, Delport R. The effect of a subnormal vitamin B-6 status on homocysteine metabolism. J Clin Invest . 1996; 98 177-184
37 Boers G H, Smals A G, Trijbels F J. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med . 1985; 313 709-715
38 Engbersen A M, Franken D G, Boers G H. Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet . 1995; 56 142-150
39 Franken D G, Boers G HJ, Blom H J, Trijbels F JM, Kloppenborg P WC. Treatment of mild hyperhomocysteinemia in vascular disease patients. Arterioscler Thromb . 1994; 14 465-470
40 Ueland P M, Refsum H, Brattström L. Plasma homocysteine and cardiovascular disease. in: Francis RBI, ed. Atherosclerotic Cardiovascular Disease, Hemostasis, and Endothelial Function New York: Marcel Dekker, 1992: 183-236
41 Kang S S, Zhou J, Wong P W, Kowalisyn J, Strokosch G. Intermediate homocysteinemia: A thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet . 1988; 43 414-421
42 Guttormsen A B, Ueland P M, Nesthus I. Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (> or = 40 micromol/liter). The Hordaland Homocysteine Study. J Clin Invest . 1996; 98 2174-2183
43 Matthews R G, Sheppard C, Goulding C. Methylenetetrahydrofolate reductase and methionine synthase: Biochemistry and molecular biology. Eur J Pediatr . 1998; S54-S59 (S54-S59)
44 Finkelstein J D, Martin J J. Methionine metabolism in mammals. Distribution of homocysteine between competing pathways. J Biol Chem . 1984; 259 9508-9513
45 Mansoor M A, Guttormsen A B, Fiskerstrand T. Redox status and protein binding of plasma aminothiols during the transient hyperhomocysteinemia that follows homocysteine administration. Clin Chem . 1993; 39 980-985
46 Ueland P M, Mansoor M A, Guttormsen A B. Reduced, oxidized and protein-bound forms of homocysteine and other aminothiols in plasma comprise the redox thiol status-a possible element of the extracellular antioxidant defense system. J Nutr . 1996; 126 1281S-1284S
47 Guttormsen A B, Schneede J, Fiskerstrand T, Ueland P M, Refsum H M. Plasma concentrations of homocysteine and other aminothiol compounds are related to food intake in healthy human subjects. J Nutr . 1994; 124 1934-1941
48 Andersson A, Brattström L, Israelsson B, Isaksson A, Hultberg B. The effect of excess daily methionine intake on plasma homocysteine after a methionine loading test in humans. Clin Chim Acta . 1990; 192 69-76
49 den Heijer M, Bos G MJ, Brouwer I A, Gerrits W BJ, Blom H J. Variability of the methionine loading test: No effect of a low protein diet. Ann Clin Biochem . 1996; 33 551-554
50 Shimakawa T, Nieto F J, Malinow M R. Vitamin intake: A possible determinant of plasma homocyst(e)ine among middle-aged adults. Ann Epidemiol . 1997; 7 285-293
51 Stolzenberg-Solomon R Z, Miller E R, Maguire M G, Selhub J, Appel L J. Association of dietary protein intake and coffee consumption with serum homocysteine concentrations in an older population. Am J Clin Nutr . 1999; 69 467-475
52 Verhoef P, Stampfer M J, Buring J E. Homocysteine metabolism and risk of myocardial infarction: Relation with vitamins B₆, B₁₂, and folate. Am J Epidemiol . 1996; 143 845-859
53 Mann N J, Dudman N, Guo X W, Li D, Sinclair A J. The effect of diet on homocysteine levels in healthy male subjects. Neth J Med . 1998; 52 S10
54 Nygård O, Refsum H, Ueland P M, Vollset S E. Major lifestyle determinants of plasma total homocysteine distribution: The Hordaland Homocysteine Study. Am J Clin Nutr . 1998; 67 263-270
55 Wei M M, Gregory J F. Organic acids in selected foods inhibit intestinal brush border pteroylpolyglutamate hydrolase in vitro: Potential mechanisms affecting the bioavailability of dietary polyglutamyl folate. J Agr Food Chem . 1998; 46 211-219
56 Omenn G S, Beresford S A, Motulsky A G. Preventing coronary heart disease: B vitamins and homocysteine. Circulation . 1998; 97 421-424
57 Lowering blood homocysteine with folic acid based supplements: Meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ . 1998; 316 894-898
58 Jacob R A, Wu M M, Henning S M, Swendseid M E. Homocysteine increases as folate decreases in plasma of healthy men during short-term dietary folate and methyl group restriction. J Nutr . 1994; 124 1072-1080
59 O'Keefe C A, Bailey L B, Thomas E A. Controlled dietary folate affects folate status in nonpregnant women. J Nutr . 1995; 125 2717-2725
60 Malinow M R, Duell P B, Hess D L. 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
61 Ubbink J B, Becker P J, Vermaak W J, Delport R. Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine. Clin Chem . 1995; 41 1033-1037
62 Rasmussen K, Moller J, Lyngbak M, Pedersen A M, Dybkjaer L. Age- and gender-specific reference intervals for total homocysteine and methylmalonic acid in plasma before and after vitamin supplementation. Clin Chem . 1996; 42 630-663
63 Joosten E, Lesaffre E, Riezler R. Are different reference intervals for methylmalonic acid and total homocysteine necessary in elderly people?. Eur J Haematol . 1996; 57 222-226
64 Gregory J F. Chemical and nutritional aspects of folate research-analytical procedures, methods of folate synthesis, stability, and bioavailability of dietary folates. Adv Food Nutr Res . 1990; 33 1-101
65 Seyoum E, Selhub J. Properties of food folates determined by stability and susceptibility to intestinal pteroylpolyglutamate hydrolase action. J Nutr . 1998; 128 1956-1960
66 Rogers L M, Pfeiffer C M, Bailey L B, Gregory J F. A dual-label stable-isotopic protocol is suitable for determination of folate bioavailability in humans: Evaluation of urinary excretion and plasma folate kinetics of intravenous and oral doses of [13C5] and [2H2] folic acid. J Nutr . 1997; 127 2321-2327
67 Bailey L B. Evaluation of a new Recommended Dietary Allowance for folate. J Am Diet Assoc . 1992; 92 463-478
68 Gimsing P, Melgaard B, Andersen K, Vilstrup H, Hippe E. Vitamin B-12 and folate function in chronic alcoholic men with peripheral neuropathy and encephalopathy. J Nutr . 1989; 119 416-424
69 Piyathilake C J, Hine R J, Dasanayake A P. Effect of smoking on folate levels in buccal mucosal cells. Int J Cancer . 1992; 52 566-569
70 Halsted C H, Villaneuva J, Chandler C J. Ethanol feeding of micropigs alters methionine metabolism and increases hepatocellular apoptosis and proliferation. Hepatology . 1996; 23 497-505
71 Gloria L, Cravo M, Camilo M E. Nutritional deficiencies in chronic alcoholics: Relation to dietary intake and alcohol consumption. Am J Gastroenterol . 1997; 92 485-489
72 Aubin H J, Laureaux C, Zerah F. Joint influence of alcohol, tobacco, and coffee on biological markers of heavy drinking in alcoholics. Biol Psychiatry . 1998; 44 638-643
73 Chen J, Giovannucci E L, Hunter D J. MTHFR polymorphism, methyl-replete diets and the risk of colorectal carcinoma and adenoma among U.S men and women: An example of gene-environment interactions in colorectal tumorigenesis. J Nutr . 1999; 129 560S-564S
74 Wu L L, Wu J, Hunt S C. Plasma homocyst(e)ine as a risk factor for early familial coronary artery disease. Clin Chem . 1994; 40 552-561
75 Bergmark C, Mansoor M A, Swedenborg J. Hyperhomocysteinemia in patients operated for lower extremity ischaemia below the age of 50-effect of smoking and extent of disease. Eur J Vasc Surg . 1993; 7 391-396
76 Mansoor M A, Bergmark C, Svardal A M, Lonning P E, Ueland P M. Redox status and protein binding of plasma homocysteine and other aminothiols in patients with early-onset peripheral vascular disease. Homocysteine and peripheral vascular disease. Arterioscler Thromb Vasc Biol . 1995; 15 232-240
77 Fernandez-Banares F, Gine J J, Cabre E. Factors associated with low values of biochemical vitamin parameters in healthy subjects. Int J Vitam Nutr Res . 1994; 64 68-74
78 Ortega R M, Lopez-Sobaler A M, Gonzalez-Gross M M. Influence of smoking on folate intake and blood folate concentrations in a group of elderly Spanish men. J Am Coll Nutr . 1994; 13 68-72
79 Mansoor M A, Kristensen O, Hervig T. Low concentrations of folate in serum and erythrocytes of smokers: Methionine loading decreases folate concentrations in serum of smokers and nonsmokers. Clin Chem . 1997; 43 2192-2194
80 Wright A J, Finglas P M, Southon S. Erythrocyte folate analysis: A cause for concern?. Clin Chem . 1998; 44 1886-1891
81 Berger J, Wynder E L. The correlation of epidemiological variables. J Clin Epidemiol . 1994; 47 941-952
82 Preston A M. Cigarette smoking-nutritional implications. Prog Food Nutr Sci . 1991; 15 183-217
83 Zondervan K T, Ocke M C, Smit H A, Seidell J C. Do dietary and supplementary intakes of antioxidants differ with smoking status?. Int J Epidemiol . 1996; 25 70-79
84 Piyathilake C J, Macaluso M, Hine R J, Richards E W, Krumdieck C L. Local and systemic effects of cigarette smoking on folate and vitamin B-12. Am J Clin Nutr . 1994; 60 559-566
85 Vermaak W JH, Ubbink J B, Barnard H C. Vitamin B-6 nutrition status and cigarette smoking. Am J Clin Nutr . 1990; 51 1058-1061
86 Giraud D W, Martin H D, Driskell J A. Erythrocyte and plasma B-6 vitamin concentrations of long-term tobacco smokers, chewers, and nonusers. Am J Clin Nutr . 1995; 62 104-109
87 Eiserich J P, Vandervliet A, Handelman G J, Halliwell B, Cross C E. Dietary antioxidants and cigarette smoke-induced biomolecular damage: A complex interaction. Am J Clin Nutr . 1995; 62 S1490-S1500
88 Ueland P M. Homocysteine species as components of plasma redox thiol status. Clin Chem . 1995; 41 340-342
89 Nygård O, Refsum H, Ueland P M. Coffee consumption and plasma total homocysteine: The Hordaland Homocysteine Study. Am J Clin Nutr . 1997; 65 136-143
90 Folsom A R, Nieto F J, McGovern P G. 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
91 Jacobsen B K, Thelle D S. The Tromsø Heart Study: Is coffee drinking an indicator of life style with high risk for ischemic heart disease?. Acta Med Scand . 1987; 222 215-221
92 Schwarz B, Bischof H P, Kunze M. Coffee, tea, and lifestyle. Prev Med . 1994; 23 377-384
93 Holycross B J, Jackson E K. Effects of chronic treatment with caffeine on kidney responses to angiotensin II. Eur J Pharmacol . 1992; 219 361-367
94 Vollset S E, Nygård O, Kvåle G, Ueland P M, Refsum H. Lifestyle and total plasma homocysteine in Western Norway. in: Graham I, Refsum H, Rosenberg IH, Ueland PM, eds. Homocysteine Metabolism. From Basic Science to Clinical Medicine Boston: Kluwer Academic Publisher, 1997: 177-182
96 Hultberg B, Andersson A, Masson P, Larson M, Tunek A. Plasma homocysteine and thiol compound fractions after oral administration of N-acetylcysteine. Scand J Clin Lab Invest . 1995; 54 417-422
97 Kenyon S H, Nicolaou A, Gibbons W A. The effect of ethanol and its metabolites upon methionine synthase activity in vitro. Alcohol . 1998; 15 305-309
98 Cravo M L, Gloria L M, Selhub J. Hyperhomocysteinemia in chronic alcoholism: Correlation with folate, vitamin B-12, and vitamin B-6 status. Am J Clin Nutr . 1996; 63 220-224
99 Lindenbaum J. Malabsorption of vitamin B₁₂ and folate. Curr Concepts Nutr . 1980; 9 105-123
100 Blocker D E, Thenen S W. Intestinal absorption, liver update, and excretion of 3H-folic acid in folic acid-deficient, alcohol-consuming nonhuman primates. Am J Clin Nutr . 1987; 46 503-510
101 Halsted C H. Jejunal brush-border folate hydrolase. A novel enzyme. West J Med . 1991; 155 605-609
102 Lussier-Cacan S, Xhignesse M, Piolot A. Plasma total homocysteine in healthy subjects: Sex-specific relation with biological traits. Am J Clin Nutr . 1996; 64 587-593
103 Malinow M R, Levenson J, Giral P. Role of blood pressure, uric acid, and hemorrheological parameters on plasma homocyst(e)ine concentration. Atherosclerosis . 1995; 114 175-183
104 Brolin R E, Gorman R C, Milgrim L M, Kenler H A. Multivitamin prophylaxis in prevention of post-gastric bypass vitamin and mineral deficiencies. Int J Obes . 1991; 15 661-667
105 Gurewitsch E D, Smith-Levitin M, Mack J. Pregnancy following gastric bypass surgery for morbid obesity. Obstet Gynecol . 1996; 88 658-661
106 Provenzale D, Reinhold R B, Golner B. Evidence for diminished B₁₂ absorption after gastric bypass: Oral supplementation does not prevent low plasma B₁₂ levels in bypass patients. J Am Coll Nutr . 1992; 11 29-35
107 Rhode B M, Arseneau P, Cooper B A. Vitamin B₁₂ deficiency after gastric surgery for obesity. Am J Clin Nutr . 1996; 63 103-109
108 Allen R H, Stabler S P, Savage D G, Lindenbaum J. Metabolic abnormalities in cobalamin (vitamin B₁₂) and folate deficiency. FASEB J . 1993; 7 1344-1353
109 Ubbink J B. The role of vitamins in the pathogenesis and treatment of hyperhomocyst(e)inaemia. J Inherit Metab Dis . 1997; 20 316-325
110 Lewis R. Anemia-a common but never a normal concomitant of aging. Geriatrics . 1976; 31 53-60
111 Lindenbaum J. Aspects of vitamin B₁₂ and folate metabolism in malabsorption syndromes. Am J Med . 1979; 67 1037-1048
112 Russell R M. Changes in gastrointestinal function attributed to aging. Am J Clin Nutr . 1992; 1203S-1207S (1203S-1207S)
113 Matthews J H. Cobalamin and folate deficiency in the elderly. Baillieres Clin Haematol . 1995; 8 679-697
114 Chanarin I, Deacon R, Lumb M, Muir M, Perry J. Cobalamin-folate interrelations: A critical review. Blood . 1985; 66 479-489
115 Shane B, Stokstad E L. Vitamin B₁₂-folate interrelationships. Annu Rev Nutr . 1985; 5 115-141
116 Miller J W, Nadeau M R, Smith D, Selhub J. Vitamin B-6 deficiency vs folate deficiency-comparison of responses to methionine loading in rats. Am J Clin Nutr . 1994; 59 1033-1039
117 Pietrzik K, Bronstrup A. Vitamins B₁₂, B₆ and folate as determinants of homocysteine concentration in the healthy population. Eur J Pediatr . 1998; S135-S138 (S135-S138)
118 Dierkes J, Kroesen M, Pietrzik K. Folic acid and vitamin B₆ supplementation and plasma homocysteine concentrations in healthy young women. Int J Vitam Nutr Res . 1998; 68 98-103
119 Selhub J, Jacques P F, Wilson P W, Rush D, Rosenberg I H. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA . 1993; 270 2693-2698
120 Joosten E, van den Berg A, Riezler R. Metabolic evidence that deficiencies of vitamin B-12 (cobalamin), folate, and vitamin B-6 occur commonly in elderly people. Am J Clin Nutr . 1993; 58 468-476
121 Ellis J M, McCully K S. Prevention of myocardial infarction by vitamin B₆ . Res Commun Mol Pathol Pharmacol . 1995; 89 208-220
122 Robinson K, Mayer E L, Miller D P. Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease. Circulation . 1995; 92 2825-2830
123 Chasan-Taber L, Selhub J, Rosenberg I H. A prospective study of folate and vitamin B₆ and risk of myocardial infarction in US physicians. J Am Coll Nutr . 1996; 15 136-143
124 Malinow M R, Nieto F J, Kruger W D. The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler Thromb Vasc Biol . 1997; 17 1157-1162
125 Riley W J, Toskes P P, Maclaren N K, Silverstein J H. Predictive value of gastric parietal cell autoantibodies as a marker for gastric and hematologic abnormalities associated with insulin-dependent diabetes. Diabetes . 1982; 31 1051-1055
126 Stene-Larsen G, Mosvold J, Ly B. Selective vitamin B₁₂ malabsorption in adult coeliac disease. Report on three cases with associated autoimmune diseases. Scand J Gastroenterol . 1988; 23 1105-1108
127 Ottesen M, Feldt-Rasmussen U, Andersen J, Hippe E, Schouboe A. Thyroid function and autoimmunity in pernicious anemia before and during cyanocobalamin treatment. J Endocrinol Invest . 1995; 18 91-97
128 Gupta A, Robinson K. Hyperhomocysteinaemia and end stage renal disease. J Nephrol . 1997; 10 77-84
129 Hoogstraten B, Baker H, Gilbert H S. Serum folate and serum vitamin B₁₂ in patients with malignant hematologic diseases. Cancer Res . 1965; 25 1933-1938
130 Hines J D, Halsted C H, Griggs R C, Harris J W. Megaloblastic anemia secondary to folate deficiency associated with hypothyroidism. Ann Intern Med . 1968; 68 792-805
131 Stokstad E L, Chan M M, Watson J E, Brody T. Nutritional interactions of vitamin B₁₂, folic acid, and thyroxine. Ann N Y Acad Sci . 1980; 355 119-129
132 Levitt A J, Joffe R T. Folate, B₁₂ and thyroid function in depression. Biol Psychiatry . 1993; 33 52-53
133 Ambrosi P, Barlatier A, Habib G. Hyperhomocysteinaemia in heart transplant recipients. Eur Heart J . 1994; 15 1191-1195
134 Berger P B, Jones J D, Olson L J. Increase in total plasma homocysteine concentration after cardiac transplantation. Mayo Clin Proc . 1995; 70 125-131
135 Ambrosi P, Garcon D, Riberi A. Association of mild hyperhomocysteinemia with cardiac graft vascular disease. Atherosclerosis . 1998; 138 347-350
136 Cole D E, Ross H J, Evrovski J. Correlation between total homocysteine and cyclosporine concentrations in cardiac transplant recipients. Clin Chem . 1998; 44 2307-2312
137 Fodinger M, Wolfl G, Fischer G. Effect of MTHFR 677C > T on plasma total homocysteine levels in renal graft recipients. Kidney Int . 1999; 55 1072-1080
138 Gupta A, Moustapha A, Jacobsen D W. High homocysteine, low folate, and low vitamin B₆ concentrations: Prevalent risk factors for vascular disease in heart transplant recipients. Transplantation . 1998; 65 544-550
139 Ueland P M, Refsum H. Plasma homocysteine, a risk factor for vascular disease: Plasma levels in health, disease, and drug therapy. J Lab Clin Med . 1989; 114 473-501
140 Refsum H, Ueland P M. Clinical significance of pharmacological modulation of homocysteine metabolism. Trends Pharmacol Sci . 1990; 11 411-416
141 Ueland P M, Fiskerstrand T, Lien E A, Refsum H. Homocysteine and drug therapy. in: Graham I, Refsum H, Rosenberg IH, Ueland PM, eds. Homocysteine Metabolism. From Basic Science to Clinical Medicine Boston: Kluwer Academic Publisher, 1997: 145-152
142 Ueland P M, Refsum H, Schneede J. Determinants of plasma homocysteine. In:Robinson K, ed. Homocysteine and Vascular Disease. Dordrecht, The Netherlands: Kluwer Academic; 2000: 45-54
143 Refsum H, Ueland P M, Kvinnsland S. Acute and long-term effects of high-dose methotrexate treatment on homocysteine in plasma and urine. Cancer Res . 1986; 46 5385-5391
144 Refsum H, Wesenberg F, Ueland P M. Plasma homocysteine in children with acute lymphoblastic leukemia: Changes during a chemotherapeutic regimen including methotrexate. Cancer Res . 1991; 51 828-835
145 Refsum H, Helland S, Ueland P M. Fasting plasma homocysteine as a sensitive parameter of antifolate effect: A study of psoriasis patients receiving low-dose methotrexate treatment. Clin Pharmacol Ther . 1989; 46 510-520
146 Morgan S L, Baggott J E, Refsum H, Ueland P M. Homocysteine levels in patients with rheumatoid arthritis treated with low-dose methotrexate. Clin Pharmacol Ther . 1991; 50 547-556
147 Morgan S L, Baggott J E, Lee J Y, Alarcon G S. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: Implications for cardiovascular disease prevention. J Rheumatol . 1998; 25 441-446
148 van Ede A E, Laan R F, Blom H J, De Abreau R A, van de Putte L B. Methotrexate in rheumatoid arthritis: An update with focus on mechanisms involved in toxicity. Semin Arthritis Rheum . 1998; 27 277-292
149 James G K, Jones M W, Pudek M R. Homocyst(e)ine levels in patients on phenytoin therapy. Clin Biochem . 1997; 30 647-649
150 Ono H, Sakamoto A, Eguchi T. Plasma total homocysteine concentrations in epileptic patients taking anticonvulsants. Metabolism . 1997; 46 959-962
151 Carl G F, Smith M L, Furman G M. Phenytoin treatment and folate supplementation affect folate concentrations and methylation capacity in rats. J Nutr . 1991; 121 1214-1221
152 Yoo J H, Hong S B. A common mutation in the methylenetetrahydrofolate reductase gene is a determinant of hyperhomocysteinemia in epileptic patients receiving anticonvulsants. Metabolism . 1999; 48 1047-1051
153 Blankenhorn D H, Malinow M R, Mack W J. Colestipol plus niacin therapy elevates plasma homocyst(e)ine levels. Coron Artery Disease . 1991; 2 357-360
154 Tonstad S, Refsum H, Ose L, Ueland P M. The C677T mutation in the methylenetetrahydrofolate reductase gene predisposes to hyperhomocysteinemia in children with familial hypercholesterolemia treated with cholestyramine. J Pediatr . 1998; 132 365-368
155 Ermens A A, Schoester M, Spijkers L J, Lindemans J, Abels J. Toxicity of methotrexate in rats preexposed to nitrous oxide. Cancer Res . 1989; 49 6337-6341
156 Christensen B, Guttormsen A B, Schneede J. Preoperative methionine loading enhances restoration of the cobalamin-dependent enzyme methionine synthase after nitrous oxide anesthesia. Anesthesiology . 1994; 80 1046-1056
157 Guttormsen A B, Refsum H, Ueland P M. The interaction between nitrous oxide and cobalamin. Biochemical effects and clinical consequences. Acta Anaesthesiol Scand . 1994; 38 753-756
158 Drummond J T, Matthews R G. Nitrous oxide inactivation of cobalamin-dependent methionine synthase from Escherichia coli: Characterization of the damage to the enzyme and prosthetic group. Biochemistry . 1994; 33 3742-3750
159 Drummond J T, Matthews R G. Nitrous oxide degradation by cobalamin-dependent methionine synthase: Characterization of the reactants and products in the inactivation reaction. Biochemistry . 1994; 33 3732-3741
160 Coronato A, Glass G B. Depression of the intestinal uptake of radio-vitamin B₁₂ by cholestyramine. Proc Soc Exp Biol Med . 1973; 142 1341-1344
161 Force R W, Nahata M C. Effect of histamine H2-receptor antagonists on vitamin B₁₂ absorption. Ann Pharmacother . 1992; 26 1283-1286
162 Saltzman J R, Kemp J A, Golner B B. Effect of hypochlorhydria due to omeprazole treatment or atrophic gastritis on protein-bound vitamin B₁₂ absorption. J Am Coll Nutr . 1994; 13 584-591
163 Bellou A, Aimone-Gastin I, De Korwin J D. Cobalamin deficiency with megaloblastic anaemia in one patient under long-term omeprazole therapy. J Intern Med . 1996; 240 161-164
164 Schenk B E, Festen H P, Kuipers E J, Klinkenberg-Knol E C, Meuwissen S G. Effect of short- and long-term treatment with omeprazole on the absorption and serum levels of cobalamin. Aliment Pharmacol Ther . 1996; 10 541-545
165 Termanini B, Gibril F, Sutliff V E. Effect of long-term gastric acid suppressive therapy on serum vitamin B₁₂ levels in patients with Zollinger-Ellison syndrome. Am J Med . 1998; 104 422-430
166 Tomkin G H, Hadden D R, Weaver J A, Montgomery D A. Vitamin-B₁₂ status of patients on long-term metformin therapy. BMJ . 1971; 2 685-687
167 Tomkin G H. Malabsorption of vitamin B₁₂ in diabetic patients treated with phenformin: A comparison with metformin. BMJ . 1973; 3 673-675
168 Callaghan T S, Hadden D R, Tomkin G H. Megaloblastic anaemia due to vitamin B₁₂ malabsorption associated with long-term metformin treatment. BMJ . 1980; 280 1214-1215
169 Adams J F, Clark J S, Ireland J T, Kesson C M, Watson W S. Malabsorption of vitamin B₁₂ and intrinsic factor secretion during biguanide therapy. Diabetologia . 1983; 24 16-18
170 Tonstad S, Knudtzon J, Sivertsen M, Refsum H, Ose L. Efficacy and safety of cholestyramine therapy in peripubertal and prepubertal children with familial hypercholesterolemia. J Pediatr . 1996; 129 42-49
171 Carlsen S M, Folling I, Grill V. Metformin increases total serum homocysteine levels in non-diabetic male patients with coronary heart disease. Scand J Clin Lab Invest . 1997; 57 521-527
172 Hoogeveen E K, Kostense P J, Jakobs C. Does metformin increase the serum total homocysteine level in non-insulin-dependent diabetes mellitus?. J Intern Med . 1997; 242 389-394
173 Aarsand A K, Carlsen S M. Folate administration reduces circulating homocysteine levels in NIDDM patients on long-term metformin treatment. J Intern Med . 1998; 244 169-174
174 Shaw J T, McWhinney B, Tate J R. Plasma homocysteine levels in indigenous Australians. Med J Aust . 1999; 170 19-22
175 Laine-Cessac P, Cailleux A, Allain P. Mechanisms of the inhibition of human erythrocyte pyridoxal kinase by drugs. Biochem Pharmacol . 1997; 54 863-870
176 Drell W, Welch A D. Azaribine-homocystinemia-thrombosis in historical perspective. Pharmacol Ther . 1989; 41 195-206
177 Krishnaswamy K. Isonicotinic acid hydrazide and pyridoxine deficiency. Int J Vitam Nutr Res . 1974; 44 457-465
178 Basu T K, Mann S. Vitamin B-6 normalizes the altered sulfur amino acid status of rats fed diets containing pharmacological levels of niacin without reducing niacin's hypolipidemic effects. J Nutr . 1997; 127 117-121
179 Brattström L, Israelsson B, Olsson A, Andersson A, Hultberg B. Plasma homocysteine in women in oral oestrogen-containing contraceptives and in men with oestrogen-treated prostatic carcinoma. Scand J Clin Lab Invest . 1992; 52 283-287
180 van der Mooren M J, Demacker P N, Blom H J, de Rijke Y B, Rolland R. The effect of sequential three-monthly hormone replacement therapy on several cardiovascular risk estimators in postmenopausal women. Fertil Steril . 1997; 67 67-73
181 Giri S, Thompson P D, Taxel P. Oral estrogen improves serum lipids, homocysteine and fibrinolysis in elderly men. Atherosclerosis . 1998; 137 359-366
182 Giltay E J, Hoogeveen E K, Elbers J M. Effects of sex steroids on plasma total homocysteine levels: A study in transsexual males and females. J Clin Endocrinol Metab . 1998; 83 550-553
183 Steegers-Theunissen R P, Boers G H, Steegers E A. Effects of sub-50 oral contraceptives on homocysteine metabolism: A preliminary study. Contraception . 1992; 45 129-139
184 Shojania A M. Oral contraceptives: Effect of folate and vitamin B₁₂ metabolism. Can Med Assoc J . 1982; 126 244-247
185 Miller L T. Do oral contraceptive agents affect nutrient requirements-vitamin B-6?. J Nutr . 1986; 116 1344-1345
186 Arnadottir M, Hultberg B, Vladov V, Nilsson-Ehle P, Thysell H. Hyperhomocysteinemia in cyclosporine-treated renal transplant recipients. Transplantation . 1996; 61 509-512
187 Dennis V W, Robinson K. Homocysteinemia and vascular disease in end-stage renal disease. Kidney Int Suppl . 1996; 57 S11-S17
188 Robinson K, Gupta A, Dennis V. Hyperhomocysteinemia confers an independent increased risk of atherosclerosis in end-stage renal disease and is closely linked to plasma folate and pyridoxine concentrations. Circulation . 1996; 94 2743-2748
189 Bostom A G, Shemin D, Verhoef P. Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients. A prospective study. Arterioscler Thromb Vasc Biol . 1997; 17 2554-2558
190 van Guldener C, Janssen M J, Stehouwer C D. The effect of renal transplantation on hyperhomocysteinaemia in dialysis patients, and the estimation of renal homocysteine extraction in patients with normal renal function. Neth J Med . 1998; 52 58-64
191 Bostom A, Brosnan J T, Hall B, Nadeau M R, Selhub J. Net uptake of plasma homocysteine by the rat kidney in vivo. Atherosclerosis . 1995; 116 59-62
192 van<&&>Guldener C, Donker A J, Jakobs C. No net renal extraction of homocysteine in fasting humans. Kidney Int . 1998; 54 166-169
193 Bostom A G, Shemin D, Lapane K L. Folate status is the major determinant of fasting total plasma homocysteine levels in maintenance dialysis patients. Atherosclerosis . 1996; 123 193-202
194 Bostom A G, Shemin D, Lapane K L. High dose-B-vitamin treatment of hyperhomocysteinemia in dialysis patients. Kidney Int . 1996; 49 147-152
195 Dierkes J, Domrose U, Ambrosch A. Response of hyperhomocysteinemia to folic acid supplementation in patients with end-stage renal disease. Clin Nephrol . 1999; 51 108-115
196 House A A, Donnelly J G. Effect of multivitamins on plasma homocysteine and folate levels in patients on hemodialysis. ASAIO J . 1999; 45 94-97
197 Ramirez G, Chen M, Boyce<&&>Jr H W. Longitudinal follow-up of chronic hemodialysis patients without vitamin supplementation. Kidney Int . 1986; 30 99-106
198 Stein G, Sperschneider H, Koppe S. Vitamin levels in chronic renal failure and need for supplementation. Blood Purif . 1985; 3 52-62
199 Dierkes J, Domröse U, Ambrosch A. Supplementation with vitamin B₁₂ decreases homocysteine and methylmalonic acid but also serum folate in patients with end-stage renal disease. Metabolism . 1999; 48 631-635
200 Refsum H, Wesenberg F, Ueland P M. Plasma homocysteine in children with acute lymphoblastic leukemia. Changes during a chemotherapeutic regimen including methotrexate. Cancer Res . 1991; 51 828-835
201 Christensen B, Refsum H, Vintermyr O, Ueland P M. Homocysteine export from cells cultured in the presence of physiological or superfluous levels of methionine: Methionine loading of non-transformed, transformed, proliferating and quiescent cells in culture. J Cell Physiol . 1991; 146 52-62
202 Bates C J, Pentieva K D, Prentice A, Mansoor M A, Finch S. Plasma pyridoxal phosphate and pyridoxic acid and their relationship to plasma homocysteine in a representative sample of British men and women aged 65 years and over. Br J Nutr . 1999; 81 191-201
203 Haagsma C J, Blom H J, van Riel P L. Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis . 1999; 58 79-84
204 Hernanz A, Plaza A, Martin-Mola E, De Miguel E. Increased plasma levels of homocysteine and other thiol compounds in rheumatoid arthritis women. Clin Biochem . 1999; 32 65-70
205 Pettersson T, Friman C, Abrahamsson L, Nilsson B, Norberg B. Serum homocysteine and methylmalonic acid in patients with rheumatoid arthritis and cobalaminopenia. J Rheumatol . 1998; 25 859-863
206 Petterson T, Friman C, Abrahamson L, Nilsson B, Norberg B. Serum homocysteine and methylmalonic acid in patients with rheumatoid arthritis and cobalaminopenia. J Rheumatol . 1998; 25 859-863
207 Roubenoff R, Dellaripa P, Nadeau M R. Abnormal homocysteine metabolism in rheumatoid arthritis. Arthritis Rheum . 1997; 40 718-722
208 Krogh<&&>Jensen M, Ekelund S, Svendsen L. Folate and homocysteine status and haemolysis in patients treated with sulphasalazine for arthritis. Scand J Clin Lab Invest . 1996; 56 421-429
209 Perrett D. The metabolism and pharmacology of D-penicillamine in man. J Rheumatol Suppl . 1981; 7 41-50
210 Kang S S, Wong P W, Glickman P B, MacLeod C M, Jaffe I A. Protein-bound homocyst(e)ine in patients with rheumatoid arthritis undergoing D-penicillamine treatment. J Clin Pharmacol . 1986; 26 712-725
211 Cattaneo M, Vecchi M, Zighetti M L. High prevalence of hyperhomocysteinemia in patients with inflammatory bowel disease: A pathogenic link with thromboembolic complications?. Thromb Haemost . 1998; 80 542-545
212 Mahmud N, Molloy A, McPartlin J. Increased prevalence of methylenetetrahydrofolate reductase C677T variant in patients with inflammatory bowel disease, and its clinical implications. Gut . 1999; 45 389-394
213 Hultberg B, Agardh E, Andersson A. Increased levels of plasma homocysteine are associated with nephropathy but not severe retinopathy in type 1 diabetes mellitus. Scand J Lab Clin Invest . 1991; 51 277-282
214 Agardh C D, Agardh E, Andersson A, Hultberg B. Lack of association between plasma homocysteine levels and microangiopathy in type 1 diabetes mellitus. Scand J Lab Invest . 1987; 54 637-641
215 Chico A, Perez A, Cordoba A. Plasma homocysteine is related to albumin excretion rate in patients with diabetes mellitus: A new link between diabetic nephropathy and cardiovascular disease?. Diabetologia . 1998; 41 684-693
216 Hultberg B, Agardh C D, Agardh E, Lovestam-Adrian M. Poor metabolic control, early age at onset, and marginal folate deficiency are associated with increasing levels of plasma homocysteine in insulin-dependent diabetes mellitus. A five-year follow-up study. Scand J Clin Lab Invest . 1997; 57 595-600
217 Caspary W F, Zavada I, Reimold W. Alteration of bile acid metabolism and vitamin-B₁₂-absorption in diabetics on biguanides. Diabetologia . 1977; 13 187-193
218 Araki A, Sako Y, Ito H. Plasma homocysteine concentrations in Japanese patients with non-insulin-dependent diabetes mellitus: Effect of parenteral methylcobalamin treatment. Atherosclerosis . 1993; 103 149-157
219 Hofmann M A, Kohl B, Zumbach M S. Hyperhomocyst(e)inemia and endothelial dysfunction in IDDM. Diabetes Care . 1998; 21 841-848
220 Hoogeveen E K, Kostense P J, Beks P J. Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus: A population-based study. Arterioscler Thromb Vasc Biol . 1998; 18 133-138
221 Munshi M N, Stone A, Fink L, Fonseca V. Hyperhomocysteinemia following a methionine load in patients with non-insulin-dependent diabetes mellitus and macrovascular disease. Metabolism . 1996; 45 133-135
222 Vaccaro O, Ingrosso D, Rivellese A, Greco G, Riccardi G. Moderate hyperhomocysteinaemia and retinopathy in insulin-dependent diabetes. Lancet . 1997; 349 1102-1103
223 Neugebauer S, Baba T, Kurokawa K, Watanabe T. Defective homocysteine metabolism as a risk factor for diabetic retinopathy. Lancet . 1997; 349 473-474
224 Lanfredini M, Fiorina P, Peca M G. Fasting and post-methionine load homocyst(e)ine values are correlated with microalbuminuria and could contribute to worsening vascular damage in non-insulin-dependent diabetes mellitus patients. Metabolism . 1998; 47 915-921
225 Hoogeveen E K, Kostense P J, Jager A. Serum homocysteine level and protein intake are related to risk of microalbuminuria: The Hoorn Study. Kidney Int . 1998; 54 203-209
226 Robillon J F, Canivet B, Candito M. Type 1 diabetes mellitus and homocyst(e)ine. Diabetes Metab . 1994; 20 494-496
227 Wollesen F, Brattstrom L, Refsum H. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int . 1999; 55 1028-1035
228 Giltay E J, Hoogeveen E K, Elbers J M. Insulin resistance is associated with elevated plasma total homocysteine levels in healthy, non-obese subjects. Atherosclerosis . 1998; 139 197-198
229 Fonseca V A, Mudaliar S, Schmidt B. Plasma homocysteine concentrations are regulated by acute hyperinsulinemia in nondiabetic but not type 2 diabetic subjects. Metabolism . 1998; 47 686-689
230 Nedrebo B G, Ericsson U B, Nygård O. Plasma total homocysteine levels in hyperthyroid and hypothyroid patients. Metabolism . 1998; 47 89-93
231 Cimino J A, Jhangiani S, Schwartz E, Cooperman J M. Riboflavin metabolism in the hypothyroid human adult. Proc Soc Exp Biol Med . 1987; 184 151-153
232 Nair C P, Viswanathan G, Noronha J M. Folate-mediated incorporation of ring-2-carbon of histidine into nucleic acids: Influence of thyroid hormone. Metabolism . 1994; 43 1575-1578
233 Montenegro J, Gonzalez O, Saracho R, Aguirre R, Martinez I. Changes in renal function in primary hypothyroidism. Am J Kidney Dis . 1996; 27 195-198
234 Capasso G, De<&&>Tommaso G, Pica A. Effects of thyroid hormones on heart and kidney functions. Miner Electrolyte Metab . 1999; 25 56-64
235 Kreisman S H, Hennessey J V. Consistent reversible elevations of serum creatinine levels in severe hypothyroidism. Arch Intern Med . 1999; 159 79-82
236 Hussein W I, Green R, Jacobsen D W, Faiman C. Normalization of hyperhomocysteinemia with L-thyroxine in hypothyroidism. Ann Intern Med . 1999; 131 348-351
237 Lien E A, Nedrebø B G, Varhaug J E. Plasma total homocysteine levels during short-term iatrogenic hypothyroidism. J Clin Endocrinol Metabol . 2000; 85 1049-1053
238 Fernandez-Banares F, Abad-Lacruz A, Xiol X. Vitamin status in patients with inflammatory bowel disease. Am J Gastroenterol . 1989; 84 744-748
239 Gonera R K, Timmerhuis T P, Leyten A C, van der Heul C. Two thrombotic complications in a patient with active ulcerative colitis. Neth J Med . 1997; 50 88-91
240 Slot W B, van Kasteel V, Coerkamp E G, Seelen P J, van der Werf S D. Severe thrombotic complications in a postpartum patient with active Crohn's disease resulting in ischemic spinal cord injury. Dig Dis Sci . 1995; 40 1395-1399
241 Lambert D, Benhayoun S, Adjalla C. Crohn's disease and vitamin B₁₂ metabolism. Dig Dis Sci . 1996; 41 1417-1422
242 Penix L P. Ischemic strokes secondary to vitamin B₁₂ deficiency-induced hyperhomocystinemia. Neurology . 1998; 51 622-624
243 Hoffbrand A V, Douglas A P, Fry L, Stewart J S. Malabsorption of dietary folate (Pteroylpolyglutamates) in adult coeliac disease and dermatitis herpetiformis. BMJ . 1970; 4 85-89
244 Elsborg L, Larsen L. Folate deficiency in chronic inflammatory bowel diseases. Scand J Gastroenterol . 1979; 14 1019-1024
245 Bechi P, Briganti S, Borsotti M. Folate deficiency in operated terminal ileitis (Crohn's disease). Ital J Surg Sci . 1983; 13 13-19
246 Imes S, Pinchbeck B R, Dinwoodie A, Walker K, Thomson A B. Iron, folate, vitamin B-12, zinc, and copper status in outpatients with Crohn's disease: Effect of diet counseling. J Am Diet Assoc . 1987; 87 928-930
247 Steger G G, Mader R M, Vogelsang H. Folate absorption in Crohn's disease. Digestion . 1994; 55 234-238
248 Pittschieler K. Neutropenia, granulocytic hypersegmentation and coeliac disease. Acta Paediatr . 1995; 84 705-706
249 Burke A, Lichtenstein G R, Rombeau J L. Nutrition and ulcerative colitis. Baillieres Clin Gastroenterol . 1997; 11 153-174
250 Kennedy H J, Callender S T, Truelove S C, Warner G T. Haematological aspects of life with an ileostomy. Br J Haematol . 1982; 52 445-454
251 Fiorentini M T, Locatelli L, Ceccopieri B. Physiology of ileoanal anastomosis with ileal reservoir for ulcerative colitis and adenomatosis coli. Dis Colon Rectum . 1987; 30 267-272
252 Neale G, Gompertz D, Schonsby H, Tabaqchali S, Booth C C. The metabolic and nutritional consequences of bacterial overgrowth in the small intestine. Am J Clin Nutr . 1972; 25 1409-1417
253 Gracey M. Mechanisms of malabsorption in the ``contaminated small-bowel syndrome''. Nahrung . 1984; 28 659-666
254 Franklin J L, Rosenberg H H. Impaired folic acid absorption in inflammatory bowel disease: Effects of salicylazosulfapyridine (Azulfidine). Gastroenterology . 1973; 64 517-525
255 Baum C L, Selhub J, Rosenberg I H. Antifolate actions of sulfasalazine on intact lymphocytes. J Lab Clin Med . 1981; 97 779-784
256 Swinson C M, Perry J, Lumb M, Levi A J. Role of sulphasalazine in the aetiology of folate deficiency in ulcerative colitis. Gut . 1981; 22 456-461
257 Pironi L, Cornia G L, Ursitti M A. Evaluation of oral administration of folic and folinic acid to prevent folate deficiency in patients with inflammatory bowel disease treated with salicylazosulfapyridine. Int J Clin Pharmacol Res . 1988; 8 143-148
258 Lucas M L, Cooper B T, Lei F H. Acid microclimate in coeliac and Crohn's disease: A model for folate malabsorption. Gut . 1978; 19 735-742
259 Lucas M L, Mathan V I. Jejunal surface pH measurements in tropical sprue. Trans R Soc Trop Med Hyg . 1989; 83 138-142
260 Harju E. Metabolic problems after gastric surgery. Int Surg . 1990; 75 27-35
261 Avinoah E, Ovnat A, Charuzi I. Nutritional status seven years after Roux-en-Y gastric bypass surgery. Surgery . 1992; 111 137-142
262 Grange D K, Finlay J L. Nutritional vitamin B₁₂ deficiency in a breastfed infant following maternal gastric bypass. Pediatr Hematol Oncol . 1994; 11 311-318
263 Sumner A E, Chin M M, Abrahm J L. Elevated methylmalonic acid and total homocysteine levels show high prevalence of vitamin B₁₂ deficiency after gastric surgery. Ann Intern Med . 1996; 124 469-476
264 Borson-Chazot F, Harthe C, Teboul F. Occurrence of hyperhomocysteinemia 1 year after gastroplasty for severe obesity. J Clin Endocrinol Metab . 1999; 84 541-545
265 Loeschke K, Bolkert T, Kiefhaber P. Bacterial overgrowth in ileal reservoirs (Koch pouch): Extended functional studies. Hepatogastroenterology . 1980; 27 310-316
266 Teria A, Okada Y, Shichiri Y. Vitamin B₁₂ deficiency in patients with urinary intestinal diversion. Int J Urol . 1997; 4 21-25
267 Christl S U, Scheppach W. Metabolic consequences of total colectomy. Scand J Gastroenterol Suppl . 1997; 222 20-24
268 Isaacs P E, Kim Y S. The contaminated small bowel syndrome. Am J Med . 1979; 67 1049-1057
269 Murphy M F, Sourial N A, Burman J F. Megaloblastic anaemia due to vitamin B₁₂ deficiency caused by small intestinal bacterial overgrowth: Possible role of vitamin B₁₂ analogues. Br J Haematol . 1986; 62 7-12
270 Riordan S M, McIver C J, Wakefield D. Small intestinal bacterial overgrowth in the symptomatic elderly. Am J Gastroenterol . 1997; 92 47-51
271 Swan R W. Stagnant loop syndrome resulting from small-bowel irradiation injury and intestinal by-pass. Gynecol Oncol . 1974; 2 441-445
272 Kinn A C, Lantz B. Vitamin B₁₂ deficiency after irradiation for bladder carcinoma. J Urol . 1984; 131 888-890
273 Lantz B, Einhorn N. Intestinal damage and malabsorption after treatment for cervical carcinoma. Acta Radiol Oncol . 1984; 23 33-36
274 Yeoh E K, Lui D, Lee N Y. The mechanism of diarrhoea resulting from pelvic and abdominal radiotherapy; a prospective study using selenium-75 labelled conjugated bile acid and cobalt-58 labelled cyanocobalamin. Br J Radiol . 1984; 57 1131-1136
275 Ludgate S M, Merrick M V. The pathogenesis of post-irradiation chronic diarrhoea: Measurement of SeHCAT and B₁₂ absorption for differential diagnosis determines treatment. Clin Radiol . 1985; 36 275-278
276 Festen H P. Intrinsic factor secretion and cobalamin absorption. Physiology and pathophysiology in the gastrointestinal tract. Scand J Gastroenterol Suppl . 1991; 188 1-7
277 Snijders-Keilholz A, Griffioen G, Davelaar J, Trimbos J B, Leer J W. Vitamin B₁₂ malabsorption after irradiation for gynaecological tumours. Anticancer Res . 1993; 13 1877-1881
278 Yeoh E, Horowitz M, Russo A. Effect of pelvic irradiation on gastrointestinal function: A prospective longitudinal study. Am J Med . 1993; 95 397-406
279 Gee M I, Grace M G, Wensel R H, Sherbaniuk R W, Thomson A B. Nutritional status of gastroenterology outpatients: Comparison of inflammatory bowel disease with functional disorders. J Am Diet Assoc . 1985; 85 1591-1599
280 Lashner B A, Heidenreich P A, Su G L, Kane S V, Hanauer S B. Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. A case-control study. Gastroenterology . 1989; 97 255-259
281 Levin B. Ulcerative colitis and colon cancer: Biology and surveillance. J Cell Biochem Suppl . 1992; 47-50
282 Lashner B A. Red blood cell folate is associated with the development of dysplasia and cancer in ulcerative colitis. J Cancer Res Clin Oncol . 1993; 119 549-554
283 Glynn S A, Albanes D, Pietinen P. Colorectal cancer and folate status: A nested case-control study among male smokers. Cancer Epidemiol Biomarkers Prev . 1996; 5 487-494
284 Biasco G, Zannoni U, Paganelli G M. Folic acid supplementation and cell kinetics of rectal mucosa in patients with ulcerative colitis. Cancer Epidemiol Biomarkers Prev . 1997; 6 469-471
285 Itzkowitz S H. Inflammatory bowel disease and cancer. Gastroenterol Clin North Am . 1997; 26 129-139
286 Ma J, Stampfer M J, Giovannucci E. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res . 1997; 57 1098-1102
287 Mouzas I A, Papavassiliou E, Koutroubakis I. Chemoprevention of colorectal cancer in inflammatory bowel disease?. A potential role for folate. Ital J Gastroenterol Hepatol . 1998; 30 421-425
288 Nexo E, Hansen M, Rasmussen K, Lindgren A, Grasbeck R. How to diagnose cobalamin deficiency. Scand J Clin Lab Invest Suppl . 1994; 219 61-76
289 Savage D G, Lindenbaum J, Stabler S P, Allen R H. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med . 1994; 96 239-246
290 Stabler S P, Lindenbaum J, Allen R H. The use of homocysteine and other metabolites in the specific diagnosis of vitamin B-12 deficiency. J Nutr . 1996; 126 1266S-1272S
291 Rasmussen K, Vyberg B, Pedersen K O, Brochner-Mortensen J. Methylmalonic acid in renal insufficiency: Evidence of accumulation and implications for diagnosis of cobalamin deficiency. Clin Chem . 1990; 36 1523-1524
292 Landgren F, Israelsson B, Lindgren A. Plasma homocysteine in acute myocardial infarction: Homocysteine-lowering effect of folic acid. J Intern Med . 1995; 237 381-388
293 Egerton W, Silberberg J, Crooks R. Serial measures of plasma homocyst(e)ine after acute myocardial infarction. Am J Cardiol . 1996; 77 759-761
294 Lindgren A, Brattstrom L, Norrving B. Plasma homocysteine in the acute and convalescent phases after stroke. Stroke . 1995; 26 795-800
295 Sheehan N J, Stanton-King K. Polyautoimmunity in a young woman. Br J Rheumatol . 1993; 32 254-256