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Reduction of plasma homocysteine and serum methylmalonate concentrations in apparently healthy elderly subjects after treatment with folic acid, vitamin B12 and vitamin B6: a randomised trial

European Journal of Clinical Nutrition volume 57, pages 1426–1436 (2003)Cite this article

Abstract

Objectives: To investigate, in an elderly population: (1) the effects of oral B-vitamin therapy on P-tHcys, S-MMA and Hb/MCV, (2) the appropriate decision limit for ‘high’ metabolite concentrations and (3) the estimated prevalence of vitamin B12/folate deficiency on the basis of different decision limits.

Design: Double-blind placebo-controlled intervention study.

Setting: Outpatient clinic.

Subjects: A total of 209 community-dwelling subjects, median age 76 y (range 70–93) y.

Interventions: Four months of oral daily supplementation with 0.5 mg cyanocobalamin, 0.8 mg folic acid and 3 mg vitamin B6.

Results: High P- tHcys was found in 64% of men and 45% of women, high S-MMA in 11% of both. Vitamin B12 deficiency was observed in 7.2% and folate deficiency in 11% of all subjects. Health-related upper reference limits for the metabolites at the start were higher than the laboratory's upper reference limits. The latter were, however, similar to those of the vitamin replete group. There was a significant decrease in P-tHcys (P<0.001) and S-MMA (P=0.009) after 4 months of vitamin treatment. In a multivariate analysis, the P-Hcys change correlated positively with baseline P-tHcys and inversely with baseline P-folate and transferrin saturation (Fe/TIBC ratio). The S-MMA change correlated with baseline S-MMA and inversely with baseline vitamin B12 and age.

Conclusions: Suboptimal vitamin status is an important cause of elevated P-tHcys and S-MMA in apparently healthy elderly subjects. Oral B-vitamin therapy is an effective and convenient way to normalise P-tHcys and S-MMA.

Sponsorship: Support—Recip AB.

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References

  • Adams JF, Clark JS, Ireland JT, Kesson CM & Watson WS (1983): Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide therapy. Diabetologia 24, 16–18.

    Article  CAS  Google Scholar 

  • Alpert JE & Fava M (1997): Nutrition and depression: the role of folate. Nutr. Rev. 55, 145–149.

    Article  CAS  Google Scholar 

  • Apeland T, Mansoor MA, Strandjord RE, Vefring H & Kristensen O (2001): Folate, homocysteine and methionine loading in patients on carbamazepine. Acta Neurol. Scand. 103, 294–299.

    Article  CAS  Google Scholar 

  • Augustsson O, Eriksson BG, Rosenhall U, Rothenberg E, Warne B & Steen B (1994): The Johanneberg study—a sociomedical survey in an urban elderly population. I. General presentation of the study including an analysis of non-response and identification of risk groups. Scand. J. Soc. Med. 22, 283–292.

    Article  CAS  Google Scholar 

  • Bailey LB & Gregory JF (1999): Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J. Nutr. 129, 919–922.

    Article  CAS  Google Scholar 

  • Bald E & Sypniewski S (1994): Ion-pair high-performance liquid chromatography of cysteine and metabolically related compounds in the form of their S-pyridinium derivates. J. Chromatogr. A 676, 321–330.

    Article  Google Scholar 

  • Bates CJ, Pentieva KD, Prentice A, Mansoor MA & Finch S (1999): 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. 81, 191–201.

    CAS  PubMed  Google Scholar 

  • Belaiche J, Zittoun J, Marquet J, Nurit Y & Yvart J (1983): Effet de la ranitidine sur la secretion de facteur intrinseque gastrique et sur l'absorption de la vitamine B12. Gastroenterol. Clin. Biol. 7, 381–384.

    CAS  PubMed  Google Scholar 

  • Berg MJ (1999): The importance of folic acid. J. Gend. Specif. Med. 2, 24–28.

    CAS  PubMed  Google Scholar 

  • Bostom AG, Bausserman L, Jacques PF, Liaugaudas G, Selhub J & Rosenberg IH (1999): Cystatin c as a determinant of fasting plasma total homocysteine levels in coronary artery disease patients with normal serum creatinine. Arterioscler. Thromb. Vasc. Biol. 19, 2241–2244.

    Article  CAS  Google Scholar 

  • Bottiglieri T (1996): Folate, vitamin B-12, and neuropsychiatric disorders. Nutr. Rev. 54, 382–390.

    Article  CAS  Google Scholar 

  • Brattström L & Wilcken DE (2000): Homocysteine and cardiovascular disease: cause or effect? Am. J. Clin. Nutr. 72, 315–323.

    Article  Google Scholar 

  • Brouwer DAJ, Welten HTME, Reijngoud DJ, Vandoormaal JJ & Muskiet FAJ (1998): Plasma folic acid cutoff value, derived from its relationship with homocyst(e)ine. Clin. Chem. 44, 1545–1550.

    CAS  Google Scholar 

  • Carmel R, Sinow RM & Karnaze DS (1987): Atypical cobalamin deficiency. Subtle biochemical evidence of deficiency is commonly demonstrable in patients without megaloblastic anemia and is often associated with protein-bound cobalamin malabsorption. J. Lab. Clin. Med. 109, 454–463.

    CAS  PubMed  Google Scholar 

  • Chanarin I & Metz J (1998): Diagnosis of cobalamin deficiency: a reply. Br. J. Haematol. 100, 617–618.

    Article  CAS  Google Scholar 

  • Clarke R (1998): Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ 316, 894–898.

    Article  Google Scholar 

  • de Bree A, van Dusseldorp M, Brouwer IA, van het Hof KH & Steegers-Theunissen RP (1997): Folate intake in europe: recommended, actual and desired intake. Eur. J. Clin. Nutr. 51, 643–660.

    Article  CAS  Google Scholar 

  • de Bree A, Verschuren WM, Blom HJ & Kromhout D (2001): Lifestyle factors and plasma homocysteine concentrations in a general population sample. Am. J. Epidemiol. 154, 150–154.

    Article  CAS  Google Scholar 

  • Fava M, Borus JS, Alpert JE, Nierenberg AA, Rosenbaum JF & Bottiglieri T (1997): Folate, vitamin B12, and homocysteine in major depressive disorder. Am. J. Psychiatry 154, 426–428.

    Article  CAS  Google Scholar 

  • Fioravanti M, Ferrario E, Massaia M, Cappa G, Rivolta G, Grossi E & Buckley AE (1997): Low folate levels in the cognitive decline of elderly patients and the efficacy of folate as a treatment for improving memory deficits. Arch. Gerontol. Geriatr. 26, 1–13.

    Article  CAS  Google Scholar 

  • Haller J, Lowik MR, Ferry M & Ferro Luzzi A (1991): Nutritional status: blood vitamins A, E, B6, B12, folic acid and carotene. Euronut SENECA investigators. Eur. J. Clin. Nutr. 45(Suppl 3), 63–82.

    PubMed  Google Scholar 

  • Hathcock JN & Troendle GJ (1991): Oral cobalamin for treatment of pernicious anemia? JAMA 265, 96–97.

    Article  CAS  Google Scholar 

  • Healton EB, Savage DG, Brust JC, Garrett TJ & Lindenbaum J (1991): Neurologic aspects of cobalamin deficiency. Medicine (Baltimore) 70, 229–245.

    Article  CAS  Google Scholar 

  • Herrmann W, Quast S, Ullrich M, Schultze H, Bodis M & Geisel J (1999): Hyperhomocysteinemia in high-aged subjects: relation of b-vitamins, folic acid, renal function and the methylenetetrahydrofolate reductase mutation. Atherosclerosis 144, 91–101.

    Article  CAS  Google Scholar 

  • Hussein WI, Green R, Jacobsen DW & Faiman C (1999): Normalization of hyperhomocysteinemia with l-thyroxine in hypothyroidism. Ann. Intern. Med. 131, 348–351.

    Article  CAS  Google Scholar 

  • Hvas AM, Ellegaard J & Nexo E (2001): Vitamin B12 treatment normalizes metabolic markers but has limited clinical effect: a randomized placebo-controlled study. Clin. Chem. 47, 1396–1404.

    CAS  PubMed  Google Scholar 

  • Hvas AM, Juul S, Gerdes LU & Nexo E (2000): The marker of cobalamin deficiency, plasma methylmalonic acid, correlates to plasma creatinine. J. Intern. Med. 247, 507–512.

    Article  CAS  Google Scholar 

  • Ihamäki T, Varis K & Siurala M (1979): Morphological, functional and immunological state of the gastric mucosa in gastric carcinoma families. Comparison with a computer-matched family sample. Scand. J. Gastroenterol. 11, 817–822.

    Google Scholar 

  • Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J & Rozen R (1996): Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 93, 7–9.

    Article  CAS  Google Scholar 

  • Jones BP, Broomhead AF, Kwan YL & Grace CS (1987): Incidence and clinical significance of protein-bound vitamin B12 malabsorption. Eur. J. Haematol. 38, 131–136.

    Article  CAS  Google Scholar 

  • Joosten E, van den Berg A, Riezler R, Naurath HJ, Lindenbaum J, Stabler SP & Allen RH (1993): Metabolic evidence that deficiencies of vitamin B-12 (cobalamin), folate, and vitamin B-6 occur commonly in elderly people. Am. J. Clin. Nutr. 58, 468–476.

    Article  CAS  Google Scholar 

  • Kittang E & Schjönsby H (1987): Effect of gastric anacidity on the release of cobalamins from food and their subsequent binding to R-protein. Scand. J. Gastroenterol. 22, 1031–1037.

    Article  CAS  Google Scholar 

  • Krasinski SD, Russell RM, Samloff IM, Jacob RA, Dallal GE, McGandy RB & Hartz SC (1986): Fundic atrophic gastritis in an elderly population. Effect on hemoglobin and several serum nutritional indicators. J. Am. Geriatr. Soc. 34, 800–806.

    Article  CAS  Google Scholar 

  • Lehmann M, Gottfries CG & Regland B (1999): Identification of cognitive impairment in the elderly: homocysteine is an early marker. Dementia Geriatr. Cognitive Disorders 10, 12–20.

    Article  CAS  Google Scholar 

  • Lindenbaum J, Healton EB, Savage DG, Brust JCM, Garrett TJ, Podell ER, Marcell PD, Stabler SP & Allen RH (1988): Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N. Engl. J. Med. 318, 1720–1728.

    Article  CAS  Google Scholar 

  • Lindenbaum J, Rosenberg IH, Wilson PW, Stabler SP & Allen RH (1994): Prevalence of cobalamin deficiency in the Framingham elderly population. Am. J. Clin. Nutr. 60, 2–11.

    Article  CAS  Google Scholar 

  • Lindenbaum J, Savage DG, Stabler SP & Allen RH (1990): Diagnosis of cobalamin deficiency II: relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am. J. Hematol. 34, 99–107.

    Article  CAS  Google Scholar 

  • Lindstedt G (1999): Nitrous oxide may cause cobalamin deficiency syndrome; vitamin B12 a simple and inexpensive remedy. Lakartidningen 96, 4801–4805.

    CAS  PubMed  Google Scholar 

  • Matthews JH (1995): Cobalamin and folate deficiency in the elderly. Baillieres. Clin. Haematol. 8, 679–697.

    Article  CAS  Google Scholar 

  • McKinley MC, McNulty H, McPartlin J, Strain JJ, Pentieva K, Ward M, Weir DG & Scott JM (2001): Low-dose vitamin B-6 effectively lowers fasting plasma homocysteine in healthy elderly persons who are folate and riboflavin replete. Am. J. Clin. Nutr. 73, 759–764.

    Article  CAS  Google Scholar 

  • Molloy AM, Daly S, Mills JL, Kirke PN, Whitehead AS, Ramsbottom D, Conley MR, Weir DG & Scott JM (1997): Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet 349, 1591–1593.

    Article  CAS  Google Scholar 

  • Morgan SL, Baggott JE, Lee JY & Alarcon GS (1998): 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. 25, 441–446.

    CAS  PubMed  Google Scholar 

  • Naurath HJ, Joosten E, Riezler R, Stabler SP, Allen RH & Lindenbaum J (1995): Effects of vitamin B12, folate, and vitamin B6 supplements in elderly people with normal serum vitamin concentrations. Lancet 346, 85–89.

    Article  CAS  Google Scholar 

  • Nilsson-Ehle H (1998): Age-related changes in cobalamin (vitamin B12) handling. Implications for therapy. Drugs Aging 12, 277–292.

    Article  CAS  Google Scholar 

  • Nilsson-Ehle H, Jagenburg R, Landahl S, Lindstedt S, Svanborg A & Westin J (1991): Serum cobalamins in the elderly: a longitudinal study of a representative population sample from age 70 to 81. Eur. J. Haematol. 47, 10–16.

    Article  CAS  Google Scholar 

  • Nilsson-Ehle H, Landahl S, Lindstedt G, Netterblad L, Stockbruegger R, Westin J & Åhren C (1989): Low serum cobalamin levels in a population study of 70- and 75-year-old subjects. Gastrointestinal causes and hematological effects. Dig. Dis. Sci. 34, 716–723.

    Article  CAS  Google Scholar 

  • Norlund L, Grubb A, Fex G, Leksell H, Nilsson JE, Schenck H & Hultberg B (1998): 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. 36, 175–178.

    Article  CAS  Google Scholar 

  • Nygård O, Refsum H, Ueland PM & Vollset SE (1998): Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland homocysteine study. Am. J. Clin. Nutr. 67, 263–270.

    Article  Google Scholar 

  • Olsson KS, Vaisanen M, Konar J & Bruce A (1997): The effect of withdrawal of food iron fortification in Sweden as studied with phlebotomy in subjects with genetic hemochromatosis. Eur. J. Clin. Nutr. 51, 782–786.

    Article  CAS  Google Scholar 

  • Rasmussen K (1989): Solid-phase sample extraction for rapid determination of methylmalonic acid in serum and urine by a stable-isotope-dilution method. Clin. Chem. 35, 260–264.

    CAS  PubMed  Google Scholar 

  • Rasmussen K & Möller J (2000): Total homocysteine measurement in clinical practice. Ann. Clin. Biochem. 37, 627–648.

    Article  CAS  Google Scholar 

  • Rasmussen K, Moller J, Lyngbak M, Pedersen AM & Dybkjaer L (1996): Age- and gender-specific reference intervals for total homocysteine and methylmalonic acid in plasma before and after vitamin supplementation [see comments]. Clin. Chem. 42, 630–636.

    CAS  Google Scholar 

  • Rothenberg SP (1999): Increasing the dietary intake of folate: Pros and cons. Semin. Hematol. 36, 65–74.

    CAS  PubMed  Google Scholar 

  • Russell RM & Suter PM (1993): Vitamin requirements of elderly people: an update. Am. J. Clin. Nutr. 58, 4–14.

    Article  CAS  Google Scholar 

  • Schumann K (1999): Interactions between drugs and vitamins at advanced age. Int. J. Vitam. Nutr Res 69, 173–178.

    Article  CAS  Google Scholar 

  • Selhub J, Jacques PF, Rosenberg IH, Rogers G, Bowman BA, Gunter EW, Wright JD & Johnson CL (1999): Serum total homocysteine concentrations in the third national health and nutrition examination survey (1991–1994): population reference ranges and contribution of vitamin status to high serum concentrations. Ann. Intern. Med. 131, 331–339.

    Article  CAS  Google Scholar 

  • Solberg HE (1983): The theory of reference values Part 5. Statistical treatment of collected reference values. Determination of reference limits. J. Clin. Chem. Clin. Biochem. 21, 749–760.

    CAS  PubMed  Google Scholar 

  • Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG & Lindenbaum J (1988): Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography–mass spectrometry. J. Clin. Invest. 81, 466–474.

    Article  CAS  Google Scholar 

  • Stolzenberg-Solomon RZ, Miller ER, Maguire MG, Selhub J & Appel LJ (1999): Association of dietary protein intake and coffee consumption with serum homocysteine concentrations in an older population. Am. J. Clin. Nutr. 69, 467–475.

    Article  CAS  Google Scholar 

  • Streeter AM, Shum H-Y, Duncombe VM, Hewson JW & Thorpe MEC (1976): Vitamin B12 malabsorption associated with a normal Schilling test result. Med. J. Aust. 1, 54–55.

    CAS  PubMed  Google Scholar 

  • Ubbink JB, van der Merwe A, Delport R, Allen RH, Stabler SP, Riezler R & Vermaak WJ (1996): The effect of a subnormal vitamin B-6 status on homocysteine metabolism. J. Clin. Invest. 98, 177–184.

    Article  CAS  Google Scholar 

  • Wald DS, Bishop L, Wald NJ, Law M, Hennessy E, Weir D, McPartlin J & Scott J (2001): Randomized trial of folic acid supplementation and serum homocysteine levels. Arch. Intern. Med. 161, 695–700.

    Article  CAS  Google Scholar 

  • Watanabe F, Abe K, Fujita T, Goto M, Hiemori M & Nakano Y (1998): Effects of microwave heating on the loss of vitamin B-12 in foods. J. Agric. Food Chem. 46, 206–210.

    Article  CAS  Google Scholar 

  • Webster SGP & Leeming JT (1979): Erythrocyte folate levels in young and old. J. Am. Geriatr. Soc. 27, 451–454.

    Article  CAS  Google Scholar 

  • Wharton B & Booth I (2001): Fortification of flour with folic acid. BMJ 323, 1198–1199.

    Article  CAS  Google Scholar 

  • Yao Y, Yao SL, Yao SS, Yao G & Lou W (1992): Prevalence of vitamin B12 deficiency among geriatric outpatients. J. Fam. Pract. 35, 524–528.

    CAS  PubMed  Google Scholar 

  • Zimmerman J, Selhub J & Rosenberg IH (1987): Competitive inhibition of folate absorption by dihydrofolate reductase inhibitors, trimethoprim and pyrimethamine. Am. J. Clin. Nutr. 46, 518–522.

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to Recip AB for support of the study and for providing the vitamin and placebo tablets.

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Author notes

  1. C Lewerin, H Nilsson-Ehle, M Matousek, G Lindstedt and B Steen: Contributors: B Steen, H Nilsson-Ehle and M Matousek designed the study. G Lindstedt contributed expertise and supervision on the laboratory assays. C Lewerin, with H Nilsson-Ehle as her tutor, gathered data and was responsible for the statistical calculations and for the preliminary preparation of the manuscript. All authors contributed to revision of the final draft of the manuscript. Recip AB manufactured both the vitamin and placebo tablets.

Authors and Affiliations

  1. Department of Haematology and Coagulation, Göteborg University, Göteborg, Sweden

    C Lewerin & H Nilsson-Ehle

  2. Department of Geriatric Medicine, Göteborg University, Göteborg, Sweden

    M Matousek & B Steen

  3. Department of Clinical Chemistry and Transfusion Medicine, Göteborg University, Göteborg, Sweden

    G Lindstedt

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  1. C Lewerin
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Correspondence to H Nilsson-Ehle.

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Lewerin, C., Nilsson-Ehle, H., Matousek, M. et al. Reduction of plasma homocysteine and serum methylmalonate concentrations in apparently healthy elderly subjects after treatment with folic acid, vitamin B12 and vitamin B6: a randomised trial. Eur J Clin Nutr 57, 1426–1436 (2003). https://doi.org/10.1038/sj.ejcn.1601707

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