Advertisement
Original article| Volume 132, ISSUE 1, P67-72, July 1998

Methionine loading test is necessary for detection of hyperhomocysteinemia

  • René Van Der Griend
    Correspondence
    Reprint requests: René van der Griend, MD, Department of Internal Medicine, F02.126, University Hospital, Post Office Box 85500, 3508 GA, Utrecht, The Netherlands.
    Affiliations
    Departments of Internal Medicine and Clinical Chemistry Sint Antonius Hospital, Nieuwegein, Netherlands

    Department of Metabolic Disease, University Children's Hospital “Het Wilhelmina Kinderziekenhuis”, Utrecht, Netherlands

    Department of Internal Medicine, University Hospital Utrecht, Utrecht, Netherlands
    Search for articles by this author
  • Fred J.L.M. Haas
    Affiliations
    Departments of Internal Medicine and Clinical Chemistry Sint Antonius Hospital, Nieuwegein, Netherlands

    Department of Metabolic Disease, University Children's Hospital “Het Wilhelmina Kinderziekenhuis”, Utrecht, Netherlands

    Department of Internal Medicine, University Hospital Utrecht, Utrecht, Netherlands
    Search for articles by this author
  • Marinus Duran
    Affiliations
    Departments of Internal Medicine and Clinical Chemistry Sint Antonius Hospital, Nieuwegein, Netherlands

    Department of Metabolic Disease, University Children's Hospital “Het Wilhelmina Kinderziekenhuis”, Utrecht, Netherlands

    Department of Internal Medicine, University Hospital Utrecht, Utrecht, Netherlands
    Search for articles by this author
  • Douwe H. Biesma
    Affiliations
    Departments of Internal Medicine and Clinical Chemistry Sint Antonius Hospital, Nieuwegein, Netherlands

    Department of Metabolic Disease, University Children's Hospital “Het Wilhelmina Kinderziekenhuis”, Utrecht, Netherlands

    Department of Internal Medicine, University Hospital Utrecht, Utrecht, Netherlands
    Search for articles by this author
  • Otger J.A.T.H. Meuwissen
    Affiliations
    Departments of Internal Medicine and Clinical Chemistry Sint Antonius Hospital, Nieuwegein, Netherlands

    Department of Metabolic Disease, University Children's Hospital “Het Wilhelmina Kinderziekenhuis”, Utrecht, Netherlands

    Department of Internal Medicine, University Hospital Utrecht, Utrecht, Netherlands
    Search for articles by this author
  • Jan-Dirk Banga
    Affiliations
    Departments of Internal Medicine and Clinical Chemistry Sint Antonius Hospital, Nieuwegein, Netherlands

    Department of Metabolic Disease, University Children's Hospital “Het Wilhelmina Kinderziekenhuis”, Utrecht, Netherlands

    Department of Internal Medicine, University Hospital Utrecht, Utrecht, Netherlands
    Search for articles by this author
      This paper is only available as a PDF. To read, Please Download here.

      Abstract

      Hyperhomocysteinemia, defined as an elevated concentration of homocysteine in the fasting state or after methionine loading, is an independent risk factor for premature atherosclerosis and venous thrombosis. The role of the methionine loading test (MLT) is, however, controversial. To determine the additional value of the MLT for diagnosis of hyperhomocysteinemia, we prospectively studied 281 patients with premature arterial disease and 148 of their first-degree relatives in the outpatient clinic of a general hospital. Total plasma homocysteine (fasting and 6 hours after methionine loading), folic acid, cobalamin, pyridoxine, and creatinine concentrations were measured. Hyperhomocysteinemia was defined as a fasting homocysteine concentration and/or an increase in homocysteine concentration after methionine loading exceeding the 95th percentile of a healthy control group. Hyperhomocysteinemia was found in 141 (33%) of the 429 subjects: 15% were diagnosed by fasting homocysteine concentration and 18% by MLT. Seventy-eight (55%) of the 141 hyperhomocysteinemic persons were diagnosed only by the MLT. Folic acid was lower in the group with an elevated fasting homocysteine concentration than in those with only an abnormal MLT result (11 versus 15 nmol/L, p = 0.002). Folic acid was significantly negatively correlated, and creatinine significantly positively correlated, with both fasting homocysteine concentration and increase in homocysteine concentration. Negative correlations of cobalamin and pyridoxine with fasting homocysteine concentration were found. In conclusion, the MLT is necessary for diagnosis of hyperhomocysteinemia, because a considerable number of hyperhomocysteinemic persons (55%) remain undiagnosed with the determination of a fasting homocysteine concentration alone.

      Abbreviations:

      HPLC (High performance liquid chromatography), MLT (methionine loading test)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Mudd SH
        • Levy HL
        • Skovby F
        Disorders of transsulfuration.
        in: Scriver CR Beaudet AL Sly WS Valle D The metabolic and molecular bases of inherited disease. 7th ed. McGraw-Hill, New York1995: 1279-1327
        • Fowler B
        • Sardharwalla IB
        • Robins AJ
        The detection of heterozygotes for homocystinuria by oral loading with Lmethionine.
        Biochem J. 1971; 122: 23P-24P
        • Wilcken DEL
        • Wilcken B
        The pathogenesis of coronary artery disease: a possible role for methionine metabolism.
        J Clin Invest. 1976; 57: 1079-1082
        • Boers GHJ
        • Smals AGH
        • Trijbels FJM
        • Fowler B
        • Bakkeren JAJM
        • Schoonderwaldt HC
        • et al.
        Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease.
        N Engl J Med. 1985; 313: 709-715
        • Clarke R
        • Daly L
        • Robinson K
        • Naughten E
        • Cahalane S
        • Fowler B
        • et al.
        Hyperhomocysteinemia: an independent risk factor for vascular disease.
        N Engl J Med. 1991; 324: 1149-1155
        • den Heijer M
        • Blom HJ
        • Gerrits WBJ
        • Rosendaal FR
        • Haak HL
        • Wijermans PW
        • et al.
        Is hyperhomocysteinemia a risk factor for recurrent venous thrombosis?.
        Lancet. 1995; 345: 882-885
        • Fermo I
        • Vigano' D'Angelo S
        • Paroni R
        • Mazzola G
        • Calori G
        • D'Angelo A
        Prevalence of moderate hyperhomocysteinemia in patients with early-onset venous and arterial occlusive disease.
        Ann Intern Med. 1995; 123: 747-753
        • den Heijer M
        • Koster T
        • Blom HJ
        • Bos GMJ
        • Briet E
        • Reitsma PH
        • et al.
        Hyperhomocysteinaemia as a risk factor for deep-vein thrombosis.
        N Engl J Med. 1996; 334: 759-762
        • Stampfer MJ
        • Malinow MR
        • Willett WC
        • Newcomer LM
        • Upson B
        • Ullman D
        • et al.
        A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians.
        JAMA. 1992; 268: 877-881
        • 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
        • Arnesen E
        • Refsum H
        • Bønaa KH
        • Ueland PM
        • Førde OV
        • Nordrehaug JE
        Serum total homocysteine and coronary heart disease.
        Int J Epidemiol. 1995; 24: 704-709
        • den Heijer M
        • Blom HJ
        • Rosendaal FR
        Hyperhomocysteinemia as a risk factor for deep-vein thrombosis.
        N Engl J Med. 1996; 335 ([correspondence]): 975-976
        • Ueland PM
        • Refsum H
        • Brattstrom L
        Plasma homocysteine and cardiovascular disease.
        in: Francis Jr, RB Atherosclerotic cardiovascular disease, hemostasis, and endothelial function. Marcel Dekker, New York1992: 183-236
        • Graham IM
        • Daly LE
        • Refsum HM
        • Robinson K
        • Brattström LE
        • Ueland PM
        • et al.
        Plasma homocysteine as a risk factor for vascular disease.
        in: The European Concerted Action Project. JAMA. 277. 1997: 1775-1781
        • Verhoef P
        • Kok FJ
        • Kruyssen DACM
        • Schouten EG
        • Witteman JCM
        • Grobbee DE
        • et al.
        Plasma total homocysteine, B-vitamins and risk of coronary atherosclerosis.
        Arterioscler Thromb Vase Biol. 1997; 17: 989-995
        • Steegers-Theunissen RPM
        • Boers GHJ
        • Steegers EAP
        • Trijbels FJM
        • Thomas CMG
        • Eskes Tkab
        Effects of sub-SO oral contraceptives on homocysteine metabolism: a preliminary study.
        Contraception. 1992; 45: 129-139
        • Araki A
        • Sako Y
        Determination of free and total homocysteine in human plasma by high performance liquid chromatography with fluoresence detection.
        J Chromatogr. 1987; 422: 43-52
        • Kluijtmans LAJ
        • van den Heuvel LPWJ
        • Boers GHJ
        • Frosst P
        • Stevens EMB
        • van Oost BA
        • et al.
        Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease.
        Am J Hum Genet. 1996; 58: 35-41
        • Bostom AG
        • Jacques PF
        • Nadeau MR
        • Williams RR
        • Ellison RC
        • Selhub J
        Post-methionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine: initial results from the NHLBI Family Heart Study.
        Atherosclerosis. 1995; 116: 147-151
        • Cattaneo M
        • Martinelli I
        • Mannucci PM
        Hyperhomocysteinemia as a risk factor for deep-vein thrombosis.
        N Engl J Med. 1996; 335 ([letter]): 974-975
        • van den Berg M
        • Stehouwer CDA
        • Bierdrager E
        • Rauwerda JA
        Plasma homocysteine and severity of atherosclerosis in young patients with lower extremity atherosclerotic disease.
        Arterioscler Thromb Vasc Biol. 1996; 16: 165-171
        • Franken DG
        • Boers GHJ
        • Blom HJ
        • Cruysberg JRM
        • Trijbels FJM
        • Hamel BCJ
        Prevalence of familial mild hyperhomocysteinemia.
        Atherosclerosis. 1996; 125: 71-80
        • Brattstrom L
        • Lindgren A
        • Israelsson B
        • Andersson A
        • Hultberg B
        Homocysteine and cysteine: determinants of plasma levels in middle-aged and elderly subjects.
        J Intern Med. 1994; 236: 633-641
        • den Heijer M
        • Bos GMJ
        • van der Boor RPGM
        • van Geel AACM
        • Lamers H-J
        • van der Put N
        • et al.
        Mutated methylenetetrahydrofolate reductase and other determinants of plasma homocysteine before and after methionine loading in a general Dutch population.
        in: den Heijer M Hyperhomocysteinemia and venous thrombosis. Leiden University, Leiden1997: 37-55 ([dissertation])