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Relationship Between Methylmalonic Acid, Homocysteine, Vitamin B 12

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Relationship Between Methylmalonic Acid, Homocysteine, Vitamin B 12 European Journal of Clinical Nutrition (2003) 57, 349–357 ß 2003 Nature Publishing Group All rights reserved 0954–3007/03 $25.00 www.nature.com/ejcn ORIGINAL COMMUNICATION Relationship between methylmalonic acid, homocysteine, vitamin B12 intake and status and socio-economic indices, in a subset of participants in the British National Diet and Nutrition Survey of people aged 65 y and over CJ Bates1*, J Schneede2, G Mishra1, A Prentice1 and MA Mansoor3 1MRC Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, UK; 2Department of Pharmacology and Toxicology, University of Bergen, Haukeland Hospital, Bergen, Norway; and 3Department of Clinical Chemistry, Central Hospital in Rogaland, Stavanger, Norway Objective: Assessment of functional vitamin B12 status in a subset of the respondents in the British National Diet and Nutrition Survey of people aged 65 y and over. Setting: National Diet and Nutrition Survey: a British nationwide cross-sectional sample of people aged 65 y and over, living either in the community or in institutions such as nursing homes, during one calendar year spanning 1994 – 1995. Methods: Methylmalonic acid (MMA) concentrations were measured in plasma samples from 313 subjects (ca 14% of those originally enrolled in the survey). The results were compared with those for serum vitamin B12, vitamin B12 intakes and other status and intake estimates and with socio-demographic indices. Results: Of the NDNS participants overall, 20% had serum vitamin B12 concentrations < 150 pmol=l. In the subset studied here, 24% of free-living and 46% of institution-living participants had MMA >0.5 mmol=l. Geometric mean MMA increased with age, from 0.25 mmol=l in people aged 65 – 74 y to 0.38 mmol=l in people aged 85 þ y. There was little evidence for any gender difference in MMA. It was inversely correlated with serum vitamin B12 and with red blood cell folate; it was positively correlated directly with total homocysteine, but not significantly with serum folate or with vitamin B12 intake. Among respondents with high MMA, a subgroup had normal serum vitamin B12 but higher-than-average plasma urea and creatinine. Socio-demographic co-variates of MMA included receipt of State income benefits, social class of head of household, and educational attainment. These indices were not correlated with serum vitamin B12. Conclusions: The progressive increase in MMA with age is metabolic evidence for increasing risk of functional vitamin B12 deficiency with increasing age in older people. There is evidence that renal function is linked to high MMA in some older people. Age and renal function are thus both important when establishing upper reference limits for MMA. The socio-demographic observations suggest a link between poverty and poor functional vitamin B12 status in older British people. Sponsorship: The Department of Health. European Journal of Clinical Nutrition (2003) 57, 349 – 357. doi:10.1038=sj.ejcn.1601540 Keywords: methylmalonic acid; vitamin B12; biochemical status; elderly; national survey *Correspondence: CJ Bates, MRC Human Nutrition Research, Elsie Introduction Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK. E-mail: [email protected] During the past few decades, a number of studies worldwide Guarantor: Dr CJ Bates. have demonstrated the unique value of serum or plasma Contributors: CJB co-ordinated the analyses, contributed to data-analysis and interpretation and drafted the manuscript; JS and MAM performed methylmalonic acid (MMA) as a specific marker of functional the methylmalonic acid analyses and contributed to the interpretation; vitamin B12 status. Following the early studies that demon- MAM performed the homocysteine analyses; GM provided statistical strated the basic relationship between vitamin B12 and MMA advice and AP directed the project in Cambridge, contributed to the in man (Gompertz et al, 1967; Chanarin et al, 1973; Norman study design and contributed to the interpretation. Received 30 October 2001; revised 15 February 2002; et al, 1982; Carmel, 2000), and which established reliable accepted 28 May 2002 assay techniques for MMA (Stabler et al, 1986), were a Functional vitamin B12 status CJ Bates et al 350 number of key studies showing a surprisingly high preva- September 1995, thereby spanning all four seasons. People lence of raised MMA levels in the plasma of older people, living in institutions such as nursing homes were sampled where it appeared to provide a more reliable indicator of separately. Of an eligible sample of 2172 people living in the functional vitamin B12 status than serum or plasma vitamin community, 944 (43%) provided a blood sample. Of a sample B12 concentrations per se (Lindenbaum et al, 1988; Rasmus- of 454 people living in institutions 267 (59%) provided a sen et al, 1989; Moelby et al, 1990; Joosten et al, 1993; Allen & blood sample. The MMA assays were performed on a subset Casterline, 1994; Lindenbaum et al, 1994; Koehler of the blood samples, comprising 256 from free-living sub- et al, 1996; Baik & Russell, 1999; Bjorkegren & Svardsudd, jects and 57 from institution-living ones. 1999; Herrmann et al, 2000). Clearly, the ageing process Demographic, socio-economic and lifestyle information in itself, and the increasing prevalence of age-related was obtained by questionnaire, by a trained interviewer in medical conditions that impair vitamin B12 absorption, the respondents’ homes or institution residence, and the 4 both increase the probability that people will become vita- day weighed diet record was likewise supervised (Finch et al, min B12-deficient as they grow older. Functional deficiency 1998). An early morning, usually fasting, blood sample was may occur even in people whose serum vitamin B12 taken by a trained nurse. Part was sent to a haematology concentrations are in the normal (ie reference) range laboratory; the remainder (with lithium heparin anticoagu- (Joosten et al, 1993). lant) was taken in a cool-box to a local hospital laboratory The relationships between MMA, tHcy and cysteine are for immediate separation and storage of the blood fractions potentially important because both tHcy (Ueland et al, 1992) at 7 40C for up to 3 months and then at 7 80C, for up to and cysteine (Mansoor et al, 1995; El-Khairy et al, 1999) can 5 y. A wide range of status analyses was carried out at the independently predict vascular disease risk, tHcy is increased Micronutrient Status Laboratory, formerly of the MRC Dunn in vitamin B12 deficiency as one among several determi- Nutrition Unit and now part of MRC Human Nutrition nants, and the combination of serum vitamin B12 and Research. Plasma tHcy and cysteine were measured in MMA estimates can therefore be used to distinguish the Dr MA Mansoor’s laboratory in Stavanger, Norway (Mansoor vitamin B12-deficiency-effects on tHcy from those of other et al, 1992; Bates et al, 1997). nutrient deficiencies and influences. MMA was measured by capillary electrophoresis The purpose of the present study was to examine vitamin (Schneede & Ueland, 1995). The local reference range of B12, MMA and their correlates in a sample of older British the assay for non-elderly adults is 0.05 – 0.26 mmol=l and people who participated in a recent National Survey of diet the CV is below 10% for MMA concentration within the and nutrition (NDNS). normal range. About half of the MMA analyses were carried out by Dr J Schneede in Bergen, Norway while the rest were Subjects and methods performed by Dr Mansoor using an identical assay. Those As part of a series of government-commissioned surveys of performed in Bergen included all those with the lowest 3.5% several age-groups of the British population in the final and highest 3.5% of serum vitamin B12 values; those ana- decade of the twentieth century, a survey of people aged lysed in Stavanger were randomly selected from the remain- 65 y and over was carried out in 1994 – 1995 (Finch et al, der. The mean CV% for QC samples with values between 1998; Bates et al, 1999). Estimates of mean daily nutrient 0.05 and 0.51 mmol=l was 7.1% in Stavanger. Good agree- intakes (from a 4 day weighed diet record), a socio- ment was obtained by comparison with a mass spectrometric demographic questionnaire and a fasting blood sample for method performed at the Centers for Disease Control (CDC) biochemical and other status measurements were included. Atlanta, Georgia, USA (CDC-value ¼ 0.013 þ 1.142Â The blood measurements included, inter alia, serum vitamin Stavanger-value, n ¼ 9, r2 ¼ 0.999), and good agreement B12 and serum and red cell folate concentrations, and a with a mass-spectrometric assay was also achieved in separate study examined plasma total homocysteine (tHcy) Bergen. The inter-assay CV in Bergen was 8% at 0.18 and and plasma cysteine concentrations (Bates et al, 1997). For 0.36 mmol=l MMA levels, and the intra-assay CV was < 5%. the present study, measurements of plasma MMA concentra- Participation in an external QA scheme (Moller et al, 1999) tions were performed in two laboratories, on a subset of the provided further evidence of validity and accuracy. To remaining unused plasma samples. These measurements achieve inter-laboratory harmonization between the Stavan- have enabled a comparison to be made with key socio- ger and the Bergen data-sets, 15 of the samples were analysed demographic indices as well as with other biochemical (blind) in both laboratories. These exhibited a log – linear indices of micronutrient status. relationship (r ¼ 0.89) with an intercept indistinguishable The survey plan and procedures have been described in from zero, and a slope which differed significantly (by detail elsewhere (Finch et al, 1998), therefore only a brief 14%) from unity. Therefore the two sets of results, on the summary is included here. A representative cross-sectional log scale, were harmonized to a common mean slope.
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