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Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111
3To whom correspondence should be addressed. E-mail: martha.morris{at}tufts.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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20% of participants 
65 y old, serum MMA was >370 nmol/L, the 90th percentile of the distribution of participants aged 30–39 y. Consistent with previous reports, we observed strong, independent positive associations between serum MMA concentration and serum concentrations of creatinine and homocysteine. After controlling for demographic factors and creatinine, geometric mean MMA concentration was lower in non-Hispanic blacks [223.6 nmol/L; 95% confidence interval (CI), 198.8–251.5] than non-Hispanic whites (265.1 nmol/L; 95% CI, 240.3–292.4). However, the prevalence of elevated levels did not vary with race/ethnicity. Serum MMA concentration bore a strong inverse relation to serum vitamin B-12 concentration. Nevertheless, elevated serum MMA concentrations affected 15% of those with both normal serum creatinine concentrations and serum B-12 concentrations >148 pmol/L. We conclude that many elderly Americans demonstrate metabolic evidence of low B-12 status, that elevations occur frequently in the absence of traditional deficiency indicators and that levels vary with race/ethnicity and renal function.
KEY WORDS: • methylmalonic acid • cobalamin deficiency • vitamin B-12 • survey • elderly people
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–5
). This age-related difference was once thought to be of no consequence, because many elderly people with low serum vitamin B-12 concentrations lacked hematologic signs of deficiency (1
,2
,6
,7
). It is now known that hematologic and neurologic abnormalities are inversely correlated in vitamin B-12 deficiency (8
), and that correction of anemia by folate administration can accelerate demyelinization (9
–12
). Another important development is the recognition that clinically important low vitamin B-12 status occurs at serum vitamin B-12 concentrations above the conventionally used cut-off point for deficiency of 148 pmol/L (13
–15
). These cases, with their lower likelihood of diagnosis than cases with classical symptoms, may be particularly susceptible to the most serious sequelae, because consequences may be irreversible when vitamin B-12 deficiency goes untreated (12
,17
–19
). Hence, there is a need for a more sensitive test.
Elevated serum levels of homocysteine (tHcy)4
and methylmalonic acid (MMA) are frequently referred to in the literature as metabolic indicators of vitamin B-12 deficiency (1
,6
,16
,17
,20
–23
). The status of tHcy and MMA as markers of vitamin B-12 deficiency derives from the vitamin’s role as a cofactor for the enzymes methionine synthase and L-methylmalonyl-CoA mutase, which catalyze the conversion of homocysteine to methionine and methylmalonyl-CoA to succinyl-CoA, respectively (24
). The serum MMA concentration is the preferred indicator because, although serum tHcy concentrations can be elevated under circumstances other than low vitamin B-12 status, an elevated serum MMA level is believed to be highly specific for low vitamin B-12 status (1
,5
,8
).
Recent studies of community-dwelling elderly people in various parts of the world have described them in terms of serum MMA concentrations and have examined relationships between serum MMA concentration and other factors (1
,2
,16
,23
,25
). However, no study published thus far has described elderly Americans, in all their ethnic diversity, in terms of their serum MMA concentrations. Furthermore, only two studies have investigated possible relationships between serum MMA concentration and ethnicity (2
,25
), and neither was population based.
The National Health and Nutrition Examination Surveys (NHANES) are specifically designed to obtain nationally representative data on the health and nutritional status of the civilian, noninstitutionalized U.S. population. Furthermore, oversampling of non-Hispanic blacks, Mexican-Americans and the elderly allows for the specific characterization of these population subgroups. Finally, serum MMA concentrations were recently measured in surplus serum samples from participants in Phase 2 (1991–1994) of the NHANES III. Consequently, NHANES III data are the best data available for describing the serum MMA concentrations of elderly Americans and examining possible relationships between serum MMA concentration and other factors.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The NHANES, conducted by the National Center for Health Statistics (NCHS), Centers for Disease Control and Prevention (CDC), obtained nationally representative data on the health and nutritional status of the civilian, noninstitutionalized U.S. population through interviews and direct physical examinations (26
). Toward this goal, some population subgroups (i.e., young children, older persons, blacks and Mexican Americans) were oversampled. All respondents gave their informed consent, and the NHANES III protocol was reviewed and approved by the NCHS NHANES Institutional Review Board. Results presented here pertain to participants in Phase 2 (1991–1994) of the survey (1988–1991), the only phase in which serum concentrations of MMA were measured.
Laboratory measurements.
Blood drawn from subjects across a range of fasting states was processed according to a standard protocol (25
). Measurement of serum concentrations of folate, vitamin B-12 and creatinine, as well as the determination of hematocrit and mean cell volume (MCV), were priority analyses carried out by the central laboratory of the CDC. Serum vitamin B-12 and folate concentrations were measured by commercial RIA kit (Bio-Rad Quanta Phase I and Quanta Phase II; Bio-Rad Laboratories, Hercules, CA). Creatinine was measured by the modified kinetic Jaffe reaction using a Hitachi 737 analyzer (Boehringer Mannheim, Indianapolis, IN). RBC counts were made using a fully automated Coulter S-Plus Jr. hematology analyzer (Coulter Electronics, Hialeah, FL), which measured the mean red cell volume directly, using a process of continuous integration of pulse heights divided by the pulse number. Hematocrits were calculated as the product of MCV and RBC.
Concentrations of MMA and tHcy were measured as phase 2 surplus serum projects carried out at the U.S. Department of Agriculture Human Nutrition Research Center on Aging after approval by the New England Medical Center Human Investigations Review Committee and the Surplus Sera Bank Steering Committee. Surplus sera were stored at -70°C for 
3 y and underwent one to four freeze-thaw cycles before tHcy analyses. tHcy and MMA concentrations have been shown to remain stable in long-frozen samples (27
,28
). In 1994, tHcy concentrations were measured in sera from participants 12 y old by the HPLC method of Araki and Sako (29
). In 1998, MMA concentrations were measured from participants 65 y old (n = 1145), and, for comparison purposes, in a random sample of available sera from participants 30–39 y old (n = 1026). Serum MMA concentrations were measured by gas chromatography/mass spectrometry using the solid extraction method and derivatization with cyclohexanol as described by Rasmussen (30
).
Statistical analyses.
Data were prepared for analyses using SAS (version 8.1; SAS Institute, Cary, NC). All statistical analyses were performed using SUDAAN (version 7.5; Research Triangle Institute, Research Triangle Park, NC) to account for the survey’s staged sampling scheme and unequal probability of subject selection and nonresponse. Differences with P < 0.05 were considered significant for all tests.
To compare the MMA distribution of elderly NHANES III participants to that of the young adult sample, we plotted the sample-weighted percentages of subjects in the two age groups associated with each of 20 equally spaced serum MMA intervals.
We evaluated relationships between serum MMA concentration and serum concentrations of vitamin B-12, folate, tHcy, and creatinine by dividing the elderly subjects into five groups at the 20th, 40th, 60th and 80th percentiles of the various distributions and using multiple linear regression analysis to generate the least-square geometric mean serum MMA concentration associated with each category after controlling for age, gender, and race-ethnicity. We reported P-values for t tests comparing the mean for each category to the mean for the referent (i.e., lowest) category, as well as the P-value for the test for trend over the five categories. We performed the trend tests by modeling the serum concentration as a single term, for which the subject’s value was the median of the quintile category to which the subject belonged. Additional terms were added to the multivariate models to test specific alternatives to the hypothesis that serum MMA and the variable under investigation were related.
We used proportions, as well as geometric least-square means controlled for age, gender, race/ethnicity and serum creatinine concentration, to describe elderly Americans of both genders, two age groups (i.e., 72 y and >72 y), three racial/ethnic categories (i.e., non-Hispanic white, non-Hispanic black and Mexican American), and two serum vitamin B-12 levels (i.e., 148 pmol/L and >148 pmol/L) in terms of serum MMA concentrations and proportion with an elevated MMA level, defined as >370 nmol/L, the 90th percentile of the young adult sample. The proportions were calculated after excluding subjects with serum creatinine concentrations indicative of impaired renal function (i.e., men, >133 µmol/L; women, >115 µmol/L), the principal cause of falsely elevated serum MMA concentrations (19
). We used Wald F-tests from multiple logistic regression analysis to perform between-group comparisons of the odds of an elevated MMA level after controlling for the demographic factors and serum creatinine.
We also studied the relationship between an elevated serum MMA concentration and anemia (defined as hematocrit <0.40 for men and <0.37 for women) and macrocytosis (defined as MCV >95fL) and further explored associations between serum MMA concentration and both renal dysfunction and race/ethnicity. For renal dysfunction, we attempted to identify a range of serum MMA concentrations unlikely to be due to this cause by examining the serum MMA distribution of the 27 elderly NHANES III participants who were in the highest quintile categories for both serum creatinine and serum vitamin B-12, after vitamin/mineral supplement users were excluded. Additionally, we used multiple logistic regression analysis to compare the odds of an elevated serum MMA concentration among three subgroups of elderly NHANES III participants, i.e., those with both serum vitamin B-12 concentrations 148 pmol/L and serum creatinine concentrations within the normal range (n = 44), those with elevated serum creatinine concentrations and a serum vitamin B-12 concentration >148 pmol/L (referent category, n = 151) and those with neither risk factor (n = 936). (Only four elderly subjects had both risk factors.) Finally, to shed more light on racial/ethnic differences in serum MMA concentration, we plotted the sample-weighted percentages of subjects in the three racial/ethnic groups associated with each of the 20 serum MMA categories, after exclusion of subjects with elevated serum creatinine concentrations.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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), half of elderly Americans had serum MMA concentrations >300 nmol/L that were unexplained by renal dysfunction. Values >550 nmol/L, which characterized 4% of elderly Americans, almost never occurred in young adults.
|
. Relationships between serum MMA and serum tHcy and between serum MMA and creatinine concentration were independent. However, the significant relationship we observed between serum MMA concentration and folate status was explained by the association between folate and vitamin B-12 concentrations.
|
. Furthermore, although geometric mean serum MMA concentration was higher in older members of the elderly subgroup compared with younger members, and lower in non-Hispanic blacks than non-Hispanic whites, the percentage of elderly Americans with elevated MMA concentrations did not vary with any demographic factor after controlling for the other demographic factors and serum creatinine concentration. Although the serum MMA concentrations of elderly Americans with serum vitamin B-12 concentrations 148 pmol/L were much higher than those of the group with higher serum vitamin B-12 levels, 15% of elderly Americans with serum creatinine concentrations within the normal range and serum vitamin B-12 concentrations >148 pmol/L had elevated serum MMA concentrations.
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After excluding supplement users, 100% of elderly NHANES III participants in the highest quintile category for both serum creatinine and serum vitamin B-12 had serum MMA concentrations <600 nmol/L; 94% had serum MMA concentrations <500 nmol/L. Furthermore, although the odds of an elevated serum MMA concentration were significantly lower among elderly NHANES III participants with neither an elevated serum creatinine concentration nor a low serum vitamin B-12 concentration than it was among those with evidence of renal insufficiency alone [odds ratio (OR), 0.3; 95% confidence interval (CI), 0.2–0.4], subjects with low serum vitamin B-12 concentrations alone were more than three times as likely as those with evidence of renal dysfunction alone to have an elevated serum MMA concentration (OR, 3.2; 95% CI, 1.2–8.3).
Comparison of the serum MMA distributions of non-Hispanic whites, non-Hispanic blacks and Mexican Americans (Fig. 2
) helps to clarify the finding of low mean serum MMA concentration in non-Hispanic blacks despite similar percentages of elderly non-Hispanic blacks and non-Hispanic whites with elevated MMA concentrations. Specifically, 60% of the MMA concentrations of non-Hispanic whites and Mexican Americans were broadly distributed between 150 nmol/L and 300 nmol/L, and an equivalent proportion of the MMA concentrations of non-Hispanic blacks fell in a sharp peak at between 100 nmol/L and 200 nmol/L. Nevertheless, similar portions of the two curves fell above 370 nmol/L.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,2
,25
). The prevalence of a serum MMA concentration >370 nmol/L was 15.8% among members of the Framingham Study original cohort (1
) and 16.6% among elderly Los Angeles residents with serum creatinine concentrations within the normal range (2
). Our findings are also in line with the report of Stabler et al. (25
) in which 15.8% of elderly, disabled women had serum cobalamin and MMA levels suggestive of cobalamin deficiency. In contrast, studies from Europe reported prevalence estimates that differed substantially among themselves and from those gleaned from American studies. For example, in a small general population study of persons 70 y old conducted in Sweden, the prevalence of an elevated serum MMA concentration was only 9% (16
). In a small German study, however, 23% of younger seniors and 62% of older seniors had elevated serum MMA concentrations (23
).
All studies of community-dwelling elderly including this one have demonstrated inverse relations between serum MMA concentration and serum vitamin B-12 concentration, as well as positive associations between serum MMA concentration and age, serum homocysteine concentration and serum creatinine concentration (1
,2
,16
,23
,25
). Renal dysfunction is recognized as the principal source of falsely elevated serum MMA concentrations (19
), but NHANES III data indicate that levels >500 nmol/L are unlikely to be due solely to this.
Lindenbaum et al. (1
,20
) reported previously that vitamin B-12 deficiency in the elderly is rarely accompanied by hematologic abnormalities. Our findings regarding anemia and macrocytosis support this conclusion. Although these hematologic abnormalities occurred relatively frequently in elderly Americans, 66% of elderly NHANES III participants with elevated serum MMA levels and serum creatinine concentrations within the normal range were neither anemic nor macrocytic.
Racial/ethnic differences in serum MMA concentration are of interest, because African-Americans have higher serum vitamin B-12 concentrations than Caucasians. Data from the NHANES III have also shown Mexican Americans to have higher serum vitamin B-12 concentrations than non-Hispanic whites (3
). Using convenience samples, Carmel et al. (2
) found that African-Americans tended to be less likely than Caucasians and Latin Americans to have elevated serum MMA concentrations, although the difference was not significant. Similarly, Stabler et al. (25
) found lower serum MMA concentrations and a lower frequency of cobalamin deficiency among elderly, disabled African-American women than among a comparable group of Caucasians. In our study, mean serum MMA concentration was significantly lower in non-Hispanic blacks than non-Hispanic whites, but the proportions with elevated serum MMA levels in the two racial/ethnic groups were similar. This would also have been true had we used the definition of Stabler et al. (25
) for "elevated serum MMA concentration," i.e., the combination of a serum cobalamin concentration <258 pmol/L and a serum MMA concentration >271 nmol/L. Furthermore, we did not find clear differences between Mexican Americans and non-Hispanic whites. Thus, although our data generally support the conclusion that the relatively high serum vitamin B-12 concentrations of African-Americans reflect higher tissue vitamin B-12 status, they also suggest that low tissue vitamin B-12 status occurs frequently among elderly African-Americans and Mexican Americans, perhaps because an age-related cause of vitamin B-12 deficiency affects different racial/ethnic groups equally.
In conclusion, our findings for the U.S. population confirm the results of previous investigations showing that elevated serum MMA concentrations are common in the elderly, increase with age, and occur frequently in the absence of traditional deficiency indicators. We have also confirmed positive, independent associations between serum MMA concentration and serum concentrations of creatinine (as an indicator of renal function) and tHcy. Finally, we have shed light on the association between race/ethnicity and serum MMA concentration.
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FOOTNOTES |
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2 The contents of this publication do not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.
4 Abbreviations used: CDC, Centers for Disease Control and Prevention; CI, confidence interval; HNRCA, Human Nutrition Research Center on Aging; MCV, mean cell volume; MMA, methylmalonic acid; NCHS, National Center for Health Statistics; NHANES, National Health and Nutrition Examination Survey; OR, odds ratio; tHcy, total homocysteine.
Manuscript received 7 May 2002. Initial review completed 20 May 2002. Revision accepted 20 June 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Lindenbaum, J., Rosenberg, I. H., Wilson, P. W., Stabler, S. P. & Allen, R. H. (1994) Prevalence of cobalamin deficiency in the Framingham elderly population. Am. J. Clin. Nutr. 60:2-11.
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3. Wright, J. D., Bialostosky, K., Gunter, E. W., Carroll, M. D., Najjar, M. F., Bowman, B. A. & Johnson, C. L. (1998) Blood folate and vitamin B12: United States, 1988–94. Vital Health Stat. 11:1-78.
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16. Bjorkegren, K. & Svardsudd, K. (2001) Serum cobalamin, folate, methylmalonic acid and total homocysteine as vitamin B-12 and folate tissue deficiency markers amongst elderly Swedes—a population-based study. J. Intern. Med. 249:423-432.[Medline]
17. Elin, R. J. & Winter, W. E. (2001) Methylmalonic acid: a test whose time has come?. Arch. Pathol. Lab. Med. 125:824-827.[Medline]
18. Holleland, G., Schneede, J., Ueland, P. M., Lund, P. K., Refsum, H. & Sandberg, S. (1999) Cobalamin deficiency in general practice. Assessment of the diagnostic utility and cost-benefit analysis of methylmalonic acid determination in relation to current diagnostic strategies. Clin. Chem. 45:189-198.
19. Savage, D. G., Lindenbaum, J., Stabler, S. P. & Allen, R. H. (1994) Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am. J. Med. 96:239-246.[Medline]
20. Lindenbaum, J., Savage, D. G., Stabler, S. P. & Allen, R. H. (1990) Diagnosis of cobalamin deficiency: II Relative sensitivities of serum cobalamin methylmalonic acid, and total homocysteine concentrations. Am. J. Hematol. 34:99-107.[Medline]
21. Joosten, E., van den Berg, A., Riezler, R., Naurath, H. J., Lindenbaum, J., Stabler, S. P. & Allen, R. H. (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.
22. Moelby, L., Nielsen, G., Rasmussen, K., Jensen, M. K. & Pedersen, K. O. (1997) Metabolic cobalamin deficiency in patients with low to low-normal plasma cobalamins. Scand. J. Clin. Lab. Invest. 57:209-215.[Medline]
23. Herrmann, W., Schorr, H., Bodis, M., Knapp, J. P., Muller, A., Stein, G. & Geisel, J. (2000) Role of homocysteine, cystathionine and methylmalonic acid measurement for diagnosis of vitamin deficiency in high-aged subjects. Eur. J. Clin. Invest. 30:1083-1089.[Medline]
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25. Stabler, S. P., Allen, R. H., Fried, L. P., Pahor, M., Kittner, S. J., Penninx, B. W. & Guralnik, J. M. (1999) Racial differences in prevalence of cobalamin and folate deficiencies in disabled elderly women. Am. J. Clin. Nutr. 70:911-919.
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