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Department of Nutrition, Program in International Nutrition, University of California, Davis, CA;
* Department of Medical Pathology, University of California Davis School of Medicine, Davis, CA;
University of Michigan, School of Public Health, Department of Epidemiology, Ann Arbor, MI
3To whom correspondence should be addressed. No reprints are available. E-mail:lhallen{at}ucdavis.edu.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • vitamin B-12 • homocysteine • dietary intake • serum gastrin • elderly
The reported prevalence of low plasma vitamin B-12 (p-B12)3 concentrations among the elderly ranges from 5 to 40% (1–5), with a higher prevalence of deficient concentrations among Anglos and Latinos compared with African Americans or Asian Americans (5,6). These prevalences are substantially higher than can be explained by the reported prevalence of pernicious anemia or low dietary intake of the vitamin. Reported mean and median vitamin B-12 intakes among the elderly range from 2.5 to 6.0 µg/d (7–9), exceeding the Estimated Average Requirement (EAR) of 2.0 µg/d (10).
The high prevalence of low p-B12 and vitamin B-12 deficiency in the elderly is believed to result from gastric atrophy and the consequent malabsorption of food-bound vitamin B-12 (1,4,11–16). Some 25–35% of elderly with low plasma B-12 concentrations have abnormal protein-bound vitamin B-12 absorption tests (2,17,18). Because of the potential for malabsorption of vitamin B-12 from food, the Institute of Medicine (IOM) recommends that people aged >50 y consume most of their vitamin B-12 from fortified foods or vitamin B-12–containing supplements (10). However, there is little information on the prevalence of atrophic gastritis with aging, or whether these dietary recommendations would be effective.
This research was designed to investigate the prevalence of p-B12 deficiency in a population-based sample of Latino elderly living in the Sacramento, CA area. Potential predictors of p-B12 concentration, including serum gastrin, the amount and source of vitamin B-12 consumed, and use of medications that putatively affect vitamin B-12 absorption, were assessed in a subsample with deficient, marginal and normal p-B12 concentrations. The hypotheses were that there would be a high prevalence of low p-B12 in this population; that gastric atrophy, indicated by elevated serum gastrin, and a history of gastric acid suppressant use would contribute to low p-B12 concentrations; and that crystalline vitamin B-12 intake from supplements and fortified foods, but not total vitamin B-12 intake, would predict higher p-B12 concentrations in those with evidence of gastric atrophy.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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This cross-sectional substudy was conducted in conjunction with the Sacramento Area Latino Study on Aging (SALSA), an epidemiologic cohort study of the relationship between chronic diseases, including type 2 diabetes, and cognitive function and dementia in an Elderly Latino population. Eligible subjects were community dwelling older adults (age > 60 y) of Latino ancestry living in Sacramento, CA and surrounding communities. Census tracts from 1990 and more recent sampling lists from other sources were used to identify areas in which at least 5% of the population was potentially eligible for participation based on age and ethnicity. Subjects were recruited by methods that included mailings, telephone and door-to-door contacts. Of those contacted, 82% enrolled (n = 1789). Age and gender distributions in the final SALSA sample were comparable to those in data collected during a 1998 Sacramento-area dress rehearsal for the 2000 United States Census, and were considered generally representative of the target population (19).
Participants for the substudy of predictors of vitamin B-12 status were recruited from the SALSA population on the basis of their SALSA baseline p-B12 concentration (n = 1546 with available vitamin B-12 data). Written informed consent was obtained from all participants. The Office of Human Research Protection at the University of California, Davis, approved the research protocol. The three groups in this substudy were: deficient (p-B12 < 148 pmol/L or <200 pg/mL), marginal (p-B12 = 148–221 pmol/L or 200–300 pg/mL), and normal (p-B12 > 221 pmol/L or >300 pg/mL) p-B12. All individuals with p-B12 deficiency in the larger SALSA study were recruited into the substudy. A similar number of subjects were randomly selected from those with marginal and normal concentrations, and recruited for the substudy. All SALSA participants identified as having deficient p-B12 (<148 pmol/L) were notified of this fact and referred to their primary health care provider for confirmation of deficiency and treatment.
Data collection.
Demographic information and medical history, including medication use by medicine cabinet inventory, were collected during interviews in the larger SALSA study.
Blood collection and analysis.
In the SALSA population, blood was collected from fasting subjects by venipuncture at baseline into vacutainer tubes with and without EDTA. Sampling took place during a 1.5-y period starting in February 1998. The blood was transported on ice to the University of California Medical Center Clinical Laboratory for processing within 4 h of collection. Plasma and serum were separated and stored frozen at -80°C until analysis.
All SALSA baseline samples were analyzed for p-B12, plasma folate, erythrocyte folate, plasma homocysteine (p-tHcy) and serum methylmalonic acid (MMA). The baseline samples of the substudy participants were also analyzed for serum gastrin. p-B12, folate and serum gastrin were determined in duplicate samples by RIA (Quantaphase II, BioRad Diagnostics, Hercules, CA, and Diagnostic Products, Los Angeles, CA, respectively). Erythrocyte folate was assessed by an automated chemiluminescence assay (ACS 180, Chiron Diagnostics, now Bayer Diagnostics, Tarrytown, NY). P-tHcy was analyzed by HPLC with postcolumn fluorescence detection (20). Serum MMA was analyzed by tandem MS (21). Serum creatinine was measured by standard spectrophotometric assay because elevated p-tHcy and MMA can be caused by impaired renal function. All assays were performed using at least two controls, one high and one low. The cut-off values for abnormal concentrations were as follows: deficient p-B12, <148 pmol/L; marginal p-B12, 148–221 pmol/L; low plasma folate, 
3.0 µg/L; elevated serum gastrin, 
100 ng/L and elevated serum creatinine, >14 mg/L (20).
Diet history and analysis.
Diet histories were taken by face-to-face interview using an abbreviated form of the food list from the Southwest Food Frequency Questionnaire (FFQ), which was developed at the University of Arizona for use in the U.S. Latino population (22,23). The original questionnaire was edited to include only potential sources of vitamin B-12, i.e., animal source foods and fortified beverages and breakfast cereals. The questionnaire referred to the year before the follow-up interview. Portion sizes (small, medium, large) were estimated using actual size pictures of specific weights of foods. Vitamin B-12 intake was calculated using USDA food composition values. Vitamin supplement intake was also assessed by specific questions about the frequency of vitamin B-12 supplement use and the vitamin B-12 content of the supplements.
Data analysis.
Correlations between age and biochemical variables were determined by multiple regression analysis. To examine differences among the vitamin B-12 status groups, continuous variables were analyzed by ANOVA followed by the Tukey-Kramer test for multiple comparisons. The 
2 test was used to analyze categorical variables. Factors explaining p-B12 concentrations were examined using linear regression analysis. A regression model was used to predict p-B12 concentration from intake of vitamin B-12 at a given serum concentration. Values for variables were transformed to conform to assumptions for normality as needed. Values in the text are means ± SD unless otherwise stated. Differences were considered significant if P 0.05. SAS statistical software (SAS Institute, Cary, NC) was used for the analyses.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The mean age of the SALSA population with baseline p-B12 values available (n = 1546) was 70.5 ± 7.0 y; of these, 43% were men. The mean p-B12 concentration was 340 ± 177 pmol/L (461 ± 238 pg/mL). In the sample of 1546 individuals with p-B12 measures, 6.5% had a concentration indicating deficiency, and 16.4% had a marginal concentration. Mean p-tHcy concentrations were 10.9 ± 6.06 µmol/L with 17% having an elevated concentration (>13 µmol/L). Median plasma folate concentration was 33.3 nmol/L (14.7 µg/L) [range 5.25 to >45.3 nmol/L (2.32 to >20 µg/L)] and 0.4% had a low concentration (<6.8 nmol/L, <3.0 µg/L). A low prevalence of folate deficiency was confirmed by the mean erythrocyte folate concentration of 1144 ± 363 nmol/L (505 ± 160 µg/L) and 0.8% low concentrations (<363 nmol/L, <160 µg/L). Older age predicted lower p-B12 (r2 = -0.09, P = 0.0006) and higher homocysteine (r2 = 0.31, P < 0.0001) but not lower plasma folate (r2 = 0.04, P = 0.16) or erythrocyte folate (r2 = -0.03, P = 0.33) (24).
Status of substudy participants.
No differences were found in age or gender among the vitamin B-12 status groups (Table 1). Older age was significantly correlated with higher p-tHcy (r2 = 0.23, P = 0.0018) but not with p-B12 (r2 = -0.06, P = 0.43) or MMA (r2 = 0.13, P = 0.14), plasma or erythrocyte folate (r2 = 0.06, P = 0.40 and r2 = -0.02, P = 0.78) or serum gastrin (r2 = -0.04, P = 0.59). Plasma folate concentration did not differ between status groups. Only one substudy participant had low plasma folate. Mean serum homocysteine and the proportion of elevated concentrations were significantly higher in the deficient p-B12 status group than in the marginal and normal p-B12 groups. MMA was also higher in the deficient p-B12 group than in the marginal and normal p-B12 groups (P < 0.001). The difference between the marginal and normal group was not as great (P = 0.05). The proportion of elevated MMA concentrations was higher in the deficient p-B12 group than in the marginal and normal p-B12 groups (P 0.005). The difference in the proportion of elevated concentrations between the marginal and normal p-B12 groups was also reduced (P = 0.06). Serum gastrin concentration was analyzed for the substudy subjects with available samples (n = 183), and approximately one third of the substudy subjects had elevated concentrations. Mean serum gastrin and the prevalence of elevated concentrations were significantly higher in the deficient p-B12 group compared with both the marginal and the normal p-B12 status groups. The prevalence of elevated serum creatinine did not differ among the vitamin B-12 status groups.
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From the 177 FFQ that were completed, total median dietary intake of vitamin B-12, or vitamin B-12 intake from unfortified foods did not differ among the vitamin B-12 status groups (Table 2). There was also no difference in the proportion of subjects consuming less than the Recommended Dietary Allowance (RDA = 2.4 µg/d) or the Estimated Average Requirement (EAR = 2.0 µg/d) among the groups.
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Intake of vitamin B-12 from supplements and fortified beverages was significantly lower in the deficient p-B12 group than in either the marginal or normal p-B12 groups. Fortified beverages were rarely consumed and included liquid dietary supplements and meal replacements. Vitamin supplement use was common in this population with 55% reporting that they took some vitamin or mineral supplement at least weekly, and usually daily (Table 2). A smaller proportion (43%) of these elderly consumed supplements containing vitamin B-12. The amount of vitamin B-12 in multivitamin supplements clustered around 6 µg (32% n = 63) or 25 µg (25%, n = 63) per pill in multivitamin supplements, and 500 µg per pill (44%, n = 9) in supplements containing only vitamin B-12.
Intake of crystalline vitamin B-12 (from supplements, fortified beverages and fortified cereals combined) was lower in the deficient p-B12 group than in the normal p-B12 group (P = 0.001) and tended to be lower than in the marginal group (P = 0.062). There was a significant difference between status groups in the proportion of subjects consuming less than the RDA or EAR for vitamin B-12 from crystalline sources; a higher proportion of subjects in the normal p-B12 group had intakes that met or exceeded the recommendations (P < 0.0037).
Medication use.
The reported use of histamine H2-receptor antagonists including cimetidine (Tagamet) and ranitidine (Zantac), proton pump inhibitors including omeprazole (Prilosec) and lansoprazole (Prevacid), and the antihyperglycemic agent metformin (Glucophage), did not differ among vitamin B-12 status groups in the substudy (Table 3). This was also true among these p-B12 groups in the SALSA population as a whole, 12–15% of whom took at least one of these drugs, predominantly metformin and omeprazole (data not reported here). There were no differences in p-B12 concentrations or p-tHcy between medication users and nonusers except for unexpectedly higher p-B12 concentrations in cimetidine users (552 ± 280 vs. 459 ± 237 pmol/L, P = 0.0227).
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Plasma vitamin B-12 concentrations were significantly lower in the high gastrin group compared with those with normal gastrin levels. When subjects were compared on the basis of their serum gastrin and p-B12 concentrations, within the deficient p-B12 group, p-B12 was lower (P < 0.05) in those with high vs. normal gastrin, in spite of their slightly higher intakes of crystalline vitamin B-12 (P = 0.076, Table 4).
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Regression coefficients were not different for vitamin B-12 intake from supplements, fortified beverages or fortified cereals, indicating that these were associated similarly with the p-B12 concentrations. For this reason, intake from these sources was combined and described in other analyses as "crystalline vitamin B-12." Crystalline vitamin B-12 predicted p-B12 concentrations across the range of serum gastrin values. The relatively flat slope, indicated by a small regression coefficient (0.046) associated with crystalline vitamin B-12 intake, indicates that within the range of intakes observed, a large change in crystalline intake would lead to relatively small changes in plasma concentrations. In a model assuming a serum gastrin concentration at the 75th percentile (152 ng/L) and a vitamin B-12 intake from food sources equal to the EAR (2.0 µg/d), a projected crystalline vitamin B-12 intake of 575 µg/d would predict an average p-B12 concentration > 221 pmol/L (300 pg/mL). At projected intakes of crystalline vitamin B-12 of 1000 µg/d, the mean plasma concentration would be 227 pmol/L (308 pg/mL). At this level of intake, 48% of this population would have a plasma concentration < 221 pmol/L, and 18% < 148 pmol/L. When the assumptions are changed to include serum gastrin at the 25th percentile (37 ng/L), an intake of crystalline vitamin B-12 of 20 µg/d would predict a mean p-B12 concentration of 223 pmol/L (302 pg/mL).
The relationship between serum gastrin and vitamin B-12 from food was such that as serum gastrin increased, the influence of vitamin B-12 from food on p-B12 was reduced. The contribution of food sources to p-B12 was significant at the 25th percentile (37 ng/L) of serum gastrin, but not at the 50th percentile (55 ng/L).
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Among the vitamin B-12 substudy participants, deficiency occurred in spite of their total dietary vitamin B-12 intakes exceeding the RDA and EAR, and there was no difference in the estimated total vitamin B-12 intake, or intake from unfortified foods, among status groups. This agrees with a previous report in U.S. elderly (26). However, serum gastrin was a significant predictor of lower p-B12 concentrations supporting the hypothesis that food-cobalamin malabsorption is a major cause of low plasma concentrations. The causes of food-cobalamin malabsorption have been reviewed elsewhere (16) and frequently include gastric dysfunction.
Crystalline vitamin B-12 intake (from supplements and fortified foods combined) was a significant predictor of p-B12 concentrations in the substudy, supporting previous reports that supplements and fortified cereal are protective against low p-B12 concentrations in the elderly (8,25–27). Our results, indicating a continuing influence of crystalline vitamin B-12 intake on p-B12 across serum gastrin concentrations, but a decreasing influence of vitamin B-12 from food at higher serum gastrin concentrations, support the findings of Suter et al. (29) who showed that crystalline vitamin B-12 was absorbed equally well by subjects with and without atrophic gastritis, but that the latter group absorbed less protein-bound vitamin B-12. However, our model indicates some decrease in the influence of crystalline vitamin B-12 on p-B12 at high serum gastrin concentrations. Interestingly, in Suter’s subjects who had atrophic gastritis, absorption of the food-bound vitamin was rapidly normalized by antibiotic treatment, indicating that microbial overgrowth played a major role in vitamin B-12 malabsorption.
Higher intakes of crystalline vitamin B-12 appeared to be necessary to maintain adequate p-B12 concentrations when serum gastrin was more elevated. High intakes of crystalline vitamin B-12 from supplements (1000–2000 µg/d) certainly improved vitamin B-12 status in patients with malabsorption (28,30), and 300 µg/d was reportedly sufficient for maintenance after parenteral repletion (31). Tucker et al. (25) suggested that the standard dose (
6 µg) from multivitamins is adequate in a healthy adult population, but this was not the case in an elderly population living in a nursing home (32). The deficient p-B12 group in our substudy had a mean intake of 5.0 µg/d from crystalline sources compared with 9.4 µg/d in the normal p-B12 group. The deficient p-B12 group also had a significantly higher prevalence of elevated serum gastrin than the normal or marginal p-B12 groups. Therefore, the 6 µg supplied by many multivitamin supplements may be inadequate in a population in which there is a high prevalence of food-bound vitamin B-12 malabsorption due to gastric atrophy. This requires further testing.
Elevated serum gastrin is a sensitive predictor of moderate-to-severe atrophy of the gastric body (15) and pernicious anemia (33). Adequate gastric acidity is required for pepsin activity to release vitamin B-12 from proteins in food. In our model, serum gastrin may also be predicting malabsorption because of a lack of intrinsic factor, due either to inadequate production, which can occur in severe atrophic gastritis, or to pernicious anemia. In the absence of intrinsic factor, 1% of a large dose of crystalline vitamin B-12 can be absorbed passively without intrinsic factor (28). The relatively small changes in p-B12 predicted by large increases in crystalline vitamin B-12 intake may be explained by the small percentage of crystalline vitamin B-12 passively absorbed in pernicious anemia.
Low p-B12 concentrations were ameliorated similarly by intake of the vitamin from fortified foods and supplements. The Continuing Survey of Food Intake of Individuals indicates that 3–6% of the vitamin B-12 consumed by adults in the United States comes from fortified cereals (10). Vitamin B-12 from fortified grain products is absorbed efficiently (34). Even though fortified cereals contributed to total intakes for 18% of the substudy population, intakes from this source were low, which may explain why they did not predict p-B12 concentration. A greater use of these foods or higher levels of fortification would protect more of these elderly against vitamin B-12 deficiency.
These analyses are subject to the limitations of self-reported dietary data. FFQ were used here because the accuracy of intake reported by the elderly is better for recognition tasks rather than recall tasks, such as a 24-h dietary recalls (35). Also, foods such as organ meats that are concentrated sources of vitamin B-12 may be consumed relatively infrequently and therefore missed in a 24-h recall or 3-d record. Because a smaller percentage of a high intake of vitamin B-12 is absorbed, the contribution of the vitamin from concentrated sources such as organ meats is potentially overestimated.
Our model may underestimate predicted plasma vitamin B-12 concentrations at high crystalline vitamin B-12 intakes compared with high intakes in intervention studies, due in part to inaccuracy in supplement reporting in our study, and the small number of participants with high intakes. Of the 174 participants 153 had a mean intake of crystalline vitamin B-12 < 100 µg/d. Billion (36) found a post-treatment p-B12 of 674 pmol/L (pretreatment p-B12 = 432 pmol/L) in a group of hemodialysis patients with elevated p-tHcy prescribed 1000 µg oral vitamin B-12/d for 2 mo. After 4 mo of oral treatment with 2000 µg B-12/d, Kuzminski (28) found a mean p-B12 concentration of 740 pmol/L (1005 pg/mL) among a group of previously deficient patients (mean pretreatment p-B12 = 68 pmol/L).
This study could also have been strengthened by a larger sample size, diagnosis of pernicious anemia and separation of atrophic gastritis from pernicious anemia with more precise and sensitive and specific diagnostic methods (15). Although serum gastrin is recognized as a marker of decreased gastric acid production, pepsinogen I (PGI) with serum gastrin and the ratio of PGI to pepsinogen II have been shown to be more sensitive indicators of mild atrophic gastritis than serum gastrin alone (15). Elevated serum gastrin is possible in conditions other than atrophic gastritis, such as Zollinger-Ellison syndrome and gastrin-producing tumors.
Serum gastrin concentrations were not correlated with age in this study. This may be due to the lack of sensitivity of serum gastrin to detect milder degrees of gastric atrophy (15,37) and the fact that all participants were >60 y old. Other studies have presented mixed results on the relationship between age and gastric atrophy or acid production (16,37,38).
Histamine H2-receptor antagonists, proton pump inhibitors and metformin have been shown in some cases to be associated with vitamin B-12 malabsorption (39–46). The relationship appears to depend on the dose and duration of therapy, with little effect seen on vitamin B-12 status with medication use up to 4 y. Our failure to find a significant relationship between medication use and p-B12 concentrations may be due to a lack of statistical power to detect a difference because of the low reported use of these medications, and possibly a relatively short duration of use, although this was not investigated. P-B12 concentrations or p-tHcy did not differ between medication users and nonusers, except for surprisingly higher p-B12 in those who took cimetidine. However, cimetidine is a less effective gastric acid suppressant than ranitidine (47).
In summary, the prevalence of vitamin B-12 deficiency was high in this elderly Latino population. Gastric atrophy, identified by elevated serum gastrin, affected about half of the individuals in the deficient p-B12 group and 20% of those in the other groups. Gastric atrophy was probably causing malabsorption of vitamin B-12 from food, as indicated by the associations among serum gastrin, p-B12 concentrations and food sources of vitamin B-12. Even though serum gastrin did not alter the relationship between p-B12 and intake of crystalline vitamin B-12 in the regression analysis, it did influence the relationship between p-B12 and all dietary sources of vitamin B-12. If serum gastrin is normal, current vitamin B-12 intake from all sources appears to be adequate to maintain mean p-B12 concentrations at normal levels. If serum gastrin is elevated, vitamin B-12 from food sources will not contribute to plasma concentrations, and a relatively high intake of crystalline vitamin B-12 is required to maintain adequate p-B12 concentrations. Given the potential for the adverse hematological and neurological consequences of vitamin B-12 deficiency, and the absence of known adverse effects of high levels of vitamin B-12 intake (10), it may be advisable to target the elderly with vitamin B-12 fortification and supplementation at levels higher than those reported for the deficient and marginal groups in this population.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by U.S. Department of Agriculture grant 5456 and National Institutes of Health grant RO1 AG12975–01.
4 Abbreviations used: EAR, Estimated Average Requirement; FFQ, food frequency questionnaire; IOM, Institute of Medicine; MMA, methylmalonic acid; p-B12, plasma vitamin B-12; p-tHcy, plasma total homocysteine; PGI, pepsinogen I; RDA, Recommended Dietary Allowance; SALSA, Sacramento Area Latino Study on Aging.
Manuscript received 12 February 2003. Initial review completed 4 March 2003. Revision accepted 9 June 2003.
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LITERATURE CITED |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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