METABOLIC SIGNS OF VITAMIN B12 DEFICIENCY IN ADULTS WITH LOW B12 AND HIGH FOLATE STATUS
Miller JW, Garrod MG, Allen LH, Haan MN, and Green R. Metabolic evidence of vitamin B-12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin, is more pronounced in older adults with elevated plasma folate. Am J Clin Nutr. 2009;90:1586–1592.
Mandatory fortification of flour with folic acid was initiated in the United States in 1996 to reduce the risk of neural tube defects. However, fortification has come under scrutiny due to the possibility that high levels of folic acid may be associated with progression of tumor growth, inhibition of natural killer cell activity, and changes in epigenetic programming during development. Of particular concern is that an estimated 11% of the US population ingests more than the tolerable upper limit of 1 mg/d folic acid as a result of fortified food consumption in addition to increased use of supplements. Recent work using the NHANES dataset has shown that high folate status in the presence of low vitamin B12 is associated with higher levels of homocysteine and methylmalonic acid and with cognitive impairment relative to normal folate and low B12 status. Given the scope of folic acid fortification and the nature of these findings, more research is needed to confirm these observations. In the present study, Miller et al. assessed the relationship between folate and vitamin B12 status and markers for B12 deficiency. Additionally, comparisons were made between folate and vitamin B12 status and cognitive and depressive status.
Participants were enrolled in the Sacramento Area Latino Study on Aging (SALSA). This cohort includes 1,789 community-dwelling Latino elderly (≥60 y). Baseline enrollment into the study took place between 1998 and 1999, after mandatory fortification had begun. Data reported by Miller et al. include a subset of 1,535 participants with valid plasma vitamin B12 and folate measurements. Participants were categorized into four groups based on low (<148 pmol/L) or non-low (≥148 pmol/L) vitamin B12 levels and non-elevated (≤45.3 nmol/L) or elevated (>45.3 nmol/L) plasma folate levels. Blood samples were analyzed for total plasma homocysteine, methylmalonic acid, holotranscobalamin, and serum creatinine. The ratio of holotranscobalamin to B12 was calculated and expressed as a percentage. Cognitive performance was assessed using the Modified Mini-Mental State Exam and word-list learning tasks. Depressive symptoms were determined using the Center for Epidemiologic Studies Depression Scale. Performance on cognitive tasks and self-reported depressive symptoms did not vary as a function of either folate or vitamin B12 status. In individuals with high folate status in the presence of low vitamin B12 levels, homocysteine and methylmalonic acid concentrations were significantly higher than in the other groups. Holotranscobalamin and the ratio of holotranscobalamin to vitamin B12 were significantly lower in individuals with high folate status in the presence of low vitamin B12 levels relative to the other groups. These changes suggest that metabolic evidence of vitamin B12 deficiency is exacerbated in the presence of high folate in older individuals. The observations regarding holotranscobalamin levels and the ratio of holotranscobalamin to vitamin B12 are novel and suggest that the effects of high folate may alter the relative biovailability of B12. Importantly, only 28–50% of individuals in the high plasma folate groups were taking folic acid in supplement form, indicating it is possible to achieve high concentrations of folate from natural and fortified food sources. The authors suggest that this be taken into consideration by health professionals when making recommendations regarding quantities of supplementary folic acid.
Comment: In an accompanying editorial, Dr. Carmel highlights several considerations relating to the recent observations on high folate and low B12 status. Although the overall rates of the disease are low, pernicious anemia is the primary cause of clinical vitamin B12 deficiency. The negative effects of high folate status with low B12 have thus far only been observed with clinically deficient levels of vitamin B12, not in cases of subclinical deficiency. It is possible that some of the observed effects may be confined to individuals with malabsorptive disease such as pernicious anemia. Another issue is the current focus on measuring cognitive performance while not assessing more specific neurologic functioning. Cognitive testing can be problematic in that there is a plurality of tests used to assess function across a variety of domains, and studies frequently report different findings using different tests. Still, he argues, there are many important questions relating to the nature of vitamin B12 deficiency in the presence of widespread folic acid supplementation and fortification that remain to be answered.
Comment: Carmel R. Does high folic acid intake affect unrecognized cobalamin deficiency, and how will we know it if we see it? Am J Clin Nutr. 2009;90:1449–1550.
LACK OF ASSOCIATION BETWEEN DIETARY POLYUNSATURATED FATTY ACIDS AND ATTENTION-DEFICIT/HYPERACTIVITY DISEASE SYMPTOMS
Ng KH, Meyer BJ, Reece L, and Sinn N. Dietary PUFA intakes in children with attention-deficit/hyperactivity disorder symptoms. Br J Nutr. 2009;102:1635–1641.
Attention-deficit/hyperactivity disorder (ADHD) is one of the most commonly diagnosed psychological disorders in children and is characterized by poor impulse control, poor attention, and hyperactivity. Some research suggests that ADHD may be associated with low dietary intake of long-chain polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid and eicosapentaenoic acid. Long-chain PUFAs are critical in brain development and in ongoing brain functioning. Some studies show improvement of ADHD symptoms following supplementation with PUFA relative to placebo, but thus far evidence is lacking as to whether children with ADHD are consuming low levels of PUFA. The present report by Ng et al. describes PUFA status in children with ADHD and compares intake levels using population-based data on children's PUFA intake.
Eighty-six participants with ADHD between the ages of 6 and 13 years who were not taking fish-oil supplements or stimulant medication were included in this trial. Participants were originally enrolled in an omega-3 fatty acid intervention trial, and baseline data from that trial are reported here. PUFA intake was estimated from 3-day food records. Dietary intakes were recorded on 2 non-consecutive weekdays and 1 weekend day. Participant dietary data were compared with age-matched intake data from the Australian National Nutrition Survey (NNS). Average daily PUFA intake was compared with total ADHD symptoms and individual inattention and hyperactivity scores. In comparison to NNS data, children with ADHD consumed significantly less meat, eggs, fish, and seafood. Total dietary PUFAs, however, did not differ between the groups. No significant associations were seen between ADHD symptoms and PUFA intake.
SESAME SEED SUPPLEMENTATION AND CARDIOVASCULAR DISEASE RISK FACTORS
Wu JHY, Hodgson JM, Puddey IB, Belski R, Burke V, and Croft KD. Sesame supplementation does not improve cardiovascular disease risk markers in overweight men and women. Nutr Metab Cardiovas Dis. 2009;19:774–780.
Diets rich in plant lignans, or dietary phytoestrogens, are associated with reduced risk for cardiovascular disease. One important dietary source of plant lignans is seeds, including sesame seeds. The major lignan contained in sesame seeds, sesamin, is a precursor to the mammalian lignans enterolactone and enterodiol and is hypothesized to have protective effects in cardiovascular disease. Animal studies support this hypothesis, but little research has investigated the role of sesame intake on cardiovascular disease risk factors in humans. In the present intervention trial, Wu et al. provided 25 g/d of sesame seeds to participants with elevated risk of cardiovascular disease.
Overweight men and women (N = 33) were enrolled in a randomized, placebo-controlled, crossover intervention trial. Following an initial 4-week washout period, participants were given either sesame-containing or placebo breakfast bars to eat for 5 weeks. After an intervening 4-week washout period, participants were given the other type of bar for 5 weeks. The breakfast bars were isocaloric and the sesame bar contained approximately 25 g of whole sesame seeds, which contributed 39.5 mg/d sesamin to the diet. The breakfast bars were distinguishable by both taste and appearance. To avoid expectation bias, participants were told the study was examining the effect of different sources of dietary fat and fiber on cardiovascular risk factors. Aside from consuming the breakfast bars in lieu of their normal breakfast, participants were instructed to not otherwise alter their dietary or activity patterns. Outcome measures included urinary excretion of enterolactone and enterodiol, blood pressure, and levels of blood lipids, C-reactive protein, interleukin-6, F2 -isoprostanes, and plasma glucose. Following 5 weeks of sesame supplementation, urinary excretion of enterolactone and enterodiol was significantly elevated relative to placebo; however, no biomarkers for cardiovascular disease risk were altered in the study. The sample size in this trial was small, and although the authors argue that prior research supports the statistical power of the present study, it is possible that the heterogeneity of the study participants contributed to the observed findings. The present findings indicate that supplementation with sesame seed can increase physiological levels of mammalian lignans, but the utility of sesame in cardiovascular disease prevention remains unknown.
SOY FOOD INTAKE AND BREAST CANCER SURVIVAL IN CHINESE WOMEN
Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, and Lu W. Soy food intake and breast cancer survival. JAMA. 2009;302:2437–2443.
Intake of soy foods is epidemiologically linked with reduced risk for breast cancer. Soy foods contain isoflavones, which are phytoestrogens that exert both estrogen-like and anti-estrogen effects. While the anti-estrogen effects of soy are hypothesized to be beneficial in modifying the risk of breast cancer, it is also proposed that the estrogen-like effects of soy foods could promote cell proliferation and cancer recurrence and impact overall cancer survival. Additionally, soy may interact with tamoxifen at the estrogen receptor and there is some concern that intake of soy may antagonize the beneficial effects of tamoxifen treatment. Therefore, the increasing ubiquity of soy foods, soy proteins, and soy isoflavones in commercially available products is a growing concern. The objective of the present study by Shu et al. was to evaluate the effects of soy food intake on breast cancer recurrence and mortality in women diagnosed with breast cancer.
Participants comprised a subset of the Shanghai Breast Cancer Survival Study, which is a longitudinal study of women diagnosed with primary breast cancer between 2002 and 2006. Women between the ages of 20 and 75 years (N = 5,042) were recruited into the study approximately 6 months after their initial diagnosis and were projected to be followed for up to 60 months. The present analysis includes data from participants who completed up to the 36-month interview (n = 4,354) and up to the 60-month interview (n = 1,868). Data collection in this group is ongoing at the time of publication. Dietary intake was assessed using food frequency questionnaires designed to measure consumption of commonly consumed soy foods, including tofu, soy milk, and soybeans, as well as meat, fish, and cruciferous vegetables. Endpoint outcome measures included recurrence of cancer or breast-cancer-related death. Soy food intake was inversely related to cancer mortality or recurrence. This relationship was observed both in estrogen receptor-positive and -negative breast cancer, and in users and non-users of tamoxifen. Reduction in risk was linear and dose-dependent until soy intake reached 11 g/d soy protein, after which no additional benefits were seen. In this population of Chinese women, soy isoflavone intake reached 47 mg/d, which is a significantly greater amount than the 1–6 mg/d consumed by women in the United States. Women in the present trial generally consumed soy in “whole food” form, rather than as isolated isoflavone supplements, and other research has shown positive effects of soy milk or soy protein on menopausal symptoms and reductions in circulating estrogen where isoflavones have had no effect. The present data suggest that consumption of soy foods can have positive effects on breast cancer survival.
Comment: Drs. Ballard-Barbash and Neuhouser address key differences in the patterns of soy isoflavone consumption between the women described by Shu et al. and in typical women in the United States. In China, soy is generally consumed in the form of tofu, soy milk, whole fresh or dried soybeans, and miso or fermented bean pastes. In the United States, soy is typically consumed as supplements, in protein meat substitutes, and in processed foods, although whole soy foods continue to grow in popularity. Ballard-Barbash and Neuhouser caution that clinicians should be aware of differences in the quality of soy foods when advising patients about soy intake, and they should remind patients that the findings reported here are limited to soy foods rather than supplements. They enumerate the strengths of the Shu et al. study, but they note that the follow-up time of 4 years is relatively short and there are likely limitations in the study's power to adequately address subgroups reflecting tamoxifen use or estrogen receptor status. Overall, Drs. Ballard-Barbash and Neuhouser indicate that consumption of soy-containing foods is safe for breast cancer patients and may confer some benefit.
Comment: Ballard-Barbash R, and Neuhouser ML. Challenges in design and interpretation of observational research on health behaviors and cancer survival. JAMA. 2009;302:2483–2484.