Aspirin and folic acid for the prevention of recurrent colorectal adenomas

BACKGROUND & AIMS: Although observational studies have found regular aspirin use to be associated with a reduced risk of colorectal neoplasia, results from randomized trials using aspirin have been inconsistent. Dietary folate intake also has been found to be associated with a reduced risk of colorectal neoplasms in observational studies.

METHODS: A multicenter, randomized, double-blind trial of aspirin (300 mg/day) and folate supplements (0.5 mg/day) to prevent colorectal adenoma recurrence was performed using a 2 x 2 factorial design. All patients had an adenoma (>/=0.5 cm) removed in the 6 months before recruitment and were followed-up at 4-month intervals with a second colonoscopy after approximately 3 years. The primary outcome measure was a colorectal adenoma diagnosed after baseline.

RESULTS: A total of 945 patients were recruited into the study, of whom 853 (90.3%) underwent a second colonoscopy. In total, 99 (22.8%) of 434 patients receiving aspirin had a recurrent adenoma compared with 121 (28.9%) of 419 patients receiving placebo (relative risk, 0.79; 95% confidence interval [CI], 0.63-0.99). A total of 104 patients developed an advanced colorectal adenoma; 41 (9.4%) of these were in the aspirin group and 63 (15.0%) were in the placebo group (relative risk, 0.63; 95% CI, 0.43-0.91). Folate supplementation was found to have no effect on adenoma recurrence (relative risk, 1.07; 95% CI, 0.85-1.34).

CONCLUSIONS: Aspirin (300 mg/day) but not folate (0.5 mg/day) use was found to reduce the risk of colorectal adenoma recurrence, with evidence that aspirin could have a significant role in preventing the development of advanced lesions.

Biomarker responses to folic acid intervention in healthy adults: a meta-analysis of randomized controlled trials

BACKGROUND: The task of revising dietary folate recommendations for optimal health is complicated by a lack of data quantifying the biomarker response that reliably reflects a given folate intake.

OBJECTIVE: We conducted a dose-response meta-analysis in healthy adults to quantify the typical response of recognized folate biomarkers to a change in folic acid intake.

DESIGN: Electronic and bibliographic searches identified 19 randomized controlled trials that supplemented with folic acid and measured folate biomarkers before and after the intervention in apparently healthy adults aged ≥18 y. For each biomarker response, the regression coefficient (β) for individual studies and the overall pooled β were calculated by using random-effects meta-analysis.

RESULTS: Folate biomarkers (serum/plasma and red blood cell folate) increased in response to folic acid in a dose-response manner only up to an intake of 400 μg/d. Calculation of the overall pooled β for studies in the range of 50 to 400 μg/d indicated that a doubling of folic acid intake resulted in an increase in serum/plasma folate by 63% (71% for microbiological assay; 61% for nonmicrobiological assay) and red blood cell folate by 31% (irrespective of whether microbiological or other assay was used). Studies that used the microbiological assay indicated lower heterogeneity compared with studies using nonmicrobiological assays for determining serum/plasma (I(2) = 13.5% compared with I(2) = 77.2%) and red blood cell (I(2) = 45.9% compared with I(2) = 70.2%) folate.

CONCLUSIONS: Studies administering >400 μg folic acid/d show no dose-response relation and thus will not yield meaningful results for consideration when generating dietary folate recommendations. The calculated folate biomarker response to a given folic acid intake may be more robust with the use of a microbiological assay rather than alternative methods for blood folate measurement.

Knowledge about folate and the contribution of nutrient supplements to the intake of folic acid and vitamin B12 in Australian adults in 1995 and 1996

The present paper reports knowledge about folate and the contribution of supplements to the intake of folic acid and vitamin B12 in Australian adults during 1995 and 1996. Data were obtained from two population survey monitor surveys conducted in a sample of 5422 adults in 1995-96. The surveys were designed to complement food intake data from the 1995 National Nutrition Survey and to provide an estimate of total folate intake prior to the implementation of voluntary fortification of foods with folic acid. The proportion with knowledge about folate increased with education level and socioeconomic status and was greater in women than men. It was also greater in those who were married, and in those residing in Western Australia and the Australian Capital Territory than in other states and territories. Five per cent of men and 10% of women had taken a supplement containing folio acid on the previous day. The equivalent figures for vitamin B12 were 7.5% for men and 12.5% for women. On average, intake of folic acid from supplements was 11 micro g per day for men and 28 micro g per day for women and intake of vitamin B12 was 2.6 micro g per day for men and 4.5 micro g per day for women. For individuals who consumed a supplement containing folic acid on the day before the survey the median folic acid contribution was 200 micro g. In 1995 and 1996 only one in two adult Australians had heard of folate and only one in ten women of child-bearing age had taken a supplement containing folic acid.

Assessment of three levels of folic acid on serum folate and plasma homocysteine: a randomised placebo-controlled double-blind dietary intervention trial.

Objective: To determine the minimum effective dose of folic acid required to appreciably increase serum folate and to produce a significant reduction in plasma total homocysteine (tHcy).

Design: Double-blind, randomised placebo-controlled intervention trial.

Setting: Community-based project in a New Zealand city.

Subjects: Seventy free living men and women with tHcy10 µmol/l. Mean age (range) was 58 (29-90) y.

Interventions: Daily consumption over 4 weeks of 20 g breakfast cereal either unfortified (placebo) or fortified with 100, 200 or 300 µg folic acid. Dietary intake was determined by weighed diet records and consumption of commercially fortified products was avoided.

Main outcome measures: Plasma tHcy and serum folate concentrations.

Results: Average serum folate concentrations (95% CI) increased significantly in the treatment groups relative to the control group by 28(9-51)%, 60(37-87)% and 79(51-114)% for supplementation with 100, 200 and 300 µg folic acid, respectively. A reduction in tHcy was observed, being 16(8-22)%, 12(4-18)% and 17(9-24)% in the three treatment groups, respectively.

Conclusions: A regular intake of as little as 100 µg folic acid per day was sufficient to lower tHcy in persons at the upper end of the normal range for tHcy. Low-level fortification may also be appropriate for lowering the risk of neural tube defects given that, when aggregated from all sources, the total intake of folic acid may be sufficiently high to adequately improve the folate status of young women.

Mandatory fortification with folic acid: what would hippocrates say?

In October 2006, the Australian and New Zealand Food Regulation Ministerial Council asked for a review of the proposed food standard permitting mandatory fortification of bread with folic acid. This article contributes to the policy debate associated with the standard’s review by discussing the potential benefits and risks to the target population and the wider Australian population with emphasis on recent (2006) literature.

Examination of selected national policies towards mandatory folic acid fortification

The purpose of this paper is to present an examination of the contrasting policies towards mandatory folic acid fortification in six countries from different regions of the world. Three questions are addressed: 1) What is the policy of the country? 2) Why was the policy adopted? 3) What lessons have been learned? Policy contrasts among countries were assessed as reflecting different interpretations of the potential risks and benefits associated with folic acid fortification. Although commonalities were identified, it was considered unlikely that there could be a standard policy response for all countries. Instead, a country-by-country policy response based on national circumstances is indicated.

The effect of folic acid supplementation on dna biomarkers of colorectal cancer risk (uracil misincorporation, global and gene-specific dna hypomethylation) : a randomised intervention study

Background - Alterations in folate status are associated with colorectal carcinogenesis. Folate’s role has been postulated to be either via prevention of changes in DNA methylation or uracil misincorporation.
Objective - To investigate the effect of folic acid supplementation on colonocyte folate status and DNA biomarkers.
Design - Twenty individuals harbouring colonic adenomas were randomised to receive folic acid (600 g daily) or placebo for 6 months post polypectomy. Systemic and colonocyte folate status was determined at baseline and following the intervention. Modified Comet assays were used to determine uracil misincorporation and global DNA hypomethylation at the site adjacent to the polyp and a site distal to the polyp.
Outcomes - Supplementation resulted in increased colonocyte folate, which approached significance, at the site adjacent to the polyp (P= 0.06) but not distal to the polyp (P= 0.36); correspondingly there was a reduction in uracil misincorporation at the site adjacent to the polyp (P = 0.02) and the distal site showed no such trend (P= 0.39). There were no significant changes in global DNA hypomethylation at either site post-intervention.
Conclusions - Folic acid supplementation resulted in increased colonocyte folate and decreased uracil misincorporation at the site of the adenoma but not distal to the adenoma. This supports the hypothesis that localised areas of folate deficiency may exist in human colonic mucosa which respond to folic acid supplementation through increasing colonocyte folate and improving folate-related DNA biomarkers of cancer risk.

Estimating the impact of mandatory folic acid fortification on the folic acid intake of Australian women of childbearing age

Objective: The primary aim of this study was to estimate the impact of mandatory folic acid (FA) fortification of bread-making flour on the FA intake of Australian women of childbearing age (16-44 years). The secondary objective was to investigate the relationship between estimated FA intake and socio-economic status (SES) and age.

Method: Dietary modelling was used to estimate FA intake under four mandatory fortification scenarios – no supplement use, supplement use unrelated to FA intake, supplement use only among the highest consumers of bread, and increased supplement use. Data were obtained from the 1995 National Nutrition Survey for food intake patterns, the 2007 Victorian Population Health Survey for FA supplement use, and a marketplace survey.

Results: It is estimated that the National Health and Medical Research Council (NHMRC) recommendation for an additional 400 mg/day FA will be achieved by a minimum of 3.9, 25.4, 21.7 and 30% of the target population under scenarios 1-4, respectively. The FA upper level of intake is exceeded by a maximum of 0.1, 1.7, 6.1 and 4.1% of the target population for scenarios 1-4, respectively.

Conclusions: Mandatory FA fortification is not sufficient for the NHMRC recommendations for minimum and maximum intakes to be met by all of the target population under a number of plausible behaviour scenarios.

Implications: Targeted nutrition education campaigns are needed for SES and age sub-groups and research of this nature should be extended to other population groups. Monitoring and evaluation of this policy will be important to ensure appropriate FA intake.