Untitled

Colon cancer in Chile before and after the start of the flourfortification program with folic acidSandra Hirsch, Hugo Sanchez, Cecilia Albala, Marı´a Pı´a de la Maza,Gladys Barrera, Laura Leiva and Daniel Bunout Background Folate depletion is associated with an ratio: 2.6, confidence interval: 99% 2.93–2.58) and increased risk of colorectal carcinogenesis. A temporal in the 65–79 years (rate ratio: 2.9, confidence interval: 99% association between folic acid fortification of enriched cereal grains and an increase in the incidence of colorectalcancer in the United States and Canada has, however, been Conclusion Our data provide new evidence that a folate fortification program could be associated with anadditional risk of colon cancer. Eur J Gastroenterol Hepatol Aim To compare the rates of hospital discharges owing to colon cancer in Chile before and after the start of the mandatory flour fortification program with 220 lg ofsynthetic folic acid/100 g of wheat flour.
European Journal of Gastroenterology & Hepatology 2008, 00:000–000 Keywords: cancer, colon, folate, fortification Methods Cancer and cardiovascular hospital dischargerates were compared using rate ratios between two study Aging and chronic diseases program, INTA, University of Chile, Santiago, Chile periods, 1992–1996, before folic acid fortification and2001–2004, after the flour fortification with folic acid was Correspondence to Sandra Hirsch, MD, MSc, INTA, University of Chile, PO Box138-11, Santiago, Chile established in the country. Standard errors of the log rate Tel: + 56 2 9781495; fax: + 56 2 2214030; ratio to derive confidence intervals, and to test the null hypothesis of no difference, were calculated.
Received 13 December 2007 Accepted 29 April 2008 Results The highest rate ratio between the two periodswas for colon cancer in the group aged 45–64 years (rate [2]. In women of reproductive age, serum folate levels Epidemiological and experimental studies have demon- increased from 9.7 to 37 nmol/l [3]. The possible effects strated a relationship between the risk of colorectal of this fortification on CRC incidence have not been cancer (CRC) and alterations of one carbon metabolism, which have a critical function in methylation reactionsand in DNA synthesis and repair. Folate, vitamin B12, B6, Therefore, the aim of this study was to compare the rates riboflavin, choline, betaine, and methionine, each play of hospital discharges because of colon cancer in Chile important roles in this metabolism. Although folate before and after the start of the flour fortification depletion is associated with an increased risk of colorectal carcinogenesis, a temporal association between folic acidfortification of enriched cereal grains and an increase inthe incidence of CRC in the United States and Canada This is a descriptive, population-based study, analyzingcancer and cardiovascular discharge trends in the last 20 In January 2000, the Chilean government initiated a years in Chile, comparing two periods: the period 1992– mandatory program of folic acid fortification, with 220 mg 1996, before folic acid fortification and 2001–2004, after of synthetic folic acid/100 g of wheat flour. This program flour fortification with folic acid was established in the showed a 40% reduction in the rate of neural tube defects in 1 year. In elderly people, who consumed an average of220 g of bread/day, equivalent to 185 g of flour and containing 410 mg folic acid (fortification), serum folate Data were gathered from official sources of information.
levels increased from 162 to 32 nmol/l. Serum folate The trends in cancer and cardiovascular discharges levels reached above 40 nmol/l in 37% of these individuals presented, are based on aggregate data sets collected c 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins European Journal of Gastroenterology & Hepatology routinely by the Chilean Ministry of Health and the were calculated. All statistical analyses were carried out National Institute for Statistics. A form informing about using STATA 7.0 for Windows (STATA Corporation, the length of hospital stay, discharge diagnosis, and condition and occurrence of nosocomial infections, mustbe completed by the treating physician for every patient that is discharged from all public or private hospitals. A The rates of hospital discharges before and after the start patient cannot be discharged unless this form is of the folate fortification program are depicted in Table 1.
completed and rendered to the hospital authorities.
In the group of participants aged 45–64 years, the rate of The Ministry of Health collects, audits, and tabulates hospital discharges owing to colon cancer increased by this information that is universally available. The study 162%. The figures for breast cancer and ischemic heart was approved by Institute of Nutrition and Food disease were 108 and 43%, respectively. Discharges owing to hypertensive disease decreased by 16% and thoseattributable to cerebrovascular disease and gastric cancer did not change in the two periods. In the group of Cancer and cardiovascular hospital discharges by age participants aged 65–79 years, colon, breast, and gastric group were defined according to the International cancer discharges increased by 190, 90, and 17%, Classification of Diseases (ICD). Discharge causes by respectively. Discharges because of ischemic and cere- age group, were published according to the detailed list of brovascular diseases increased by 27 and 6%, respectively, 999 causes of the ICD, Ninth Revision (ICD-IX) [4], and decreased by 12% owing to hypertensive diseases.
from 1992 to 1997 and according the ICD, Tenth The highest rate ratios between the two periods were Revision (ICD-X), since 1997 [5]. Both revisions were observed for colon cancer in the groups of participants rendered compatible, for the purpose of this study. Age- aged 45–64 and 65–79 years (rate ratio: 2.6, confidence specific discharge rates for colorectal, breast, gastric interval: 99% 2.93–2.58 and rate ratio: 2.9, confidence cancer, ischemic, hypertensive, and cerebrovascular dis- interval: 99% 3.25–2.86, respectively) (Figs 1 and 2).
eases are presented as two periods (period 1: 1992–1993–1996 and period 2: 2002–2004) to stabilize rate compar- The mortality trends for breast, colorectal, and gastric isons. The years used corresponded to those in which the cancer, were similar to those observed for hospital information was complete and audited. Cancer and discharge, but fail to reach statistical significance as cardiovascular hospital discharge rates were compared using rate ratios between the two periods. Mortality ratesfor breast, colorectal, and gastric cancer, in the same period were used to validate whether the information This study finds a temporal relationship between folate provided by hospital discharge is a reflection of disease supplementation and a rise in CRC hospital discharge rate. One possible explanation for this finding is that thisincrease is causally related to folate supplementation. In Standard errors of the log rate ratio to derive confidence Chile, the rates of hospital discharges attributable to intervals, and to test the null hypothesis of no difference, colon cancer showed a rise after the start of the folic acid Rates of hospital discharge causes by age group (per 100 000 inhabitants) before and after the start of the mandatory flour fortification program with 220 lg of synthetic folic acid/100 g of wheat flour CI, confidence interval; ICD, International Classification of Diseases.
Colorectal cancer and folic acid Hirsch et al.
Rate/ratio of hospital discharge because of colon cancer in adults aged Mortality rate/ratio for colorectal, breast, and gastric cancer before and 45–64 years, before and after the start of the mandatory flour after the start of the mandatory flour fortification program with 220 mg of fortification program with 220 mg of synthetic folic acid/100 g of wheat synthetic folic acid/100 g of wheat flour. Rate /ratios are expressed as flour. Rate /ratios are expressed as the rate for each year/the rate for the rate for each year/the rate for 1992.
tion with 1 mg of folic acid during 5 years was associatedwith a tendency to increase the risk of advanced lesions and in adenoma multiplicity. Moreover, a higher rate of non-CRCs, owing to an excess of prostate cancer, was observed among participants allocated to the folic acid group [6]. Another randomized trial of folic acid supplementation in combination with B vitamins for vascular disease suggested that treatment with these vitamins increased the risk of colon cancer and did notreduce the risk of major cardiovascular events [7]. A decreased risk of CRC among patients with low folatestatus was also reported [8].
In animal models, there are evidences that supplementa-tion with folic acid has a promoting effect on carcinogen- esis [9], and that folate deficiency reduces the development of CRC [10] and ileal polyps [11]. In neoplastic cell cultures, interruption of folate metabolism Rate/ratio of hospital discharge because of colon cancer in adults aged generates an inhibition of tumoral cell replication, as a 65–79 years, before and after the start of the mandatory flour result of ineffective DNA synthesis [12–14]. This is the fortification program with 220 mg of synthetic folic acid/100 g of wheat basis of antifolate agent used for cancer chemotherapy in flour. Rate /ratios are expressed as the rate for each year/the rate for1992.
These results are in conflict with earlier epidemiologicalresults from cohort and case–control studies, showing an fortification program. These results are consistent with inverse association among colon adenomas, CRC, and the increase in CRC incidence that occurred in Canada plasma folate levels [15]. Most of these studies were, and the USA, after the mandatory folic acid fortification, however, conducted among individuals not taking multi- recently reported by Mason et al. [1]. These evidences vitamins or in deficient populations. In addition, there are raise a concern that there is a temporal relationship experimental evidences suggesting that folate deficiency between folic acid overload and risk of CRC. In the in normal tissues promotes the development of neoplastic aspirin–folate polyp prevention trial, folate supplementa- European Journal of Gastroenterology & Hepatology In our study, we also observed an increase in hospital necessary to prevent neural tube defects and to minimize discharge rates for breast cancer, after the start of folate fortification, but of lesser magnitude than that of coloncancer. This increase may, however, be related to a program for early detection of breast cancer and to the This study was supported by FONDECYT Grant fact that in the same period (2000) the government started a program of integral system of healthcare (AccesoUniversal con garantı´as explicitas en salud) that guaran-teed universal access to breast cancer treatment. There- fore, these programs may have triggered the higher Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G,Rosenberg IH. A temporal association between folic acid fortification and an discharge rates for breast cancer. Up to the moment, increase in colorectal cancer rates may be illuminating important biological however, CRC diagnosis and treatment are not included principles: a hypothesis. Cancer Epidemiol Biomarkers Prev 2007; Hirsch S, de la Maza P, Barrera G, Gattas V, Petermann M, Bunout D.
The Chilean flour folic acid fortification program reduces serum Other explanations to understand the boost in the homocysteine levels and masks vitamin B-12 deficiency in elderly people.
J Nutr 2002; 132:289–291.
discharge rates for colon and breast cancer in the last Hertramf E. Cortes F Folic acid fortification of wheat flour: Chile. Nutr Rev years could be an increase in the incidence of risk factors 2004; 62:S44–S48; discussion S49. Review.
such as obesity, low intake of fiber, calcium, and high PAHO/WHO. International Classification of Diseases. 9th Revision 1975.
Scientific Publication 353-A, Washington, DC intake in fat and red meat. The prevalence of obesity WHO. International Classification of Diseases. 10th Revision XXX. Scientific increased from 19.7% in 1997, to 22% in 2003 [17].
Unfortunately, we do not have data of other attributable Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS,et al. Polyp Prevention Study Group. Folic acid for the prevention of risk of these factors, but according to the Food and colorectal adenomas: a randomized clinical trial. J Am Med Assoc 2007; Agricultural Organization data, the supply of calories and Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, protein have not changed significantly in the last period.
et al. Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators.
Homocysteine lowering with folic acid and B vitamins in vascular disease. NEngl J Med 2006; 354:1567–1577.
Folic acid fortification program had an effect on homo- Van Guelpen B, Hultdin J, Johansson I, Hallmans G, Stenling R, Riboli E, cysteine levels, as reported previously [2]. We therefore et al. Low folate levels may protect against colorectal cancer. Gut 2006; expected a decline in the rates cardiovascular disease, as Kim Y-I. Folate, colorectal carcinogenesis and DNA methylation: lessons hyperhomocysteinemia is considered as a cardiovascular from animal studies. Environ Mol Mutagen 2004; 4:10–25.
risk factor [18,19] The discharge rates for cardiovascular Le Leu RK, Young GP, McIntosh GH. Folate deficiency reduces the diseases, however, did not change in the two study development of colorectal cancer in rats. Carcinogenesis 2000; 21:2261–2265.
periods. This is consistent with folic acid supplementa- Song J, Medline A, Mason JB, Gallinger S, Kim YI. Effects of dietary folate tion trials that have not reported a reduction in the n intestinal tumorigenesis in the apcMin mouse. Cancer Res 2000; incidence of cardiovascular events [20,21].
Kim Y-I. Folate and carcinogenesis: evidence, mechanisms, and implications.
J Nutr Biochem 1999; 10:66–88.
There is no cancer registry in Chile. Therefore, the only Rosen F. Nichol Ca Inhibition of the growth of an ame-thopterin-refractorytumor by dietary restriction of folic acid. Cancer Res 1962; 22:495–500.
means to study the impact of fortification on CRC Keyes MK, Jang H, Mason JB, Liu Z, Crott JW, Smith DE, Friso S, Choi SW.
incidence is to use indirect data. As a form indicating the Older age and dietary folate are determinants of genomic and p16-specific diagnosis and other variables must be completed for every DNA methylation in mouse colon. J Nutr 2007; 137:1713–1717.
Giovannucci E. Epidemologic studies of folate and colorectal neplasia: discharge from every hospital in Chile, this information, a review. J Nutr 2002; 132:2350s–2355s.
that is, complete and reliable, can be used as a proxy for Knock E, Deng L, Wu Q, Leclerc D, Wang XL, Rozen R. Low dietary folate disease incidence. Thus, we used it to study the trends in initiates intestinal tumors in mice, with altered expression of G2-Mcheckpoint regulators polo-like kinase 1 and cell division cycle 25c. Cancer the incidence of CRC and compare it with that of other diseases as a control. The changes in disease frequency Vio F, Albala C, Kain J. Nutrition transition in Chile revisited: mid-term detected using hospital discharge data, coincided with evaluation of obesity goals for the period 2000–2010. Public Health Nutr.
2008; 11:405–412.
mortality trends for breast, colorectal, and gastric cancer.
Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, et al.
This coincidence gives further support to the validity of Hyperhomocysteinemia: an independent risk factor for vascular disease.
hospital discharge data as a proxy for disease incidence.
Bostom AG, Silbershatz H, Rosenberg IH, Selhub J, D’Agostino RB, WolfPA, et al. Nonfasting plasma total homocysteine levels and all-cause andcardiovascular disease mortality in elderly Framingham men and women.
In summary, our data provide new evidence that a folic Arch Intern Med 1999; 159:1077–1080.
acid fortification program with 220 mg of synthetic folic Woodman RJ, Celermajer DE, Thompson PL, Hung J. Folic acid does not acid/100 g of wheat flour could be associated with an improve endothelial function in healthy hyperhomocysteinaemic subjects.
Clin Sci (Lond) 2004; 106:353–358.
additional risk of colon cancer. Thus, we need to evaluate Wierzbicki AS. Homocysteine and cardiovascular disease: a review of the this finding to determine the amount of folic acid evidence. Diab Vasc Dis Res 2007; 4:143–150.
LIPPINCOTT
WILLIAMS and WILKINS
JOURNAL NAME: MEG
ARTICLE NO:
QUERIES AND / OR REMARKS
Details Required
Author's Response

Source: http://www.centronut.cl/documentos/documentos/Acido_folico.pdf