Folic Acid: Health Benefits and

Disease Risk Reduction

New perspectives on benefit and risk

Namsoo ChangDept. of Nutritional Science and

Food Management

Ewha Womans University

IADSA Scientific Forum 2009Moscow, Russia, June 17, 2009

Folic Acid: Health Benefits and Disease Risk Reduction

• Chemistry, function, metabolism

• Dietary intake, adverse effects

• Diseases associated with folate and Hcy

New perspectives on benefit and risk

• Diseases associated with folate and Hcy

• Review of studies on the use of folic acid

• Conclusion

IADSA Scientific Forum 2009Moscow, Russia, June 17, 2009

Folic acid and one-carbon units

• Methylene tetrahydrofolate(CH2=THF) is formed from tetrahydrofolate by the addition of methylene groups from one of three carbon donors: formaldehyde, serine, or glycine.

• Methyl tetrahydrofolate (CH3-THF) can be made from methylene

5

10

6

7

can be made from methylene tetrahydrofolate by reduction of the methylene.

• Formyl tetrahydrofolate (CHO-THF) is made by oxidation of the methylene tetrahydrofolate.

R• N5 formyl THF -CHO• N10 formyl THF -CHO• N5 formimino THF -CH=NH• N5,10 methenyl THF >CH• N5,10 methylene THF >CH2• N5 methyl THF -CH3

7

8

F → DHF → THF

THF → CH2-THF → Formyl-THF ↔ Methenyl-THF ↔ Methylene-THF → Methyl-THF

Dietary Folate Equivalents (DFE):

• Most food folates are peterolypolyglutamates

(1∼6 additional glutamate molecules)

• Folic acid is the most oxidized form of folate (rare in food,

form used in vitamin supplements & fortified food products)

• Bioavailabilities are different

• 1 µg of food folate provides 1 µg of DFE

• 1 µg of folic acid taken with meals or as fortified food

provides 1.7 µg of DFE

• 1 µg of folic acid (supplement) taken on an empty

stomach provides 2 µg of DFE

• Bioavailabilities are different

Food sources, dietary intake

Folate intake of

Russian Federation:Russian Federation:

∼ 162µg/1000kcal

(estimation by the food

disappearance data,

Greece 259 µg/1000kcal,

Japan 244 µg/1000kcal)

Connor, et al., JADA 2004

Connor, et al., JADA 2004

Adverse effects, ULs

• Neurological effects: masking vitamin B12

deficiency leads to neurological damage

• Upper levels for folate: 1,000 ㎍/d for

ages 19 years and older (including ages 19 years and older (including

pregnant or breastfeeding women).

Folate metabolism

Function

• DNA synthesis

• Purine synthesis

• Generation of formate into the formate pool• Generation of formate into the formate pool

• Interconversions of amino acids

• Regeneration of methionine, precursor of the

physiological methyl donor, S-adenosylmethionine

(SAMe)

Selected folate and homocysteine-related

genetic polymorphisms

• MTHFR (5,10-Methylene tetrahydrofolate reductase): C677T (ala222val), A1298C

• MTR(Methionine synthase): A2756G

• MTRR (Methionine synthase reductase) A66G• MTRR (Methionine synthase reductase) A66G

• MTHFD1 (5,10-Methylene tetrahydrofolate dehydrogenase): G1958A

• BHMT (Betaine homocysteine methyltransferase)

• CBS (Cystathionine β synthase)

• CTH (Cystathionine γ lyase)

• eNOS (Endothelial nitric oxide synthase): G894T(glu298asp)

METHIONINEMETHIONINE

SS--ADENOSYLADENOSYL--METHIONIEMETHIONIE

SS--ADENOSYLADENOSYL--HOMOCYSTEINEHOMOCYSTEINE

N,NN,N--DIMETHYL DIMETHYL GLYCINEGLYCINE

BETAINBETAIN

BHMTBHMT

TETRAHYDROFOLATETETRAHYDROFOLATE

55--METHYLMETHYL--TETRATETRA--HYDROFOLATEHYDROFOLATE

MTHFRMTHFR

MTHFD1MTHFD1

MTRMTR

MTRRMTRR

5,105,10--METHYLENEMETHYLENE--TETRAHYDROFOLATETETRAHYDROFOLATE

C677TA1298C

G1958A

A2756G

HOMOCYSTEINEHOMOCYSTEINE

CYSTATHIONINECYSTATHIONINE

CYSTEINECYSTEINE (SO(SO44))22--

CBSCBS

HYDROFOLATEHYDROFOLATE

CTHCTH

Selected folate and homocysteine-related genetic polymorphism

I.GuidiI.Guidi et et al.Neurobiologyal.Neurobiology of Aging 26 (2005)789of Aging 26 (2005)789--794794

G1364T

Others:

eNOS (Endothelial nitric oxide synthase):

G894T(glu298asp)

Diseases associated with folate and

homocysteine-related genetic polymorphisms

Genetic polymorphisms Diseases and conditions

• MTHFR C428T Severe MTHFR deficiency, cerebrovascular disease, developmental delay

• 〃 C677T NTD, CHD, CVD, DM, late onset AD, mood disorder, triosmy 21, placental abruptio, peripheral arterial disease, Cushing, lymphoma, leukemia, colorectal cancer, cervical cancer, venous thromboembolism, cancer, cervical cancer, venous thromboembolism, ↓DNA methylation, ↓ ACE inhibitor response

• 〃 A1298C Protective for LBW

• MTHFD1 G1958A Abruptio placenta

• MTRR A66G Down syndrome

• MTR A2756G Hypertension, ACE inhibitor response

• CBS, CTH G1364T ↑Hcy

• eNOS G894T Venous thrombosis, AD

Diseases or conditions associated with folate

• Megalobastic anemia

• NTD, birth defects, pregnancy complications

• Heart disease, stroke, vascular diseases,

hyperhomocysteinemia , AMD, hearing losshyperhomocysteinemia , AMD, hearing loss

• Cancer: colorectum, breast, cervix, endometrium, esophagus,

stomach, pancreas

• Cognitive performance, depression, AD

• Osteoporosis and fracture

• Arsenic poisoning

The list grows ………….

Folic acid fortification and NTD (Canada)

Figure 1. Prevalence of Neural-Tube Defects, According to Diagnostic Category, in Seven Canadian Provinces from 1993 through 2002.

De Wals et al. NEJM.357:135-142 (2007)

Folic acid supplements and NTD (China)

• Subjects: 347,831 women (130,142 women took folic acid, 117,689 women did not)

• Dosage and duration: 400 ㎍ from the time of premarital examination until the end of first trimester

• NTD rates

Berry et al. NEJM.341:1485-1490 (1999)

• NTD rates

Baseline: 1.0/1000 (south) and 4.8/1000 (north)

After supplements: 0.6 (south) and 1.0 (north)

• The greatest reductions in women of northern region with periconceptional use of folic acid pills more than 80% of the time

Folic acid and facial clefts (Norway study)

Wilcox et al. BMJ 3;334(7591):464, Epub 2007

� Folic acid supplementation (400µg/d) during early pregnancy was associated with a

reduced risk of cleft lip by about a third.

Table 2. Changes in birth prevalence of severe, conotruncal and non-conotruncal, congenital heart defects (CHD) before (1990-8) and after (1999-2005) mandatory fortification of flour and pasta products with folic acid. Birth prevalence shown with 95% confidence intervals

Folic acid fortification and congenital heart defects

Time trends in birth prevalence of severe congenital heart disease before and after 1 January 1999 cut off (see methods) representing introduction of mandatory fortification of flour and pasta products with folic acid (vertical grey bars), including (top) and excluding (bottom, sensitivity analysis) year 2005. Time trends estimated in each period by Poisson regressionwith calendar time as independent variable

Raluca Ionescu-Ittu, et al., BMJ, 2009

Folic acid supplementation and NTDs(An update of the evidence for USPSTF)

• Purpose: To search for new evidence published since 1996 on the

benefits and harms of folic acid supplementation for women of

childbearing age to prevent NTDs in offspring.

• Conclusion: New observational evidence supports previous • Conclusion: New observational evidence supports previous

evidence from a RCT that folic acid-containing supplements reduce

the risk for NTD-affected pregnancies. The association of folic acid

use with twin pregnancies may be confounded by fertility

interventions.

Ann Intern Med, 2009

Steady state folate concentrations: comparison of 5 to 1.1mg folic acid

When compared 5 to 1.1mg folic acid

supplementation, steady state folate

concentrations achieved with 5 mg folic

acid were greater among women of

childbearing age

Plasma folate

Needs for individualized counselingNeeds for individualized counseling�Low folate statusFor women at risk for suboptimal folate

status (RBC folate <906µmol/L), 5mg

rather than 1mg folate is recommended

for the preventions of NTDs

Nguyen, et al., AJCN 2009

RBC folate

Folate and colorectal cancer

Cohort

Figure 1. Estimated relative risks and 95% confidence intervals of colorectal cancer associated with dietary and total folate intake (folate from foods and folate from foods plus supplements, respectively) among cohort and case-control studies

Sanjoaquin et al. Int J Cancer 2005;113:825

Case- control

Association of folate intake and breast cancer

Ericson et al, Am J Clin Nutr. 86:434-443 (2007)

Association of folate intake and breast cancer

Ericson et al, Am J Clin Nutr. 86:434-443 (2007)

B vitamin supplementation on

cancer risks in women

• Women (n=5,442) enrolled in WAFACS trial

• B vitamin supplementations for 7.3 y

• No significant effect on overall risk of total invasive • No significant effect on overall risk of total invasive

cancer or breast cancer among women during the

folic acid fortification era.

Zhang, et al., JAMA, 2008

Folate supplemention and Colorectal Adenomas

• Aspirin/Folate Polyp Prevention Study

• Diet and supplement use by FFQ

• Protective association of the highest tertile of dietary and

total intake as well as circulating folate with risk of any

adenomas among those in the placebo group (not in the adenomas among those in the placebo group (not in the

treatment group)

• Although moderate doses of folate may be protective

compared with deficiency, at some point of sufficiency,

supplementation provides no additional benefit.

Figueiredo, et al., CEBP, 2008

�Baseline dietary and circulating folate levels

Folic acid (5mg for 3 y) supplementation

folic acid inhibits recurrence of colorectal

adenomas

Recurrence rate 0.36 vs 0.82

Jaszewski, et al., World J Gastroenterol 2008

�Patients below 70 years of age and those with left-sided

adenomas or advanced adenomas responded better to folic acid

supplementations

Actual and estimated age-adjusted stroke mortality per 100 000 in the United States and Canada and in England and Wales, 1990 to 2002

Folic acid fortification and stroke

Men Women

Copyright ©2006 American Heart AssociationYang, Q. et al. Circulation 2006;113:1335-1343

FIGURE 2. Change (and 95% CIs) in the percentage of flow-mediated dilatation (%FMD) due to folic acid supplementation per included intervention group and the overall estimated change

(and 95% CI)

Folic acid and vascular reactivity

Copyright ©2007 The American Society for Nutritionde Bree, A. et al. Am J Clin Nutr 2007;86:610-617

Beneficial for small artery elasticity

Mashavi et al., Atherosclerosis, 2008

Mashavi et al., Atherosclerosis, 2008

�Beneficial for small artery elasticity

B vitamin supplementation and

subclinical atherosclerosis

• Double-blind clinical trial

• Subjects: 506 participants, 40-89 years, tHcy >8.5µmol/L, no DM,

CVD

• Dosage: 5mg folic acid+ 0.4mg vitamin B12+ 50mg vitamin B6• Dosage: 5mg folic acid+ 0.4mg vitamin B12+ 50mg vitamin B6

• Duration: 3.1 years

• Results: tHcy 9.5→8.8 µmol/L, folate 9.7 →75.4 ng/mL,

vitamin B12 400 →748 pg/mL, vitamin B6 65 →350 pmol/mL

Hodis, et al., Stroke 2009

�Timing (stage): Beneficial for subclinical atherosclerosis

Table CIMT progression by treatment group

Hodis, et al., Stroke 2009

Conclusions: Compared to the placebo, low average rate of the CIMT (carotid artery intima thickness) progression rate among the vitamin B-supplemented group of

participants with high tHcy (>9.1 µmol/L) �Baseline circulating homocysteine levels

Folic acid supplementation on hearing

Durga et al. Arch Intern Med.146:1-9 (2007)

Age-related macular degeneration

• The Women’s Antioxidant and Folic Acid

Cardiovascular study (WAFACS)

– Subjects: 5,205 women > 40 yr

– Dosage: – Dosage: • Folic acid 2.5mg/d

• Pyridoxine-HCl (50mg/d)

• Cyanocobalamine 1mg/d

– Duration: 7.3years

– Outcome measures: Total AMD

Visually significant AMD

Christen, et al., Arch Intern Med, 2009

RR: 0.59 (CI, 0.36-0.95)

Christen, et al., Arch Intern Med, 2009

RR: 0.66 (CI, 0.47-0.93)

Daily supplementation with combined B vitamins may reduce the risk of AMD.

Folic acid supplementation on cognitive function

(800 µg/d for 3 years, n=818)

Durga et al, Lancet. 369(9557):208-216 (2007)

Short-term memory, mental agility and verbal fluency were all

found to be better among people who took 800 µg of folic

acid than those who took placebo

Association between plasma folate and

cognitive performance

• Rotterdam Scan Study: n=1,033, aged 60-90yr

• Increasing plasma folate was associated with higher scores

for global cognitive function and psychomotor speed

• The volume of subcortical white matter lesions (WML) and • The volume of subcortical white matter lesions (WML) and

the presence of severe WML (cerebral small vessel

damages) decreased with increasing plasma folate

de Lau et al, AJCN 2007;86:728

�Cerebral small vessel diseases are responsive to folate status

B vitamin supplementation and

cognitive function

• Women’s Antioxidant and Folic Acid Cardiovascular Study(WAFACS)

(women at high risk of cardiovascular disease)

Aged ≥65 years

• 2.5mg folic acid, 50mg vitamin B-6, 1mg vitamin B-12 for 6.5 years

• Mean cognitive change not different between treatment and

placebo

• Supplementation preserved cognition among women

with a low baseline dietary intake of B vitamins• Folate: < 279 µg/d, vitamin B-6: < 1.9 mg/d, Vitamin B-12: < 2.4 µg/d

Kang, et al., AJCN 2008

�The role of baseline dietary intake level for B vitamins

Folate intake and risk of Alzheimer disease

Total folate intake data was measured by FFQ

Follow-up period: 6.1 yrs

Luchsinger et al, Arch Neurol. 64:86-92 (2007)

�The risk of AD decreased with the increasing quartile of total folate intake, and this association was statistically significant after adjustment for intake of vitamins B6 and B12

�When only intake of high-dose supplements of folic acid (400 µg) was considered, the association between folic acid intake and AD remained nonsignificant (HR, 0.7; 95% CI, 0.5-1.2) but in a direction suggesting a lower risk.

Conclusions• Beneficial: NTDs and other birth defects, pregnancy

complications, vascular reactivity, stroke . . .

• Beneficial effects of folic acid supplementation are

observed:

• Low vitamin intake and/or low vitamin status

– Compared to deficiency moderate supplementation may be – Compared to deficiency moderate supplementation may be

protective

• High baseline homocysteine level

• Microvascular diseases

– Stroke, AMD, hearing

– ? macrovascular diseases

• Timing/stage and Dose

– Early/preclinical stage of diseases (ie, early atherosclerosis,

cancer….)

– Moderate dose (ie, 400µg/d) is better than high doses

When it comes to folic acid

supplementation,

individualize recommendation!!!