Folate, homocysteine and CVD

Question 1

What is folate and folic acid?

Answer 1

• A group of related compounds
• Folates are naturally occurring and folic acid is synthetic form
• active form in vivo is derivatives of tetrahydrofolic acid (THF)

Question 2

What is the biochemical function of folate and folic acid?

Answer 2

Involved with B12 in methylation reactions necessary for DNA synthesis and thus important for cell devision
It is very important in pregnancy

Question 3

What is the difference between the structure of folic acid and tetrahydrofolic acid?

Answer 3

They are very similar but tetrahydrofolic acid has more hydrogenation so less double bonds

Question 4

What is folic acid from?

Answer 4

Supplements or fortified foods

Question 5

What can folic acid be converted to instantly?

Answer 5

Unmetabolised folic acid (one of the major types in blood)

Question 6

If folic acid is metabolised to 5-methyltetrahydrofolate, how does this occur?

Answer 6

Folic acid –> dihydrofolate (by dihydrofolate reductase - slow)

dihydrofolate –> tetrahydrofolate (by dihydrofolate reductase - fast)

tetrahydrofolate –> 10 formyl-THF (can leave for purine synthesis)

10 formyl-THF –> 5,10-methenyl-THF (can convert to 5-formyl-THF)

5,10-methenyl-THF –> 5,10-methylene-THF (can convert back to THF by serine hydroxymethyltransferase causing glycine –> serine)

5,10-methylene-THF –> 5-MTHF (by methylene tetrahydrofolate reductase)

Question 7

What folates are the major types found in blood?

Answer 7

Unmetabolised folic acid
THF
5-formyl-THF
5,10-methenyl-THF
5-MTHF (most)

Question 8

What are the main dietary sources of folate?

Answer 8

Unmetabolised folic acid

Question 9

How are folate measurements used in megaloblastic anaemia?

Answer 9

Folate measurements are used in the diagnosis and management of megaloblastic anaemia. The reference range of the plasma folate level varies by age, as follows : Adults - 2-20 ng/mL, 2-20 μg/L, or 4.5-45.3 nmol/L.

Question 10

What is folate recommendation?

Answer 10

UK RNI is 200µg/day

Question 11

What should a woman child bearing age do?

Answer 11

to take supplements of 400µg/day

Question 12

What is the LRNI?

Answer 12

100µg/day

Question 13

What is American RDA?

Answer 13

400µg/day

Question 14

What is mandatory in the US?

Answer 14

Folate fortification since 1998 for all cereal grain products with 140µg/100g

Question 15

What is the case in the UK?

Answer 15

In the UK folate fortification has been recommended (COMA, 2000, expert report), but not been implemented
UK: voluntary fortification of many cereal based products

Question 16

What do folate blood tests suggest?

Answer 16

If the test is done on your blood plasma, a normal range for folate is 2 to 10 ng/mL. If the test is done on red blood cells, a normal range is 140 to 960 ng/mL. If your folate results are low, it may mean you have a diet that doesn’t provide enough folate.

Question 17

What is the relationship between folate and cardiovascular health?

Answer 17

Homocysteine

Question 18

Describe a disorder to do with homocysteine?

Answer 18

Rare genetic disorder causes high plasma homocysteine and people have a 50% chance of CVD by age of 20-30 years
Typically plasma homocysteine >100µM/L
Usually due to deficiency of enzyme cystathione β-synthase
first observed in 1968 when 2 young children died from stroke

Question 19

What is raised plasma homocysteine?

Answer 19

an independent marker of CHD and stroke
considered as such since the late 1990s
5µM/L higher homocysteine level – OR for CHD of 1.6

Question 20

What is the homocysteine hypothesis?

Answer 20

Elevated plasma homocysteine concentrations (8-15µM/L) may cause atherosclerotic vascular disease

Question 21

What is the prevalence of hyperhomocysteinaemia?

Answer 21

general population = 5-10%

elderly = 30-40%

patients with vascular disease = 20-40%

Question 22

What are three functions to do with homocysteine?

Answer 22

Atherogenic properties
Impairment of endothelium function
Procoagulant

Question 23

Describe Atherogenic properties

Answer 23

Undergoes redox cycling in presence of transition metals
Formation of superoxide radical – oxidative damage to LDL
May react with cysteine – SH groups and modify apolipoproteins (impairment of receptor mediated LDL uptake and increased macrophage scavenger receptor uptake)

Question 24

Describe Impairment of endothelium function

Answer 24

Reacts with NO to form superoxide radical

Loss of vasodilatation action and generation of superoxide

Question 25

Describe procoagulant

Answer 25

Alter coagulation properties of the blood

Inhibition of anticoagulant action and activation of procoagulants

Question 26

What is hyperhomocysteinemia also linked to?

Answer 26

osteoporosis
cognitive impairment and decline
chronic kidney disease
pre-natal complications

Question 27

What is Hyperhomocysteine normally associated with?

Answer 27

low plasma folate levels

Question 28

What do studies confirm that folate supplementation does?

Answer 28

significantly reduce plasma homocysteine levels

• in those with high baseline levels
• role of B6 and B12 not clear, may help in some people

Question 29

What is the controversial part?

Answer 29

intervention studies with folate do not appear to substantially reduce the risk of CHD

Hence the causative nature of homocysteine is questionable

Question 30

What does fortification comparison studies indicate?

Answer 30

Steeper rate of reduction in US and Canada compared to England and wales
Indicates that fortification may have made a difference

Question 31

What is the folate/homocysteine controversy?

Answer 31

Meta-analysis on stroke does suggest 18-30% reduction in risk in those without pre-existing condition
More recent meta-analysis on effects of folate and other B-vitamins on CHD events and stroke

Question 32

What happens with folic acid supplementation?

Answer 32

10% lower risk of stroke
4% lower risk of overall CVD
No significant effect on risk of CHD
Greater benefit for CVD observed among perticipants with lower plasma folate levels and without pre-existing CVD and in studies with larger decrease in homocysteine level
Large heterogeneity for baseline folate levels, pre-existing desease, extent of homocysteine reduction

Question 33

What is MTHFR?

Answer 33

methylene tetrahydrofolate reductase

Question 34

What is TT?

Answer 34

low activity of MTHFR; 1-20% of population

Question 35

What does TT result in?

Answer 35

results in an increased level of plasma homocysteine

Availability of methyl-THF, hence THF is lower

Question 36

What are high homocysteine and low folate in TT individuals?

Answer 36

substantially more at risk, and appear to benefit from supplementation

Question 37

What do meta analyses show regarding TT?

Answer 37

meta-analyses show 14-21% reduced risk of CHD in TT (low activity) individuals, but a dose of 0.8 mg/d required

Question 38

What does greatly elevated homocysteine levels in people with inherited condition lead to?

Answer 38

predisposed them to premature vascular disease

Question 39

What might moderate elevation of homocysteine levels (due to folate deficiency) lead to?

Answer 39

increase cardiovascular risk

Question 40

What might folate supplementation do?

Answer 40

Folate supplementation may be effective in hyperhomocystinuria and reduce risk for heart disease and stroke

Question 41

What is the conflicting evidence regarding folate supplementation?

Answer 41

that supplements of folic acid are beneficial for CVD in primary or secondary prevention trials, even though they might significantly reduce plasma homocysteine levels

Question 42

What are other possible consequences of folate?

Answer 42

Reduced incidence of bowel cancer after high intake of natural folate (from food)
Low folate status might lead to cancerous changes in the bowel
Epidemiological evidence that high folate intake is associated with reduced risk of Alzheimers (but no benefit of folic acid supplements in clinical trials)