A critical review of the antioxidant controversy/safety issues for fat-

soluble vitamins

Hans K. Biesalski MD PhDDept. Biological

Chemistry

and Nutrition

University Stuttgart-Hohenheim

More than

hundred

studies

exist

describing beneficial

effects

of antioxidants

on

different diseases.

A few

large intervention

studies

could

not confirm

the

results. Some

of them

even

described

harmful

outcome

Nevertheless

„bad news

are

good news“ antioxidants

are

claimed

to be

not

even

unnecessary

but

harmfull!

Mortality

in randomized

trials

of antioxidant supplements

for

primary

and secondary

prevention: systematic

review and meta- analysis.

Bjelakovic

G, Nikolova

D, Gluud

LL, Simonetti

RG, Gluud

C.

CONCLUSIONS:

Treatment with beta carotene, vitamin A, and vitamin E may increase mortality.

Bjelkovic

et al., 2007:

No increase

of mortality

in all 68 RCT

Low risk

of bias: 5% in increase

of mortality

in 47 studies13 Studies

with

less

than

1000 participants: 1% risk

reduction

High risk

of bias: signifcant

decrease

of mortality

21 out of 68 mentioned

mortality

Mean

duration

of vitamin

intake: 2.7 years

Intervention effect of antioxidant supplements vs placebo on mortality in trials with low risk of bias (14 out of 47 with only one death!)

5% increase

of mortality

Intervention effect

of antioxidant

supplements

vs placebo

or

no intervention

on mortality

in trials

with

high risk

of bias

Evaluation of the 68 studies of Bjelakovic according to the study goal:

Total PP SP TT

Positive outcome 27 3 15 9

No effect 36 13 13 10

Negative outcome 5 1 3 1

Vitamin deficiencies are not healthy!

Treatment of the deficiency might result in a decrease of mortality.

However, there is no evidence that vitamins can reduce mortality in the absence of a deficiency.

Method

of evaluation:Questionnaire

regarding

multivitamin

intake

in the

last twelve

month

in 10.241 men

with

prostate

cancer

Result: Those

who

supplied

multivitamins

(>7/week) plus selenium

were

primarily

affected.

(RR 5.8 for

fatal prostate

cancer

n=8) men

with

a genetic

history

in the

family

(RR 16.41 n=3)

Genetic

?

0.05

0.04

0.03

0.02

0.01

0

-0.01

-0.02

-0.03

10 20 50 100 200 500 1000 2000 IU Vitamin E

Vitamine EHarmful

Vitamin EBeneficial

All

case

mor

talit

yris

kdi

ffere

nce

Meta Analysis: High-Dosage Vitamin E Supplementation MayIncrease All-Cause Mortality. Ann Intern. Med 2004 Miller et al.

135 967 participants in 19 clinical trials. 9 tested vitamin E alone10 tested vitamin E combined with other vitamins and minerals

Non-linearlinear

The lack of a salutary effect was seen consistently for various doses of vitamins in diverse populations.

Our results combined with the lack of mechanistic data for efficacy of vitamin E, do not support the routine use of vitamine E.

D. Vivekananthan et al., Lancet Vol 348 June 14 2003

Use of antioxidant vitamins for the preventionof cardiovascular disease: meta analysis of

randomised trials.

Odds ratios (95% Cl) of the combined endpoint of cardiovascular death or non-fatal MI for individuals treated with vitamin E or control

therapy.

Source: Vivekananthan DP, The Lancet 361, 2003

Odds ratios (95% Cl) of all-cause mortality for individuals treated with vitamin E or control therapy.

Source: Vivekananthan DP, The Lancet 361, 2003

Number of events in the CHAOS-Study

α-Tocopherol (800/400 IE)Placebo

P<0.001

P<0.015

Stephens et al., Lancet 1996

Non Fatal MI Major CV Events CV death All death

60

50

40

30

20

10

Dosis ?Mono ?

Six year effect of combined vitamin C and E supplementation on atherosclerotic progression.

Salonen et al. Circulation 107: 2003

3 years supplementation with 136mg vitamin E and 250mg vitamin C twice daily slowed down progressionof carotid atherosclerosis in men but not in women.

Further slow down of progression in hypercholesteronemic persons.

Intima Media Durchmesser der Carotis bei supplementierten (3 Jahre 136mg Vitamin E und 250mg Vitamin C 2xtäglich) und Placebo

Source: Salonen RM, Circulation, 2002 * Common-carotid artery-intima media thickness

What can vitamins (or essential micronutrients) in general really do?

In physiological doses they can act within their usual homoeostatic control and can compensate an inadequate intake and not more!

Consequence: If they work in physiological doses there must have been a deficiency or inadequate supply!

The major question is: what was the reason for the deficiency?

Up to 50% of patients

with

chronic

musculo-sceletal pain

have

an insufficient

Vitamin D supply

(NHANES III)

Supplementation

with

moderate doses

of vitamin

D completely

abolished

pain

Even vitamin

D acts

as a pain

killer

this

effect

is

based on the

compensation

of a vitamin

D-deficiency.

Special risk

groups: Elderly

and Immigrants

Vitamin D-deficiency

in „healthy“

groups

Vailed

and non-vailed

turkish

women

in Germany or

Turkey(Erkal

et al., 2006)

25(OH)D Plasmalevel

and muscolo-sceletal

pain(Erkal

et al., 2006)

With increasing age the ability of the skin to synthesize vitamin D decreases. In elderly > 65 years the vitamin D ysynthesis drops to 25% of normal.

Paradoxically the plasma vitamin D levels are higher in northern than southern Europe.

Lips P.JSB2007

Low 25 hydroxyvitamin D and 1,25- dihydroxyvitamin D levels are independently associated with all cause (RR 2.08) and cardiovascular mortality (RR 2.22). (Dobnig et al., Arch Int Med. 2008)

Women who are vitamin D-deficient have a 253% increased risk for developing colorectal cancer, and women who ingested 1500mg Ca/da and 1100 IU/d vitamin D3 for 4yr reduced risk for developing cancer by 60% (Holick MF JANS 2008)

If there is a deficiency the compensation works!!

For a marginal or subclinical deficiency only a few marker – if at all – exist.

To measure effectiveness of antioxidants it is not enough to look at an „endpoint“

It is of importance to show that supplementaion with antioxidant has indeed an antioxidative effect!

If there is an antioxidative effect, there was a need!

If there is a deficiency the compensation works!!

Time course of reduction in plasma concentration of F2-isoprostanes in participants supplemented with 3200 IU/day Vitamin E

Plasma concentrations of vitamin E measured after 16 weeks of supplementation with variing doses of vitamin E or placebo

Roberts LJ et al., FRBM 43: 2007

Change in F2-isoprostane by quintile of baseline F2 Isopro

Vitamin C supplementation (1000mg/d 2 month) reduced F2Isopro 22% when F2 baseline levels were > 50µg/ml (Block G. FRBM 2008)

One participant died due to a car accident – if not mentioned antioxidants might have killed him!

Baseline F2 Isopro levels > 50µg/ml was strongly associated with BMI and was present in 42% of the sample (Block G et al., FRBM 2008)

The

activity

depends

on the

underlying oxidative

stress

Can Vitamins or antioxidants reduce mortality if supplied in higher doses?

28% risk reduction for mortality in trauma patients (2.272 vs control 2.022) exposed to high doses of antioxidants (Vit. C, E , Se) for 7 days (Collier et al., JPEN 32: 2008)

Plasma concentrations in a subset of patients receiving antioxidant supplementation and those receiving standard care

Nathens et al., Ann Surg 236:2002

Risk of multiple organ failure among 301 patients receiving antioxidant supplementation and 294 pateints receiving standard care

AOX

Is

there

a need

for

aditional

vitamins

or should

we

follow

the

general

paradigm:

There

is

enough

nutrition

for all, additional vitamins

are

not

needed!

100%

90

80

70

60

50

40

30

20

10

00VD FA VE Ca VA Mg Zn

B1 B2

% not

reaching

the

recommendations in the

National Nutrition Survey

2008

male

female

Main dietary

sources

for

Vitamin E

Intake of vitamins in consumers of supplements from different sources: (usual and fortified food; fortified instant beverages; supplements)

Sichert-Hellert et al., 2006

Mean intake in Germany: 12mg/dayRecommendation 2006: 15mg/day

100% only with fortified food andbeverages

Sufficient Vitamin E intake cannot easily achieved via nutrition.

What about prevention?

Plasma a-tocopherol concentration

by

tertile

of a-tocopherol

intake among

all subjects

(602)

A or

non-supplement users

B (272)

75% of the

US- population

do not

even

meet

the

EAR for Vitamin E

(NHANES III)

Gao

et al., J Nutr. 136; 2006

What can vitamins (or essentiel micronutrients) in general really do in secondary prevention?

Diseases and xenobiotics have different impacts on micronutrient requirement and turnover.

Consequently, the appropriate dosis to ensure the individual need in a disease state may vary.

Consequently, in secondary prevention the doses needed to compensate an inadequate supply may be higher than the doses needed for primary prevention

Malnutrition Malnutrition increasesincreases

complications (n=709)complications (n=709)

Correia et al, Clin Nutrition 2003; 22: 235- 239

01234567

Pulmon

ary inf

ection

Urinary

infec

tion

Wound

infec

tionSep

sis

Intraa

bdom

inal ab

sces

s

Extra

perito

neal a

bsce

ss

Septic

coag

ulopa

thy

Respir

atory

failur

eCard

iac ar

rest

Cardiac

arryt

hmia

Cardiac

failur

e

Wound

dehis

cenc

e

Well

nourished

(SGA)Malnourished

(SGA)

% p

atie

nts

100

80

60

40

20

10

00

33%

67%

89%

11%

AOX intake between66% to 100% of RDA

AOX intake below66% of RDA

Worsening in oxidative stress (Lipidperoxidation, protein-oxidation) accordingto intake of antioxidant vitamins prior ICU administration in critically ill.

Abiles et al. Crit Care 2006

Higher

ox.stress

Lower

ox.stress

Risk groups for poor antioxidant statusElderlyStrong vegetariansSmokerChronic alcohol intake (more than moderate)ObesityDieting (< 1.500 kcal)DiabetesCOPDChronic imflammatory diseasesCancerFat Malabsorption

Low intake

of antioxidants

may

have

an impact

in the

long term

(CHD, Cancer, Neurological

diseases)

What can vitamins (or essentiel micronutrients) in general really do in primary prevention?

A diet rich in all essentiel micronutrients protects from a couple of diseases in later life.

Consequently, in primary prevention micronutrients protect from deficiency in physiological doses.

What can vitamins (or essentiel micronutrients) in general really do?

In pharmacological doses they can act as micronutrients and in addition by circumventing the homoeostatic control may also act in a different way !

Consequence: If they work in pharmacological doses they may or should be treated like xenobiotics!

Conclusion

The

primary

goal

to supplement

antioxidants is

to ensure

an adequate

supply

adapted

to the

life cycle.

Normal intake

achievable

via nutrition

(RDA) may

be

enough

in a healthy

status. However,

diseases

may

result

in a higher

need.

Antioxidants

are

not

recommended

to increse life span

but

to improve

life quality

in chronic

diseases