NUTRITION
December 1, 1999

Vitamin Supplements — Too Much of a Good Thing?

The Patient

JM
A young woman who I recently treated, influenced by several reports in the local paper about beta-carotene's cancer and heart disease preventive benefits, began taking a single tablet of supplemental beta-carotene on a daily basis. Unaware of the dose of carotene in these pills, she noticed, after two months, that her skin had a yellowish tone. Except for the yellow skin color, she had no medical problems.

The yellow was particularly intense in the creases of her palms and other skin folds but lighter and different from patients who I have seen with jaundice due to liver disease. I told her that I suspected that the culprit was beta-carotene.

She asked me if she had produced any permanent damage to herself.

RMR
That's unlikely. Her skin color will undoubtedly return to normal in 30 days once she stops the carotene. Though beta-carotene is a Vitamin A precursor, and excess Vitamin A can make you sick with symptoms related to liver damage (fatigue and jaundice), too much beta-carotene will not produce serious consequences because the breakdown of beta-carotene to vitamin A is very inefficient. But I would ask this patient to stop the supplementation — there is no evidence that doses as large as hers are doing any good. One other important point. There have been highly publicized studies which showed the harmful effects of excess beta-carotene in heavy smokers. I assume, Joel, that your patient never smoked?

JM
That's correct. I hesitated to answer her question about whether she'd harmed herself because while studies have shown no benefit of taking beta-carotene for the prevention of certain types of cancer, two studies have indicated that there is a very small but significant increased risk of lung cancer in individuals taking beta-carotene.

Table 1.
B-Carotene Trial Summary
Study Study Subjects B-Carotene Outcome
ATBC Smokers 20 mg/day More lung cancer if B-carotene treated

No effect on CV disease
CARET Smokers and asbestos exposed 30 mg/day Trend toward more lung cancer if B-carotene treated
Physicians' Health Study 90% non smoking physicians 50 mg every other day No increase or decrease in cancer or cardiovascular disease

RMR
The first of the studies, the ATBC Study (Alpha Tocopherol/Beta-Carotene Cancer Prevention Study), involved giving 20 mg of beta-carotene to a well nourished population of about 30,000 Finnish men. These men were 50 to 70 years old and were heavy smokers. After six years, it was found that those taking beta-carotene had approximately a 20% higher risk of getting lung cancer but no protective effects with regard to cardiovascular disease.

The second study, the so-called "CARET Trial" (pun intended, I'd imagine), evaluated about 20,000 men and women who had a history of smoking and/or prolonged exposure to asbestos from past occupations. These individuals were assigned to either a placebo pill or a pill containing 30 mg of beta-carotene, and 25,000 international units of vitamin A. After four years of treatment, there were more deaths in the beta-carotene group and there was an increased number of cases of both lung cancer and cardiovascular disease among those assigned to beta-carotene and vitamin A. These were rather surprising findings, to say the least.

The third study, the Physician's Health Study, involved approximately 20,000 male physicians, approximately 11% of whom were smokers and 40% were past smokers. The participants were randomized to receive beta-carotene, 50 mg every other day, or placebo. After 12 years of follow-up, there were neither protective effects nor toxic effects of the beta-carotene treatment.

JM
It's true these three trials certainly do not provide compelling evidence of a health benefit of supplemental carotene, but there must have been observations made in the past that prompted investigators to conduct these trials? Otherwise, why do such large and expensive studies?

RMR
We did have consistent findings about the apparent protective effect of high intakes of fruits and vegetables in regard to cancer and cardiovascular disease and suspected that beta-carotene was the nutrient responsible for their beneficial effects.

Oddly enough, the protective effects seemed to be most strong against lung cancer. That is, the higher the intake of fruits and vegetables (and thus, beta-carotene) and the higher the blood level of beta-carotene, the more protection there seems to be against the development of lung cancer, and this was found to be particularly true in smokers. These intervention trials were undertaken with the idea that beneficial outcomes were going to come from the beta-carotene treatment. You're right, Joel, it was a huge surprise when this did not happen.

JM
So, what are we to make of this? Should people not take beta-carotene supplements?

RMR
I think the evidence is pretty clear that supplemental beta-carotene is not going to give any benefit to the individual in terms of cancer prevention or prevention of cardiovascular disease. And in smokers, there may be harmful affects of beta-carotene. In the body, some beta-carotene is broken down to vitamin A. Sometimes, though, it breaks down to products that just look like vitamin and the cell is fooled, thinking that vitamin A is around when in fact it is not. Other beta-carotene breakdown products may actually block the action of vitamin A or act as a tumor-promoting agent.

JM
The bottom line is that nutrient supplementation in the prevention of disease is not so straightforward as one might hope. And, in these massive doses, nutrient supplementation can create problems. For example, taking vitamin A in doses that are as little as three to five times the Recommended Daily Allowance (RDA) can cause mutations in fetuses. In Table 2 below, we see that large doses of one micronutrient can interfere with how the body uses other micronutrients.

Table 2.
Examples of Detrimental Nutrient/Nutrient Interactions
Carotenoids Possible Health Effect
B-carotene

Lycopene

Lutein/Zeaxanthin
Secondary prevention of heart attacks

Prostate cancer prevention

Cataract, macular degeneration prevention

The Natural Way

JM
We have found that a diet that provides these nutrients in the form of intact foods is more effective for disease prevention than when the nutrients are taken by themselves. The reasons for this are not clear. Among the possible explanations are that other compounds contained in fresh fruits and vegetables, such as the so called "phytochemicals," are the beneficial components. Also, taking a large dose of a particular nutrient may not provide the same benefits that taking smaller doses over an extended period of time might.

There is no single "magic bullet" in regard to micronutrient supplementation. We should continue to counsel everyone to follow a high fruit and vegetable diet and one that is low in animal fat and one that is high in fiber.

RMR
That's right. Your patient, Joel, would have been better off simply increasing her daily intake of fruits and vegetables.

Are Supplements Ever Useful?

JM
Single nutrient supplementation is beneficial for certain groups of people. For example, modest supplementation with vitamin E appears to lessen arteriosclerotic disease in patients who are prone to that condition. But, does all this evidence mean that carotenoid research and supplementation is a dead issue?

RMR
One of the things that scientists in this area are trying to figure out is exactly what did happen in these beta-carotene trials to produce the harmful effect that was seen. There is preliminary data from the Physician's Health Study that men who have already experienced an episode of cardiovascular disease (i.e., heart attack, coronary artery bypass, etc.) were in fact protected against a second cardiovascular event if they were taking beta-carotene. So the entire story is not yet in and trials continue to go on using beta-carotene among populations at high risk of a second heart attack.

Table 3.
Areas of Ongoing Investigation in Carotenes
Carotenoids Possible Health Effect
B-carotene Secondary prevention of heart attacks
Lycopene Prostate cancer prevention
Lutein/Zeaxanthin Cataract, macular degeneration prevention

Pizza for the Prostate? Carrots for the Eyes?

RMR
Beta-carotene is just one of hundreds of carotenoids that circulate in the blood, most in trace amounts. Other carotenoids which circulate in fairly plentiful amounts in the human include lycopene, lutein and zeaxanthin. Lycopene is found in tomatoes. Some people have higher concentrations of lycopene in their blood than beta-carotene, perhaps as a result of eating a great deal of food with tomato sauce, such as pizza and pasta. Lycopene levels have been related, in several studies, to a lower risk of prostate cancer. So this is an area of active investigation.

The pigments that carry the carotenoids lutein and zeaxanthin are highly concentrated in the macula of the eye (that part of the eye that we use for day vision). We do not know exactly the reason that it gets concentrated there or the mechanism by which it gets concentrated, but the concentration is higher there than in any other tissue of the body. Thus, there is speculation that these pigments might play some protective role against senile macular degeneration. Once again, this is far from being proven, so don't run to the health food store to buy concentrates of these pigments.

JM
The last point that I would like to make is that there appears to be no harm in taking a daily multi-vitamin and mineral supplement. In fact, there is reasonable evidence that this may convey several health benefits to otherwise healthy people.
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