Vitamin A & beta-carotene

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Philip Rouchotas

The History of Vitamin A - a Narrative of Emerging Harms
By: Philip Rouchotas MSc, ND
Bolton Naturopathic Clinic
64 King St W, Bolton, ON L7E1C7
www.boltonnaturopathic.ca
info@boltonnaturopathic.ca


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Vitamin A and the Early Evidence


Part I: Vitamin S and the Early Evidence

Vitamin A (retinol) is a fat-soluble antioxidant and vitamin; and beta-carotene is its primary plant-derived precursor. Vitamin A has a long history of use as a pharmacologic agent, dating from the 1970s.(1,2,3) Over the past 10-15 years, a large body of evidence has accumulated, which overwhelmingly indicates a range of specific harmful effects associated with supplementation of this nutrient. It may be difficult for some to imagine harms associated with a naturally occurring and essential micronutrient. Nonetheless, this substantial body of research has reproducibly demonstrated these effects in large, well-controlled randomized controlled trials, making these points increasingly irrefutable. The evidence can no longer be ignored: vitamin A and beta carotene are two single agents that deserve to be treated with a very high degree of caution with respect to nutrient supplementation. This four part series will unravel the story of vitamin A, describing its path from an exciting new agent in the 1970s to the discovery of its having serious harmful effects in the 1990s.

During the 1970s and 80s, considerable research interest was generated regarding vitamin A and beta carotene. First, scientists made the groundbreaking discovery that people with higher levels of vitamin A and beta carotene in their blood had much lower rates of serious chronic diseases such as heart disease and cancer.(4,5) For instance, Salonen et al found that retinol (vitamin A) levels were 26% lower among men with cancer, compared to men without cancer.(5) Another study found that when the participants were divided into five groups according to their vitamin A levels, those in the lowest group had more than double the risk of developing cancer at any site compared with participants with the highest levels.(6) This led the authors to conclude that “measures taken to increase serum-retinol levels [such as supplementation]… may lead to a reduction in cancer risk”.(6)

These were revolutionary findings at the time. They seemed to promise a simple, pill-based cure for deadly diseases such as heart disease and cancer. Following upon these findings, scientists began experimenting with vitamin A and beta carotene in a lab environment. In cancer cells isolated on petri dishes, vitamin A was shown to have anti-proliferative effects.(7) In animal models of cancer, vitamin A was able to prevent progression to lung cancer in animals exposed to carcinogens.(8,9) With respect to heart disease, it was hypothesized that antioxidants such as vitamin A may protect against the oxidative damage of the blood vessel walls that is known to cause artherosclerosis.(5) This theory of damage to blood vessels causing heart disease over time is called the response-to-injury hypothesis of atherosclerosis.(10)

In summary, the early research on vitamin A and beta carotene yielded very encouraging results, and led to excitement among scientists that a cure for heart disease and for cancer may be at hand. In the subsequent Parts of this article, we will discuss the flaws of this thinking, and show how vitamin A came to be known as an agent capable of serious harms, including increasing risk of death, risk of cancer, poorer perinatal health outcomes, and possible adverse effects on bone.(1,11-14)



The History of Vitamin A - a Narrative of Emerging Harms

Part II Vitamin A: The Mega Trials
by: Philip Rouchotas, MSc, ND
Bolton Naturopathic Clinic
64 King St W, Bolton, ON L7E1C7
www.boltonnaturopathic.ca
info@boltonnaturopathic.ca


Vitamin A: The Mega TrialsIn Part I we discussed the early promising results of vitamin A and beta carotene research. Following these findings, scientists assembled the resources to conduct large, well-controlled, randomized controlled trials (RCTs). The most important of these trials assessed whether vitamin A and beta carotene could reduce risk of cancer if given to high risk patients such as smokers. Other similar trials assessed whether supplementing these nutrients could help reduce risk of heart disease. In this installment, we discuss the surprising findings of these momentous studies.

Cancer Prevention Trials
In the 90s, scientists conducted two large RCTs of vitamin A and/ or beta carotene for the reduction of lung cancer risk among smokers and asbestos workers. The expected outcome was a reduction in risk due to supplementation with these antioxidants, which seemed to have an affinity for the lung epithelial tissue.

The Carotene and Retinol Efficacy Trial (CARET) was a multicenter study conducted in the United States. A total of 18,314 smokers and asbestos workers were randomized to receive a combination of 25,000 IU retinyl palmitate plus 30mg beta carotene, or placebo, for four years.(1) Researchers planned to continue the trial for several years, however, interim results part way through the study forced them to stop the study early. Instead of a decrease, there was a significant increase in the rate of lung cancer, by 28%. Risk of death from all causes was increased by 18%; death from lung cancer was increased a shocking 46%; and death from cardiovascular disease was increased by 26%.(1)

The Alpha Tocopherol Beta Carotene (ATBC) trial was a second large cancer prevention study conducted among Finnish male smokers.(2) In this study, a total of 29,133 men were placed in one of four treatment groups: they were given either 1) 20mg beta carotene, 2) 50mg alpha tocopherol, 3) both, or 4) placebo, for between 5-8 years. Like in the CARET study, investigators found that supplementation of beta carotene increased incidence of lung cancers by 16% compared to those not receiving beta carotene.(2) Researchers were stunned by these unexpected results.

Cardiovascular Disease
The Physicians’ Health Study was a randomized, double blind, placebo controlled trial including 22,071 male physicians.(3) Physicians were given 50mg beta carotene on alternating days, or placebo, for 13 years. This study found that there were no significant differences in the numbers of men who experienced heart attacks, strokes, or any death related to cardiovascular disease, when the beta carotene and placebo groups were compared.

Conditional Pro-oxidant Theory
What scientists had not anticipated in designing these studies was the conditional pro-oxidant activity that vitamin A and beta carotene exert in the presence of powerful pro-oxidants like cigarette smoke.(4) Oxidative potential (the capacity of a substance to either cause oxidation to another substance, or to be oxidized itself) is relative. That means a weak anti-oxidant can be itself oxidized by a stronger pro-oxidant, like cigarette smoke, and may itself act as a conditional pro-oxidant. It is well established in the field of chemistry that each ion possesses a relative redox potential, which determines whether it is reduced or oxidized in reaction with other substances. Similarly, a weak antioxidant may be oxidized by a stronger pro-oxidant or vice versa. The resultant new free radical may perpetuate the chain of oxidative damage on other targets. Vitamin A and beta carotene are particularly vulnerable to such oxidation due to their long chains of conjugated double bonds,(4) and animal studies have since confirmed that in the presence of cigarette smoke, vitamin A and beta carotene do indeed act as pro-oxidants, with the potential for pro-carcinogenic effects in the body.(5,6)

Since these important studies, vitamin A and beta carotene supplementation should be considered as contraindicated for anyone who is a current or former smoker. Food sources of beta carotene like carrots are not included in this category however, and are still encouraged as part of a healthy diet, as will be explained in the next parts of this article. In addition, Part III will discuss the concept of nutrient status in the context of supplementation.



The History of Vitamin A - a Narrative of Emerging Harms

Part III African Studies and the Concept of Nutrient Status
by: Philip Rouchotas, MSc, ND
Bolton Naturopathic Clinic
64 King St W, Bolton, ON L7E1C7
www.boltonnaturopathic.ca
info@boltonnaturopathic.ca


African Studies and the Concept of Nutrient StatusIn Parts I and II we reviewed some of the early, conflicting results derived from preliminary research and the large mega-trials on cancer and heart disease. We saw that vitamin A and beta carotene could act as conditional pro-oxidants and could actually contribute to cancer development. In this part we continue examining the findings of large randomized controlled trials (RCTs) of vitamin A/ beta carotene and the concept of baseline status.

First, we need to understand that when evaluating intervention trials of any nutritional agent, the concept of baseline status of the population must be taken into consideration. For example, supplementation among individuals on the brink of scurvy with vitamin C would be expected to deliver an important magnitude of benefit to an array of outcome measures, while the same intervention administered to a population of citrus farmers is far less likely to yield benefit, given the expectation that citrus farmers enjoy a relatively high dietary intake of the vitamin.

This part of the series examines a large study of HIV positive, pregnant women in Tanzania Africa, in light of this concept. These women were recruited to the study and assigned to one of four treatment groups; 1) multivitamin; 2) vitamin A (5000IU) and beta carotene (30mg); 3) multivitamin free of vitamin A and beta carotene; and 4) placebo. Study outcomes were presented in a series of papers, following the women throughout their pregnancy, as well as following the resulting offspring until age 18 months.(1-4)

The multivitamin free from vitamin A and beta carotene achieved significant benefit to the following outcomes relative to placebo; improved weight gain during pregnancy, reduced risk of low weight gain (<100g/wk),(4) reduced risk of progression to stage IV AIDS or reduced risk of death from AIDS related causes, reduced risk of the following AIDS- related complications (thrush, gingival erythema, angular cheilitis, oral ulcer, reported mouth and throat ulcer, painful tongue and mouth, difficult or painful swallowing, nausea and vomiting, dysentery, fatigue, rash, and acute URTI), increased immune cell counts (CD4 cells), reduced viral load,(1) reduced risk of development of hypertension during pregnancy,(3) improved psychomotor development index score in resulting offspring, and reduced risk of developmental delay on the motor scale.(2)

The multivitamin containing vitamin A and beta carotene achieved significant benefit to the following outcomes relative to placebo; improved weight gain during pregnancy, reduced risk of low weight gain (<100g/wk),(4) reduced risk of the following AIDS- related complications (thrush, angular cheilitis, rash),(1) reduced risk of development of hypertension during pregnancy,(3) and improved the psychomotor development index score in resulting offspring.(2)

Vitamin A and beta carotene supplementation on their own produced no outcomes significantly different from placebo. The authors highlight that the relative magnitude of benefit for outcomes impacted by multivitamins with or without vitamin A and beta carotene was greater across the board for the group receiving the multi free from vitamin A and beta carotene. Also, as described above, the multi free from vitamin A and beta carotene achieved benefit to a far broader and clinically relevant range of outcomes relative to the group receiving a multi containing vitamin A and beta carotene. These results suggest that the inclusion of vitamin A and beta carotene in the multi reversed the benefit expected from delivery of a multi to this malnourished population. The team followed this trial up with a trial among 8468 pregnant, HIV- negative women in Tanzania, Africa. In this follow- up trial, subjects were assigned to one of two groups; placebo or multi free of vitamin A and beta carotene. Importantly, in this trial, it was deemed unethical to include a group that received vitamin A and beta carotene.(5)

This poses the question: If vitamin A and beta carotene are incapable of materially benefiting this obviously malnourished population, what benefit can possibly be hoped for when supplementing relatively well- nourished, free- living North American populations?

Indeed, in an excellent review of vitamin A’s safety published in the American Journal of Clinical Nutrition, Penniston argues that hypervitaminosis A is a growing problem in Western populations, in part due to an increasing numbers of fortified sources containing vitamin A that have become a part of our diet.(6) These include many fortified sources: multivitamins, cod liver oil, and the fortification of common foods such as milk, butter, margarine, breakfast cereals, and some snack foods.(6) Indeed, among Western populations, vitamin A deficiency is virtually non-existent, with the possible exceptions of select cases among limited subgroups, such as patients who have undergone bariatric surgery or who are severely anorexic.(7-9)

In the light of this discussion, one question remains: how was it that higher blood levels of vitamin A were associated with reduced cancer and heart disease in the 1970s and 80s?



The History of Vitamin A - a Narrative of Emerging Harms

Part IV The Biomarker Hypothesis
by: Philip Rouchotas, MSc, ND
Bolton Naturopathic Clinic
64 King St W, Bolton, ON L7E1C7
www.boltonnaturopathic.ca
info@boltonnaturopathic.ca


The Biomarker HypothesisIn the last installment of this series, we discuss the last “missing link” in making sense of the vitamin A story. So far we have seen that vitamin A and beta carotene showed no benefit on a range of endpoints related to immune function and growth among malnourished, HIV-positive, pregnant African women; it is not expected to be of benefit among the well- nourished population of North America, where many food sources are also fortified with it. We have seen that vitamin A/ beta carotene showed early promising results in lab animals with respect to anticancer effects; but this did not translate into humans because vitamin A/ beta carotene act as conditional pro-oxidants in combination with cigarette smoke and other carcinogens.

However, we have not yet explained why in some of the very first observational studies done, those people with higher blood levels of vitamin A and beta carotene seemed to have dramatically lower risk of cancer and heart disease. How could this be, since the large RCTs showed obvious harm from supplementation? Were these studies just wrong?

To explain these results, one must take into account the concept of biomarker. The very nature of observational evidence is that it does not include an intervention (no treatment is given). Therefore, when plasma beta carotene levels are determined, we must ask ourselves: where is the beta carotene coming from? It is most certainly not coming from supplementation. Hindsight has taught us that plasma beta carotene is the single best available biomarker of exposure to fruit and vegetables. It is erroneous to conclude “blood beta carotene levels of X reduced risk of chronic disease.” It is far more appropriate to conclude “fruit and vegetable consumption of X, objectively confirmed by assessment of blood beta carotene levels, protected against risk of chronic degenerative disease.”

A landmark investigation, the BASEL study, prospectively followed 4858 men for 12 years. Participants were divided into five groups based on baseline determination of blood beta carotene levels. Individuals in the lowest group of plasma beta carotene were found to be at a 60% elevated risk of developing cancer.(1) Similarly, in another study 1720 men were divided into quartiles based on baseline determination of blood beta carotene levels. Individuals in the highest quartile were found to be at a 48% reduced risk of death from any cause, and a 43% reduced risk of death from cardiovascular disease.(2) This second observational study also included an intervention arm; in each group of beta carotene blood levels, the subjects were randomly divided to receive either a beta carotene supplement or placebo. As could be anticipated, individuals in the highest quartile of baseline plasma beta carotene received no benefit from the intervention. Surprisingly, yet completely in- line with the biomarker hypothesis of plasma beta carotene status, subjects in the lowest quartile of baseline plasma beta carotene also achieved no benefit from intervention with a beta carotene supplement.(2) Beta carotene in itself has no benefit on cancer risk or heart disease; however, beta carotene is a marker of the spectrum of other plant nutrients and molecules present in fruits and vegetables that do protect against cancer and heart disease.

Hindsight has indeed proven 20/20. The community of nutritional scientists as a whole has recognized the importance of blood beta carotene levels as an accurate marker of fruit and vegetable consumption, and likewise recognized its lack of importance as a “nutrient unto itself” for impact to risk of chronic degenerative disease. Modern observational trials demonstrating beta carotene as protective against chronic degenerative disease conclude that their outcomes strengthen recommendations for the public to consume more fruit and vegetables.(3) Modern intervention trials that include dietary modification as part of the intervention utilize determination of blood beta carotene levels to assess compliance; if participants comply with recommendations for increased consumption of fruit and vegetables, plasma beta carotene of the intervention group is elevated relative to the control group.(4,5)

Conclusion
Over the past 20 years, an eloquent and well developed body of research has emerged that clearly delineates the detrimental effects associated with the use of supplemental vitamin A and beta carotene. Concrete harm has been reproducibly documented with respect to a number of important clinical outcomes, including death from any cause, cancer incidence, and perinatal morbidity. Given the range of safe and effective interventions available, we recommend against the routine use of vitamin A and beta carotene supplementation in North American healthcare practice.