Vitamin D ~ Down but not out

Vitamin D remains a vitamin of great interest at present with opinions favouring and opposing its role in obesity and the associated morbidity of obesity, the metabolic syndrome, specifically, the glycaemic side of the metabolic syndrome. One recent paper has used a rather clever approach to ascertain the role of vitamin D in obesity[1]. They used data from 21 adult cohorts amounting to over 42,000 subjects for whom data was available on body weight (body mass index) and for whom detailed data on various aspects of gene sequence was also available.  The authors selected 12 genetic variations (single nucleotide polymorphisms) linked to obesity. Based on a previous meta-analysis of the observed effect of each genetic variation on BMI, the authors assigned a score of 0, 1 or 2 to each BMI related gene variant where 2 was a high degree of association with 0 at the lower end of the gene-BMI association. Each subject was thus assigned a score with a maximum of 24 and a minimum of zero. As the BMI gene score increased, so too did BMI. And as it did, the levels of plasma vitamin D fell. Thus for each unit rise in BMI, there was a 1.2% fall in plasma vitamin D. This tells us that as BMI rises, plasma vitamin D falls, a trend that has been observed before. But is it that low levels of vitamin D in blood lead to obesity or is it that high levels of obesity lead to lower plasma vitamin D levels. The latter is of course an attractive hypothesis since vitamin D is a fat-soluble vitamin and it remains possible that this vitamin moves out of plasma into the fatty environment of adipose tissue. To answer that question, the researchers also looked at two forms of genetic variation in vitamin D metabolism – an assortment of genetic variants, which drive vitamin D synthesis and another group, which drive vitamin D breakdown. Based on the mix of inherited genes, vitamin D levels varied but this variation showed absolutely no association with obesity. Together, these data show that the lower levels of vitamin D found in obesity are due solely to the dilution of plasma vitamin D with the migration of significant quantities from blood to adipose tissue.

Obesity is however, a very crude measure of phenotype and it is associated with many metabolic abnormalities, one of which is insulin sensitivity. Inadequate blood levels of vitamin D have been linked to disorders of glucose metabolism including impaired insulin sensitivity. Thus a recent study investigated the effects of supplementing the diets of adolescents with plasma vitamin D on a wide variety of glucose metabolic aspects of metabolism[2].  A group of 18 obese adolescents were given vitamin d for 6 months while a second group of 17 subjects received a placebo. Plasma vitamin D levels {25(OH)} doubled in the treatment group and remained unchanged in the placebo group. No effects were observed on BMI although the group as a whole was severely obese (39kg/m²). A highly significant improvement in insulin sensitivity was found for the vitamin D group but not the placebo group using two reliable methods of measuring (HOMA-IR and QUICKI). Fasting plasma glucose was not altered by vitamin D supplementation although fasting plasma insulin levels showed a significant reduction with vitamin D treatment. Thus a lower level of insulin managed to maintain comparable levels of blood glucose indicating an enhanced efficiency of the function of plasma insulin. Two key hormones associated with energy metabolism leptin and adiponectin did show a change in their ratio (leptin to adiponectin) and the greater the response observed to vitamin D supplementation, the greater was the change in in this ratio.

Clearly, vitamin D is not directly linked to obesity but it continues to display a role in the area of enhanced insulin secretion, enhanced insulin function and improved overall glucose metabolism. The present study would suggest that vitamin D supplementation might be a useful adjunct to standard metabolic management of severe obesity but the results of the present study would need to be replicated and with a larger sample size.

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[1] Vimaleswaran KS et al (2013) PLoS Medicine, 10(2), e1001383

[2] Belenchia MA et al (2013) Am J Clin Nutr 97, 774-781

Google Authors Talk on my book

Google Authors Talk

http://www.youtube.com/watch?v=Ktmi-HCDosc&list=UUbmNph6atAoGfqLoCL_duAg&index=1

Todays blog is a video of a talk I gave on my book as part of the Google Authors series

Nutritional epidemiology ~ Faith or facts

In the course of a recent lecture on the subject of obesity, an issue arose in the discussion about an incremental approach to solutions for obesity. Thus individual action plans might seem very modest but a suite of such action plans could be successful in treating obesity. Allied to this viewpoint about incremental solutions came the old chestnut that sometimes, in epidemiology, we need to take action even if we don’t have definitive proof of the efficacy of that action. This chestnut, hankers back to the founder of modern day epidemiology, John Snow, who disconnected the tap from the water pump in Broad Street London, thereby ending a cholera outbreak. It is argued that Snow did not have definitive proof and this is the root of the view that sometimes, epidemiology needs to take a leap of faith. However, as Snow himself points out, of the 71 deaths he investigated, 61 were of people living in the vicinity of Broad Street and thus users of the pump. Three deaths occurred in children who lived nearer another pump but who went to school close to the Broad Street pump. Five others “preferred” the water at Broad street over their local pump. Only two deaths could not be linked to the guilty pump. All of this happened prior to our understanding of pathogenic microorganisms so Snow clearly couldn’t have used culture techniques to verify the organisms presence. He could have asked persons living away from the pump in question to drink the water in question but even in Snow’s time, the unwritten ethical position was: “First do no harm”. And so, armed with a dot map and his 71 case histories, the pump was disabled. This may have been a leap of faith in that definitive proof of cause and effect wasn’t to hand, but the quality of Snow’s data was excellent and compelling.

So in the field of human nutrition, how much of our public health nutrition policy is based on fact and how much on faith. In the early 1950’s. Ancel Keys studies the relationship between dietary fats, plasma cholesterol and the rate of heart disease in seven countries across the globe. Keys and his colleague Paco Grande then completed a series of human intervention studies in which patients in a psychiatric hospital were fen on reconstituted milk with a wide variety of fats and oils. The net outcome was definitive proof that the effects of dietary fat on plasma cholesterol could be accurately predicted using equations derived in their studies. But was there proof that lowering cholesterol would reduce the risk of heart disease. Endless studies ensued and all showed that high levels of plasma cholesterol were , at a population level, predictive of a higher risk of heart disease. Thus the dietary lipid hypothesis was upheld and entered the policy arena of public health nutrition.

A contrasting story is that of antioxidant micronutrients, particularly vitamins C and E. In the early 1980s, there was a widespread belief that plasma antioxidant levels played a major role in cardiovascular disease, in cancer and in ageing. The data was dominated by associations studies linking published levels of plasma antioxidant status in different countries with national disease rates. The relationships were most impressive. Animal studies also added to the theory and in vitro studies abounded showing how anti-oxidant vitamins could protect fractions such as low-density lipoprotein from oxidative damage which would otherwise render them very atherogenic. As often happens in the field of health research, someone wanted to cut to the chase and head for glory with a human intervention study. And so the ATBC (alpha tocopherol {vitamin E} beta carotene) study was designed and implemented. It failed to uphold the hypothesis and many reasons were put forward as to why the study was “unsuccessful”. Based on knowledge of these flaws, more intervention studies were rushed along and, all in all, the antioxidant theory was abandoned.

We can look at some other “successes” and “failures” in nutritional epidemiology. The protective role of folic acid in reducing the risk of a neural tube defect birth was shown in a randomized controlled trial leading to a major initiative in public health nutrition with the fortification of flour with folic acid. Trans fatty acids were removed from the food chain wherever possible on the basis of a strong human intervention study. In contrast, notwithstanding the strong evidence from correlational studies in humans of a link between fish oil fatty acids and cognitive decline, endless intervention studies have failed to show a protective effect.

Thus we have an excellent track record in human nutrition in translating observational studies that show an association between some aspect of diet and some health attribute into dietary intervention studies and then basing our policy interventions on food of those intervention studies.

Taxing sugar-sweetened beverages to reduce the incidence of obesity requires data from human intervention studies that show a direct link between weight gain and consumption of such beverages at rates that correspond to reality before anything is done. There are intervention studies and meta-analyses of such studies and the evidence is very weak if non-existent. To suggest that we trust these data so much and that we are fully confident that fiscal measures will be always positive and rarely negative is simply wrong and is bad science. To argue that sometimes we need to take leaps of faith in nutrition policy flies in the face of 6 decades of rigorous research on which nutrition policy has been built. Facts and not faith should drive policy. Facts are universal but faith is a subjective value.

Dietary supplements ~ useless or useful?

There is a general tenet in human nutrition that if one eats a healthy diet, then there is no incremental benefit from taking additional nutrients either as fortified food or as supplements. A healthy diet should provide all of one’s nutrient requirements. I would go so far as to say that, among nutritionists, this is more a doctrine than a mere tenet. In recent times, several papers have been published which challenge this concept. A good place to start is with a major survey of 12,000 US adults to ascertain and characterise usage of dietary supplements[1]. In 2011, Americans spent $30 billion on dietary supplements, which, to put it into perspective is equal to or greater than the annual GDP of Ethiopia, Jordan or Bolivia. Some 77% of the users of dietary supplements do so through their own choice with 23% doing so on professional advice. In general, users of supplements are happier with their health than non-users, which suggests that they use supplements as some sort of insurance. The vast majority of respondents stated that they took supplements to “improve” or “maintain” health. So, are they wasting their money?  A recent meta-analysis would say that indeed they are wasting their money where the end point was mortality. In this study, the authors completed a meta-analysis of dietary supplement (multi-minerals and multi-vitamins) intervention studies, which involved a final list of 21 publications, involving 91,074 adults, with a mean age of 62 and a mean duration of supplement use of 43 months. A total of 8,794 deaths was recorded. When the death rate of those assigned to intervention with the supplements was compared to that of those receiving a placebo, no statistically significant differences in death rate were seen. So, taking dietary supplements doesn’t make you live longer. But do they make you healthier?

Late in 2012, two papers were published from the “Physicians’ Health Study II Randomized Controlled Trial”. This began in 1997 with 14,641 male physicians aged 50 years or greater entering the study. There were several treatments. One involved a multi-vitamin supplement. Two others involved either vitamin E alone or vitamin C alone. A final group received a placebo. After an average follow up of 11.2 years, 1,732 cases of major cardiovascular events (non-fatal serious heart attack or stroke) were observed[2]. No statistically significant differences were observed in cardiovascular events between treatment and placebo. So supplements wont make you live longer and wont make your heart any healthier. However, a second paper from the same Physicians Health Study Randomized Controlled trial did show that the overall risk of cancer was moderately reduced in those assigned to the vitamin supplements as opposed to those assigned to the placebo[3]. The authors conclude that: “Although the main reason to take multivitamins is to prevent nutritional deficiencies, these data provide support for the potential use of multivitamin supplements in the prevention of cancer in middle-aged and older men.” What a pity these studies didn’t employ modern genomics and metabolomics technology to look at responders and non-responders. When will nutritional epidemiology enter the 21^st century?

The issue of vitamin supplementation was the subject of yet another recent paper, this time with a focus on folic acid supplementation in the pre-natal period and during pregnancy. Normally the end-point of such interventions would be neural tube defects such as spina bifida but in this case it was autism. The study was within the Norwegian Mother and Child Cohort study, which recorded the use of folic acid prior to conception and in the first 8 weeks of pregnancy[4]. Among the 85,176 children born in the cohort after exclusion of some births (12,000) for reasons such as premature delivery or lack of data on folic acid use, some 114 cases of autism were observed, equating to a rate of 0.14%. Among women who took folic acid supplements the rate was 0.10% while among women who didn’t take folic acid supplements the rate was 0.21%. This difference was statistically significant even when controlled for maternal and paternal education and age, a planned pregnancy, parity, year of birth and maternal BMI and smoking habits.

Clearly, some people benefit from dietary supplement use and the challenge to nutritional science must be to use modern technologies to ascertain those that do and don’t benefit with a view to customizing supplement use to optimise health. The doctrine that states that you should get all your nutrients from foodstuffs is codswallop.

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[1] Bailey RL et al (2013) JAMA Int Med, On line February 4th

[2] Sesso et al (2012) JAMA, 308, 1751

[3] Gaziano JM et al (2012) JAMA, 308, 2012

[4] Suren P et al (2013) JAMA, 309, 570

Diet and cancer: a damning analysis

This month’s edition of the American Journal of Clinical Nutrition carries a very important review of the epidemiological data relating food to cancer[1]. It is well written and sensitive in its conclusions but, reading between the lines, it is quite simply damning of the quality of the epidemiological research basis linking food intakes and cancer. The authors started off with The Boston Cooking-School Cook Book.  Using a random number generator to correspond to page numbers, they searched the cook-book for recipes. All of the unique ingredients in each recipe was identified and the process was repeated until 50 unique food ingredients were identified. The next stage of the process was to explore the scientific literature to examine the most recent studies, if any, linking any one of the 50 ingredients to cancer. The 10 most recent studies were selected and if there were less than 10 studies available, synonyms (e.g. mutton for lamb) were used to further explore the availability of studies. In addition to individual studies, the authors also searched for meta-analysis studies that combine data from several individual studies to increase statistical power.

 

The next stage of the process was to extract data from each individual study or meta-analysis. This involved an examination of the abstract with an emphasis on the author’s conclusions, an analysis of the statistical methodology used and an assessment of the exposure levels examined for each ingredient. From the 50 ingredients randomly chosen from the cookbook, 40 (80%) were found to be the subject of a scientific investigation into its links with cancer. The food ingredients included: veal, salt, pepper spice, flour, egg, bread, pork, butter, tomato, lemon, duck, onion, celery, carrot, parsley, mace, sherry, olive, mushroom, tripe, milk, cheese, coffee, bacon, sugar, lobster, potato, beef, lamb, mustard, nuts, wine, peas, corn, cinnamon, cayenne, orange, tea, rum and raisin. A total of 216 publications were found linking these ingredients to cancer. Of the 40 ingredients, 36 were identified in at least one study as either increasing or decreasing the risk of cancer. In their examination of the statistical analysis used, the authors of the review concluded that, of the studies that claimed an increased risk of cancer, 75% were associated with “weak or non-nominally significant” effects and for those that reported a negative effect, the corresponding figure was 76%.  In 65% of the studies, these effects were based on comparison of extremes of consumption such as >43 drinks per week versus none or “often” compared with “never”.  The authors compared the calculated risk from individual studies with the risk calculated from meta-analyses where like studies were pooled. The latter showed a narrow range of risk where as the former showed a huge range of positive and negative risk.  

The authors conclude that the vast majority of claims for increased or decreased risk were based on “weak statistical evidence”. Moreover, they show an appalling practice of relegating negative or weak results to the fine detail of the text of the paper but excluding such from the abstract. The abstract is most likely to be read and certainly to be the basis of any media interpretation of the study.

All in all, this is a damning analysis of the field of nutritional epidemiology. It would be wrong to throw the baby out with the bathwater since nutritional epidemiology has been the basis for many substantiated diet-disease links (folic acid and neural tube defects, atherosclerosis and dietary lipids, calcium intake and osteoporosis and so on).  The problem with diet and cancer is that intervention studies to experimentally prove a cause and effect relationship are simply not possible. Heart disease relates to one organ, the heart, whereas cancer can relate to almost all organs. In the study of diet and heart disease we can use biomarkers (plasma HDL and LDL cholesterol for example) while no such biomarkers exist for cancer.

In the analysis of how extremes of exposure were used, the authors found that the meta-analysis approach was almost exclusively based (92%) on extremes of consumption of the particular food ingredient. Epidemiological studies, by definition are very large and as such, the tools to measure diet must be relatively simple and this usually involves a food frequency questionnaire, which examines frequency of intake. However, nutritional epidemiology absolutely ignores the well know phenomenon of under-reporting of food intake.  Thus, when extremes of food intake are compared, they are largely based on truly flawed measures of food intake. This was not considered in the present study and more often than not, insufficient data is presented in papers to allow readers to make any conclusions as to the extent of under-reporting based on the match of reported energy intake and estimated energy requirements. The editorial boards of journals should insist that all studies involving food intake have a section in which the authors explain the extent of energy under-reporting and the specific implications for the study in question.

No doubt, this damning review of the epidemiology of diet and cancer will be swept under the carpet by the field of nutritional epidemiology. However, this blogger has always held the view that bad science will always be found out.

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[1] Schoenfeld JD & Ioannidis JPA (2013) “Is everything we eat associated with cancer? A systematic cookbook review” Am J Clin Nutr 97, 127