How on earth can my disease risk in adulthood have fetal origins?

When I think of the word Latency in medicine, I think of just one thing: Cancer. Although latency can also refer to viral infections such as HIV, Cancer Latency is the time between the initial exposure of a carcinogen (such as radiation), and eventual development of cancer. When I think of latency, I often times think of inevitability. It gives the impression that you know what the outcome will be, but there’s nothing you can do to change it. Or for those who did not know the origins of their cancer, the reality is they were already harboring the cancerous cells and would eventually develop the disease, and unfortunately the available interventions to prevent the outcome would have been insufficient.

With our current knowledge of cancer biology, latency makes sense. Take radiation for example. Ionizing radiation is very good at causing trouble for DNA in your cells. Not only can it directly damage DNA, it can actually ionize water within your cells, generating highly reactive hydroxyl anion radicals. So this means our lovely H₂O that fills our cells can become HO^·- (that's Hydrogen attached to Oxygen, and it is negatively charged with an extra electron, or a free radical as we call them). And if there’s one thing HO^·- knows how to do, it’s damage DNA and anything else it can get its hands on. In fact, HO^·- is the most powerful free radical oxidant that ever appears in our cells. So, with all this bad stuff going on after radiation exposure, we get mutations in our DNA. In cancer biology, this is called initiation, this is when the timer starts for our latency period.

Normally, our cells can detect these mutations, and gratefully, these cells decide to kill themselves before anything bad happens. Next time you get sunburned (UV light is a form of ionizing radiation) and a few days later you pull off the dead skin, give a little thanks to their wonderful sacrifice. But, every once in a while, a damaged cell will escape the programmed death. Now, without the control to know when to die, these cells can gather further mutations, continue to divide and proliferate, and with a certain amount of time, a cancer will appear. The time between the initiation from the first radiation exposure, to the time when the cancer appeared is the latency, and typically we think of these times in the forms of years to decades. This is not to say that everyone who is exposed to a carcinogen like this will develop cancer, not at all, but for those who do develop cancer, there has been effort to understand what the latency periods are. Arsenic, for example, is good at causing skin cancers, and this typically takes 10-15 years. Latency period for cigarette smoke and lung cancer, is somewhere around 30 years. The latency period for radiation exposure when looking at medically exposed radiation therapies has been observed to be between 4 and 44 years.

This concept that an initiating step can predetermine one’s risk of disease decades later makes sense in cancer, and we accept it. But, can we think this way about other diseases? Can our risk of a heart attack at age 60 be predetermined from an exposure that happened decades earlier? Can our risk of developing Parkinson’s Disease already be set in childhood? Or can our child’s risk of developing autism already be determined at birth? These questions fall into the field of “fetal origins of adult disease,” where there is growing evidence that our risk of disease in adulthood may be strongly influenced by what exposures occurred during fetal and early life development.

Fetal origins of adult disease

Interestingly, the story of this field begins with World War II. In the winter of 1944, the Nazi occupied region of the Netherlands had grown scarce with food supplies. With active attempts from the Allied Forces to liberate the country, liberation efforts stalled upon failure to gain control of a crucial bridge, which would give much needed access and food supply. In response, the former Dutch government influenced the national railways to go on strike to aid the Allied Forces. In September of 1944, as a retaliation effort to the railway strike, the German government placed an embargo on the transport of all food into the western Netherlands. An unusually cold winter had come early to the Netherlands, and although the embargo was partially lifted in November of that year, canals had already frozen over, preventing the transport of food by barge.

As a result, food stocks began to run out, and daily rations for adults dropped to below 1,000 Cal in large cities such as Amsterdam in November of 1944, and reached as low as 580 Cal in February of 1945 (compare that to our recommended caloric intake of somewhere around 2,500). The famine ended in May of 1945 upon the liberation of the western Netherlands. During this winter, millions of Dutch people were exposed to famine conditions, and roughly 22,000 people died. This terrible winter is called the Hongerwinter, or the Dutch Hunger Famine. 

http://www.precisionnutrition.com/epigenetics-feast-famine-and-fatness

Out of nearly 4.5 million people who suffered from the rations, you can imagine how roughly half of these victims are women. Out of over 2 million women affected, you can expect than many of these women would be pregnant. This is exactly what happened. In an unexpected positive outcome of this historical event, these children became the perfect group to study the effects of starvation during pregnancy, low birthweight, and adult disease. When those children reached 19, they registered for national service, which included a visit with a physician and a clinical exam. At this point, there was the creation of a large cohort of Dutch men and women who were either exposed or not exposed to the famine conditions during their in utero (in the womb) development. In addition, with nationalized medicine, there was routine follow-up with these individuals that allowed for a lifetime of clinical data to be collected.

The first publications examining this cohort began to emerge in the mid 1970’s, where it was reported in the New England Journal of Medicine that young men exposed to famine conditions during the first trimester of pregnancy were more likely to be obese.

http://www.nejm.org/doi/pdf/10.1056/NEJM197608122950701

These initial observations were subsequently followed up with many more extensive analyses, predominantly by the physician and clinical epidemiologist Dr. David Barker. In examining these individuals exposed to prenatal famine conditions, Dr. Barker discovered that malnutrition during pregnancy increases adult risk of obesity, diabetes, and other cardiovascular disorders including hypertension (high blood pressure) and coronary artery disease (plaque build up within arteries). These discoveries led to what is widely known as the “Barker Hypothesis”, which is that maternal malnutrition during pregnancy ‘programs’ the developing fetus to be more susceptible to metabolic disorders. Dr. Barker just passed away September, 2013 at age 75.

http://www.theguardian.com/society/2013/sep/11/david-barker

In his obituary in The Guardian, they gave this quote that I think is fantastic and quite correct:

"Across the world there is now general agreement that human beings are like motor cars. They break down either because they are being driven on rough roads or because they were badly made in the first place. Rolls-Royce cars do not break down no matter where they are being driven. How do we build stronger people? By improving the nutrition of babies in the womb. The greatest gift we could give the next generation is to improve the nutrition and growth of girls and young women."

So how do we build stronger people? I think before we can answer that question, we need to understand what is leading these children to be more susceptible to disease.

When we think about disease, we often times think of genetics. We will hear ourselves saying, “oh it’s probably due to genetics…” And there are a lot of reasons why this makes perfect sense, as we know that genetics and mutations to our DNA code can be very important in determining disease risk. But, there is another aspect of genetics that might be more important to our health than just the order in which our A’s, T’s, C’s, and G’s line-up. This field is called “Epigenetics,” or literally, “above” the genome. Our DNA code is used to make proteins, and these proteins do their specific jobs. But, what proteins should be made? How much protein should be made? Under what conditions? Determining what proteins to make and how much is what truly influences disease, and it is called transcriptional regulation. Epigenetics is now known to be one of the principle factors of transcriptional regulation. Since our DNA is tightly wrapped up around proteins (called histones, the complex DNA and protein package is called chromatin) the vast majority of it is unavailable to be turned into protein. So our cells have evolved amazingly complex machinery to regulate the access to the DNA. In particular, we have two dueling epigenetic mechanisms working with each other, 1) chromatin modification, and 2) DNA methylation. With chromatin modification, the protein can be modified to either open up the DNA or close the DNA. When it is opened, proteins that turn on the protein making machinery get in there and get to work. With DNA methylation, the C’s of our DNA can be modified by the addition of a small methyl group (-CH₃). As a result, the DNA methylation typically prevents that DNA from being turned into protein.

Below is an image that diagrams chromatin modification and DNA methylation.

Gluckman, NEJM 2008

Now all this epigenetics stuff may sound pretty technical and obscure, but, one thing that we’re realizing is that much of these epigenetic markings, in particular DNA methylation, is passed down each time a cell divides. In addition, we’re finding that certain environmental stressors, such as malnutrition, inflammation, injury, and toxic exposures, can cause changes in DNA methylation. So think about that, if you are pregnant and exposed to famine conditions, as the heart, lungs, brain of your child develop in the womb, the epigenetic make-up might be altered. And what we know from Barker is that these children are more susceptible to disease.

The general theory is that if you are exposed to famine conditions during pregnancy, the developing fetus adapts by changing the epigenetic profile to ensure immediate survival. But these adaptations in the womb may have adverse consequences later on. In particular, the developing infant in some ways “expects” a low nutrient environment, this is called the “predictive adaptive response.” When the infant is born, it is expecting a low nutrient environment, but when it actually is living in a nutrient rich environment, it is almost too good at using all the available energy and this is why we see increased risk of obesity, diabetes, cardiovascular disease, etc.

Below is a figure that shows how the adult risk of metabolic disease (obesity, diabetes, cardiovascular disease), is a product of the genetic and epigenetic inheritance, followed by subsequent prenatal and postnatal cues. The belief is that if there is a predicted sparse environment, but the child is met with a nutritionally rich environment, metabolic disease risk is increased. Alternatively, if there is a predicted rich environment, and is met with a nutritionally rich environment, metabolic disease risk is not increased.

Gluckman, NEJM 2008

 In utero toxic exposure as the origin of adult disease

Barker’s work gave us the understanding that a malnourished environment during fetal development can predispose to cardiovascular disease, and his quote above gives his prescription for fixing this; improve the nutrition of babies in the womb. But what about those mothers who are perfectly well nourished? Can other toxic exposures cause the same or similar long lasting effect on cardiovascular disease?

In my postdoctoral fellowship at UW, I have focused on trying to answer this question using the exposure model of air pollution. Exposure to air pollution during pregnancy is known to promote a reduction in birthweight, and with the Barker Hypothesis, it stands to reason that those with a reduced birthweight would be at a higher risk of cardiovascular disease.

What we’re trying to test here is not an easy thing to test. We are asking the question of whether or not an in utero exposure to something can promote cardiovascular disease in adulthood. To date, there aren’t any epidemiological studies with human populations and air pollution to try and answer this, so we began this study with a bit of an acceptance that it’s a high-risk project. By using mouse models, we have the ability to test the effect of an in utero exposure on adult susceptibility to cardiovascular disease in roughly 4-5 months, this gives us a way to address this in a reasonable amount of time (FYI, a mouse lives roughly 2 years, and we generally consider a mouse that is 2 months of age to be an adult).

In our first experiment, we exposed mice to diesel exhaust air pollution, at a level roughly the same of what you would find in Beijing on a modestly bad air day, during their in utero development. We let the offspring be raised in normal filtered air conditions, then when the offspring reached adulthood (3 months of age), we measured how well their hearts functioned by echocardiography at 1) baseline, and 2) after we performed a surgery that simulated a high blood pressure. Our hypothesis is that the in utero exposure to diesel exhaust would produce a long lasting susceptibility to heart failure, so when we performed the surgery to simulate high blood pressure, we predicted the hearts wouldn’t do as well and would fail.

Below is a video of a normal mouse heart under echocardiography.

The view in this video is called the parasternal short axis view, where we hold the probe directly on the chest and look at a slice of the heart perpendicular to the orientation of the heart. This allows us to see the left ventricle, measure how well it contracts, as well as determine the size of the heart and the ventricle walls. In cardiology, when the heart gets big, the walls of the ventricles get thick, and when the heart doesn’t contract as well, it means there’s trouble. When the heart fails to pump well enough, and there is not enough blood flow making it to the organs, it is heart failure, and this is one of the major causes of death worldwide. The heart in the video above is normal, since the mouse heart beats around 500-600 bpm, this is slowed down so we can get a good look. You can see that the walls of the ventricle contracts so there is almost no blood left inside the lumen of the ventricle, and this is what we want, good pumping means good blood flow around the body.

So after our baseline measurements, we performed a surgery on the mice to cause high pressure, allowing us to ask how well the heart responds to a stress. What we found was that the in utero exposure to diesel exhaust caused the hearts to respond in a much worse way. Below are two videos that show how a typical control mouse, as well as an in utero diesel exhaust mouse would respond to the increased pressure.

What you can see in the second video is that the heart begins to fail. Pumping doesn’t work as well, and the heart has enlarged to a much greater extent. What this says is that the in utero diesel exhaust exposure appears to cause a long lasting effect on how well the mouse hearts can respond to stress.

In my view, this is important. This means that the in utero diesel exhaust exposure is programming the adult mouse to be more susceptible to heart failure. In follow-up studies, we also found that the in utero diesel exhaust exposure causes direct effects to the placenta, that crucial organ that regulates blood and nutrient flow to the fetus, and that in addition to increased susceptibility to heart failure, the mice gain more weight and have altered blood pressure.

Overall, we believe that an in utero and early life exposure to air pollution can promote a long lasting susceptibility to heart failure in mice, and it is very likely that a similar effect happens in humans, but this has yet to be determined.

What can we do about this?

Our findings with air pollution are not completely unique. Similar findings have been made with in utero caffeine exposure, cocaine exposure, as well as exposure to anti-retroviral medications used on patients with HIV.

We believe all of this comes down to epigenetics. As I discussed above, epigenetics, those changes on DNA without changing the DNA sequence, can alter how well genes are turned into proteins. When the heart is under stress, it needs to be able to turn those genes on in very regulated ways, but if the epigenetics in the heart is altered as a fetus, it’s very likely the same changes will be present in adulthood, and it could prevent how well the heart responds to those stressors. We are currently trying to figure this out, but I believe there are two paths forward that we should start to think about.

1) Let’s build stronger people

If we expose developing infants to such things as air pollution, we are likely setting a trajectory of their health that won’t reach their potential. If we want to improve public health, we need to begin to realize that health begins before birth, and our regulatory policies around environmental exposures need to take this into account.

2) New clinical therapies should push hard on epigenetics and cardiovascular disease

            Epigenetics and pharmaceutical development has largely focused on cancer so far. Cancer cells have very messy epigenetics, and it may be a fantastic way to treat cancer patients, but we now understand that epigenetic factors are likely at play in cardiovascular disease, and we need to push this. But, as of now, we don’t have enough basic science research to fully understand what’s going on. The path to new therapies that will address the epigenetic regulation of cardiovascular disease needs simultaneous basic science research funding as well as pharmaceutical company interest.

With latency in cancer, there is a clear line that can be traced between the initiating event and the subsequent disease. With fetal origins of adult cardiovascular disease, there isn’t a clear line, but in many ways I feel that we can think of it as a latency. With the Barker Hypothesis, the initiating event is the epigenetic or morphologic change that occurred during fetal development, which inevitably will lead to a higher disease risk. With our growing understanding of how developmental factors can contribute to adult disease, we need to start changing how we look at disease progression. If disease progression has a developmental origin, we need to work to understand what programming occurs and work to prevent and treat these patients.

              Chad Weldy

P.S. If you are interested in reading more about our work, we recently published these reports describing our findings. They are available open access, meaning they are free for anyone to access.

1. Weldy CS, Liu Y, Chang YC, Medvedev IO, Fox JR, Larson TV, Chien WM, Chin MT. In utero and early life exposure to diesel exhaust air pollution increases adult susceptibility to heart failure in mice. Particle and fibre toxicology. 2013;10(1):59. Epub 2013/11/28. doi: 10.1186/1743-8977-10-59. PubMed PMID: 24279743. 
2. Weldy CS, Liu Y, Liggitt HD, Chin MT (2014) In Utero Exposure to Diesel Exhaust Air Pollution Promotes Adverse Intrauterine Conditions, Resulting in Weight Gain, Altered Blood Pressure, and Increased Susceptibility to Heart Failure in Adult Mice. PLoS ONE 9(2): e88582. doi:10.1371/journal.pone.0088582. 

Does body weight tell us much about our health?

When I was in college, I had the luxury of being able to stay incredibly active with collegiate Ultimate Frisbee. And as cliché as it sounds to be an undergrad at Western, playing Ultimate in the rain in Bellingham (which we now know is the wettest place in the lower 48 http://www.seattlepi.com/local/connelly/article/Bellingham-tops-list-of-cities-with-least-sunshine-4954055.php), our team had some ~15 hrs/week of practice, including weekend tournaments all across the region. It was an exhausting sport! Throughout college, I don’t know if I ever thought that I could ‘over eat’. At that time, I basically believed that the more I ate, the better I felt. And even though I look back on this time with a bit of dread, remembering my hands freezing off when the turf field froze over and the snow didn’t melt for months, I think of this time as a luxurious occasion where I literally felt that anything I ate was perfectly okay.

But, as other collegiate athletes have corroborated, going from athlete to non-athlete is awful. You go from eating anything and everything you can possibly get your hands on to, to looking at your gut and thinking, “huh?” For me, the ‘eat everything and anything’ attitude maintained for a couple of years after college. I continued to play Ultimate Frisbee for a year or two, playing for a year with UW while in grad school, then for a club team over the summers, and my body consumed the energy about as fast as I could put it in. But at some point, when I realized I needed to focus on graduate school, when it seemed like I had less time available for the sport, and when I continually fought off injuries, I found myself lacking the energy and excitement to get back into it. I continued to play every once in a while and I got to play for an awesome club team in Germany when I was in Heidelberg (http://www.heidees.de/pages/heidees-news.php), but my competitive training continued to dwindle. Although it was, and sometimes still continues to be, a little painful to stop playing, I feel that I’m learning I need to plan for my health and fitness for the long haul, and training for Frisbee wasn’t going to be sustainable for me. Kudos to those who’ve made it work!

But, when I felt that I fully stepped off the Frisbee field, and I stopped burning thousands of calories a day from training, I did not become less hungry. A normal daily diet for my years of doing sports still seemed…normal. And as predictably as an overfilled glass of water will spill over its edge, I found myself gaining weight, something I never felt was even an option before. What ensued was a continual battle, that I know many, many, people are also fighting, where eating became a thought process. I found myself no longer able to just eat ‘everything and anything’. So, after years of sports, I joined the many who actually have to think about what they eat, so lame!

So, with wanting to think about what I eat, and trying to eat a balanced and ‘healthy’ diet, I find myself asking, what is healthy? To me, health is a vague concept. What does it mean to be healthy? Can one be healthy because they lack disease? Or does it also imply a certain trajectory of disease free survival for the long term? I sometimes just feel healthier if I eat at an organic co-op, does that make me healthier? And why do I feel so unhealthy if I eat, even a relatively low fat, low caloric meal, at a fast-food restaurant? And how on earth can Trader Joe’s, selling to an organic and health conscious market, get away with calling this coconut oil? http://www.amazon.com/Trader-Joes-Organic-Virgin-Coconut/dp/B007UWNBYS. This is a side tangent, but an ‘oil’ implies that it’s liquid at room temperature, this is solid saturated fats, just as bad as any butter or animal fat, but it feels pretty healthy, right?

In my mind, ‘being healthy’ implies a trajectory of long-term survival in the absence of disease. The aspect of ‘feeling healthy’ is when you feel good doing it, and it may include some Trader Joe’s coconut oil, because it’s delicious!

So how can we measure how healthy we are? Of course there a many clinical tests in combination with clinical symptoms that a physician can use to elucidate the presence of a disease. And of course there are clinical measures that are good a predicting disease risk (such as blood pressure, hemoglobin A1C levels, blood lipids, etc…). And of course there are functional measures that can assess general physical fitness and overall wellbeing (i.e. how well one can walk, exercise, etc…). But the simplest measure that can actually be fairly good at predicting risk of disease, and can be measured by anyone in his or her own home, is body weight.

When I last went to the doctor for an annual checkup, after they measured my height, and took my weight, they quickly reported my BMI (body mass index, kg/m²) to be 25.0. As I expected it to be roughly around 25, this wasn’t a surprise to me. But I knew that 25 was the cut-off between what is considered ‘normal weight’ (18.5 – 24.9) and ‘over weight’ (25-30), with obese being 30+. So by just a smidgen, I was considered ‘over weight’. But no one at the clinic seemed to care! With such a daunting clinical condition as ‘over weight’, there has got to be some real evidence to say that I am entering into a category that has an increased risk of mortality, right? Should I be trying to drop that weight to join my ‘normal weight’ counterparts? Can I calculate the number of years I’ll lose by now entering into a trajectory of a health span as an ‘over weight’ person? Well, I don’t quite think that I’m ‘over weight’ in a true sense, although I should definitely try and maintain an active life full of exercise with a diet rich in fruits and vegetables for many reasons, and perhaps my weight will come down a little. But seeing the BMI in action made me want to look more into what evidence we actually have for using the BMI, and try and answer, how bad is being ‘over weight’ or even obese?

Looking into a few recent studies that have conducted large meta-analyses looking into the association between BMI and mortality, it becomes clear that there is some real evidence that being obese (BMI, 30+) increases risk of mortality. In addition, there is real evidence that being underweight (BMI, <18.5) increases risk of mortality. These data appear to show what is considered a J-shaped curve, where, starting at an underweight BMI, as BMI increases mortality drops to an ‘ideal’ level, then mortality risk continues to increase as BMI continues onwards towards the obese range. But what is the ideal BMI? Is there a specific BMI we should all be shooting for? And how normal is the ‘normal’ BMI of 18.5 to 24.9?

In an extremely comprehensive analysis, published by Gonzalez et al. in the NEJM in 2009 http://www.nejm.org/doi/full/10.1056/NEJMoa1000367, the complex relationship between BMI and risk of mortality becomes clear. For this study, the median BMI in 1.46 million white adults of their study population was 26.2. So right away, I’m starting to think that a 'normal' BMI of 18.5 to 24.9, isn’t so ‘normal’. The crux of their data is the non-linear relationship between mortality risk and BMI, as shown below.

Looking at the data, it becomes clear that those in the study population with a BMI of 17.5 seemed to be a part of a category that had a significant increase in mortality risk, upwards of a 2-fold increase in risk to the referent population being those with a BMI between 22.5 and 24.9. The risk of mortality drops as BMI increases, to what appears to be an ‘ideal’ BMI of something around 23-24 in both men and women. When BMI goes above this ‘ideal’, the risk in mortality doesn’t seem to dramatically increase right away. In both men and women, when BMI reached 26, there appeared to be a 6-9% increase in mortality risk in non-smokers. But then it begins to really climb, reaching a 44% increase in mortality risk with those with BMIs of 31, and over 100% increase in risk for those with BMIs above 36 and even greater for those with BMIs above 40.

In almost complete agreement with the Gonzalez study, the Prospective Studies Collaboration, within the British Heart Foundation and Oxford published in Lancet their meta-analysis from 57 studies, looking at BMI and mortality in 900,000 adults http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60318-4/fulltext. Their main findings of BMI and mortality risk are shown in the figure below.

What they report is that mortality risk is lowest for those with a BMI between 22.5 and 25. Where again, this J-shaped curve appears, where risk of mortality is higher for those with BMIs below 22.5, and increases for those above 25. But really, mortality risk for those with BMIs between 20 and roughly 27.5 appear to be nearly the same, likely small increases in risk for those with 20-22.5 and for those 25-27.5.

So looking at these data, it makes sense why a recent study by Flegal et al. in JAMA in 2013 http://jama.jamanetwork.com/article.aspx?articleid=1555137, found a significant decrease in mortality risk for those with BMIs between 25 and 30 compared to those with BMIs between 18.5 and 24.9. Their table showing hazard ratios (HRs) and BMI is shown below.

This publication got a lot of press, and people seemed to feel that there must be something that’s missing, but when looking at the data before it, these results aren’t too surprising. We know that mortality risk is higher for those with BMIs lower than 22.5, and we know that it begins to climb again for those with BMIs above 25, but not at a very fast rate. So if you combine the people with BMIs between 18.5 and 24.9, you’re going to catch the people with the higher risk of mortality with BMIs below 22.5 and the group with BMIs between 25 and 30, includes those with higher risk between 27.5 and 30, but combined, the overall risk is lower for the 'over weight' group compared to the 'normal weight' group.

So what can we learn from these studies? I think we can safely say that an ‘ideal’ BMI is between 22.5 and 25, and if one is a little lower than that, or a little higher than that, there isn’t really any strong evidence to say that risk of mortality increases. But there does consistently show strong evidence for increased mortality for those with low BMIs and with high BMIs. Overall, I think the ‘normal’ BMI range of 18.5 to 24.9, is a little off, and should probably be more like 22-27, perhaps this will change in the future.

But of course, this analysis is severely limited by the main problem with these studies: BMI is a measure that is adequate at best to predict mortality risk. We all know the examples of the incredibly athletic and muscular person who is not obese, but his/her BMI puts them into a category they don’t want to be in.

The reality is that in these studies, those individuals with high BMIs have a higher risk of mortality due to cardiovascular disease, diabetes, renal disease, cancer, etc., diseases often times due to improper metabolic health. Metabolic health refers to really how our body deals with energy and our diet, such as our blood sugar and insulin sensitivity and our blood lipids and cholesterols. We know that these factors play important causal roles in disease progression and it’s important to get an idea as to how we’re doing on these fronts. What the BMI hopes to assess is metabolic health, and what we really want to know is what is someone’s chance of developing disease due to these improper metabolic controls? And unfortunately, BMI is only a crude and limited measure.

This is why a call for better metrics for metabolic health was made recently in the journal Science http://www.sciencemag.org/content/341/6148/856.full, where the authors discuss how we now know that there are people with normal as well as obese BMIs who are metabolically healthy, just as there are people who have normal as well as obese BMIs who are metabolically unhealthy.

In the figure above, risk of mortality is shown by the elongated triangle at the top, where you can see that risk of mortality is greatest for those who are obese and metabolically unhealthy. But interestingly, someone who is of ‘normal’ BMI but metabolically unhealthy has a higher risk of mortality than someone who is obese but metabolically healthy.

What this highlights is the lack of mortality risk prediction one can get from BMI alone, and of course, any good physician will work with the patient to understand other metabolic factors that are greater predictors of risk, but what can we do at home? When I step on the scale, and reveal my BMI, am I appropriately gauging where I am ‘health’ wise? I don’t think my body weight will tell me everything, but I think if I work to keep my diet and exercise in check, in combination with keeping an eye on such things as cholesterols, blood lipids, blood sugars, and blood pressure, my body weight may help me keep a frame of reference as to how I’m doing, and for now, my BMI of 25 doesn’t sound too bad.

Chad Weldy

Should doctors care about environmental health while treating patients?

For the majority of my graduate and postgraduate training, I have studied the pulmonary and cardiovascular effects of air pollution. Through this time, I can recognize that my mindset and understanding of the importance of air pollution in public health continues to shift. In many ways, I would like to think that as I spend more time in this field, I gain greater distance from the minute details, allowing me to put the complex research into a cohesive story that gives me freedom to see this type of public health problem with perspective. As I have written in my previous post, it is challenging to distinguish between environmental exposures that are truly hazardous from those that are mostly hype, and I am still grappling with placing certain highly talked about environmental exposures in one category or another, but air pollution is not confusing for me. In my perspective, fine particulate air pollution (aerosolized particles with a diameter less than 2.5 um, PM_2.5) is truly hazardous, and it has serious public health implications on a population level. I am not alone on this either, in the most recent Global Burdens of Disease report published in Lancet, ambient fine particulate air pollution was found to be the #9 cause of disease worldwide, reaching as high as the #4 cause of disease in East Asia. Even worse, household air pollution, resulting from the practice of combusting solid fuels indoor for cooking, is believed to be the #4 cause of disease worldwide, reaching as high as the #1 cause of disease in South Asia. Household air pollution doesn’t make the list in North America, Western Europe, or Australia, as this cooking practice is generally rare in these areas. Even worse still, tobacco smoking and second hand smoke, is the #2 cause of disease worldwide. Although tobacco smoking isn’t quite the same as ambient or household air pollution, there are many similarities.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61766-8/abstract

My belief in the importance of air pollution in public health continues to shift due to my own research, where I am becoming exceedingly convinced that in utero and early life exposure to air pollution will have life long effects on susceptibility to cardiovascular disease. As we publish on this, I will write about this more, and my hope is that these observations will be translated to epidemiological studies to investigate if these effects are observed in human populations. In any event, the actual effect of air pollution on disease may very likely be much greater than what we currently know.

But, looking at the top 10 on this list, it is almost amazing to realize that nearly all of these seem to be modifiable factors. Let’s look at the top 10:

1) high blood pressure

2) tobacco smoke

3) alcohol use

4) household air pollution

5) diet low in fruits

6) high BMI

7) high fasting glucose

8) childhood underweight

9) ambient particulate matter

10) physical inactivity

Now, I recognize that there are always going to be many outside factors that influence these risks, and not all of them are easily modified. In the U.S., socioeconomic status, education level, access to fruits and vegetables, access to safe places to exercise, etc., all of these will influence factors such as diet, alcohol use, and physical activity, which will have major impacts on health. But when I look at this list, I ask myself, how does the physician address each one of these?

When looking at the #1 cause of disease, high blood pressure, I know that the physician will treat this in many ways. The physician may utilize behavior modification strategies to try and change diet and activity, encouraging weight loss and lower sodium intake, but also the physician will likely use one of several good pharmacological options to try and drop BP. Looking at tobacco smoke, nearly every physician will counsel their patient on tobacco smoke, they may even be required to counsel their patient on this depending on where they practice. Perhaps the doctor will pull out the 5A’s and 5R’s of tobacco cessation (Ask, Advise, Assess, Assist, and Arrange, Relevance, Risk, Rewards, Roadblocks, Repetition (http://www.primaris.org/sites/default/files/resources/Smoking%20Cessation/sc_algorithm.pdf), and there seems to be evidence that it works (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628990/). The same trend goes with alcohol consumption, diet low in fruits, high BMI, high fasting glucose, and physical inactivity, the clinician has a plan for each one of these… except for air pollution.

Two years ago, a very reputable cardiologist and environmental health researcher from the US EPA and University of North Carolina came to the UW to give several talks and to meet with our group investigating traffic related air pollution and cardiovascular disease. With his visit, he gave the early morning Cardiology Grand Rounds talk at UW, where he met the weary eyes of the residents, fellows, and attendings, looking for CME credit before they start their day in their clinics or hospital units. He gave what was in my opinion, a fascinating talk that highlighted the truly exciting work coming out of the US EPA on air pollution and cardiovascular disease. Looking around the room, I mostly saw physicians sleeping, but a few people seemed to be engaged. After his talk, I was standing around, talking with some colleagues, when one of the highly influential cardiology attendings at UW proceeded to explain to us PhD dimwits, “there is simply no place for air pollution in the cardiology clinics!” At first, I was taken aback by what I thought was a short sighted view of the role of air pollution in population level cardiovascular mortality, but with letting his comments sit for a while, I asked myself, “Is he right? Is there no place for air pollution to be discussed in the clinic?”

Not too long after this encounter, I was invited by a group of physicians in Whatcom County to give my own CME Grand Rounds seminar at St. Joseph Medical Center in Bellingham, WA, on the health effects of fine particulate air pollution. When preparing for this seminar, I was asked to produce a document that would explain what the clinicians would gain from attending my seminar, and specifically, how it would influence their practice of medicine. In trying to answer this question, I had to do a little exploring.

The reality is that air pollution is a major contributor to disease, but the answer to reduce the adverse effects of this type of exposure is simple yet complex: eliminate exposure. Although the concept is simple, unfortunately, reducing exposure isn’t easy. This is why strong air quality policies are critical in playing this role. So what can the physician do? Well, the EPA has some very simple guidelines for clinicians, 1) teach your patients about the air quality index, find it at http://airnow.gov/, and teach them to use it, and 2) if air quality gets bad, make certain recommendations such as, reduce prolonged heavy exertion when air pollution is moderate, to completely avoid physical activity outside when air pollution is truly bad, here are the recommendations http://www.airnow.gov/index.cfm?action=pubs.aqguidepart.

When answering the question of how my seminar will add to doctors' clinical practices, I reluctantly put the EPA guidelines down, but there’s more to it than that, and I wasn’t satisfied with these simple guidelines being the only way clinicians would use air pollution in their clinics.

I find these recommendations to be sound, solid recommendations. They are pretty simple, potentially easy to follow, but will following these guidelines really make a big difference? In a region such as the PNW, bad air pollution events only happen once or twice a year, and perhaps there would be some modest benefit to advise patients who are living with current heart or lung diseases to avoid physical activity outside during this time, but the overall benefit is likely to be quite small. So, other than simple recommendations for those with chronic lung and heart diseases, can the physician play a role in trying to bring air pollution down on the list of causes of disease?

After trying to understand the role for the clinician in environmental health, I have come to believe that the physician has an extremely important role to play in reducing risk of disease from environmental exposures, although my reasoning may be somewhat convoluted, stick with me. As I mentioned above, in nearly every environmental exposure, the way to reduce an adverse effect of exposure on disease risk is to eliminate exposure. Certain environmental exposures can be modified by the individual (take smoking for example, or exposure to consumer products, or heavy metals in fish), but more often than not, environmental exposures occur without permission, where someone passively inhales the fine particulate that emerged from a diesel engine, and subsequently suffers from increased risk of disease. With looking at air pollution, exposure can be looked at as the product of concentration and time (C x T), the physician can advise patients to avoid outdoors and prolonged exercise in bad air pollution events (decreasing T), but if C doesn’t change, it’s going to be tough to truly drop exposure over the long run. This is why I am an avid proponent of a strong regulatory body such as the US EPA, setting regulatory standards that protect those who would suffer the health impacts from the hands of development without any of the financial profit. But what can the physician do in setting regulatory standards?

The reality is that when a patient has questions about health and the environment, they ask their doctor. There is an excellent 2003 review article in Pediatrics, titled “Environmental Risk Communication for the Clinician”, for those who are clinical doctors, I recommend it. When I read this, there were 3 important concepts that stuck with me, 1) clinicians are the #1 trusted and credible source of information on environmental health risks, 2) questions about environmental health rank among the top in questions patients have for their clinicians, yet clinicians have a hard time answering them, and 3) overall, most people go to their doctors. Meaning that when people have questions about environmental health risks, they’re more than likely to ask their doctor.

http://pediatrics.aappublications.org/content/112/Supplement_1/211.full.pdf

So what does this mean for regulatory policy? How will the information the doctor knows about environmental health influence any US EPA standard and reduce exposures? The answer is that our regulatory policies change when the public demands change. As much as we would like to believe that our regulatory standards are set with a perfect communication between environmental health researchers and EPA policy makers (who are obligated by law to set standards without the influence of politics or economics), the public has historically played a critical role to influence policy by demanding change.

Below is an image of the air pollutants sulfur and nitrogen oxides in the Eastern Half of the U.S., comparing the differences in concentration between 1989 and 2004 (From Casarett and Doull’s Toxicology). What is obvious is that air pollution has dramatically improved since reaching its worst in the 60s, 70s, and 80s. The reason it has improved is due to the Clean Air Act and subsequent additions to the law, increasing its regulatory strength. Prior to the CAA, the public was fed up with the poor air quality, and vigorously advocated for change. Even today, nearly everyone I have met who lived in Southern California in those decades remember how bad it was and have their own personalized stories of eyes and lungs burning. The public’s advocacy is what led to this major policy, reducing exposures of air pollution for millions of Americans and improving the health of the public.

http://books.google.com/books/about/Casarett_Doull_s_Toxicology_The_Basic_Sc.html?id=4yi7-j48uhIC, Casarett and Doull’s Toxicology, page 1123

Today, our health hazards from environmental exposures are less obvious. With particulate air pollution, people may not even notice when air quality is truly bad, yet the human health risks are still there. My belief is that physicians, whether they like it or not, have a role to play in educating the public when it comes to environmental exposures. When the public is educated about real and potential health risks from environmental exposures, public advocacy demanding regulatory changes will follow. Although I recognize that with 15 min clinic visits, bringing up environmental health isn’t necessarily at the top of the list (and it shouldn’t be), I do believe that physicians need to have a strong understanding of these risks to better counsel patients when they have questions, or when exposures do become a serious clinical concern.

I would be very interested to hear from any clinicians about their experiences with counseling patients on environmental exposures, is it something that ever comes up in your clinics? Do you have any advice on how to answer these questions?

Thinking back to the influential attending who didn't t believe air pollution had a role in the cardiology clinic; in my view, air pollution is a major cause of cardiovascular disease, and if the goal in medicine is to improve health and ease suffering, air pollution and other environmental factors will be a part of the equation until the exposures are zero, until then, I believe it will always have a place in the clinic.

Chad Weldy