Good morning. Dr. Luca Valenti, my co-moderator, and I are delighted to welcome everybody to this exciting session about steatohepatitis in Europe and the U.S. Dr. Petta and Younassi will provide brief summaries of the public health burdens of NAFLD in Europe and the U.S.A. Then each of the next three speakers will address potential public health opportunities that might be targeted to stem this epidemic. Dr. Obin will tell us about measures that might be adopted to improve the obesogenic environment. Dr. McLean will follow with potential strategies to reduce exposure to disease accelerants. And finally, Dr. Moreland will wrap up the session by discussing opportunities for interventions early in life. Our speakers will be available to address your questions in real time during the symposium via the text chat feature on the right-hand side of your screen. And you should be able to see this as the presentations are being delivered. Please feel free to type in if you have any questions. Thanks again for joining the symposium. Let's get started. Hello, I'm Zubair Younassi. I'm the President of Innova Medicine Services and Chairman and Professor of Medicine at the North Fairfax Hospital in Fallshurst, Virginia. It is my pleasure to spend the next 15 minutes to give you an update on the public health implications of non-alcoholic drug-delivered disease burden in the United States. Before starting, let me thank AACLD and the organizers for inviting me to present here. These are my disclosures. Before discussing the actual data, let me define some terminology. So when I talk about comprehensive burden, I'm talking about how common is the disease in terms of prevalence and incidence, and what are some of the outcomes that they're providing, the different outcomes that we can look at. When you're looking at the clinical burden, which is measured by mortality outcome, the surrogates are for overall mortality, things like crude death rates, life expectancy. You also understand that there is going to be liver-related mortality related to cirrhosis and STC, as well as extra hepatic mortality related to subcardiovascular mortality and diseases, as well as non-liver cancer, sarcopenia, and other extra hepatic manifestations. Patient experience outcomes, or the PRO burden, is really measured by things like quality of life, both in terms of physical, mental, and social health impact. The functional burden of malperties is measured by surrogates, such as functional status, DALYs. And then the resource utilization outcome or economic burden of malperties is measured by cost-effectiveness, and also cost-effectiveness analysis of different sort of treatment that you look at. So let me just take you through some of the data that actually support the different types of burden for non-cardiovascular reasons. First of all, how common is malperty in the United States? Globally, the prevalence of malperties is 25 percent. In the United States, it's about 24 percent. In the type 2 diabetic, the global prevalence of malperties is estimated to be about 55 percent. In the United States, about 52 percent. The global prevalence of malperties among children is about 7.6 percent. In the United States, it's about 6.5 percent. It's also important that the prevalence of NASH, which is going to only be estimated, and the general population is about 1.5 to 6.5 percent. That probably is also applicable to the United States. And the prevalence of NASH among type 2 diabetics is about 37 percent or so. The second component of the burden of non-cardiovascular diseases is really its progressiveness in this context. All non-fatty patients, regardless of underlying histology, are at risk for increased cardiovascular mortality. On the other hand, patients who have underlying NASH are those who are predominantly at risk for hepatic outcomes, in terms of cirrhosis, liver cancer, and decompensation. And this is probably about 15 percent or so over about a 20-year period of time. It's important to remember there are two peculiarities about this disease. First of all, that patients with NASH, even in the absence of cirrhosis, can develop HCC. That rate is actually lower than what is actually considered to be the cost-effectiveness threshold for screening for HCC. So screening is actually only limited to patients with cirrhosis and NASH. And the second part of this has to do with the fact that the progression is non-linear. Some patients progress while others actually regress or remain stable. And this, of course, leads to significant, significant placebo rate in clinical trials, making this disease a pretty complicated disease. When you're looking at the data from the United States, it shows clearly from the NHANES data in the past three decades, the prevalence of NAFLD is increasing while the prevalence of hepatitis C is decreasing. Hepatitis B and alcoholic liver disease are basically stable. The second piece of information that's affected here shows that, again from NHANES data, that mortality of patients with NAFLD increases with increasing components of metabolic syndrome. The third piece of data from Sears' database suggests that NAFLD is among the top three causes of liver cancer in the United States, and this probably is associated with poor prognosis. And finally, death rates from non-required factors is increasing. So let me just show you now some of the specific data from this. Now let's look at liver transplantation as an important outcome. And this data is from the SRTR database between 2002 and 2019 for almost 168,000 patients. And as you can see in figure A, you see that hepatitis C is declining as an indication of liver transplantation. In contrast, alcoholic and non-alcoholic livers disease is increasing, and non-alcoholic liver disease in green is now the second indication of liver transplantation in the United States. When you look at the rate of increase or proportion relative to 2002, you see that the rate of increase is highest for patients with non-alcoholic hepatitis or NAFLD. And in this context, in fact, in a number of subgroups, NAFLD and NASH are already the most common indication of liver transplantation for female patients, for those who are 55 or older, and those who are Medicaid recipients, making, again, the point that NASH is rapidly becoming the most common indication of liver transplantation in the United States. Now let's look at mortality-related NAFLD. In fact, this rate, mortality rate, was increasing in the United States between 2007 and 2016, as depicted on the left side, both for men and women. However, the annual increases in NAFLD-related death were observed to be higher in women, about 3%, and about 1.2% in men. Additionally, from 2007 to 2016, the largest annual increases were observed among whites and among American Indians. And finally, when you look at the percent distribution of NAFLD-related deaths according to underlying cause of death for 2016, you'll see that the annual increase was highest for HCC, followed by diabetes-related death, non-liver cancer-related death, cardiovascular death, and cirrhosis deaths. Now when you compare NAFLD to other liver diseases, such as chronic hepatitis C and hepatitis B and alcoholic liver disease, you can see that the mortality from hepatitis C, both from cirrhosis and HCC, are coming down, while those for NAFLD and alcoholic liver disease in this context are both going up. And in fact, when you model this, you'll see that between 2015-2030, there is a doubling rate of advanced fibrosis in patients with NAFLD, and the complication of NAFLD-related cirrhosis, decompensated cirrhosis, etc., is actually increasing. In fact, it's been estimated that by 2030, there will be about 800,000 excess deaths, liver-related deaths, in the United States. Now let's put the use date in the context of GPD dataset. And when you look at the incidence rates, you'll see that for high-income North America, which is primarily the United States and Canada, you'll see that the red boxes related to NASH suggest that there's an increase in liver cancer incidence related to NASH, as well as cirrhosis related to NASH. When you look at mortality, a similar picture for North America related to liver cancer and cirrhosis-related mortality arises. Now another important surrogate for burden of disease is DALYs, or disability-adjusted life years, which quantifies the burden of disease in terms of both mortality and morbidity. And you can look at one DALY as loss of one year of healthy life. And this is a study, again, from GPD that was published recently, looking at between 2077 and 2017. In North America, the most constant increase in age-standardized DALYs was observed in patients with NAFLD. So that actually is related to not only liver cancer, but also cirrhosis-related DALYs. Another important issue to remember is that non-alcoholic fatty liver disease is a part of a multisystemic disease and is associated with a number of extrapartic outcomes, such as cardiovascular, an outcome which you already mentioned, malignancies, extrapartic malignancies, sarcopenia, chronic kidney disease, obstructive sleep apnea, et cetera. Let me just now spend a few minutes and cover these for you. As I mentioned previously, cardiovascular mortality and cardiovascular diseases are common in patients with non-alcoholic fatty liver disease. And CBD is the most common cause of death among patients with NAFLD. And, of course, this has to do with common pathways between these two diseases. Let me just spend a couple of minutes discussing the CV and overall mortality rates of non-alcoholic risks and its association with NAFLD. So here is another study from NAHMS, adults with NAFLD, followed for up to about 21 years of follow-up. And risk for cardiovascular disease was defined according to the arthrosporotic cardiovascular disease score. And if that score was 7.5% or higher, then these patients were considered to have high risk for CBD. And as you can see that those patients that have high scores, their overall mortality, as well as cardiovascular mortality, was significantly higher versus those NAFLD patients that have a low score for cardiovascular risk. This, of course, suggests that if you have NAFLD patients and you calculate this ASCBD risk score, you can determine which patients would be at highest risk for CV mortality or adverse outcomes. This is another interesting study looking at the impact of modifiable CV risk factors on the long-term outcome of patients with NAFLD. In fact, these risk factors include BMI, smoking, physical activity, healthy diet, total cholesterol, blood pressure, and glycemic control. First, NAFLD patients were shown to be less likely to have ideal CV health metrics, as depicted in the figure above. Second, NAFLD patients with five or more ideal metrics reduced their risk of all-cause mortality and CV mortality substantially. This, of course, suggests that these patients should have a should actually focus on improving these risk factors that are potentially modifiable. Another extrepidic complication of NAFLD related to cancer, extrepidic cancers, is a study from Olmstead County of 4,700 patients with 14,000 controls for two decades or so, and shown clearly that NAFLD was associated with a higher risk of incident cancers. In fact, not only colon cancer, pancreatic cancer, gastric cancer, and uterine cancer. Sarcopenia is an underappreciated complication associated with NAFLD. It is considered an extrepidic manifestation of NAFLD. This is a study, again, from Haines, between 1999 and 2004, really showing two things that's going to be important. First of all, active activity is inversely associated with sarcopenia, meaning that patients who are inactive have higher rate of sarcopenia than those who are active among the non-oncologic father-of-a-difference patients. And second point is that presence of sarcopenia is associated with all-cause mortality, cardiac-specific mortality, and cancer-specific mortality among NAFLD. Of course, this suggests that for patients with NAFLD, sarcopenia is an important complication, and it's something that needs to be assessed carefully. Finally, I'm going to spend a few minutes talking about the NAFLD in the United States. This is data from a different part of the world, but I'm just going to focus on data from the United States. And this data from Haines' data set suggests that the prevalence of lean NAFLD in the United States is about 7%. And of course, here, lean was defined according to Bonneville's index. Although most studies of lean NAFLD focused on BMI, it's probably more appropriate to look at waist circumference when defining lean NAFLD. This is a study of an H3 that looked at NAFLD patients as well as a control group. There are two points that are important. When you look at patients who have NAFLD, even in the context of being lean according to BMI, when they're obese according to waist circumference, the prevalence of hypertension, hyperlipidemia, diabetes, and even metabolic abnormality is much higher in patients who have vestibular obesity. And second, and probably more important, is that mortality is independently associated with vestibular obesity. And the risk of mortality in NAFLD is affected by the presence of vestibular obesity, especially in the lean BMI subgroup. Finally, let me just actually give you an overview of the PRO burden and economic burden of NAFLD. First, in contrast to what you've heard in the past, NAFLD is not an asymptomatic disease. Fatigue is very common as a symptom in patients with NAFLD. In fact, from a global registry, and this is both from the United States as well as outside the United States, you can see that severe fatigue can actually be experienced in about 30 to 40% of patients. And fatigue has a negative impact on quality of life of these patients, and quality of life actually worsens with more advanced liver disease among NAFLD patients. So, in this context, NAFLD can impact patients' experience and their quality of life. The final type of outcome that I'm going to look at is the economic burden. And we've done a number of different Markov models. This is one of them that was published a few years ago, looking at the economic burden of non-ecologic liver disease. And in this context, non-ecologic is severe hepatitis. And the bottom line is that when you look at lifetime direct costs of patients with NASH and advanced fibrosis, it's over about $100 billion or so. So, this is a very expensive disease from a societal cost perspective. So, to summarize, assessment of burden of NAFLD should include clinical outcomes, which is both hepatic and extrapathic, patient-reported outcome, and economic outcome. This comprehensive burden of NAFLD in the United States is enormous and continuously growing. In this context, a multifaceted public health strategy in conjunction with a national policy is needed to address the burden of NAFLD in the United States. Thank you very much for your attention. Dear colleagues, ladies and gentlemen, first of all, let me thank the organizers for the kind invitation, for the opportunity to speak with you about the public health implications of the non-ecologic fatty liver disease burden in Europe and Asia. Is really NAFLD a public health talent in Europe and Asia? First of all, let me look at the epidemiological burden. This is a recent updated meta-analysis pooling available evidence about NAFLD prevalence in Europe and finally reporting a mean NAFLD prevalence of 27.6%. And we're moving to Europe and Asia. This other recent meta-analysis shows a very high heterogeneity and an overall prevalence of NAFLD of 29.6%. The same meta-analysis also shows a very interesting data, so a prevalence of lean NAFLD of about 12%. However, these are only mean data. And if you look, for example, at age, we can see that the prevalence of a non-ecologic fatty liver disease progressively increased according to age, being highest in individuals older than 45 years. And we're looking at the metabolic risk factors. So, for example, in this slide from an Italian study, but quite validated, we can observe that the prevalence of NAFLD is higher than 50% in this population. And what about diabetes? So, these other recent meta-analyses report the mean NAFLD prevalence in diabetic European patients of 68% and in Asia, ranging from 52 to 67%, again, higher than 50%. This is the picture today with the forecast for the future. So, this is a model with limitations related to data input into the model. But this model estimated an increased prevalence of NAFLD from 2016 to 2030 in Europe, ranging from 11.3% in Burma to 12% in Spain. And what about the Asiatic populations? There's other similar models estimated an increase in NAFLD prevalence of 29% in China in the same period of time, and in the other Asiatic regions, ranging from 6 to 20%. But why NAFLD epidemiological burden is growing? This is probably related to the two main clinical drivers of NAFLD, obesity and diabetes. But if you look at the epidemiological burden of obesity in Europe, and these are data from WUAT 2016, we can see that the mean prevalence of obesity is 23% and the mean prevalence of weight is 58%. And moving on to the figure, the same data from WUAT 2016, report the prevalence of obesity in China was 6% and it's a decision of 4.7%. And of WUAT, 34% in China and 22% in Southeast Asia. The problem is that this is not a flat picture, but looking from 1975 to 2016, there was a double in the prevalence of an aphrodisiac, and a five-time increase in Southeast Asia. And the problem is that the increase was about over 10 times among children and adolescents. And what about diabetes? So this is the estimated prevalence of diabetes in Europe at 2019 by ADF, 6.3%. Again, estimated to increase at 7.8% at 2045. And moving from Europe to Asia, so the situation is worse because we have an estimated prevalence now of diabetes of about 11%. Estimated to increase at 13% at 2045. So I think that all this data are enough to say that the epidemiological burden of an oncological liver disease in Europe and Asia is really a public health problem. And what about the clinical part? These are data from the Global Burden of Diseases at 2017, and in this slide you can see the global and regional incidence cases of liver cancer in green and cirrhosis in orange. So you can see from 2012 to 2017, incidence cases increased over 21% for liver cancer and 7% for cirrhosis. And these pictures are true for both Europe and Asia. The problem is whether we have to account for this observed increase of incidence of type of chronic liver disease. First of all, let's look at hepatic-level fibrosis. This is a good review article summarizing available evidence about the prevalence of hepatic fibrosis in general population. As you can see, this study reported a very wide range of prevalence from 0.9% to 26%. And it depends on baseline characteristics of the studied population, tools used to diagnose fibrosis, and most relevant, cut-off used to diagnose fibrosis. In fact, if you look at the paper from Wong and colleagues, and Zira, Selber, Sarge and colleagues, the studies looked at the advance of fibrosis by FibroScan and FibroTest respectively, reporting prevalence of advanced fibrosis ranging from 0.9% to 2%. In terms of absolute numbers, very high, very big numbers. And it is clinically relevant because it gives to patients a higher risk For example, diabetic populations, they estimated the prevalence of advanced fibrosis is 13% in Europe, it is in China, and 17% in Asia. And again, it is clinically relevant because the recently updated meta-analysis confirmed that the risk of developing a liver imbalance is 2.5 or 5 or 12 times higher in patients with F3 and F4 fibrosis, compared to those with F1 fibrosis. So, let me look at complications of nerve and hepatocellular carcinoma and liver decontamination. When speaking about hepatocellular carcinoma, this is one of the first European studies from UK, 600 patients with a newly diagnosed hepatocellular carcinoma, recorded from 2000 to 2010. As you can see, over time, NAPLD in Orange was the most growing cause of hepatocellular carcinoma. And consistent with this data, data from the European Liver Transplant Registry, 60,000 patients who underwent liver transplantation between 2007 and 2017, 28% of them for hepatocellular carcinoma, showing that, discriminating through different periods of time, according to the kind of antiviral therapy for ACV, the proportion of necessary patients who underwent liver transplantation increased from 0.3% to 1.1%, a three-time increase. And moving from Europe to Asia, there is this recent study that reports the etiological trend of patients with a newly diagnosed hepatocellular carcinoma from 1991 to 2015, 7,000 patients. And as you can see in red, the proportion of patients with hepatocellular carcinoma not related to ACV and APD infection, so including non-alcoholic effect liver disease, increased three times from about 10% to 30%. And what about liver decompensation? I show you again data from the European Liver Transplant Registry. In this case, patients underwent liver transplantation for decompensated cirrhosis, and you can again see that the proportion of naturally decompensated cirrhosis when they underwent liver transplantation increased from 1.2% to 3.1%, again, a two-time increase. And finally, data related to NAFTA. So these are data from the Global Bargain of Diseases 2017. In this slide, you can see the contribution of different liver diseases on age-standardized death rates for cirrhosis. And as you can see, in both Europe and Asia, the proportion of patients in blue with NAFTA is irrelevant. And as you can see in this other slide, it's the same for liver cancer. This slide gave, in fact, the age-standardized death rate for liver cancer. And finally, what about forecasts? The forecasts are bad because the same models reported an irrelevant increase from 2015 to 2030 in incident cases where protocellular carcinoma liver decompensation and liver death from NAFTA. And this is a picture in Asia. We have a similar picture also in Asia, two different models. Again, in China, Japan, Taiwan, Singapore, Hong Kong, and South Korea, it's expected a relevant increase in the protocellular carcinoma liver decompensation related to NAFTA. So I think that overall, these data are enough to say that the clinical burden of NAFTA in Asia and in Europe is really a public health hazard. What about the quality of life of burden? Another interesting point. So this is an European study from five European countries comparing NAFTA patients with individuals from general population and diabetic patients. So this study reported that the patients with NASH compared to general population had a significant impairment in both mental and physical components of the scopes. And NASH compared to diabetic patients also impairment in mental components of the scopes. The same study reported an increase in NAFTA compared to general population in anxiety, depression, and sleep disabilities. And finally, the same study reported a higher percentage of overall work impairment and activity impairment in NASH and a lower percentage in NASH compared to general population. Let's look at another problem. So different in the quality of life in patients with NAFTA according to severity of liver fibrosis. This study on a large cohort of patients with frequent liver fibrosis from stellar trials including whole-body patients from this study demonstrated a further impairment in quality of life in patients with liver fibrosis compared to those with epithelial liver fibrosis. So I think that shows that NAFTA is a symptomatic disease and that the quality of life of burden of NAFTA in Europe and Asia is really a public talent. And finally, what about cost burden? This is an Italian study on 9,000 NAFTA patients from 2011 to 2017 identified by administrative databases of Italian local health units. So, briefly speaking, this study showed that NAFTA has a relevant economic impact on the national health care system and that costs are higher in patients with cirrhosis compared to without and progressively increased according to the past with the over-compensated cirrhosis and paroxysmal carcinoma and liver transplantation. Further insight arises from Europe and from Sweden about this topic. So this is a Sweden study on a cohort of 600 patients with biopsies of NAFTA when NAFTA rolled from 1971 to 1929 compared to mentioned contours and followed till 2014. As you can see in the left, this study showed that hospitalization costs in NAFTA are significantly higher than in contours subjects. And this is true for both patients with mild, moderate, and advanced fibrosis. And again, this study in the right showed that costs are higher in patients with advanced fibrosis compared to the milder stage of liver fibrosis. And looking again at Europe, there is this other interesting study, the GAIN study from five European countries and the US. So this study is relevant because it does not report only direct medical costs, but it showed also that direct and non-medical and indirect productivity costs are relevant for NAFTA. And finally, this study also confirmed higher costs for patients with advanced fibrosis. And moving from Europe to Asia, there is an interesting analysis from Hong Kong looking at costs in a lifetime horizon modelled by biochemical models for all stages of NAFTA. And finally, this study confirmed pressures at the nation with costs of $1.3 billion and 124 liver transplants over 20 years with an average cost per year of $250. So very relevant data that are enough to say that the cost burden of NAFTA in Europe and Asia is a real public health target. And if NAFLD overall is a public health target in Europe and Asia, what are we doing? In front of a disease that is a clinical, economical, epidemiological relevant disease. So this analysis, in summary, from the European Association for the Study of Liver showed that 999 participating countries had official national strategies for NAFTA. So, if you look at different domains, all of the specialist and referral algorithms in primary care, national or regional registries, ongoing or essentially non-epidemiological studies, we have positive feedback only from a few countries. In conclusion, I think that NAFLD is a public health target in Europe and Asia in terms of epidemiological, clinical and cost burdens. NAFLD awareness should be promoted across physicians, patients and policymakers. Prevention strategies are necessary and the identification of NAFLD patients at risk of liver disease is demanding. Thanks for your attention. I have received advisory boards and consultancy fees from the companies listed below, but I have no shares or financial interests in any of them. I'm also indebted to members of my lab at UCL and KCR past and present, colleagues at Guy's and St Thomas' Hospital London and my national and international collaborators. I received a recent referral, dear Dr Oban, my colleague passed on your contact details. Please will you kindly see Mrs JB, a 40-year-old lady with Nash cirrhosis, decompensated with ascites and peripheral edema, referred from a local district general hospital. She has three young children. Gastroscopy has shown no varices and she continues to work full-time as an exams officer in a secondary school. She weighs 165 kilos, BMI 56 kilos per meter squared. Based on her BMI, she was not deemed a suitable candidate for liver transplantation, nor indeed for bariatric surgery. Kindly see and advise regarding metabolic endoscopic therapy. Otherwise, we are looking at palliative care. Many thanks for your input. Best regards. Palliative care, 40 years old, three young children. As of course you know, the projected numbers of liver transplants for hepatitis C is going down and that for NAFLD is rising. And Nash is now also the most rapidly growing cause of ACC amongst US patients listed for liver transplantation. We were pleased in a way then, when in 2019, EASL, European Association for the Study of the Liver, came out with a policy statement categorically stating that obesity is feeding the rise in NAFLD across Europe and that the cost of this was horrendous. The projected annual cost something like 35 billion euros without societal cost and with societal cost something like 200 billion euros. The projected obesity rates up to 2030 in the United States is up to 40 or 45% and in Britain, in England, about 35%. In 2020, there are no licensed pharmaceutical options for NAFLD and all the guidelines tell us to give our patients lifestyle advice or lifestyle intervention. But how do you give them lifestyle advice when as you know, as a doctor, I don't eat anything and if I do, I only eat salads or it's in my bones or it runs in my family or I eat lots of fruit. But how much fruit do you eat? Two kilos per day? Really? Are they lying to us or are they ill-educated about the subject at hand? I suggest to you that they are ill-educated about the subject at hand and one of the things we need to do therefore to improve the obesogenic environment is education but more about that later. So how do we improve the obesogenic environment? Well, you could argue that the first thing to do is to exert influence on the food industry and this is what we decided we should do when colleagues and I launched the Obesity Action Campaign at the House of Lords several years ago. I suggest to you though that you do not go down the line of brand-shaming because if you do, that may be legally difficult because you may be sued. The solution I propose to you is fourfold. 1. Advocacy 2. Education 3. Research and 4. Taxation What then is advocacy? Well, as I said already, Obesity Action Campaign, which we launched several years ago has now merged with Obesity Health Alliance and there are now something like 42 organisations in Obesity Health Alliance and the whole purpose of this is to exert pressure on governments. Obesity Health Alliance now includes Action on Sugar the Royal College of Physicians the Royal College of Nursing the College of General Practitioners British Health Foundation College of the Least Disc the BSG College of Surgeons Edinburgh College of Surgeons London and Cancer Research UK and so on and so on. About 42 organisations, of course, including Basel, the British equivalent of ASLD. OK, how then to exert influence on the food industry? Well, the main way to do it, the best way to do it, is to exert influence on policymakers by persuading them that obesity and indeed NASH are the HIV of the age and most importantly, that there are votes in obesity. And of course, we now know that obesity is tightly linked with COVID. We've managed, through Obesity Health Alliance, to persuade the Mayor of London to set up a London Child Obesity Task Force. And this is us trying to persuade the previous Health Secretary that the NHS was spending too much money on obesity and complications something like 8 billion pounds, or sorry, 8 billion dollars yearly. Now, through Obesity Health Alliance, we've agreed 10 action points. We've agreed that reducing obesity should be all government's priority. Two, protect children from junk food marketing everywhere. Three, expand the soft drinks levy, i.e. raise the taxation on soft drinks. Four, ambitious reformulation to reduce the amount of sugar in commonly consumed foods. Five, create a healthier retail environment and no more two-for-one junk food advertising. Six, evidence-based training for health and social care professionals. Four, mandatory clear labelling on food and drinks. Sorry, that should be seven even. Seven, mandatory clear labelling on food and drinks labelling. Eight, all schools and early years set in to be healthy environments. Nine, sustainable funding for public health. And ten, healthy hospital food. It may surprise you that some hospitals don't have healthy food, really? Answer, yes. Ok, so Public Health England agreed with the food industry back in 2015 that they should aim over the next several years to reduce the amount of sugar in commonly consumed foods. These are the latest figures, published several weeks ago, showing that the amount of sugar in breakfast cereals is reducing, as is that in ice cream, as is that in yoghurts and fromages. So yes, we're making some progress vis-a-vis sugar, ok? Secondarily then, education. Two odd years ago, Cancer Research UK came out with an advertising campaign clearly stating that obesity caused cancer. The advertising campaign caused an almighty stare in the United Kingdom. But great, because people were arguing, no it doesn't cause cancer, no it doesn't cause cancer, where's the evidence? My friend, go and read the literature, of course it causes cancer, at least 13, 14 cancers. So yes, educating the public is important, ok? Research then. Right, my group and I, through the Obesity Curriculum Analysis of Medical Schools, we've set off to analyse the amount of education that junior doctors who are graduating this year received during their education. And at KCL, obesity, number of hours, eight in total. Nutrition, 15 in total. This is over five years. And education on physical activity and exercise, over five years, six hours. In total therefore, over five to six years at KCL, 29 hours. Edinburgh, even worse, over five, six years, number of hours on obesity, nutrition, physical activity and exercise, four hours. Having got the evidence now from Edinburgh and KCL, we're now interrogating all the medical schools in Britain to get similar evidence, which we hope to present through the General Medical Council, in the hope that we will get more education of doctors on obesity, nutrition, physical activity and exercise. Alright, so finally then, taxation. I was in Australia recently and I happened to pop into a store and I asked a friend, how much do packs of cigarettes cost here? I was outstanded to learn that a pack of cigarettes, a pack of 20 in Australia, costs something like 75 Australian dollars, equivalent to 53 US dollars. And cigarette prices in Australia are highest in the world. And of course, cigarette smoking, the evidence is, is markedly reducing, of course, in Australia because of the taxation. So then, in terms of sugar, what do we do? Well, clearly, we would argue, in Obesity Health Alliance, that the best thing to do is educate the public and also tax them. Because if you don't do that, nothing else is going to work. Okay, is there evidence that if you do tax them, that will reduce the consumption of sugary foods? Well, actually, yes, there is. There is this paper, Shilbur Katawa and others, showing if you increase, if you increase the price of high sugar snacks by about 20%, that that could reduce energy intake, because you reduce the consumption of those foods. This, of course, was in a UK context, but we don't expect that it's going to be different in any other, in the context of any other country. I'm grateful for your attention. Thank you. It's a pleasure to be here today and to participate in this virtual workshop and discuss reducing exposure to disease accelerants, specifically alcohol and environmental toxins. I'm Craig McLean. I'm Associate Vice President for Health Affairs at the University of Louisville. And I have nothing to disclose related to this particular talk. So we'll talk about alcohol first. And there are a variety of groups that deal with impacting alcohol consumption in the United States, including the NIAAA. And they have a great website on rethinking drinking, professional organizations, industry, dietary guidelines, which we'll talk about a little bit later, and others. So the good thing about alcohol is that we have a standard drink. So that is 14 grams of alcohol. So whether you're a beer drinker over here on the left, a wine drinker like my wife, or a bourbon drinker like me, we're talking about the same amount of alcohol. Now it's important to understand drinking patterns as well as amounts. So moderate drinking is defined as currently one drink a day or less for women and two or less per man. We'll talk, that's going to probably change. Binge drinking is four drinks on one occasion for women and five for men. And importantly, shown at the bottom in red is what patients admitted to our alcoholic hepatitis study are drinking, which is 13 to 15 drinks a day, which is about 2000 empty calories, which shows the nutritional impact. Patterns of drinking are very important. So one drink a day throughout the week is seven drinks, which is not the same as drinking seven drinks in one day on Saturday. This is a great study that'll never be reproduced, but it highlights the importance of drinking, and that we probably markedly underestimate alcoholic liver disease. So Manny Rubin and Charles Lieber took 12 NYU students, hospitalized them in the Clinical Research Center at Mount Sinai, fed them alcohol throughout the day, and did baseline and follow-up liver biopsies at two weeks. Amazing. They had mildly elevated liver enzymes, but as shown here, everybody got pretty prominent fatty liver disease, and on electron microscopy, major mitochondrial changes. So basically, everyone who drinks heavily for a couple of weeks gets fatty liver. So there's probably a lot of that going around with COVID. And as shown up here in the right, alcoholic liver disease deaths are increasing in the United States, while hepatitis C deaths are decreasing. So a big problem. Well, what about moderate drinking? So the dietary guidelines, which are updated every five years, so there's a new edition coming out, says that, quote, healthy drinking or moderate drinking, again, is one drink for a woman, two for a man, and that's going to probably be reduced to one for a man. So the idea actually kind of stemmed back from the 60 Minutes show with Morley Safer and the idea of the French paradox, where the French have low heart attack rates, but high consumption of fat, and there's actually a J-shaped curve related to heart attack rates in drinking. So a little bit of alcohol may be safe or even beneficial, is the concept. Now, that clearly only occurs to healthy people and not people with underlying liver disease who shouldn't drink at all. So we have our typical phenotypes for alcohol on the left and industrial shown on the right. So this is one of my patients on the left in a clinical trial with alcoholic liver disease. And on the right is a person being dipped into a vat to clean out the vinyl chloride. So he has to be skinny to get in there. But as we can see in the middle, nutrition has intervened. And so we have NASH and we have BASH, so alcohol plus obesity. And so nutrition interacts extensively with both alcohol and environmental toxins. So what are the strategies to potentially mitigate the impact of alcohol? Well, you can have drinks that don't have actual alcohol in them. And this was actually starting to become very popular in social circles. So the drinks taste good and you can be walking around holding a drink and be very socially acceptable. You can educate versus legislate. So we tried to legislate abstinence in the United States. It didn't work out very well. Some European countries are looking at this carefully. Education has probably worked best in colleges where we try and get our students not to binge drink and very often are successful there. Now, what about environmental liver disease? A variety of government agencies impact our environmental exposures. We have professional societies, but it's mainly the society of toxicology, ASPET, and little less our liver organizations. What is environmental liver disease? Well, environmental hepatology is a disease that hepatology is an emerging field focused on the environmental contribution to liver health and liver disease. And it's important to note that, again, nutrition and alcohol intake impact environmental liver disease and have to be taken into consideration. So there are over 116 million chemicals that have been defined. So as opposed to one alcohol, 116 million chemicals. If you look at the NIOSH pocket guide, a third of the chemicals in there have hepatotoxicity. If you look at the EPA over at the right, again, about over 25% of the over 25% of their chemicals that they have noted have liver risk. So the liver is by far the most at-risk organ. And that's because it's responsible for xenobiotic metabolism and detoxification. And steatohepatitis is by far the most common pathologic feature. So shown here are different types of liver pathology with associated environmental hepatotoxins. And again, by far the most common histology is steatohepatitis. But there can be some very specific ones like hemangiosarcoma associated with vinyl chloride that we'll talk about a little later. Now, this is taken from an article that we wrote concerning the overlap of alcohol, foods, and environmental toxins, all causing one histologic type of liver disease. So again, there are a host of chemicals that are associated with toxicant-associated steatohepatitis, as noted here. Now, we actually described TASH. Matt K was the lead author on this and is actually probably the world's expert in environmental liver disease in our group. Described this in 2010. And it was an offshoot of work that we had done actually over the years with a thing called Rubber Town, which is an area in Louisville that actually made rubber in the 1940s related to the war effort. And in 1974, there was a rare liver tumor that was described called hemangiosarcoma related to vinyl chloride in this Rubber Town factory group of workers. And shown in the box here is Hans Popper's reading of the liver histology where he talks about the extensive steatosis and large droplet fat. So remember, TASH wasn't described back in 1974. So Matt K went on to take a look at liver biopsies that were done from people exposed to vinyl chloride but who did not get hemangiosarcoma. And he found that 84% of them had fatty liver, 80% of them had steatohepatitis, but they weren't obese or had alcohol exposure, and 55% actually had fibrosis. So he coined the term TASH, toxicant-associated steatohepatitis. Now, the company actually tried to do the right thing. They set up a surveillance program to monitor for the development of hemangiosarcoma, but they used liver enzymes as their main monitoring feature. And as shown here, the AST and the ALT weren't elevated in TASH patients. So that was the problem. But subsequently, we were able to show that cytokeratin-18, now termed keratin-18, the M65 component, was elevated. And so these patients end up actually being very much like alcoholic hepatitis patients, with a lot of inflammatory markers that are elevated, but AST and ALT levels aren't very elevated. Now, the Europeans actually have developed guidelines on occupational liver disease, which is great. They're ahead of us, but it's tough to have guidelines with such limited data, and so we really need more information. The federal government in the United States actually talks about TASH. And so Dr. Cave and I are in clinic at our VA every Wednesday afternoon, and we see people with fatty liver, we see people with fatty liver disease that have been at Camp Lejeune and have had contamination from the water supply in the past. So the key hypothesis is that there are metabolism-disrupting chemicals, or MCDs, and these are different from endocrine-disrupting chemicals. And it's kind of the Nash two-hit hypothesis that there's exposure to a toxicant and something else causing a second hit. And so that's shown here conceptually with Western diet as the first hit, and then arsenic exposure is a toxicant. And you can get arsenic exposure from well waters, from fracking, etc. And as Gavin Arteel's group showed here, a high-fat diet will cause an elevated ALT in black, but the high-fat diet plus arsenic causes much worse liver injury. And so that's the problem in the United States now. We have less probably environmental exposure, but we have more obesity and more alcohol that brings out the environmental exposure. And so again, studies by Matt Cave looking at a specific PCB 153. So he has control animals here, PCB animals, high-fat diet, and high-fat diet plus PCB. And the high-fat diet plus PCB has marked visceral adiposity and marked fatty liver disease. And this is translated into humans, where if you look at NHANES data, PCBs are markedly associated with unexplained liver enzymes, which is really environmental tash. And at this particular meeting, there's a great poster from Matt Cave, Naga Kalashani, Dean's Jones group in Atlanta, talking about the exposome associated with metabolic disruption in NAFL. And they've taken serum from a variety of NAFL patients and have found that there are industrial toxicants that are clustered related to fat, as shown in the yellow here, and different ones associated with fibrosis, associated with the kind of brownish color here. And if you look at the right, the flame retardants, these last three things here, are toxicants that affect many metabolic pathways. So we're seeing how these toxicants affect different pathways and affect different types of liver injury. So what are the ways that we can mitigate the impact of environmental toxicants? Well, we can empower individuals to reduce their exposure. We can reduce the burden of persistent pollutants that bioaccumulate. And we can develop therapeutic and dietary approaches to antagonize the deleterious effects of these exposures. So in summary, our takeaways are we need to understand the standard drink. We need to understand that environmental toxicants are ubiquitous. There are major dietary and alcohol interactions. And that pollutants can be persistent and have long-term consequences, such as vinyl chloride. Thank you very much. Good afternoon. I'd like to thank the AASLD and our moderators for giving me the opportunity to speak with you about early life interventions as potential solutions to the growing public health burden of NAFLD in the United States and in Europe. My name is Cindy Moylan, and I'm a hepatologist at Duke University and the Durham Veterans Affairs Medical Center here in Durham, North Carolina. I have no relevant disclosures for today's talk. As we've heard, there are no current public health policies to address the NAFLD epidemic, and this represents an important unmet need. My objectives for today are to review the scope of the NAFLD problem and the projected impacts if we do nothing. Then I hope to convince you that early life interventions can provide key solutions in NAFLD. Unfortunately, we don't have time to cover all of the mounting data in support of these ideas, but I'll do my best in the short timeframe to discuss those with the most evidence and how interventions made prenatally, postnatally, and in early childhood could inform new public health policies to have lasting impacts on the epidemics of both obesity and NAFLD. So this slide shows the projected impact of NAFLD by 2030 if we do nothing, with the total NAFLD population in the United States projected to increase to more than 100 million in 2030. Similarly, the number of non-alcoholic steatohepatitis cases is projected to increase an astounding 63% from 16.5 million cases in 2015 to a projected 27 million cases in 2030. The proportion of cases classified as NASH is expected to increase from 20% to 27% as a reflection of disease progression, more diabetes, and an aging population. And as you can see among NASH cases, 3.3 million are expected to have advanced liver disease or F3, F4 fibrosis. And if we do nothing, these increases in NAFLD and NASH will translate into more liver disease and to more liver-related morbidity and mortality. As you can see, the authors project that the number of incident cases of decompensated cirrhosis, hepatocellular carcinoma, and liver-related deaths due to NAFLD and NASH would increase astoundingly more than 137% up to 180% nearly between 2015 and 2030. So what can we do to try to mitigate these massive increases? You've heard about several suggestions already from the other speakers in today's session. I would suggest that one solution is to intervene even earlier in this continuum, such as prior to conception or during pregnancy and via addressing obesity and diabetes in parents, as well as postnatally through infant nutrition and breastfeeding exposures. And if you're not sure how to do this, I would encourage you to check out the link in the description below. So these interventions are really important to consider for several reasons. First, in the correctly targeted populations, they may have tremendous impact through long-lasting benefits. They may even also provide benefit to future generations, as we'll see, and they have the real potential to prevent NAFLD or to delay its progression to non-alcoholic steatohepatitis. And finally, they may have a significant impact on the overall health of the infant. And this may be due to non-alcoholic steatohepatitis or cirrhosis. Over the last five to 10 years or so, it's been really incredible to see how much we've learned about the impact of these early life influences. From animal models and human studies, we've come to understand that there are important links between in utero exposures and their later life increased susceptibility to and development of cardiometabolic diseases, including NAFLD and obesity. And some of the most convincing data are on the slide, including maternal obesity and altered diet and nutritional stress, particularly in the form of a Western or a high-fat diet, as well as gestational diabetes. We're also learning more about the impact of paternal obesity, socioeconomic status and genetics and how they play a role. Postnatally, there's evidence which we'll discuss that associate birth weight and breastfeeding with susceptibility to and severity of NAFLD as well. So the concept that in utero or early life exposures to an adverse environment can influence one's susceptibility to chronic disease later in life is known as the developmental origins of health and disease. And this hypothesis was coined by Dr. David Barker more than 20 years ago. And it posits that during critical periods of development, changes in the local environment can impact the programming of gene expression pathways with consequent long-term changes in organ function and or growth. We've seen through multiple observational and experimental studies that they've demonstrated that fetal exposure to an altered maternal nutrition in the form of under and over nutrition, obesity, stress, smoking and medications, just to name a few. These factors then lead to developmental programming of disease that's primarily mediated by epigenetic mechanisms, which then lead to alterations in organ and tissue function and increase a person's risk for metabolic syndrome, obesity, diabetes, and NAFLD throughout life. The association between maternal obesity and NAFLD and childhood obesity is really the most well-established thus far. There've been many studies. I'm showing two of those here. The first one was one of the earliest published in 2012. And they used a small cohort of mothers and their newborns to investigate the association between adiposity and hepatic fat content in infants born to obese mothers with and without gestational diabetes. They used MR to quantify intrahepatic fat and found the maternal pre-pregnancy BMI was associated with an intrahepatic fat storage at one to three weeks of life. They also found a mean 68% increase in hepatic fat content in newborns exposed to maternal obesity and gestational diabetes in utero. And that's shown in the figure on the right-hand side. The second bullet shows data from the Western Australian Pregnancy Study or the RAIN cohort, which is a longitudinal birth cohort that has contributed a lot of evidence in this space. And in this study, they assessed the relationship between maternal pre-pregnancy obesity and ultrasound diagnosis of NAFLD at 17 years of age. They concluded that pre-pregnancy obesity was independently associated with more than a twofold increased risk for NAFLD. The same investigators from the RAIN study also published a more comprehensive look at the association between various perinatal adverse metabolic factors and their association with the development of NAFLD in adolescents. Notably, they identified sex-specific associations with parental factors at the time of delivery on NAFLD. Specifically, they found that maternal pre-pregnancy obesity was associated with a higher prevalence of NAFLD in both male and female offspring, whereas maternal age, whereas maternal age, parity, and gestational weight gain were associated with NAFLD only in female offspring, whereas paternal obesity and socioeconomic status at the time of childbirth was associated with an increased prevalence of NAFLD only in male offspring. The study couldn't provide a cause for these sex-selective effects, but they speculated that this may be driven by sex differences in gene environment interactions that influence the NAFLD phenotype, and that this may be modifiable by breastfeeding, nutrition, and other things that happen postnatally. So while we don't really know the mechanisms behind the association between early life exposures and metabolic dysfunction later in life, epigenetic mechanisms such as DNA methylation have been suggested and investigated as the proposed link for the early life origins of obesity and NAFLD. And this is due to the fact that these mechanisms help to control the gene environment or interactions, and they can lead to a heritable phenotype and changes in that phenotype without modifications in the DNA sequence. There's evidence to support this link between DNA methylation and obesity, and that link is relatively robust, but the data in NAFLD remains in its infancy. So some of the proposed transgenerational effects of in utero exposures are shown here. And you can see how epigenetic mechanisms could link these exposures to metabolic dysfunction throughout life and program a persistent vicious cycle of increased risk for metabolic dysfunction that affects generation to generation. So for example, if you have mothers with obesity, gestational diabetes, NAFLD, that leads to maternal dysglycemia and exposure of the fetus to hyperglycemia. This leads to fetal hyperinsulinemia and excessive fetal growth, shifts in lipid metabolism, increased placental transfer of free fatty acids, which then leads to hepatic steatosis. And this in utero exposure can then provide the foundation for lifelong predisposition to metabolic dysfunction, obesity in offspring, and increased risk for obesity, type 2 diabetes, metabolic syndrome, and NAFLD throughout their lives. And this you can see can be propelled generation to generation. So let's move next to what we know about potential postnatal impacts on NAFLD, and these include birth weight and breastfeeding. This is a nice study that was done by the Nash Clinical Research Network investigating the association between birth weight and the severity of biopsy-proven NAFLD in kids around the age of 13. The authors used birth weight as a surrogate marker of undernutrition or overnutrition in utero. And the details of the cohort are listed below the table, but in essence, what they found was that children with a high birth weight had significantly greater odds of having more severe steatosis than kids born with a normal birth weight. The same was true of Nash. Those kids born with a high birth weight had a twofold increased risk of having Nash. And those, interestingly, born with a low birth weight compared to a normal birth weight had an increased risk of advanced fibrosis on biopsy at the age of 13. And so this was true even after adjusting for childhood BMI. So the authors suggest that this is probably due to fetal programming through metabolic stress in the form of under or overnutrition, which increased the risk for NAFLD and fibrosis in childhood. And breastfeeding is something that we could recommend in the fight against NAFLD, because there is good data to suggest that breastfeeding is protective against NAFLD. There've been several studies. One here conducted by Dr. Nobley and his colleagues investigated breastfeeding versus formula feeding and their duration in children with biopsy-proven NAFLD between the ages of three and 18. And they concluded that the odds of biopsy-proven NASH and fibrosis were significantly reduced in those children who are breastfed versus formula fed, even after controlling for confounders like age and weight. They also found evidence that the odds of having biopsy-proven NASH or fibrosis decreased with every month of breastfeeding. The RAINN cohort also looked at breastfeeding and they found that if mothers breastfed for six months or more, this was associated with a reduced odds of NAFLD by 36% in 17-year-old children. I also would like to give a shameless shout out for some data from our group at Duke. Dr. Suzuki is presenting our breastfeeding data. This is abstract number 87, and it's presented at the parallel session on November 15th. So check it out. So finally, what interventions could be made in early childhood as a solution for the NAFLD epidemic? We know that diet is really important. Several studies have supported that eating less carbohydrates and fructose can make a difference. Dr. Schwimmer and his colleagues recently showed in a nice study published in JAMA that reducing free sugars in the diets of children can significantly reduce hepatic steatosis in a very short timeframe of about eight weeks. We know that exercise is also important as a lack of routine physical activity has been independently associated with NAFLD and more fibrosis in children. Interventions over 12 weeks have also been shown to reduce ALT, reduce hepatic fat on MRI, and improve insulin resistance in children. And we know that these are cost-effective. This is one modeling study that looked at an intervention for childhood obesity in children aged six to 12 years that would cost about $120 per child. And they estimated that over 10 years, they would expect to over 40,000 cases of childhood obesity at a net cost of just over $4,000 per child. And so how do we put this all together? You know, we know that these things do not occur in isolation. And Dr. Mosca and Dr. Nobile just published this in Journal of Pediatrics in 2019, asking a similar question to try to see how all of these gestational environmental variables sort of fit together. And while this data is retrospective, it is informative because it looks at a combination of these factors. And it suggests that there are many places that we could make interventions that could have a real impact on the trajectory of NAFLD and its complications. And many of those things you can see are shown in these slides, such as parental obesity, sugar consumption, obesity in the mother prenatally. So putting them all together can have a real big impact. And so why is this important? Well, we know that the numbers are really huge. We know that 10% of women of childbearing age have NAFLD, more than 55% of women of childbearing age are overweight or obese. We know that type two diabetes and insulin resistance are increasing. And pregnancies up to 10% are complicated by gestational diabetes. And there are millions and millions of obese children in the world that we could make a real impact on. So key takeaways from today are first, don't panic. There's things that we can do. Really what we should advise for everyone is to just get healthier. Tell your family, your friends, people that you know are going to have babies to get healthier. You should advise yourself and your patients to do the same. And really we need more research in this area to make more pointed recommendations for people. So from the talk today, what I would say would make a big impact in the trajectory of NAFLD would be these recommendations for future parents and people in general. So it's important to maintain a healthy weight prior to conception in both moms and dads, eat a healthy non-Western diet, avoid high fructose corn syrup and sugar, breastfeed when possible, and try to do that for at least six months if you can, and then recommend that children get regular exercise. And these are really easy and cheap things that we can do to address the NAFLD epidemic in the future. And thank you very much for listening today. The Pregnancy and Childhood Epigenetics Consortium, or PACE, recently published a similar but much larger assessment of in utero exposure to maternal obesity and the development of childhood obesity using data from 19 cohorts and just over 9,000 mother-child pairs. Similarly, they assessed DNA methylation in umbilical cord blood, as well as the peripheral blood of adolescents to determine if DNA methylation changes persisted over time, and were associated with maternal obesity. The authors identified significant effects of maternal obesity on DNA methylation in umbilical cord blood, and these occurred across the whole genome. The alterations were significant at 86 CBG sites after controlling for multiple comparisons and key clinical factors. The effect sizes were small, but in the same direction of change for many of these CBG sites and genes, suggesting a robust association.

NAFLD

public health burden

United States

Europe

liver-related outcomes

early life interventions

prenatal

postnatal exposures

maternal obesity

gestational diabetes

breastfeeding

metabolic programming