and thanks for the invitation to be here today. Though cirrhosis doesn't figure into that top four, over the next... stage of chronic disease. At the same time, though, there's hope that these trends can be curbed with the right strategies, which we'll learn about in the talks that follow mine. So we'll start by reviewing the impact of cirrhosis through the lens of mortality, morbidity, and economic impact. And then we'll consider trends in four major chronic liver disease etiologies, non-alcoholic fatty liver disease, alcohol, and both hepatitis B and C. And then we'll consider trends in five specific countries through the talk. So cirrhosis is the 11th leading cause of global mortality, accounting for 1.2 million deaths in 2016. And by point of comparison, you can see that TB caused about 1.3 million deaths that same year and diabetes 1.5 million. So cirrhosis wasn't far behind. Over time, the total number of annual deaths from cirrhosis have, in fact, increased. So as you can see here, the total number of deaths since 1980 attributed to cirrhosis have actually doubled. In addition, the percent of total deaths attributed to cirrhosis have also increased over time. Somewhat paradoxically, age-adjusted death rates from cirrhosis have dropped a little bit and stayed stable over the past 10 years. I attribute this in part to changes in population, aging, maybe some changes in how we document death from cirrhosis. But some of this decline is real. So this map represents percent change in age-adjusted liver cirrhosis mortality over 1980 to 2010. The purple-blue hues represent the largest mortality reductions, the yellows moderate reductions, and the reds and oranges represent actual increases in mortality. And as you can appreciate, this map looks like a veritable rainbow, demonstrating stark differences throughout the world. When you take a closer look, you'll see that the patterns really vary across the world with no real consistency or pattern that follows regional or country income patterns. For example, there have been significant reductions in cirrhosis-related mortality in countries as diverse as China to France and the United States. There are countries where there have been significant reductions in cirrhosis-related mortality, but they still face persistently high mortality rates, for example, Egypt and Mexico. And finally, there are areas that have had tremendous increases in cirrhosis-related mortality. They include Mongolia, India, Russia, and the United Kingdom. And the reasons are fairly diverse in Mongolia and India. For example, it's largely due to viral hepatitis, and in the UK, largely due to alcohol. Cirrhosis is also a leading cause of morbidity globally. So we can measure morbidity using something called the disability-adjusted life years, DALYs for short. And this is a composite measure of both premature death from a disease as well as years lost due to disability from that illness. So in 2016, cirrhosis was the number 15 leading cause of morbidity worldwide, accounting for 45 million DALYs globally. So you can compare it to diabetes, COPD, and ischemic heart disease, the other major WHO chronic disease priorities, and cirrhosis is not quite as high, but it is significant. And I suspect the DALYs are as they are, because as we all know, in end-stage liver disease or cirrhosis, death... adverse economic effects on society. It has both indirect effects, disability and premature death translate to a loss of workforce, and this has a greater impact on lower income countries compared to higher income countries. In addition, cirrhosis has direct effects on healthcare costs. So drawing from the United States experience, for one year it was estimated that the inpatient cost for cirrhosis was around $10 billion, and the overall annual cost for chronic liver disease in general, both inpatient and outpatient, was estimated to be about three times that amount. So in summary, cirrhosis does have significant public health implications. It's the 11th leading cause of global mortality, the 15th leading cause of global morbidity, and it's associated with very high economic cost. But all of that data comes from events over the past years, and a burning question is, really, what can we anticipate going forward? And here's a snapshot of chronic liver disease today. So it's been estimated that the absolute number of chronic liver disease cases in 2017 was a whopping 1.5 billion, meaning 1.5 billion people across the world affected with any stage of chronic liver disease. And as a point of comparison, you can compare it to other WHO cases. So the major causes of chronic liver disease worldwide is, number one, NASH, followed by hepatitis B, then hepatitis C, and finally, alcohol. So let's start by examining non-alcoholic fatty liver disease, the leading cause of chronic liver disease. So it's estimated that there is a 24% global prevalence of this disease, with estimates as high as 30% in the Middle East and South America. Of course, not all NAFLD actually progresses to cirrhosis. It's really the NASH subtype that carries risk of fibrotic progression to cirrhosis. It's estimated from studies that include biopsied NAFLD cohorts that about 59% of people with biopsied NAFLD will have NASH, and approximately a fifth of those might progress to cirrhosis. Now we don't have that level of detail on a population level. It's nearly impossible to get exact prevalence rates of NASH and fibrosis assessments on population levels, but diabetes and obesity are strong clinical risk factors for disease progression, and if we use obesity and diabetes rates of markers of potential disease progression, the trends are concerning. Both have steadily climbed in prevalence from 1975. It's important to note that obesity is a problem that really doesn't know any borders. Really, all parts of the world have been affected. Of course, the prevalence of obesity varies widely. For example, the United States has prevalence rates above 35%, and countries like China and India have obesity prevalence rates right around 5%. That said, because of sheer population size, China and India actually account for some of the largest numbers of obese adults worldwide, and the following countries additionally account for the highest absolute numbers of adults with obesity. Those are Egypt, Russia, United States, and Mexico. So what can we expect for NAFLD-related cirrhosis in the future? Well, we don't really have longitudinal data on a population level to guide our predictions, but mathematical modeling studies that are based on current estimates of NAFLD, obesity, and diabetes have forecasted a few things for the year 2030. First, the forecast is that NASH burden will increase. Second, at least in the United States, we can expect more than a 150. It's thought that China, again, because of sheer population size, will have the largest absolute number of NAFLD-related deaths. So alcoholic liver disease is the next non-communicable liver disease to consider. So while the proportion of liver disease entirely attributed to alcohol alone is low, when we consider it both as a primary cause of liver disease and a co-factor for cirrhosis, a very large proportion of liver disease burden can be attributed to it. And in fact, it's been estimated that anywhere from 30 to 50% of global cirrhosis mortality is related to alcohol. Like with NAFLD, there aren't any direct measures that we can use to identify specifically patterns of cirrhosis from alcohol within populations. But per capita alcohol consumption is directly related to alcoholic liver disease burden within countries and regions and is a useful marker to understand trends within regions and over time. So that's what this figure represents. For example, in areas of the world, for example, the WHO region of the Eastern Mediterranean and Southeast Asia, where less than 40% of proportion of cirrhosis is attributed to alcohol, the per capita consumption of alcohol is roughly 1 to 2 litres per year. This is as opposed to countries or regions of the world where more than 60% of cirrhosis is attributed to alcohol, where the per capita consumption of evaluate those five countries of interest and their per capita alcohol consumption. And that's what this map from... Russia has amongst the highest per capita annual alcohol consumption of more than 12 liters per year. The United States is up there. There's indications that alcoholic liver disease is on the rise worldwide. So the first indication is that since 2005, per capita alcohol consumption has increased throughout the globe. Second, it's expected that these increases in alcohol consumption will continue in Southeast Asia, which includes India, Western Pacific, which includes China, and the Americas until the year 2025. And in some parts of the world, this impact is already felt. So for example, China, the United States, and Denmark have actually documented a doubling in alcohol liver disease-related hospitalizations over the past decade. And a particularly troubling trend is that this is a condition that seems So, moving on to viral hepatitis, viral hepatitis, particularly hepatitis B, is one where we have longer and more direct views of trends and patterns. Which varies widely throughout the world with the highest prevalence rates in low and middle income countries. For example, prevalence rates range somewhere over 8% in many parts of sub-Saharan Africa and pockets of And, again, China and India have the highest burden of absolute number of hepatitis B cases followed by Nigeria. So childhood acquisition represents the highest risk for chronic hepatitis B infection. Typically it's acquired vertically, mother-to-child transmission, or horizontally among children under the age of five. In fact, most of those 257 million people living with the infection were born before the vaccine was widely available in their regions. Other major routes for hepatitis B transmission, as we all know, include IV drug use, sexual transmission. declines have been attributed mainly to vaccination programs, so vaccinations among children and healthcare workers, improved medical precautions in some parts of the world, and hepatitis B awareness campaigns, and some linkage to treatment. However, the declines, again, have varied across regions with four main patterns that you can observe. So, in areas of the world that experience high baseline endemic rates of hepatitis B, there's areas that have actually experienced significant increases in hepatitis B prevalence. Russia is one of those countries. In areas with high endemic rates, historically, areas of the world that historically have had low endemic rates of Some part of this variability is because of hepatitis B vaccine coverage throughout the world. So, hepatitis B vaccine coverage has been variable throughout and within regions. And that's what this figure depicts. The x-axis is time in years, and the y-axis is percent of young children who've received three doses of hepatitis B vaccine. So, in 1992, the WHO recommended incorporation of the hepatitis B vaccine into the U.S. vaccine programs in about 2005. However, as of 2015, many regions of the world still have not reached the WHO benchmark of 90%. So, that's one reason for the variability in hepatitis B prevalence reductions that we've seen over time. Of note, where these hepatitis B vaccines have been successful, we do see an impact as childhood hepatitis B prevalence has dropped from 5 to 1%, but it can take up to 20 years to see the impact of these childhood vaccine programs in adult hepatitis B prevalence rates. But there's hope here, because with improved vaccine coverage, we can expect to see reductions in hepatitis B long-term. There are some threats. C infection, again lower as compared to hepatitis B. But interestingly, more than half of all contaminated blood products. transmission, and then less common but important to consider are traditional practices, some degree of vertical transmission, and household contacts. So temporal trends in hepatitis C prevalence have not been as... But where we've seen reductions, it's attributed mainly to improved blood product screening in some regions. So 2004 was a very hopeful year because that was the time of the entry of direct acting antiviral treatments. And some regions of the world have had success. For example, there's about 1.8 new infections estimated annually which exceeds the number of those who are successfully treated or die from the infection. There's been, like I said previously, an upswing in IV drug use and this year Finally, though there Here I tried to summarize that, so for global trends and across those five countries of interest. So globally, we can expect increases in NAFLD and alcohol, mainly based on trends and risk factors for those two conditions. Hepatitis C virus infection seems to be increasing and driven by IV drug use patterns and iatrogenia—iatrogenium. Hepatitis B is currently very high, but if hepatitis B vaccine rates continue as they have—continue to increase worldwide—I think we can be hopeful that the prevalence of hepatitis B will drop long term. adjusted death rates from cirrhosis, and both are endemic areas. have a high burden of hepatitis B currently, but long term I think we can expect declines based on the progress of their vaccination programs. Egypt started off with a very high cirrhosis death rates, but because of very aggressive hep C triple threat from NAFLD, alcohol, and IV drug use, and we can expect if current trends to hold. that have scaled up since 2005-2010, but it's going to take about 15-20 years to see the full effect of this among adults. Hep C rates are increasing based on many indicators, mainly driven by IV drug use. Screening for chronic liver disease in the population at large and NAFLD and high-risk groups are gonna be key for targeting the prevention and treatment of these two etiologies, as we'll soon hear. Finally, country-specific strategies will really need to be tailored to local trends and risk factors. Thanks for your attention. Thank you.

cirrhosis

global mortality

economic implications

chronic liver diseases

risk factors

prevention strategies