Hello, this is Ashwani Singhal from University of South Dakota, Sioux Falls, and I'm here as the chair of this ALD SIG, and on behalf of the chairpersons of this symposium, Dr. Vijay Shah and Dr. Pranoti Mandrekar, I welcome you all for this symposium on ALD in special populations. Well, we all know that alcohol is a major driver for morbidity and mortality in patients with cirrhosis, especially it contributes in 48% of all cirrhosis cases as etiology and contributes to over a quarter of cirrhosis-related deaths, and also to hugely to economic burden from this disease to the nation. It is also becoming the leading indication for liver transplant in the U.S., as we all know. For example, in 2019, of 7,000 transplants performed in the U.S., almost 40 to 45% were due to alcohol-associated liver disease. We also know that everyone who is exposed to the risk factor of liver disease from alcohol, which is heavy alcohol use, not everyone would develop the liver disease, and that forms the basis of today's symposium to talk about some of the disease modifiers and risk factors related to the host, which is predominantly what the demographics of the person is, and certain environmental factors, especially comorbidities in the person, which drive not only the risk, but also the severity of liver disease. So over the next two hours or so, you can see during this symposium, there are five talks here focusing on special populations who develop ALD. And these five talks will be delivered over the next two hours. After the first talk from me on ALD in young adults, the second talk would focus on ALD in women by Dr. Szabo from Boston, Massachusetts, then followed by ALD in obese population by Dr. Winston Dunn from Kansas, and then ALD in ethnic minorities, focusing especially on Hispanics and American Indians from University of Chile by Dr. Arab. And then finally, ALD and comorbidities, especially viral hepatitis and other substance use disorder by Dr. Im from Mount Sinai. All these talks are about 20 minutes each, and I hope the speakers would adhere to the time allotted to them. And for the attendees, if you have any questions, please use the chat box to post your questions, and the speakers during or at the end of the symposium would respond in a written format. I hope that there will be a lot of key takeaways from these talks for all the attendees and the participants, not only to manage their patients better in their respective practices, but also take away some research ideas to apply to individual research in their practices and institutions. With those words, I would stop here and would welcome you all again for the symposium on ALD in Special Populations and the ALD Sick of the ASLD. Thank you. Hello, this is Ashwani Singhal, and I will be talking about alcohol-associated liver disease in young population. At the outset, I would like to thank the ASLD for this opportunity, so I have no disclosures to make related to the talk. So this is a study over three decades ago from India, and you can see that young predisposed to alcohol-associated liver disease has been recognized for that long. For example, 63 patients in young who had cirrhosis, defined by age less than 35 in this study. You could see alcohol drove the cirrhosis in this 16 percent of the young individuals in this particular study. Now, we know that alcohol-associated liver disease, and there are certain disease modifiers which predispose an individual to develop liver disease, and these modifiers could be related to the host or environment. Age is not mentioned in one of the risk factor or disease modifier in this list of risk factors. Now, when you talk about liver disease of any spectrum, whether it is fatty liver or state of hepatitis or fibrosis or cirrhosis and its complications, young individuals are predisposed to every spectrum of liver disease from alcohol, and this has been recognized more and more in the last few years. For example, alcohol-associated fatty liver, as analyzed in this NHANES database study of over 34,000 individuals between 2001 to 2016, the overall prevalence of fatty liver disease was 4.3 percent, but it was much higher at about 6.5 percent in younger individuals between 20 to 44 years of age. Another study using this CDC vital statistics data in the U.S., the individuals between 25 to 34 years of age were at higher risk compared to other age groups of developing alcohol-related liver disease. So, the proportion of ALD in this population was a little over 10 percent compared to less than 5 percent in the remaining age groups. What about cirrhosis? And this is the Canadian Registry database study. It was shown that people who were born in 1980 or more, they were at higher risk of developing cirrhosis compared to the older individuals. This is a busy slide, and I'll take a minute to explain it. For example, on the left-hand side, lower panel, if you see that individuals who were diagnosed at the age of 35 with cirrhosis, the chances of diagnosis of cirrhosis in that age group was much higher in individuals who were born in 1980 or later compared to the people born earlier than that. And after controlling for the other disease modifiers, which can predispose an individual to develop liver disease, it was seen that those born in 1980 or later were at about 47-odd higher risk of developing cirrhosis compared to the other age groups. And this risk persisted if this analysis was done for cirrhosis diagnosis at age 60. Those baby boomers were at higher risk compared to people born in 25 to 44. And then those who were diagnosed with cirrhosis at age 80, those born in 1924 to 44 were at higher risk compared to individuals born before 1925. And this was the analysis from 98,000-odd males and 67,000-odd females between 1997 to 2016. What about alcoholic hepatitis? And we know that alcoholic hepatitis is one of the severe forms of ALD, and this is the data from four states in the U.S., Massachusetts, Washington, Florida, and New York. And one finding in this study was that of all the four states, the highest rate of alcoholic hepatitis or incidence of alcoholic hepatitis in population is in Massachusetts compared to the other three states. And if you focus at the age group that is 20 to 29 and 30 to 39, you can see over time between 2010 and 2014, the incidence of alcoholic hepatitis had the steepest rise in the younger individuals compared to the other age groups. What about hospitalizations for alcohol-associated liver disease? So on the left, you see the admissions for alcohol-associated cirrhosis, and on the right, you see admissions for alcohol-associated hepatitis or alcoholic hepatitis with jaundice. The young individuals compared to the remaining age groups, the young individuals are shown in the black bars. You could see there was an increase for alcohol-associated cirrhosis, but the steepest increase was in admissions for alcoholic hepatitis from about 8 percent in 2006 to about 20 percent of all the admissions in 2016 contributed by younger individuals. Another study using the National Inpatient Sample Database of acute and chronic liver failure admissions due to alcohol in the United States. And we know that acute and chronic liver failure is the most severe form of any cirrhosis presentation. On the left is shown in younger individuals' admissions and less than 35 years of age, and on the right, you see the admissions in older individuals above the age of 35. And if you look at the proportions of the gray bar, which is represented by alcoholic hepatitis, you could see, although increased in both age groups, but the steepest increase from about 15 percent in 2006 to close to 45-50 percent in 2014 in younger individuals. And this increase was not that steep in older individuals. And as the admissions with more severe disease with alcoholic hepatitis and ACLF are increasing in young individuals, as I showed you in the previous slides, there is no surprise that liver transplants would also be driven with higher incidence and higher prevalence in younger folks. And in this UNOS database study, that's what exactly what was shown, that over time between 2007 to 2016, the steepest rise in contribution to all the liver transplants for alcohol was contributed by 18 to 40 years of age group, followed by 40 to 60 years of age group, and least by 60 and over. Similar kind of data using the UNOS database again showed when we analyzed this database this year, and on the left you see between 2006 to 2016, alcohol cirrhosis driving alcohol for liver transplant, the increase was from about 4 percent to maybe about 7 or 8 percent. But if you look at the right side, the transplants for alcoholic hepatitis and those contributed by young, shown in black bars, increased from 10 percent to close to 40 percent in 2016. So clearly driven by alcoholic hepatitis. What about natural history comparing young to adult or more older individuals? And I have no hesitation to say that the studies addressing this question are very minimal or not there. I come back to the same study which we saw earlier over three decades ago from India. That's the only study I'm aware of where a comparison was made between young and older individuals on the natural history. The number of deaths, 40 percent in young and 44 percent in older individuals, not statistically significant, and this applied to any child status. As expected, the mortality increased with child grade, but between the two age groups there was no difference. And they looked at five-year survival, 62 percent in young, 66 percent in older individuals, not statistically significant. If we look at the cause of death, there was a slight increase, although not statistically significant in GI bleed as a cause of death was more often in younger individuals, while liver failure was more common in adults. Why younger individuals are more prone to develop not only liver disease, but also driving more severe forms of liver disease in this age group, as we all saw in the epidemiology data from U.S. and the rest of the world. It is one of the risk factors of this finding is probably increasing harmful alcohol use in the U.S. in young adults and worldwide, obviously. And this was analyzed using the NHANES database, as you can see here, on about 16,000 individuals analysis between 2006 and 2016. The prevalence of harmful alcohol use was about 30 percent in younger individuals, which is less than 35, about 15 percent in 35 to 64 years, and only about 5 percent in 65 and above. And after controlling for other disease modifiers or risk modifiers, you could see that younger individuals, they were at 11-fold higher risk of harmful alcohol use compared to those 65 and above. What about binge drinking in younger individuals? And this is the analysis from the WHO study or report in 2018. And you can see on the left-hand side, if you focus, and this is the data from 2016, so the latest data reported in this report. So if the upper panel, you see overall binge drinking was about 18 percent worldwide, but it was higher in individuals who were 20 to 25 years of age group at about 22 percent. But this difference was more striking when the binge drinking among drinkers was analyzed. So about 40 percent worldwide, it was close to 50 percent, those who were 20 to 25 years of age group. And the behavior of drinking and pattern of drinking in younger age is associated with what will happen later in life, especially bad outcomes related to liver-like cirrhosis. So this is a study on about 43,000-odd individuals who were in military in 1970. So they were surveyed on their pattern of alcohol use, as shown in the table on the left. And 400, close to 400 of these developed over time cirrhosis or complications. And this study retrospectively then associated their pattern when they were young to development of cirrhosis on follow-up. And as you can see, two of the drinking behaviors when they were young, especially whether they were apprehended for being drunk or not, and whether they used alcohol as first thing in the morning to start their work, was clearly associated with development of cirrhosis later in life. And unfortunately, this pattern or harmful alcohol use in younger individuals could be picked up early on. And this is a missed opportunity. And this was shown in Danish registry of over 36,000 individuals who were followed for 50 years between 1988 and 2002. At the end of the study, about 5% risk of cirrhosis in females and 6% in males, or the other way, 5% in males and 6% in females, you could see that over two-third of these individuals had some kind of healthcare provider in these 15 years before they developed cirrhosis. So clearly, there was an opportunity to screen for alcohol use and liver disease and probably prevented development of cirrhosis. So how do you screen for alcohol use in this population? As we all know, this is an audit tool, a more comprehensive evaluation using a 10-item questionnaire and each question reported by the patient himself or herself on a scale between zero to four, so a possible score of 40 maximum. However, this is a comprehensive score used mostly in research settings. A shorter version, or Audit C, is more efficient and quick and can be used in clinical practice. And it is as accurate as the whole audit tool. And a total score of four or more in females and five or more in males can identify those at high risk of developing bad outcomes of liver disease. And those who are identified at risk should then be screened for liver disease using at least a CBC, liver chemistry, and liver imaging, and this has been endorsed by all the society guidelines. And those who are identified to have cirrhosis on clinical evaluation and this screening labs should then be referred to hepatology for the further management of cirrhosis. And those who do not have cirrhosis on this initial evaluation, it is recommended to have a non-invasive assessment using serological markers and FibroScan to assess the risk of fibrosis. Irrespective of whatever is the risk of fibrosis or a spectrum of liver disease, if they have liver disease, alcohol abstinence should be promoted and alcohol use disorder should be managed in these individuals to improve their long-term outcome. It has been shown that screening in these adults and further counseling intervention improves their alcohol use. For example, in this meta-analysis, it was mostly on young adults. The trials of 58, 51 out of 58 trials were in young adults. And the screening of alcohol use was done using audit in each trial. And it was shown that counseling interventions to reduce alcohol use was successful in the intervention arm compared to the placebo arm or non-intervention arm by about 1.6 drinks per week, 40% reduction in exceeding drinking limits beyond harmful alcohol use, and 33% reduction in heavy drinking episode. And based on these data, the USPS task force recommended screening for alcohol use in adults and those at high risk of alcohol use or those reported to have harmful alcohol use should have counseling interventions to improve their long-term outcomes. However, this is not what is followed or what is observed in clinical practice. And this is the data in the most advanced spectrum of liver disease of cirrhosis from veterans, about 39,000 individuals, 93% of those had some kind of AUD treatment opportunity. So they all had cirrhosis and alcohol use disorder. And opportunity existed to treat over 90% of these individuals for their concomitant alcohol use disorder. However, the data showed only 15 or less than 15% were engaged in some kind of alcohol use disorder treatment, less than 0.5% in drugs. So drugs were used only in one out of 200 patients. And clearly, we need to overcome barriers and develop strategies to implement and promote concomitant management of alcohol use disorder, which is clearly a second pathology in these patients with liver disease. So just managing and focusing on their liver disease will not improve their long-term outcome to manage both the pathologies. If not, at least concomitant treatment of both the diseases, preferably integrated fashion with a multidisciplinary care model. And if you focus on, this is what we recommend, and focus on the right-hand side of the panel, that those who have liver disease of any spectrum, which is the focus of the talk today, and if they have moderate to severe alcohol use disorder, which is an audit score of more than 15, should then have an integrated multidisciplinary clinic engagement with hepatology and addiction teams who can manage both the diseases at the same time and improve their long-term outcomes. Those who have mild alcohol use disorder may be treated using brief intervention strategy by the hepatologist or the primary care wherever the patient is and those who do not improve their alcohol use after a period of observation should then be integrated with addiction. What about primary prevention or reducing alcohol consumption in this target group of young individuals? And we had the opportunity to study a relationship between federal policies in reducing alcohol availability and consumption with the cirrhosis from alcohol-related mortality. And this was countries in South America and there was, on the left you see the number of policies implemented in that individual country was inversely related to mortality from alcohol-associated cirrhosis. And the eight policies which have been shown to be effective are written on the right-hand side, especially targeting youth as drinking age and focus policies or driving-related alcohol policies and control on advertising and promotion, control of taxes and prices so that you reduce the availability of alcohol, also restrictions to alcohol access in terms of the age limit in which you can allow someone to buy alcohol. And finally, government monitoring systems and then also the licensing restriction or mandate on production and selling of alcohol. And there was another study which I think is interesting and I showed it here on warning labels on alcohol bottles or alcohol sale, which could be looked at by the individuals who are buying alcohol, similar to the smoking, that smoking is injurious to health on cigarette packets, which is shown to be effective in reducing smoking. And this study was done as a survey on over 76,000 individuals from 29 countries, and seven alcohol health warning labels were surveyed. One, the bad effect of alcohol on heart, on liver, and in promoting gun violence, and also on cancer development. And also on weight gain from empty calories consumed from alcohol. And then two days off in a week from alcohol is beneficial. And finally, that moderate alcohol use is beneficial as a health myth was another warning. So, if you see that if the individuals were aware of these seven alcohol health warning labels, or if they believed in it, and or there was some personal relevance to these seven promotions or seven warning labels, you could see there was across the whole population, they were more likely to reduce their alcohol use, if they were aware, or if they believed it, or if they thought that is personally relevant to them. But if you target the youth, which I think is the focus of the talk today, two warning labels, especially related to the calories or empty calories that weight gain associated with increasing amount of alcohol use, and then two days off in a week is beneficial, but more effective in reducing alcohol consumption. So, maybe those could be also used in addition to the federal policy, which I showed you in the previous slide. So, this is the summary slide and some take home messages from today's presentation. So, I think we saw enough data to show that the healthcare burden of liver disease is disproportionately and enormously increasing in young individuals, becoming like an epidemic worldwide. So, we clearly need strategies to improve screening of alcohol use at every healthcare encounter, and those at risk should be screened for liver disease. The amount and harmful pattern of alcohol use is a major contributor, and you clearly need strategies to reduce availability of alcohol targeting youth. And we also need long-term natural history studies comparing young individuals to older individuals who have alcohol-associated liver disease. So, I would thank you, everybody, here, and I would stop here and I'll be happy to take questions. Thanks. Thank you for the opportunity to talk about alcohol-associated liver disease in women today. These are my disclosures. None of them has relevance to the presentation. So, the prevalence of alcoholic fatty liver disease among U.S. adults in the last 15 years has grown, and this study used a cutoff of 28 grams per day alcohol use in women and 42 grams per day in men. And as you can see, in the last eight years, the total fatty liver numbers went up, and this also was trailed by an increase in the number of stage 2 fibrosis in alcoholic fatty livers. Furthermore, mortality due to alcoholic cirrhosis is also rising in the U.S., especially in young adults. So, in this study, if you look on the left side, in the 25 to 34 age group, there was a major increase in the alcohol use disorder, alcoholic liver disease, and cirrhosis when we look at the average annual percentage change in the past years between 1999 and 2016. I think this is compounded by the fact that women now drink as much as men. And if you look at the 2019 national survey, then 59% of men and 51% of women actually reported drinking in the past month. But more importantly, the gender gap in alcohol consumption is narrowing and has essentially gone. So, previously, there was a 3 to 1 ratio for risky drinking behavior in men versus women that is now closer to 1 to 1 globally based on 2016 statistics. In the U.S., from 2019, studies show that women in their teens and in early 20s report drinking and getting drunk at a higher risk than men. This really is a very new and alarming change. Women and alcohol use are showing that about 4 million American women suffer from alcohol abuse or dependence are less likely to seek help than men. The frequency of alcohol use disorders among women has increased by 83% between 2002 and 2013, and the incidence of liver damage also increased parallel with this. Women make up approximately 30% of all cases of alcohol associated liver disease. So, from here on, I'm going to talk about sex-related differences, because sex is assigned at birth and gender is how a person identifies. So, sex differences exist in all aspects of alcohol use disorder and alcohol liver disease. However, this is only partially recognized. The tension to sex differences in alcohol use and its biological effect is minimal, both in medicine and in the society. That is a major concern. Furthermore, sex differences in alcohol's effects are not considered in many studies and clinical trials. Just to show a few of them, some of the major clinical trials and studies in alcoholic hepatitis and alcoholic liver disease mention no sex-specific differences. This was also true for some of the clinical guidelines from societies, including ACG and ESL. The recent hepatology guideline published in 2019 on alcohol-associated liver disease, however, took the gender differences into consideration and concluded that particular attention should be paid to diversity of sex, racial background, and age. That is going to be very important to recognize in future communications and studies. So, today, I wanted to go through a few special considerations in women when it comes to alcohol use disorder and alcoholic liver disease. Drinking pattern, genetics of biological effects, natural history, response to treatment and transplant allocation, and mortality. If we look at the drinking patterns, those vary by gender, age, and country. So, in this cross-country analysis of international alcohol control study, shows that the blue bars on the top are data from men and the red ones are from women in the same countries. Just looking at it, you get the appreciation that typically a greater percentage of society consumes alcohol in men than women, but the difference is not that huge. It is across the various age groups and some of the patterns are different between countries. Now, further recent studies, however, definitely show narrowing of the gender gap in, for example, past-month reports on alcohol use and alcohol use disorders. So, on the left side, this is a study from 2020. In persons ages 12 and older, if you look at the past-month alcohol use on the top with the blue boxes in males and the black circles in females, shows that the gap between the two genders, between 2012 and 2018, really narrows. That's also true if you look at the bottom of the same panel with past-year DSMV for alcohol use disorder diagnosis, then the males and females seem to have very similar likelihood and percentage of the alcohol use. Most importantly, 12th graders took this test, this survey, and we found that the gender gap that was between 1976 is essentially totally disappeared by 2018 when it came to reports of being drunk in the past month or even drinking in the past month. On the right-hand side, we are looking at ages 18 to 22, which is the young adult population, and here the reports on using alcohol in blue and being drunk in the black bars between males and females is really not that much different. In fact, in some of the aspects, the percentage of individuals reporting being drunk or using alcohol in females is higher than men. Interestingly, there is no difference between being college-educated or non-educated in college. The loss of the gender gap in alcohol use is also true for an older population. This study from Norway recently reported that the odd ratio of frequent drinking and current drinkers across time has actually changed. Compared to the mid-'90s, in the mid-2015, at least 2016, women ages 6 to 69 show an 8-fold increase in alcohol use and also the older women compared to men. That suggests that this tendency actually is real pretty much across all age groups. Now, what are the genetics and biological effects affected by the gender? Here, if you look at sex differences in genetic predisposition to develop alcohol use disorders, various studies looked at genes associated with alcohol use disorder or alcohol use disorder and related phenotypes. I'm not going to have time to go through the individual genes here, but you get the sense that there are differences in the distribution of these genes between males and females in these different studies. We have to recognize that the limitation is that some of these studies have relatively small cohorts. Therefore, further evaluation of these genes and their role in alcohol use disorder is warranted. The genetics of alcoholic hepatitis by gender is also interesting to look at. PMPLA3 and HSD17B13 are genes that have been identified in relation to fatty liver and alcoholic liver disease. Here, perhaps not surprising, that both in men and women, the PMPLA3 shows a significant correlation. If you look at the extent of the significance that it's a difference, and particularly high in women, and then there seems to be some difference in the HSD17B13, which again suggests that there might be some genetic factors contributing to the gender differences. I think the most alarming, as I was going through the literature, is the fact that I don't think that we have very good understanding of the biological factors that contribute to the alcohol-associated liver disease in women and the sex differences. In this review article, it's nicely summarized that there are multiple mechanisms that have been proposed, including differences in the alcohol dehydrogenic activity in the stomach and the first-best metabolism. Other studies indicated that potentially differences in the gut barrier function between women and men may contribute to increased gut leakiness and increased LPS levels in females after alcohol binge that correlates with an activation of Kupfer cells and inflammation. Some of this was attributed to estrogen levels in females. Alcohol metabolism in the hepatocytes was suggested that potentially differences in the activity of CYP2E1 and increased ROS production could contribute. Definitely, the increase of alcohol-associated liver disease in women compared to men is important to recognize because alcoholic hepatitis develops after a lower daily cumulative amount of alcohol intake. There is also an increased risk to and shorter duration to development of liver cirrhosis in women. The natural history is in a way that if you look at the prevalence of fatty liver by gender, age, and alcohol intake, in non-drinkers, there is clearly a difference between those who have fatty liver and no fatty liver in various age groups. But when we look at the moderate and heavy drinkers, this difference is even more pronounced, suggesting that, again, not only the age, but the gender differences have a major impact on developing fatty liver. But I think the most compelling component are the studies that identified the differences in the threshold for alcohol-associated liver disease risk. In women, somewhere around 24-25 grams of alcohol already increases the risk of alcoholic liver disease. If you look at this graph, it definitely shows that by increasing the daily alcohol intake, it kind of linearly increases the hazard ratio for developing alcoholic liver disease in women. The threshold is much greater, about 36 or so grams of alcohol per day in men. Gender differences and sex differences are also reported in response to treatment and transplant allocation that I will show you in a second. Again, gender disparities in alcohol use disorder treatment among privately insured patients with alcohol-associated disorders was nicely summarized in this study in about 60,000 cases, and one-third of those were women. They found that women were less likely to utilize alcohol use disorder treatment visits. The data for this is shown on the bar graph on the right side, where essentially the darker bars are representing men and the lighter one women. There is a significant difference in whether we look at the mental health visits and medication use, or on the middle, only the visits, and on the right-hand side is the approved alcohol relapse medication use. In both cases, women seem to use these resources to a significantly lower extent than men. In terms of liver transplantation, which is a life-saving measure for those in acute alcoholic hepatitis in a well-selected group of patients, in this study, we looked at the practices in UNOS registry and found that actually the cumulative index of delisting for sickness is much greater in women than in men in this population. Furthermore, sex-based disparities and delisting practices were significant. Women were 10% more likely to be delisted than men. The reason for this is because they are perceived to be more frail and ultimately deemed to be too thick and therefore delisted. Women also had a longer chance of late times compared to men. These are differences that we probably need to look into more closely and in the special considerations. Finally, I wanted to talk about mortality. This post-transplant survival study that was recently published showed that women surviving to one year post-transplant show a different probability of survival compared to men, particularly in the alcoholic liver disease category. If you look on the left with the red dotted line, those are young women who have a much lower probability of survival compared to men than post-transplant for alcoholic liver disease in 2, 3, 4, 5 years out of transplant. In fact, the difference in adjusted 5-year mortality for alcoholic liver disease versus non-alcoholic liver disease among women and men is obvious. If you look at this data, it shows the absolute difference in adjusted 5-year survival. Particularly in the age group of 18 to 29 and the age group of 30 to 39, women have a much larger difference compared to men. That is an alarming observation. In summary and in terms of recommendations, I would suggest that there is an urgent need to educate women about sex differences in the effects of alcohol on the liver and also on other organs. Particular attention should be given to young adult women about alcohol use disorder and alcoholic liver disease and the increased susceptibility of women to all of these conditions. Women should be included in clinical trials in alcoholic liver disease to better understand outcomes. Most importantly, I think we need new studies to better understand the biology behind the sex differences in the effects of alcohol. Thank you very much for your attention. Thank you, Ashwani, for this opportunity to speak here with you today. I'm going to discuss about alcohol-associated liver disease in the obese population. There has been increased preference of metabolic syndrome and namely obesity in patients with alcohol-associated liver disease. This is the data from NHANES. We are going to look at the cohort in 2009 to 2014 versus the historic cohort in 1999 to 2001. Alcohol-associated liver disease is defined as men that drink three drinks or more and women that drink two drinks or more and have elevated liver enzyme. We see that there has been an increase in the preference of the metabolic syndrome and namely the obesity. And the preference of obesity is increased from 50 percent in 1999 to 66 percent in 2009. I want to point out that the diagnosis of metabolic-associated fatty liver disease and alcohol-associated liver disease is not mutually exclusive. In terms of the interactions between alcohol and obesity mechanism, I would like to point out an excellent review article by Richard Parker. With excessive alcohol intake, there is an injury to the adipocyte that leads to macrophage infiltrations into the adipose tissue that leads to nepolysis and the increase in circulating non-acidified fatty acid that is taken up by the liver and leads to insulin resistance and de novo lipogenesis and therefore hepatic steatosis. There is also increased secretion of adipokines and cells to kinds and leads to cover cell activations and hepatic stellar cell activations as well and finally hepatic inflammations and fibrosis. There is interaction of alcohol obesity at many levels and at the level of prevalence we see there is a study in Germany using ultrasound that showed with increasing alcohol consumption there is an increased prevalence of hepatic steatosis with increasing BMI in both men and women and the same association can be seen in binge drinking. We can see this interaction of alcohol obesity with the incident of cirrhosis. This is the United Kingdom Million Women Study. Participants were recruited from 1996 to 2001 in the Breast Screening Center. The records were linked to hospital admissions and death over 1 million women with the average follow-up of 6.2 years. The main outcome is hospital admission or death from cirrhosis and we can see that with increasing BMI there is a very little increase in the risk of cirrhosis. With increasing alcohol use there is a moderate increase in the risk of cirrhosis. However, with a combined increase in BMI and the increased alcohol use we can see a substantial increase in the risk of cirrhosis. After seeing the relationship in women we are going to look at this relationship in men. The Mid-Span Prospective Cohort Study looked at this relationship in men. The participants were workers in Scotland. We can see the same relationship with increasing BMI. There is almost no increase in the risk in cirrhosis. With increasing alcohol intake there is a moderate increase and with combined increase in BMI and alcohol intake there is a substantial increase in the risk of liver-related outcome. This is the Finnish population-based study. There are two studies published. One looked at heavy alcohol intake and the other looked at binge drinking. One published in hepatology and the other study published in Liver International. What is interesting here is that when they look at the interactions with BMI the interactions actually could not be observed. Only when they look at the interactions with waist circumference then the interactions with heavy alcohol drinking with the waist circumference can clearly be observed. The same relationship can also be observed with heavy alcohol consumption and diabetes as well. The same association can also be observed with binge drinking and metabolic syndrome component. Now let's look at the interactions with alcohol, obesity, and liver cancer. This is a study performed in Taiwan with 23,000 residents of Taiwan followed for 11 years. Again with increasing BMI there is almost no increase in the risk of liver cancer. With increasing alcohol intake there is a modest increase in the risk of liver cancer and with combined increase in BMI and alcohol intake it is a substantial increase in the risk of liver cancer. Now let's look at the risk of death in acute alcoholic hepatitis. This study used corrected BMI. The definition of corrected BMI is that they are corrected for the ascites on the effect of BMI. They also noted that on the dashed line in the very bottom is the patient with underweight. Patients with underweight has the most worse prognosis and they showed that a patient with obese has the worst prognosis than normal weight and overweight. Now what about modest alcohol consumption? So far we have a look at heavy alcohol consumption and we have demonstrated that heavy alcohol consumption has interactions with obesity and is associated with a worse outcome. What about modest alcohol consumption in patients with obesity? These patients with obesity often have existing fatty liver. Is modest alcohol consumption safe or beneficial in these patients? Really a cross-sectional study such as this study in the NASH CLN suggests that modest alcohol consumption is associated with a lower prevalence of steatohepatitis and fibrosis. However there are criticisms that these studies may be biased because of the associations of alcohol consumption with healthier lifestyles. Later studies namely the prospective cohort study shows that modest alcohol consumption is actually associated with a lower odds of having steatohepatitis resolution while the odds of fibrosis improvement or worsening is actually not affected in that study. This is an extremely interesting study called mandelian randomization. It looks at a gene called the alcohol dehydrogenase. This gene does not directly affect the liver but affects the odds of a person either consume alcohol or not consume alcohol. In this study it verifies that the carriers of the mutations either the AG or AA are more likely to be abstinent from alcohol and it shows that the carrier of these mutations is actually more likely to have a lower NASH score. We call this the mandelian randomization because it is a randomization by genetics. If you are genetically randomized to have this allele then you are randomized to be more likely to be abstinent from alcohol and it shows that by this randomization the effect is that you will end up having a lower NASH score. This study shows that is a study is done in Korean. It shows that in patients with existing fatty liver by ultrasound and they excluded anyone that has existing advanced fibrosis either abstinent from alcohol or the use of light alcohol is not associated with progressions to advanced fibrosis and the definition of advanced fibrosis is based on a FIT-4 score. However, moderate alcohol consumption is associated with a progression to advanced fibrosis in those that is obese. This is the fin risk study. It tried to look at the J-shape relationship and the therapeutic window of modest alcohol consumption. It shows that the therapeutic window of modest alcohol consumption is, in fact, extremely narrow. If a patient is obese the therapeutic window of modest alcohol consumption is actually very, very narrow and much less than one drink per day. In summary, obesity is becoming more prevalent and up to 66% in patients with alcohol-associated liver disease. The inflammation in adipose tissue caused by alcohol consumption in part accounts for the interaction between obesity and alcohol-associated liver disease. With harmful drinking, obese people have disproportionately high prevalence of hepatic steatosis and high incidence of cirrhosis liver-related outcome including liver cancer. While early cross-sectional study shows potential benefit of light drinking, later prospective cohort study and Mendelian randomization study failed to show benefit and possible harm. With obesity, the therapeutic window of alcohol is very narrow. Thank you very much for your attention. Thank you so much for inviting me to discuss about ALD in ethnic minorities today. My name is Juan Pablo Arava and I'm a transplant hepatologist and assistant professor of medicine at the Pontificio Nacional Católico de Chile School of Medicine. I have nothing to disclose. The aims for this talk are to discuss disparities in alcohol consumption worldwide, the ethnic groups that are particularly affected by ALD and potential solutions for this problem. As you may know, 90% of subjects with heavy alcohol consumption will develop hepatic steatosis. This can be influenced by additional risk factors. Of those, 20% to 40% will develop fibrosis and another percent will progress to cirrhosis. At any point, with or without cirrhosis, patients can develop the inflammatory form of the disease as an acute alcohol-associated hepatitis or AH. First, we are going to talk about global disparities on alcohol consumption. Globally, alcohol consumption is high. 43% of the population currently drinks alcohol and varies across regions. 60% in the European region, as you can see in the graph, and 2.9% in the Eastern Mediterranean region. Also, the amount of alcohol consumed varies across the globe. There is an average of 6.4 liters of pure alcohol per capita, according to the Global Status Report on Alcohol and Health in 2018. The region of America ranks second, following the European region. You can see how the U.S. is among the countries with the highest alcohol consumption in America's region. Similar to the rest of the world, this varies importantly among countries. Indeed, the prevalence of heavy episodic drinking among current drinkers can be as high as 60% in some regions. Regarding the type of beverage consumed, the most consumed ones are spirits, 45%, followed by beer, 34%, and wine, 12%. Alcohol use disorder is defined as a chronic disease characterized by unhealthy alcohol use and several neurobiological features that can include positive reinforcement, compulsive search of alcohol, and negative emotional state when alcohol is not used. The prevalence of AUD globally is 5%, but it can be as high as 8.8% in the European region. The liver is one of the main affected organs by the alcohol. Indeed, alcohol represents more than 50% of the attributable fraction of cirrhosis in America and Europe. Mortality rates for ALD have been increasing over the past years, as you can see in this graph, different to what is happening, for example, with hepatitis C. So, the question is, in view of this geographical difference in alcohol consumption, AUD and ALD, the question is, are there any ethnic groups, particularly in the U.S., the question is, are there any ethnic groups particularly affected? In this study from 2020, the authors aimed to perform a comprehensive assessment of liver transplant outcomes among U.S. adults with a specific focus on understanding race or ethnicity specific disparities. They found that compared with non-Hispanic whites, significantly lower likelihood of receiving liver transplant was observed in African Americans, Hispanics, and Asians. Also, compared to non-Hispanic whites, African Americans had a significantly higher five-year post-liver transplant death. In this cohort, interestingly, 25% of the patients were listed for ALD. Alcohol-associated liver disease, both alcohol-associated cirrhosis and alcohol-associated hepatitis, has been significantly increasing during the last year, not in all ethnic groups, but as you can see in this graph, in particular in Hispanics, according to this study from this year. In this study, using the National Health and Nutrition Examination Survey, NHANES, the National Inpatient Sample, and the UNOS databases from 2006 to 2016, we found that young age, female gender, and Hispanic race are independently associated with ALD-related burden, ALD-related burden, and also ACLF in the United States. In this another study, the authors found that ALD-related hospitalizations are increasing in young in the United States, mainly because of the increasing frequency of alcohol-associated hepatitis. Furthermore, this disease burden in young is increasing with a higher frequency of admission with more severe ACLF and obviously consumption of hospital resources. Interestingly, compared to older patients with ACLF related to alcohol-associated hepatitis, in young had more Hispanics. This was 29% versus 18%. Information regarding AEH in Black patients is unclear. In this study, they found that inpatient mortality in AEH are lower in African American compared to whites. And this study additionally found that total hospitalization costs in AEH are higher in Spanish compared to whites. More recently, Dr. Singal analyzed the National Inpatient Sample on almost 200,000 cirrhotic-related hospitalizations. We found that ALD and or AEH is the most common etiology among cirrhosis-related hospitalizations in the U.S. in American Indians or American Native individuals. In-hospital mortality was observed in about 6% of admission, which was higher in Blacks and similar in other races compared to admissions in American Indians or American Natives. Consistently, in this graph, you can see how the mortality from ALD in the U.S. has been increasing by ethnic groups. This has been significantly high in Native Americans. But are there any potential explanations for this? One potential explanation is genetics. Each Asian has less functional enzymes to metabolize alcohol. Additionally, we found that Chileans with Native American ancestry carry up to 80% of the PNL-PLA3-GG polymorphism, which is a known risk factor for the development of advanced liver disease. Another explanation is cultural. For example, I wanted to put here, in Bolivia, the miners bring offerings to the devil who rules the underwall of Bolivia's mine, which is called the Anko. These offers are alcohol, which is called the Cocoroco, and is 96% pure cane alcohol, which is drunk alone to be protected during the mining labors. Another explanation is related to socioeconomic status and access to healthcare. The prevalence of alcohol use disorder is higher in the high-income group. However, as we showed in this paper with Dr. Luis Antonio Diaz, subjects from low socioeconomic status develop more alcohol-associated liver disease despite lower alcohol consumption. This has been called the alcohol-harm paradox. One protection explanation for this is related to nutrition or access to healthcare. Four is obesity and malnutrition. Obesity has increased almost three times since 1975. Black adults have the highest age-adjust prevalence of obesity, followed by Hispanic adults, non-Hispanic white adults, or Asians. So are there any potential solutions for these problems? Well, number one is to recognize the problem. Having the opportunity of discussing these at the liver meeting make the problem visible and help us to start thinking about solutions. Number two is integrating cultural aspects into ALD clinics. Discussing alcohol consumption, considering cultural backgrounds, and identifying risk factors is key. Number three is we need to think about the alcohol problem as a whole society approach. So far, we have been doing it one patient at a time, but we need to implement public health policies. In this paper from Dr. Luis Antonio Diaz from my group, we show that countries with higher number of public health policies have lower mortality due to ALD and lower prevalence of AUD. So in summary, global total alcohol consumption varies across regions. There are any groups who are particularly affected among those Asians, African-Americans, Hispanics, and American Indians. Potential explanation for these are genetics, cultural, socioeconomic status and access to healthcare, and obesity or undernutrition. The potential solutions will be to recognize the problem, integrate cultural aspect into ALD clinics, and a whole society approach considering developing public health policies. With this, I would like to thank you again for the invitation, and I will be happy to take questions. Hi, my name is Gene Im from the Icahn School of Medicine at Mount Sinai in New York City, and I'm pleased to present to you today alcohol-associated liver disease and comorbidities, viral hepatitis, and other substance use disorders. You can follow me on Twitter there, and that's my bio. I have no financial disclosures. So my objectives today are to have you understand the impact of alcohol in patients with various viral hepatitis and with other substance use disorders. So let's talk about, first, what comes to mind when we talk about the impact of alcohol in viral hepatitis, which is hepatitis C. So historically, concomitant hepatitis C infection is common in patients with alcohol misuse or alcohol use disorder in up to about a third of all patients. Now, things have changed now, but that's older data. And a classic teaching point is that alcohol impacts patients with chronic hepatitis C by causing synergistic, not additive, liver injury. And it does that in several different ways. First is that alcohol will increase the rate of hepatitis C replication. And as you can see here in this older study that's often cited in a hepatitis C replicon model, application of alcohol at 72 hours will more than twofold increase the viral expression of hepatitis C. In addition, alcohol will decrease host cellular immunity, increase oxidative stress through the production of reactive oxygen species, and will promote the increase of hep C quasi-species. There are three main clinical consequences of superimposed alcohol on chronic hepatitis C, and the evidence is pretty robust for this. The first is the increasing rate of fibrosis progression and the risk of developing cirrhosis with alcohol and hep C versus hep C alone. Look at this prospective French study of over 2000 patients with chronic hepatitis C who underwent liver biopsy. It demonstrated the impact of alcohol. And you can see the figure on the right that in patients who drank four or more drinks a day, their fibrosis stage was accelerated relative to the duration of infections versus hep C patients who drank less than that. A meta-analysis of 16 studies looking at alcohol and chronic hep C demonstrated that in patients who drink more than two and a half drinks a day, that's more than half a bottle of wine, for example, plus having chronic hepatitis C, their pooled relative risk of developing cirrhosis was 2.33, more than twofold. And you can see the forest plot favoring that increased risk of cirrhosis. On the right compared to chronic hepatitis C patients who drank less than that. So pretty profound impact. The second consequence of alcohol with chronic hepatitis C is that alcohol increases the risk of mortality versus hep C alone. And that's all cause and liver related mortality. This is an illustrative study using the NHANES-3 prospective database where they gathered alcohol and hep C information from the early 90s of almost 9,000 patients with 14 year follow-up. And you can see that even with kind of borderline threshold level amount of drinking, according to the NAAA of two or more drinks with concomitant hep C infection that increased the all cause and liver related mortality, very dramatically, even more so than hep C alone. And certainly more than patients without hepatitis C but who drink perhaps in a misuse type of way. And the third consequence is the increased risk of developing HCC. So this shouldn't necessarily be so much of a surprise because alcohol is a recognized carcinogen and primarily related to acid aldehyde toxicity and the formation of reactive oxygen species causing DNA damage. And there's many different studies regarding this, various qualities, but one off-site study from Italy demonstrated that those patients who drank more than five drinks a day, so more than a bottle of wine a day, for example, with chronic hepatitis C, those patients had a doubling of their risk of HCC versus if they had hep C alone and drank less than that. And you can see that on the figure to the right, looking at alcohol intake on the X-axis and on the Y-axis, the logarithmic scale of increased odds ratio of developing HCC with hep C where the star is and below that, looking ahead a little bit to a future slide for hep B compared to those patients without viral hepatitis. So with those three clinical consequences, it's not a surprise that the HCV guidance from the ASLD and IDSA suggest that for patients with active hep C infection, abstinence and interventions to facilitate abstinence should be advised for all these patients. So then I wondered, is there an impact of alcohol on modern day hep C treatment? So I found this and another study from George Ioannou's group from Seattle, Washington, looking at a cohort of veterans and a study of over 15,000 veterans who received direct acting antiviral therapy, they found that low or heavy drinking did not impact SVR rates at all. You can see the really impressive SVR rates on the right side of the slide with no drinking, light drinking and heavy drinking, all being statistically the same. So patients are still drinking, you should still treat them with DAA therapy. What about the receipt of alcohol use disorder treatment in those patients with hep C? So looking at over 20,000 veterans with newly diagnosed alcohol misuse with or without hep C in the first year, vast majority received brief interventions, which is great, but only about a quarter underwent alcohol rehabilitation, although that was higher in the hep C positive group and consistent with other historical and more recent studies, very few received alcohol use disorder for pharmacotherapy, unfortunately. And that's even in this group who we just described had the highest risk of negative liver outcomes with the combination of alcohol and hep C. So it suggests that we all need to do better in tackling this problem. So switching over now to alcohol in patients with chronic hepatitis B, the story is very similar to that of hepatitis C in that the combination of alcohol with hep B, there's an association with an increased risk of liver injury, cirrhosis, HCC, and mortality. I wanted to highlight this prospective study of over 20,000 Taiwanese patients from Roit Lumba. And he demonstrated an association between obesity with BMI greater than 30 with alcohol that is defined as drinking four days out of the week, that the combination of that with chronic hepatitis B synergistically increased the risk of HCC. You can see that on the risk curve on the right where the star depicts that highest risk scenario in terms of a pretty impressive cumulative risk of HCC versus various other forms of these variables. So sort of a triple hit, obesity, alcohol, and hep B. So it's not surprising that the ASLD hep B guidance from 2018 suggests that abstinence or only limited use of alcohol is recommended in patients with chronic hepatitis B. Now, what about hepatitis E? Sort of the newer kid on the block. I did find this study that of 53 symptomatic hep E patients in England who got it in a non-pandemic sort of way, that there was an increased infection risk in those patients who drank more than three drinks a day. And there was a higher disease severity and mortality rate in this small study in patients that had preexisting alcohol-associated liver disease who then got super infected with hep E. However, a study looking at alcohol-associated hepatitis patients from France demonstrated a low prevalence of acute hep E serologies. And that was looked at because hep E seemed to be an under-recognized form of acute chronic liver failure, but that didn't really pan out in the Alkep group, at least in this study. So I think the jury is still out, but it is kind of an interesting, some interesting data. What about alcohol and HIV? HIV is not necessarily specifically a, excuse me, liver disease, but we see these patients commonly with comorbid liver disease. So I wanted to include this. So about a quarter of HIV-positive patients report risky drinking on Audit C, and alcohol misuse is associated with an increased rate of HIV acquisition, like related to higher risk behaviors, increased viral loads, probably related to lower rates of ART adherence, and increased mortality. And I put on the right side a figure from a Wellside article that demonstrated a shift in the causes of mortality away from AIDS and HIV-related illnesses, and more to concomitant viral hepatitis. Also remind you beyond co-infection that liver injury historically in HIV-positive patients was very common from ART hepatotoxicity, particularly ritonavir, which has really fallen out of favor and replaced by safer agents. Now switching gears a little bit to substance use potential, I wanted to talk about alcohol and cocaine. So we know that cocaine alone can cause acute hepatic necrosis. Interestingly, a majority of cocaine users also drink alcohol, and when you combine the two, alcohol and cocaine, it actually forms in the human body a new metabolite called cocaethylene, and you can see the depiction of that molecule in the corner. And this cocaethylene actually has a longer half-life and greater risk of cardiotoxicity than the cocaine molecule itself. So alcohol plus cocaine is a bad combination. A reminder that cocaine causes zone three necrosis and some fatty change, the central lobular injury, that's actually very similar to acetaminophen, and you can see the histopathology slide on the right there with arrows pointing to preserve portal tracts and zone three injury near the central veins with some remarkable fatty change there, which could also be related to alcohol use in this case. Now what about marijuana? This is an understudied area, but this one study looked at the nationwide inpatient sample of greater than 30,000 patients, and using ICD-9 codes to classify patients as being, quote, marijuana or cannabis-dependent and alcohol-dependent or not, patients that had both of those diagnoses of marijuana and alcohol were associated with lower rates of various alcohol, so see liver disease stages compared to patients that had just the labeling of alcohol dependence or misuse alone. As you can see, steatosis, hepatitis, cirrhosis, and HCC. I think this is an interesting preliminary study, but further prospective studies are really needed with very careful history-taking, because oftentimes patients are not necessarily just using one agent versus another, and this would help avoid misclassification bias, which I think is a concern with this study. So the jury's still out there. I tried to look for human evidence looking at the combination of alcohol with heroin, alcohol with MDMA, like ecstasy, alcohol with amphetamines, and I was able to find some animal data that suggests that the combination, not surprisingly, is bad, and it potentiates liver damage, but really there's insufficient evidence in humans that have been published to date regarding this. And I just wanted to finish this talk by discussing alcohol and caffeine. So we know that high-dose caffeine alone has been characterized by the NIH Liver Tox website as being a probable rare cause of hepatotoxicity. When you combine the two, it can cause a lot of problems, and in fact, the FDA banned these kinds of beverages, like 4-Loco, in young patients primarily, who they were targeted to, these caffeinated alcohol drinks because of non-related alcohol injuries, sort of high-risk behaviors. Now, that being said, you don't necessarily, you can kind of create one on your own, and things like Red Bull and vodka is a pretty popular drink still, and so that's still a concern. Not a lot of human data, but I did find one study in rats that demonstrated liver and kidney injury from when exposed to alcohol and high-dose caffeine. However, there is maybe some good news related to caffeine-containing products, particularly with coffee. So there is growing evidence of liver protection with coffee consumption, as defined by greater than three cups of coffee per day, and with an association with decreased risk of developing cirrhosis, decreased risk of HCC, and more recently, a decreased risk of liver stiffness, or an association with lower liver stiffness in regular higher-use, higher consumers of coffee. On the right-hand side is a meta-analysis of studies looking at various levels of cups of coffee and the decreased risk of cirrhosis, and you can see that the top of the y-axis starts at one, and all the lines go below one, so this is a pretty uniform form of liver protection. I bring up caffeine because in the DSM-5, for more for research purposes, caffeine was put in the DSM-5 as a substance of potential interest as a substance use disorder, so more to come, I think, about caffeine and coffee. And good news for us coffee drinkers. So key takeaways. I think I've been able to demonstrate that alcohol superimposed on chronic Hep B or Hep C is associated with increased cirrhosis, HCC, and mortality. Alcohol with HIV and perhaps Hep E lead to poorer outcomes. Alcohol with cocaine or other substances of abuse are likely bad, but it's not a lot of evidence in humans for that. Besides anecdotal. And alcohol superimposed with marijuana or caffeine, more evidence is needed in this area. Thank you for listening. Take care.

alcohol consumption

liver disease

hepatitis C

cirrhosis

HCC

antiviral therapy

HIV

cocaine

cardiotoxicity

marijuana

caffeine

substance use disorders