My name is Michael Lucey and it is my honor to moderate the Thomas E. Starzl transplant surgery state-of-the-art lecture. This year our lecturer is Sumit Asrani. Dr. Asrani is chief of hepatology and liver transplantation at Baylor University Medical Center Dallas Fort Worth and the title of his lecture is Alcohol-Associated Liver Disease Transplant Triumphs and Challenges. So let's welcome Dr. Asrani. The Dr. Lucy and the ASLD leadership, again, thank you. Alcohol consumption, its acceptance, availability, is sort of embedded in the fabric of our global culture. For centuries, alcohol has served as a focal point of celebration, stress reliever, an alternative to bad water in ancient Europe, building connections, a status symbol. But as many of us see in this room, this relationship between alcohol consumption and our society is polarizing, nuanced. And its detriment is often not recognized until it's too late. The same bottle of wine that conjures up images of wedding celebrations, weekend relaxation, also conjures up images of a drunk man in the ER, the car accident, and in our case, the need for liver transplantation. So on that sober note, that's my dad joke for the day, I would like to start off by honoring the past and where we were and how Dr. Starzl, though recognized for many, many accomplishments in the field, in the end, also turned out to play a pivotal role in establishing liver transplantation as the standard of care for advanced liver disease. Now, there have been many turning points that have sort of punctuated the history of ALD and liver transplantation in the US. The first pivotal point may have been a consensus conference organized by the NIH, whereby ALD found itself in the company of other indications, such as hepatitis and PBC, as being recognized as an indication for transplantation. And in a small section buried towards the end of the document was a proclamation that liver transplantation might be considered in a small proportion of patients in whom evidence of progressive liver failure has developed despite current medical treatment and abstinence from alcohol. Now, the intent likely may have been to call out its use to be restricted. However, maybe this was the first time that it really made ALD mainstream. And then Dr. Starzl really made it mainstream. He believed that transplant for ALD, again, unless you were a mean drunk, was something that should be done. And in a quote often ascribed to Dr. Starzl and in a personal conversation with Dr. John Fung, he got that liver transplantation is the ultimate sobering experience. And then he painstakingly put together a narrative that enabled ALD to be accepted as an indication for transplant. And in a seminal paper in JAMA, he described the experience of transplantation for ALD-related cirrhosis. And the first experience from the 1960s to 1970s to 1970s was horrible. Mind you, so if you look at in the pre-cyclosporin era, the first experience, there were a large number of early deaths. However, subsequently, with the turning point being the widespread use of cyclosporin, he showed that patients transplanted for ALD had similar survival as compared to other indications. Once this was put on the map, a young 35-year-old, who's currently sharing the stage right here, in 1990, probably described the first ALD pathway at the University of Michigan, incorporating a network of psychosocial assessment, transplant psychology, assessment of relapse risk. Michael, Lucy, and colleagues showed that liver transplantation for ALD was associated with acceptable outcomes, and the alternative, being no transplant, was associated with dismal outcomes. And this figure sort of foreshadowed the famous New England Journal of Study to follow about 20 years later. And the debates about the sanctity of transplant for liver transplantation for ALD, though seem recent, have percolated for decades. So even 40 years ago, these were some of the things that were happening. The Michigan court system ruled that alcoholism alone did not contraindicate transplant. Tom Beresford, psychiatrist in Lucy, said that six months did not equate with prognostic indicators of ALD success. Mentions of objections being moralistic, undermining the modern understanding of alcoholism, including recognition that this is a treatable disease, not a vice, and the fact that the imposition of an arbitrary period of abstinence before going forward with transplantation would seem medically unsound, or even inhumane. By waiting unnecessarily, reasonable candidates would be allowed to deteriorate to a poor risk category, and those at a poor risk from the outset would almost surely die during the interim. And again, conversations that we think happen now, but started 40 years ago. So indeed, these conversations and the national dialogue that started still resonate and punctuate our current landscape on a daily basis, whether it's on the inpatient setting, in clinic, or in the national news. And as we collectively emerged from the COVID pandemic, we all made the same observations. Something's going on. Patients we saw were younger and younger, and the CDC death data sort of confirms that, that the younger members of our society continue to be impacted, and the transplant landscape reflected that. This steep purple line is transplantation for ALD, which is leaving several other indications behind. Now, it may have just filled the void of left by the cure for hepatitis C, but its ascent in this transplant derby seems multifactorial. And so, in our era, the triumph and the challenge has been liver transplantation for alcohol-associated hepatitis. And Dr. Mathurin and Luwe's study really marked that inflection point for this trend in the US. The Franco-Belgian study placed the conversation of alcohol-associated hepatitis front and center in our hepatology community. And slowly, over the last 30 to 40 years, the experience for liver transplantation for alcohol-associated hepatitis has grown. This figure on the left highlights a majority of the experience reported to date showing experience with this indication. And then, later on, as time goes on, with expedited assessment for liver transplantation for ALKEP, and survival, as we see, starting off from the STARSIL study to the recent QUICTRANS study, suggesting that survival with this indication remains excellent. On the other hand, relapse to alcohol remains a concern. There's significant variation in reporting of return to alcohol use after transplantation, ranging from 10% to 30%. And more importantly, the return to heavy alcohol use ranges from 10% to 15% to 20%. And if we take some of these studies out and look at some of the selected studies, what we see is that relapse for patients with clinically severe alcohol-associated hepatitis, if stringent alcohol criteria are used, is about 14%. The risk of relapse is not different between alcohol-associated hepatitis and alcohol cirrhosis, where the confidence interval is across one. And the six-month survival is also not different between alcohol-associated hepatitis and alcohol cirrhosis. But, in the current landscape, this still remains the wild, wild west. Hard to predict responders versus responders. Hard to predict relapsers. Hard to obtain alcohol use disorder support. Candidate selection is not standardized. And in the end, liver transplantation may favor the well-connected. Women and minorities don't get a chance. And so let me go over some of these factors. So first, we're not good at predicting non-responders, right? So if you have two people up here, one is a MELD score of six and MELD score of 31, the C-statistic is 0.85, suggesting that 85 out of 100 times, the person with the higher score will die before the person with the lower score. So that we get. But, what if it was 27 versus 31? Here, it's a flip of a coin. If the person with the 31 is gonna die before the person who's 27. So we're really not good at predicting non-responders. On the other hand, what about relapse? What score do we use? How do we assess who is gonna relapse back to heavy alcohol use? And there are multiple scores out there. And then the goal of this slide is not for you to go through it in detail, but just to suggest that if you really look at the, you know, four or five representative scores, the themes are about the same. It's drinks per day, it's social support, it's prior rehab, it's legal issues, it's other substance use, it's psychiatric comorbidities. And this has been something that we've been debated and trying to refine for the last 40 to 50 years. Now, I could probably fill this whole discussion with every single study Brian Lee has done on behalf of Accelerate, but I'll pick on one. You know, one thing that he's shown is that can we really predict the pattern of alcohol use? And what this shows is four different scenarios and four different patterns. And at this point, the pattern could be, let's say, just a slip all the way to heavy daily use. But what you can see is that the pattern of alcohol use does matter after transplant, and not all alcohol use may be equal. Candidate selection. Are we truly stringent in the United States? If we really look at the seminal studies from 2011, you sort of had to go through this mechanism where you had to have clear consensus as well as buy-in for several members of the transplant team. And is this really happening on a daily basis across every single program? And the concern is that it probably is not. Recipient selection. What we've seen is that on the left side is women are disadvantaged, they are race differences, there are concerns with geography. So in this study showing predictors of patients who don't make it to transplant, it tends to be older patients that may be in certain geographic regions and being female. And then there are concerns about having resources for living donor liver transplants, for living donor liver transplantation, donor factors and coercion. And then the big sort of looming factor is that are certain programs and the decisions being driven by financial pressures? So where are we going? What does the future of ALD really look like? Whether it's 1923 or 2023, alcohol will remain part of the fabric of our lives. However, it will become easier and easier to access. And the single most important predictor of where things are headed is not what our patients ask us, but what our patients ask Google. Google knows before we know what's going on and can really help tell us wherever you've been and where we're going. So if we look at the search term, which was very popular during the COVID pandemic, liquor store near me. And if you really map it out, what you see in the bottom is how people have been searching for this term, liquor store near me. And this thing, we thought it started during COVID, but it started way before in 2015. And of course, peaked during that time, and now we're seeing the consequences. But what this tale tells us, at the end you see that numbers are stabilizing, is that either numbers will go down or we found all the liquor stores around us. And the countries where folks are searching most is you look at North America, you look at India, you look at South Africa, you look at Australia, but you also see New Zealand, you also see United Arab Emirates. So we already have the signals of where our interventions and places where we need to be to really impact a change. So where does the future of ALD and liver transplantation lie? And I would suggest four things. One is structure, two is biomarkers and biosensors, three is integration of AUD care, and fourth, I think, is redefining what we mean with success after liver transplantation. And I'll go over this in detail. So one is structure. So here's an example of the Dallas Consensus Conference. So we organized a conference about four years ago now where we got stakeholders from hepatology, surgery, social work, psychology, and other disciplines to really come together and say, okay, if we're going to do this as a community, can we sort of, you know, establish some kind of structure? And the components of the Dallas Consensus Conference was one is structure in the workup in terms of selective evaluation and early psychosocial assessment. Two is structure in selection, getting some form of consensus for committee for listing. But the most important part also was follow-through and how do we really invest in alcohol use disorder management and monitoring of our outcomes, primarily internally and then regionally. Now I'll give you an example of how we've done it. So, you know, as a program we were late to the game and part of the reason was is we really wanted to build out the infrastructure before we started offering liver transplantation for alcohol-associated hepatitis at our program. And the components of the way we do it in our clinic is it always starts off with a hepatology advocate. Then it's referred to a specialized ALD clinic, which is a core member of a psychologist, hepatology, surgeon, social worker, and nurse. You have to get consensus for liver transplantation evaluation, and this process might take a while. Sometimes it's a week. Sometimes it's a month or two. And then once we have that, having structured post-transplant follow-up. So during this time, during this multidisciplinary evaluation, we have linkage to ALD support. So we've built out support structure for our patients who come across Texas, where we have identified resources close to home. We have a structural way of sort of testing, PATH test, while they're waiting for transplantation or even prior to being considered. And then also a contract. We do a biweekly review to go over this and refer and talk amongst ourselves. And then once we have that, we proceed to transplantation. And even during transplantation, the criteria is that they will follow with transplant psychology once a month, continue AUD treatment, and see one of the physicians every three months, and also get monthly testing. And the role of monthly testing, you know, as it's evolved, is not punitive. What it is, it's a recognition that, you know what, you need more resources. And I think that itself also has been a frame shift, where we're talking more about PATH, not as an aha moment, but also as a way to really engage with our patients. And with this, we've been now doing this for about 24 months. So my guess is that during this time, we've probably seen about 500 to 800 patients with alcohol-associated hepatitis. We have not evaluated everybody in our clinic. We probably only made it to the first screening stage to see about 80 to 90 patients through our clinic, once they have a hepatology advocate. We've transplanted about 18 patients through this mechanism. Survival has been 100 percent, and relapse has been in three people, especially in those ones where we sort of rush the process. So this has been the structure that we've used. So one, I think, you know, any program that is embracing it needs to form and maybe publicize what is their structure of helping this population. Second is tools. I think biomarkers and biosensors will sort of help this out. And I'm going to start with one side, is at one of the spectrum, at the population level, we will be able to generate genetic profiles and clinical factors, such as diabetes, to identify high patients that are at risk for development of cirrhosis. That is possible. That's been published. That could be the future. And on the right side, what we may evolve into, and some of the work that Tiffany Wu is doing with her mentor Vijay Shah at Mayo Clinic, is really thinking about sort of this digital ALD clinic, where we have this digital phenotyping, behavior markers for personalized ALD care. So what one can imagine is that, let's say if you have a patient on the wait list or somebody who is post-transplant, a future state where not only do we combine data that patients may enter about craving and the desire to drink, but now you're combining this with location, you're combining this with maybe, you know, a shaky phone, combining this with the cadence of voice, Google searches, you know, all these things theoretically can help tailor interventions. Yes, big brother, but what you can imagine is, what if it could be is that based on the amount of intervention you need, it could be, one, at a green level, a simple single text, two, at a yellow level, it may be engagement by your sponsor or a phone call, and red, maybe on-demand meeting with an addiction psychologist virtually. These things are possible, and I think, you know, we need to evolve into using the tools that we have to really help our patients. The crux, I think, is going to be early recognition and treatment of alcohol use disorder. This is where the biggest bang for the buck is going to be, mainly to treat early and integrate early, and this, I think, you know, has been a paradigm shift for our society, which is so focused on just the hepatology and the physician, the hepatology aspect, where we really need to integrate more with treatment for AUD. So here's a study that showed that on the y-axis is years, so in patients that received medical addiction therapy, and these patients were followed, treated versus untreated, for future development of decompensation, what we saw is that there's a lower time to hepatic decompensation in patients that receive treatment early. Second thing is integrating early. So here's a study now about 10 years ago that showed that for patients that come for transplant, if you can integrate some services of an alcohol addiction unit, these patients have a lower return to alcohol, and so treat early and integrate early, I think, would be very important. And I think we need to think about AUD simply as an extension of frailty. You know, we think about frailty, but everybody sort of has a different definition, and in our program, what we think is when you think about frailty, there can be psychosocial frailty, where you need mental health, there can be sort of financial frailty, need for resources for our frail patients, they need social work. Frailty from a medical condition standpoint, which is chronic conditions, where we treat cardiac and renal on the transplant list. A physical frailty, where we think about freehab, AUD as a frailty, and is this where addiction plays a role, and nutrition, dietician. So why does AUD need to stay in isolation on an island? Why can't we just think about it as something that we do as just another thing that we do to help our patients? And it's very interesting. So Gene, his paper just came out yesterday on this, is what does success mean? Is it total abstinence, still the benchmark? So what he did is he surveyed hepatologists, surgeons, in person, doing a mock selections committee at two major society meetings, including one hosted by the ASLD. And he asked the audience, okay, what is success? If you're transplanting patients with alcohol-associated hepatitis, what is success? What's the most important? What's the least important? Number one for your colleagues was good allograft function, good quality of life, survival regardless of drinking, mostly abstinent, which is occasional slips may be okay, benefit to society, and complete abstinence actually was number six on this list. So I feel like, you know, the field is moving where we're sort of, you know, being willing to accept that, you know what, our definition of success may need to change with time so that we can help more patients. And so I feel this is sort of the paradigm for liver transplantation for ALD. And I'll sort of walk you through, you know, all of these components. There's sort of four pillars. I think one is prior to transplantation, an integrated multidisciplinary approach, transparency in the evaluation process, outcome monitoring. Then you're sort of taking care of ALD and AUD at the same time. From the ALD standpoint, whether it's steroids, N-acetylcysteine, nutrition, infection management, consideration of AKI management. From the AUD standpoint, there is a toolkit, you know, how do we incorporate relapse prevention, whether it's group, virtual programs, social networks, helping each other out, digital ALD clinic. Then some way to identify responders. On the medical side, I think we have a handle when we think about, you know, non-responders trajectories. On the AUD side, that's where we need the work. Could it be some kind of framework like the Dallas Consensus or something based like that, but we still don't have a relapse risk? And then I think, you know, at the other side is that once we get patients across, really using our biomarkers and biosensors to help our patients and continuing to have resources for integrated AUD care. Now this sounds great, but who's going to fund it? And I think we really need to convince our healthcare systems that we do need to invest in this. But even bigger than that, I think we need to pivot as a society to really deliver health. And I think for this, I really want to zoom out. So I'm going to zoom out, and then I'm going to zoom in. So I think the zoom out is, this is where most of us in our room spend energy, right? We have our patients end up in the hospital, three to four hospitalizations per patient, 30,000 per hospital, system spends 120,000. But what if we just invested 10,000 back there? What if we invested in education? What if we invested in AUD? What if we invested in sort of, you know, really building up our community resources? We avoid the 60,000 in medications, imaging, lab. We avoid the 100,000 in procedures, medications, blasphemy to say we avoid transplant, repeat hospitalizations. And for our patients, we avoid premature death and lost productivity for our patients dying in their 40s and 60s. So as a society, you save 10,000, and I made it really round number, you save a million, right? And is this kind of argument that we go to our healthcare systems and say, to really move the needle, we need this. And then finally, I want to sort of zoom in and recognize our personal narrative, okay? So I'm going to start off with something 45 years ago. So there was this controversial paper called taking care of the hateful patient. And in this patient, they described the patient with alcohol use disorder in the New England Journal of Medicine as somebody who is self-destructive, a denier, chronically self-murderous patient, where they sort of inflict turmoil on all those around them and bring chaos, right? But the point of that paper was not really to, you know, point this population as hateful, but what it was is to really say, you know, what is our personal narrative? Is it that the reason we feel a certain feeling towards patients with alcohol liver disease is because of our own experiences with alcohol, whether it's personal or having seen it impact our family members or those that surround us? And maybe what we need to divest away from is away from this aspect and really take the Michigan approach, and Jessica and Scott Winder, Jessica Mellinger, Dr. Mellinger, and Dr. Winder have sort of, you know, really pioneered this and really thinking about wrapping our patients in a myriad of services that really treat all dimensions of the disease. So here's my nuanced view of ALD and liver transplantation for the last, you know, 40, 50 years. To start off, liver transplantation for ALD was acceptable in the 80s. We built on this, started showing excellent outcomes. The perception shift was seen in both the physician as well as the community. Liver transplantation in the 2010s, acceptable for alcohol-associated hepatitis. The pivot away from six months to really a comprehensive review, and now in this decade, our job is to really think about integration of AUD therapy, transparency and selection, center accountability, and really looking at digital ALD care. And with that, from the Aswani family as well as the ASLD family, happy Diwali. Well, thank you, Sumit, for a really superb overview of both the history and the future of liver transplantation for patients with alcohol-associated liver disease. This brings to the end the Thomas E. Starzl state-of-the-art lecture.

Sumit Asrani

Thomas E. Starzl

Alcohol-Associated Liver Disease

Liver Transplantation

Alcohol Use Disorder

Patient Evaluation