Good morning. I think we will start the session on time. We have a potpourri of subjects, so that reflects our, say, clinical practice. My co-moderator is Mitch Muhammad. He's a professor of medicine at Duke University. I am based in Baltimore, Maryland. And I want to invite the speaker, first speaker. Each one will have 15 minutes to give the talk. At the end of the session, we will have 30 minutes of Q&A. So I hope everyone will stick to their time, so we'll have plenty of time to ask questions to our speakers. The first speaker is Dr. Nadeem Muhammad. He's from University of Pennsylvania. He recently developed the scoring system for risk management of patients undergoing surgery, major surgery. Many of us use it in our practice. So Dr. Muhammad. Set this down here for a moment, if that's OK. I'll move that. All right, there you go. All right, well, thank you to the organizers for the opportunity to speak about this. I love talking about cirrhosis surgical risk. Stay here. So my name is Nadeem Mahmood. I'm an assistant professor at the University of Pennsylvania. Here are my disclosures. So I was tasked with discussing, I guess, improving our understanding of how to assess risks associated with non-transplant surgery in patients with cirrhosis. And what I'd like to do is talk a little bit about the reciprocal nature of surgical risk in patients with cirrhosis. We'll then talk about preoperative risk stratification approaches and tools available to us. And then I'll close with some potential risk mitigation strategies that we should discuss. So first, it has to be said that patients with cirrhosis have a uniformly higher risk of postoperative mortality as compared to patients who do not have cirrhosis. But why is this? The way I like to think of this, cirrhosis clearly impacts the risk of surgery, but surgery also does impact the stability of cirrhosis. And this is the reciprocal nature of cirrhosis surgical risk. So going through some of the pertinent factors on the cirrhosis side, patients with cirrhosis have impaired synthetic dysfunction. They're in a highly catabolic state. This leads to malnutrition, sarcopenia, and relative frailty that can, in the postoperative setting, lead to slow wound healing and poor physical recovery. There are data demonstrating that frailty is strongly associated with increased postoperative mortality in patients with cirrhosis. These are data from a Veterans Affairs dataset, 804 major surgeries in patients with cirrhosis, where preoperatively they were stratified into low, intermediate, and high risk of frailty using a validated algorithm. And we found that there was a 74% increased hazard of postoperative mortality in highly frail individuals relative to patients with low risk frailty. So clearly these factors are very important. What about portal hypertension? So portal hypertension is a major driver of risk, increases the risk of bleeding, presents challenges to hemostasis, in particular with these open abdominal surgeries or chest or cardiovascular surgeries where surgeons are directly interfacing with the portal venous circulation. Here are some excellent data from Journal of Hepatology in 2019. It's a prospective cohort study, 140 patients with cirrhosis who underwent major open abdominal surgeries. All of the patients had preoperative hepatic venous pressure gradients that were measured. The authors found that with increasing degrees of portal hypertension, this was independently associated with an increased risk of postoperative mortality. So an HVPG over 16 was associated with high risk and an HVPG of 20 or more was associated with extremely high risk of postoperative mortality. Another way of thinking of this from a more simplistic standpoint is just to look at a simple surrogate like the platelet count. We demonstrated that as the platelet count drops below 150, the risk of postoperative mortality, even at a relatively short interval of 30 days begins to rise near exponentially. So portal hypertension is a major, major driver of this risk. Of course, patients with cirrhosis have disruptions to hemostatic parameters. They have thrombocytopenia, and this can lead to this scenario where some patients are more likely to bleed, some are more likely to clot. It can be difficult to predict this. And finally, there's cirrhosis-associated immune dysfunction. As the severity of liver disease increases, this scales with this systemic inflammation that over time can lead to immune tolerance, relative immune paresis, and immune dysfunction. So this leads to an increased risk of postoperative infection. So what about factors on the surgery side? So it has to be said that surgery type and the surgical compartment being operated on, and the surgical complexity has a dramatic impact on risk of postoperative mortality. These are data from two national datasets that demonstrate that it's primarily these open abdominal major surgeries and these chest and cardiovascular surgeries that confer the highest risk of postoperative mortality. And on the other end of the spectrum, laparoscopic abdominal surgeries, abdominal wall repairs like hernia repairs are much lower risk. So surgery type is important, and much of this risk, or at least a component of it, is driven by anesthesia. So anesthesia induction, the duration of anesthesia, and the exposure to it. This can result in reductions in cardiac output, and in many cases, dramatic reductions in hepatic blood flow. So depending on the type of anesthetic that's used, the experience of the anesthesiologist, reductions in hepatic blood flow can range from 20 to 60% decreases. This can precipitate hepatic ischemic and hypoxemic injury that results in worsened hepatic synthetic function, and an increased risk of postoperative decompensation and death that can occur even weeks after the operation is performed. So here's kind of an overview of the pathophysiologic drivers of risks. Let's talk now a little bit about risk stratification approaches. I like to think of this conceptual framework when I'm approaching a patient that may need an operation. And this is driven and built upon the pathophysiology that we just discussed. So there are cirrhosis factors, there are patient factors, and there are surgery-specific factors that all combine to impact the risk of various postoperative complications, including potential death. I like this framework because an ideal risk stratification tool should actually incorporate elements from each of these domains of risk factors. Some of the most commonly used tools, of course, are the MELD score and the Child-Turkopuse score, which we calculate in virtually every patient, but recognize that these are really only interrogating the severity of liver disease and the degree of portal hypertension. It's ignoring these patient factors and surgery-specific factors. So I want to talk about two additional risk prediction models. There's the Mayo Cirrhosis Surgical Risk Score that does incorporate some of these additional patient factors, age and ASA physical status classification, and the most recently published VocalPEN score, which I'll talk about in some more detail, that one of the major innovations that incorporates some of these surgery-specific factors that impact risk, in addition to trying to more comprehensively account for cirrhosis and patient-related factors. So here's the Mayo Cirrhosis Surgical Risk Score. As you can see, it's very simple to calculate. It relies on the MELD laboratory values, age, ASA score, and etiology of cirrhosis. This was published in 2007 from a large cohort of patients who underwent surgery in the Mayo Clinic. This was an excellent study, and one of the most important features of it is that it shined a spotlight on the fact that patients with cirrhosis really do need dedicated risk stratification tools, given that there's a very complex pathophysiology, as we've discussed, that contributes to surgical risk. This tool has been dominant over the past 15 years or so, and it's widely, widely used, and it's been very effective. However, one of the major drawbacks of the Mayo score currently is that its predictive value has degraded over time. I'm showing you calibration curves here. So on the x-axis, you're looking at the predicted probability of postoperative mortality, according to the Mayo risk score. On the y-axis, you're looking at the observed actual event rates of mortality. So a perfectly calibrated model should follow this dashed 45-degree line, that gray line, where the predictions should match the observations exactly. I'm showing you four different calibration curves here that correspond to different time windows. So the orange line is from 2008 to 2010. So this is in a large VA dataset of major cirrhosis surgeries. In that period, shortly after the publication of the score, the calibration was actually reasonable. It did overestimate risk a little bit, but it did scale at least properly with the reference line. But with every subsequent three-year interval that went by, the calibration degraded further and further, such that currently the Mayo risk score significantly overestimates postoperative mortality risk in the modern surgical era. This has been demonstrated in quite a few studies now, and I should say that this is actually expected. This is a reflection of the fact that we've actually gotten better at taking care of patients with cirrhosis who need surgery. If there is progress in medicine and we had better outcomes, you expect any static prediction score to have a degradation like this over time. So in some ways, I view this as something that's favorable to see a calibration change like this. Nonetheless, this was a major catalyst for members of our research group to pursue a novel risk prediction score that's more reflective of modern surgical practice. We used a large dataset from the Veterans Affairs cohort, well-adjudicated, well-validated cohort of patients with cirrhosis that's fairly reflective of etiologies of liver disease at the national level. This was a dataset that also incorporated manually adjudicated surgical intraoperative and postoperative outcomes data. So very granular dataset. We identified 4,700 major surgeries from different categories. And I'll show you the tool in a moment, but some of the predictive analytic metrics in terms of discrimination calibration are presented here from the initial study. And I'm showing you receiver operating characteristic curves in the area under the ROC curve with a C-statistic for the BOCAL-PEN score, the Mayo Risk score, MELD, and child abuse. The BOCAL-PEN score in these cohorts had the highest discrimination, which is the ability of the model to separate out individuals in terms of high risk versus low risk. And then in terms of calibration, which I think is the more important of these two parameters, the BOCAL-PEN score, again, was very tightly calibrated as shown in the orange and the blue lines. The score has now been externally validated in at least three or four studies. As far as I'm aware, I'm showing you data from just two of them. So on the left, these are data from two large academic centers in the US. The BOCAL-PEN score had the highest C-statistic for discrimination, and again, was very well calibrated. On the right, the most recently published data I'm aware of are from a large Spanish cohort, 512 patients, and the BOCAL-PEN score had a C-statistic of 0.876 here. They also evaluated multiple overall performance metrics, and the BOCAL-PEN score had a superior performance as compared to all other models. So here's the tool. It's available at BOCAL-PENscore.com. You'll see that there are nine different inputs. There are different surgery categories they can select that are shown here. And when you complete this form of data, you're given projections of postoperative mortality risk, but also of a 90-day postoperative decompensation probability. And we did publish additional data that extended the utility of the score, recognizing that many patients will not die after a surgery, but they may have a very complicated postoperative decompensation course, which is obviously relevant to prognostic discussions. So I've introduced a number of different risk assessment tools. There's the ASA score, Child-Turkopew, MELD score, Mayo risk score, BOCAL-PEN score. There's a lot of things out there. And if you have access to perform a hepatic venous pressure gradient measure preoperatively, you can consider that as well. I recommend utilizing multiple risk scores. Part of this is because empirical literature looking at risks of specific surgeries oftentimes rely on thresholds for one score, but not another one. A MELD score versus a Child-Pew score. So it is important, I think, to assess multiple scores, get a sense of the landscape of overall risk. And I use these scores as a tool for shared decision-making discussions with patients. There is this, you know, surgical risk is a gradient. It's on a continuous scale. There's no one cut point where you can say beyond X percent, you should not operate. Every patient and clinician and surgeon have different risk-seeking behaviors and profiles, and this needs to be decided upon in a shared decision-making framework, but these tools can assist you with that discussion. And I need to say that no score should substitute for your clinical judgment. If your clinical intuition tells you something very different from what these scores are telling you, you should listen to that because clinical judgment is not captured in any of these risk prediction scores. So finally, I'll close by talking a little bit about some potential risk mitigation strategies. We wanna talk not just about how to risk stratify patients, but what can we do to actually mitigate surgical risk? And I'll talk about just a couple of principles here. So first, it's my view that elective versus emergency surgery actually is a potentially modifiable risk factor. That may sound strange, but consider the umbilical hernia repair. These are data from George Ionu and Kay Johnson. This is an excellent study of VA patients with cirrhosis who underwent umbilical hernia repairs. The authors basically identified which patients had ascites in different degrees of ascites. They identified elective versus emergent surgery. The first major finding is that emergency surgery was uniformly higher risk than elective surgery, 12 versus 2% risk of 30-day mortality, so a striking difference. But then in chart reviews, the authors found that 30% of the emergency surgeries could have been performed electively with a reasonable risk in most patients. And many of these patients were never actually consulted to see a surgeon to consider a possible repair. So this raises the question of when you were faced with a potentially elective surgical decision, might there be potential benefit in pursuing elective surgery to mitigate the risk associated with the development of a potential emergent scenario? So our group performed a very detailed Markov modeling decision analysis study, where you start with, at the top left in this diagram, a patient with a symptomatic abdominal hernia. You can decide to either operate electively or not. If you choose not to operate, that hernia may become incarcerated, it may rupture, and that leads to an emergency surgery that is uniformly higher risk. So the question is, is there a decision threshold beyond which a particular decision approach is favored? And we found in this study that the expected value or the quality adjusted life years favored surgery up to a MELD score of 21, which I think is higher than most would have expected. But I do think this is a reflection of this historic culture of risk aversion, where we're empirically been very, I think, afraid to operate on patients with cirrhosis due to perceived high operative risk. But I do think this culture will begin to change as we take a little bit more risk in higher MELD patients, and hopefully they do well with these surgeries. Second study I wanted to briefly mention, these are data that are being presented, actually, at the liver meeting, I think on either Sunday or Monday, I'm not sure. In this study, the authors looked at the impact of preoperative outpatient visits with a PCP provider or a GI slash hepatologist and the impact on postoperative mortality. There's a propensity score analysis, 3,800 patients who underwent major surgeries. And the authors found that in patients who had a preoperative visit with a primary care provider or a GI slash hepatologist, these patients had lower postoperative mortality. And in patients who saw both providers, both a PCP and a GI hepatologist, there was further risk mitigation that was observed. Interestingly, the features that appeared to be different, patients who saw outpatient providers, they were more likely to have their diuretics titrated, they were more likely to have SVP prophylaxis initiated, and in patients with ascites, they were more likely to have preoperative paracenteses. This is a really interesting finding, I think, in the study because this comprised both elective and emergent surgeries. So not all of these visits were dedicated preoperative risk stratification visits. And my takeaway here is that patients who are routinely followed, regularly followed, are most likely to have guideline-directed optimization of their cirrhosis and be on appropriate medications so that if an indication for surgery develops, elective or emergent, they're best prepared to do well. And finally, and in the last minute here, I'll talk about some additional preoperative management considerations, a little bit of a potpourri here. So there are insufficient data to recommend preoperative tips at this time. All the data that exists are either case series or there are some emerging retrospective data. It's very difficult to adequately control for confounding in these studies, but this can be a consideration on a case-by-case basis that may mitigate risk in some patients with poor hypertension. Nutritional optimization and concepts of prehabilitation may mitigate risk related to malnutrition, sarcopenia, and frailty. There's a wealth of data on this in the non-cirrhosis setting but one would expect that you'd see similar findings in patients with cirrhosis. I'd recommend considering a preoperative liver transplant evaluation for elective surgery if the patient meets some of these criteria. If they have an estimated postoperative mortality risk at 90 days over 15% or a MELD score that's in the range of 15 to 20, these are patients where if they're a potential transplant candidate, you should consider evaluating them prior to elective surgery. There are no established thresholds for labs related to bleeding or clotting. If you have access to thromboelastography or TEG, these can be considered as an assessment of whole blood's ability to clot and that can guide transfusion recommendations. In the absence of that, here are some reasonable thresholds for platelets and fibrinogen that are based primarily on expert opinion. And then finally, I'll emphasize that it's extremely important to have these major surgeries performed at an experienced center with an experienced anesthesiology team. This mitigates a vast amount of the risk. There are plenty of data that suggests this. And if there is an option to select between a simpler surgery and a more complex surgery or a minimally invasive and a more invasive surgery, select the simpler, least invasive surgery to minimize risk. So in summary, we talked about the reciprocal nature of cirrhosis and surgery when it comes to risk assessment. Preoperative risk stratification should incorporate elements of cirrhosis, patient and surgery-related risk factors. I recommend computing multiple of the different scores and assessments that we discussed. And these scores do not substitute for your clinical judgment. Again, here are some general thresholds to think about for preoperative liver transplant evaluation. And then we talked about several different modifiable risk factors, some of which need to be further studied, but this includes being proactive and thinking about elective surgery rather than waiting for an emergent indication to develop, especially for things like hernias, focus on adherence to routine outpatient management so that patients are optimized from a cirrhosis standpoint, and thinking about nutritional optimization and prehabilitation. So thanks for your time. And again, thanks again to the organizers for inviting me, and I'll look forward to any discussion in the panel. Thank you, Dr. Mahmood for that excellent synopsis of what we know about the risk management. And these tools are very helpful until artificial intelligence takes over our role. So next speaker is a very well-known speaker to all of you, Professor Abdul Malik. She is from Mayo Clinic Rochester, has contributed significantly to this field of fatty liver disease. And Dr. Malik is going to talk to us about how to assess the severity of fatty liver disease using non-invasive markers. Thank you. Excellent. Sorry, I went over time a little bit. Let's see here. Well, I thank Dr. Tilavath and Dr. Mahmood for the invitation to be here today. See if I can get my presentation up. Thank you. I'm going to turn it over to you. We can some in the next fifteen minutes I've been asked to talk about non invasive assessment I do do a lot of clinical trials but nothing to disclose relevant to this presentation. So before we talk about. Risk assessment and clinical practice I think it's really important to just highlight what the most reading of this is. We are asked to approach all metabolic dysfunction associated steatotic liver disease is not recommended. But we're asked to approach targeted screening populations at increased risk for advanced hepatic fibrosis. Fibrosis stage three or four in clinically significant fibrosis. And this is going to have implications on pharmacotherapies in the future those patients with Nash with stage. Two fibrosis so that early identification. At risk for advanced hepatitis C. chronic liver disease and progression. And complications of chronic liver disease so create screening currently for type two diabetics. Patients with metabolically complicated obesity a family history of cirrhosis. Or alcohol use. So this is a silent condition one that's progressive with no avert symptoms that patients with chronic liver disease may not be able to see. So this is one of the most clinically meaningful outcomes and given the variable does rates of disease progression. As clinicians we can very rarely cherry pick out from a crowd who has advanced hepatic fibrosis. And liver biopsy certainly comes at an added cost- an added potential discomfort to the provider as well as our patients. So the issue of biomarker use as a replacement of biopsy has. Been a lot of work to identify a biomarker as a defined characteristic. That is measured as an indicator of normal. Biological processes. To measure. And a response to an exposure or an intervention and these biomarkers are going to have implications as we embark on a pharmacologic- landscape of therapies that will be soon be it out in our armamentarium. So basically stated this is a test it's a biopsy. It's a biopsy it's a test that can measure molecular histologic radiologic physiologic. Types of processes to ascertain severity of disease. But a biomarker is not one that assesses how a patient feel functions and survives and thus we- are yet at a loss to replace a meaningful clinical endpoint with a- surrogate biomarker for such endpoints- but these clinical outcomes of how. Patients feel function or function. And so we are in search for drug approval and we're in search of the biomarker to replace what is currently the gold standard of of histology. There are many types of biomarkers there are blood based biomarkers which are simple calculations a score that use- readily available labs or clinical parameters to. Define a calculator based assessment and those are tests like the fib four score the apri score the naffled fibrosis score. And there are other biomarkers that are very similar to- blood based biomarkers- markers like macro to globulin or how uronic acid. That in an algorithmic proprietary manner can give us a- blood based biomarkers such as fiber test of score. And others and then we have imaging based biomarkers- of course you're all familiar with these. But as we move from blood based biomarkers to imaging based biomarkers. Clearly we decrease the number of biomarkers that we use in our assessment so this will be important- as we define how to use these- this armamentarium markers. The critical issues is when using the markers are there several factors to consider there's a context of eucs how we going to use them where we going to use them who's going to be using them. And which setting are they going to be used because the performance of such biomarkers will differ on the setting- and prevalence of those biomarkers. And how we bring them out and how will the read inform and guide clinical care. There's also issues related to the analytical robustness of a biomarker how it's measured- the conditions in which it's measured potential confounding of an outcome for which it's measured. So it's accuracy repeatability reduce reduce it up produce re reproduce ability. And the day to day variation of these biomarkers is one that's really currently under investigation- and the question is how do we measure their specificity- do they have optimal thresholds. That perform and it can be validated globally- and so I hope to share some of this with you. From a clinical practice standpoint the assessment of disease severity changes for us as clinicians for those patients with advanced hepatic fibrosis fibrosis stage three or four because it alters our ability to predict- and we've come to learn that fibrosis and only fibrosis is a predictor of clinically meaningful outcomes from a transplant free for survival and liver- survival events. And so the accuracy of the biomarker for predicting advanced hepatic fibrosis as you could see here the serum based biomarker. Fib four has an area under the receiver operative curve of point eight three. And elf which is a blood sample. And it's a point of care. Imaging biomarkers V. C. T. E. point nine three and M. R. elastography point nine three so fib four is free. Elf comes at about a cost of a hundred and eighty to two hundred dollars if we were to send it out but comparable. V. C. T. E. as a point of care also- under typically a hundred two hundred dollars in a clinical setting but MRI certainly comparable come but comes at less. Availability and accuracy. So the F. test is the only FDA approved proprietary blood test currently. It measures three elements of the matrix turnover as you can see here. And a threshold above nine point eight is a real liable identifier of patients with massive and increased risk for hepatic fibrosis. So with regards to the imaging based my biomarkers and its use in clinical practice. As you can see here if we were to cherry pick. Transient elastography by a fiber scan comes at the largest availability the lowest cost and a really quite low of failure rate- but as you can see here. Even lower failure rate with M. R. E. but certainly less availability higher cost. So with regards to the context of use in the settings if we were to really say we want to stratify those patients out for assessment to have advanced hepatic fibrosis. You could see that the prevalence is in a primary care setting versus a hepatology clinic where we have in risk enrichment. Of patients with- mass old mash or fibrosis and if we were to keep the sensitivity and specificity. Of the biomarker stable what you'll notice here assuming a prevalence of 5% in a general population. The positive predictive value seventeen negative predictive value 99% for a biomarker. But certainly if the prevalence is 20% in the population where we'll have a higher positive predictive value and just a slightly lower- negative predictive value but still performs very well. So content of use is important and we've recognized that sequential use of these algorithms as has been. Advocated by easel A. G. A. A. C. G. ace and A. S. L. D. can optimize our ability using a fib four followed by- V. C. T. E. or fib four followed by M. R. E. to detect those patients- who have advanced hepatic fibrosis. So this assessment of mass old severity to kind of put it all in a nutshell here. At as a take home message in a primary care clinic we recommend risk assessment by a fib four score. And if that fib four score is less than one point one these patients can stay in a primary care practice but if higher than one point I'm sorry one point three. And certainly higher than two point six seven such patients who have high fib four scores can be referred. And other patients who are in this intermediate zone can get a secondary analysis- with either a V. C. T. E. or an elf score to risk stratify whether they can be followed conservatively or referred. And upon referral our job as hepatologist is to manage and care for those patients with advanced hepatic fibrosis. And so we want to confirm a fib four we want to confirm an indeterminate V. C. T. E. and we can have the armamentarium of using advanced imaging like MRI based elastography. For discerning that advanced hepatic fibrosis because it has more sensitivity. But we're going to be confronted soon with. These this bucket here the stage two hepatic fibrosis because the FDA has said. Clinically meaningful. Hepatic fibrosis stage two or higher might be eligible for pharmacotherapies so assessment of the at risk mash patient. For consideration of pharmacotherapies is what is going to fall in our arena for care and management so where should we go. The primary goal for a G. I. liver clinic in the setting is to it going to be to identify that at at risk patient. M. R. elastography can be used to further stratify patients. Or to identify that at at risk patient. M. R. elastography can be used to further stratify patients. For whom other non invasive markers are indeterminate. And the liver biopsy should be considered when there is diagnostic uncertainty. So focusing here at this take up of stage two fibrosis you'll see that this. Threshold defines quote like clinically significant increase in rise in both liver related mortality as well as liver related events. So when we identify that at at risk patient we're finding that at risk patient we really start. Modeling these biomarkers together and so I'll introduce you this fast score which is a combination of. Transient elastography by fiber scan the cap a controlled attenuation parameter and an A. S. T. for detecting active Nash and advanced fibrosis this was initially studied by Steve Harrison in Texas. In a- a discovery cohort. And subsequently validated in a multi center validation core and it basically models both fat both fibrosis and necro inflammation is measured by A. C. T. to figure out who has Nash was stage two fibrosis and as you can see here. The area under the curve is point nine four. For a rule in and rule out and so it can rule out. With an A. U. C. of point eight one and rule in with an A. U. C. of seven point seven three and this was a meta analysis of twelve studies with over five thousand patients with biopsy proven Nash. We've also modeled the mass score which is an MRI based- stiffness assessment- coupled with an A. S. T. this was a court of patients from two thousand sixteen to twenty twenty- led by Mazen or Dean and- wrote limbo. And as you could see here there was a derivation cohort in a validation cohort to find that at risk patient. And the mass score actually out performed the fast score probably because the sensitivity of MRI- and here area under the- curve is point nine three- versus point six seven not much difference- but the mass outpour perform the fast. And we've coupled MRE also with the fib four called the met fibs for a four score the met fibs for score. And this is predominantly driven by- the elastography and the fib four in a- multivariate analysis. And a threshold of above- point three three KPAs coupled with the fib four score but above. Point one six lent a positive predictive value of nearly what ninety one percent so there. Consideration of common combining imaging and zero but serum biomarkers yielded a high percentage of positive predictive value of nearly one ninety one percent. And when doing a head to head comparison of the fast and the mass and the met fib- population cohort from UCSD and one from Japan. Where they compared- these studies performed you know more or less the same. But the difference between the two is that- the- the- the- the that- the difference between the two is that- the- the different studies performed you know multiple. Endpoints including histology and modeled- performance of these mile biomarkers the met fibs- score was superior to mast and fast. And the met fib score- more accurately defined the at risk patient- but if we had no ability to access. MRI platforms on a population based level there are some serum biomarkers one called the NIS four. There is a booth here at the- convention in a- the project products here which is being presented. Which actually is a blood based biomarker of four markers for inflammation and fibrosis. And this blood based biomarker has an- area under the curve of point eight- and performs- a little bit more calm- favorable than even fib four. So we're gonna see an emergence of transcriptomic biomarkers and we're gonna see an emergence of transcriptomic biomarkers in the near future coupling genomic transcriptomic and proteomic where we can have higher sensitivity. And frankly we're starting to apply AI based therapies- discovery. To integrating transcriptomics with machine learning with clinical algorithms that can ultimately potentially increase our sensitivity specificity and performance for that at risk patient so. Many many consortia working on this front for both diagnostic and prognostic biomarkers. So the take home point is the primary assessment using fib four is ideal. For the primary care setting secondary risk assessment should be performed- potentially using- V. C. T. E. or elf- if the fit for is above two point six the guidelines are all aligned. With a combination or sequential- diagnostic therapy we recommend referring to a liver clinic if the V. C. T. E. is above eight or the elf above seven point seven. And detecting patients with at risk who are in the future going to be eligible for pharmacotherapy is going to necessitate combination or sequential therapy. The fast is cost effective- for the at risk assessment but the met fib and the mast outperform the fast slightly. But will be limited because of cost and wide availability. So that's the cost and wide availability. But ultimately we need to extend knowledge around an awareness around the biomarkers- to our generalist and other Pratt non hepatology practitioners to improve case finding- of patients with advanced liver disease and I would add at risk liver disease in anticipation of- pharmacotherapies in the near future. Thank you. Thank you very much doctor Mano- Malik for your excellent talk. Our next speaker does not need an introduction- if she's here. Okay so we're gonna move on then so on this because doctor Emanuela- Juliette Emanuele- she's gonna be speaking to us on. The management of Fontaine- surgery. I'm sorry I didn't quite catch that could you please say that. Thank you so much for the invitation- as a surgeon in this. Crowd of people who are really outstanding hepatologist I appreciate the opportunity- I'm Juliette Emanuele I'm a transplant surgeon at USC in children's hospital Los Angeles. And I'm gonna talk to you about Fontaine associated liver disease and just out of curiosity how many of you in this audience have patients with this disease. All right they're making it to the hepatologist thankfully. So okay. All right here we are. All right- so I'm gonna talk to you about the history of Fontaine associated liver disease are followed some of the clinical features- what is the role for liver transplant in these patients considering heart failure transplant alone versus combined heart liver transplant. As well as indications for transplant and then some special situations including the pediatric population and an emerging population with hepatocellular carcinoma. So what is FALD and when I talk about this I sometimes feel like the the canary in the coal mine talking about something that many people don't understand is out there. So the Fontan procedure was described by two French surgeons as a surgical repair for children born with single ventricle congenital heart disease. First reported in 1971 but it has evolved to be the third stage in the palliative surgical series for patients with this single ventricle congenital heart disease. So initially in the first few weeks of life patients will undergo the Norwood procedure where they get graft reconstruction of their arch, they get a BT shunt and they get closure of the PDA and then usually around six months of age they undergo the Glenn procedure and the thing to know about the Glenn is that the post hepatic blood flow from the vena cava goes into the systemic circulation without ever passing into the lungs and so if you talk to congenital cardiologists these patients get a lot of shunts in their lungs and so they hypothesize that something called hepatic factor which I don't know any liver specialist who's actually heard of is required to prevent the shunting in the lungs. So ultimately what the Fontan does is it connects the vena cava above the liver with the pulmonary artery so that it puts the post hepatic blood flow in line with the single ventricle physiology and as a consequence there's this highly pressurized non pulsatile constant venous outflow obstruction essentially to the liver of these patients. So you might say this is quite rare well about 300 children every year are born with biliary atresia in the United States which is the most common form of pediatric liver disease and indication for pediatric liver transplant and there are many many many more patients with a Fontan out there than you realize and essentially this population is expanding substantially and as I'll tell you all of them have chronic liver disease. So the current population is estimated to be over 70,000 most of these patients are under the age of 18 and it's estimated that the 30 year survival after this procedure is about eighty five to ninety percent. So as these patients have begun to survive into adulthood people started to notice that there was something not right with their liver and the first descriptions were in the mid 2000s and in autopsy series and reviewing some patients they observed some imaging findings so you can see this enhancement pattern that's reticular and then in some patients you can see they develop these nodules and in some patients advanced liver disease with ascites and portal hypertension. On the biopsy you can see the changes associated with this congestive distribution with sinusoidal dilatation and sinusoidal fibrosis and bridging fibrosis and cirrhosis in some patients. So multiple single center biopsy series have shown that virtually a hundred percent of the adult Fontan population has this liver disease with anywhere between 40 and 70 percent having bridging fibrosis and cirrhosis that is mostly compensated in every patient. We looked at our own series at Children's Hospital and we have over 600 Fontans have been performed and we perform surveillance biopsies during a cardiac cath at 10 years post Fontan so about 15 years of age and in our series of outpatient well compensated patients who don't have a failing Fontan yet 100 percent have fibrosis and 40 percent have bridging fibrosis or cirrhosis by the congestive hepatic fibrosis score. We also showed that having a bridging fibrosis was associated with late mortality something happens where you get sepsis or failing Fontan and the liver starts to fall apart and these patients die from multi-organ failure. So we wanted to know how many patients actually get fall this is a very difficult clinical question because there's not a CPT code or ICD code for Fontan associated liver disease and so we were fortunate to use the California HCAI data which allows you to track patients through their hospitalizations across their lifetime in our state so you can track them by having undergone the Fontan procedure and what we observed in this population is that it's a good surrogate marker for the American population. 20 year survival exceeded 90 percent and when we used a composite of chronic liver disease codes at least half of them had a liver disease code by the age of 25 which confirms that it's highly prevalent although this still underestimates the burden of disease. So through the American Society for Transplantation we prepared this white paper where we talked about many of the challenges in these patients and the things we do and don't understand we don't know how to monitor for disease progression we don't know who will develop clinically significant liver disease who needs a transplant and what is the risk for developing liver cancer so I'll just talk a little bit about the need for a biopsy do we really need it well we don't have we just heard a beautiful talk about a non-invasive testing for muscle we just don't have that data yet on this population. Our series of biopsies were quite safe and in other centers it is as well you can perform it transjugularly actually the cardiologists are trained to perform those biopsies at our center and when we look at the biopsy correlation with liver explants that it never overestimates the degree of fibrosis and sometimes can underestimate the degree of fibrosis so it's really the only true way to diagnose severity of fibrosis in these patients and what we do is we do two passes from two different geographic regions transjugularly and we have pretty good correlation. So in terms of the part one of my talk VALD is much more common than you realize we do not have biopsy match validated non-invasive testing strategies yet most patients are very well compensated they're young they're in their early 20s so they don't see all the things that you would think of with decompensated liver disease and that liver biopsy is to this point the gold standard for diagnosis. So what about transplant do they actually really need a liver transplant there's so much conversation about this topic. The first combined heart liver transplant was performed in the early 1980s by Dr. Starzl with a young woman a child from Texas with familial hypercholesterolemia she actually survived for seven years and died from complications of chronic rejection in the pre-calcineurin inhibitor era. When we think about transplant in these patients there's always this dialogue heart transplant alone combined heart liver transplant so when we think about heart transplant alone there's sort of four potential possibilities you know will the liver regress a lot of people say well the liver's not bad they're not decompensated it's only mild fibrosis it should recover what about progression to cirrhosis the dreaded post-operative hepatic decompensation or the risk of developing cancer even if you remove the insult of the Fontan physiology whereas with combined heart liver transplant we know that there's good outcomes and that there may be this immunologic benefit when you're thinking about transplanting young patients you want to get the best graft survival over time and heart transplant alone for all comers has about a 70% five-year survival because they get chronic allograft vasculopathy and rejection when you have a combined heart liver transplant that mitigates that risk quite substantially so the most recent report looking at all comers for combined heart liver transplant in the U.S. by Alexopolis and colleagues found that when they broke down case volume into eras the first early eras were really related to restrictive cardiomyopathy but over the last 10 years congenital heart disease and presumably Fontan associated liver disease again there's not a code for it has become the leading indication for combined heart liver transplant between 2018 and 2020 there were more cases performed than the previous 20 years and I'll show you when you update this most recent curve there's been double case volume in the last two years so people are recognizing this patient population and more and more of these patients are getting transplanted although only a limited number of centers are performing this very complex and multidisciplinary procedure so what about just doing heart transplant alone and expecting the liver to regress in terms of its fibrosis there was one case report out of Europe with a 22 year old male who did have biopsy proven regression although this hasn't really panned out in larger series and this one from the Emory group when they looked at patients the liver disease was stable but it did not regress I personally don't think that this is a something that will reverse for a variety of reasons but this is certainly a topic of much discussion I hope that one of the things you'll take away from today and maybe go and read are the two really excellent studies led by Matt Lewis from Columbia an ACHD specialist called the foster study which was a multi-center retrospective review of all patients both referred and transplanted for with a single ventricle congenital heart disease in the first paper they looked at morbidity and mortality for all transplants both heart transplant alone and combined heart liver transplant and what they found was that late referral with pretty bad failing Fontan physiology bad New York Heart Association functional status and lower extremity varicosities and veno venous collaterals as a sign of multi-organ dysfunction were significant risk factors for post-transplant mortality and morbidity in either heart transplant or combined heart liver transplant next they separated the patients into those who underwent heart transplant alone versus combined heart liver transplant and what they observed is that when they did a variety of different controls that patients who had any evidence of liver disease did much better with a combined heart liver transplant so they have this criteria called the FALD score which was essentially you get one point for either having ascites evidence of portal hypertension cirrhotic morphology on imaging or having undergone two paracentesis in the past so not very strict criteria two out of the four substantially worse outcomes following heart transplant alone and if you look at these two patient populations the heart transplant alone patients were slightly younger but look at the liver numbers in the combined heart group these are not indicators of really advanced liver disease when they had the 79 patients had biopsies only 14 or 18 percent had cirrhosis or stage four fibrosis so despite having not very severe liver disease by our standards it's a significant risk factor for bad outcomes following heart transplant alone and when they look at what happened to these patients guess what multi-organ dysfunction cardiogenic shock and bleeding were the top two causes of death which you can imagine that if you try to put a diseased liver and expose it to a heart transplant operation with some right ventricle dysfunction as well as cardiopulmonary bypass the liver doesn't like it and it contributes to these bad outcomes if you look at these unadjusted survivals this is significant and we're talking about very young patients that we've invested a lot of health core resources in so this conversation you know for me says we need to be doing more combined heart liver transplant so from the foster study we know that late referral advanced fontan failure poor functional status were all associated with post-transplant mortality in either type of transplant well compensated falled was strongly associated with better survival with a combined procedure and they have another paper coming out where they're going to show that nearly forty percent of the patients who were referred were declined transplant altogether because they were late referrals with multi-organ dysfunction and that is why when we look at the overall case volume CHLT still only represents less than one percent of all liver transplant activity so we don't know the denominator but many many of these patients are not getting transplanted and essentially the alternative is hospice care so what happens if you do a heart transplant alone and then list patients for a liver transplant well we looked at that and we have this manuscript where we showed that only one of ten of these patients we found ever received a liver offer and that the adults died waiting for a liver offer so this is not a good strategy for salvage for these patients so we propose this algorithm which is in our circulation paper that's based on severity of fibrosis but if you have any evidence of bridging fibrosis we would argue that they should be considered for combined heart liver transplant the data from the foster study supports that there was this thing some centers like Penn were doing where they would look at the liver at the time of transplant have a backup in house and if the liver looked okay do a heart transplant alone versus if the liver looked bad just do the combined procedure they have just as of since then they don't do this visualization they just proceed with combined heart liver transplant so what I would say is that combined heart liver transplant is increasing exponentially in the U.S. with this patient population being the leading indication for this procedure FALD may stabilize but I think is really unlikely to regress following heart transplant alone and those patients may limp along with other problems related to their chronic liver disease well compensated FALD you know normal platelet count normal bilirubin still associated with much better outcomes following a combined heart liver transplant and the bigger problem here is that many patients who undergo heart transplant alone who are subsequently listed for liver transplant are not going to get a liver offer so just to close on a couple special situations I'm thinking about the pediatric population we looked at the UNOS data very rare number of cases at this point through 2000 2020 it was 14 patients since in the low 20s our center has done four this is the leading indication for pediatric combined heart liver transplant and I will say that they have very good outcomes it's extremely highly selected patient population but we recently evaluated a patient who had CHFS grade four biopsy proven FALD a failing Fontan ascites varices age seven twenty five kilos that's a big undertaking to take to go on as a program so these are complicated decisions lastly a subset of these patients are developing bad HCC because they're not seeing all of you and when they're showing up it has they have multifocal disease when they looked at this retrospective series of nine ACHD centers they identified 54 patients and only 21 of 49 were offered curative treatment and 50% the initial treatment intent was palliative the one year survival is less than 50% the average age is 30 years old this is a big problem so the take-home messages I will say by the way there is absolutely no way for the liver to pull the heart in the United States right now for a patient listed for combined heart liver transplant with primarily a liver indication like HCC and as we go into continuous distribution with no new liver allocation policies as a community we really need to advocate for these patients so the take-home message is that FALD is more prevalent than you think this population is rapidly expanding more than 90% of them are surviving into adulthood you're going to see more and more and more of these patients in your practice I hope every patient post FONTAN has some degree of FALD most are very well compensated liver biopsy is the gold standard we need non-invasive techniques to follow them serially it's an area of active research in my group and others and combined heart liver transplant results in the best outcome for patients with bridging fibrosis and FONTAN there is some controversy over the pediatric population but I think we're leaning towards performing this procedure and HCC and FALD is increasingly being diagnosed and I know some folks like Dan Ganger at Northwestern has some patients who say they don't want to have transplants so we have to figure out other strategies like local regional therapy and Y90 to stabilize their disease but it's really a hard decision because they're otherwise very young and functional patients so I look forward to our discussion I did present some research from my team and I appreciate the opportunity thank you. Thank you very much Dr. Emma Morley for the excellent review on FONTAN associated liver disease it's my pleasure to welcome our next speaker who doesn't need an introduction she's Dr. Lufe Garcia-Chal a professor of medicine at Yale University and past president of our society she will speak to us on therapeutic window for better blockage in patients with cirrhosis. Thank you Dr. Mahmood I first of all I have to apologize for being late my smart watch ran out of battery and died so which has there's some kind of conclusion there you may be as smart as you want but your battery dies that's it right anyhow I was biding my time so I'm going to talk about the window of beta blockers I have nothing to disclose how do you go to the next slide how do it yeah okay and there's a pointer right oh you do you see the pointer okay so there are three stages of cirrhosis that we can now clearly define each associated with a higher mortality first one is compensated cirrhosis the patient has may or may not have batteries but the various have not bled the moment they develop a clinical event we call that the patient has now passed into a decompensated stage with ascites various cell hemorrhage or hepatic encephalopathy and or they can come together but and the main driver of this decompensation is what we call clinically significant portal hypertension then we have now described a stage of further decompensation where the patient develops a second event so if they came in with a site and I have various cell hemorrhage or vice versa or the ascites or hemorrhage or encephalopathy or various cell hemorrhage become difficult to treat, right? They're not responding to standard therapy. And the hallmark of Fersi compensation is actually hepatorenal syndrome. Jaundice indicates liver insufficiency, so- and this is what- oh, you're not seeing the arrow, right? Oh, you see it, okay. Jaundice is a hallmark- it's an indication of liver insufficiency, and therefore that's why it already indicates a further decompensated stage. Even though portal pressure is still playing a role here, there's inflammation and vasodilatation that are playing the major role in further decompensation. And SVP, of course, is an infection that is characteristic of the patient with cirrhosis, and this is a driver of inflammation and makes everything worse. So median survival in the compensated stage exceeds 15 years. Median survival in the decompensated stage is about two years, so at two years, half of the patients will be dead. And in the further decompensated stage, it's around nine months. So this is really bad. So at the end of the day, you want to identify the compensated patient and prevent them from decompensation. And since this is the main driver, you know, you want to lower this pressure. And this is what non-selected beta blockers do. This is a seminal work by the PRADESI trial, which did not just look at variceal hemorrhage, which is what we had been looking at traditionally. What they did is compare beta blockers to placebo in preventing any decompensating event, ascites, variceal hemorrhage, or overt encephalopathy. And you can see here that beta blockers had a significantly lower rate of decompensation. And the primary endpoint occurred in 16 percent of the beta blocker group versus 27 percent. This is an absolute risk reduction of 11 percent. So you only need to treat nine patients to get a lower outcome. And you would ask, well, now, in this study, CSPH was defined as you should by measuring the pressure by the hepatic venous pressure greater or equal to 10. But we now have non-invasive ways to sort of figure out what patients have or do not have clinically significant poor hepatitis without having to measure the pressure. And the question also is, what non-selected beta blocker are we going to use? And I would have to say that in this study, two-thirds received propranolol and one-third received carbetol. I don't have time to go into this, but you need a non-selected beta blocker because you need both the beta and the alpha adrenergic blockade. And this is a study that shows that even within the non-selected beta blockers, carbetolol is more effective than propranolol in reducing HVPG. And in this meta-analysis, which includes actually the PRADESI trial, it shows that also carbetol compared to other treatment strategies is reduced, improves outcomes. This was not entirely significant, but there's clearly a tendency for carbetol to be better than other strategies. So in the most recent ASLD practice guide, and Dr. Kaplan is here, carbetol is recommended as a preferred non-selected beta blocker for the treatment of portal hypertension in patients with cirrhosis. So we have changed the paradigm. It used to be propranolol, now we prefer carbetol. And so the old paradigm also said if you have a compensated patient, you do an endoscopy and you see if they have viruses or not, and then you start beta blockers or do ligation. And if they were small, you would do beta blockers are optional. If there are no viruses, you would repeat the endoscopy every two years and not do anything. The new paradigm is we have the compensated patients that we now define non-invasively. And the non-invasive definition of compensated cirrhosis is based on liver stiffness and platelet count. And we call that compensated advanced chronic liver disease. So CACL is the surrogate of a biopsy showing cirrhosis. And in a patient, these two criteria define clinically significant portal hypertension. A stiffness of 20 to 25 with a platelet count less than 150, or a liver stiffness more than 25. And in these patients, in the guideline, it is suggested that non-selected beta blockers should use, and preferably carvetyl 12.5 milligrams per day. If you do not meet the non-invasive criteria for CSPH, then you just repeat liver stiffness and platelet count yearly. This is a non-invasive way to do this, right? And then, of course, if there's the promise that there's intolerance or contraindications to beta blockers, then you go back to the old paradigm, right? And then you would do an upper endoscopy. And then if the patient has high-risk varices, you would end up having to do ligation, right? Because the patient is intolerant to beta blockers. Now, the old paradigm, if you think about it, the goal was to prevent variceal hemorrhage. One in actually variceal hemorrhage, we're seeing less and less of, whereas in the new paradigm, what we're trying to do is prevent clinical decompensation. Not only variceal hemorrhage, but mostly ascites, which is the most common decompensating event. Now, think about this. These are all compensated patients. So what happens with a patient who already has developed ascites? The patient has already decompensated. So this is a study out of Scotland that looked at carvetilol versus ligation to prevent first variceal hemorrhage. The thing about this study is that half of the patients had ascites. So they were already decompensated. Nevertheless, carvetilol was more effective than ligation in preventing first variceal hemorrhage. And later on, they did an analysis of these patients later on, and they found that decompensation, so first decompensation in those who had already ascites was lower also with carvetilol, as well as all-cause mortality. And they did a subgroup analysis, and they saw that these findings were exactly the same in patients with or without ascites. So that's why in our guideline, we now conclude that patients with decompensated cirrhosis who have never bled from varices should undergo annual endoscopy screening. If they're high-risk varices, you could do beta blockers or variceal ligation, but the preference is to non-selected beta blockers. Is my time over? No. Okay. In patients with variceal hemorrhage, goals of therapy are to control hemorrhage and prevent recurrent hemorrhage. I'm sure to God I'm not doing anything. All right. Anyhow, so now let's talk about the decompensated patient. And in these patients, particularly regarding the beta blocker use, we're talking about variceal hemorrhage, and the main goal would be to prevent recurrent variceal hemorrhage. So we're not going to talk about the treatment of variceal hemorrhage. We're talking about beta blockers. So in the acute setting, this is our initial management of any patient that comes in with variceal hemorrhage, there is no role for non-selected beta blockers in controlling variceal hemorrhage. In fact, you want to take them off the beta blockers because these then will reduce blood pressure. So you do the endoscopy, you do ligation, and then you consider whether the patient is candidate or not for preemptive tips or any other type of tips. And then depending on whether the tips was placed during admission or not, you will decide. If the tips was placed, you have already reduced the portal pressure to the goal. There's no need for non-selected beta blockers in this setting, all right, unless, and this is a new paradigm shift, if when you put in the tips, the portal systemic gradient did not go under 12 and it remained above 12, you may supplement the tips, you know, with the use of non-selected beta blockers. But in the majority of the cases, you would not need non-selected beta blockers. If tips was not placed during admission, then once you, and they re-bleed, you may need a rescue tip. But if everything goes well, like it happens in the majority of patients, the patients do not bleed, you discontinue actreotide antibiotics and you start secondary prophylaxis with non-selected beta blockers and the ligation. And let's talk about beta blockers and ligation in this setting. And we did a meta-analysis, because at the time that all these trials were being done, they just lumped everybody together. So now we did a meta-analysis comparing compensated and decompensated patients. And in the compensated patient, child aid patient, really, there was no difference if you did ligation alone or you added the beta blockers. But it's very important that decompensated patients that you do beta blockers clearly decrease, this is survival, all right, decrease mortality. So therefore, non-selected beta blockers are the key component of combination therapy to prevent recurrent variceal hemorrhage, particularly in child B and C patients. And so the decompensated patient that has to get a beta blocker, everybody thinks, oh, we're going to kill these patients, right? There's this study that actually showed that outcomes were, if you maintain that map more than 65 on non-selected beta blockers, your survival was better in ascites-recurring LVP. And it was the same in patients who had a map of less than 65, but not lower, same. But you got an advantage if you kept that map over 65. And actually, in ascites with SVP, the same results arise. So in the further decompensated patient, these were further decompensated patients, beta blockers still have a benefit, particularly if you can keep that pressure high. Now there's this very nice study that looked at the effects of renal perfusion pressure. And they looked at diuretic-responsive ascites versus refractory ascites. You can see here there's a systolic function versus renal perfusion pressure. And in the diuretic-responsive patients, there was no changes really in systolic function. But the renal perfusion went down. But only one patient decreased below the threshold that actually perfuses the kidneys. Whereas in refractory ascites, there was a significant decrease in systolic ejection function. And almost half, or a little bit over half, actually dropped their renal perfusion pressure below that threshold. And actually, four of them developed HRSA-KI. So based on this, what we concluded in Valveno was that in patients with ascites, non-selected beta blockers or carvetol should be those reduced or discontinued in case of persistently low pressure, mean arterial pressure less than 65, or systolic pressure less than 90, and or if they develop HRSA-KI. And we have a similar recommendation in our new guideline. So to conclude, when is our window? So the window opens when the compensated patient with cirrhosis, you have diagnosed CSPH. The goal here is you're preventing decompensation. This is really a lofty goal. In the decompensated patient that has ascites, without a history of variceal hemorrhage, you want to now prevent variceal hemorrhage, and you give them beta blockers, ideally. You could do ligation, but I prefer beta blockers. After variceal hemorrhage, if no TIPS was placed during admission, the goal is to prevent recurrent variceal hemorrhage, and you have to give them beta blockers together with ligation. So when is the window closed? Well the window is, you will not start beta blockers, the patient is super compensated, they have not yet developed CSPH. There's no sense in doing that. You can close the window after TIPS, provided the post-cyst portal systemic gradient is less than 12. If that pressure was higher than that, I would actually still give beta blockers. And someone who has persistently low blood pressure, their window is definitely closed. Thank you very much for your attention. Thank you very much, Dr. Garcia-Charles, for your excellent talk. It is now my pleasure to welcome our last speaker, Dr. Michael Charlton. He's a professor of medicine and the co-director of the Transplant Institute at the University of Chicago. He will speak to us on TIPS, or living donor liver transplantation in patients with low MELD, and complications of portal hypertension. Well thank you, I'd like to thank the organizers for inviting me to speak on what I think is a very prescient topic. I'm not able to get the mouse to move at all here. Yeah, do the arrow. It's very hard to do that one now. Is that it? I love your presentation. Do you want to help? I got to figure it out. I always thought that you just needed to do the heart and not the liver, actually. But you said no, right, even if you did early, the heart, you can get away with a heart transplant alone. It's very early. Okay. Okay, that's fine. All right, thank you. My disclosures. Same thing happened with mine. No, no, but then it'll. There's no one here. We're very slow. Okay. All right, thank you, finally. So I think the first thing to consider, this is a heat map of death rates per 100,000 in the United States. There is a six-fold variance between states, and the states with the highest incidence, there are five contiguous states with not a single liver transplant center between them. So access to liver and liver transplantation antitypes is highly variant in the United States. So let's consider a case. This is a 56-year-old man. It's going to be a case that many of us in the room will see on a regular basis, 56-year-old man with alcohol use disorder-related cirrhosis, male sodium is 14, has the CITES and has had four large-volume paracenteses in the last 90 days, serum creatinine 1.6, and they're listed for liver transplantation. Should we do a TIPS for this patient, or should we move forward with living donor liver transplantation evaluation? Now, the reason to select any treatment modality for any patient is the same as the FDA will approve any treatment modality overall, which is that it affects or improves the way a patient feels, functions, or survives. So this would just be the basis of our decision-making for these patients, and let's consider the role of TIPS in these low-MELD patients. This looks at the predictivity over time of MELD score for death, shown in the blue line, and for liver transplantation, shown in the dashed orange line. And you'll see that the predictivity for death is good. There's about an 8% increase in likelihood of death per unit increase in MELD score. We've got better at allocating organs to sickest first, and so the predictivity for transplant has improved over time. But it is an important consideration, and the lower the MELD, the lower the likelihood of transplant or death. These are the most recent data published from the SRTR, and there's a national death rate on the wait list of around 12%, which we all keep in our minds. It varies from center to center, but overall 12%. But a further 18% either die or get too sick for transplantation. So the overall risk of not getting a transplant once you're placed on the list, if you take all comers across MELD scores, is around 30%, so a really substantial portion of patients. So this is all comers with MELD scores, not necessarily in the low end of the range. These are data from Spain, I think largely from the Barcelona group, looking at patients with alcohol use disorder, hepatitis C, and the paper was described as NASH, and looking at outcomes in terms of how many people get better, how many get transplanted, and how many die or become too sick. And you'll see in the low MELD score range, the frequency of dying or becoming too sick is around 20%. But the numbers here are quite small, 70 for one group, 64 for another. So in preparation for this, we went into SRTR, and we looked at every single patient who was listed for liver transplantation in the United States in the last five years. We had over about 1.2 million records, 88,000 unique registrations of every patient in the United States. One of the interesting aspects is the number of patients listed with a low MELD score is actually quite high. It's around 35% of patients who are placed on the wait list have a low MELD score, 15 or less at the time of listing. So not an unusual scenario at all to be in. And this looks at what happens over time. So on the first column is the MELD score band at the time of listing. And then at the top column, it's the MELD score in six months after a patient is placed on the list. Almost no one decreases their MELD score, the great majority of them either increase or they die or they get liver transplantation or become too sick and delisted. So 12% in this low MELD score band died, 5% became too sick. So overall, for our patient, a key piece of information to have when we're choosing tips versus living donor liver transplantation is that there's about a 20% risk of dying or becoming too sick for this patient, even in this low MELD group and about a 70% likelihood of getting transplanted in the course of a year. So with those numbers in mind, I think you can safely presume when you're interacting with these patients that for patients with low MELD score, 15 and less at listing, the likelihood of a sustained improvement in MELD sodium or clinical condition is much less than progression of disease, liver transplantation or death. This is a recent meta-analysis of randomized controlled trials of people who are undergoing tips for a host of indications including gastric or esophageal hemorrhage, refractory ascites, et cetera. And the benefit to the decrease in likelihood of mortality was about 50%. So you're half as likely to die if you have a tips than if you do not undergo tips. And this is with a MELD score of exactly that seen in our patient, a MELD score of 15 and this is 3,900 patients. The benefit is immediate. So the Kaplan-Meier separates immediately and they stay separated for about the same magnitude for the duration of follow-up, in this case, for two years. If you have an older group, this is Adrian Elliott Tapper's group from Michigan looking at Medicare population in the United States as a whole, 63,000 enrollees. So this is an older group. No medical thing gets better with age and it's certainly true with outcomes for ascites. So if you have an older patient, 65 or more, the average survival once you have your first paracentesis is about one year. So it's a high risk. And once you have your first paracentesis, it's about a 0.38 year survival. And once you develop ascites, it's about one year if you're over the age of 65. Our patient younger than this, so these particularly harsh data don't apply. If you're looking not just for TIPS overall, but TIPS for refractory ascites, this is an RCT of a meta-analysis for TIPS for paracenteses in people with refractory ascites. And again, just under a 50% reduction in likelihood of death if you have a TIPS for refractory ascites. So overwhelming evidence that TIPS has a survival benefit in this population. But if you go back to the previous data, only 2.7% of people with ascites who are over 65 get a TIPS in the United States. It's very unusual. There's about the same number of TIPS as there are liver transplants performed in the U.S., around 10,000 per year total. Does it make transplant worse? A good reason not to do a TIPS is if it makes the life worse for surgeons or for the patients. And it turns out that it doesn't. This is a meta-analysis of 4,000 recipients. And pre-transplant TIPS has no discernible or important trend for effects on blood products, ICU stay, operating time, or overall length of stay. And this is true for right lobe as well as whole grafts. It's important to remember this is for intra-hepatic TIPS. If you're going to have, say, a transplenic TIPS thrombectomy where you may end up with an extra-hepatic portal vein TIPS, that's another animal altogether. You should certainly discuss that in detail with your surgeons before proceeding with that. So when is the MELD score too high? With the data that we have in mind, if you have a MELD score of less than 20, the net risk of dying is much less with TIPS than it is without a TIPS. And the 90-day mortality of getting too sick is around 10%. That doesn't really exceed the mortality post-TIPS until you get above 20. So a patient with a MELD score of 20 and less, you should absolutely be thinking about TIPS unless you have almost immediate access to living donor liver transplantation if they have access to a TIPS procedure. 20 to 25 range is much less clear. You're really starting to get a steep drop-off in survivability at that point. So I'd say overall, if you have MELD score of 6 to 15, it's easy. You should really consider a TIPS if they meet criteria. So gastroesophageal criteria or refractory ascites and no living donor in imminent access, you should do it. 21 to 25, much harder to figure out what the right thing to do is. And above that, you're looking at the mean MELD at transplantation for many patients across the United States. So single slide for a second case where you wouldn't want to do a TIPS. And this is a patient with an HCC, a little bit older. MELD score is 12. HCC, cholangiocarcinoma, and polycystic liver disease are good reasons not to do a TIPS for practical sense. You can get away with it sometimes if it's a peripheral HCC. But in general, because of the risk of breaching the tumor and causing systemic spread, I think you should avoid it generally in these patients. So living donor, this is Alyssa Smith, the first patient to get a living donor in the world. She was at the University of Chicago, still going strong. This is Rudy Bralsch, who died not very long ago, having returned to Germany. Now, since living donor liver transplantation was assessed in the NIH consortium, the A to All study, there's been this canon that if you've done 20 or more transplants, you're good, your outcomes level off. We looked at it more recently for the whole United States living donor experience. It turns out that's really no longer true. It's much more important at what your most recent experience is. If you have done five or less transplants in the last three years, you have a nearly three-fold increase in graft loss compared to centers that have done five to 20. And 20 and above, you have a 33% survivability of the graft. And just to illustrate this, this is every living donor center in the United States, north of 1.0 is a hazard ratio for graft loss. If you go to a center that's done five or less in the last two and a half years, which is what these graphics shows, no one does better than expected. The best you can hope for is average, and you're much more likely to get less than average survival. All of the good survival is really occurring in the higher volume centers. So I think the decision should be affected by the volume, the recent volume of the living donor transplant center. Don't be sending your patients to low-volume centers. Living donor liver transplantation is increasing in the United States. Right now it's six to seven percent, so it's not happening very much, though it is increasing. And it's increased 45% if HCC is the indication. But it's not available everywhere. So there are entire regions where almost no living donor liver transplantation is performed. And these are areas where you should really think more quickly about tips in the context of standard indications like refractory ascites. So I will conclude that consider tips in low-MELD patients who have had a decompensating complication of portal hypertension, likely survival benefits in MELD score of less than or equal to 20. A living donor is a potentially ideal option, but it's worth considering only 50% of people who pursue living donation, who want to have a living donor, are able to identify one, 50%. And finally, tips does not affect transplant procedure or transplant outcomes. And slightly ahead of time, I will conclude. Thank you. Thank you, Mike, for the excellent talk. I think we have 10 minutes to take a few questions. I think if you could be very brief with the questions and identify before you speak. I'm Ragesh from Little Rock. My question is to Dr. Mehmood regarding the vocal PEN score. So in that list of surgeries, we don't see the head and neck surgeries or intracranial surgeries. So how do we account for them? Do we group them along with chest or cardiac surgeries? That's a great question. So, you know, in the data sets that we use to derive the score, there are not enough sample size of those types of surgeries to really accurately, you know, really perform a risk assessment. So we excluded surgeries such as CNS surgeries, other kind of less commonly performed surgeries. So you can't, I would not recommend using the vocal PEN score specifically for those types of surgeries because they're not incorporated into the derivation of the tool. I'd probably rely more on the other tools that we talked about, you know, MELD score, child abuse score, and it's really kind of assessing on the case by case basis. So it's not really, it's not built into the design of the scores. It's not intended to use, be used for those types of surgeries. I have two very quick questions. One for Mike. Mike, you talk about a MELD score of less than 20 as a sort of a safe place to start to thinking about tips. What about frailty scores in those patients? I've had many patients with MELD scores that are relatively okay, and then they go into severe decompensation after tips, especially with bad frailty scores. That's an excellent and really important question. One thing to consider is when every liter of ascites has around 1500 or more calories in each liter, and it's got just slightly less albumin than you do in a liter of blood. So you may be frail going in, but if the patient can tolerate the tips, even though it is an increase in risk, there's no question for the initial risk of the tips placement. Ultimately, you're much more likely to have a less frail patient by not taking out 25 to 50 grams of albumin with each liter and all the calories that a patient cannot eat their way through to catch up with large volume paracenteses on a regular basis. It's an important question, but there's a tipping point. I have a question for Lupita as well. Can I expand a little bit on that? And I agree entirely with what we have seen is actually that they become better nourished because the edema in the bowel and everything goes away. So I would not consider that. And I think that adding to what Mike did in his brilliant presentation is that, you know, what we now have is controlled expansion stents, right? Even for the variceal bleeder, but if you can start with a very small diameter, right? You can either supplement beta blockers, but with a size, you have time. It doesn't matter, right? If a small stent will allow you to not have encephalopathy and the ascites is controlled, leave it that way. If the patient is still having ascites, but no encephalopathy, you can go ahead and expand the stent in another procedure. So, so there's more flexibility now in what you do with tips. I am totally in agreement with we're thinking too late about putting a tips. Rupita, in your presentation, you presented the new guidance. I'm having another session sometime. And we follow the fact that patients should be started on Carvedilol when their kilopascal score is more than 20 and their platelets are low. What is the role of endoscopy in those patients before starting Carvedilol? And what is the role of endoscopy as a follow-up? Zero. Zero. Because once you've given them the Carvedilol, so in essentially endoscopy you do in patients who are not, would not tolerate or have contraindications to non-selected beta block. Well, the only point that I want to make is that some of those patients have. Because of that time limitation, could we stick to one question, please? Thanks. Thank you. Excellent presentations. Can you talk a little bit more about preemptive tips once the initial bleed's been controlled, and particularly at places that may not have access and would have to transfer out for that? Lupe, do you want to take that? Preemptive tips. There are randomized controlled trials showing benefits of preemptive tips. So it didn't make its way into the guidance because it wasn't felt that there was a substantial enough body of data. But there's certainly good enough that you can consider it, I think, as an option in the right patient. Okay. Regarding tips, I think, you know, what do you think about dividing the tips patients into, like, what we call destination tips versus bridge to transplant tips? Because in refractory ascites, sometimes when we do tips, you're losing one leg of the meld and meld sodium also. So the sodium side and the creatinine side might, so then you're dealing with just coagulopathy and bilirubin. So some of these patients can be disadvantaged in terms of getting to a transplant. So is there any move to give them some priority after tips? I think you have to consider that there's a survival benefit pretty much as soon as you put the tips in, regardless. And I think that destination tips, you see that more likely if you have a disease where you can cure it. So alcohol and hepatitis C, I think those may end up as destinations. I have patients, like, we had tips 20 years ago that I still see every six months. And I don't know that it's purgatory for them. They can do quite well. Question for Dr. Charlton. So clearly, a meld less than or equal to 20 has a survival benefit. When do you consider a patient too old for tips? Excellent question. So as I said, nothing gets better with age. The meld score predictivity was enhanced by age in the original meld score development. And it was kept out because it was felt it would lead to an ageist allocation policy. So it would be nice to see age maybe brought back in for the utility of deciding what's the risk for tips. We don't really have that data to have as an excellent question. Jody Olson, a quick question about elective hernia repair. In your center, how does large volume refractory ascites impact your decision for an elective hernia repair prior to an incarcerating event? Yeah, it's a really important question. So it impacts it hugely. I think I mentioned this very briefly, but there needs to be some sort of plan to manage ascites if you're going to pursue an elective hernia repair. If the patient has massive ascites, they're likely to have wound dehiscence, hernia recurrence. The hernia repair may not end up benefiting the patient. So it's preferentially performed, I think, in patients who can have their ascites managed well medically with diuretics or potentially considering a preoperative tips in patients that have large volume ascites that could pose a potential problem in the postoperative setting. My question is also about surgery. What do you think the risk for bariatric surgery before liver transplant in patients in preparation for the transplant? This is one question. And then my second question for Dr. Imamali, with the increased number of Fontan-associated liver disease or Fontan patient, do you think there is a role for early intervention from a cardiac perspective so we don't run in a situation where the combined heart-liver is a significant number of patients that compete for a scarce organ? Thank you. Yeah, so the bariatric surgery question is really, it's a great question. I didn't touch on this at all, but they're accumulating data about this. I think in general, this is especially important for a lot of our kind of mashed patients who may continue to struggle with issues related to weight in the post-transplant setting. There are some centers that are doing kind of combined bariatric surgery immediately prior or concurrent with liver transplantation. I'll do a kind of gastric sleeve along with that. I think in patients who have compensated cirrhosis, it can be done safely. And I think a lot of our risk stratification projections show that you can perform bariatric surgery, especially laparoscopic bariatric surgery in patients with compensated cirrhosis prior to transplant. It's a bit more challenging in these patients with decompensated cirrhosis where there actually still is considerable risk. So I wouldn't necessarily pursue bariatric surgery prior to transplant in those patients, but potentially concurrently with surgery is becoming a more viable option. Can I just comment as a surgeon? Sure. Don't do the bariatric surgery. The long-acting GLP-1 medications now are showing really equivalent weight loss and are safe in cirrhotic patients. And so from a, you know, the bariatric centers are tracked with outcomes like we are in transplant, and they're really reluctant to take on these high-risk patients. And so coordinating also bariatric surgery at the time of transplant, I'm in LA, we do them in the middle of the night and on the weekends. It's just logistically kind of a nightmare. So I think that there's a huge role for those medications and there's also data that was released at the AHA today showing a significant cardioprotective benefit in patients. So I think that those medications are something in our community we should be studying a lot for weight-listed patients. I think we'll take one last question because of the time limitation. Dr. Mandut from India. I didn't get my answer for the Fontaine question. But it's okay. You can find me after. Yeah, Dr. Mandut from India. This is regarding beta blockers in cirrhotic cardiomyopathy, especially with diastolic dysfunction. Would you give beta blockers or would avoid? So the cause of cirrhotic cardiomyopathy is very broad. In a way, it could be also due to high pressure and all the pathophysiological mechanisms that lead to formation of varices. So in a way, you could test them and see what happens. But we don't do cardiac. We do a cardiac before tips because then you would have a huge load of volume coming to the circulation that could precipitate heart failure. But we don't do this before we start beta blockers. Thank you. So I want to thank all speakers and my co-moderator for this excellent session. Those who celebrate Festival of Lights, Diwali, I wish you all a happy Diwali. Thank you.

Fontan-associated liver disease

FALD

Fontan procedure

congenital heart disease

liver biopsy

fibrosis

cirrhosis

liver transplant

combined heart-liver transplant

post-transplant survival

late referrals

liver disease management

multidisciplinary approach