Welcome, everybody, to the combined SIG program between the cholestasis and autoimmune SIG and the liver transplant SIG. My name is Cynthia Levy, and I'm going to be co-moderating this session with Rich Kwon. So our first speaker is Monica Tinkova. She's an assistant professor at UCSD, and she's going to be talking to us about evolving epidemiology and disparities in listing and transplantation in patients with autoimmune liver diseases. Okay, thank you, everyone, for the opportunity to speak with you today. There's a lot of data on this topic, so I've tried to just highlight the major ones, and obviously there's studies that I was not able to include, so if you have any questions, I'm happy to answer them at the end. I don't have any relevant disclosures. Can you start the timer for us, please? Do I have to do something to start the timer? Okay, perfect. Thank you. Okay, so we'll start by just going over the evolving epidemiology of autoimmune liver disease, and to be specific, I will include autoimmune hepatitis, primary biliary cholangitis, as well as primary sclerosing cholangitis. Focusing on disparities in autoimmune liver disease, we will touch on listing for liver transplantation, liver transplant wait list outcomes, and rates of transplantation. So to start with epidemiology, I will start by saying that there is not a lot of robust data on this topic, specifically in terms of populations within the United States in general. A lot of the literature comes from European populations, and there are a lot of unknowns and a lot of the data is very heterogeneous. Depending on what study you look on, the rates vary a lot based on geography of that population, and then really the prevalence of associated risk factors in those populations. So as you're aware, both autoimmune hepatitis and PBC are much more common in females, depending on the proportion of females in the studies, and then related to PSC, similarly, it's higher in rates of men, so depending on the percentage of men in that population. In general, the data has shown that for both autoimmune hepatitis and PSC, there seems to be a rise in incidence and prevalence. Again, most of this data is coming out of European populations. In general, we think that it's up to a 50% increase in prevalence in terms of both autoimmune hepatitis and PSC. For PBC, there also is data suggesting that there's a rise in prevalence, and this comes from data from European populations, North America, and as well as the Asian Pacific populations. Going into specifics, both incidence and prevalence are reported per 100,000 patients. So you can see here, the incidence isn't as variable, but for PBC, it's anywhere from 0.8 to 2.7, PSC is 0.4 to 2.4, and autoimmune hepatitis, 0.4 to 2.39. When you move down to prevalence, however, you can see that the ranges are much more variable. So for PBC, it's anywhere from 1.9 to 40, PSC is 0.7 to 31. And autoimmune hepatitis ranges from 4.8 to 42.9. So again, this data is not all that helpful, because depending on what study you look at, it's highly variable. Some of this has to do with, again, as I said, the population, so percentage of males versus females, race and ethnicity, and other medical co-factors. So some data coming out of New Zealand, looking at the increasing incidence and prevalence specifically of autoimmune hepatitis. So here, data from the early 2000s up until 2016, and they trended autoimmune hepatitis, PBC, and PSC. As you can see, autoimmune hepatitis here in blue, there is a significant rise in incidence. And then when they looked at prevalence, same thing. So both incidence and prevalence of autoimmune hepatitis seem to be significantly higher from the early 2000s to 2016, and this was published in 2021. Here is some interesting data looking at the impact of geography on epidemiology in autoimmune liver disease. So you may have heard, depending on your latitude, there are higher rates of these autoimmune liver conditions. So this, again, looking at both incidence and prevalence, and they separated out between data in PBC, PSC, and autoimmune hepatitis. The bottom graphs are adjusted. So here, they adjusted for sex, age, smoking, and what they call the deprivation quintile. So in the UK, it's similar to a way for adjusting for socioeconomic status. And you can see, for both PBC and autoimmune hepatitis, there's a significant association even when you adjust for these other relevant variables in terms of latitude. So individuals living at more northern latitude had higher incidence and prevalence of PBC and autoimmune hepatitis. So trying to summarize the data on epidemiology, as I said, it's really important to take into account what are potential moderating risk factors that are impacting why these rates are so variable, depending on what study you're looking at. So I broke this down into demographic, genetic, and other medical cofactors, and then environmental risk factors. So for autoimmune hepatitis and, as I said, PBC, these are much more common in females, whereas PSC is more common in males. Age is relevant because each of these conditions tends to present at a different age range. And then in terms of medical cofactors, both autoimmune hepatitis and PBC, they're much higher incidence rates if you have additional autoimmune disease. Family history of PBC tends to be pretty important in terms of your individual risk of having PBC. And then, obviously, for PSC, concomitant IBD is an important risk factor. There is pretty interesting data in terms of environmental risk factors for these different forms of autoimmune liver disease. So for all three of them, there have been associations with smoking. For autoimmune hepatitis, hormone exposure in females seems to be important. So history of OCP use, hormone replacement therapy, pregnancy history has also been associated. And then, as you are aware, drug-induced autoimmune hepatitis has become very important and highly prevalent. Interestingly, a history of recurrent UTIs has been significantly associated with all three of these, whether that has to do with antibiotic exposure and, thus, drug exposure or changes in the microbiome as a response to these antibiotics exposures or just the infectious history as well. There have been different infectious risk factors for autoimmune hepatitis, as you can see here. Interestingly, in PSC, there seems to be an association in terms of dietary habits. So a lower fish intake and then a history of having high amounts of red meats, particularly well-done red meats, seems to be associated with PSC. So again, taking into context what the prevalence and incidence rates are reported in these specific risk factors that be me moderating the reports that they found in each study. Moving on to listing waitlist outcomes and transplantation. What I will say is, obviously, there's a huge body of literature looking at disparities in terms of access to and transplantation rates in general, and a lot of that overlaps with specifics in terms of autoimmune liver disease. So in terms of the impact of sex, the impact of age, and race and ethnicity. So I've tried to pull out those factors as it specifically relates to autoimmune liver disease. So looking at race and ethnicity, this is a study looking at transplantation rates in both the UK and the United States from 1994 until 2014, looking at listing per million across the three forms of autoimmune liver disease, and then, interestingly, looking at the time of listing based on MELD score. As you can see here, in the United States, over that time frame, the rates of listing for all three of these autoimmune liver diseases went down, compared to in the UK, the rate of listing for PBC went down, but not also seen in PSC and autoimmune hepatitis. I think what's important here is when you look at the data in terms of listing MELD for these indications, in the United States, specifically, what we found is that African Americans and Hispanic populations were initially listed at higher MELDs. In terms of what might explain this, some of this has to do with the aggressiveness or disease severity seen in these populations, but there's also data to suggest that these populations have a lower access to treatment, and thus, at time of presentation, they present at higher MELDs. Additional data looking at race and ethnicity in autoimmune liver disease, so this, again, trending over time in terms of wait list additions, and then rates of liver transplantation, this study specifically focused on PBC, and what it saw is that individuals with PBC who were Hispanic had a higher wait list mortality, so the adjusted hazard ratios for Hispanics was 1.4. They also had a lower rate of transplantation, so the adjusted hazard ratio for this population was 0.7, and their comparison was Caucasians and African Americans, so, again, this is specific to PBC, but showing that they have worse wait list outcomes and also a decreased access to liver transplantation. Additional data here, this is looking not only at PBC, but also autoimmune hepatitis and PSC, so similarly, looking at competing risks, so when you compare to access to transplantation versus death or removal from liver transplantation wait list, and what they saw here is that African Americans had a higher hazard ratio for either dying or being removed from the transplant list. If you look at this table here on the left, the other things that you see that are significant were age, gender, and the reference group was female. Let's see here. The initial MELD, as you would suspect. In terms of payment source, that also seemed to be potentially relevant. You know this region, as you would expect, but, again, when they accounted for all of these other potential competing risk factors, African Americans had lower access to transplantation, and that's showed here on the graph on the right. Looking specifically at wait list outcomes across these three forms of autoimmune liver disease, so this graph here on the left looks at a 10-year intent to treat, so looking at your intention to treat them with liver transplantation, and then on the right, a 10-year wait list survival. You can see here it's categorized as autoimmune liver disease as compared to the other major forms of liver disease for which we list individuals for transplant. You can see on the curve on the left, individuals with autoimmune liver disease had a lower percentage intent to treat survival. When you look on the right graph here, same thing. Autoimmune liver disease had a lower wait list survival. The only one that wasn't significantly different in that graph was actually alcoholic liver disease. Here this is data from UNUS from 2016 to 2019, again, looking at competing risks, so whether you are at risk for either dying or being removed from the liver transplantation list. Here in their multivariate analysis, they saw that both autoimmune hepatitis and PBC had higher hazard ratios of either dying or being removed from the transplant list. This will become relevant in the lecture later on today, trying to better understand why it isn't also seen in PSC, but definitely there seems to be a signal in terms of PBC and autoimmune hepatitis. This is data from UNUS from 1987 to 2016, again, comparing the three different forms of autoimmune liver disease. Similarly, what you see here is access to liver transplantation. Individuals with autoimmune hepatitis and PBC were more likely to be removed from the liver transplant list and less likely to be transplanted when you compare it to populations who were listed for PSC. There's also been a lot of interest in terms of what the impact of MELD and MELD-sodium has had in terms of access to transplant in autoimmune liver disease. So here in the left graph, what you can see is the hazard ratio for individuals with PBC compared to alcoholic liver disease or NASH. And so once MELD-sodium has been implemented, what they found was that individuals with PBC had a much higher risk of weightless mortality as compared to individuals with either alcoholic liver disease or NASH. And then in the second study here, that was, so the first one was published in 2022, so just this year. The other one is a little bit older, so 2018. So they did a multivariate analysis looking at competing risks of either weightless mortality or transplantation, specifically only looking at PBC or PSC. And what you see here is individuals with PBC, their hazard ratio of weightless mortality was 2.95. Interestingly, this increased to 4.2 after the MELD score was introduced. And so the question is, why might this be the case? You know, as we mentioned, a lot of this is impacted by sex. So females tend to have lower GFRs, which is implemented in the MELD calculations. And we know, in general, females tend to have lower access to transplantation. So this here just looks at kind of patterns over time in terms of access to transplant. So this looked at UNOS data from 2000 to 2021, so pretty recent data. And again, looking at the different forms of liver disease, so green encompasses all forms of autoimmune liver disease. And then you can see HCC in blue, alcohol-related liver disease in red, viral hepatitis is in purple, and then NASH is in kind of the orangish color. So when you look at percent of transplant over these eras, in general, autoimmune hepatitis or autoimmune liver conditions is much lower than other forms. And then when you look at percent transplanted to weightless years, same thing. So when they created these adjusted probabilities of transplantation across different forms of liver disease, autoimmune liver disease had the lowest likelihood of getting transplanted. So that was 0.92 as compared to other forms. So alcohol was 0.97, HCC had the highest at 1.0, viral hepatitis was 0.99, as was NASH. So in general, individuals with autoimmune liver disease had a lower likelihood of getting transplanted as compared to other etiologies of liver disease up until 2021. So to summarize this data, as I said, there is still a lot of work that has to be done in terms of getting a better understanding of the epidemiology, specifically in the United States and this area of the world. A lot of the data does come out of Europe. So the data that we do have is fairly limited, is very heterogeneous, but in general, there seems to be indications that autoimmune liver disease is on the rise, in particular autoimmune hepatitis. These data do seem to be mediated through demographic, genetic, and medical comorbidities in terms of, you know, female sex, other autoimmune liver disease, geographically where someone may live, and then environmental risk factors are becoming more and more relevant. As dietary and lifestyle habits are changing, there does seem to be an association with low amounts of white meats and lean meats and higher amounts of red meats. In terms of disparities in listing weightless outcomes in transplantation, as I said, there's a lot of overlap in terms of these factors in liver transplantation in general, but specifically within autoimmune-related liver disease, race and ethnicity do seem to be associated with access to treatment. So African Americans and Hispanics do seem to have higher weightless mortality and likelihood to be removed from the transplant waiting list, and they do seem to have lower access to transplantation in general. In looking at the specific different forms of autoimmune liver disease, or autoimmune liver disease compared to other forms of liver disease, individuals with autoimmune liver disease tend to have, in general, lower access to transplant. But within those three forms, PBC and autoimmune hepatitis seem to have higher weightless mortality, lower access to transplant, as compared to individuals who have PSC. So that's all I have for you, so if you have questions, I'm happy to answer them later. Thank you. So we're going to hold the questions until the very end for our question and answer session. The next speaker is Dr. Levy, who is from the University of Miami and is a professor there. She will be speaking on optimizing weightless management of patients with autoimmune liver disease, utility of exception points in PSC, and immunosuppression in autoimmune hepatitis. Thank you, Rich. Can you hear me? Yes? No? All right. Yes. So I was given two controversial topics, which are the utility of exception points in PSC and the utility of immunosuppression in weight-listed patients with autoimmune hepatitis. Different from Monica, we don't have as much data in this field, but let's build on what we have and come to a conclusion, hopefully. All right, those are my disclosures, which are irrelevant. All right, so let's start with the utility of exception points in PSC. To bring us together, liver transplantation for PSC represents approximately 5% of all the transplants in the United States. So roughly 12% of patients who are on the wait list for PSC get transplanted yearly. And as expected with the demographics for this disease, they are mostly males, median age 49. The indications for transplant for our patients with PSC will be predominantly decompensated cirrhosis and also patients with cholangiocarcinoma, recurrent cholangitis, and rarely the intractable pruritus group. Outcomes are pretty good. We have patient survival at 10 years approaching 80%, but recurrent PSC occurs in about 40% of patients by five years, so it depends on how long you follow up on them. And recurrent PSC does increase the risk of graft failure or death. So those are important pieces of information here. Now, with this thought that male allocation system possibly could disadvantage some groups, there is a system in place to allow male exception points to compensate for possible disadvantages. So we have the group of standardized indications for male exception points. When we know, when there is enough data, that that condition increases mortality without transplant, and you see them listed there, cholangiocarcinoma, cystic fibrosis, hepatopulmonary syndrome, portopulmonary hypertension, all of that, these are standardized, which means you have a set of criteria to define what the condition is, and then once you meet this criteria, there are pre-specified male points allocated for that disease, for that patient. Now, on the flip side, there are conditions which we believe could increase mortality for our patients, but for which data may not be as convincing. And here we have the refractory ascites, the bleeders, and we have our patients with recurrent cholangitis, and because of that assumption that recurrent cholangitis would increase the risk of, the morbidity and increase risk of death on these patients, it was proposed that patients of two or more episodes of cholangitis with documented bacteremia, or at least one septic complication within the previous six months, could potentially be eligible for male exception points. Those indications on the right, though, are what we call customized indications, so there is no specific criteria that patients need to meet, and there are no pre-specified number of male points that they will receive if they meet that criteria. As an example, for cholangiocarcinoma, which is a standardized condition, if a patient with PSC, for instance, has a malignant stricture that's suggestive of cholangio, and they meet one of those criteria listed there, then they meet the requirement by UNOS, and they are assigned, in the case at least 18 years old, median male with a transplant minus three, so everybody gets the same. There is no room for debate. Now, what happens with the customized conditions, right? In the case of PSE and cholangitis, we know there is lack of standardization in this exception points. And I want to make it clear to you, these studies were done a few years back, when in the United States the system was that of a regional review board. So we used to have 11 regional review boards, one for each region, who would receive these applications for mild exception points and determine if they would apply or not. So with that in mind, we found that 12% of patients with PSE used to get these mild exception points, which was far more than patients without PSE. In this study, so David Goldberg actually looked into this in more detail, and he found that a large number of these applications didn't really meet the presumptive criteria for cholangitis that I mentioned, the two episodes of bacteremia or at least one episode of sepsis. And despite that, the vast majority would be accepted. He also saw that there were very important disparities in terms of how these applications were received, right? So first of all, there are discrepancies across regions. Some regions would apply more than others. And within the same region, discrepancies among centers. Some centers would apply more than others, and also some centers would get more applications accepted than others. So a lot of disparities there. He also looked to see, okay, what happens to our patients with PSE who have cholangitis? Do they really drop out of the list? What is happening? So granted, this is a retrospective study, including only two centers, UPenn and Colorado. But what he found was that, no, patients with PSE and cholangitis actually fared better. They had lower rates of waitlist removal than patients with PSE without cholangitis. Well, I mentioned to you that these studies were done at a time when we had regional review boards to review the applications. Since 2019, a new system was implemented. Now there is a national review board, which is composed of volunteer medical experts, and each transplant center is allowed to have a representative in that board. So now the transplant hepatologist has a patient who they think could benefit from this. They would prepare a narrative, send to this national board. The board will review and make a decision, and if the decision is not favorable, the center can actually appeal up to three times that decision. Okay, and this was created exactly to improve equity, to improve transparency, and consistency with the UNOS processes. However, there are no studies since this implementation determining in the United States what's the situation for the PSE patients with cholangitis. So how did that impact the malallocation, the extra points for patients with PSE? We don't have data on that. So I think the actual question for us should be, are patients with PSE disadvantaged then by the current malallocation system? And you heard data from Monica. Let's see, it doesn't look like. So again, ten years ago when David Goldberg first looked at this, actually patients with PSE had lower waitlist mortality than patients without PSE, and that was adjusted for MELD score at listing, portal hypertension, living donor transplantation, various exception points that were given. So we don't have evidence, we didn't have evidence that patients with PSE would not do as well as other indications. And more recently, and Monica showed you this, also in this competing risk regression analysis, patients with PSE actually were less likely to be removed from the waitlist compared to those with autoimmune hepatitis and PBC. And this is not just in the United States. There are data from the Nordic countries and data from the Netherlands. I picked the study to illustrate this. So this is looking at patients on the waitlist for PSE in the Netherlands. And you see that, you look at the green area or teal color there, patients listed for PSE stay longer, for longer period of time in the waitlist compared to patients listed for other indications. But they are transplanted at the same rates as patients with other indications. Then on sub-analysis, looking at the benefit of MELD exception points. So patients who received MELD exception points had higher chance of getting a liver transplant, both for PSE indication and non-PSE indication. But if you look at the bottom, patients with PSE were more favored. So the hazard ratio there was 9.86. They were far more likely to get a transplant. PSE patients with MELD exception points, even when you compare to non-PSE patients with MELD exception points. This study from the Netherlands also showed that patients with PSE have lower risk of death, lower risk of death, and then higher relisting rates compared to non-PSE patients, which I found was pretty interesting, probably related to recurrent PSE. But that hasn't, the study lacked granularity to really determine the causes for that. Right, and then the subsequent question. Okay, PSE, patients with PSE as a group are not disadvantaged, doesn't seem so, but are there specific groups within the group of patients with PSE who may be disadvantaged? And you heard a lot about it in the previous talk. I just want to highlight a couple of points. So blacks do have worse survival free of liver transplantation. I call your attention to this poster from the North American Consortium. We presented this on Monday. And whether you determine, so this is mortality from the time of diagnosis, whether you make it according to abnormal liver tests or according to the first cholangiogram that was abnormal, it's significantly reduced in blacks with PSE. We also have data, so this is from our North American Consortium patients, but we also have data from units showing that patients with PSE who are black had higher risk of post transplant death compared to non-Hispanic whites. Hispanics had lower probability of receiving a liver transplant, similar to what we saw with PBC. However, again, this study lacked granularity for us to understand the reasons for this. It was not increased mortality actually. And there may be some disparities related to age and gender as well. This study by Jacqueline Hansen, so out of Duke, she looked at patients with PSE weight listed from younger to older. So she divided younger than 40, 40 to 60, and older than 60 as the three age groups. The younger patients tend to be more males, black, with IBD, or overlap with autoimmune hepatitis. They had more rejection, more recurrence, more graft failure, and higher rates of re-transplantation. Whereas the older patients were listed with more portal hypertension, more synthetic dysfunction, kidney dysfunction, so probably more advanced fibrosis and other comorbidities. And when she looked at the five-year post-transplant mortality, that also increased with age, which is not totally unexpected. Again, we need to look into other factors that could be contributing to that. And of course, gender inequity. We know that does not pertain only to PSE, but for every condition, women with cirrhosis are less likely to receive a transplant, whether it is due to underestimation of risk, given lower creatinine, short stature, and scarcity of size-appropriate livers, or simply implicit biases. But this is a reality that we need to address. And possibly MELD 3.0 will be one of the answers, right? So the key takeaways for the first part, the role of MELD exception points in PSE remains unclear. If we are to use them, we need standardization of this process, and how many points will be assigned to reduce inequity. So first of all, we need studies to assess the impact of this National Liver Review Board, comparing to the regional review boards, in evaluating and accepting MELD exception points. Then, waitlist mortality is not increased for patients with PSE, but disparities still exist in waitlist and transplant outcomes regarding age, gender, race, and ethnicity, and things that we certainly need to explore more. Future studies should evaluate the potential for MELD 3.0 to address this. Right, now let's switch gears to the second part of the talk, which is the utility of immunosuppression in patients with autoimmune hepatitis on the waitlist. This group knows very well what autoimmune hepatitis is. I want to remind everybody the goals of treatment for autoimmune hepatitis are to achieve complete normalization of liver chemistries and IgG, symptom resolution, prevent disease progression, prevent transplant and death, right? However, in the real world, we know that about half of the patients do not achieve remission with standard of care, especially those patients who are younger, have more acute presentation, higher MELD, higher bilirubin at the time of diagnosis. The indication, so liver transplant remains, of course, an option for patients with autoimmune hepatitis. The indications will be predominantly they have acute or fulminant presentation, the decompensated liver cirrhosis, and more rarely HCC, which still occurs in this group. Now, outcomes are also excellent with patient survival of 81 and 77 percent at 5 and 10 years, with a disease recurrence rate that is highly variable depending on how this is studied, but 7 to 70 percent with up to 10 years of follow-up. And this group has an increased risk of acute cellular rejection and chronic doptopenic rejection as well. So with those facts in mind, the controversy here is should we be pro or against immunosuppression when they are on the wait list? So in favor of keeping immunosuppression is the fact that high inflammatory activity pre-transplant is associated with autoimmune hepatitis recurrence, and we'll review how important that is. Now, against immunosuppression is our attempt to minimize the risk of infections, minimize the risk of osteoporosis and fractures, and the poor tolerance to azathioprine in decompensated cirrhotic patients. Now, that one is not even an issue because current guidelines, both European and American, do not recommend azathioprine for decompensated patients. So if you have a decompensated cirrhotic patient who is wait-listed, should stop azathioprine. The question is do we maintain steroids or not? So let's discuss the factors that play a role or should play a role in this decision. So one is recurrent autoimmune hepatitis, and over and over again studies will show us that the extent of inflammatory activity at the time of transplant, high IgG at the time of transplant, are associated with recurrent autoimmune hepatitis. Also, low dose immunosuppression or steroid withdrawal, HLA mismatch, black race, use of CellCept or microphenolic products have also been associated with recurrence. In this largest data set from the International Autoimmune Study Group, Autoimmune Hepatitis Study Group, that included over 700 patients from 33 centers. Here we have US, Europe, South America, and Asia included, so data can be generalized. We see the same factors, so Asia transplant being younger than 42, use of microphenolate, donor-recipient sex mismatch, and again the IgG at the time of transplant, reminding us of the inflammatory activity at the time of transplant as being important. Now why do we care? We care because recurrent autoimmune hepatitis is associated with significant rates of graft failure. In this study, the hazard ratio was 9.6, so you can see how the curves separate very early. So we want to prevent recurrence. Now those groups that use long-term immunosuppression, long-term steroid use after transplant, are the ones with the lowest recurrent autoimmune hepatitis rates. In this study from the UK, we see that the survival free of recurrence is pretty high. That's on panel A, but on panel B, we also see increased rates of infection and osteoporosis, although rarely fatal in this study, but frequent. Now several groups have looked into steroid withdrawal protocols. In this meta-analysis from the Cochrane group included 16 studies. They were all high risk for bias, and they couldn't identify any difference in mortality, graft loss, or infection. As expected, there was more rejection with steroid withdrawal, as well as less diabetes and less hypertension. The ASLD also commissioned the meta-analysis to look into that a couple of years ago when designing the new guidelines, and again, we couldn't identify a difference, couldn't establish a difference in outcomes with or without long-term steroids. So the current recommendation from ASLD is to gradually withdraw steroids after transplant. Conditional recommendation, very low certainty. Truth is, most groups who attempt steroid withdrawal are successful. However, reintroduction is required in about 20% of the patients due to rejection, recurrence, or complications of the calcineurin inhibitory. So the more sensitive approach here is to offer an individualized approach, right? And that's where we go back to, why did we talk about recurrent AIH? Why are we talking about long-term steroids when the topic was weight-listing, immunosuppression? That's because it's all related. People who will be more likely to discontinue steroids successfully after transplant are the patients who have low risk for recurrence. So those are the patients who had optimally controlled activity before transplant. Now, to show you on the flip side of this, in this European study, they again showed, okay, autoimmune hepatitis patients who received the transplant had worse patient and graft survival comparing to other autoimmune liver diseases. We knew that, but what's interesting here in this study is that the main cause of death, patient death, was infection. Look at panel A on the left. And a lot of that was due to fungal infections. Even more interesting, when you look at the graph there in B, you see that most of these infections occur in the first year and more than half in the first three months post-transplant, which suggests that this is related to high dose immunosuppression, high dose steroids in the perioperative period. Infection was also the first cause for graft loss, but here we also see rejection and recurrent disease. So, back to the weight list. What can we do to reduce the risk of infection? Let's think about the patients who require a high dose of steroids in this perioperative period. Those will be predominantly those acute, severe, or fulminant patients with AIH, because 60% of them, up to 60% of them, will require a transplant. Current ESO and ASLD guidelines advise us to assess response by 7 to 14 days. So, that's up to 14 days they're getting high dose steroids. This is associated with increased risk of fungal infection. The French group, led by Eliana Demartini, proposed this new score called SURFACE that can be evaluated at day 3 with excellent predictive ability to differentiate patients who are likely to survive without a transplant or those who are not. And so, perhaps considering early steroid discontinuation as early as day 3 will have a positive impact on the rate of infection post-transplant. So, what have we learned with AIH? Well, recurrent AIH occurs in 10 to 50% of the patients. Recurrent autoimmune hepatitis is strongly associated with graft loss, and treatment of active cirrhosis and optimal control of inflammation pre-transplant minimizes the risk of AIH. Then, we also learned that fatal infections are more common in the first three months after transplant, and the risk can be minimized by minimizing, sorry about that, the use of high dose steroids pre-transplant and in this immediate post-transplant period. So, specifically for patients with acute liver failure or the severe AIH, consider stopping high-dose steroids early, as early as three days possibly in the non-responders. So, the takeaway, immunosuppression pre-transplant is not one-size-fits-all. For decompensated cirrhosis, certainly we can stop the azathioprine, but maintain low-dose steroids to control inflammation and decrease the chance of recurrent AIH, which will then allow a low-dose maintenance or even steroid withdrawal after transplant. For the acute liver failure patients, limiting duration of high-dose steroids can reduce the risk of infections. So, with that, I'm going to conclude, and we'll have time for questions at the end. Thank you. I should introduce our next speaker, Rich Korn, who is an Associate Professor at University of Michigan, and will be talking to us about dominant strictures in PSC. Good afternoon, everybody. Thank you to Dr. Sharma and Dr. Levy for the invitation. If I've learned anything from this as an advanced endoscopist, my wife is a transplant hepatologist, and I often tell her or ask her, you know, this guy's sick, transplant him already. And she says it's not that simple, and I now get why. All right, so today I've been tasked with talking about the diagnosis and management of dominant strictures and cholangiocarcinoma in PSC. I do not have any relevant disclosures. So, during this talk, I'll talk very briefly about the epidemiology of strictures and cholangiocarcinoma, and then talk about the diagnosis and management of these conditions, and intersperse the future directions or new things coming out in the field in the midst of that discussion. So, the dominant stricture in PSC has been defined as a stricture, a biliary stricture, of less than or equal to 1.5 millimeters in the common hepatic duct or common bile duct, or less than 1 millimeter, less than or equal to 1 millimeter in an intrahepatic duct. It's been described as being found in up to 15 to 20 percent of PSC patients, and of those strictures that are found, up to 25 percent of them are malignant. There's a lot of data to associate this dominant stricture with not only a worse long-term prognosis, but an increased risk of cholangiocarcinoma. It's important to consider the differential diagnosis when dealing with biliary strictures, so besides primary sclerosing cholangitis, there are other benign conditions, whether it be autoimmune pancreatitis and cholangiopathy, ischemia, or iatrogenic strictures due to biliary trauma, for instance. There are also other malignant conditions to consider, including pancreatic cancer, gallbladder cancer, lymphoma, or metastatic disease. The diagnostic challenge as it pertains specifically to cholangiocarcinoma is that it's a desmoplastic lesion with a tropism for bile. In other words, the extension grows and extends along the bile duct rather than growing in a radial fashion within the duct, and as we will discuss in the talk, the current biopsy techniques have a high specificity, but generally are limited by a lower sensitivity. So positive is positive, but negative doesn't always mean negative. So in terms of diagnosis, typically everything starts with cross-sectional imaging, usually ultrasound or CAT scan, but eventually it leads to the MR or MRCP. The goal of cross-sectional imaging is to not only confirm the diagnosis of PSC, but also to rule in or out cholangiocarcinoma. As I mentioned, the test of choice is MR and MRCP, and what we're looking for in particular is the presence of a mass, both intrapartic or extrapartic, the presence of a dominant stricture, and then also the assessment of the biliary anatomy in terms of which segments of the liver are actually occluded. The next test is of choice is an ERCP, but given its morbidities, we do tend to limit it and no longer use it as a diagnostic test. The current indications for an ERCP are for the evaluation of a relevant or dominant stricture, a new onset or worsening puritis, unexplained weight loss, worsening liver function tests, arising serum CA99, recurrent bacterial cholangitis, or progressive bile duct dilation. The goal of ERCP is mostly therapeutic in that we seek to relieve biliary obstruction, but also, equally importantly, we'd like to rule out cholangiocarcinoma. Just nuts and bolts about the procedure, which I'm sure all of you are aware, but all of these patients receive pre- and post-procedure antibiotics. Post-ERCP pancreatitis prophylaxis is important for these patients, and so typically we use lactated ringers, endomethsin, and or pancreatic duct stents. And IV fluids and endomethsin we are careful with in those patients with advanced liver disease or renal disease. All patients, at least all of my patients, get biliary sphincterotomies. The reason why we do this is that they inevitably will have repeat ERCPs, and so it allows for easier cannulation, and then also, depending, it allows easier passage of instruments to get biopsies. In general, the recommendations that we inject contrast very gently. The goal is to give enough to define the anatomy without exceeding the capabilities of drainage and without increasing the risk of cholangitis. All right, so typically, this is a fairly typical PSC patient. What we find is a dominant stricture. You see there in the left hepatic duct. So the question is, now what do we do with this? Treatment management is dictated in part, very importantly, by the question of who actually gets cholangiocarcinoma. We know that the risk factors include older age, particularly above the age of 30. We know that pediatric patients and patients in their 20s have a very, very, very low incidence of cholangiocarcinoma. There's data to suggest that newly diagnosed PSC, in other words, within the first one to three years, have a higher incidence of cholangiocarcinoma. We know that PSC patients with IBD, specifically ulcerative colitis, have a markedly increased risk of cholangiocarcinoma, and that male patients tend to get the cholangiocarcinoma more often than females. So this patient selection will dictate how aggressive or unaggressive we are. The tools of diagnosis that are available to us doing ERCP include cytology, biopsies, cholangioscopy and cholangioscopy-directed biopsies, intraductal ultrasound, and then there are new advanced imaging techniques that are starting to take hold. In terms of cytology, this is performed using standard cytology brushes, typically over a wire through the stricture. I'm part of the ASGE Standards of Practice Committee, and we just are soon to publish our own guidelines with regards to diagnostic recommendations for biliary obstructions. We did our own meta-analysis looking at brush cytology and found that the sensitivity and specificity were 40 and 98 percent. The positive likelihood ratio is 10.6, but there's a low negative likelihood ratio of 0.6. So as well known to all of us, longstanding brush cytology is limited by its relatively low sensitivities. So positive is positive again, and then negative is not always negative. There is debate in the literature and amongst endoscopists as to whether or not the yield increases if you perform the brushings after dilation. The next added test to cytology is fluorescent in situ hybridization. This is a process that uses fluorescently labeled oligonucleotide probes used to detect chromosomal aberrations, in particular change in number, so disomy, trisomy, for instance, at loci associated with biliary malignancy. It's reported to increase the sensitivity of cytology to as high as 68 percent without compromising the specificity. So what happens at our institution is that typically the brushings will get split in half, one half for thin prep and the other half for fish testing, which is performed if there's a presence of atypical cells. As mentioned before, there's also forceps biopsy of the bile duct or questionable mass. This is technically challenging because this is taking a standard biopsy forcep and cannulating the bile duct freehand and manipulating it up to the mass, suspected mass, and taking biopsies. This does require that there's a preexisting sphincterotomy, and then this does require free cannulation. There is one set of biopsy forceps that go over a wire. That's not available to us, unfortunately. So depending on the anatomy, cannulating with the bile duct may not always be straightforward. But it does, according to our meta-analysis, increase the sensitivity moderately to near 50 percent while maintaining the other performance parameters. Chalangioscopy is the next test that is available to us. This involves putting a chalangioscope up into the bile duct and characterizing the stricture visually. So we have any number of variety of appearances of strictures. So the left and the right both, I would argue, are markedly noticeably different in appearance, but yet both turned out to be malignant. There are chalangioscopic findings that predict malignancy. This is the most current model called the Mendoza criteria proposed by a cohort of endoscopists. This includes the presence of tortuous and dilated vessels, the presence of irregular nodulations, the presence of raised intraductal lesions, the presence of irregular surface with or without ulcerations, the presence of friability. The diagnostic accuracy was reported to be 77 percent, and the agreement was reported to be anywhere from 70 to 90 percent. I would argue by the picture that that may be a little optimistic, but nevertheless, we are trying very desperately to better characterize lesions via chalangioscopy. Now we are able to take biopsies through the chalangioscope. There's a lot of debate as to its incremental value. The main limitation, as you can see on the picture on the left, is that the biopsy is forceps is tiny, and therefore our forceps, our pathology samples are quite tiny. Our pathologists quite honestly do not like when we send samples because they claim that we do not get deep enough. But nevertheless, the other limitation is that there's limited motility, mobility within the bile duct. So as you can see here, it's not easy to turn your forceps into a lesion to get biopsies. So that's the other limitation. Ideally you would have a really nice lesion that's straightforward that you can ram your forceps into, but that doesn't always happen. There's new advanced imaging, confocal endomicroscopy has been well described. It's a high, gives high-resolution cellular images of tissue by illumination. It's basically a glorified pinhole camera, and that you get very high-detailed images. This has shown some promise in terms of characterization of biliary strictures. It's not yet standard of care, but there's a lot of ongoing research to determine its utility. There's other interesting biliary analyses, including DNA and other analyses. The two that are getting the most traction right now in particular are the next generation sequencing. There's data from Pittsburgh and Europe, I believe, that show that it shows a lot of promise. There's also studies looking at methylated DNA. Both of these report that the sensitivity can increase anywhere from 80 to, sorry, that's supposed to be 90 percent. This is not yet standard of care. I think part of it is due to payment issues, but nevertheless, I would imagine that this is soon going to be, will become standard of care. There are studies looking at bile compositions to predict cholangiocarcinoma as well. The question is whether EOS and FNA play any role. The advantage of EOS is that it allows for visualization of masses of the extropatic bile duct and regional lymph nodes without the risks of an ERCP. But in general, the FNA of masses is discouraged because of the concern of peritoneal seeding. There's a study, small study, that came out of Mayo that said that 83 percent of those who had positive FNAs had peritoneal mets, whereas zero of negative FNAs had any peritoneal mets. The problem with this study is that A, it was very small, and B, it was a little unclear which ones were percutaneous biopsies and which ones were EOS biopsies. There's another study from Jefferson which showed that negative FNAs still have a small but tactile risk of peritoneal mets. In general, we restrict FNA to lymph nodes because it often helps who can go on to liver transplant. There's intraductal ultrasound, which is a 12 or 20 megahertz probe. The limitations is that you can only see pretty much just the duct wall. There are findings that are suggestive of malignancy, including thickening and irregular margins. However, this is not uniformly available, nor is it performed. We had a probe that we used to use, but it broke, and these are very expensive to replace, so we no longer have them. All right, so in terms of management, the question always is whether to dilate and or include a stent. It's very important that before you let someone like me monkey around in someone's bile duct that a therapeutic plan has been set. Typically, this is made in a multidisciplinary fashion, either in some sort of case conference tumor board or at least with personal discussion. The factors that come into play are patient preference, whether the stricture is malignant or benign. There's also the importance of the perceived adequacy and durability of the dilation. Things such as the ability to schedule follow-up procedures to manage stents in a timely manner also plays an important role. And then the question of surgical receptability also comes into play for cholangiocarcinomas in particular. There's some debate to argue that we should not be doing preoperative stenting. All right, so if we do dilate, typically we use balloons, as the catheters tend to be a little more flexible than passage catheter dilators, and in general, it should be done no wider than the diameter of the bile duct immediately pre and post the stricture. Stents initially should be plastic and generally removed quickly, usually within four weeks. Most would argue within one to two. And then repeat interventions are dictated by a number of factors, including the trend of the liver enzymes, post-therapy, persistent or worsening symptoms, cholangitis, and then also the perceived likelihood of malignancy. So there's two meta-analyses just very recently published. The most recent one came out in the Annals of Gastro this year that described that balloon versus balloon and stent had similar technical success, but the balloon only had a much higher clinical success rate. The overall adverse event rate was much higher for balloon plus stents, most notably cholangitis and pancreatitis. So in general, most people favor doing just balloons. In terms of cancer, the stents for cancer are dictated by where the cancer is. So distal cholangic carcinoma, like either within the pancreas or just above the pancreas. In general, ultimately, metal stents are preferred. These are associated with significant decreased rates of occlusion and recurrent intervention compared to plastic stents, very similar to pancreatic cancer. And there's data that suggests that it may increase survival and decrease the episodes of recurrent cholangitis. The decision for covered versus fully covered, uncovered metal stents is a bit debatable. Most often uncovered is preferred given the cost. For proximal cholangic carcinomas, metal stents are associated with lower occlusion rates and incidence of cholangitis, as well as higher rates of successful drainage. But it's notably doesn't have an effect on mortality. The biggest issue with doing metal stents is that there's more inevitable stent occlusion from tissue ingrowth, as these patients tend to survive quite long. There's also a question of unilateral versus bilateral. Typically, this approach should be driven by your pre-procedure imaging and what's available. People quantify liver volume. The goal is greater than 50 percent of the liver being drained by your stent. The quality of the liver is important, too, whether there's a lot of fibrosis and or mass within said segment. And then it's also important to prioritize the possible remnant liver for those that are going to go on to surgery. A meta-analysis from a few years ago, however, described that there's no difference in clinical outcomes between unilateral and bilateral stenting, which ultimately shows that it's not its quality, not quantity. So it's important to get good drainage. It just doesn't matter how many stents that requires. There are newer therapies that are coming down the pipeline that have been used. There's photodynamic therapy, which has been used, as well as radiofrequency ablation. Both of these have been shown to improve outcomes, including survival, but they are not widely used as of yet, and there's cost involved in terms of getting this equipment and then it's not necessarily very easy on the patient, particularly photodynamic therapy. All right, so how do we approach these patients at U of M? Basically, like I said, all patients are discussed at a multidisciplinary liver tumor board and or with personal discussions with the hepatologist and surgeon. Patients get ERPs with sphincterotomies, and at the minimum, they get brushings with fish as well. The use of forceps biopsies and doing cholangioscopy and biopsies, there are a number of factors that go into this. So older age or higher risk of cancer, we would do that. Ampullary adenoma may preclude the ability to do forceps biopsies. If we have a high clinical suspicion, then we will typically do cholangioscopy and biopsies sooner rather than later. However, all of these are off the table if there's rip-roaring active cholangitis and we just need to temporize the patient. In general, EOS is limited for those patients with high suspicion of cholangiocarcinoma to look for a mass or if they have confirmed cholangiocarcinoma to biopsy the lymph nodes if present. Dilation, the size of dilation is dictated by the size of the upstream and downstream ducts, like I mentioned. The timing depends on whether or not we do cholangioscopy. So in the initial ERCP, I actually prefer to do the cholangioscopy sooner rather than waiting because that way we get the most native look at the stricture. This is especially important if we have a high index of suspicion for cholangiocarcinoma. Dilating and in particular stenting will change what the stricture looks like and will make your cholangioscopy images quite ininterpretable. So the timing of it will depend. So if I do cholangioscopy, I will wait until after the cholangioscopy to do the dilation. Otherwise I will do it pre-brushing. All right, in terms of stent, for any distal cholangiocarcinoma or dominant stricture, I use plastic stents initially. We will convert to metal if confirmed malignancy. Again, there's a lot of debate as to whether to use uncovered or covered. Our group in general has been leaning more towards covered stents, particularly if they're going to go into the operating room because it leaves the most wiggle room for the surgeons for future delirium anastomosis. In terms of proximal dominant strictures, generally, like I mentioned, we dilate without stenting. We reserve plastic stents for recurring cholangitis, persistent LFT abnormalities, and if we have a strong clinical suspicion or confirmed cholangiocarcinoma, in which dilation alone will almost never do the job. Again, the number of stents and the size of these stents are dictated by the anatomy and our ability to obtain adequate drainage. In general, we reserve the metal stents for strictures that are just within the common hepatic duct. Once they go higher up, I no longer put bilateral metal stents because they've led to too much downstream trouble, but I know that there are other centers who are a little more aggressive than we are. Repeat procedures are dictated by how benign or malignant we're considering. Benign disease, we generally do it as needed or as dictated by liver tests and symptoms. If there's a concern for malignancy, particularly if there's an abnormal cytology or fish, we tend to bring them back soon, in the neighborhood of four to six weeks. Anyone who gets a plastic stent, in general, we like to get those out soon, so we try to go for two to four weeks, depending on patient availability. We might go a little longer if we're able to put in multiple stents. All right, so conclusions and key takeaways from this talk. Dominant strictures are a diagnostic challenge due to tumor characteristics and low sensitivity of current diagnostic techniques. The MR-MRCP is initial test of choice, and the ERCP is indicated for symptoms and high clinical suspicion of cholangiocarcinoma. At minimum, at ERCP, you should have cytology in fish. Introductal biopsies with or without cholangioscopy is based on equipment and expertise availability. Initial therapy should be dilation alone, and stenting is reserved for refractory disease or malignancy. And in general, plastic stents, if they're used, should be removed in a timely manner, if possible. Thank you. Thank you, Rich. Okay, we have time for questions. If people want to come forward. Introduce yourself at the mic, please. Okay, so I'm going to introduce myself. I'm going to introduce myself. This is so interesting. We have three different topics. Okay, I'll let Christophe and Pratima talk, but before you go to your question, I want to introduce everybody to the term relevant stricture as opposed to dominant stricture. I know this can be controversial in the world of the advanced endoscopist, but that's exactly why this is the right forum to discuss. Also, so we are trying to use, because when you do ERCP, you can measure your one millimeter or two millimeters, but with MR, when we do it without the forceful contrast administration, that becomes just semantics for us, and we're trying to use a term that we can apply to clinical practice. So if that stricture is associated with upstream dilatation, with worsening of symptoms, with worsening of labs, then it's relevant and it's something that we may come to you for intervention. So I just wanted to bring up, because both the ESO and the SLD guidelines introduced this new terminology. All right, let me start with Christophe. Please specify what you mean by that. Do you really split one brush or do you use two brushes? And the second question is about peri-interventional antibiotics because it's an area of uncertainty and how do you handle that in your clinical practice? Okay. Thank you for the question. The first question was the logistics of splitting my cytology. And so we do not split the brush in the endoscopy unit. So basically we'll do anywhere from 30 to 50 throws or passes and then we would send all of that to the cytologists and the cytologists themselves are the ones who split. The second question was peri-procedure antibiotics. Typically what we do is give IV antibiotics, some sort of broad-spectrum antibiotic pre- or intra-procedure, and then typically send them home anywhere from three to seven days of antibiotics, sort of dictated by how comfortable we feel that we achieved adequate drainage and how much, like if we have extensive contrast up above strictures then we may do longer. And then the other thing that comes into play is if they've had recurrent cholangitis that we may do longer. I think we lack evidence to do that, but yeah, thank you very much. Yeah, I totally agree, but that's lacking. Gideon Hershfield, Toronto. So three great talks, thank you very much for supporting our SIG. Just because you spoke last, Dr. Kwon, I'd like to ask you a more practical question which bothers me a lot with our PSC cohort is introductal calculi and stones, particularly around using Dr. Levy's terminology of relevant strictures. So I'm wondering what your approach has become with the patient, and 20% of patients with PSC will get introductal stones. You know, you've got strictures and stones, and how you tackle that challenge in the real world. Yep, I totally agree that that is a royal problem. That's where I usually turn to my wife and say transplant them, hurry, please. But in general, if I know that they have stones, that often will mean that I have a very low threshold for multiple cholangioscopies in particular. I think getting those stones through strictures can be challenging, particularly if the strictures themselves are refractory to our dilations. So that oftentimes will require that we go up and manually extract them with baskets and whatnot. But that also will dictate how quickly we bring people back and lowers the threshold for repeat ERCPs. And maybe I can be provocative. If you were a patient with PSC, would you be happy that the person in the ERCP, if they didn't have cholangioscopy, would you think that was acceptable in the 21st century? Because I'm just wondering whether, you know, the access to cholangioscopy is becoming something that all patients with PSC should have when they're having their management decided upon. Quite the provocative question. So I personally, because I love cholangioscopy, would side with your patient. I think if there's a, my personal bias is if the initial ERCP, if it's out in the community somewhere without stones, it's important to document. And it would be, I would have a very low threshold at that point to refer them to a tertiary care center that, or somewhere that does have cholangioscopy. Because I think patients are managed easier that way, better that way. Dima Sharma from Michigan. Fantastic talks, all three of them. I was just wondering if you, all three of you, can provide some perspective on IgG-4 related strictures, or IgG-4, PSC disease, some practical management points. In general, so IgG-4, well, let's take a step back. This is separate from PSC, so thanks for bringing this up. It's a secondary cause of sclerosing cholangitis, but that reminds us that we should be checking IgG-4 for all the patients with PSC, one, to help us with the differential diagnosis, and two, because it may have prognostic importance as well. Looks like maybe up to 10% of patients with PSC can have elevated IgG-4, usually not to that level that we see with the IgG-4 disease. It's usually below two times upper limit of normal, or two to four, but it's not above four. Those patients may have more rapid progression towards cirrhosis and portal hypertension. That's from the PSC perspective. With respect to IgG-4 disease, these patients tend to have more refractory biliary strictures. You will treat them with steroids, but the experience, I think in the literature, and my limited experience with IgG-4, when you stop the immunosuppression, the strictures tend to recur. You tend to keep them on long-term immunosuppression with Imuran or Celseptin in some patients, and they tend to have good prognosis if you intervene early. I would agree. In general, I try, if I can, not to stent those people and use steroids, but sometimes you just have to because they're symptomatic from jaundice and pruritus, for instance. The other thing of note, besides the Imuran, is that we've found that we've often had to go to rituximab, so at that point, I will enlist the help of a rheumatologist to help manage that, but it is a very important thing to consider on the differential. The good thing is they tend to require fewer ERCPs than a PSC patient. As long as they stay immunosuppressed. Right. All right. Let me come to this microphone first, then I'll go to Jim. Thank you. Alistair Smith, Sineos Health. Dr. Tinkopper, why do you believe that patients with autoimmune hepatitis and patients with PBC, both of whom are reliable patient groups, highly motivated patient groups, have been identified well in advance and are known to hepatologists, are disadvantaged or appear to be disadvantaged as regards access to liver transplantation? And then correspondingly, why are their transplant waiting list outcomes inferior to those of patients with other etiologies, please? Sure. As I commented on, I think a lot of the literature is looking at this from a perspective of the meld and meld sodium. The studies do try to adjust for other factors like, as I said, sex, because that's much more predominant in women, and we know that meld and meld sodium don't really, it could potentially hurt access. I think we know that for these individuals. Beyond that, I don't think we have a good understanding, once you account for things like meld and demographics, like why these patients, if they're under the care of a hepatologist at a transplant center, they're listed already, so you've addressed all the kind of preceding factors that could impact access to care, like why they're getting transplanted less and why their outcomes are so poor. Obviously, for the autoimmune hepatitis patients, a lot of it has to do with immune suppression, so sometimes they have to be removed because of infectious complications. For PBC in particular, I think is a little bit more unknown, and so that's why there are studies specifically focusing on PBC as compared to even other forms of autoimmune liver disease, but we do know that that group of patients specifically has poor waitlist outcomes and a lower access to transplant. I don't know if, Dr. Levy, if you have any other thoughts on that. I think age also plays a role. They're older, they may have comorbidities, but I also think about, I was thinking about our patients with PSC, so shifting a little bit from your question, why is it that we're seeing these disparities with Hispanics and Black? Is it all access to care? Is it all about us being more inclusive and insurance and all of that, or social discriminants of health, or is there a different phenotype, a different genetic background that accounts for part of the discrepancies that we're seeing? We haven't been able to pinpoint that specifically. When we looked in Miami for the Hispanic patients with PBC, we found that they tend to present to us already with more advanced disease, they had more portal hypertension, they were more likely to be incomplete responders to UDCA, so that could all be related to access. Also, they tend to have less private insurance than their white counterparts, so that could be one explanation. With the African-American population, we're trying to look at that in our North American consortium, but so far, maybe because of sample size, but we haven't been able to determine that it is related to income in any way. There is a trend, but it was not statistically significant there. So we need to understand these variables a little better. I believe social discriminants of health are going to play a major role here. As for what it's worth, there's one study amongst patients, wait-listed patients, who had PSC, which was published using SRTR data about 15 years ago, but it's still in an abstract form. Thank you. Jim? Well, very nice presentations. I enjoyed each of your talks. Dr. Kwon, I wanted to ask you about your statement about early diagnosis being a risk factor for, in PSC, for cholangiocarcinoma. I know that data comes from the Mayo Clinic's experience a number of years ago, but I'm wondering whether that's a universal situation. I know it certainly is in our experience, and I'm wondering whether others have confirmed that as a risk factor, other centers. I'm not sure of that data, to be quite honest. I think there's other centers that I believe that have hinted at that association, so yes. That's something that ought to be looked at, I think, again, by perhaps the other senators more clearly. Certainly our experience is that it takes some time for the cancer to develop in these patients. Cynthia, let me ask you a question, if I can. You mentioned that older patients tend to do worse and have more instance, I guess, of PSC than a tumor, rather than younger patients. Now, is that because the onset of the disease was later in those patients and they had other comorbidities, or is it because they had a longer duration of disease? Yeah, that's a great question. The study actually, that was the limitation. They did not account for duration of the disease, so they saw that the older patients had more portal hypertension and synthetic dysfunction, so suggesting perhaps more fibrosis in that group compared to the younger patients who had more stricturing and polystatic features. But they didn't adjust for, it used UNOS database. It didn't look in detail about other comorbidities and duration of the disease. They saw that the older patients, so older than 60 when they were listed, had poorer long-term survival post-transplant. Thanks. Palak? Yeah, thank you very much for three great talks. I mean, so we looked at race in the UK population-based study. We also found the same thing. So people of black race had worse transplant-free survival, but not inferior cancer outcomes or IBD outcomes. And we're a publicly funded healthcare system in the UK. So whilst there may be some inequity and socioeconomic factors, I think there is a slightly different biology to that group. Should we as a group, just on the transplant side of things, I mean, everyone says, you know, PSC patients spend longer on the list, but they don't die. But is that the wrong way of looking at things? I mean, all the x-axes on those curves are five years, seven years, but that overall life years lost, the quality-adjusted life years lost when you've got somebody in their 20s with jaundice for four years is terrible. And should we just change the way that we're thinking about it? And that's just a slightly broad question, but I think we need to move away from that question, really, when we're looking at the way that we allocate organs to this patient population. Obviously, their quality of life is terrible once their disease is progressing. But the current allocation system is not based on quality of life. That doesn't buy you any points. It's based on mortality. But the overall life, it's just the long-term life years lost for this group, not the short-term life years on the waiting list, is what I mean. I understand. So longer follow-up and years of work that they may miss after transplant? Is that what you're saying? If you've got an older patient with PBC, and I'm not discriminating PBC by any means, or ALD, or NAFLD, the life years lost for an older patient population is going to be much less compared to controls than in your young PSE population, who are the 20-year-olds, 30-year-olds, 40-year-olds, who are waiting fillies, that they will lose this many life years compared to somebody who's of an older age with another disease. So the total life years lost by being on a list and getting sicker and sicker is immense overall. So I think we need to change the way that the organ allocation is. That's a great point. Hi. This is Mitch Mahmood. Quick question for Dr. Cohn. Any practical suggestions for patients who have persistently elevated CA-19-9 levels with strictures but negative cytology for cholangiocarcinoma? In that scenario, typically that would be an indication for an EOS, and hopefully you would be able to get a good quality EOS at least to evaluate the extra hepatic duct and rule out any masses. I think it's also important that there's good serial imaging, MR of the livers as well. It's a not uncommon problem that you're describing. We have several patients of our own that I can think of that went years with elevated CA-19-9s and it took forever for the cholangio to present itself. So I don't have, other than good quality, the best quality imaging possible, I don't know that I have a great answer. There are also, if there's questionable strictures or strictures, then those are the types of patients that we do multiple cholangioscopies on and get as much tissue as possible to confirm that there is no cancer. Thank you. I can continue this question. So we've had patients with rising CA-19-9 whose image does not suggest a main dominant or relevant stricture, and these patients go for ERCP and you may not see something that is as striking as you would expect for that rising CA-19-9, 100, 300, 1,000. When you brush these patients and you send the fish, do you brush only the more significant stricture, like your relevant or dominant stricture? Do you brush multiple ducts for fish specifically? Because there is, isn't there data that if you have multiple, so you have fish, and you apply the, in different strictures, that increases your risk of cholangiocarcinoma? Right. So, and that's, in this typical scenario, or this scenario described, if there are multiple strictures, and in particular if they don't respond well to dilations, then yes, we tend to brush the most worrisome strictures, plural, depending on access to that, assuming we can get to them. But yes, we will brush those separately and put them in separate bottles. We also, like I said, would have a very, very, very low threshold to repeat cholangioscopy and get tissue that way. You basically have to keep hunting until it declares itself. It can be very frustrating when you're fishing, fishing, and nothing turns out. And then later you find a positive lymph node and this patient is no longer a transplant candidate. That's, those are the sad cases. Gideon? Well, a couple of comments. Maybe, just to pick up on what you're saying, maybe don't measure the CA99. So, I can tell you that in my practice, I don't measure CA99. I've not found it to be helpful, and I don't think I have a higher rate of cholangiocarcinoma that I'm missing. So, and the biology of CA99, as you know, there's genetic determinants of whether you have an elevated CA99. So, I think that might be one solution to the problem. I have one comment and a question. Really, I'm struck by the rate of transplantation in the U.S. for autoimmune hepatitis. And that really, I think, talks to some disparities around how people are being diagnosed and managed. Because for me, the only patients with autoimmune hepatitis who should go for transplant are patients with end-stage portal hypertensive liver disease. So, you know, I think it's very, very uncommon, apart from the very small number of fulminants, which are tiny, and which very rarely will respond, that in your clinic practice, your patient with autoimmune hepatitis should even need a transplant anymore. We have very effective treatment. So, I'm wondering whether that might be something we should be thinking about as one of the disparities that we tackle. And then, the last comment and a question to the panel really goes back to PSC and about evidence for inequity. So, you're right, and I think Dr. Trivedi mentioned it. You know, it may be that weightless mortality doesn't look different. I'm not sure whether they really accounted for the age of the patient, though, in those analyses. But, you know, in Toronto, where we have a MELD allocation system, but access to live donation, 47% of patients with PSC choose live donation. They would not choose live donation if MELD was a system that gave them access to transplant in a timely way. They would not go down that path. So, they vote with their feet to have a transplant to get back on their life because MELD allocation does not work for PSC. And I would echo what Dr. Trivedi said. If you're going to use weightless mortality as your kind of metric, then it's not really capturing the problem that we actually face. DR. That's very provocative. I am with you and with my patients, believe me, because the quality of life is really affected. But that's the system we have in terms of long-term survival, not only weightless, but post-transplant. But I agree, we can look at that in a different way and see how this can be adjusted. I think also adjusting, let's see how MELD 3.0 will change our decision-making to begin with our abilities to list and care for these patients. And yes, age. That study out of Duke was interesting, showing the different profiles of patients. And we know that also from iPSC, the different phenotypes for our young patients and older patients with PSC. So it's a very heterogeneous disease to fit into one allocation system. Christoph? Maybe a short comment to Gideon's comment, because we just had the chance to analyze the European transplant registry regarding living donor transplantation for PSC. And it seems that at least over all these centers analyzed, outcome was worse after living donor transplantation for PSC. And that is caused by an increased rate of biliary complications in those patients. So I would be a bit cautious advertising living donor for PSC. And it's a shame that Dr. Selznick is not here, because that is exactly what we don't find in a high-volume live donor program. So in a high-volume live donor program, our data is the exact opposite. And the intention to treat survival is better than for diseased donors. But your paper is important. But I think, and there was another SIG, I think, on liver transplantation happening at the same time. But I think in high-volume live donor transplant programs, that is not our experience. And we all come to Toronto, Gideon. And just as a quick plug, there is an ESOT, European Society of Transplantation, meeting next week discussing this very issue about transplanting PSC. Excellent. Well, I think with that, if anybody wants to make an additional comment, I think we had a great discussion. I thank everybody for your contribution, your questions, and for being here. Thank you.

epidemiology

disparities

listing

transplantation

autoimmune liver disease

autoimmune hepatitis

primary biliary cholangitis

primary sclerosing cholangitis

African Americans

Hispanics

diagnosis

management

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