Drs. Frenette, Karvellas, Rinella, and Terrault answer questions from course participants.
I'd like to invite all four of our speakers from this morning to participate in the panel today. That will be dr corvallis, Doctor fernet, Dr Tyrell and dr Rinella. So thank you all for your wonderful lectures today. So I'm gonna invite the audience to submit questions if you'll just hit the chat box or ask the question um ask a question um link in your connection. I will see the question pop up and we'll ask the attendees. I'd like to start uh with a an issue for dr fernet question I have is says I brought this up before so she is aware of this because I think it's important. There was a mention a D. D. W. Review by Lewis roberts from Mayo Clinic of Nature Reviews, men analysis, suggesting that a Tiso bev doesn't work if you got liver cancer due to Nash or alcohol which of course is everyone now and um that's that was a meta analysis and you had some doubts about it. But we're and obviously we're gonna see more about this because it's if it's true it's going to have um some significant ramifications. But what do you think of it caring? Well? So what it was was a paper that looked at a meta analysis of three studies of immunotherapy um that then they took the subgroups of non viral liver cancer, so mostly national alcohol, they just took those small subgroups from each of those three studies and did the meta analysis and the meta analysis there suggested that those patients do not have as much of a survival benefit as the viral hepatitis patients. Now, I think it's interesting, we do know that the viral hepatitis patients do tend to have more immuno surveillance of their livers and their tumors um in general, and so, you know, it does raise a little bit of concern. However, I do think that the science of doing a meta analysis of subgroup analysis is a little bit in question and I would not personally change any recommendations based on those that paper, but I think it would warrant further study. Um So you just have to be a little careful looking at sub groups just because the papers aren't powered for that. They are very small patient populations that were in that meta analysis. So we're talking maybe a couple 100 patients. Um So it raises some interesting thought, but I don't think it's enough data yet to change our practice of recommending a Tiso bev frontline. Okay. And I'm going to invite all the speakers to comment on this because you're all from major transplant centers and to treat plenty of liver cancer. So mary you have any thoughts about it. You noticed anything as far as treatment response between, It's too early probably to notice anything to Zobelle was just really been used in the last few months. You know, we've been using it but we have not noticed any difference in response between nash and alcohol and viral and that's not really my area of focus. But even, I mean I haven't even heard secondarily that that's the case either. So Nora or Dean any comments. Uh no, I would agree with Catherine that it's sort of, it's important that this analysis was done. I think it raises the, you know, raises the importance of potentially stratify ng future studies when they're doing, you know, these new immunotherapy. I think now we realize maybe that's important. So I think what I got out of this is that going forward, it's going to become a variable that we'll see probably patients stratified on to ensure that we do understand the contribution of underlying liver disease. It is interesting this idea of a fatty liver environment and whether that might in some ways be different in terms of how that's modified by an immune mandatory therapy. So I think conceptually, I think oh, this is really interesting and certainly we should study it more. But more importantly, future trials need to take into consideration. Great. So Dean, I noticed you you mentioned that bolts are used less frequently now and I was trying to think back when I when was the last time we placed a bolt. I remember all the bad outcomes from bolts. Of course those stick with you forever because their fatal, but we haven't really been using them carrying my wrong. We we've really gotten away from him with the noninvasive testing, something similar to what Dean brought up as well. Um, and neurosurgery has also of course they get very anxious about the risks with these patients who have significant kogelo apathy. But I'd be interested to hear what Dean does In his center. So that's a very good question. And uh so the the use of them has has gone down quite significantly. The good news is probably the bleeding risk is probably around 5%, so it's much lower than what was previously reported and as we know, the stars, a prognostic factor in a life, but it doesn't necessarily give you the risk of bleeding. So someone advantages were using more of the visco elastic test like take and roll, attempt to see to actually assess coagulation both in acute and acute on chronic book of failure. Um so often you can use this and it'll value if you do have to put a bullet in and obviously this is a small minority of patients whether you would or not. One thing we've actually done here is we have a very good critical care ultrasound group and we've started a study what we're looking at the combination of transcranial Doppler optic nerve sheet. Even from from doing cT scans you can actually look at the orb um looking at get the reformatted to look at the orbits and this actually gives you information um in not necessarily in real time but a dynamic piece of information with regards to I. C. P. So really what we're doing now is we're finding just what are the highest risk patients of having intracranial hypertension. So if you have an abnormal optic nerve sheet and cranial transcranial Doppler. Those are the people and we have a neurosurgeon colleague that's actually part of this study Uh they'll actually come into a bolt. And that's the other thing is that you don't want to have, you know, 10 different people that have no idea what you're calling about. It's a small finite group of people, you know, any other comments from mary or Nor are, I mean we do a lot. Let we used to do bolts driven of course, by either using tech at the time. Now we have road 10, but um, but now we almost never bolt anybody at this point. And it has to do, there was a change in the neurosurgeons, which probably drove a lot of, but it's really a minority of people that need it, as you know, as Dean mentioned. So, nor were they doing this at UCSD? I mean, UCSF frequently or not, we went through a period where we used them very routinely, I would say. And then, and then it it went away. We, I think it was really around the risk, even though I acknowledge that I used both quite a lot and I remember finding them quite helpful at the time when we did use them, but there was always this concern about the risk of bleeding and complications. And so I think we're always looking for um sort of a non invasive alternatives. I think these new parameters that you're suggesting to, you know, the kinds of things that I think all of us would like to be able to know if that could be an alternative. Because it gives it I think we want the information. We just don't want to take on any risk. I have a question actually for Dean, if that's okay. Um we are you're a critical care people are doing work with brain edema earlier signs of brain oedema on actually ct images. Do you do you do that or do you believe that? That's a fruitful way to look at early changes in brain edema? Because historically we didn't do that. So I'll say it's interesting because one of the one of the groups are actually collaborating with is eric Liotta and uh Bad at Northwestern. So, so uh what I would just say is that I think that there is the single read of the C. T. Which we all get, which often you find it it can be very challenging because you'll either get some cases, you can get the scan read as normal and you're actually missing probably early cerebral oedema. And then the second thing is also the problem you get with a lot of acetaminophen over those patients are young, so they don't tend to have a lot of cortical atrophy. To begin with you get a lot of over calls where everybody, every radiologist is concerned that say you can't rule out cerebral oedema. So so I think a lot of a lot of this opportunity is probably in combination with what the other information is giving you. And I noticed that the Northwestern is actually also using a lot of the transcranial Doppler and the the optic nerve sheet. We have questions for mary and nora mary for you first. What are your thoughts about endoscopic sleeve gastro gastro plastic in patients with cirrhosis and known portal hypertension? Say they've got viruses? Yeah. Yeah. I think that that's a dicey thing to do. Um I probably again we don't have data on that. It's not covered by insurance. And I I personally doesn't doesn't seem like a great idea for the obvious reason that there's you know the stomach is congested and there are there could be early fungal viruses. But also because if you look at the bariatric literature, once you have cirrhosis at all, the benefit is much much smaller. Um And then once you have cirrhosis with portal hypertension uh then it's really not going to get you much benefit and it will increase risk. So I I think that would be seems like a bad idea to me. Yeah. Too far reach nor a question. Um This actually from dr fernet, she said I've seen some guidelines suggesting that post transplant patients should have colonoscopy every five years until three normals. Do you think that's overkill or reasonable? And number two you screen for barrettes and high risk post transplant patients. So first of all the colonoscopy I think the data to support a higher frequency of doing a colonoscopy and individuals without any prior risk features is not supported by data as far as I can tell. Again, The IBD group is very very unique in in PSC. And then people have had prior to melanomas or other um identified uh kind of higher risk polyps should undergo surveillance. But nothing that should be accelerated at least on the data that I've seen. So we aren't changing our practice. We're just trying to make sure they actually stay to their schedules because they often fall off their schedules and they are post transplant. A good point about barrett. So I actually would do surveillance and barrettes. Um But I think um there's been not not as much data about that certainly in the smoker group in the L. D. Group. Again high risk groups. And I think we should be thinking about doing surveillance not only for the or affair in jail but also for a soft yield cancer in that group. That's where we're actually seeing the higher proportion or higher risk. And so I think that's a group in which E. G. D. Should be included. Is that what your practices? Um Yes I would say we we do get some pushback also from E. N. T. On occasion about doing the screening exams for the prior smokers and the alcoholic liver disease patients. So those have been a little bit difficult. But we also have seen some really terrible squamous cell carcinomas that have come up with metastatic disease and rapid progression. And we've lost it several patients in the last couple of years. So it's it's sort of tough to navigate the politics of both the insurance and the this is a useless exam kind of thing but knowing that it's important for some patients. So two questions for mary regarding nash semi glue tide has now been approved for weight loss. As you know, and it's of course already approved for diabetes. So it's likely to be approved for nash. But it's an injectable agent. It's probably gonna be lifelong and has side effects. So what will be the barriers to to actually use of this compound? Well I mean, first of all, I mean I use it regularly actually in people who have diabetes or obesity already and nash. Um of course it's not approved for nash and it will not be approved for nash until the Phase three trial is complete and it hasn't even started yet. So the big limitation from Monash perspective of this drug is that it doesn't improve fibrosis at least so far. And that may be a mechanism of action dependent problem because it's really just acting through weight loss. So so again I I think at some point it's a reasonable drug. I don't think it's a drug that will be used in isolation and people with advanced fibrosis. So that being said, I think the biggest barrier to use of those drugs now Is that firstly uh insurance is a problem, especially when the indications obesity it usually requires um to at least twice to appeal to get that covered. Um and then the most practical limitation is that about 50% like 5:00 of people started on GLP one agonists do not tolerate them due to nausea. And um this can be somewhat mitigated by starting at a really low dose anti trading upward. Um But it's still not an easy drug for some people to take. Um The other caveat too. That's important to notice that the studies and nash are looking at daily dose ng. And most of the studies um for obesity and diabetes are weekly uh dozing. So do you think we're going to end up with an oral? I mean do you think the oral form of some of blue tide would ever be useful in Nash? Not. I'm going to say probably not because I think that the as much as you know, you can look at the basic, you can look at the mechanism say, oh well it makes a lot of sense that the GLP one agonists would work for got signaling and blah blah blah. It just doesn't seem to be the case. And the semi tied oral has much lower impact on weight loss. And I really think that unless of course that could be totally wrong about this. But I don't think that it's going to be enough weight loss to move the needle enough. Most likely. There are other drugs that are the sclC two inhibitors actually are oral. Of course they give you a U. T. S. But other than that they are they're good for diabetes and they do improve fatty liver. We don't have any biopsy data on that. But that's another drug that is used that can be used for that dual benefit. And they both reduce cardiovascular events and renal failure down the road. So and survival. So they have that benefit as well. You mentioned the regenerated and Bennett colic acid which we were all disappointed was not approved for Nash. Now we have really re labelling for Osaka in patients with primary biliary cholangitis is most of the audience should know that re labelling took place in May and it was discussed yesterday in some detail by dr cowardly. But one of the key issues is if you've got compensated cirrhosis with soft viruses that drugs now contraindicated. So do you think that will that's in a cola static condition? Of course not nash. But if you look at the national cirrhosis study with Obama colic acid, I'm not sure those patients are included in that trial. So uh what's going to happen? I mean that data will be right out at the end of the year on the cirrhosis study with Obama colic acid. What's gonna be the hurdle to get that approved? Well I think that the it's going to be a very well defined um uh well compensated Sirat IQ population that's going to have to move forward. Um, and you know reverse has um, it's a it's a well compensated national cirrhosis population. The issue is going to be, you know, if people who failed to respond uh to drug, you know, there's going to have to be good communication that that needs to be stopped essentially. I I do think that there are different diseases and the risk of dili is going to be different. The dozing used for nash is more than twice that they used for PBC um to have any level of efficacy actually. So um you know, I I do think it's going to be worse than a more cola static person. Of course the nash really cold, static person and stage would be a terrible idea to give that to, I think as well. Okay, uh so where do you think we're going to end up in the next couple of years? Mm. Well I think that there are some drugs in Phase three that their Phase two B data look strong. Uh I think that the thr beta agonists, the one that's in most advanced development is the madrigal compound Um that showed very nice nash resolution compared to placebo and their Phase two B. And I think that that's likely to show benefit the biomarker data from the interim analyses certainly suggests that that's the case and hopefully that will meet its benchmark. That's going to be almost two years from now though. Um So I think that has that has promised. I think that the G Elvin semi glue tied again has promised um the are the FGF 21 analog is there are a couple in the running those have promised. But again, we're looking at a couple years from now. Um it's I think still possible that a bit of folic acid will get approved by the FDA. Um They're basically awaiting additional data as was outlined in the complete response letter that they got from the FDA. So it's possible that they'll get approval um for, you know, until something else comes along. So, so in san Diego if you don't have M. R. I. P. D. F. F. Your you know Rupert lumber considers you a diminished center but you and we've we have it and we've been using it. But um you implied that the fast score which is really what we use fiber scan plus HST is better. Yeah I mean I just yeah I've been saying this for a long time so forget the fast or just a just a liver enzymes actually. So there we have yet to see, you know an intervention where histology improved and LT did not. So I think that even just look even if you just use A. L. T. Uh if the A. L. T. Moves you're more likely to see a histological response. Um I think that P. D. F. F. Is good for certain mechanisms of action. It correlates with nash resolution, but there are certain mechanisms of action where PdF does not show a response. Um that would be you know, things like a bit of folic acid. Um Some of the P. Part data L. A. Fibrin or there's a new um there's a study I didn't present which is a p part modulator that had no effect on PdF F. Um but improve liver enzyme. So again it's it's I think if you only had to pick one I would still go with liver enzymes and maybe fat maybe fast score. But PdF again doesn't correlate with five roses response in many mechanisms of action comments from from I think it is really important. It's just the ability to triage patients towards specialists really like this is I think the main challenge that we have is that there is such a huge number of individuals at risk out there. And how do you know, what is the tool, the diagnostic tool that allows those individuals to be triage towards specialists who are gonna be able to offer, you know, all of these new drugs as they become available. And that's where I think fast, it's really very valuable. I can sort of see this becoming just an automatic algorithm that any patient who is overweight or has diabetes or what should just you know, or has abnormal liver test should get fast. You know, and we should be starting to move people towards really getting to specialist care right now, there's just such a huge number of individuals who are being seen within primary care, but even they're sort of struggling with when do I refer? And what would be a good marker for me to do referral? So I I think that's where fast really has great benefit. Yeah. And most of those tests have really good negative predictive value and they're less good positive picked area. But there was actually another abstract presented um that's basically uses um fiber scan data and other uh things like diabetes status. It's sort of like a combination of Novel Fibrosis score and the Fiber Scan. And that one had really nice positive predictive value. May end up being even better than fast score. The Iraq's for that study were like .852.9, which is, you know, obviously higher than anything we've we've seen. So that that might be interesting. It has to be validated them externally. You're faced with the fact that the average gastro gastroenterologists in practice doesn't have a type of scan machine. So they end up sending them, they have to send them effectively to, you know, at Art center, basically I spent on Thursdays or my in person clinic days and I do fiber scans all day uh all morning long basically just sorting out who's got an abnormal hyper scan from who doesn't and that's and those are referred patients from primary care and from outside you know what group. Although there are I know that people don't have fiber scans. A lot of people don't. But what they often do have is ultrasound our fee or in their institution and believe it or not, M. R. E. Access to one of those. So if we can you know get primary care doctors to you know refer or to send for liver stiffness assessment, You know 54 of 1.4 or higher. Um and then you could really get at least a little bit more refined population that's referred because it's a lot of people otherwise that'll that'll get sent for no reason really. You know, you're seeing a lot of this up in Alberta or is every everybody thin and nobody's everybody exercises and they're thin. Uh I was gonna say two things. So I uh well, me personally, I don't I don't have an outpatient practice, but what I will say 11 plan that they did here, that's very interesting is the use of an alternate level of provider that's actually been trained in fiber scan. So, one of my liver colleagues here actually has a nurse clinician that essentially has been trained on fiber scan. So she triage is everything essentially for the fiber scan. Liver enzymes work up for other causes of liver disease. And part of the idea was to triage the patients that truly needed to to see a hepatology versus those people that were low risk. So it actually, in some ways it's also cost effective. That was one of the benefits. So the number of patients that actually go on to see that need uh specialist and uh you know, uh far michael therapy um ends up becoming a minority. And we're actually working. We have a couple outreach clinics that were um we have some that are open and some that are opening and we have some traveling fiber scan. And we have the Emma do the fiber scan as part of the vitals and those outreach clinics because that is those are in the high risk areas. Um So you I mean, you can have just about anybody get trained on a fiber scan. Yeah. What about the what about the diabetic population where you're you're basically missing? If you refuse liver enzymes alone, you're gonna miss uh 70% of your fatty liver patients and probably most of your nash patients. What are you doing there? Well, I mean, we did not recommend outright screening and the last guidelines, I think that's going to change with these new iterations of the guidelines because we have a little bit more evidence behind it because I feel pretty strongly about it. It's going to change. I think it's just it's a no brainer. I mean, 17 screening diabetics. Yes, because they're still high risk. Yeah. So yeah, so um and you're right Paul. So a lot of them more than half have normal liver enzymes. So they really do need um you know, they need liver stiffness assessment. You know, 50% of those with fatty liver there have advanced fibrosis. So it's a lot of people. Um so yeah, hopefully that will change. That will change. I mean, ideally at some point in the future, centers would have the fibers can not live in the G. I. R. Hepatology office but having in radiology. So primaries can order a fiber scan for their diabetics just like they order a foot examine an eye exam in a microbe area and get a fiber scan, yep. Absolutely yeah. So easy. I don't know why we can't just do that but. Mhm. I have a question for Dean. We've we've had some we've had some patients that get they sort of with alcoholic hepatitis and they can present very similar to a sub acute er acute liver failure. Um But there are obviously a different type of a patient. Are there things in those alcoholic hepatitis patients who are presenting in that crashing sub acute place that you should use the similar type of therapy is you're using in L. F. So that's a good question. And I the one thing that I find very interesting is it's not really in in our community but you get outside of the the critical care gi and hepatology community you see to find a types, the one is the mist acetaminophen overdose and an alcoholic where they get caught up on this must be el cap and then all of a sudden there lt is 14,000 and they haven't started the neck. We have two patients like this actually just last week. But what you're mentioning about about all cap, it's you know, primarily it's more of an acute on chronic phenomenon but at the same time the um and you don't tend to get the neurological like the cerebral oedema. Um but I think a lot of the bigger, you know the big issue that or one thing that that I found very interesting especially in the covid era is when we're using, for example, will be predniSONE for Al CAPP. If they test positive for Covid 19 the decks of methadone doses actually almost equivalent. And if they end up in the ICU with septic shock, if you're using hydrocortisone for sepsis doses of steroids, the one hack that we use is that all of those doses are eventually essentially 40 to 50 mg of predniSONE. So the first thing that we do and if the patients critically ill is this kind of steroid substitution. So if you're concerned about sepsis and normally you're holding the predniSONE, We give hydrocortisone 50 mg, q6 and septic shock patients. So I'll switch patients patients to hydrocortisone. Um, I think that's one of the kind of the biggest clinical pearls because mostly otherwise, most of these occupations otherwise behave like a like an acute on chronic. And then the question just becomes uh as you're probably aware, certain we have an exceptional pathway for for the first presentation of alcohol for urgent transplant centers have at some centres only follow the six month rule. Um And then everything else. The other thing to mention too, that one difference is that um there's benefit too early CRT in acute liver failure, but there's no there's no benefit in acute on chronic liver failure. So we don't tend to, obviously there are some patients, certainly if they're not a transplant candidate, the use of renal replacement therapy becomes challenging. But there isn't really good data per se to say that we should be putting people on early renal support if they have l kept in any case you brought up an issue before we and I want to ask, we had a debate yesterday about using the liver transplantation to manage acute alcoholic hepatitis, not acute on chronic, so not not patients with underlying cirrhosis, but true, acute alcoholic hepatitis and dr fernet mentioned that we have a protocol on our center and that she's keeping track of the Number of candidates that have been evaluated and so far we've transplant 3%. Is that right? Okay. So I'm going to ask mary and Nora and Eugene, what what percentage of your patients being transplanted at your center now have acute alcoholic hepatitis. Okay. Uh sorry for asking about the denominator is the number of overall transplants or al kept patients referred for around 3 to 5%. And depending on its of the alcohol of the Al CAPP patients, of the candidates that are floor is full of patients with alcoholic liver disease. They're all sent from USC now. Yeah, it's uh it's small. I think the I will say it it does propose these new pathways kind of add a lot of challenges because it's a significant amount of work for the for the transplant program for the evaluations and I do find that on the transplant meetings these patients uh take up a significant amount of time with regards to the discussion. I will say that we don't we in some cases will even consider people if they do have underlying cirrhosis if it was their first presentation. So they were essentially means that you made it to a certain age and and did not have like your first complication of drinking. It wasn't A. D. U. I. Or or some other complication. It was it was al CAPP but in reality a lot of them actually have signs of chronic liver disease. Mm So what percentage of your Cases are getting actually transplanted? So probably the same thing. It's certainly less than five laura. I think it's around 5%. And when we looked at the accelerate data, that's also the number that we arrived at was about 5%. But I think the number is going up, There is no doubt that we're seeing more el cap this year than we've ever seen before. Um And a lot of it, it's the first presentation. They really are meeting that criteria. These are people who, you know, I don't know if it's the pandemic or what it was, but people who really increase their alcohol use during this time and are presenting for the first time with the complication of alcohol associated liver disease, whether it's alcohol for this sort of a cute presentation. Somebody who clearly had underlying chronic disease that was undiagnosed. Um So we are really evaluating many more patients, you know, for transplantation, who who have had alcohol right up until their transplantation. So we're doing many more of those valves. It's still really hard. And here in California, as you know, to get our Medicaid patients approved, we're still really trying to fight the battle to really have them understand that, you know, there there's unique patients who can be well selected who will do well without having sobriety requirements. But it's done on an individualized basis. So we're really challenged and still being able to get access to transplant. But I think the There are good candidates. I obviously I really believe that there are this is a good treatment for the right patient, but it's still the right patient, meaning they make it through all of our selection criteria is still only 5% of all those that we're seeing. So it's the minority. But I would say more in the past year. You know, we are we're definitely seeing and evaluating more per month and we did in the years before. So they don't they're all going to san Diego. We definitely have some still of in L. A. I can assure you talked a little bit yesterday. You know, one of our residents used epic slicer dicer or something to look at Alcoholic admissions, alcoholic pancreatitis and alcoholic hepatitis. And we're seeing basically about a 40% increase in all of those since the pandemic. But what I also thought was really interesting about this data is that you know, looking at where the alcohol started to increase alcoholic pancreatitis, ignition started increasing pretty quickly after alcohol sales started increasing and alcoholic hepatitis was about two months delayed in terms of the admissions and the uptick that we started seeing. So sort of an interesting little time correlation that we saw there too. Mary any comments? Yeah. I mean, of course I'm seeing the same thing. We're evaluating more and more people, but I will say, I think we don't have a handle on what the denominator actually is, because it's one thing to look at the percentage of people that we evaluate and then decide whether or not to transplant. It's a whole another thing, um, to count those people that walk in and you don't even consider them or the primary care about what you can send or you don't get even a consult or you get curbside and you're basically decide now I'm not going to do that one would be really good if we knew better what the denominator was and what the reasons for exclusion were, uh, all through the process so that we'd have a better idea. I think of that number. I agree. I think we should all be doing this the same way
