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Melanie Cole (Host):  Welcome to the UAB Med Cast. I’m Melanie Cole and today, we’re discussing early liver transplant for severe acute alcoholic hepatitis. Joining me is Dr. Meagan Gray. She’s an Assistant Professor and Transplant Hepatologist and Dr. Robbie Cannon. He’s an Assistant Professor and the Director of Liver Transplant Surgery at UAB Medicine. Doctors, thank you so much for joining us today and Dr. Gray, I’d like to start with you. Please tell us a little bit about severe acute alcoholic hepatitis. What’s the prevalence and how does this happen?

Meagan Gray, MD (Guest):  Yeah absolutely. I would love to. So, alcoholic liver disease in general, affects about one percent of the population but we really don’t know how prevalent alcoholic hepatitis is because a lot of these patients never present for medical care, especially if they have some of the milder forms. But basically, alcoholic hepatitis is severe inflammation of the liver that’s due to excessive alcohol use. So, patients will present with jaundice, high liver tests, they may have coagulopathy and of course, their workup for other reasons why this could happen is negative. Often, they will also have fever and sometimes high white blood cell counts.

So, when we think about the spectrum of alcoholic hepatitis, we do have criteria that help us to define who has a severe case. And so, there’s two different ways to define that. So, one is a measurement called the Maddrey’s discriminant function and that is a calculation that uses the prothrombin time in addition to the bilirubin and if that score is greater than 32, then that defines severe alcoholic hepatitis. And then more recently, it’s also been shown that Meld scores which is the scores we use to list patients for transplant, Meld scores greater than 20 are probably equivalent to Maddrey’s discriminant function scores greater than 32. So, either of those measures could be used to define severe cases.

So, once patients are diagnosed, it’s been shown that steroids can improve 28 day mortality and so it they’re candidates for steroid treatment; that would be the next step. Of course some patients are not candidates for steroid treatment especially if they have active infection or GI bleeding or potentially uncontrolled diabetes. But if they are candidates for steroids, we use prednisolone 40 milligrams a day and we give that for one week. And then at the end of one week, we can calculate something called the LILLE score and that can tell us whether or not the steroids are helping. So, if the LILLE score is low which is defined as less than 0.45; that tells us that the steroids are working, and we would continue the steroids for a 28 day course. And that patient, since they are getting better, really would not need to be considered for a transplant at that time.

However, patients who don’t respond to steroids, which is defined as a LILLE score greater than 0.45, then their six month mortality is actually really high. It’s about 76%. And so those are the patients that we’re targeting for early liver transplant because we don’t think that they will make it to that six month of sobriety mark that we typically use.

Host:  Well Dr. Gray, then and what an interesting topic we’re discussing today. Tell us the data behind early liver transplant for severe acute alcoholic hepatitis. Give us a little brief history about how this came about.

Dr. Gray:  Absolutely. So, this has been studied in a couple of different areas. Actually the earliest papers coming out about alcoholic hepatitis were from the New England Journal in 2011 looking at seven centers in Brussels. And so they had very select, very strict criteria for who they chose to transplant but over a period of time, from 2006 to 20q0, they transplanted 26 patients for severe acute alcoholic hepatitis. And they compared that to 26 patients with just alcoholic hepatitis that did not have a transplant. So, when they compared the two groups, in the patients who did get a transplant, their six month survival was 77% whereas the group that did not get transplanted, the survival was only 23%. So, really, this kind of started the conversation that clearly liver transplant does improve survival in this group of patients.

So, then the follow up to that was a paper published in Hepatology in 2012 which was looking at UNOS data from the United States and so they looked at transplants between 2004 and 2010 and these centers also had very strict criteria for who they would transplant. So, over the six year time period, there was only 46 patients that were transplanted for severe acute alcoholic hepatitis. And so, they compared these 46 patients to 136 patients who were just transplanted for alcohol related cirrhosis. So, when they compared graft and patient survival at five years; they were actually the same between the two groups. So, graft survival was about 75% at five years and patient survival was about 80% at five years. And that was across both groups.

And so this helped us understand that these patients who got transplanted early without the typical six month of sobriety did just as well as those who had met that six months criteria end point. So, then as follow up to that, there was a prospective trial that was published in Gastroenterology in 2018 that was a large multicenter study using twelve transplant centers across the United States and so, over this time period 147 patients were transplanted for severe acute alcoholic hepatitis and they had follow up data up to three years for these patients. So, one year survival was 94% which is excellent and it’s higher than actually some of our other etiologies. Three year survival was 84%. So, this showed even further that these patients do very well after transplant and even if they did have some slip ups and did return to alcohol use; the centers were able to support those patients and help get them back on track and long term they did very well.

Host:  Well thank you for that data Dr. Gray. And Dr. Cannon, tell us a little bit about patient selection for whom is this an option and while you’re telling us this, speak about baseline characteristics, a few of them Dr. Gray mentioned but speak about those psychosocial profiles, and substance use history and family history. Tell us a little bit about patient selection.

Robert Cannon, MD (Guest):  Certainly. Well first of all, I guess there’s the need for an actual indication for transplant and I think Meagan touched on a lot of that with the severity of alcoholic hepatitis and then not improving on medical management. As much as we love to do transplants and provide them for people when they need them; I think it’s the biggest win whenever we can get a patient to not need a transplant at all and have them recover transplant free. But for those who do have a severe disease that does not improve with medical management; that’s when we really start our eval and really start digging into their psychosocial profile and sort of their history of their alcohol use disorder. And our selection really evolved. It used to be we followed what probably most other centers in the country follow which was just a hard and fast six month rule that you can’t have had any alcohol within the last six months prior to a transplant eval. But we sort of were never comfortable with this because we knew six months is not a magic number. There’s plenty of people who had a shorter sober interval who would do just fine and on the flip side, there’s plenty of people who have been sober for much longer who then go on to problematic alcohol relapse after transplant. So, we knew we could do better.

And what’s been really important to this protocol and to evaluation is we’ve got an outstanding addiction medicine team here at UAB who has really bought into this early on. And it’s really helpful rather than having a bunch of hepatologists and surgeons trying to play addiction medicine specialist, we actually have real professionals involved here who do this day in and day out for a living. And their input is crucial.

So, we evaluate. Essentially one, the patient has to express a lifelong commitment to abstinence from alcohol which will be evaluated by our addiction medicine team. and then we look at sort of some of the patterns. So, I think we’ll touch on this later but there are some prognostic scores to predict sustained alcohol use. So, how much they are drinking at the time of hospitalization. So, if they are drinking more than ten drinks a day; that is high risk. If they failed rehab multiple times in the past; that also makes a patient higher risk. Legal issues related to alcohol is a high risk pattern and then any other illicit substance abuse is also a higher risk pattern.

So, we’ll assess that, and social support is also very important. Transplant is difficult enough as it is, and no one can really do it on their own. And when you’re coping with an alcohol disorder on top of that, that’s often the support many of these patients seek is alcohol. That’s their coping mechanism. And if there’s no coping mechanism that they fall back on, that’s not alcohol; then asking them to go through a transplant is too much and that’s going to be a high risk patient. So, those are the sorts of things we assess and then we actually have the addiction medicine counselors join us in our weekly selection committee to discuss each patient and their individualized risk profile. And then at the end of the day, it comes down to full consensus by our transplant committee. So, everyone in the room has to agree that this is a patient that we think is a low risk for sustained alcohol use post-transplant.

And it we think that, then we’ll proceed even if they were drinking right up to the time of hospitalization which is the case in many of the times. If they come through these criteria, then we’re willing to give these patients a chance.

Host:  Well so, along those lines then, Dr. Gray, is it possible to define a group of patients that will do as well as other nonacute alcoholic hepatitis liver transplant recipients and will simple changes to the selection that Dr. Cannon was just discussing, will that improve outcomes further? Tell us about prognostic instruments used to predict future drinking after liver transplantation. This is such an interesting question.

Dr. Gray:  Accelerated Alcoholic Hepatitis Consortium was actually the group who did the prospective trial looking at transplanting severe alcoholic hepatitis across the country. So, that same group took that information that they found and looked back to see what criteria would make a patient high risk or low risk to develop sustained alcohol use after transplant. And so some of the criteria are what Dr. Cannon mentioned earlier. So, we use something called the SALT score. So, this stands for Sustained Alcohol Use Post Transplant. And there’s four items that it assesses. So, the first is more than ten drinks per day at initial hospitalization. And if that’s true, you get four points. The second is multiple prior rehabilitation attempts. If that’s the case, then you also get four points. The third is prior alcohol related legal issues which gets you two points and then the last is prior illicit substance abuse which give you one point.

So, if the total score after assessing all of those things is less than 5, then that has a 95% negative predictive value for sustained alcohol use post-transplant. So, in addition to the other assessments that we use, the addiction medicine team an dour social workers also use things like the AUDIT score to help assess alcohol abuse. But we really rely on this SALT score in addition to those things to help us predict who is low risk to resume drinking after transplant.

Host:  Dr. Cannon, give us some of the arguments you’ve heard against and in favor of liver transplantation for alcoholic hepatitis. What would you like other providers to take from this and when you’ve heard these arguments; what do you say about them?

Dr. Cannon:  Oh certainly Well I think the number one argument you hear both in the public and kind of in the professional media against this is that the ethical concern that you’re using a limited resource organ for someone who has caused their own disease if often the argument you hear made. When potentially people think it may be better served in someone who had no hand in their own disease. My argument for that really is that we’re not in the business of casting judgement on people whether they are at fault for their disease or not. We’re not interested in that. That’s not what we got into this for. But we are in the business of second chances. And that’s what we do.

And really, we look at alcohol as a disease like any other, just like hepatitis, just like NASH. That’s no alcoholic fatty liver disease is probably the fastest growing indication for liver transplant in the country. And in many centers, it is probably the number one indication for liver transplant. You can just as easily argue that it’s somewhat lifestyle related from obesity, diabetes, hypertension and the overall metabolic syndrome. So, I don’t think that the patients suffering from alcoholic liver disease really deserve the stigma any different than anybody else. And we aim to treat these patients the same as anybody else. They have a disease that certainly has a risk of relapse post-transplant and if we think that we can minimize that risk of relapse and have a good outcome then we will provide transplant for them just like we would with any other disease process.

The other argument is that many patients will actually get better if they stop drinking. Their liver function may recover to the point where they don’t need a liver transplant. And we certainly agree with that argument and I think we take every step possible to reassess patients minute by minute and day by day whether they still need a liver transplant. Even patients who have met those criteria, we have even gone so far as to have patients listed for transplant but then we started to see signs that they were recovering and we held off and actually turned down offers and we’ve had some patients who have gone through the whole protocol including being listed and they wound up recovering without transplant. So, I think I said that earlier, that’s always our goal in terms of that argument. I think we’re definitely quite aware that some patients will get better and we definitely give patients the opportunity to and are reserving transplant for those who truly need it.

Arguments in favor of transplant for this again, these are patients who can do just as well as those with any other disease. And I think they deserve a chance. And what I’d like other providers to know really, is I think often other providers when they are treating a patient with liver disease struggle with whether they think they are a liver transplant candidate or not and struggle with the decision on whether they think they need to refer the patients or not. And I would just want people to know that that’s not a decision that the referring doctors need to make. If they’ve got a patient who they think would benefit from or need a liver transplant and have significant liver disease; please send them our way. We’re happy to see them.

Not everyone may be a transplant candidate but at the very least, even if we think we can’t get someone to transplant, maybe their disease is to high risk, we can at least help by getting them in contact with addiction medicine to try and help them recover from their alcohol disease. So, please just send the patient, the burden of deciding whether someone should or can get a transplant really doesn’t need to be on those in the community. We’re happy to take that ourselves. That’s what we’re here to do.

Host:  What great points you just made there Dr. Cannon. So, tell us what addiction medicine support is available to these patients for better outcomes and while you’re telling us that, we don’t have a lot of time left, but tell us about how your outcomes have been.

Dr. Cannon:  Yeah, so addiction medicine is there with our patients every step of the way. They see them while they are in the hospital. Patients will participate in group counseling sessions even during their acute hospitalization during their hepatitis flares. They will see them post-transplant. They will come in by Zoom. They will be in with group meetings online. And then when the patients go home, for patients who are close by, they have the option to do rehabilitation programs with our own group at UAB and we can hook them up with AA or any other number of centers. And where addiction medicine is really great is, they just know all the resources available whatever community the patients live in and they can link them to treatment and counseling post-transplant.

And they stay involved from the day the patient comes into the hospital for their evaluation, all the way and follow them post-transplant. And we do check up on the patients after transplant every time we see them, we ask them about alcohol, have they gone back to it, how they are doing. We check a laboratory value called a PES test which tells us if there has been any heavy alcohol use in the preceding weeks leading up to that. So, we monitor the patients that way if there is any potential problem drinking that they are not telling us about we’ll know about it so we can hopefully intervene. So it doesn’t become a sustained problem for the patient.

Outcomes have been excellent. We’ve actually had some patients have some slips and drink some post-transplant just like in the data Dr. Gray mentioned earlier but we’ve had so sustained problem drinking in our patients transplanted sort of under this protocol. The patients we have had problem drinking with actually have been ones who have been sober for several years before but the ones under this protocol have really done well. We’ve had no graft losses. So, we keep a running total of our liver transplant patients and graft survival. We update it every month. And since 2019, which is around the time we instituted this protocol; our overall patient and graft survival at one year is 98%. So, I think we’re doing excellent with this and hope to continue to do more.

Host:  You certainly are. And as we wrap up, Dr. Gray, I’d like to give the last word to you here. What would you like other providers to take away from this program at UAB Medicine and tell us a little bit about that post-transplantation care that Dr. Cannon was just bringing up and what you’d like them to know about the importance of early referral and what you want the take home message to be.

Dr. Gray:  Yeah, I think I would say two big take aways from this. One, I would say that alcohol is a disease just like any other disease that we treat. And so, as Dr. Cannon mentioned, just treating the patient the best we can and providing the best medical care that we can including transplant are all very important things for these patients. And then the second thing I would say is that there’s no magic number about six months. And so, we really want to remove that from referring providers minds that they can’t refer someone until they are six months sober. A lot of these patients won’t make it that long and so we do want them to come and see us as soon as they develop severe liver disease so that we can assess them for transplant early and get them plugged in with our addiction medicine team for additional support.

And in the clinic, as Dr. Cannon said, we do have a multidisciplinary approach to help keep these patients on track. And we’ve been extremely pleased with our results so far. I would also mention that I think we are one of the few transplant centers transplanting these patients in the southeast and so, we’re definitely committed to making sure that they get excellent care and do very well after transplant. If there are any patients out there that fit this criteria, we’d be absolutely happy to see them.

Host:  Thank you so many Doctors, for joining us today and what a great topic. Thank you again. And a community physician can refer a patient to UAB Medicine by calling the MIST line at 1-800-UAB-MIST. And that concludes this episode of UAB Med Cast. To refer your patients or more information on resources available at UAB Medicine, please visit our website at www.uabmedicine.org/physician. Please also remember to subscribe, rate and review this podcast and all the other UAB Medicine podcasts. I’m Melanie Cole.