Alan Bonder, MD, and Juan Pablo Arab, MD, on Alcohol-Related Liver Disease: Part 2

Drs Alan Bonder and Juan Pablo Arab wrap up their 2-part podcast with discussions of treatment for alcohol-related liver disease, including liver transplantation, and the importance of multidisciplinary care for treatment of ALD and alcohol use disorder.

Alan Bonder, MD, is assistant professor of medicine at Harvard University Medical School and medical director of liver transplantation at Beth Israel Deaconess Medical Center in Boston, Massachusetts. Juan Pablo Arab, MD, is associate professor of Medicine in the Division of Gastroenterology and the Department of Epidemiology and Biostatistics at the Schulich School of Medicine of Western University in London, Ontario, Canada.

TRANSCRIPT:

Dr Bonder:

My next question is, all those prescriptions and all this time that you spend with patients, do you have for example a multidisciplinary clinic, where you have hand to hand with an additional psychiatrist or basically are you handling all this prescriptions on your own and following those side effects and everything on your own?

Dr Arab:

So we are developing an ALD clinic. It has been challenging, because all the insurance issues on how to cover those things. I would say that the ideal scenario is having integrated clinics, where you will see the patient at the same day from a liver perspective and from an addiction perspective. Indeed there are some papers that have shown that a patient followed from an addiction standpoint in the same center where they are getting care for their pre-liver transplant assessment or post-liver transplant assessment, they have better outcomes.

We need to remember that alcohol stigma is not only the alcohol use disorder, it's also associated with other comorbidities, chronic pain, depression, anxiety, but also with social issues, such as many of these people are homeless or they don't have social support, they don't have access to transport. So having multiple visits sometimes is very difficult for these patients. We need to make things easier. In my practice I found that if I refer some of these patients to addiction medicine, can take months and sometimes you need to intervene in the right moment, because the patient is willing to change at that time point. So I try to start medication by myself and then my colleagues can help advising in the long-term plan, in the more behavioral therapy. But with the ALD medications, I try to start it myself.

Dr Bonder:

So what makes me to the next point, how about some patients who are coming fresh to the inpatient services, where they coming in with acute alcoholic hepatitis, they're very, very sick. Are you guys prescribing those medications on those patients coming in? If yes, what would be the right time? When do you decide when is again the right timing to start this anti ALD alcoholic use disorder medications for those type of patients?

Dr Arab:

Yeah, that's a great question and I think there is no evidence based answer for this, but what I do is I try to start it as depending on how sick they were. I mean if they have a very severe alcohol associated hepatitis MELD 40, it's probably not the right time. It was in the 20s and they are doing better, I try to prescribe before discharge. If not, I always do 1-week follow up after discharging all these patients and in the other patients I try to start the ALD medications at that time.

These medications are mainly good for reducing craving and maintaining abstinence. So when they are really sick, like MELD 40, they don't want to drink. So don't rush in trying to start this medication right away. It's fine if you do it before discharge or even after discharge. But my advice will be, put it very clear in the discharge summary, because if not, people will forget and usually the liver thing takes over and everyone forgets about the AUD part.

Dr Bonder:

We know there's a small group of patients that will really do poorly, that will actually go on to getting a liver transplant. Are you starting this type of medication on patients who already got a liver transplant? Or you rely on the psychiatry or other services or even therapy just before you start them after transplant?

Dr Arab:

Again, the most important part of the treatment is behavioral therapy and many of our patients going to liver transplant are not able to engage in behavioral therapy, because they have hepatic encephalopathy. And AUD medications with advanced liver disease, usually I try to avoid it; however, we assess this patient before transplant to have a plan in the post-transplant, because it is not the same that the patient that came with an episode of severe acute alcohol associated hepatitis, that has been drinking because he got divorced 3 months ago and never drank before, compared to a patient that has been drinking for 10 years and barely made it to transplant. That patient will have a much more severe alcohol use disorder and we need to have a plan on this patient.

And that's another important thing, that alcohol relapse is common after transplant, between 10, 30% even 50% in some studies. I will say it's 30%. How many of them will relapse in heavy alcohol drinking? it's around 10%. Alcohol relapse will happen. But alcohol relapse happen even in patients transplanted for other etiologies of liver disease. Yesterday I was seeing a patient that was transplanted for NASH like 3 months ago and was his birthday and he was drinking alcohol to his celebrate his birthday and I said, "You know that you can't drink alcohol?"

So we need to acknowledge that this is going to happen, but then we need to be able to identify the red flags, so which patients are at high risk of going back to heavy drinking? And we need to use that information not to punish the patient or decide who is worthy of a liver transplant, but we need to guide our therapy and our interventions. Maybe someone will need only pre-transplant addiction therapy. Maybe someone will need pre-transplant, post-transplant, mutual health peer support groups such as Alcoholic Anonymous, and pharmacotherapy. Maybe they will need all the armamentarium that we have in our clinic, but we need to identify risk. And there is where we are now trying to identify who are the high-risk patients. How we are going to deal with the ALD pre-, post-transplant? Sometimes the risk will be that high that precludes liver transplantation, but we need to be clear and identify that.

Dr Bonder:

And I think you bring up a great point that I think both of us should actually emphasize— the stigma of alcoholic liver disease. Alcohol use disorder is a chronic condition and I would say behave as any other chronic diseases such as high blood pressure or diabetes. I think the punishing is such a great word, Juan Pablo, that we should not be punishing our patients because they drink. So we need to find a way they understand their chronic disease and then how to deal with it in the future.

One more thing that I want to just emphasize, because again I know you just published a review paper in the New England Journal of Medicine and you went over about the inpatient treatment for acute alcoholic hepatitis, which also we just faced very regularly. I know there's a lot of medications in the past we used to use for example pentoxifylline. Can you comment a little bit what is useful today and should we only be emphasizing steroids? What should we really aiming for our treatments? And again for example, I think one more question I ask you, there's a lot of them, is are we doing the discriminative function, is it better to use males in other studies to compare them? So can you comment on all those things for us?

Dr Arab:

Those are I think the key questions regarding severe alcohol associated hepatitis. So the big trial published in New England Journal in 2015, the STOPAH trial, basically showed that pentoxifylline plus steroids is not better than steroids alone. And so pentoxifylline is no longer used. Then steroids, there was a trend on improving in mortality at 1 month, but increased the risk of infection, but was basically a negative trial. Then Alex Louvet from France published in Gastroenterology in 2018, a meta-analysis of all the studies and showed that steroids improve survival, but only at 1 month. So after those 2 studies was kind of okay, should we use steroids or not and in which patients? So the first question that we had was, okay, how we should identify these patients? So there is Glasgow alcoholic hepatitis score, is a ABIC score, it's the MELD score, it's the Maddrey score, which one we should be using?

So we did a study published in the red journal [American Journal of Gastroenterology] showing that MELD score is the best prognostic score for alcohol-associated hepatitis and the worst one is Maddrey. So the first message is that we should stop using Maddrey and start using MELD. It is available. We use it for assessment of patients for liver transplantation, is easily available.

But then the second question was, we thought maybe studies are different, because steroids are not for everyone versus no one. Maybe there is a subgroup of patients that benefit from steroids. How we can identify that subgroup of patients? And basically what we did was a global cohort study and we collected information from more than 3300 patients and we found that the sweet spot where the steroid has a maximum benefit, which we defined as at least 20 to 30% survival benefit, was with MELD score between 25 and 39.

So the patient less than 25 is probably too healthy to benefit from steroids. If it's more than 40, he's probably too sick to benefit from steroids. So it makes sense that those patients in the sweet spot are those who benefit most from the use of a steroids, and are those the patients that I use steroid.

I must say, though, that steroids is a very bad treatment. I mean the first trial was New England in 1972 and we are still using it and we don't know what we are doing. So we need better drugs and are at least a couple of clinical trials ongoing and we are probably going to have better drugs. But for now that's the sweet spot. Which is the contraindication for the use of a steroid? I would say that there are 2. Number one is infections and I would rephrase it and say unrecognized infection. Alex Louvet, again, showed in a paper in 2018 that if you identify and treat infections, you basically avoid the associated mortality. So basically it's not about having or not an infection, it's having an unrecognized infection. So what I do? Day zero I do blood culture, urine culture, CRP, everything to try to identify— chest x-ray—if they have infection. If they don't, I consider starting steroids after the 48 hours of the blood culture. There is no rush. So make sure that the patient is not infected. If the patient is infected, first treat infection, wait 2, 3 days until infection is under control and then you can start the steroids.

And the second one is upper GI bleeding. If you have an active ulcer bleeding, is probably wise not to put him on a steroids. The other one that has been referred as a contraindication is acute renal failure. But, this is not published, but reviewing the data from our cohort, we have patients on dialysis that received steroids and they still benefit from a steroid if they are within the therapeutic window.

Dr Bonder

This is great, because again I think looking back, we don't have a lot of data. The STOPAH trial was pretty significant. I think it changed what we thought about, for example, the pentoxifylline in the past. I mean if you look back the data, the acute kidney injury patient were basically, we were using pentoxifylline, because they actually in those older studies we were not able to use steroids. I think that's a good thing to understand from the new information.

So one more question and I think we can let you go. So what happens with those patients who are contraindicated to steroids? When would you basically say, okay, there's no infection, his MELD score is a lot more than 40. There's no other good treatments except transplant. When would you think about maybe giving a shot even if your MELD score is really high?

Dr Arab:

That’s a good question. Will depend on what else you have available. Sometimes you are in a transplant center and you are transplant program is doing transplant for severe AlcHep [alcohol-associated hepatitis] I would say that you can maybe avoid the steroids and go for transplant if the MELD is really, really high and the patient is really, really sick, because it's very unlikely that they are going to respond to steroids. If not, what I do is sometimes, I start steroids and do Lille score day 4 instead of day 7, to have an idea if they are responders or not to steroids. If they are not responders, well you have one more element for pushing for liver transplantation. And the other thing is clinical trials. I know that we don't have much now, but we have some, so sometimes clinical trials for patient that are not candidates for steroids or are non-responders to steroids, may be an option. Some promising data is coming from indeed the fecal microbiota transplantation trials and I think that could be an avenue that may be promising in the future, rescuing these patients.

Dr Bonder: Well that's a lot of information, Juan Pablo. We thank you again for all this information, your time and hopefully we can have you again here with maybe new information about alcohol and use disorder for the future.

Dr Arab: I'm happy to be here. Thank you very much for the invitation and I will be happy to be here again

REFERENCES:

https://pubmed.ncbi.nlm.nih.gov/36577100/

https://pubmed.ncbi.nlm.nih.gov/34725498/

https://pubmed.ncbi.nlm.nih.gov/34166722/