Melanie Cole, MS (Host): Welcome to the podcast series from the specialists at Penn Medicine. I'm Melanie Cole. And today, we're talking about alcohol-related diseases. Joining me is Dr. Jonathan Nahas. He's a transplant hepatologist in the Division of Gastroenterology and Hepatology, and he's an Assistant Professor of Clinical Medicine at Penn Medicine.

Dr. Nahas, it's a pleasure to have you join us today. Can you start by giving us a little working definition of the umbrella of alcohol-associated liver diseases? What's the spectrum of these?

Dr. Jon Nahas: It's a very important question, and thanks for having me today, Melanie. Alcohol-associated liver disease comes in a lot of different distinct forms and exists on a bit of a spectrum. So, among anyone who's a heavy drinker, in as little as a couple of weeks, nearly all of those people will develop some degree of steatosis or fat in the liver.

With abstinence, over a course of a month or two, this sort of simple steatosis or fat can be reversible, and people can go on to have normal livers. However, with continued alcohol use and exposure, about 30% of heavy drinkers will go on to develop more severe forms of alcohol-associated liver disease, namely things like steatohepatitis or inflammation related to the fat or fibrosis or scarring in the liver. Up to 20% of those will go on to develop cirrhosis or the most advanced form of scarring in the liver. And those people are at risk of severe outcomes related to their liver disease, things like liver failure, death, liver cancer.

One of the unique features of alcohol-associated liver disease is that with abstinence, people can actually allow their livers to recover and heal. For people with more advanced forms of scarring, we tend to think that this can take years, decades. Some of the earlier forms though are reversible with even shorter durations of time. When we're dealing with someone with alcohol-associated liver disease, we're really trying to target the cause of their liver disease, the alcohol, and do everything we can to avoid it and reverse the damage that's been done.

There's a unique clinical syndrome called alcohol-associated hepatitis that is an acute-on-chronic liver failure that can occur in people really anywhere on that spectrum. We know, though, among those with alcohol-associated hepatitis, the vast majority will have underlying cirrhosis. So even if they recover from their acute episode, their underlying liver function is significantly impaired.

Melanie Cole, MS: The burden of these diseases and the U.S. patients and on the U.S. Healthcare system, please speak about that and the trends that you've seen. So, have you seen more of this going on now?

Dr. Jon Nahas: In the U.S., we think that maybe about 10-15% of the U.S. population has an underlying alcohol use disorder. Among those, a fraction will go on to develop alcohol-associated liver disease. We think that prevalence estimates of alcohol-associated liver disease are anywhere from 1% to 2%, up to 8% of the U.S. population. So, it's a major issue. We also think that those numbers may actually be underestimates due to issues like underreporting alcohol use or patients actually not being able to obtain a diagnosis and not necessarily engaging with medical care.

Alcohol-associated liver disease actually drives more than half of the cirrhosis-related mortality worldwide and in the US, and the numbers are on the rise. So, costs of alcohol-associated liver disease are expected to more than double in the next 15 to 20 years. And a lot of this has been sparked by the COVID pandemic. So, alcohol-associated liver disease was on the rise prior to COVID, but that really sort of lit a match that has sort of sparked dramatic escalations in rates of alcohol-associated liver disease and some of those more severe forms, such as alcohol-associated hepatitis or alcohol-associated cirrhosis.

The numbers have picked up since the COVID pandemic, and they haven't really returned to their previous kind of trajectory, where they're sort of leveling out as a high level that we're still seeing many more patients come in that were not previously presenting to care. In this context, alcohol-associated liver disease has become actually the leading indication for liver transplant in this country, and is only continuing to increase.

Some of the unique sort of features of it are that we're seeing disproportionate effects in certain groups. The ones that we're seeing kind of the most effects on are the young, that is people under the age of 35, women and Hispanics. Not only increases in alcohol-associated liver disease, but again, some of those severe forms of alcohol-associated liver disease and specifically mortality that are increasing exponentially in these groups. So, it's something that has continued to rise, we're seeing more of it, and it's not leveling off, unfortunately.

Melanie Cole, MS: How is someone diagnosed with ALD? How is their disease monitored? What first sends them to primary care or to see a hepatologist?

Dr. Jon Nahas: It's something that we're trying to create more awareness of in the broader medical community. Oftentimes these patients will maybe have some elevated liver tests on routine blood tests, specifically the AST tends to be the sort of increased marker that will show that maybe someone's at risk of alcohol-related liver disease. Maybe someone has some abdominal pain and they get a ultrasound of their abdomen, and it shows that they have some steatosis or fat in the liver. Oftentimes those are some of the first signs. And then, what's really important about making the diagnosis is taking a thorough history for alcohol use.

So, once someone has elevated liver tests or some steatosis, doing a thorough assessment of harmful alcohol use using things like validated questionnaires such as the AUDIT or AUDIT-C, the CAGE score, using even the DSM criteria for alcohol use disorder to see who are those folks who are at high risk of harmful alcohol use or increased alcohol use disorder.

Once that happens, then we try to obtain a little bit more information and often that's when they come to see a hepatologist. So, we can use different blood tests, like biomarkers that can assess how much alcohol a person's been using in recent history. One that we use commonly is called the PEth test or phosphatidylethanol. This is a blood test that we tend to think is like a hemoglobin A1C for alcohol use. It can detect regular consistent alcohol use over the last four weeks or so, and can identify maybe those patients who are under reporting or useful as a tracker to see if someone's been able to maintain abstinence after a diagnosis.

Other things that we'll do to assess their liver disease is look for measures of fibrosis or scarring to try to stage them. Given the alcohol-associated liver disease, like any other liver disease, exists on a spectrum, we try to figure out where someone falls from that cascade of either steatosis, steatohepatitis, fibrosis, cirrhosis, and we can figure out where someone is on that. So, doing tests like a transient elastography, or an ultrasound elastography. These are non-invasive tests that can assess someone's fibrosis stage without having to do something like a biopsy. There's also blood-based tests that utilize some routinely available laboratory parameters, things like liver tests, AST and ALT, platelets.

Something called the FIB4 that can assess someone's risk of having really no significant fibrosis or be at a high risk of advanced fibrosis. So these are some easy, widely available tools that we use to try to figure out where a person falls on that ALD spectrum. One of the challenges though is that many of these patients with ALD are often diagnosed in the later stages, oftentimes when they present with severe forms such as Alcohol-associated hepatitis or even decompensated cirrhosis, partly due to the stigma around patients with alcohol use disorder, and also because oftentimes these patients aren't necessarily presenting to care earlier on and getting some of these routine biomarkers checked.

Melanie Cole, MS: As we speak about ideal management strategy for patients with ALD, how do these strategies vary for individuals with alcohol-associated hepatitis and cirrhosis? And you mentioned the different patient populations. So, how does that differ in treatment management strategies?

Dr. Jon Nahas: I think this is really kind of the essential point of managing these patients. We're dealing with two diagnoses. So certainly, as a hepatologist, I'm focused on their liver and their alcohol-associated liver disease. But we can't ignore that most of these patients have a comorbid mental health diagnosis, alcohol use disorder. And if we focus only on the liver, we're missing a huge portion of what's going to drive their long term outcomes.

So, we know that in these patients, we have to utilize strategies that will both manage, monitor, and treat their liver, but also the AUD. Something as simple as a brief intervention, talking about the harms that their alcohol is doing, things like motivational interviewing, oftentimes even pharmacotherapy or medications for alcohol use disorder, and also referral to treatment professionals, addiction specialists, psychiatrists, therapists, someone who can be more dedicated in dealing with their AUD has to be a part of the treatment strategy.

As more data has been accumulated and time has gone on, we've learned that medications for alcohol use disorder, specifically things like naltrexone, acamprosate, both of which are FDA approved, are not only safe, but effective in patients with liver disease and cirrhosis. And these are things that as hepatologists are actually becoming part of our treatment strategy that, as you said, it's a really exciting time because we're branching out from our usual sort of liver disease-focused management and thinking about their AUD and oftentimes becoming the go-to provider to treat both of these diseases.

Another thing that we've learned over time is that integrated multidisciplinary care can actually benefit patients in multiple domains. So, multidisciplinary care models that address both their ALD and AUD have been shown to not only decrease alcohol use, but it can decrease hospitalizations, improve survival, and really help these patients in the long term.

At Penn, we've been lucky enough to actually start a multidisciplinary, fully integrated, co-located clinic, with our transplant psychiatrists, social workers, mental health providers, and even our outpatient relapse prevention program called Total Recovery. Our clinic is called the iLearn Multidisciplinary AUD/ALD Care. And we take care of patients in all phases of liver disease in the transplant pathway. So, pre-transplant people who are undergoing an evaluation through the transplant and all the way to sort of consolidate their post-transplant care. And this has been something that we've found to be widely successful in helping patients achieve abstinence and do well in the long-term.

In patients who have more severe forms of alcohol-associated liver disease, things like alcohol-associated hepatitis or alcohol-associated cirrhosis, it's really a pressing need to try to make sure that we do everything we can to achieve abstinence and maintain that. We also know that abstinence might not be a realistic endpoint in everyone. So, trying to use harm reduction to even reduce heavy drinking and get patients to stabilize their liver disease becomes a focus.

And with these patients who have the more advanced forms, we know that time might be short and continued drinking in these settings of underlying advanced forms of ALD, like alcohol-associated hepatitis or cirrhosis, has a high association with negative outcomes, specifically those that are liver related. And that's when sort of the urgency is really high.

Melanie Cole, MS: Well, then, along those lines, what's the criteria? Speak about patient selection for liver transplant and how this has changed. How do we look at this differently now for patients with ALD? And how are you managing those comorbid conditions while they're on the wait list? What's different now when someone has ALD versus non-alcoholic fatty liver disease?

Dr. Jon Nahas: Yeah. And this is a really exciting time in the world of liver disease and ALD. Historically, transplants for Alcohol-associated liver disease have been done since the early days of liver transplant, since the 1960s, 1980s, and in an era where there really weren't any robust psychosocial evaluations and assessments of sobriety and relapse risk. In the 1980s or 1990s, the paradigm shifted to say that patients with recent alcohol use were not eligible for liver transplant. And many centers and insurance companies adopted what was termed sort of the six-month rule, where patients who'd had recent alcohol use were ineligible for transplant before six months of sobriety.

The problem is that patients with alcohol-associated hepatitis actually have a six-month mortality up to 70%. So, many of these folks weren't making it to that six-month metric to be eligible for a transplant. We also know that even among patients with six months of abstinence, about 15-20% of those will relapse and go on to return to drinking. So, there had to be a better system to assess the risks and allow certain patients to make it to transplant without sort of leaving them hanging.

About 15 years ago, there was a landmark publication that came out of the New England Journal that looked at what was deemed sort of early liver transplant or transplant without a pre-specified period of sobriety and found that patients who were transplanted in this manner. could actually do well over the long term with great rates of survival and also relatively low relapse rates that were not all that different from those patients who previously had been abstinent for six months.

So, this was a revolution in the field of liver transplant for ALD and was adopted at other centers across the world, specifically in the U.S. and right here at Penn. So, some of the things that need to be achieved for a person to actually be a liver candidate on that index admission is a very extensive and thorough psychosocial assessment.

An important thing to keep in mind is of those patients who are in the hospital with alcohol-associated hepatitis being evaluated for transplant, only a small fraction of them are suitable transplant candidates on that admission. So, we're talking maybe around 10%. This was documented on that initial study and has been since sort of replicated in other assessments and reviews, as it's been more widely adopted.

So for someone to be a transplant candidate on that index hospitalization with recent alcohol use, they have to meet a certain set of parameters. Things like this has to be sort of their first presentation for liver disease, what we deem their first liver decompensating event. They can't have had prior hospitalizations for things like jaundice, encephalopathy, bleeding, ascites, and return to drinking. They have to have good insight into their disease and a commitment to lifelong sobriety. They have to be willing to engage with a relapse prevention program after discharge. They have to have strong social support, and they have to have agreement by most of the medical team that's taking care of them, from the hepatologists, the surgeons, the social workers, the transplant psychiatrists, in the process of a very thorough evaluation.

So of those patients that are eligible for transplant and meet this criteria, again, only about maybe 10 or so percent of those evaluated, we found that they can do really well. And those patients can be maintained with the good abstinence support after transplant and many of them do not return to drinking and can live long healthy lives.

Melanie Cole, MS: As we wrap up, please let other providers know what you would like the key messages to be about alcohol-associated liver diseases, the work that you're doing, that multidisciplinary approach at Penn Medicine.

Dr. Jon Nahas: I think the important things to keep in mind are, one, that this is a really common liver disease that if we're not thinking about it and asking the questions. There's no sort of surrogate test that we can use on the blood to make this diagnosis. And it involves a thorough history and assessment. It's also something that we're seeing more and more of. And when treating these patients, remember, we have to deal with both diagnoses, so both their liver disease and their alcohol use disorder. And if we can successfully manage both of them, that gives the patient the best chance of a good long-term outcome.

Melanie Cole, MS: Thank you so much, Dr. Nahas, for joining us today and sharing your incredible expertise for other providers. And to refer your patient to Dr. Nahas at Penn Medicine, please call our 24/7 provider-only line at 877-937-PENN, or you can submit your referral via our secure online referral form by visiting our website at pennmedicine.org/referyourpatient. I'm Melanie Cole. Thanks so much for joining us today.