Acute Liver Failure Diagnosis and Treatment in Pediatric Patients

Podcast Transcript

Dr. Scott Steele: Butts and Guts, a Cleveland Clinic podcast exploring your digestive and surgical health from end to end.

Hi again, everyone. Welcome to another episode of Butts and Guts. I'm your host, Scott Steele, the chair of colorectal surgery here at the Cleveland Clinic in beautiful Cleveland, Ohio. And we're super excited to have today Dr. Mike Leonis, who's the medical director of pediatric liver transplantation here at the Cleveland Clinic in Cleveland Clinic Children's. Mike, thanks so much for joining us on Butts and Guts.

Dr. Mike Leonis: You're welcome. I'm glad to be here.

Dr. Scott Steele: So, we're going to talk a little bit today about acute liver failure diagnosis and specifically the treatment in pediatric patients. But before we get to that, I want to, I always start off with knowing our guests a little bit better. So, tell us a little bit about yourself, where you're from, where did you train and how did it come to the point that you're here at the Cleveland Clinic?

Dr. Mike Leonis: So, I was born and raised in Las Vegas, so western boy. But after high school, I've spent the rest of my training and career in the Midwest primarily. I did my fellowship at Cincinnati Children's Hospital Medical Center and I stayed on faculty there for another 15 to 17 years before I took a position, a similar position to what I have here at the Children's Hospital of Alabama, Birmingham. That didn't work out for me. Being south was a different experience for my family and I. So, we decided to seek opportunities elsewhere on maybe perhaps we turn back to Ohio where we enjoyed family and friends so much. So, I knew some of the folks here at Cleveland Clinic and raised my hand and they had an opportunity, and that's how I ended up here.

Dr. Scott Steele: That's fantastic, and we're sure glad to have you here. So, let's jump right into it. So, at a very high level, what is acute liver failure and how common is it?

Dr. Mike Leonis: So, acute liver failure is a rare syndrome both in adults and in kids. And it's where out of the blue, usually, in a previously healthy individual, their liver develops an insult that leads to failure of the liver's capacity to function properly for the body. The livers like a biochemical factory for the body, does lots of things silently that we're usually not paying attention to. And so, it's not until it gets really sick that it usually screams and hollers and brings itself to our attention. That manifests in people; in humans, it's their eyes turning yellow. They may have excessive bleeding or bruising; they may get very lethargic. And often, parents will suspect that something's up and they'll think the kid or the adult has a viral-like illness. So, they'll go to the emergency room and it's the caregivers that realize, oh my gosh, there's something funky going on with the liver. Checking liver function is part of routine labs that often are obtained in the doctor's office or in the emergency room, but they're focused on this of course, if the kids are yellow or the patients are yellow.

And once you see that there is some liver dysfunction where the liver's not working normally, that really should raise the alarm bells, really draw the attention to the caregivers, the doctors, to watch that patient very closely because things can rapidly deteriorate. The patient may look great and, in kids in particular, they may look just fine, but if you got any hints of liver dysfunction, you got to watch them and repeat labs frequently. It's not unusual for us to check labs every eight hours, every 12 hours, and make sure things are heading in the right direction.

Dr. Scott Steele: It kind of is a part of this. You mentioned some of the symptoms that they may experience, but I'm sure that acute liver failure kind of can be a stand-alone or there's a categorization to it. So what are some of the causes and some of the risk factors for it? And again, is it a stand-alone thing where you just, hey, I got acute liver failure, or is it more of a manifestation of an underlying disease?

Dr. Mike Leonis: Unfortunately, there's hundreds, if not thousands, of reasons that you could have acute liver failure. There are some broad, large categories where maybe the largest percentage, and again the composition, the etiology is leading to acute liver failure, differ between children and adults. In adults, one of the largest categories is a drug inducing toxicity. For example, the most well-recognized is accidental overdose of acetaminophen and that large dose ingestion can basically nuke or kill the liver fairly quickly. Thankfully, there's an antidote for that, and most of the patients, if we catch them early enough, escape without needing a liver transplant.

Other large categories leading to acute liver failure could be a viral induced acute liver failure. That's fairly common in kids; an autoimmune triggered mechanism or an immune dysregulation where it's not quite our classic autoimmune presentation, but it's something wherein the immune system gets tricked and maybe triggered by a viral infection. And then afterwards, our immune system gets revved up so much that it can't turn itself off. And so, it leads to the immune system attacking the liver.

Other categories: there could be a metabolic disorder. That's fairly more common in kids than it would be in adults because a viral illness or some other serious event leads to unmasking of the metabolic disorder and, or say, if they're not feeding, they get themselves into a catabolic state, and that can lead to all sorts of metabolic perturbations. So, there's a long list of etiologies and that is part of the conundrum for us because the etiology matters and whether or not how we're going to manage that afterwards.

Some of the etiologies, there's treatments for. Outside of just standard routine treatment of taking care of the patient, there's sometimes specific anecdotes that can be used or specific therapies for some of these etiologies. And all the time, for all patients though, we're always sitting back us liver doctors trying to decide do we need to list this patient for liver transplant or is this something that their liver's going to recover on their own and we can spare them that life-changing surgical experience. If we know the etiology, that helps guide us a little bit.

Often, though, maybe 30 to 40 percent of the time we don't establish an etiology. So, that's called indeterminate acute liver failure. And when that occurs, we kind of nowadays in the last couple years have figured out that at least in children, a majority of those indeterminate acute liver failure patients have an immune dysregulation phenotype. And so, current ongoing studies in the United States are to establish whether or not if we treat those kids differently and maybe give them some immunotherapy, can we alter the clinical course for the indeterminate liver patients that have acute liver failure?

Dr. Scott Steele: So, you talked a little bit earlier about how the etiologies may be different or the causes, the underlying causes between adults and children. But, truth or myth, acute liver failure is defined the same way in children as compared to adults. Truth or myth?

Dr. Mike Leonis: So, the fairest answer to that is its myth. For decades, we didn't have great research in kids with acute liver failure. So, the pediatric world took their guidance from what was known in the adult GI field, hepatology field, where there were hundreds of patients that had been studied across the world. And, by definition, in the adult world, you have liver failure along with encephalopathy, along with mental status changes, severe lethargy, maybe even coma, you needed those mental status changes in order to call it acute liver failure. So, we, for decades, the 1970s, 80s, 90s, even early 2000s applied the same definitions to kids and realized, the pediatric hepatologists realized, we're not catching a large subset of the kids that go on to die. Some of them never develop encephalopathy.

So, when we gathered our consortium of institutions to begin to study pediatric acute liver failure, we broadened the definition just to capture all the sick patients and then to see what would happen with them when we followed them thereafter. And lo and behold, after we collected a 1,000 patients with an expanded definition where we'd looked at not just kids that had mental status changes, but even those with just liver dysfunction, but no mental status changes, the kids who had no mental status changes ended up having bad prognosis just almost to the same degree as those with the mental status changes, or at least at a high enough level that we knew that we needed to treat them as acute liver failure, as well. So we've expanded our definition to a greater degree than a greater universe of sick patients based on lab results and clinical features than what is commonly used in the adult world now.

Dr. Scott Steele: So, we're going to change directions now and talk a little bit about treatment. So, a couple of quick questions for you. So, you mentioned about listing for transplant versus other treatments. So, couple of questions. Number one, how important is early detection? And especially with this whole idea of you don't necessarily have to have mental status changes. And then number two, when do you go in, if they're turning a little yellow, a lot yellow, the itchiness, the other things? And then, just go into some treatment options that are available for some of the acute liver failure patients.

Dr. Mike Leonis: The first question, what criteria do you use and what should you do when the kids are coming in sick: I beat on the table with all my pediatric residents that any time they detect someone has liver injury by the elevated liver enzymes, which is commonly measured in the ER or the outpatient setting with routine blood labs, anytime you have elevated liver enzymes that's new for a patient, you got to track it serially and try to understand is it going up, is it getting high, is it coming down and improving on its own? And, if it's going up or it's staying elevated, you have to check liver function markers, which are not commonly checked in the emergency room. So, that means checking to make sure your blood's clotting okay, checking to make sure the bilirubin level isn't elevated.

If you ever get liver dysfunction tests that are abnormal, that is a red flag. You need to follow that closely daily, if not every other day, until you understand is it going up or going down. And always raise your hand and call a hepatologist to help along with you so they can follow that patient, Even if you're picking them up in a rural setting. Call us, we are happy to help over the phone and follow from a distance.

If you have liver dysfunction and they're sick, they've got other acute symptoms, they probably need to be admitted to the hospital, at least in the pediatric world that's our recommendation. And there, we will watch them closely and it avoids them not returning for follow up visits or follow up labs in the outpatient world. Sometimes that's challenging.

Dr. Scott Steele: And then just what are some of the treatment options that are available?

Dr. Mike Leonis: So, we mentioned the treatment option if we have evidence that it's acetaminophen overdose, that's pretty much the classic treatment. For mushroom poisoning, a certain type of poisonous mushrooms out there - if you go pick your own mushrooms in the fields, we kind of recommend you don't do that unless you are expert at this. There is a relatively hard to obtain, but obtainable, antidote for one of the mushroom populations that can cause acute liver failure. For some of the metabolic disorders, just specific medicines that are anecdotes, like Tyrosinemia. These are not things that emergency rooms are going to diagnose. You'd have to be under the care of a multidisciplinary team to figure this one out.

And some of the immune disorders respond to steroids. For example, there are one or two viruses that have treatments, herpes acute liver failure, we will treat with a medicine called acyclovir. Aside from that, there's not really very good specific therapies and otherwise it's routine supportive care, which often involves patients being in the intensive care unit, where we're monitoring kidney function, lung function, cardiac function, because although you typically might start off with an acute liver injury, it can spread and become a multiple organ dysfunction problem very quickly.

Dr. Scott Steele: So how often can you get these patients back and have full recovery? And how often does it get to the point where either there's death or you got to list for transplant? What does that look like, the outcomes?

Dr. Mike Leonis: I wish I had great data on that. I know the numbers of patients that end up getting liver transplant, but what we don't know is what would happen to the patients that we didn't pull the trigger on. Once we pull the trigger, we're changing the natural history, and so we don't have great data on large numbers of kids before the era of liver transplant to know what happens in the universe of patients if you just left all those etiologies play itself out. Nowadays, roughly probably two-thirds of the patients are able to recover on, and I'm talking about kids primarily now, are able to recover on their own without needing a liver transplant. There's probably a subset of patients that we should have transplanted who ended up dying. And clearly, there's a subset of patients that we ended up transplanting who probably would've survived on their own, but we were too worried and we didn't want to; we felt like we were playing with fire and we couldn't take the gamble of losing that child.

So, we tend to hold off on listing someone for liver transplant unless they start to have some mental status changes. Because until then, until the things worsen to the point where that starts to occur, we are hedging our bet and hoping that they will recover on their own. But, as I mentioned earlier, there are some kids, maybe 5 percent of kids with no mental status changes who ended up dying. So, it's a very frustrating condition to be handed. And the information like what the last point I just made is why there is still going to be a little bit more tendency to be conservative and list the kid sooner than later.

Dr. Scott Steele: So, can you talk about any advancements that are either occurring now or on the horizon for acute liver failure treatments, specifically in children?

Dr. Mike Leonis: Yeah, in fact, I alluded to this already, it is because of research that was implemented on this by this consortium of pediatric hepatologists within the last 10 years on the indeterminate population of patients that we learned from looking at biomarkers and looking at the liver tissue of these patients that they have an expansion of a certain type of immune cell in their liver tissue and in peripheral blood markers based on lab tests that tell us that their immune system is hyperactivated. And normally, you don't get that degree of hyperactivation. It's a certain immune cell called a CD8 cell and usually those CD8 cells aren't as hyperactivated. In other causes of liver failure, like metabolic induced acute liver failure or acetaminophen-induced acute liver failure, we don't see those immune activation markers show up.

So, because that immune activation is present in a large percentage of the patients with indeterminate acute liver failure, that is preliminary evidence, strong preliminary evidence, for us that the next best thing to do in this patient population is to hit them with an immunosuppressive agent to keep those CD8 cells quiet. So, that's why people are testing right now, and I'm hopeful it'll turn out to be effective - is to hit them with steroids or IBIG. And if that's doesn't work, we might have to get more specific and target by immunotherapy those CD8 cells.

Dr. Scott Steele: Well, now it's time for our quick hitters where we get to know our guests a little bit better. So first of all, what's your favorite food?

Dr. Mike Leonis: By far and away pizza.

Dr. Scott Steele: Fantastic. And what's your favorite sport to play and to watch?

Dr. Mike Leonis: Oh my goodness. I'm not an active sports player, but I love watching soccer.

Dr. Scott Steele: Fantastic. And tell me a place that you would say recommend high that you really enjoy traveling to?

Dr. Mike Leonis: The most frequent place I've traveled and where I dream of keep returning to is Greece. That's where my family's from. And so, I have relatives, and of course, I love the geography.

Dr. Scott Steele: Is there a specific island you would recommend?

Dr. Mike Leonis: Of course. Crete.

Dr. Scott Steele: Yeah, I've heard nothing but great things about Crete. And then finally, you obviously you've been around, as you said, you're a West Coast boy and then kind of Midwest then down South and back up here. So, tell us something that you enjoy about Northeast Ohio.

Dr. Mike Leonis: Believe it or not, I enjoy the weather. The last two summers have been the nicest summers of my life, and I'm used to either really dry and excoriating heat or really hot and excessive humidity. And, I just cannot believe that I went through 120 days of summer with only like two or three days meeting any of those bad criteria. So, the summers are absolutely spectacular in my book. I'm a gardener, I'm an outdoors person for hiking and things like that with my wife. And so that's perfect. And we love the snow, so it's not excessive snow like maybe upstate New York or Minnesota or Wisconsin. So, we don't mind a few additional inches then what they might get in the South of Southern Ohio.

Dr. Scott Steele: Fantastic. And so, give us a final take home message regarding this acute liver failure diagnosis and treatment in pediatric patients.

Dr. Mike Leonis: I think the most important take home message for physicians, parents out there, is anytime you detect abnormal liver injury, please assess liver function. And please feel free to call a hepatologist so we can help you decide on the pace and tenor of follow up management.

Dr. Scott Steele: Fantastic, and great words. And so, for more information about Cleveland Clinic Children's Gastroenterology, Hepatology and Nutrition Department, please visit clevelandclinicchildrens.org/gi. That's clevelandclinicchildrens.org/gi. You can also call us at 216 444-5437. That's 216 444-5437. Mike, thanks so much for joining us on Butts and Guts.

Dr. Mike Leonis: You're welcome. It was fun.

Dr. Scott Steele: That wraps things up here at Cleveland Clinic. Until next time, thanks for listening to Butts and Guts.