Navigating Acute Liver Failure in Children: The Latest Updates in Diagnosis and Treatment

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 back to another episode of Butts and Guts. I'm your host, Dr. Scott Steele, the president of Main Campus here at the Cleveland Clinic in beautiful Cleveland, Ohio. It's always nice to have a repeat guest to come back to Butts and Guts, and I'm very pleased to welcome back Dr. Mike Leonis, the medical director of pediatric liver transplantation here at the Cleveland Clinic Children's. Mike, welcome back to Butts and Guts.

Dr. Mike Leonis: Thank you.

Dr. Scott Steele: So, we're going to talk about acute liver failure diagnosis and treatment in pediatric patients, but for those that didn't hear your background back in 2022, give us a little bit about where'd you train, where you're from and how long you've been here at the Cleveland Clinic.

Dr. Mike Leonis: So I did the bulk of my education in St. Louis at Washington University and then pediatric residency at Primary Care Children's Hospital in Salt Lake City, and Pediatric GI fellowship at Cincinnati Children's, where I stayed on thereafter as a faculty member for about 18 years prior to coming here to Cleveland Clinic.

Dr. Scott Steele: Well, we're super excited to have you here. So again, we're going to talk a little bit about acute liver failure diagnosis, so can you start, share a little bit about what acute liver failure is at a very high level?

Dr. Mike Leonis: Yeah. So it's a state where the liver, for unexplained reasons, suddenly fails, and this is a very rare disease state. We see about, I'm going to say, six to eight cases a year here at the Cleveland Clinic, but it can affect all age groups, and the diagnoses that lead to acute liver failure vary depending on the age. Younger infants for example tend to have metabolic disorders or infectious etiologies that are most commonly seen. Older kids, it could be drug-induced toxicities, sometimes metabolic disorders or autoimmune phenomena. And unfortunately, the symptoms are pretty vague and nondescript, so you don't really realize that your liver is failing. You typically would just present with the symptoms of illness that many of us experienced, like malaise, vomiting, nausea, and so it really takes an astute primary care provider, your pediatrician or family practice doc, when they are screening you when you can present to them with an illness, that they get a comprehensive metabolic panel or a liver profile to assess the liver to look for signs of liver injury.

Dr. Scott Steele: I want to circle back to two things that you briefly mentioned right there. We know about alcohol or Tylenol or maybe even some viral infections that can cause adult liver failure, but can you dig in a little bit more about what causes pediatric liver failure? You mentioned some metabolic... What are you talking about? How do you generally clump these things together?

Dr. Mike Leonis: Yeah. So when you first present, we can't tell. 99% of the time, we cannot tell based on your history or symptomatology what the etiology is, so we have to take a shotgun approach and cover all of our bases because we need to know as quickly as possible, if possible, what is the diagnosis. So as I mentioned, the older kids tend to have drug-induced etiologies or autoimmune etiologies to account for most of the cases of acute liver failure, where the younger kids might have a metabolic process where they were born with a congenital defect in a metabolic pathway so they can't process nutrients correctly or they build up toxins because they're not able to clear toxins properly, metabolize properly in their liver. They build up toxins and kill the liver.

So we have a long list of labs that we have to do and that helps us narrow it down or rule out certain categories of diseases and rule in others as possible etiology. Sometimes the liver biopsy provides useful information, and about 30 to 40% of the time, we never establish a diagnosis in kids. That's called indeterminate acute liver failure, and that's an important distinction between what is seen in adults. It's very unusual for adults to have the indeterminate category left over. Usually, you can figure out the etiology or identify the cause in an adult patient. That category of indeterminate acute liver failure is of grave impact to us because their outcome tends to be worse, and that's an area of active investigation right now actually.

Dr. Scott Steele: So, you mentioned that some of the signs and symptoms might not be straightforward, but if I'm a parent at home listening to this, is there anything, malaise, I get all that, but anything, jaundice, anything that could be a sign or symptom that parents should look out for?

Dr. Mike Leonis: Certainly, if you ever see a child who wasn't previously jaundice, it's common to be jaundice in the newborn period so I don't want to alarm. The vast majority of those times, that's normal physiology for an infant. But outside of infancy, if you see jaundice at any point in time in anybody, in adult or a child that deserves immediate medical attention to us, unless it's previously known and already documented by the docs what the cause of that is. So altered mental status, slurred speech, excessive irritability outside of the norm, and that's a little difficult to assess in children, but decreased energy levels that are profound, not just, "Oh, I'm a little sleepy today." So that in conjunction with other symptoms should prompt evaluation by your primary care provider. And it's the combination of symptoms, but mostly labs, that are going to tell us whether or not the liver is in dire straits or not.

Dr. Scott Steele: Truth or myth, the causes of acute liver failure in infants can differ from those of toddlers and older children.

Dr. Mike Leonis: True, for sure. For example, infants are very, very, very unlikely to have a metabolic disorder called Wilson's disease as the cause for their acute liver failure. That's more common in the teenager, second or third decades of life. A little less likely to have a drug induced, certainly a self-induced drug induced acute liver failure like the Tylenol overdose that you mentioned earlier. But there is a lot of overlap. Metabolic processes can affect you at any age. Viral etiologies, even immune dysregulation phenomena can affect you at any age, so there are differences, but there's a lot of overlap.

Dr. Scott Steele: Let's go into a little bit about how these can be treated. So you've got a child or infant with acute liver failure. What do you do?

Dr. Mike Leonis: Yeah. There are a few causes of acute liver failure that we have anecdotes for or very effective treatments. The most common one that we're aware of is for acute Tylenol ingestion. There's an acetylcysteine that we can use and that's pretty darn effective. The vast majority of patients, if we catch them early enough, who present with acute Acetaminophen or Tylenol overdose, if we get them started on this medication, 95 to 98% of them are going to avoid dying or needing the liver transplant. Mushroom poisoning, there's an antidote for. Some of the autoimmune processes respond nicely to steroids, and we're learning increasingly, we think where there's an NIH study to investigate, that we're one of the sites for this study is to investigate in the determinant population whether the combination of high dose steroids and/or equine antibodies to neutralize the immune response might be effective.

But aside from that, it's supportive care, careful watching and waiting, and if the liver care team taking care of your child is especially concerned that you're heading in the wrong direction, we can offer liver transplantation, which is not ideal, but it certainly is used and it's going to save a good chunk of the patient's lives, again, as needed.

Very important if you have a very severe liver injury that your docs get you to a liver transplant center so that they can watch you, assess and they have time to assess before having to make that decision. Unfortunately, a lot of smaller care centers will wait till Friday night, so to speak, to get those patients off to us having taken care of them for three to four days, and that doesn't allow us very much time to get the kid transplanted if they need to be, or properly evaluated.

Dr. Scott Steele: So how can a parent be the best advocate for their child as they walk through this whole process?

Dr. Mike Leonis: I don't want the average parent out there to be especially worried about this. This is a rare, rare disease process, so if the kid is acting abnormal, normal parental instincts usually kick in, and even though maybe they already sought medical care on day one, if the kid's not acting right, take them back. So disease processes change day to day, and so the initial assessment may have been absolutely appropriate, but the kiddo could worsen the next day, and so you have to advocate in the sense that you're not just relying on the information you got or the opinion you got on day one. If you're not comfortable with how the kid's doing, take them back for reassessment the following day. Honestly, I think most physicians do the right thing. They do check their labs, the appropriate labs, and so parents just need to trust the physicians, and I trust that they're going to get good care in that regard.

Dr. Scott Steele: During our last conversation, you mentioned a lot of the research that had been happening, and specifically around biomarkers and testing these cells to identify and treat liver failure. Can you give us a little bit of an update to this?

Dr. Mike Leonis: Yeah. So I can't remember how many years ago, it was maybe two years ago that we talked. In that time, in particular in the indeterminate acute liver failure population, more research publications have come out to validate those initial suggestions that in this patient population, they have immune hyper activation, possibly triggered by a viral infection. And so we've got now additional studies looking at the elephant in multiple directions, we're all arriving at the same conclusion. So that is what has really reinforced for NIH the need for this multi-center study to look to see if immunomodulation or high-dose immunosuppression would be effective in that patient population. And so that's an ongoing study where we're year two or three in a five to six year process.

Dr. Scott Steele: We have always been told that the liver can regenerate or can really do its own thing to regrow, but has there been any notable changes in the long-term outlook of children diagnosed with acute liver failure? Is it the liver recovering from this? Is it what we do or is the liver actually remodeling, or what happens here?

Dr. Mike Leonis: So yes, the liver can regenerate itself, and in particular, it's very good at doing that if it has a mild insult. So we encounter drugs all the time that maybe irritate the liver a little bit, and so you get a mild injury that's transient. Or if you have chronic alcohol use is a good example, that every time you take a drink, you're probably injuring your liver a little bit but it's usually very good about recovering from that and regenerating itself. But when the insult sets the house on fire and leads to the point where the liver fails, that's when you get yourself in the trouble of an acute liver fire event, and it's no different than a house being on fire. Sometimes you can put it out with a fire hose, and sometimes you can't save the building.

Long-term, over the last 20 years, outcomes have improved, probably because we do a better job of monitoring in the intensive care unit. We have learned to be very comprehensive in our diagnostic workup not to go by the gray-haired, old man's presumptions that, "Oh, well, because of your age and gender, it's autoimmune and it can't therefore be viral." So by forcing caregivers to be comprehensive in their evaluations, we've diagnosed patients that previously wouldn't be diagnosed with Wilson's with autoimmune disorders, and so that's led to better care. And so there has been a trend over the last 20 years of a little bit less liver transplant and a little bit less death in this patient population.

Dr. Scott Steele: Are there any additional advancements that's on the horizon regarding either the diagnosis or the treatment of liver failure in pediatric patients?

Dr. Mike Leonis: Outside of the treatment studies that I've mentioned, there aren't more research proposals that I can think of. Diagnostically, we are increasingly using whole exome sequencing where you try to get a readout of the genome of the patient, the entire genome of the patient. If we put a rapid request on this, sometimes we can get that whole readout within a week, or if not a week, at least within three weeks so it can aid us afterwards. That has really helped a lot in picking up metabolic disorders. We recently picked up a kiddo that had an indeterminate acute liver failure and we identified that there was an immune dysregulation gene disorder in this kiddo, so that will help us in helping the siblings potentially and helping the family with family planning, and potentially, if the kid has recurrent autoimmune problems, maybe aid us in what immune suppression pathway to target the next time, so that's kind of new.

Dr. Scott Steele: That's awesome. So now it's time for our quick hitters, a chance to get to know you a little bit better. So number one, are you salt or sweet?

Dr. Mike Leonis: Salt.

Dr. Scott Steele: What's your next trip that you're planning on going to on the bucket list?

Dr. Mike Leonis: Either Africa or New Zealand.

Dr. Scott Steele: Fantastic. What was your first car?

Dr. Mike Leonis: Honda Accord.

Dr. Scott Steele: And finally, who is your favorite superhero?

Dr. Mike Leonis: Spider-Man.

Dr. Scott Steele: Nice. So final take-home message for our listeners regarding acute liver failure treatment and diagnosis in the PEDS population?

Dr. Mike Leonis: If you ever see that your child's jaundice, that's never normal. Always have that evaluated. If they're acting abnormal, their illness is outside of the spectrum of time that you would anticipate for a viral illness. Seek an opinion from a healthcare provider.

Dr. Scott Steele: Fantastic. 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 for joining us on Butts and Guts.

Dr. Mike Leonis: Thank you. It was my pleasure.

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