Liver experts finally agree on what acute-on-chronic liver failure is

Liver doctors from around the world have come to agree on a definition for a common and potentially fatal liver complication. Acute-on-chronic liver failure is what happens when someone with underlying liver disease has their condition exacerbated by an acute injury. In the U.S., that often looks like long-simmering cirrhosis suddenly worsened by alcohol or a viral infection. However, the condition was defined differently based on where patients were in the world, and some people struggled to understand how it was different from acute liver failure, which comes on rapidly without an underlying illness. “It was just so confusing that, even though inherently some people believed in the concept, they didn’t know what to do with it,” said Jasmohan Bajaj, a hepatologist and professor of internal medicine at Virginia Commonwealth University’s School of Medicine. That confusion would lead to patients’ treatment getting delayed, he said. In an attempt to solve the problem, experts from five liver societies across the world — plus pharmaceutical companies and regulators — gathered in Barcelona this May to create a unified definition. Now, in order to be diagnosed with ACLF, a patient must have a bilirubin level of at least 1.5, and an international normalized ratio, or INR, of at least 5. Bilirubin, a yellowish pigment leftover from broken-down red blood cells, cannot be processed if the liver is too damaged. INR is a marker of how well the blood clots with help from proteins made in the liver. If a patient has a high bilirubin and INR, providers can then assess any dysfunction they might have in the brain, kidneys, circulatory, or respiratory systems — also markers of liver failure. The group’s position paper, published in the journal Hepatology last month, also includes guidance on drug-induced liver injury, transplant, and clinical trial endpoints for pharma companies to use when developing treatments. “We can now move forward and focus on what the patient is there for: to get healed, get better,” Bajaj said. This interview has been edited for brevity and clarity. What was the need for the new ACLF definition? The need for it is massive, because patients are suffering with this condition that everyone has their own way of defining. And because every part of the world has their own way of defining this, there is no unified approach [for] newer therapies, endpoints for clinical trials, and patients who currently could benefit from existing therapies. The patients are different. The access to care is different. So, we wanted to make sure that we had a common thread, that it was globally representative, and more importantly, it was simple to remember. Why were there all of these different definitions? Part of it is related to the etiology of the disease. Places in East Asia have a lot of hepatitis B, where we have more alcohol, and more people who have cirrhosis to start with. Just to put it in context, acute liver failure is the rare situation in which someone’s liver was fine before, and some catastrophic thing happens. You have to draw the line with what is acute and acute-on-chronic liver failure, and sometimes that line is blurred. Why is that line important? Because at least in the U.S. and some Western countries, if you have acute liver failure, you get extra points to put you on the top of the liver transplant list. But if you have acute-on-chronic liver failure, no such thing happens [right now]. That is why it is very critical for us to define: Where is the line in the sand? Was there any notable disagreement about what direction you should go in, or what factors should be central to the definition? We all were driven by the fact that our patients are currently being underserved by our differences. There were some groups which said perhaps we could further subdivide it into people who have no decompensation cirrhosis versus decompensated cirrhosis. There were also things about immune dysfunction and gut failure that were not completely resolved and were left for a future time. But, by and large, the broad strokes about this were pretty much agreed upon. And what was especially exciting was we got input from the [U.S. Food and Drug Administration]. What did the FDA help you finalize? The FDA was, as always, very instructive because amongst the many groups that we had, one of them was clinical trial endpoints. They said, “This is not going to work. This may work for your local thing, but if you want to register an intervention, this is not going to be it.” Have you gotten any feedback yet from pharma companies? We got very good unofficial feedback from them. I think everyone is breathing a sigh of relief that at least now, we can move forward and come up with better ways to actually understand this condition, so that we can actually treat these patients better, develop therapies that can actually either prevent ACLF from progressing or mortality from improving, or at least lead them to a liver transplant before things become too late. This document is huge, and there are a lot of statements. Is there anything else you want to highlight? We benchmarked it to 30-day mortality across multiple consortia. So this was not based on consensus just because we like these cut-offs; we based it off of prior definitions, added twists to it, and then we saw whether this actually helped define 30-day mortality or not. The most immediate impact is for us to move forward, and now start diagnosing and treating these people better. The second impact would be actually to train, to inform colleagues that are not within the liver world, who still deal with a lot of patients. A majority of the countries and places do not have a hepatologist. They are dealing with GI people, hospital medicine, ER, critical care, or some other specialty. So the next step is to actually bring them on board, so that they are force amplifiers for this definition, and make sure that if someone reaches a very sick point, that they can actually be transferred very quickly to a liver transplant center. STAT’s coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies. Our financial supporters are not involved in any decisions about our journalism.