Acute Liver Failure and Hepatic Encephalopathy

Arun B. Jesudian, MD: Before we move on to a really full discussion of chronic liver disease, we do see hepatic encephalopathy [HE] in some acute liver failure patients. Steve, can you tell us what is acute liver failure and why would that type of patient develop this condition, HE?

Steven L. Flamm, MD: Well, acute liver failure is a completely different entity than cirrhosis, and both of them have mental status changes that are very important. We call them both hepatic encephalopathy, but they have very different implications, and it is an important matter to discuss. Acute liver failure means not that you have an acute exacerbation of chronic liver disease, but that you don’t have any liver disease at the beginning, and suddenly your liver fails. This can be from acetaminophen toxicity, which is the leading cause in the United States of acute liver failure. Other medications can cause it. Viral hepatitis can cause it. It’s a relatively rare entity. Again, a normal liver that within days often fails. These patients have a very high mortality. They require very specialized care, often in an intensive care unit, and at a center that offers liver transplantation. And within the context of acute liver failure if it’s very progressive, patients can have mentation changes.

It is also associated with ammonia, as Elliot was just discussing with you, as chronic liver failure, cirrhosis-related hepatic encephalopathy does. But the one major difference in the two entities is when patients have acute liver failure and have high ammonia levels, they’re also at high risk for getting cerebral edema, swelling of the brain, which you very rarely get with hepatic encephalopathy in the setting of cirrhosis.

Now, cerebral edema has bad consequences, not surprisingly. You know, your brain is contained by your skull, and if your brain starts to swell, the brain can suffer herniation at the brain stem area and you die. And one of the leading causes of death in acute liver failure is cerebral edema and brain herniation. So patients with acute liver failure are monitored for this, often with scans and they’re treated specifically for this, and if there’s even a hint of it, that’s when liver transplantation is pursued. Very different from hepatic encephalopathy in the setting of cirrhosis, which is very common, which has a little bit of a different treatment paradigm and that which we will discuss in this session.

Arun B. Jesudian, MD: That’s clearly a very sick type of patient, one with acute liver failure. And commonly we see, transitioning back to chronic liver disease, patients with cirrhosis who get admitted to the hospital with an exacerbation of hepatic encephalopathy. So either it’s a new diagnosis or they’ve suddenly gotten worse. They come in confused. And we’re often teaching our trainees [that] what might have precipitated this event is probably one of the most important parts of evaluating a patient with worsened or new onset hepatic encephalopathy, again speaking about a [patient with] chronic liver disease. I just wanted to throw out some of these potential precipitants. If anybody feels like jumping in, talk about how that might make hepatic encephalopathy worse. A common one is GI [gastrointestinal] bleeding. These patients oftentimes have portal hypertension, varices, but also could bleed anywhere within their GI tract. Elliot, how would that make HE worse?

Elliot B. Tapper, MD: HE in the emergency [department] in the hospital is in many ways a biomarker that something is not right. And when it’s caused by bleeding, it’s actually a very interesting physiology. Our blood is filled with proteins, proteins like albumin and hemoglobin, which when exposed to our gut bacteria, they start to digest it. None of those proteins are particularly good for nutrition, and essentially it spills out into the blood, a massive load of glutamine, which our liver can’t handle, which the auxiliary mechanisms for glutamine handling are also overwhelmed by, and their only choice for those mechanisms are [the] kidneys. The kidney has no choice but to try to take care of that extra glutamine, and it splits it into ammonia. Patients who are at risk for hepatic encephalopathy are liable to present with HE when they’re overtly bleeding. When that person comes in with HE, you have to look for triggers; bleeding is one of those things you can’t miss.

Steven L. Flamm, MD: And to expound upon what Elliot just said, one important thing with bleeding is it’s upper GI bleeding only. Patients who have hematochezia from a lower source, from the colon, from a diverticular bleed, from anal/rectal varices, anything in the colon, they don’t get hepatic encephalopathy from that bleed. It has to be an upper GI bleed because you need the digestion of the blood in the small bowel to have what Elliot described. So, again, if people are coming in with encephalopathy and some hemorrhoidal bleeding, the hemorrhoidal bleeding is not the cause.

Arun B. Jesudian, MD: Great point because bleeding in cirrhosis, people oftentimes assume is an esophageal bleed, but we see everything, including hemorrhoids and lower GI sources.

Elliot B. Tapper, MD: That’s a key point and then carrying on that, bleeding is an important cause of intravascular volume depletion. But there’s many other reasons why patients could present dehydrated, for example, they’re frequently on diuretics or they’re not feeling well so they’re not taking in adequate fluid. And, therefore, dehydration or intravascular volume depletion is an important trigger of hepatic encephalopathy insofar as renal injury contributes to the risk of HE, and dehydration itself triggers some hormonal mechanisms that cause additional release of ammonia. So patients ought to receive hydration when they’re presenting with encephalopathy.

David M. Salerno, PharmD: Yes, I agree with Elliot. One of the first things I do when considering factors that precipitate episodes of HE is taking a look at the patient’s medication list when they came in. Looking at the different doses of the medicines trying to make a determination if the patient is on the appropriate dose of diuretics or are they having too many bowel movements per day from lactulose causing that hypovolemia, which is then precipitating this episode of HE.

Steven L. Flamm, MD: It’s very important. I do want to expound upon one thing. You mentioned this a little bit, Arun, but I think it’s very important for the viewers. In my long career of doing this and taking care of patients with chronic liver disease, I think one of the biggest mistakes with hepatic encephalopathy is not paying attention to the provocative factors or the precipitants. When people come with hepatic encephalopathy and when it’s correctly diagnosed, they all get treated with ammonia-reducing agents. People do that pretty routinely.

But one thing that’s overlooked I find is looking for the precipitating factors because most of the time there is one. And, if you don’t identify and reverse the precipitating factor, even if you get the patient better in the hospital with an ammonia-reducing agent and you send them home with the same precipitating factor from the hospital, they end up returning. And it turns into what would otherwise be an avoidable readmission. So you really have to look for these factors, which we’re going to talk more about now. It’s critically important. Identify them, correct them, in addition to using the ammonia-reducing agents. So very important, this part of care of patients with hepatic encephalopathy.

Arun B. Jesudian, MD: Absolutely.