Improved Outcomes in the Management of Hepatic Encephalopathy - Episode 3
Arun B. Jesudian, MD: Thank you for joining us for this unique AJMC®, MD Magazine®, and Pharmacy Times Peer Exchange titled “Chronic Liver Disease and Improved Outcomes in the Management of Hepatic Encephalopathy.” Hepatic encephalopathy, or HE, is an important neuropsychiatric complication of chronic liver disease, or CLD, resulting in significant morbidity and mortality worldwide. New insights into the pathogenesis of HE and efforts at improving outcomes for patients have resulted in the development and implementation of effective treatment strategies and protocols. In this Peer Exchange® panel discussion, I’m joined by a group of highly esteemed colleagues to discuss the latest understanding of CLD and HE, including precipitants, prognostic factors, and evidence-based treatment protocols.
I am Dr. Arun Jesudian, and I’m an assistant professor of medicine and the director of Inpatient Liver Services at New York-Presbyterian Hospital/Weill Cornell Medicine.
Joining me for this panel discussion are: Dr. Elliot Tapper, an assistant professor in the Department of Medicine at the University of Michigan in Ann Arbor, Michigan; Dr. Steven Flamm, a professor of medicine and surgery in the Division of Hepatology at Northwestern University Feinberg School of Medicine in Chicago, Illinois; Dr. David Salerno, clinical pharmacy manager for liver transplantation at New York-Presbyterian Hospital/Weill Cornell Medicine in New York, New York.
Thank you for joining us. Let’s begin. For our first segment, I’d like to start by talking about chronic liver disease in general. Steve, if you wouldn’t mind, tell us a little bit about some of the causes, signs and symptoms of chronic liver disease.
Steven L. Flamm, MD: Thanks, Arun. Chronic liver disease is an increasingly important problem, not only in the United States but all over the world. In fact, chronic liver disease continues to increase. There are many different causes. Lay people and even health care providers sometimes think that alcohol is the only cause of chronic liver disease, and that’s wrong. Not to say that people who drink alcohol don’t get liver disease, because they certainly do, but there are many other causes of chronic liver disease. In the United States, I would call it an epidemic in terms of fatty liver infiltration or nonalcoholic steatohepatitis [NASH]. NASH is a leading cause of abnormal liver panels and even cirrhosis in a fraction of the patients, and it’s increasing dramatically; alcohol, as we mentioned; [and] chronic viral hepatitis, either hepatitis B or C.
There are autoimmune causes of chronic liver disease, several different ones. And, believe it or not, there are some congenital causes of chronic liver disease that actually don’t present with illness until patients are middle-aged or older. So there are many different causes of chronic liver disease. When a patient who has an abnormal liver panel or signs and symptoms of chronic liver disease presents for evaluation, we in the hepatology field have to do a full work-up, including blood testing, imaging, and sometimes liver biopsy to actually make a diagnosis and then implement a treatment plan to hopefully abrogate the natural history of the disease.
Arun B. Jesudian, MD: And you mentioned signs and symptoms. What are some of these complications that a patient with chronic liver disease can present with?
Steven L. Flamm, MD: It’s a great question, too, Arun. First of all, I must say, in my experience, the majority of patients who have chronic liver disease for many years have no symptoms at all. And this tricks the patients and it tricks even health-care providers. They get lulled into a false sense of security, somebody that has an abnormal liver panel, because they don’t feel poorly, that it’s okay and that it doesn’t warrant investigation, and that’s also wrong. Many of these diseases are very serious, and if you wait until patients become symptomatic, it’s often too late to reverse.
So asymptomatic patients with evidence of liver disease on blood testing, for instance, or imaging, should be investigated. But signs and symptoms, when they do present, many are very nonspecific; fatigue, itching. When I give a talk on chronic liver disease, I ask the audience who has fatigue, and everybody puts their hand up, and they don’t have chronic liver disease. So fatigue is another one that is sometimes difficult to pin down in liver disease, but those are some of the early signs and symptoms.
And then when patients get cirrhosis and start to develop complications of cirrhosis, which is when we worry about their mortality, these are patients that should have liver transplant evaluation if they’re candidates. They can develop water in their belly, ascites. They can develop edema, swelling in their legs, they can develop confusion—which we’re going to talk about at length in this discussion—hepatic encephalopathy. They can develop large veins in the esophagus, esophageal varices or gastric varices and bleed. There are many different signs and symptoms of advanced liver disease when they develop.
Arun B. Jesudian, MD: Great. And that type of patient, Elliot, [the] decompensated patient is the type who develops hepatic encephalopathy. Can you take us through the pathophysiology? What causes this condition in someone with decompensated liver disease?
Elliot B. Tapper, MD: Thanks for the question. Hepatic encephalopathy is branded as something that’s caused by high ammonia levels. I think that’s something that most practitioners are aware of, but in reality, the story is a little more complicated. So we know that our liver when it’s functioning well ought to handle ammonia, which is largely derived from the bacteria in our gut feasting on protein that we eat and converting amino acids into ammonia that ought to be metabolized in the liver. But in the setting of cirrhosis, portal hypertension, that ammonia can be delivered to the brain. In the brain, ammonia causes a host of abnormalities, including but not limited to, a dominant inhibitory signaling that is best seen in terms of the clinical sign of asterixis where a patient can’t hold a contraction as well as a variety of other signaling changes.
But the reason why ammonia is only part of the story is that you can be walking around with a high ammonia level in the setting of cirrhosis and have no symptoms of hepatic encephalopathy, and for that reason you have to consider a couple of other factors, which are relatively difficult to measure. One of the most important ones is the burden of inflammation. It turns out that at the same time that our gut is delivering ammonia to the brain, that same bacteria that’s causing it is also getting out into the blood. And that bacteria is causing inflammation in the peripheral circulation. The amount of inflammation that a given patient has affects how much ammonia can get into the brain.
It’s one of the reasons, and I think we should talk about this down the line, that things like infections can trigger hepatic encephalopathy. And when that ammonia gets into the brain, our brain tries to scramble and convert it into something [that] should seem a little less toxic. It converts it into glutamine. Glutamine wreaks its own havoc. The so-called ammonia hypothesis of hepatic encephalopathy has to be refined to include these highly variable differences in inflammation and glutamine. So the short answer is ammonia, but it’s far from the whole story.