Precipitants of Hepatic Encephalopathy

Arun B. Jesudian, MD: We’ve mentioned GI [gastrointestinal] bleeding, we’ve mentioned hypovolemia, dehydration. Elliot, before you alluded to infections [as] a problem in this population. How do those contribute to the symptoms of HE [hepatic encephalopathy]?

Elliot B. Tapper, MD: Carrying on with what we’re talking about, HE is often triggered by something. It’s a biomarker that something else is happening, and one of the key ways that you’ve served your patients well if you really want to save a life is that you search for that infection that could be instigating this episode. In particular, and you have done some excellent research on this topic, we are underutilizing diagnostic paracentesis to look for spontaneous bacterial peritonitis [SBP]. We can’t wait for someone to show up with a tender abdomen and fever. Often, encephalopathy is the presenting symptom of that infection. And, therefore, when a patient is showing up, particularly with HE and ascites, we have to look for that infection. We have to treat that infection in a timely fashion.

Steven L. Flamm, MD: And any infection, by the way, can precipitate HE. The liver-specific one is SBP. And Elliot’s exactly right, it’s missed. The mortality of SBP for the last 30 years is unchanged. It’s about 35%. So SBP is a serious problem, and the earlier you diagnose it, the better it is. And missing it because people don’t do diagnostic paracentesis when they have ascites and hepatic encephalopathy is a no-no. But urinary tract infections, cellulitis, which our patients get frequently because they have edema, aspiration pneumonia or pneumonia in general, all of these kinds of infections can precipitate hepatic encephalopathy. And it should be automatic when a patient presents with HE that you look for infection by doing blood cultures, a urine analysis, a chest x-ray, and a careful physical exam, and, of course, a diagnostic paracentesis if ascites is present.

David M. Salerno, PharmD: I agree with those points, and I think even if there’s any delay in obtaining a diagnostic paracentesis, that’s really when we need to administer antibiotics, because the mortality for these infections is so high.

Arun B. Jesudian, MD: We often talk within my hospital and I’m sure yours about the importance of the diagnostic paracentesis, if at all possible. Just to put this to rest because we get the question a lot, if a patient is thrombocytopenic or coagulopathic, is that diagnostic paracentesis safe? Do they need platelets and FFP [fresh frozen plasma] beforehand?

Elliot B. Tapper, MD: Thank you for bringing that up. There is no reason to be afraid of performing a diagnostic paracentesis in a patient with cirrhosis who has an elevated INR [international normalized ratio] or a decreased platelet count. I understand that their platelet count is lower, their INR is higher, but it simply does not mean the same as if someone was on Coumadin (warfarin). They are not more likely to bleed from their paracentesis. There’s a wealth of data behind that, and the overwhelming need to diagnose SBP in a timely fashion outweighs all other risks.

Steven L. Flamm, MD: There’s an artery that runs along the rectus muscle that you cannot hit. If you hit that artery when you do a paracentesis, whether the INR is normal or whether it’s high, you don’t have a good outcome. So you need to do a diagnostic paracentesis in the correct area, and if you do, as Elliot says, there absolutely are no contraindications based on thrombocytopenia and high INR. If the INR is 3 or 3.5, or the platelets are 12,000 or 8000, that’s different. But with the typical thrombocytopenia that you see or INR elevations, even in the 2 to 2.5 range, which is in almost every case, Elliot is right on target, do the paracentesis. It’s critical, and if you’re doing it in the right place, you won’t have any complications.

Arun B. Jesudian, MD: That’s a very important lesson. Just to round out these precipitants of HE, Dave, can you talk to us a little bit about when you go through that med [medication] list, are you looking for sedating type medications? Can that make HE worse?

David M. Salerno, PharmD: That’s an excellent question. There are so many things that when I’m reviewing a patient’s medication list that I’m looking for, items such as benzodiazepines or narcotics for patients that have chronic pain. Other things that most clinicians aren’t necessarily thinking about, things like proton pump inhibitors, have also been associated with episodes of hepatic encephalopathy. And then again, like we had mentioned before, looking at the diuretic regimen, looking at lactulose, and other things that we’re using, for hepatic encephalopathy.

Arun B. Jesudian, MD: Before we move on, because it’s such an important topic: precipitants, any others that we’ve forgotten? Any others that you look for when you’re evaluating a patient with HE?

Elliot B. Tapper, MD: I think there’s a couple of others. One that flies under the radar is sarcopenia. If you think about a patient with hepatic encephalopathy, they tend to look a certain way—temporal wasting. They give you that antecedent history of muscle loss, their pants are falling off, their belt is extra tight. And the reason for that is that ammonia is directly toxic to the muscle and on top of that, they’re more likely to be malnourished, they’re less likely to want to eat. But in the context of portal hypertension, muscle plays a critical role in handling ammonia. It comes at a price. Every molecule of ammonia that it eats up causes muscle degradation, but the progressively sarcopenic patient is more likely to present with encephalopathy.

Steven L. Flamm, MD: There are a few others, too, Arun. I’m glad you mentioned it. Some are common, some are not. Common, constipation. Constipation in the setting of severe liver disease can actually be related or correlated with bouts of encephalopathy sometimes, probably from bacteria that are in the colon and having more time for ammonia production and ammonia to seep into the portal vein blood and eventually get to the brain. Constipation that’s severe can be contributory, certainly. And then less common ones, portal vein thrombosis and/or the development of hepatocellular carcinoma, those are potential causes by worsening portal hypertension that can cause collateral formation and bypassing of the liver by toxins such as ammonia and then eventually causing hepatic encephalopathy by these toxins getting to the brain. A good imaging procedure is very important.

We didn’t talk about TIPS [transjugular intrahepatic portosystemic shunt]. In the setting of TIPS, hepatic encephalopathy is very common, too. You don’t always even need a precipitant in the setting of TIPS placement. So, if patients have TIPS in place, hepatic encephalopathy certainly shouldn’t be a surprise.

Arun B. Jesudian, MD: Because it’s such an important thing to know about, can you describe for the audience what is a TIPS stent briefly and why might one be inserted in a patient like this?

Steven L. Flamm, MD: TIPS stands for [transjugular] intrahepatic portosystemic shunt. And the goal is to basically put in a bypass circuit or a shunt that connects the portal vein, the incoming blood flow to the liver to the hepatic vein, the outgoing blood flow of the liver. And the interventional radiologists do this at sophisticated centers. They go through the right internal jugular vein and go down to the liver in the vein, and put this shunt, which is a straw about the size of my little finger right through the liver. And the idea is it decompresses the liver. It alleviates portal hypertension because blood now coming in the portal vein doesn’t run into a fibrotic liver that causes decreased blood flow through the liver. It now goes through the straw or through the shunt. That helps a number of problems, particularly refractory ascites or severe variceal bleeding, which is important in an appropriate patient. It shouldn’t, by the way, be done outside of those two indications for the most part.

But the consequences are if you do have toxins in the portal vein, ammonia being one, they now can go right through the shunt without any filtration by the liver, go out the back of the liver, and later go to the brain and cause hepatic encephalopathy. Now, these patients aren’t typically encephalopathic all the time. They have episodes of encephalopathy typically, and precipitating factors can be important here as well. But they may not. And encephalopathy is a common problem after TIPS and it can be a vexing one to manage.

Arun B. Jesudian, MD: Thank you.