Kimberly A. Brown, MD

Any other things that you counsel your patients about? Certainly, medications can exacerbate hepatic encephalopathy. Do you go through their list in detail, and do you call out certain classes of medicines?

I do, particularly those patients who are taking any kind of narcotics. Oftentimes we struggle because those patients have often been on narcotics for a long period of time. Trying to work with their providers to see if there are alternatives and trying to help them understand that more narcotics are just not good. A dose of narcotics they may have been fine with 8 months ago may be too much for them now in terms of precipitating encephalopathy.

We try to avoid sleeping pills. I know it’s hard. You know, we tend to use the shortest-acting ones if we can—but recognizing that patients with liver disease don’t metabolize things well so they may have untoward effects from that. I think even with antidepressants, oftentimes doses might need to be adjusted in patients with advanced liver disease. Those are the biggest things.

I try to have them avoid supplements if they don’t know what’s in them because even though it’s over the counter, somehow patients think it’s safe. Oftentimes, it may not be safe, depending on what it is. I try to supplement vitamins in all of my patients, just a general multivitamin. And then, as you know, in patients who have more cholestatic liver disease or high bilirubin, they can become deficient in fat-soluble vitamins. I personally think that vitamin D is important. I know we’re not supposed to check it in all patients routinely, but I do check it in my patients with advanced liver disease. I think there’s lots of evidence that vitamin D, at least normal levels, are beneficial in patients for a variety of reasons. Those are the biggest things that I do.

People will often ask and probably ask you as well: What about milk thistle? Can I take it? What I tell them is that the studies that showed any benefit gave it in intravenous form for completely different reasons. So whether it works for their condition in oral form, I don’t really have an opinion, but I don’t think it’s harmful. Other things I think could potentially be harmful, but I think milk thistle is not harmful; but I’m not convinced it’s helpful.

That’s virtually identical to how I counsel my patients about milk thistle. But the other supplements for sure I try and dissuade them from, especially if it’s some sort of herbal supplement or multiple ingredients, because the last thing we want is some sort of liver toxicity on top of their end-stage liver disease. That would really be a bad combination.

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Hepatology experts discuss educating patients with hepatic encephalopathy on managing medications and supplements.

Counseling Patients on Managing Medication in HE

Is there a way that you educate your patients about [hepatic encephalopathy]? I find this to be challenging. Even for you and me today, it’s tough to talk through the pathophysiology. We kind of wave our hands and say we don’t fully understand it. How do you explain the conditions to your patients and why they should be taking those medications?

I have 40 minutes with a new patient. I would say 30 minutes is spent with a diagram talking about cirrhosis and portal hypertension because everything they experience is related to portal hypertension, including encephalopathy—so helping them understand sort of why these things are happening and then helping them understand how we try to mitigate those effects with sodium restriction, water pills, rifaximin, or variceal banding. So just trying to help them understand why it’s happening and then for each of those conditions, how best to manage it.

Yes, I feel the same way, and unfortunately, I’m not always able to…draw out a diagram for them, but I think it is extremely helpful when they can see a pictorial representation of portal hypertension and why these problems are happening. And when it comes to the medications themselves, do you counsel them about anything in particular? Certainly, too much lactulose would cause diarrhea, which is problematic. Do you tell them anything else so that you might improve their likelihood of staying on the medications?

I think the biggest point to try to get across is that this is not an intermittent treatment; it’s a preventative treatment. Sometimes patients walk away with a medication, and they think they’re only supposed to take it if X, Y, and Z happens—but in fact, we’re trying to prevent X, Y, and Z. So, it’s mostly adherence. With lactulose trying to really not be constipated, try to have those bowel movements every day, to take extra doses if they do become constipated, and to hold it if they get sick. We don’t want them to have ongoing diarrhea if they’re ill and losing fluids because that by itself can precipitate an event. And for rifaximin, making sure that they take it twice a day, don’t miss doses, and keep taking it to try to prevent those episodes.

And when you come across the patient who’s clearly adherent but has persistent or refractory hepatic encephalopathy, what do you do at that point? Do you conduct any further diagnostic work-up? Do you add on third-line therapies? What’s your approach?

I don’t think I have a third-line therapy, but what I do is I look for large shunts. So I will often either go back to their original cross-sectional image or repeat a cross-sectional image to look. I have had a handful of patients in whom we’ve been able to occlude very large shunts in their groin or elsewhere in the abdomen that has helped. So that’s really the next step for me. Hopefully, these patients are listed for transplantation. Unfortunately, as you know, you can’t get an exception for encephalopathy.

It’s interesting, having sat on the [Liver and Intestinal Organ Transplant Committee] , we talked about MELD [Model for End-Stage Liver Disease] exceptions and how we’ve standardized those. And really, if you look back at the philosophy, we’ve altered the way we’ve allowed exceptions based on mortality risk for the patient. I think moving forward, we’re going to see that there is a mortality difference in patients with recurrent encephalopathy. Hopefully those data can support MELD exceptions, but currently they don’t.

Right. I agree completely with you. This is such a stressful type of patient to manage. When you have that patient whom you know has brittle encephalopathy, they make you very nervous about their clinical course, particularly if their MELD score is low and if their access to transplant is low.

I also agree with imaging for spontaneous shunts as a cause of refractory encephalopathy. We found that although we’re getting MRIs usually every 6 months for HCC [hepatocellular carcinoma] screening, the radiologist is not always looking for shunts. We often have to look ourselves or ask them to revisit the images and see [whether] they can see a splenorenal shunt, for example, that we might embolize in a situation where the encephalopathy is really refractory and where we can tolerate some worsening of the portal hypertension.

Have you ever used BRTO [balloon‐occluded retrograde transvenous obliteration]?

I guess we have, but usually when there’s a combination of a bleeding problem and we find large shunts where the patient can benefit. I have not, that I can recall, used it exclusively for encephalopathy. Have you?

I thought about it in one patient. Unfortunately, that individual had an untoward event, so it was difficult to understand whether it would have been effective. But it does actually increase portal flow to the liver, so you might think it might lessen shunting. It’s just something that I’ve thought about in the past for these patients who have bad recurrent encephalopathy.

I think certainly as interventional radiologists become more comfortable with these advanced procedures, we’ll probably be utilizing them more and more than we have been traditionally. Especially if you can improve the usual flow through the liver. It has to benefit the patient in a number of ways that we might not see until after the fact.

Thinking holistically about these patients, nutrition is certainly important. Do you counsel them about nutrition? If so, what do you tell them, or…do you have a dietician or a nutritionist who’s involved?

Yeah, great points. We do have a dietician that sees all of our patients with liver disease. But one of the things that I’ve been saying for years—again, you and I were both at a meeting recently, and Jennifer Lai, MD, said out loud—eat 6 meals a day and especially the meal at night right before bed. What I do tell patients, all of my patients, is we all need glucose for our hearts and our brains. If we are not taking nutrition, our livers make it for us. And the building blocks for that are our muscle stores, those amino acids.

If it takes you and me a long period of time to move into a fasting state, it sometimes takes patients with advanced liver disease just a few hours. And so it’s critical, in my opinion, that they eat small meals throughout the day, and the most important one is that one at bedtime. In fact, we just saw some information that nighttime feedings were actually more beneficial than daytime feedings for patients with advanced liver disease. Now I don’t know exactly why that is, why night would be better than day, but I think the important point here is your longest period of fasting is going to be between bed and breakfast. So I do counsel all of my patients on that.

Certainly, sodium restriction is important. I try to help them understand how much salt they’re eating. The story that I tell is that if you’re a normal American, you’re eating about 7000 mg of salt a day. If you simply take away the saltshaker, it’s about 4000 mg. I’m asking them to get to 2000 mg, and they think that’s a big number. In some patients, in the absence of water pills, I can only get them to urinate about 600 mg out a day. So, I say do the math: You’re taking in 2000 mg, you’re peeing out 600 mg, so that means you’re going to retain salt and water every day. Water pills can only do so much. We talk about protein too. I try really hard to emphasize that protein should be taken in some form at every meal. People don’t know what protein is, so that’s where the dietitian is helpful.

Yes, I agree completely. These patients oftentimes find it difficult to eat large meals, they’re full of ascites, they’re taking lactulose, which doesn’t taste very good and bloats them, and they generally feel ill. And I think talking about what those small meals should consist of is important because usually they can only accommodate a small amount at a time. But if they’re doing that frequently and doing that before bedtime, you can offset at least some of this muscle breakdown, which is so deleterious in terms of encephalopathy, their overall trajectory, and—if they are going to become a transplant candidate—their ability to get through the surgery and recover in a timely manner after that major surgery.

Kimberly A. Brown, MD, shares approaches to educating patients on management of hepatic encephalopathy and the importance of medication adherence and nutrition.

Patient Education of HE

When we focus on patients who are going home from the hospital after an episode of OHE [overt hepatic encephalopathy], sometimes we’re not the first provider to see them. Sometimes they’re going to see their primary care provider first. Are there any tips or suggestions you would give them for when they’re managing a patient like this who’s clearly sick and has cirrhosis? Are there things they can do to assess them? Is there any comfort level you can give them when it comes to the HE [hepatic encephalopathy] therapies so that if they needed to provide a refill, they’d feel OK doing so?

There’s a lot to unpack with that. I just had a phone discussion about the disconnect between inpatient and outpatient. You’re at a big transplant center, and we’re a big transplant center. Many of the patients we start on these medications we’ve never seen before and may never see again. They get discharged to their primary care physician. There have been some data collected to suggest that the biggest reason individuals mark for not writing rifaximin is that they’re not the primary doctor responsible. So who’s responsible? We’re all responsible. I don’t think a primary care physician should avoid keeping a patient on medication in hopes that you or I is going to capture that patient, keep them on, or give them refills without seeing them.

The good news about rifaximin is that it’s very safe. That’s often the biggest concern that clinicians have when using a medication they’re not familiar with. Are they going to hurt someone? The answer is no; rifaximin is very safe. But that’s the struggle: making that connection from inpatient to outpatient. If I’ve written the prescription as an outpatient, they get refills, but once they get discharged, there’s a disconnect. We’ve started to think about ways we might be able to develop something like a cirrhosis toolbox to send to the primary care clinician with the patient to try to help them understand what’s going on, why they’re on these medications, and how important it is to stay on them.

We should emphasize how safe a medication rifaximin really is. If you’re not as familiar with it, sometimes there’s a question whether we be breeding antibiotic resistance. This is an antibiotic, so should there be a stop date on it? In reality, it’s a poorly absorbed or nonabsorbed antibiotic that we haven’t observed resistance issues with, and we’ve been using it on label for many years. Even in the studies, which were rigorous, discontinuing rifaximin for any adverse event was very rare and not any more frequent than with the placebo. It’s an uphill battle to get that message out, but it’s worth fighting so that every provider would feel comfortable prescribing these essential medications that could be the difference between a patient with decompensated cirrhosis not being readmitted shortly after their HE admission or being back in the hospital within a week or 2.

Expert hepatologists comment on primary care providers using rifaximin to manage and prevent episodes of hepatic encephalopathy.

Use of Rifaximin for Treatment of HE in Primary Care

Forrifaximin, the FDA-approved indication is preventing recurrent episodes of overt hepatic encephalopathy [HE]. For the audience, a pivotal trial in 2010 

 demonstrated that, by and large, patients who took both lactulose and rifaximin had substantial risk reduction in a breakthrough episode of overt hepatic encephalopathy and an HE-related hospitalization over 6 months. Do you find that to be true in your clinical practice? It’s been awhile since that study, and studies have continued to show that patients on dual therapy are less likely to have breakthrough episodes and be in the hospital. Is that your experience as well?

Absolutely. Rifaximin was 1 of the best tools that came about in my career for liver disease. It’s interesting to go back to that trial and think through why the FDA recommended what it did. It was because of how the trial was designed. The trial was designed where you had to have 2 episodes before you had it. If you think that through, that’s why. It’s to prevent recurrence after the initial episode. The way I’ve used it clinically is to move it forward. I don’t wait. I don’t place a patient on lactulose and then wait for another episode to occur. I’m often moving rifaximin forward, which wasn’t how the trial was designed, but it makes sense to me. Why would I wait for another episode when we know that the majority of patients on lactulose will have another episode? I move it forward and often discharge patients on both.

We do the same mainly because those recurrent episodes, especially if they lead to rehospitalization, are costly in terms of patient outcomes. The mortality is high for patients with decompensated cirrhosis who end up in the hospital. It can be 25% or so. Those who’ve been admitted with HE and are back within a month have much worse outcomes than those who can stay out of the hospital.

You’re right. To your point, the risk of death is much higher in patients who have readmission. The other thing that we don’t talk about much, because we don’t have a lot of data, is the long-term effect on the brain in patients who have recurrent episodes. It’s a little scary because this is a completely reversible phenomenon with transplant. But we’ve seen some data with MRI that changes of the brain seem to be permanent. Some testing in the post-transplant setting show that deficits remain. I worry that allowing a patient to have these severe recurrent episodes is not the best plan.

I agree.Beyond the hospitalization and the risk of mortality, the cumulative effect on their brain could be long-lasting cognitive decline—even if they get to a transplant, which is our hope for all patients in this situation.

Arun B. Jesudian, MD, and Kimberly A. Brown, MD, highlight clinical trial data of rifaximin for the treatment of hepatic encephalopathy.

Kimberly A. Brown, MD

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