Updates in the Management of Alagille Syndrome - Episode 10
Jennifer M. Vittorio, MD, leads a discussion on initial treatment approaches and new drugs on the horizon for the management of persistent pruritus in patients with Alagille syndrome.
William F. Balistreri, MD: Let’s make the move toward the problem that we’re hoping to be able to solve: persistent pruritus. We could divide it into the old approach, the standard approach, or the initial approach—perhaps that’s the best way to look at it—and some of the pros and cons, then we can maybe see what’s new on the horizon. Jennifer, you can lead off. Tell us what we traditionally do for these patients. You already mentioned [biliary] diversions. Let’s go into all of that.
Jennifer M. Vittorio, MD: Sure. Pruritus is probably [one of] the more frustrating symptoms or complications of Alagille syndrome that we encounter. Historically, there were 3 different options in terms of treatments. One would be pharmacologic therapies. Another would be surgical intervention, such as partial external biliary diversions. The third, of course, is liver transplantation. In terms of medical therapy, most of us are probably familiar with the choleretic agents and aren’t hesitant to use something like ursodeoxycholic acid. That’s one of the staples in the hepatology world and something that we’re all quite comfortable with. In some instances, this may provide some relief, but for some of the more challenging or refractory cases that we’re talking about, this is just the tip of the iceberg.
Other pharmacologic agents include things like antihistamines. Those are challenging. Certainly, they’re an advantage at night when symptoms of pruritus tend to be a lot worse. These children are often distracted during the day, but when you go to lie down at night, it becomes rather overwhelming. It isn’t ideal to have a school-aged child receiving medications that are potentially going to make them sleepy throughout the day. Rifampicin is something that we all use without hesitation in a lot of these patients as well. That has shown to have some good effects.
When these combination therapies aren’t working, we’re looking at things like opioid antagonists, such as naltrexone, potentially SSRIs [selective serotonin reuptake inhibitors], or many of the bile acid sequestrants, and the list can get a little overwhelming. Depending on the age of the patient, you’re going to encounter obstacles like palatability. Many folks absolutely refuse Questran [cholestyramine], and ultimately it isn’t worth the fight with that toddler. Not to mention that the pill burden is quite significant for many of these patients, not only with a lot of these antipruritic therapies but often we forget—our families even forget—that a lot of those vitamin supplements we’ve been focusing on are also vitally important. When you’re looking to space out medications or find a way to give these, it becomes quite overwhelming.
We’re getting into [thinking about] how we’re helping to improve the quality-of-life aspect. Historically, we were finding that a lot of our therapies were often not enough. Despite all of this, patients were still coming in miserable, with scratching and alopecia from pulling out their hair, and things like that. There are some new drugs on the horizon, which we’ll talk about in a bit, that might change the game plan. But when you’ve exhausted a lot of the medical options, it can become a bit overwhelming to talk about surgical interventions.
For patients who maybe don’t have significant fibrosis or portal hypertension, perhaps a diversion surgery is an option. We can all probably weigh in and give our own experiences or thoughts on that. But from my observations, they tend to work for some time but don’t seem to be long-lasting, or we’re met with other complications, like fat-soluble vitamin deficiencies that we can’t overcome. Being a trainee, the idea of performing a liver transplant for something like itchiness always seemed crazy to me. But then you meet a lot of these patients, and when you’re sitting in the office with them and you find yourself wanting to scratch, you understand it a little better, and suddenly it doesn’t seem like such a crazy idea. But with a liver transplant, it’s almost like trading one disease for another. We’re all advocates of liver transplantation here, but it’s met with its own challenges and complications and medications with adverse effects.
William F. Balistreri, MD: Thank you, Jennifer. Obviously, you brought up the issue, these may have some success, but at what price? Certainly with the diversion, an ostomy, which isn’t well received by many families, and with transplant, you’ve traded one disease for another, as you said. Phil, before we get into the treatment, maybe you could define or capture what itching is all about, how we score it, how we grade it, and how the families can help us in that regard.
Philip Rosenthal, MD: Itching is on a spectrum from mild to moderate to severe. In the past, we generally used the clinician scratch score, which made it possible to distinguish between a patient who has mild itching and severe itching. I’d caution that itching is a rather subjective evaluation and dependent on the family and the clinician. Because it’s on a continuum, it’s hard to distinguish between a patient who has severe-mild itching and a patient who has mild-moderate itching. Where do you draw the line? What’s to say that this is moderate and this is just mild?
There have been validated itching scoring systems. There’s the ItchRO [Itch Reported Outcome] that was developed to help with the IBAT [ileal bile acid transporter] inhibitors, which we’re going to talk about in a little while. I won’t go into the details, but that helps to assess the degree of itching that the family or patient is observing. There’s also an app available based on the ItchRO that’s called the ItchCheck that patients can utilize on their own. You can download it to your iPhone. There might also be an Android app available at this point. I’m not sure, but I have it on my own iPhone.
The nice thing is that it’s confidential and secure. You can make a PDF to show your physician your scoring over time. The best indicator isn’t how much itching you had 1 day, but over time, is your itching getting worse? Is your itching getting better? Is your itching staying about the same? When it comes to the different therapies we’ve been talking about—either the classic drugs we’ve used or some of the newer drugs—it’s useful to look at weeks to months to years rather than 1 day in a week as to the progression of what’s going on.
William F. Balistreri, MD: Phil, that certainly is key. You mentioned that it’s variable, not only from patient to patient, but variable from day to day and in fact from minute to minute. These children itch worse at night and when they’re tired or angry or frustrated, so it’s very difficult to quantify. The scoring you mentioned, ItchRO—RO means reported outcomes—has helped us, and we’ll hear more about those scoring systems.
Let’s talk about the new drugs that are available and first give a quick overview of what these new drugs are all about. Then we can get into the details of the studies. Ryan, maybe you can tell us what these new drugs are and what they do.
Ryan T. Fischer, MD: The new class of medication that we’ve been trialing at our centers and have been approved to use are the IBAT inhibitors, the intestinal bile acid transporter inhibitors. These medications work by getting into the ileum and interrupting the reabsorption or enterohepatic circulation of our serum and basically hepatic bile acids that have been put into the intestine. They are there to help us digest food and absorb the nutrients that we need, and our body recycles them.
You can imagine that when you have cholestatic liver disease and you have trouble getting bile out of the liver to begin with, that recycling and bringing it back in may contribute to some of that increased serum bile acid and hepatic bile acid load. Therefore, the logic of blocking that reuptake, blocking those bile acids from coming back into the system, and perhaps blocking some of those detergent or proinflammatory effects that those bile acids may have inside our liver, could make sense. Not only that, but we’re affecting those serum bile acid levels again. They’re elevated in children with cholestatic disease. When we inhibit that reuptake from the intestines and can lower those levels, we’re seeing data that show that these patients can itch less. That goes to that still unknown—to me—mechanism of that association between having those elevated serum bile acid levels and the increased itch that goes with it.
It stinks because we certainly see patients who have elevated levels without much reported itching, and those with itching but with without the high levels. Obviously, there are other factors going into it. But for the most part, the more elevated those bile acids can get, the more we tend to see those children itch. By interrupting that with these newer medications, we seem to have what is close to a game-changing option to make the lives of these children so much better and prevent one of those major indications from transplantation—that severe itch—from taking over.
William F. Balistreri, MD: Thank you, Ryan. Well said. I simplistically think about this as a medical biliary diversion. What Jennifer talked about was an external biliary diversion. This is a medical diversion. You’re blocking bile acid uptake, dumping bile acids into the colon, reducing bile acid pool size. Granted, you said bile acids may not be the pruritogen, but it certainly runs in the same neighborhood. We now know that lysophosphatidic acid, lysophosphatidylcholine, and autaxinall may play a role. But the biomarker may well be serum bile acids.
TRANSCRIPT EDITED FOR CLARITY