Transcription
All right. Um, I think this was, this is more of like, um, a little bit of a grab bag. Trying to, Craig and I were brainstorming about this talk, and he said, "These are hot topics." So, these are things that are often at the back of your mind, maybe questions you've been wondering, and so I'm, I'm trying to answer those questions. So, when he gave me this topic, the first thing I thought of was this. Does anybody know what this is? So, this is from the Mall of America. This is Hot Topic. So, that's what we're going to be talking about today.
All right. So, um, these are the four topics that, um, we came up with. They're actually a longer list, but I have 20 minutes, and so I think I might be able to get through this in 20 minutes. I should be able to. The first one is what we call drug-induced autoimmune-like hepatitis, or DIH. Um, that's a mouthful, and I'll tell you what that is. Talk about TGN monitoring, and I think there was a question about that. That's the azathioprine monitoring. Fatigue, I'm only going to talk a very little bit about that because Nadia is going to have a talk about that tomorrow. And then this term biologics. Um, I'll, I'll try to demystify what those are and talk about those for a little bit.
All right. So, um, this is the Cordalis plant. Um, it's beautiful. It is. You can actually get tincture of Cordalis in the bottom right if you go on Amazon or one of the websites. And in the middle, this thing is a Midnight by 1906. It's a, um, it's a THC supplement with Cordalis in it. And why am I telling you about this? Because this was one of these eye-opening experiences for me where I had a patient who had a diagnosis of autoimmune hepatitis. And after two years, she came in and said, "I don't have autoimmune hepatitis." And I said, "What do you mean?" She said, "Yeah, I took this thing, Midnight. I didn't tell you about it, but I was taking it to help me sleep, and apparently this causes autoimmune hepatitis." And I stopped taking it, and I stopped taking the medication you gave me, and my numbers are fine. I said, "Huh?" And this is great because the reason I'm starting with this is because I'm always learning from you. And I, you know, I, she showed me the articles, and it was true. This is, this causes something like what we call drug-induced autoimmune-like hepatitis, and it is incredibly hard to figure out. The most important thing is the history. So, we used to call it drug-induced autoimmune hepatitis, but we changed that because really, it's not autoimmune hepatitis, it's *like* autoimmune hepatitis. And drug-induced autoimmune-like hepatitis is under the umbrella of what we call drug-induced liver injuries. And this is a good percent of what I see in my liver practice. Is you take a medication, oh, now your liver enzymes are up. What do I do? Is it the medication? Baby. Um, and it can take many forms. Sorry, I, I'll speak, uh, closer to the mic. It can be cholestatic. So, what is cholestatic? Means, usually that's itching and jaundice. Um, it can cause steatosis. Drug-induced liver injury can put fat in the liver. The things that typically cause this, we see this with, um, some of the seizure medications. And it can cause hepatitis. And that's inflammation. And if that hepatitis can be caused by a virus, or if it's not, we tend to call it an autoimmune hepatitis or autoimmune-like hepatitis.
So, this is a study. Does it come out well? Maybe it's, this is my old eyes. Um, this is a study. There's Craig's face. And Craig did this study. It is a really cool study. And the reason I'm talking about this is because, um, Craig and, and Naga, who came in earlier, and some of his colleagues here at Indiana University wanted to understand drug-induced liver injury. And they looked at the 20 most common drugs, uh, that have caused drug-induced liver injury in a cohort, uh, I think within the state of Indiana, right? Yeah, within the state of Indiana. And they found the incidence of drug-induced liver injury is very low. So, the most common ones that they saw, this is not, um, autoimmune-like hepatitis. This is just drug-induced liver injury in general. Atorvastatin was one of the most common ones. But you can see there are so many more scripts of atorvastatin. That's probably, uh, that's Lipitor. It's probably the most common statin that we use. But you can see the ones above atorvastatin, it's a lot of antibiotics. So, antibiotics can cause drug-induced autoimmune-like hepatitis. They cause them at a very low rate. So, even the most common drug on that list, levofloxacin, it's almost about one in 2,000. So, it's high. It's very uncommon for a drug to do this, but they can do this. And if you prescribe it enough, um, pneumonia, respiratory tract infections. So, that's what you see with levofloxacin and, and, um, azithromycin. Nitrofurantoin, I don't think Bactrim's on there. We just don't use it that much. Oh, it is, but they didn't see any cases of that. So, um, there was a paper that was put out, um, about two years ago to focus on drug-induced autoimmune-like hepatitis. And on the left side are drugs that are likely to cause this. And so, if someone has started one of those drugs on the left, and we see liver enzymes going, you know, elevated after starting these, and a liver biopsy that looks like autoimmune hepatitis, but they've started these drugs, we consider this not autoimmune hepatitis, but drug-induced autoimmune-like hepatitis. And you can see there's a lot of common drugs on there. Um, some statins and antibiotics. And, and then on the right, we have a few other drugs that it's possible to cause an injury there too. Um, and then some of these are supplements, like you see turmeric on there too. So, sometimes you might be hearing about the, you know, the, the, the health benefits of turmeric, but also know that it's possible to cause, um, hepatitis.
So, this is part of that study where they were trying to show, well, how do we know if it's drug-induced autoimmune-like hepatitis or what we call idiopathic autoimmune hepatitis? What we know in this room is autoimmune hepatitis, or classic autoimmune hepatitis. Um, and this, what I like about this picture is it makes it seem so simple, and really, in actuality, it is complicated. It is not easy to, to diagnose this. How do we know? It really has to do with, uh, drug withdrawal and immunosuppression withdrawal. Um, but there also has to be, um, we, there has to be a drug that has been, uh, likely to cause this too. So, without the drug there, it's less likely that it's a drug-induced liver injury. Um, but we can withdraw immunosuppression, as I talked to you about the, the sort of patient example, to start off this talk. Uh, if it is drug-induced autoimmune-like hepatitis, after withdrawal of the drug, we will still treat with immunosuppression because that injury is still there. But then we can typically take someone off of long-term immunosuppression.
So, how do we determine whether it's drug-induced autoimmune-like hepatitis or classic autoimmune hepatitis? So, the details are in the liver biopsy. And again, I'm going to pick on Craig because this was actually, this was a great study that they published last year. It's hard to read. Um, Craig, I wish you had made a better figure than this, but this is what you guys did. [laughter] Um, the details are that there are features. So, in the top, oh, sorry, in this little, those top four, five, uh, lines thing, you see it says portal inflammation, portal, uh, plasma cells, um, and then sort of fibrosis, interface hepatitis. So, there are features that you see more likely in classic autoimmune hepatitis that are less likely to be seen in drug-induced autoimmune-like hepatitis. But I want to show you patient 14. Very much fits into the, um, you know, if, if I were just looking at this, I would say that looks like classic autoimmune hepatitis on a biopsy, but indeed, it was a drug. So, it, this is not foolproof. It is, it is highly suggestive based on a liver biopsy, but again, clinical context is really important. So, have you, if you've taken a drug that could cause this in that, that time frame?
So, how can you help? So, here I am. I'm talking to people and caregivers, uh, about autoimmune hepatitis, and here I'm talking about something that looks like it, but it's not it. Um, so, how can you help? And what, what I would say is, um, you know, I can understand that a fear would be, well, I have autoimmune hepatitis, I don't want to develop drug-induced autoimmune-like hepatitis. That, you know, that would, that would not be good. Um, so, tell your provider any medications you're taking or supplements. Um, and so it's important also to know what the risk is. It's, it's very unlikely to develop drug-induced autoimmune-like hepatitis, but it happens. And so, if, if we don't know, you know, we talked about flares. One of these things, it could be a medication that causes a flare. Um, and then, should I ask permission to start a medication? And I think you asked this question a little bit earlier. It's, you probably don't need to. If you want to, you can, but it's unlikely that you'll develop this, uh, this sort of symptoms. Um, but again, if you do, if your enzymes go up, if you've told your doctor that you're then taking it, then that's okay. This is just sort of my practical advice about it because it can be tough as you're going on and off medications. Um, do you need to ask every time you start a medication? No. But if you know that you started it and then you have a flare afterwards, it could be the medication.
All right. What about monitoring? So, um, azathioprine in general, we try to do weight-based azathioprine, um, milligrams per kilogram per day. What does that mean in, in pounds? If you're 150 pounds, I tend to use about 100 milligrams of azathioprine because that puts me, it's right in the middle between 68 or almost in the middle between 68 and 136. 250 pounds, maybe I'm using between 150 and 200 a day. Um, and we can monitor azathioprine for efficacy and toxicity. So, on the right, this is just our little, uh, schematic of, of, sorry, um, of how azathioprine is, is broken down. It leads to these two big byproducts, the 6-MPR and 6-TGN. And what we want is we want a little bit more of that 6-TGN, but we don't want too much. And this is where it can be a little bit difficult. You want it to be high enough that you get efficacy, but not too high that you're causing some bone marrow toxicity. So, if you're in this room and your provider has not been doing monitoring, that may be okay. And the reason it may be okay, um, sorry, this is the reason it may be okay. The reason it may be okay is if your numbers are normal and your, and your labs are generally normal, then it's, you're, you're okay. Now, this is the long version of what it looks like in the guidelines, and this is my short version of what I'm going to tell you. So, that picture is what Craig and Aparna and I look at, but this is the way I distill it. If you're on azathioprine and your labs are normal, and your, if your liver labs are normal and your CBC is normal, you're probably fine. Now, this is just my take on it, and if you ask Craig and Aparna, they may have different takes. They may monitor things more closely, but I think this is generally fine. If your liver labs are abnormal and you're not experiencing azathioprine-associated side effects, consider monitoring because we may be able to increase that dose. If your CBC or hem profile is abnormal, particularly if you're anemic or your white blood cell count is low, consider TGN monitoring because that could be a toxicity from the azathioprine. That's sort of my, uh, practical way of looking at it. But in the questions, we can also talk about, you know, how people have used this. If any of you have experiences with monitoring, um, feel free to, to let me know about that too.
Uh, fatigue. And ah, this is, uh, uh, we have a whole, uh, lecture that Nadia is going to give tomorrow on this, but I just, I want to acknowledge it's the most common disease-associated symptom, and it's the last symptom to resolve with treatment, and a lot of time, it doesn't completely resolve with treatment. So, um, I, liver enzymes are normal, IGG is normal, fatigue is still there in some capacity, and it can contribute to depression and anxiety. Um, this was a study actually done by the AIHA looking at the use of CAM. So, CAM is complementary and alternative medicines, and they looked at uses of, you know, this is many of you may have actually participated in these questions. Um, I think this was maybe done during, if not during the pandemic, then a little bit before. Um, we looked, they looked at vitamin mineral use, dietary modifications, physical treatments, mental therapy, and nearly 80% reported symptom improvement in fatigue, uh, using CAM. Um, and so you can see on the right, this is, uh, over half of, of people in this room or in, in prior AIH, uh, prior AIH respondents said they've used it before. Um, and this is the, the list of sort of different things that were done really frequently. Um, if you have fatigue, consider one of these approaches. Um, now, just know that the first approach might not work. Uh, if you don't like to exercise, then I'm not saying you should go exercise, but these are the different things that have worked for different people in this room, and they may work for you too. But Nadia will talk to you guys more about this tomorrow too.
Biologics. How many in this room have heard this term biologic? Is this a, yeah? It is. And you say, what does that even mean? So, to distill it to its essence, it's a medicinal product or a drug that's made from a biological source. So, we typically think of antibodies. That ends in those are things, drugs that end in MAB. What about hormones? Really complex hormones can't be really made in a lab. They have to be made by, uh, by bacteria or cell, sort of cell to then produce it, and then we then get the hormone. Vaccines can be, um, made from biological sources, and microbial products, like, um, fecal transplant is also a microbial product. So, we tend to think of biologics as injections, but that's not, it's not necessarily the case. Mycophenolate, which we, it's that Mycophenolate is like, it's like it's showcased at this, at this conference. That's made from fungi. And bacteria make tacrolimus. Um, so, these are, I guess in the truest sense, biologics, but we tend to think of biologics more when we're talking about injections. Am I done? All right. I'll wrap it up. All right.
So, this is what an antibody looks like. Um, just, there are no FDA-approved medications for AIH. Uh, corticosteroids, azathioprine, mycophenolate, I think of those as, I guess, as off-label. And then off-off-label is infliximab and rituximab. These are those MABs or biologics. And, um, infliximab, there was a, a publication recently about sort of a case series of using infliximab. What's strange about this one to me is that it actually is something that can cause this drug-induced autoimmune-like hepatitis. Um, some patients did well on it. I haven't had experience with it yet. Rituximab is something that we tend to use after, um, all of those pills that we talked about don't work. Um, what does rituximab do? It's, it's used in lymphoma and leukemia routinely, um, and it's used by my rheumatology colleagues. It depletes B cells, and those are cells that make antibodies. It only, it's only given every six months. In a review, the most recent review I could find said that about 55% achieved remission, but very few of the people that achieved remission had actually received mycophenolate or tacrolimus. So, there's scant evidence on this. Um, these are biologics in development by, um, three of the companies are actually helping sponsor this study, and Novartis has one that's, um, we should be hearing about the results of that soon. Um, so, all right, I was more or less on time. All right. Uh, now is questions now, or do we want another questions later? Okay, thanks everyone. [applause]