Transcription
So, every AIH patient that I've ever met loves to do case-based discussion and you just went through a boot camp essentially to understand this disease, to understand your disease, but understand others disease. Are you any good? So, we're going to look at your extensive knowledge of AIH and manage your patients and we're going to look at the guidelines to see if we can think a little bit outside the box and kind of what Nadia Blessing and I do on a daily basis. So, this is our first case. Hepatitis hidden in plain script.
So, a 20-year-old Caucasian female named Jessica, these are AI generated images, by the way, presents to your office for evaluation for abnormal liver test and feeling warm. This has really been happening over the past few weeks. Change something. She had a urinary tract infection eight weeks ago, but otherwise, her pediatrician has always told her she is healthy. Can I have the dongle for the advancer so I can walk around? I don't see it in here. So, she's a sophomore in Indiana. She just recently decided to rush a sorority as well. So, she states that she's been feeling more rundown over the past five weeks and school's been busy, but on top of that, there's many functions going on at sorority house. She hasn't been sleeping well and her forearms are really itchy and keep her up. It's driving her boyfriend crazy. Her new sisters though are very jealous of her new tan. Um, they they want to know how she does it. So at her primary care doctor two weeks ago, she had an ALT of 250. That uln is upper limit normal. That's here at Indiana University. ALT was 322. Her total Billy Rubin 1.1 alfos 150. There was a TSH that was normal. Uh, at that point in time primary care doctors going to do what primary care doctors do and get an ultrasound. We see a diffusely echogenic liver. So I'll highlight that that's probably it could be a few things. It could be an inflamed liver but it also could be a fatty liver too. The Doppler which is how we look at the blood vessels to look the eb and flow to make sure that they're open are patent. So open findings are consistent just like I said fatty infiltration and/or hepatic inflammation.
So, as you dig into her a little bit more, her urinary tract infection symptoms got better since she's been treated. And he put in, this was a primary care doctor, put in a medication, which commonly she has no idea what it's called, and took it for five days. She also notices that she's been drinking heavier since Rush. Remember, she's been binging most days per week, up to 10 drinks a night. We call that doing a Vupilanche is what that is. So, remember her labs that I showed you earlier. So today in your office you see her and she looked just like that. However, her A and ALT are now more elevated. Uh, her Billy Rubin is also elevated at 2.9. Alfos is about the same. Her INR which again is a measure of synthetic or liver function, um, is 1.3 should be about one. When you look at her really her vitals are okay. Her temperature is a little bit low grade temperature 99.5 but she's got this flat effect. She but she's just kind of scared. She looks yellow her liver you can actually feel it right below her right costal margin her rib cage and it's actually tender when you push on it legs and her her look fine but on her arm you can see these linear what we call excoriations or scratch marks, um, otherwise, you know neurologically she looks fine so what do you guys think this is where I'm going to ask for the room to maybe engage and then we'll ask Dr. uh either Valanche or Nadia Blessing to comment.
>> So, we haven't done that yet, but we got to decide what we're going to send. So, you're you're worried about mono. Has anybody had mono and had jaundice or elevated liver tests related to mono? Yeah. So, we we know that's a a very heterotropic virus that can cause significant liver injury in patients with or just adult patients in general. What other things? What differential though? You're at an AIH conference, so we know it's maybe AIH. So, there's a concern about the drug, correct? So, is this a drug induced autoimmune like injury or is it just a drug induced liver injury, which we don't need to debate those pieces, but can be probably a different process.
>> So, some Okay. Did you say alcohol though?
>> Yeah. So, so heavy alcohol use and again we got her history. Maybe she's lying to we don't we don't know but she was drinking heavy more recently. What other things can cause this? So, viral hepatitis outside of EBV or Epstein bar even acute hepatitis B or hepatitis A can come with the same picture. So, there's a, there's a few things and actually these are listed here. You guys did really good. But, as we kind of decide this, my first question to you is you're you're her doctor. Do you have to hospitalize her? Why do you have to hospitalize her?
>> She's yellow. I see a lot of yellow people walking around the hospital. They walk into my clinic all the time, you know. So, this is this is supposed to be a challenging question. So, if she is very motivated and I have good contact with her and I can get labs and I can initiate things and get things started, yes, I probably can keep her out of the hospital. However, she's not taking oral input. she can't keep up with her fluids, she feels terrible. I may hospitalize her to expedite the workup and maybe even get the liver biopsy done in patient. So, it really depends clinically kind of what she looks like. But I am alarmed. You know, I'm I'm telling her, hey, your INR increasing tells me this inflammation is enough to cause impact on your liver. It's not necessarily working well. Now, nobody mentioned this, but pregnancy is an important part of this pregnancy. There are pregnancy related liver issues. It is reassuring. And when I did this before, I made that that pregnancy test positive. But being negative is actually very reassuring. This should have been done hopefully by the primary care doctor, but it wasn't also then the viral corology. So that means I've checked her for her hepatitis A, B, and C. Those are all negative. We can throw in the monospot to look for Epstein bar as negative. But here's her auto antibody profile. And this is where you guys are experts. Can someone interpret that for me? Whoever's mumbling, speak up for me. Why does it look a mean to you?
>> Oh, >> it's look really similar to numbers I had done.
>> There you go. That's right. So, [clears throat] you're right. I I'm a simple human tomb. I'm pattern recognition, right? So, anti smooth muscle and anti-neutrophil antibody. We've all talked about this in this disease and is part of the diagnostic criteria we use. I'm going to tell you today that I don't necessarily care so much about what your ANA or anti smooth muscle antibody is. I really care more about what you have told me in your liver biopsy as we've also seen that we can Raj talked about the seronegative AIH but being more than 1 to 40 is probably a significant level for anti smooth muscle ANA 1 to 40 is positive above two but what if I told you that 10% of the population has a positive anti-neutrophil antibody so that's important to know antimitochondria antibody is an antibody that we see associated with a disease called primary biliary colitis I just happened to click on that button as I was also ordering labs and then her IGG came back and that's high as well which we've talked a little bit about IGG. This is that other marker of inflammation. So we all decide you know what the best way to sort this out is liver biopsy. What did we see? So on the biopsy we see the classic piece of autoimmune hepatitis. This what we call interface hepatitis. This doesn't show it incredibly well and you can look on our website for a pathologist describing what biopsies look like, but there's a functional unit called the portal tract and is completely obliterated by lymphoplasmacytic infiltrates. And there we usually see autoimmune, but we can also see that in a drug induced liver injury, sometimes viral, too. It just depends. But we've done that workup. So, you know, you're telling her, "Hey, bad news. You're sick. um you have AIH or maybe drug induced autoimmune like it's arbitrary at this point but she said I have this fall formal coming up.
>> Does every AI patient need steroids at at the front of their diagnosis?
>> Diagnosed her with that.
>> Say that again.
>> Have we diagnosed her with that yet?
>> Let's say that based on the biopsy I feel quite comfortable that this is autoimmune but it could be a drug induced autoimmune like it's at the point that I think steroids may benefit her or maybe do I need to not give steroids and can I go to another therapy?
>> So, and maybe it's so you could say budesonide and here's what I'll say about budesonide. Most hepatologists think that budesonide is probably lower potency. And this idea of being steroid free or systemic steroid side effects. As you swallow budesonide, it goes straight to the liver. It's metabolized there. The blood that leaves the liver and goes everywhere else supposedly doesn't have any budesonide in it. The problem is we get escape in about 15%. Also, an inflamed liver, the enzyme profile of the liver that metabolizes budesonide probably doesn't work very well. So, you're probably going to get systemic steroids anyway. And if you're going to give steroids, I'd probably just give prednisone. I'll remind you, she's jaundiced and she has an elevated INR. And time is a little bit of the essence if we're not going to hospitalize her to look at this.
>> So yeah.
>> Um [snorts] well, and and would you put her on a course of steroids and then say testing every few days and if it goes down then you've got a pretty good.
>> I think you're right. Yes. So you know, I would probably try to convince her, listen, it would be high risk to go without steroids. However, flip this around. The liver tests are a couple hundred. Her bilirubin's normal. Her INR is normal. I actually in my practice in pushing the envelope a little with some guard rails. I will try to move to steroid free options. So, the more mild disease, I will try to skip steroids only because I've seen the detriment of steroids. Patients after three to six months of steroids, they look different three to six years later. Right? So if we think about the metabolic complications, the hypertension, the high cholesterol, the weight gain, and in fact, AIH, you guys did a steroid survey for us this last year. We're presenting that data at ASLD or the liver meeting this year. People change the burden of steroids here in this room and outside of here is incredible. And in fact, up to 30% of patients at any given time with AIH are on steroids. Now, if that isn't a message for how bad standard of care is, I don't know what is. So we need to echo that sentiment. So we talked about this a little bit when to start the other immunosuppression. So we have a list of drugs. Does anybody have a preference and why?
>> Well um the cell because the study that came out in 2023 that showed faster resolution of the biomarkers or whatever. Um, and there's less. Now, with her though, taking two pills a day might be a problem because she has to drink at night.
>> Okay. So, she's talking about maybe some faster onset.
>> And does anybody want to say why that may still be a problem?
>> She I'm not okay. I'm not sure. But if she wants to eventually have children, could that impact?
>> Eventually? What if she does? She's got a boyfriend, right? So for CEP, this is the point of that, right? So she's probably sexually active. I'm assuming I should assume. And in fact, anyone that was CLEP probably should have, not probably should, two forms of birth control. Do we do that all the time? No. And in fact, studies that look at cell and impact on pregnancy teratogenic in about 30% of patients if they're on cell at the time of pregnancy. So this is a big problem. I agree with you. Rapid onset. I love CPT in the non childbearing potential patient. How about azathioprine though?
>> Okay. So, I didn't put that part in here, but the TPMT is what you're asking for. So, we know there are genetic mutations. Most people can process a Okay. But there is a quarter to a third of people that are slow and then maybe even lower that are really bad metabolizers that increase their risk for liver injury related azaathioprine. A good point. Yes, she's normal. How about the onset of azathioprine? How quick?
>> Yeah. So, like four to six weeks it takes to get up to level to that immunologic arm for me. It's too slow. I'll tell you what my doctor did. Mine did like 40 30 20 15 10 taper of prednisone. So, it was done within about five weeks and started me immediately on azathioprine. um with Yeah. with the prednisone together. So, and it worked.
>> Yeah.
>> Yes.
>> So, I I do tend to start it earlier if I'm going to use azathioprine. There's some idea in the liver community that maybe you should be careful because it has a potential for hepatotoxicity. I'm not so worried about it. I'm starting in low dose, but I actually may even talk to her about tacrolimus or prograf. realize as well as I uh I'm my practice is a little bit more extreme and aggressive. Uh only because if I have to use steroids, I want to do everything as possible to get her off sooner the better for me. Again though, I think TAC or azathioprine is still a fair approach. Um, when am I getting labs again?
>> Yeah.
>> Yes. So I listen weekly is good. I think that's what I'm doing. And in fact, I'm telling her in the meantime, if she doesn't feel well, she needs to go to the emergency department. Again, if I trust her, I'm comfortable with that. So, within six months of starting 50 milligrams of azathioprine, so that would be the initial low dose. Here are liver tests. So, liver test alt is still 98 actually, uh, you know, down a little bit. This is six months later, remember? And remember, six months is a good endpoint for clinical outcomes. We need improved or normalized liver tests by then. She's also been on a whole bunch of different levels of steroids. So, someone's kind of been chasing it. Bilirubin's still a little high. There's that pesky TGN. So, we had a lot of I've had questions about this. Checking your azathioprine metabolites gives you these two numbers. TGN level 230 or so is what we're shooting for. Even up to 300 I'll be fine with. That's the immunologic arm. The other pathway that MMPN that's another metabolite that it actually does no purpose for us besides as it gets closer to 2400 it can hurt the liver so I use this test there is and I told others I don't like to use this word but a poor man's test to look and see if your doctor's not sending your azathioprine metabolites you can look at how big your your red blood cell is so on your complete or your CBC if you look at something called MCV or mean corpuscular volume typically if If your thioguanine levels are at in range, even though you're not testing them, if your red blood cell is about 35 or sorry, 95 to 100, you're probably close to range. What azathioprine does is when you start taking it, your red blood cells get bigger. It's part of the it's part of its pathway. Not deleterious. It's just one of the ways we can kind of measure kind of off the cuff. So then at 12 months, so I'm sorry. The point of this is we probably need to increase, right? So when you look at this six months later, her thioguanine levels have gone to 230. MMPM has not changed that much. That's good. And look at how great her liver tests are. And she's not on any steroids. And you can see she's smiling once again. So at your one-year follow-up, inadvertently she comes in and says, "Can I ever get off this?" What do you guys What do you guys tell her?
>> Not yet.
>> Not yet. Why not yet? Because you want at least a couple of years and you just want to be really careful because if you go off it too soon you can rebound and it's worse.
>> What if she says but what about that drug I took?
>> You told me that could be drug induced autoimmune like hepatitis. So we do know that those cases are easier to treat typically. We also know that we can pull therapy off sooner, maybe six to 12 months. And actually part of the diagnostic criteria for that is once you withdraw six to 12 months, if within the next six months they relapse, it was probably not drug induced. It was probably just plain old AIH all along. If they stay good, it's probably drug. And I'm saying that for a reason because that's the resolution that we understand these diseases. There's not a better biomarker. So it's really clinical experience in that idea as well.
So case two, the next two cases I'll go through a little bit quicker just for time sake. So this is when two livers collide. So this 51-year-old female, she came to your office. She wanted to be evaluated for some abnormal liver tests during this past year. And she talks about she's always been heavy. Her weight's always, you know, much many of us weight's been increasing, particularly since her first pregnancy when she was 21. And she currently has a BMI of 39. She's been seeing her primary care doctor for five years. He he's told her she's had fatty liver disease, much like everyone with abnormal liver tests, right? She was supposed to lose weight, but like many of us, she didn't. Uh, she gained another 25 pounds since five years and really no other symptoms, but you know, she says this right upper quadrant pain. I have this kind of intermittent fatigue. My right knee kind of hurts. Uh, and she doesn't have any other high-risk behaviors per se. By the way, does anybody's right upper quadrant hurt? Can everybody look around and see that? My very first question at a very first AIH conference. This was bugging me for years because I hear about right upper quadrant pain all the time. You're not crazy. I'm just going to say that. I don't know why though. Even if your liver tests are normal, I don't know why. That being said, if you ever deviate from that baseline, you probably need to be looking a little bit deeper. But not [snorts] all right upper quadrant pain is gallbladder pain. Okay. So her primary care doctor had labs two weeks ago. Similarly, so about 1.3 1.4 times upper limit normal for her ALT. Everything else actually looks pretty good. Her creatinine is a little bit high, which is a measure of her kidney function. You see that these labs have really been consistent over the past few years. So she has a whole metabolic syndrome. She has type two diabetes, high blood pressure. Uh, she does have the dreaded hypothyroidism that many people have, particularly females. Some back pain, some depression, anxiety, and then that chronic right knee pain. Mom though had cirrhosis, too, which is interesting. She does drink intermittently, but really nothing substantial in her mind. And then she's on a whole list of medicines that you would classically see in patients with fatty liver disease or metabolic syndrome. She's been taking naproxen one tab two times daily as needed for pain. So, let's answer this question too. Tylenol or non-steroidal anti-inflammatories. So, this is an educated audience. Does anybody staunchly disagree with that? I The only time I've ever exchanged words with a patient on social media is about the Tylenol. This was years ago, by the way. Tylenol 2,000 milligrams a day is probably safe for you. Again, talk to your doctor, but we avoid NSAIDs if we can. Sometimes NSAIDs control pain better, but they're NSAIDs are renally cleared and in fact renal injury related to NSAIDs is probably substantial and maybe a part of why her creatinine is up a little bit too. So differential diagnosis I kind of skipped to the punch here but the same things that we talked about but this may just be plain old fatty liver disease. There's some iron overload problems. We can talk about drug induced injury, AIH and drug induced autoimmune like. And by the way, NSAIDs have been linked as another drug that's been associated with drug induced autoimmune like liver injury as well. So again, it gets a little bit complex disentangling these pieces.
So her workup that you drive, we see an elevated IGG. We see the kind of classic autoimmune piece. We see some things with her iron. So her ferritin, which is a long-term iron storage protein. Anybody see their ferritin ever? Anybody ever see their ferritin when they were diagnosed and you said, "Why in the heck is my ferritin high?" It's not that your iron overloaded probably. Now, we should look at it. A ferritin is what's called an acute phase reactant. So, when people have liver inflammation, ferritin tends to climb. However, we should follow up on it and make sure because actually one of the most common genetic disorders of of Caucasians is actually hemochromatosis, which is an iron overload syndrome. So I often get genetic testing for that when I see this just to make sure. So competing diagnosis fatty liver disease and by the way that's the wrong nomenclature. This is an old slide. So it's now called MASLD or metabolic dysfunction associated steatotic liver disease. So mouthful, um, but important name change. We see positive auto antibodies particularly ASMA or anti smooth muscle positive in up to 20 to 30%. Which is actually makes our job really hard. We also will see elevated IGG in those patients as well. On top of that, we talked a little bit about hemochromatosis. We did the gene testing, it was negative. My question is how do we decipher AIH in a patient that just doesn't look like AIH? I ask my hepatology colleagues all the time, what is your threshold for not believing fatty liver is not fatty liver when it looks like fatty liver?
>> And it looks to me like she might have PCOS and that's leading to the NAFLD.
>> So she has all these metabolic things. So it makes you believe that this is just plain old fatty liver disease.
>> What if we do this? So Dr. V just highlighted that. Okay. So her fat score or CAP score is 293. Anything over 250 in my book is high. But what about her stiffness? 10.4. And maybe I can Nadia, what would you do with this in the clinic? A 10.4 in a patient like this.
>> No improvement in liver enzymes.
>> With what?
>> Well, it's a good question.
>> We just saw her.
>> Yeah.
>> Haven't done any treatment yet. I So, if it's my first time seeing her, um, we've seen a trend of these elevated liver tests for a while. We haven't really had a chance to go through dietary lifestyle changes yet, but if this is the FibroScan, I would probably get a biopsy.
>> Okay.
>> So I think that's what we did. And so, really the bottom of the biopsy is the biopsy shows both. So, she has fatty liver. So, those clear vacuoles that you see on the screen, it's hard for me to show here. That's what steatosis in the liver looks like. Um, outside of that, the blue staining on B is just some of the fibrosis that we see. So she had about stage two fibrosis and then in C we see a lot of those inflammatory cells that is consistent with autoimmune hepatitis. So Dr. V talked about this kind of concomitant disorder of AIH and fatty liver disease. We actually see that maybe it can actually make the other one worse. So it's really important that we address this and these are the questions that I think you should think about in those patients. So do we give her steroids? Why not? Could make it worse, right? So, steroids may exacerbate fatty liver disease. So, I think she's worth a shot to go without steroids, honestly. And in fact, if she doesn't improve on her own and and maybe she's a cell patient. She's 51. I don't know if I have to ask her more about her history, but that may be a strategy we can consider. I'd stay away from TAC because of the kidney stuff. Rapamycin, I know we haven't talked a lot about it during this this course. Sirolimus is the other name for it. This is kind of a third or fourth line drug that we sometimes use. When do I get labs again? Because again, I asked that question because I get that often. So, do I need to get it in a week?
>> No.
>> Probably not urgent. She can come back in a month. I'm probably comfortable with that. And by the way, 100 hepatitis may tell you a hundred different things. But again, in terms of the symptoms, based on her presentation, it's been chronic. We've established this diagnosis. She can get to work. Really what you're monitoring more is not for liver worsening but more for toxicity. So CEP we may just see in the next three or four weeks would be great just to make sure her white count's good.
Last case in a shorter case, he's an autoimmune heavyweight. He's 32 years old and your local GI guy was bragging to you. He said you know what I diagnosed this AIH patient. I've been managing them all by myself for the past two years. I say that's great. Good. Yeah. You're one patient in your your local GI practice. But he says, 'You know, but I'm actually getting a little uncomfortable because I got labs about four weeks ago. His liver tests are still high. Um, and if you look at his labs from three months ago, it actually looks like they're getting worse. So, he is uh he's currently on 125 milligrams azathioprine and 10 milligrams of prednisone. Again, this is after two years, mind you. His thioguanine levels are good. So, they're above that 230. And, you know, I I take a look at I look through all the medical records and I'm like, "Yeah, I think he does have AIH." So, I've confirmed the diagnosis. So, when we think about what's going on here, I think we need to think about other liver diseases, some other autoimmune disease that actually could cause abnormal liver tests, and at the end, the dreaded hard to treat autoimmune hepatitis, which I know we have a few of those patients with us. So, all the things that we've talked about excluding is kind of the things that I think about, but then the other autoimmune disease. So, I need to ask him about his GI symptoms. Does he have inflammatory bowel disease? We sometimes see abnormal liver tests in those patients. Celiac disease, we talked earlier, did we exclude that? Other connective tissue disorder, lupus in fact can also impact the liver inflammation as well. And then uh question about hard to treat. What supports this? I'll give you the answer. It's because the the thioguanine levels are good. He's been on azathioprine. He's still on prednisone. His liver tests are still no good. However, it's been a few years and you want to clarify. So certainly what do we do? We biopsy and he has a very classic picture of AIH and actually has now have stage three fibrosis. So how do we approach a hard to treat patient? This is a bigger question. In fact, I've given whole talks on this and how we should cycle through it. Um, we've talked a little bit to some of our hard control patients. They've been almost every drug under the sun, right? So it's an escalating pattern. My concern is some doctors don't necessarily do that. They're comfortable only with azathioprine and maybe only CLS and that's where we kind of get referred. So the very final piece is this is the challenging this is a lot going on but down in the bottom right corner when we have patients that fail treatment there's a whole thing that I look at some of these combinations here I just want to show you the data is poor when we think about hard to treat AIH the data for CLEP or prograf or combination therapy to rescue those patients is actually pretty low but again you don't know until you try so now with infliximab being a little bit more hotter recently there is some data for some rescue and then rituximab the best we got from the most recent rituximab paper is there was a meaningful reduction in ALT so what I want to bring to you today is there's a ton of variables right there's so many steps to really get down to establish the diagnosis but you guys know a lot you can participate actively you guys were shouting out answers so again engage your doctor engage those questions they're hard decisions press your doctors and understand why? Because I think really with the knowledge that you have, I think you can get yourself better outcomes, maybe even more satisfaction with your overall care. [snorts] Um, active participation. Thanks.