All right, we're going to move on. I know Dr. Yamam has developed a case for those of us, the speakers, if you guys want to come back up. You're not off the hook yet. So we'll have one opportunity to go through a case and then we'll pause, we'll take a pause. And if anybody has any other questions from their own clinical practice about cases in pregnancy, whether it's related to these lectures or not, we welcome those. Sure. So I'm going to start out with a case of hepatic adenoma for our panelists. So we have a 30-year-old female who presented with an abdominal pain to the emergency department. An initial ultrasound followed by a multi-phasic dynamic MRI ended up confirming a six centimeter hepatic adenoma in the right lobe of the liver. She was referred to your liver clinic for further discussion of this, further discussion in the management of this lesion. And when we saw her in clinic, she mentioned that she recently got married and is planning on getting pregnant, hopefully soon. So what is the discussion that you may have with this patient regarding her hepatocellular adenoma? Mainly, it's implication in pregnancy as well as your treatment approach. So we have a six centimeter lesion in a young woman who's thinking about pregnancy. So what are some of the discussions you may have with her? So I guess one of the questions I would have is was her abdominal pain related to the adenoma or was it an incidental finding and is she on the oral contraceptive pill? From what we heard, her abdominal pain is right upper quadrant and is suspicious that it could be related to this lesion. In terms of oral contraceptive pills, she's actually taking a combination OCP. So I guess, and there's no evidence of bleeding into the lesion on the MRI, you would have told us that? No. So I guess if she's really interested in getting pregnant, the fact that she has, I mean, there is a chance that if she were to stop the oral contraceptive pill, she might have regression of the adenoma. But if she wants to get pregnant right away, then I think you need to counsel her about having the adenoma resected. Because with pregnancy, it carries a risk of rupture. It could grow and rupture, but pregnancy itself carries a risk of rupture. And if she's already having pain from it and she's symptomatic, that would be another reason to consider. Okay. Any other comments? So I agree entirely. It's location, location, location. If this is a peripheral lesion, I'd certainly be very keen for this to be intervened with resection, ideally. I think it would be somewhat irresponsible to let her go forward, particularly with a symptomatic adenoma. Okay. And then just kind of weighing the risk and the risk. looked at how lesions were progressing. All of these women had lesions that were under five centimeters, so we have no prospective data about what happens with bigger lesions. So it's really hard to say with the. I'm also somebody who's on the more, less invasive side, and so if she does still have a large lesion, I might also discuss with her the opportunity for a bland embolization and see if you can get it down in size. But again, a more peripherally located lesion certainly has the opportunity to be lobbed off pretty simply. So question for you, Monica. If she's not going to get pregnant right away, you take her off the pill, the adenoma regresses in size to less than five centimeters, and you let her get pregnant, do you worry that pregnancy is going to make it grow again? So there is certainly a risk of, right? So way more than oral contraceptives are the estrogen exposures related to pregnancy. That's as high as it's going to get. What was really interesting about that, Kate, the prospective study that was just published, is that only a quarter of those lesions that were less than five centimeters actually grew in size in pregnancy, and we kind of say that's the rule. It's hepatic adenoma, they're exposed to estrogens, they're going to get bigger. So I was really surprised by that finding in the particular publication, but perhaps if this particular lesion shrunk down when you removed estrogen, perhaps it's also more responsive to estrogen and may indeed grow over time. So I think it's really how small are we getting before we do something about it. It sounded like you guys kind of covered my subsequent questions. So she was interested in getting pregnant immediately, and it sounded that it was a large lesion, peripheral, symptomatic, with a higher risk of fracture. I think surgery was what was recommended. She was asking you about a less invasive approach, and any comment on location or what type of lesions you would recommend, embolization or ablation versus surgery? Well, the size of six centimeters is too big for ablation. I think the largest is three, maybe four centimeters at the utmost. So ablation would not be an option. Transarterial embolization I've seen has really generally been for the adenomas that are bleeding to temporize before you take them to the OR. I think it's also just a lot about what's your own expertise at your center. How good are your surgeons? How good are your interventional radiologists? So at UCSF, we do... to your consultants, and then kind of taking it from there. My next point was, how is your recommendation going to change if it's a smaller lesion? And I think, Monica, you reviewed the recent study published from the Netherlands group that showed that these smaller lesions monitored over time only, I think, 25% only grew, and I think they had one woman whose lesion grew to seven centimeters requiring embolization, I think, in her second trimester. So I think everybody's in agreement about monitoring the smaller lesions. Yeah, absolutely. I think the bigger challenge comes not necessarily with this type of patient, but the patient with multiple adenomas, and I think that's something that we grapple much more with difficulty with. Monica, any thoughts? Well, if you have, that's a great point. So if you have a woman with multiple adenomas, some small, some large, so do you recommend not to get pregnant? What would be your recommendation for such a patient? How would you advise about pregnancy? I actually have one patient with multiple adenomas. I always counsel to the largest lesion, so it's the largest lesion that tends to dominate what's going to happen with their outcome, and it's pretty similar, actually, for women who have a single versus a multiple. It's like treating the biggest lesion that confers the greatest risk of having bleeding during pregnancy. And it's really a similar, it's more challenging if you've got multiple big lesions and resection is not possible. I have a patient who's in this situation right now, and it's challenging, and for her, what we've elected to do is at least try to do bland embolization of the two biggest lesions, see where we get. But she's pretty adamant about pregnancy, and as I mentioned before, I don't tell people they can't get pregnant. I try to counsel them and give them the data as best as I can, and I think it's challenging because when you, a lot of the mortality data surrounding adenomas came from a time before we actually had interventional radiology services to be able to embolize. But that being said, a low risk of mortality, death is death, right? So that's the worst outcome that you can have, and so it's really about counseling what are your available services and trying to do as little harm to her as possible. Going back to your prior point, Monica, the ones that you advise holding oral contraceptives in and monitor, for how long do you monitor? How about if you monitored for a year and there was no significant regression? Is there a timeframe where you would say, oh, this is not really shrinking with not taking the OCPC, and so they should have surgery? Is there a timeline or frame that people use? Is there any data? There's not, and I think it's really the lesions that are growing that you get the most concerned about. So the large lesions... help prognosticate also conversion to hepatocellular carcinoma, which is the other kind of long-term risk to these women. But yeah, I continue to monitor, and depending on the size, it's really how is it behaving over time that really guides what I'm doing. And also urgency in terms of trying to get pregnant, right. When you're monitoring the smaller lesions during pregnancy, what's your imaging modality of choice, and how often do we image these pregnant women? Or what do you do? So I think if you have had a chance to look at the lesions and study them before pregnancy, obviously, if you can see them on ultrasound, it's great, and actually have the index lesions visible, I think that that's the easiest for patients, subjecting them to repeated MR in pregnancy, even if it is relatively safe. I think... Ultrasound. Ultrasound, if possible. How often? How often? Well, we know from the Dutch data where they scanned every six weeks, the change was relatively small. Once a trimester is what I would do, and then immediately, soon after delivery, but I don't think there's any... No. I've been doing it once a trimester. Okay. And what are some of the scenarios as you monitor these lesions during pregnancy, warranty treatment? What are some of the things you look for? Well, certainly if they bleed, you have to treat them for sure. And I think that if you're seeing growth of at least 20%, that you start to get nervous and you might consider a bland implant. where she could actually access interventional radiology. Is this a patient who lives out in the middle of nowhere and is coming to see you four and a half hours away? Like, what are the resources counseling her about the symptoms of abdominal pain and having a lower threshold for seeking care? And whether it's a peripheral lesion or not a peripheral lesion. I think Natalie, as you commented, there is a recommendation to consider if they are bleeding to do embolization first and then in surgery. Because I think it does decrease complications overall. In second trimester, certainly safer for the baby and the fetus. So I'm gonna kind of pause here and have a couple more questions. With the emerging data about different phenotypes of hepatic adenomas having different complication rates, do you guys recommend molecular or phenotypic classifications of these lesions to advise your patients about what to do? You know, the inflammatory type is associated with bleeding and beta-catenin type with malignancy. But most of the risks that we worry about is growth and rupture and pregnancies. Have you guys used any of these modalities to guide your treatment? I think that's part of the bigger overall long-term strategy rather than the acute strategy. I think when you're faced with this, it's about getting through the next three months, three months, three months, and then bigger picture, get a biopsy, make a plan. How about the emerging data on MRI being able to characterize some of these lesions? Would you consider that instead of biopsy with risk of bleeding? Or have you guys used that modality to help you classify? Well, I, you know, I have to say I'm not that familiar with this literature. I know that it, I think these lesions enhance on MRI. It's how the, what they do in the. We haven't been utilizing it for the purposes of differentiating between these different subtypes. I mean, I think when you see a lesion on imaging and it has this background of steatosis, it tends to be more of the benign form with a lower risk of transformation to HCC, so that's a nice feature if you happen to see it. I don't do contrast enhanced studies in the setting of pregnancy, but I think it's really elucidating data. I think it's interesting. Just because you happen to see a particular feature on imaging doesn't mean that that's what you're going to see when you biopsy the lesion, so I think it is reassuring. The one feature I like to see is I like to see fats, so that's the one that makes me a little bit more encouraged when I see that. I think there is emerging data to look forward to in terms of the specific characteristics of these lesions, though I think beta-catenin subtype seems to have variable appearance. I think you may be able to pick up the inflammatory one with the risk of bleeding, but not necessarily the ones with the risk of cancer transformation, so I'm going to open up the floor for a couple of questions, and if we have time, I have one other case to go through. Any question in relation to what we just discussed? This is actually back to the topic of varices in pregnancy. When you do that second trimester endoscopy and I see large varices, I've been reluctant to band them because of the need for follow-up banding. I think what I heard you saying is that you do a one-time banding and then beta blockers. Can you elaborate on that? No, I think I would qualify that by saying if you've been brave enough to band in the second trimester, you're going to be obliged to look again two weeks later and keep going until the bitter end. Once you commit, you commit, even in the context of beta blockers. Monica? Yeah, I agree. I would agree with that as well. Hi, Priya Madhur from Northwestern. I just wanted to say this was excellent, and so thank you for putting this on. Not sure if you answered this, so I apologize if this is redundant, but my question is about hepatic adenomas and their management. So quite often I run into these women who have large adenomas who also are on OCPs because of heavy menstrual periods, and so they're adamantly against doing the copper IUDs, and I'm kind of stuck as a clinician as to what to do because they want something, and I can't give them the estrogen-based therapies. So I was just wondering what your practice was. So it's challenging, and I will say that I have women also who have adenomas and who are taking combined hormonal contraception. Usually patients who have headaches, like really debilitating migraines, that's the only thing that we've been able to find, menstrual bleeding, and then I'll try just to talk with the reproductive endocrinologist about any other modalities that we can use to treat their bleeding. Is this related to fibroids? Could we do something to remove their fibroids? Because when they're smaller lesions, I'm okay with it. If it's a lesion that's less than five centimeter and she needs it for a medical benefit of something, otherwise it's importance, then she needs to be treated, but I think it's just really sinking, or there are really no other alternatives when they're really large adenomas, and I do want her to come off of OCPs if possible. And I know you covered the data on progesterone-based therapies, and I have some partners that will do progesterone alone, so what are your thoughts on that? Absolutely. So I have no concerns with using progesterone-only agents, and then IUDs, which is the same, and then levoneurogesterol is a low-dose progestin. So I have no concerns, and it's in line with how we practice at UCSF in our women's health contraceptive clinic, is that they can both access progesterone. Hi, I'm Jen Fleming from Queen's University in Canada, and I see you're going to talk about an autoimmune hepatitis case, and I'm hoping maybe to hijack your case, because I have a case that my colleagues and I have been struggling with, and since I have this amazing expert panel in front of me, I was hoping to run, see kind of what the thoughts were. So, I have a 29-year-old nurse who we've been following in our clinic for a long period of time. She presented with acute hepatitis when she was 16 years old. Biopsy had been consistent with autoimmune hepatitis. She had F3 fibrosis at that time. She responded to steroids, got into remission, was put on Imuran. Then she developed severe cytopenias on Imuran, and it wasn't clear if it was the Imuran because she was also EBV positive. She'd been tested for CMV at that time as well. She was CMV IgG positive. So overall, the thought at that time was that her and her parents at that time wanted to transition into steroids, low-dose steroids for maintenance for a long period of time, and her disease has been very difficult to control over a long period of time. Fast forward several years later, her transaminases usually run between the 40s to 60s, feeling well. She gets married. She comes into clinic. She's talking about wanting to become pregnant. So we talk about the pros and cons. A decision was made. We went back and looked at her old data and said, you know, it was probably acute EBV that caused these cytopenias, maybe not the Imuran. So we transitioned her to Imuran, 125 milligrams a day. She's about 70 kilos, transaminases in the 40s to 50s. She gets pregnant. She's super ecstatic. Her transaminase is actually normalized. She maintains on the Imuran. She has fetal demise at 16 weeks. The fetus is sent for pathology and shows CMV volitis. She had serum done which showed positive CMV titers. She saw a specialist who thought that this was likely a CMV reactivation as opposed to the de novo infection because of the previous CMV IgG. She comes back to clinic wanting to get pregnant and is terrified about using Imuran because she's talked to people across the world and has found someone else in who this happened. So we sat down and we had the discussion on how to proceed forward. And the options her and I discussed were one, staying on Imuran and hoping that this was a one in a million thing and we wanted to try and control her disease, switching her over to steroids, not knowing whether or not that was less immunosuppressive than the Imuran, coming off treatment altogether and watching her disease during pregnancy. So I'm wanting to see what the panel thought and then I'll tell you what's kind of happened since then. Is she cirrhotic? Oh, so that's the other important point. So throughout her course of disease, we had fibroscanned her probably three or four years ago. Her KPA was about five. So we re-biopsied her and her fibrosis was minimal now, zero to one compared to the F3 when she was originally diagnosed when she was 15. And how big is her spleen? Normal. And she had had an endoscopy done several years ago and it was normal as well. So of course, pregnancy is an immune-tolerant state and there are many situations, including what was described by yourself beside me, actually, those patients not on treatment did fine during the course of their pregnancy. And I have a bunch of patients who the only time they go into remission is when they're pregnant. Oh, and I should mention too, after she had her fetal demise, her disease did flare. Yeah. Of course, the issue is you've got to deal with any CMV that might be in the background. That has to be dealt with, or I'm sure you dealt with it. CMV titers are negative now. They became negative. Yeah. So... While still on the Imuran, CMV titers became negative. She continued on the Imuran because she had the flare post-fetal demise. So she's non-cirrhotic, so the consequences of a flare should be relatively mild. It's completely different if you were going into pregnancy in somebody with cirrhosis. I think you will do less harm with steroids, and there are many patients that you can manage just fine with steroid monotherapy, relatively modest doses, five to seven and a half milligrams of prednisone a day. Many will do just fine. It's like a recipe book. There are many different ways that you can achieve the same good outcome. The trouble is you cannot predict the outcome of any of them when you start. It's only in retrospect you can make a judgment. She's nervous about using the azathioprine now. I think I would probably just offer her steroids alone and see how she does. I would too, and just kind of really going back to the point... So, if you're converting and somebody has relatively well-preserved AST-ALT less than 50, 7.5 or 5 is probably enough, and then respond accordingly. You don't want to give her so much that you reactivate EBV or CMV or anything else and check for hepatitis E and all of these other things that have implications. I think when things are going in an unusual way, you've got to look for unusual stuff. Do you have a sense of when she reactivates her autoimmune hepatitis when you've tapered steroids in the past? She does, yeah. So, we've tried on multiple occasions over the years to get her down to the low level, and she's very sensitive. We've never really been able to normalize her liver enzymes, except when she was pregnant. That was one of the first times where her enzymes did normalize. Right. So, you might pick a dose of steroids where her disease is relatively well-controlled from historical data on her. You know, the other point would be how long do you wait as you switch from AST-ALT hyperlipidem to prednisone, and depending on if that's the right dose for her, you're risking a flare, and for how long do you watch before really recommending you can get pregnant now? Yeah, I think there's really no good data to tell us that. I would say that probably three months may be too soon, and six months is... So tolerating some liver enzymes in the 40s, 50s isn't terrible in somebody who has minimal fibrosis. So you better tell us what happened. Yeah. So we had this prolonged discussion. We talked about steroids and we talked about, I don't know if that's any more or less immunosuppressive. We talked about the potential cleft lip, all of that. So her decision at the end of the day was to come off everything and follow her liver enzymes. So I said, okay. So we just slowly brought her Imuran down over a month or so, following her enzymes. And I get a note from my secretary, she's pregnant. And so then her liver enzymes start to slowly go up again. So they'd been around the 40s. So they go up to around the 60s. So I see her in clinic a couple of weeks ago. She's about 12 weeks pregnant right now. She's feeling well. And so I think the plan that we had discussed along with her obstetrician, as long as she's feeling well and the enzymes weren't continuing to escalate, that we would monitor on no therapy. But if it got to the point where they were escalating, then prednisone was going to be the medication that we were going to institute. Has anybody seen any cases of CMV reactivation in this setting? No. I haven't. In transplant, yes, but more immunosuppression, but not in this setting. So would you, given the series from King's College where there were flares postpartum, would you put her on therapy postpartum, this particular patient? Well she has demonstrated that after she lost her baby that she flared. So I think she's mandated to have treatment as soon as she's willing to take it. And you may see that her liver enzymes are going to go up as she hits her third trimester and she's less immunotolerant. I know we're running out of time, but I really want to get this case in because it's... Thank you for that. Thank you, Jennifer. Yeah, that was a good case. Yeah. I know, that was great. What time is it? So we have a 35-year-old female who, I would be brief, who... I know, sorry, I think we're like five minutes over the session. But... Do you want to go? We might have to wrap up. Yeah. Should we just briefly... If you guys want to stay for the next few minutes, then you can go for it. Yeah. We'll be brief. It's a 35-year-old female who came to your clinic. She transferred care to you from another practice. She had AIH type 1 diagnosed in 2009. She's been on ESA type 3, 125 milligram, which is around 1.9 milligram per kilogram per day, and bedecinide, three milligram daily. Her liver enzymes showed mildly elevated ALT 30 to 40. Her IgG was 1,800, which is slightly higher than the upper limit of normal, and intermittently, she has not been compliant. She recently got married, and she wants to get pregnant. So this is a woman with optimized ESA type 3 mildly elevated IgG, but bedecinide just does three milligram per day time to get pregnant. So what would you do for this patient? Well, I guess I worry that her disease is not completely well controlled. So I would probably consider biopsying her, she's not pregnant yet, to get a sense of how active her disease is, how much fibrosis she has. So her hepatologist did do a liver biopsy and did additional mild lymphoplasmicytic portal interface hepatitis, but without significant fibrosis in, you know, holding the pregnancy till AIH is in remission was discussed. How would you optimize her regimen? F-note, since she's been on adequate dose of ESA type 3 for her weight, her 6TG was low, her 6MMP was high. What would you do for her? So the low 6TGN level would suggest she's not compliant, but the elevated 6MMP levels would suggest she's somehow preferentially metabolizing to that. So you know, I get really nervous when I have these women that are what I call funky metabolizers. They're not normal metabolizers. So I personally would take her off the azathioprine and switch her to something else. I also have not used budesonide in pregnancy, so I would probably switch her to, I can't use cell sept if she wants to get pregnant, I would consider putting her on prednisone and Prograf personally. That sounds like a good option. So her hepatologist did increase her budesonide 3mg TID to just optimize and left her azathioprine with a concern for, you know, if it stops, there is a flare. She was worried about prednisone with the risk of cleft palate, but the azathioprine was, dose was decreased to minimize toxicity. I guess Natalie mentioned about no known data on safety of budesonide in pregnancy. Do you have any experience with that? I have no experience. I don't know of any data specifically for budesonide in pregnancy. Almost all of the data, you know, both in transplant and other disease states is really with prednisone. Okay. So how about, so Natalie mentioned that she's a shunter, right? So would you use oliprenol to preferentially drive the metabolism to 6TG in this patient? Can't you start her on 6TG? Just give her 6... 6MP? No, 6TG. Uh-huh. There's recent data outside pregnancy that is relatively safe, well-tolerated, and while you can go for much lower doses, you can, I think, keep her on remission if you give her 5 milligrams of prednisone to get over 10 milligrams of 6TG. Okay. Yeah, we don't. So that's a very European approach, Dutch approach. It certainly works. The other option would be 6 mercaptopurine rather than 6MP. Again, it would potentially help. There are a couple of reports of olipurinol use in pregnancy. It's not terrible, but I think in the field, we're not really that used to using olipurinol with azathioprine. It's different in inflammatory bowel disease where you have a therapeutic window of thiopurine metabolites. We're surmising that our thiopurine metabolites more or less fit within the same kind of range, but the data is not strong in relation to that, whether it's in terms of dosing, underlying liver disease, and so forth. That would be my take. Actually, if you want to get on and she wants to get pregnant, you switch her to TAC. You know that it will have an effect quickly. Within a few weeks, you get good levels and move on. Exactly. Keep it simple. Can I just make a comment about the azathioprine levels? They're not for liver disease, they're for IBD. The second thing is shunting is common, particularly in the late stages of pregnancy, and you can simply split the dose, use a BD dose, and that will help the shunting if you are concerned about it. So you don't need to use olipurinol. There is an Australian series on olipurinol in pregnancy and IBD in relatively small numbers, sitting around the 20 mark, which doesn't show any problems, but there is a case report of a mycophenolate-like embryopathy, and they do use the same pathway, and so there is some theoretical concern about the use of olipurinol, and I personally wouldn't recommend it to anyone. Okay. I agree. All right. I'm sorry we went a little bit over today. This will end our session. We would like to thank our speakers and experts in the field for joining us for this excellent program today, and I also would like to thank all my co-chair and everyone at the Women's Initiative Committee for creating this important program. We definitely want to continue the same platform at future liver meetings, advocating or pushing for more education in women and liver disease. In terms of evaluation, please make sure that you give us your feedback and evaluation on the CME evaluation link, which is actually available on the meeting app, or you can also go on the ASLD website. Your feedback and suggestions for future topics would be very helpful. Thanks everyone. Thank you.

liver diseases in pregnancy

hepatic adenomas

autoimmune hepatitis

pregnancy planning

medication use

monitoring during pregnancy

treatment regimens