Okay, we'll start just by seeing if anyone in the audience had questions directed towards our speakers before we get into the case presentations. Anybody? Okay. Let me just open this up. I guess we covered everything. I thought there was a Washington microphone. Well, as I said, we really wanted to try and make this session more interactive, and because this is prime nap time and I'm also the gatekeeper before the break, I strongly encourage you all, as you have questions, to please feel free to interject. You know, so the focus of this, I'm a visual person, so hopefully the slides help direct our conversation, but as a transplant hepatologist, to think about what are the cases that commonly come up, what are the questions that we are usually faced with, and what data do we have to direct our management for this very challenging patient population. So I have no disclosures. So this is our first case, with the focus being, is this post-transplant recurrence of NASH, or is it something else? So it's a 66-year-old gentleman. He has a history of NASH-related cirrhosis, and he's presenting six months after his liver transplant. In terms of post-op course, it's fairly uncomplicated. He had some mild renal insufficiency, was discharged to a physical rehabilitation center for about a month, but then did well and transitioned back home. In terms of relevant past medical history, as you can probably guess, has a history of type 2 diabetes, hypertension, CAD, and had a previous PCI, dyslipidemia, obstructive sleep apnea. Prior to getting decompensated cirrhosis, had class 3 obesity, but at time of listing, had class 1 obesity. In terms of social history, no alcohol use, denies any illicit use, no tobacco use. In terms of medications, at the time that you see the patient, they're currently on tacrolimus, 4 milligrams. Prednisone, still on 5 milligrams. They are on a statin, so some statin, 40 milligrams. Lisinopril-10 and metformin, 1,000, twice a day. In terms of physical exam, blood pressure looks pretty good, 130 over 80, heart rate is 70, and the BMI today is 34. So you get your labs. Creatinine comes back at 1.1, the tacro level is 5, AST is 50, ALT is 60. Your bilirubin is normal, as is your alkafos, albumin, platelets are 170, and your complete blood cell count looks pretty good too. So you look back at what their prior liver enzymes were, and the liver enzymes have been slowly uptrending over the past two months. Prior to that, they were normal. So your nurse looks at you, your patient looks at you, what do you do? Thoughts? So we were commenting as you were giving the case, it is a relatively hefty dose of tacro, but it looks like it's level-directed and the level is 5, so it's six months out. I guess I can't argue with that. It's a lot of tacrolimus to get to 5, I suspect. Still on prednisone at six months out. Again, just sort of thinking, are there other things we could do to perhaps permanently get off steroid? As was alluded to in one of the other talks, weight gain after transplant. We see it and it's a problem, and that's what looks like has happened here, that the patient's obesity has persisted, and it sounds like the weight has continued to go up. Broadly, these patients wind up getting an ultrasound or something and we will see steatosis. But post-transplant, I'm much more of an advocate of biopsy here when the transaminases become abnormal. I think a lot of our non-invasive testing for fatty liver and disease severity in the pre-transplant population don't really apply here and are, in fact, inappropriate to use. So this is somebody who I would start off with some simple imaging, but this person may be on their way to a liver biopsy as we see if we can perhaps finesse their immunosuppression. Okay, so we talked a little bit about these questions. So what is your threshold and what criteria do you use when you figure out whether or not you want to biopsy someone who's post-transplant and they have elevated liver enzymes? You touched on this too. So what's the use of other non-invasive modalities, including ultrasound, transient elastography, and then more sophisticated imaging technique? What is your level of concern for alternative etiologies in post-transplant patients? So specifically, if you're under a year out from transplant, what's your level of concern in terms of evaluating for rejection versus infectious processes versus other etiologies? And what factors impact what type of diagnostic approach you use? So how far out they're from transplant, what their metabolic risk factors are. Are there other things that we haven't talked about that go into your decision-making in terms of how you approach this patient? Any comments on any of that? Well, I guess I'm having trouble deciding whether I would react at all to a tiny bit of transaminemia at this point. You know, certainly the list of workup is quite conventional, you know, ultrasound, rule-out biliary imaging, or I should say biliary dilation, MRI if you're worried. You have no cholestatic features here on this one. Your immunosuppression is just right. I think... or I should say your tacro level is reasonable, although, you know, the question is whether you're clearly not a steroid-free program. A lot of people would have had them off steroids as was alluded to earlier and whether this person... You know, again, I don't know if you are a team that uses a triple immunosuppression or if you're really, you know, CNI. The last comment would be that I'm impressed at how good the renal function is given everything he's been through. So if you want to repeat the labs, when do you repeat them? Say you don't want to react too much to a one-time ultrasound elevation, so when do you repeat the labs? Well, he's probably in a once a month, once, you know, schedule at this point. I don't know what your protocol is, but it's... I have to say it's very likely they'll be worse next time unless you've figured out a... Maybe you've sent him to the gym. You gave him gym membership and he'll be better. Okay. And the only other... As for other pieces of information, maybe recent experience always guides my current practice for better or for worse. What was the CMV status of donor and recipient and is this somebody who's now just... He's six months out, has come off his Val site or reduced his dose? You know, we've seen that recurrence in this timeframe as well too. Right. So say this patient is low risk CMV based on donor-recipient. Does that change what you do? Keep... Stay the course. Stay the course. Look again. I've threatened him with the needle of truth. Okay. So you get an ultrasound as, again, you suspect. It comments on the presence of hepatic steatosis. You brought this up. We did check a CMV that was undetectable and the patient did get a liver biopsy. So the biopsy showed no evidence of rejection, no fibrosis, did show moderate steatosis with some mild lobular inflammation. They graded it as an NAS score of four out of eight. So what do you do now? What do you tell your patient? What's your management? There's a lot of hepatologists in the crowd. Maybe you could get some help. I think it's time for a pep talk. This is a guy who was transplanted for fatty liver disease. You know, depending on his personal experience with his journey through cirrhosis and decompensated cirrhosis, you know, a lot of these patients have had almost PTSD symptoms because of their ascites or variceal bleeding or things like that. And to show that, hey, you know, you are on your way back, you've got NAS. You've got four out of eight on your NAS score. And while you may not have any scar tissue, you know, this is six months with a new liver. And so I think that sort of pep talk really ground him in the reality of what we're seeing here and what we're going to have to do, acknowledging that he has to fight this uphill battle against insulin resistance and his immunosuppressive regimen. That's getting him back into the nutritionist. That's getting him to see the clinical psychologist. Something was referenced about gym memberships. He's 66. He can be eligible for silver sneakers, a Medicare program that will help fund taking him to the gym. So I think a robust pep talk is in order here. So that is my favorite answer. I'm very big on lifestyle modification. So thankfully in our transplant clinic we do have an embedded nutritionist who focuses on hepatology care, so both in the pre- and post-transplant settings, so they can be seen the same day. And she's excellent in terms of following up. So even for patients who live far away, she'll call them at whatever interval the patient is interested in following up with them. And we've actually had pretty good success, I think, as you mentioned, particularly for our patients who are transplanted for NAS. We do a biopsy. We show, again, that they have the disease. Even if they don't have fibrosis for a lot of our patients, that's really motivating for them. And so in this specific case, we had the nutritionist see the patient. They had very close follow-up, and over time we were able to get their BMI back down. We did kind of focus on the immunosuppression too, so we were kind of more cognizant of the steroids, tried to wean that off sooner. And so this would be a very happy, successful story. Okay, case number two is about long-term optimization. So this is a 52-year-old female. Again, had a history of NAS-related cirrhosis. This patient is two years out from transplant. Again, fairly uncomplicated post-op course, had some renal insufficiency, was at a physical rehabilitation center for about two months. This patient did have a liver biopsy fairly soon into their post-transplant course, so at two months, given persistently elevated liver enzymes. That biopsy showed some moderate steatosis, no steatohepatitis, however, and no evidence of rejection. Again, this is going to seem pretty familiar, so past medical history, type 2 diabetes, high blood pressure, coronary artery disease, dyslipidemia, OSA, and class 2 obesity. Again, in terms of social history, no red flags there. Their medications, only on 2 milligrams of tacrolimus, on lisinopril, metformin, and is also on insulin. In terms of their physical exam, blood pressure is a little elevated at 140 over 85. Heart rate is 75. Their BMI is 37. Labs from today's visit, the creatinine is 1.3. Tacro level, again, is good at 4. AST is 75. ALT is 100. Bilirubin, Alcapos, Albumin, all normal. Platelets are 180. Rest of the CBC looks good. You get a hemoglobin A1c, and it's 8.5. And then you have this beautiful lipid panel here. So, triglycerides, 400. This was fasting. HDL, 35, and LDL, 160. Of note, their liver enzymes were previously normal, last checked 3 months ago. So, of course, you get an ultrasound with Doppler, same thing. Shows you steatosis, nothing else really all that exciting. What do you do? Hepatologist in the crowd can also answer, if you want to participate. So, this patient needs risk factor control. Diabetes with an A1c of 8.5 is not managed to goal. The dyslipidemia is certainly there with the triglycerides and the LDL being through the roof. This is a problem that I see in, again, my broad catchment area, where they'll come to UNC for their post-transplant care, but perhaps they're seeing a local provider. And so the first question is, well, who is managing your diabetes? And if it's the primary care in a rural town in eastern North Carolina, I'm sure they're doing the best they can, but it's time, perhaps, to come back and see one of our endocrinologists. They're on metformin, they're on insulin. With the weight, laryngotide would be a reasonable choice, maybe to try to get the diabetes under better control and augment some weight loss with that BMI of 37. The patient needs a statin. They're not on one. I don't know how many times I can write in the chart, statins are safe in liver disease, statins are safe in liver disease, statins are safe in liver disease. So they need those things. Quite frankly, with steatosis but no inflammation and no fibrosis, that BMI, that A1C in those lipids, this patient's going to have a heart attack. Okay, so we can work on all of those things, but the I guess the new piece of information is a new Increase in the liver enzymes. Do you do anything about that? Okay, one answer is check them again depending on your Center some people are very Prone to biopsy you had mentioned a preview how how recent was that biopsy that you mentioned that was two months post-transplant They're now two years post-transplant Yeah, I think I think you have a clinical diagnosis here you have evidence of fat you have a Abnormality that's limited to transaminemia So, you know and and you have all these quite alarming Comorbidities that are not being managed. So you have a lot of work to do You can watch the liver enzymes in the background without doing a biopsy now because it'll probably just show a fatty liver inflammation So I think there is a lot of debate and it's very practiced The practice patterns are very center dependent. So I don't know if anyone in the crowd has her Opinion or want to comment some centers have a fairly low threshold to biopsy in this situation if you previously had the metabolic risk factors But didn't have the liver enzyme elevations and now that's a new problem versus if you've kind of chronically had them So I think the the reason in this instance Even though they've always had the metabolic risk factors the liver enzyme elevation issue is new and so again It's very challenging in the post-transplant setting to try and find your balance in terms of what your threshold is going to be for when You would do a biopsy. So again in this case, the biopsy was obtained Once again, no evidence of rejection They did have steatohepatitis with an NAS NAS scorp 7 and now they have peri sinusoidal fibrosis And they do comment that steatosis was seen involving over 60% of the biopsy and the ballooning hepatocyte Degeneration was very prominent So what happened? I I have a question Yeah, you didn't mention anything about the donor liver in either case were they good livers without a lot of fat to start with? So both cases they had a pretty robust donor So we talked a little bit about this what factors influence the likelihood of recurrent NASH So, you know the BMI post-transplant increased from 33 to 37 as you mentioned the diabetes is very poorly controlled So they're unmet formant and insulin insulin does cause patients to gain weight and in this case because you asked it is managed by the PCP alone, which for a lot of our patients who live very far away that typically is the case This lipidemia is also poorly controlled. They're not on any medications for this We do spend a lot of time talking about safety of statins and trying to be a proponent to get our patients on statin therapy if they aren't on it a lot of Times they had been on it and then we're actually taken off of it Just because a lot of primary care providers are very wary of any quote-unquote liver patient being on a statin And so we talked about this too. How can we further optimize their care? So, you know, what's the role for an endocrinology referral? What do you do in terms of your thought process for choice of medications? I think you had mentioned, you know considering GLP one agonists and the situation we talked about the role statins and then the other question that had come up and that we talked a little bit about and we'll have a longer discussion in the Next section is at what point do you start talking to your patients in the post-transplant setting about bariatric surgery? What's your thought process in terms of who you refer? And what's the practice patterns for your bariatric surgery practice there? I don't know if you have any thoughts Do you refer any of your post-transplant patients for bariatric surgery? Yeah, we we've been struggling For years our renal team is very Aggressive and interested in developing a stronger role for bariatric surgery. We talked to tie to one For a long time about what it takes to embed Bariatric surgery in a transplant practice. It's a little bit of an extreme and maybe we'll hear some more about that later so we've done a handful of Bariatric patients before and a few after liver transplantation and one thing though It's it's no picnic that one slide. We saw and we'll hear about it later Those those patients have long length of stay and a lot of a lot of struggles after After surgery Yeah, I think there's certainly a role first here for optimization of medical management the low-hanging fruit here is okay Let's get on a stat and let's control the diabetes and see if we can do that first So to what extent do you as the transplant hepatologist take over those things or do you essentially say these are my recommendations? But ultimately I'm going to defer to your endocrinologist your cardiologist your primary care doctor Because I think that's where a lot of patients get caught in limbo Yeah, this is done on a very case-by-case basis because I don't have the bandwidth that would be everybody's primary care physician I've written Refills, of course for for statins the anti-diabetic medications I don't do as frequently because I think those require a little bit more intensive management that I can't provide for Patients over the long term. I do make referrals to my local Colleagues and endocrinology or if I have somebody from a larger city There are colleagues throughout the state who can help take care of them and aren't afraid of a transplant patient So it's all about building that network And to have the endocrinologist involved here because they've got not just the diabetes but the dyslipidemia is an endocrinology Phenomenon, so I think having an endocrinologist here is important Okay, great. So our last case before the break There is always a question about the role of fiber scan in these patients whether how sensitivity of fiber scanning detection of stethosis or fibrosis and whether what's the What place fibroscan has if it can be placed? Frequent biopsy in these patients just for the sake of fibrosis Yeah, again, I think the question ultimately comes down to what is your main question you're trying to answer with biopsy So if your main question is how much steatosis how much fibrosis? I think there is a fair proportion of us who will use Fiber scan in the post-transplant setting obviously, you know kind of the real question that a lot of times The only other way we can answer is rejection. So it depends on what your level of concern is for rejection Obviously fiber scan can't answer that question for you Yeah, it seems like it's more of am I missing something question Okay, so last case And this is focusing on recurrent advanced fibrosis and cirrhosis. So this is a 68 year old female again Naturally the cirrhosis this person is now seven years post transplant They had a little bit more in terms of complications. They had AKI, but they also had a bioleak Requiring stenting they have had persistently elevated liver enzymes since the time of transplant and That of course led to the following liver biopsy at one year showed moderate steatosis. No steatohepatitis. No fibrosis Biopsy at year three showed steatohepatitis with an NAS score of five out of eight, but again, no fibrosis Biopsy at year six again, it's very dependent on where you practice, but this patient had a lot of biopsies They had steatohepatitis now NAS of six and stage three fibrosis Again, this is going to seem very familiar has type 2 diabetes hypertension dyslipidemia Also had hypothyroidism OSA and class 2 obesity no red flags in terms of social history In terms of medications around two milligrams twice a day of tacrolimus, lisinopril, insulin This patient is on a statin. So simpa satin 40 blood pressure again slightly high 140 over 80 heart rate looks good. Their BMI is 36 and these are your labs Creatinine 1.2. Tacro level looks good at 4 AST is a hundred ALT is 80 bilirubin alkafos albumin Look, okay Platelets are now 130 hemoglobin 12 white blitz. I'll count for their a1c is 9 Hdl is 35 triglycerides 300 LDL 110 again. This is a fasting lipid profile How do you manage this patient? The once again the Elephant in the room is the a1c of 9 and the market dyslipidemia If nothing else if we can get a silver lining to this case Is that she has taught us something where you know in the pre-transplant liver? We see fatty liver evolve on a glacial scare scale years decades to advance the cirrhosis This patient has gone from what was presumably a liver with no steatosis and no fibrosis to cirrhosis in seven years so Getting on this earlier and being aggressive as much as we can I suppose should be the lesson now that she's 68 cirrhotic post-transplant with an a1c of 9 Not going to be a retransplant candidate. And I think what we need to do is Get her into the endocrinologist control that that diabetes Expect her creatinine elevation is in part from her diabetes, but also probably in part from her long-term tacro I Think we have to medically manage this as best we can So in terms of medication choices you you talked about the antibet diabetic regimen So again to what extent you want to weigh in versus having somebody like this who has very poorly controlled diabetes Specifically managed by one of your endocrinology colleagues I don't know if you have any specific thoughts in terms of how much you care which statin they are on Once you get to the point of somebody having either f3 fibrosis or cirrhosis And then what do you do in terms of progression of fibrosis technically the biopsy said f3 didn't necessarily say cirrhosis But with the platelets and other things in mind you worry about that and then okay Of course that brings up the questions of at what interval what modality do you use if somebody has f3 as opposed to? Cirrhosis, what do you do in terms of your thought process for HTC screening? Obviously, we talked a lot about multidisciplinary management And then you brought up also So for a lot of these patients particularly if they're getting transplanted in their 50s 60s at what point? Do we have to start talking about? retransplanting this patient population for the patients who didn't modify their lifestyle risk factors ultimately going to get Recurrent disease so that we're going to be left with a fair number of patients who essentially get cirrhosis again You Ruled them out. You ruled her out for retransplant right it was off the bat. I But even if you didn't rule them out, how are you gonna get them transplanted? You know, they're Once they're Billy Rubin and Kratten go up. They're gonna be Undoable and they're not going to get access to retransplantation. So you might as well Optimize medical management, which is what we've been doing I Worried that once this patient would have a competitive meld score to get transplanted They're not going to look like anybody that you're going to want to transplant In terms of some of the other questions monitoring for progression to fibrosis It sounds like we've got a biopsy that may say stage three but our clinical gestalt is that she does have cirrhosis So, I don't know that monitoring for progression of fibrosis through further biopsy or imaging or anything else like that from a fibrosis perspective Changes our management. I think screening for varices if we think that she's erotic and has a low platelet count Sorry, I forget what the platelet count was. I think that's a reasonable thing to do I think screening for hepatocellular carcinoma is a reasonable thing to do because we have modalities Short of transplant in which we could treat hepatocellular carcinoma if it arised So I think routine cirrhosis care and risk factor Modification is a is the thing to do So your major concerns in terms of retransplantation is the fact that their diabetes is so poorly controlled or why? Did you automatically say this is not a patient that I would consider retransplanting the the combination of age medical comorbidities? and lack of change and lifestyle that led to relatively rapid progression of Post post transplant cirrhosis. Got it. Okay. Well, our time is essentially up. So in terms of key takeaway Recurrent NAFLD and NASH are very common post transplant. Although the precise incidence remains unknown Recurrent disease can make evaluation of elevated liver enzymes post transplant very challenging and liver biopsy remains a key modality to definitively assess this Specifically if you're concerned about rejection Medication management should include evaluation for the role of statins specific choices of antidiabetic agents specifically whether or not There's a role for changing or adding a GLP one agonist obviously also focusing on anti hypertensives ideally, this is done in conjunction with endocrinology and cardiology because as we said, you know, it's hard to all of a sudden become the PCP for these patients and Then lastly recurrent advanced fibrosis and cirrhosis will pose challenges in the long term for this patient population Ultimately with the questions that we'll have to answer is what's the impact and role for retransplanting these patients? Thank you very much

post-transplant patients

NASH-related cirrhosis

elevated liver enzymes

metabolic risk factors

liver biopsies

retransplantation considerations