Well, thank you very much for inviting me and good afternoon everyone. So my charge today is to discuss optimizing the management for the long term and the problem of post-transplant recurrence of NASH. And these are my disclosures. And I'll hit on very similar themes to what some of the other speakers have discussed and I'll take you through part of the burden of pre-transplant non-alcoholic fatty liver disease, steatosis in the donor population, some perioperative considerations that are germane to NASH and the metabolic syndrome, review the post-liver transplant outcomes for patient with NASH, and what can we possibly do to prevent recurrence. So a central theme that you're seeing here at the liver meeting and that you've all experienced clinically is that non-alcoholic fatty liver disease is common. The prevalence depends on what population you look at. One in three Americans has some degree of fat in the liver. There's some ultrasound studies that estimate the prevalence at up to 50%. And if you go into enriched populations like bariatric surgery clinics, you're going to see 55% of patients with NASH and up to 12% with purging fibrosis. And unfortunately, we're seeing more and more new NASH. The incidence of new non-alcoholic fatty liver disease continues to increase in a stepwise fashion with obesity, with diabetes, and with leisure time, physical inactivity. And you can see by the darker colors in all of these heat maps that these are highly prevalent problems throughout all of the United States. To do a sort of a back of the napkin calculation to really put some hard numbers here in terms of the burden of non-alcoholic fatty liver disease, if you look at the entire United States population, ballpark about 325 million people, and you estimate that maybe about 30% of the population has some degree of fat in the liver, that gets us 97 million people. Of those patients, 20% are going to have NASH or will progress to NASH over several years. That's 20 million people. And even if only 5% to 20% of these patients with NASH progress to cirrhosis over a 5 to 20 year period, that leaves us with almost 4 million people. 4 million people with cirrhosis from NASH. And to put this in perspective, we've heard a lot about hepatitis C over the decades. Well, there are 3.5 million people with hepatitis C of all fibrosis scales. And when my GI colleagues talk about how bad ulcerative colitis and Crohn's disease and inflammatory bowel disease are, well, I show them these data. 1.5 million people with IBD in the United States compared to my 4 million people with NASH cirrhosis. To further put this in perspective, if we only listed 1% of the patients with NASH cirrhosis, more than double the size of the national transplant wait list. To show these data in another form, we all are well aware, and you've seen various forms of these graphs in the other talks, we are now seeing NASH increasing as an indication and etiology for liver transplant. Whereas hepatitis C goes down, thanks to the success of our treatment of viral hepatitis, we are seeing NASH increase along with alcohol, and we suspect that NASH is going to become the leading indication for liver transplant in both the U.S. and Europe within the next several years. While we're also seeing NASH in our patients with chronic liver disease, well, we're seeing the same fatty liver in our donor population as what was previous alluded to. And so, as the incidence and prevalence of NAFLD increase, you see it in the donors, and this sort of gives us a lot of pause when it comes to using these organs for liver transplantation. Historically, steotic livers have been associated with increased primary non-function and decrease to your survival at a threshold of about 30% steatosis. When it comes to living donor liver transplant, again, as alluded to earlier, most centers are really hesitant to use patients with greater than 30% steatosis, and ideally, they would have less than 10%. And a lot of this data that informs our personal belief of the risk of steatosis in liver grafts comes from a variety of studies that showed patients with 20%, 25%, 30% steatosis and longer cold ischemia times have decreased graft survival, decreased patient survival. And patients with greater than 30% steatosis in the graft have decreased patient survival. And so, you think about these problems that we're seeing within the community of increased fatty liver in the general population, and also some of the strategies that we're trying to use to expand the donor pool, like say donation after cardiac death, we're running into some problems. Around 2006, donation after cardiac death started to become more common. Unfortunately, instead of expanding the donor pool, what we found is that donation after cardiac death in a lot of situations was actually just replacing our standard donors, replacing donation after brain death. And with that, we saw a flattening of the amount of grafts that were donated and an increase in liver non-use when an organ from the same donor was able to be successfully transplanted. So, it wasn't a problem per se with the donor, like infectious disease or HIV, but the liver was bad and the kidneys were good. So, if you bring together these perfect storms of increased diabetes in the general population, increased steatosis in the general population, increased BMI in the general population, and you look at our current practices and utilization of donation after cardiac death grafts, we did this thought experiment that showed that if we continue our same practices, we're going to turn down more and more livers and we're going to do fewer and fewer liver transplants. Fortunately, this thought experiment has not completely come to fruition because a lot of aggressive centers and aggressive surgeons are challenging that old dogma about steatosis. And so, what we need to do is expand the donor pool, but also do it in a fashion that's safe for our patients. And I bring this study here that I was actually just e-pubbed a few months ago looking at using extended criteria donors, meaning our older donors, our donors with greater steatosis, our donors with longer warm ischemia times, and how do these donors perform when they're also DCD donors? And what the group out of Indiana University showed is they had a protocol, and when they were first learning, their outcomes were inferior. But through protocol optimization, through minimizing ischemia times, through doing different back table prep, and by their team getting all of their grafts, they were able to show that using these ECD, DCD livers, they had similar outcomes to their standard donors. So perhaps we do need to challenge some of the dogma about steatosis to continue to expand our donor pool. As we bring these patients with non-alcoholic fatty liver disease to transplant, there are a lot of perioperative considerations that we need to be aware of. Throughout all of the surgical literature, throughout the transplant literature, and throughout the ICU care literature, we realize that glucose control is very important. And it continues to be important at the time of liver transplant and shortly after liver transplant. Some of our fellows at UNC performed a qualitative systematic review of almost 4,000 transplants from 14 studies. And what they found were perioperative glucose levels greater than 150 to 200 milligrams per deciliter were associated with a lot of bad outcomes, including mortality, graft rejection, infections, but also problems with developing chronic kidney disease, as we've seen as a problem with a lot of our post-transplant patients. And among patients who did not have diabetes at the time of liver transplant, these hyperglycemic episodes in the perioperative phase were also associated with de novo diabetes after liver transplant. This intersects with the metabolic syndrome that we see in so many of our patients after liver transplant. We know that liver transplant doesn't cure the metabolic syndrome. In fact, liver transplant makes the metabolic syndrome worse because of what we have to do to try to control rejection. And so if you look at the effects of all of our immunosuppressive regimens on the metabolic syndrome, we see, of course, that corticosteroids make diabetes worse. We see that calcineurin inhibitors can impact new onset diabetes. They can make hypertension worse. They can contribute to chronic kidney disease. And our mTOR inhibitors make dyslipidemia worse. So our patients here are fighting an uphill battle and we need to be cognizant of this. We do see a lot of post-transplant diabetes. In a single center study that one of our fellows did, we looked at all of our patients who did not have diabetes going into liver transplant and found at one, three, and five years, a third and a half developed new diabetes after transplant. So I think this is something we have to be very cognizant of as we're worried about our patients with non-alcoholic fatty liver disease getting transplanted and then developing diabetes even if they didn't have it. Unfortunately, we didn't have a lot of great predictors about who was going to develop it. It was just higher risk in our older patient population. So with problems like metabolic syndrome from immunosuppression, with problems like new onset diabetes after transplant, of course we have to worry about the recurrence of NASH after transplant. This is a little bit older study that reviewed more than 2,000 transplants done at Baylor from the 80s up until the early 2000s. And what they found was that 20% of patients transplanted for NASH had recurrent steatosis at one year. So one in five had recurrent disease. At five years, 20% of these patients had recurrent steatosis, inflammation, and fibrosis. And they had a cirrhosis rate of about 1% per year. These patients suffered from bad cardiovascular outcomes. But fortunately, what they found was that long-term survival was similar to other indications for liver transplant. Now take this data. These data are from the 80s, 90s, and early 2000s. And so saying that long-term outcomes for NASH are similar to other indications for transplant, like say hepatitis C, well, that may be presenting a relatively low bar. Because now we know that our transplant outcomes for hepatitis C are going to be a whole lot better because we can cure hep C after transplant, whereas that may not have been the case during this timeframe. So again, we have to be vigilant. Looking at other studies that look at NAFL transplant outcomes, this is a summary of 11 single center studies that showed one year survival for NASH transplant between 76% and 90% and three year survival between 60% and 85%. A UNOS study done over the same time period showed similar survival again to other indications for transplant and summarized the survival at about 87% to 75% at one and three years respectively. Again, we're seeing similar themes of infection and cardiovascular outcomes as the cause of death. The national NAFL transplant experience through other studies has been the same. So just to reinforce this idea that to date NASH transplants have been the same as other indications for liver transplant. But as we're better about hepatitis C after transplant, again, this may be a bit of a straw man argument. Well, is it the non-alcoholic fatty liver disease or is it the other metabolic syndrome problems that cause or that contribute to our post-transplant outcomes? This is a single center study that we did back at UNC back when I was a fellow and looked at fatty liver as an indication for transplant say compared to other metabolic syndrome risk factors, particularly diabetes. And what we saw was that over the long term the transplant outcomes for fatty liver were the same, but where we saw a real decrement in long term survival was in our patients with diabetes. So again, hitting on a similar theme of diabetes before transplant being a risk factor for bad outcomes, diabetes in the perioperative phase being a risk factor for bad outcomes. Well, what can we do to prevent recurrence? This is an excellent review performed by the International Liver Transplant Society by Dr. Watt and colleagues who will speak later. And what they did is they went through 10 questions that were posed to a panel of experts, germane to NASH and the liver. Are there differences between pre-transplant NASH and post-transplant NASH? Are there differences in how we can do risk factor modification? What about recurrent NASH in the patient transplanted for NASH versus say de novo fatty liver in the patient transplanted for something else? In summary, we don't know. There is a lot of work left to be done and I suppose this could have been a really short talk if I could have said we don't know what to do about pre-transplant NASH, we don't know what to do about post-transplant NASH. But I found this paper thought-provoking nevertheless. So other things that we can do, thinking outside the box because we've been over this tired ground of diet and exercise which is really challenging to succeed with. Well, we talked about bariatric surgery before transplant for our NASH patients. Well, what about bariatric surgery after transplant for our NASH patients? And I thought this was a thought-provoking paper that was just published about two months ago looking at sleeve gastrectomy following liver transplant. The one thing to note here, this is a five-year experience with only 15 patients. So again, not a tremendous amount of data here but at least as a hypothesis building thought-provoking study, I found it interesting. Mortality rejection rate, 0%. So clearly that's a reasonable outcome in this very highly selected, highly hand-picked population and they were able to reduce the BMI of these patients from 43 to 36. What was most promising here though is 60% of these patients were able to get much better control of their diabetes and stop their insulin. Well, what about other things for treating recurrent NASH? Well, again, there are no FDA-approved medications for the treatment of pre-transplant NASH and none of these clinical trials have included post-transplant patients in their protocols. So we go back to looking at risk factor control. Again, hitting on diabetes, diabetes, diabetes, lifestyle interventions, diet and exercise. I had practice in Chapel Hill, North Carolina and I get people from three hours away in the coast and three hours away in the mountains and I can guarantee you every single one of those people knew about diet and exercise before they got in the car to drive to Chapel Hill, right? So how can I make this real? How can I make this tangible, reasonable? Well, I work with some really talented people in our clinic. Within our GI and liver clinics, we actually have an embedded clinical psychologist. And at first I was getting a lot of pushback about seeing a clinical psychologist. Doc, I'm not crazy. Well, I know you're not crazy. So what our clinical psychologist does is she works as a health coach. She helps us with adherence. Lots of people have the experience of sticking to an exercise regimen for six weeks or eight weeks and then real life gets in the way and everything falls to pieces, right? So she can help with adherence. The other thing that she's really good at though is within the liver world, of course we all recognize the patient with alcohol-induced liver disease who self-medicates with alcohol. Well, so many of my patients with non-alcoholic fatty liver disease do this with food, comfort eating, stress eating. And so unless we address the whole patient, unless we address themes of anxiety, depression, comfort eating, stress eating, we're not going to make a whole lot of headway with diet and exercise. It doesn't help the patient for me to say, hey, you've got to eat better. So we work with professionals who can go through their calorie content, how much protein, how much fat, how much carbohydrate. The line that I give my patients is that all of these diets work as you've seen previously. It's just whatever you can stick to over the long time. Portion control I think is an important theme here. There may be future clinical therapies, future medications that we can give based on the drugs that are in development now. And I'm a strong believer that not one of these drugs is going to work by itself and that it's combination therapy that's going to be the future. Finally, patient empowerment. No matter what medications we develop, much of NASH and the metabolic syndrome is going to be up to our patients. So we're really good at hammering into our patient's adherence to their immunosuppressive regimens. Well, it's also got to be adherence to glucose control. It's got to be adherence to their exercise regimen, dietary tracking. And through that, we can leverage technology. And again, one of our very talented fellows at UNC has developed this Live White app to try to help empower our patients. So in summary, keys to success in the age of NASH and liver transplantation include recognizing that NASH is going to be the number one indication for transplant and we really can't escape it. Patients and donors are going to have steatosis. Liver transplant does not cure the metabolic syndrome. It makes it worse through our efforts to prevent rejection. Diabetes, diabetes, diabetes. We have to optimize diabetes control before transplant, in the perioperative phase, and after transplant. Transplant outcomes for NASH, as we've defined them, have been similar to other indications for transplant, which is good news, but we have to be vigilant. And finally, innovation is the key. You just heard about organ perfusion techniques. We have to increase organ donations, perhaps through opt-out rather than opt-in strategies. Patient engagement, patient empowerment. And then finally, addressing NASH prior to cirrhosis, end-stage liver disease, and liver transplant. Thank you.

long-term management

post-transplant recurrence

NASH

non-alcoholic fatty liver disease

metabolic syndrome