It's a great honor to debate my good friend and mentor, Dr. Kim Watt, who also happened to be my boss at Mayo. So I'm holding Dr. Eckstead responsible if I lose my job after this debate. So before we get started, if you may raise your hand if you've ever seen cirrhosis from recurrent fatty liver after liver transplantation. So not too many hands, that makes my job a little more difficult. So let me walk you through the data. You know, I don't want to tell you that NASH is common indication for liver transplantation, but I want to tell you something a little bit different, that NASH is the most rapidly increasing indication for liver transplantation in young adults, in young adults aged between 18 and 40 in the United States. Those folks who are young and you expect to live long enough after liver transplantation. So let's start with something we all agree on, which is steatosis is very, very common after liver transplantation, whether patients underwent transplant for NASH cirrhosis. So recurrent steatosis happen in up to 60, 70% of these patients at five years after transplant, or de novo steatosis, de novo steatosis among patients who underwent transplant for different indications other than NASH, around 30 to 40% of them have steatosis at five years. So I think it's not debatable that steatosis is very, very common after transplant. What we are debating today, whether steatosis matters after liver transplant. Dr. Watt going to persuade you perhaps with this paper from Mayo Clinic that showed steatosis does not matter after transplant, that does not affect survival outcome after transplant. You see here steatosis post-transplant and no steatosis post-transplant and the two lines like overlap where there is no statistically significant difference between the two groups. However, we're not talking about steatosis. I mean, we know from the non-transplant world, outside transplant, that really fibrosis matters. We know that the most important predictors of clinical outcome, including liver-related outcome and all-cause mortality would be fibrosis and steatohepatitis rather than steatosis. I tell my fellows that steatosis with fibrosis matters, steatosis without fibrosis, arguably perhaps doesn't matter that much. So is fibrosis common then after transplant? The answer is yes. This is old paper from Pittsburgh Group, but I found it very important because they end up doing protocol liver biopsy in patients who underwent transplant for NASH, similar to what we did for a long time for hepatitis C, protocol liver biopsy. And if you take, they follow these patients, the mean follow-up time was approximately 18 months, and you will see that around 50% of patients with NASH had stage 1 fibrosis during that 18-month mean follow-up compared to 32% hepatitis C. What's frightening, actually, at that relatively short follow-up period, 7.6% of those patients had advanced hepatic fibrosis, stage 3 fibrosis. I did a paper with Dr. Ektesad some years ago, similar paper, where we looked at the Cleveland Clinic at the progression of hepatic fibrosis after liver transplant in NASH compared to hepatitis C. So you will see here at approximately three years after transplant, close to 50%, 50%, half of the patients who underwent transplant for NASH already have some degree of fibrosis progression. It's still much worse with hepatitis C, but I would argue it's fairly significant. So why then I didn't see many hands in the room about the presence of cirrhosis after transplant? Why Dr. Watt could not see a difference in the Mayo Clinic paper? And the reason why, I believe, because when you talk about NASH, relatively speaking, it's a slowly progressive disease. We know that to see a clinically significant outcome, you need to follow these patients long enough. We know from the non-transplant world that this is a Minnesota, Olmstead County paper showed that really the two lines between NASH versus general population start to separate at approximately seven to eight years. So and speaking of long follow-up, Dr. Al-Khoury and I did a paper looking at the UNOS database. We looked at the long-term outcome of liver transplant in young adults, young adults. We chose that populations because we were looking for long-term outcome. And you will see, if you look at the long-term outcome of liver transplantation in young adults with NASH, around 4% underwent re-transplant for a current fatty liver, for a current fatty liver. The re-transplant rate in this paper was close to 11%, but only 4% to 5% underwent transplant for re-transplant for a current NASH. So I'll switch gear here a little bit and let me take you outside the liver. Let's forget about the liver for a second. Dr. Watt once said in a landmark paper in 2010, the two most common causes of morbidity and mortality after liver transplantation, number one, cardiovascular event, and number two, de novo malignancy. So let's talk about cardiovascular event then, the most common cause of problems after transplant. We know that NASH is associated with the production and secretion of VLDL, which is rich in triglyceride. It gets into the bloodstream and will be slowly metabolized and oxidized into LDL. It will be subject to replacement process that leads to the formation of the LDL, which as you know, it has an important role in atherosclerosis. Additionally, NASH is associated with the production of inflammatory markers and vasoactive thrombogenic markers that also contribute to atherosclerosis. This intimate relationship between NASH and dyslipidemia has been highlighted recently in post-health analysis in the PIVEN trial, where they showed that resolution of NASH is associated with improvement in triglyceride and HDL. This is, of course, outside the liver transplant. And we know that the patients with NASH had endothelial dysfunction, which plays an important and early role in atherosclerosis. You will see here that patients with NAFL had endothelial dysfunction that gets worse when you develop steatohepatitis and fibrosis. In a recent paper published in Hepatology, looking at the relationship between NASH and atherosclerosis in close to 2,500 patients, they showed that the prevalence of carotid stenosis is more common in patients with NASH, and the same, the prevalence of coronary artery calcification is more prevalent in patients with NASH. And this is after adjusting for confounding risk factors. So indeed, in that paper, they showed that the presence of NAFL, the presence of NAFL is independent risk factor of atherosclerosis, independent of other traditional risk factors such as age and other traditional cardiovascular risk factors. And if you add the fatty liver index to the traditional cardiovascular risk factor in Framingham score, you will better predict who will end up with cardiovascular outcome. Of course, everything I just presented in the last minute or so was non-transplant data simply because, unfortunately, we don't have a lot of post-transplant data. But I highlight this paper also from Mayo Clinic. Looking at risk factor of cardiovascular event post-transplant, the presence of pre-transplant NASH is an important risk factor with odds ratio of 2.35. So let's go to malignancy, the second most common cause of morbidity and mortality after liver transplant. We know that NAFL is independent risk factor of malignancy. It's associated with increased risk of breast cancer in women, colon cancer in men, and liver cancer in both men and women. Someone may say, well, this is all about the obesity, right? We know forever that obesity is risk factor for malignancy. Well, guess what? When they split the study population into two groups based on the BMI, they found that the association between NAFL and breast cancer was stronger in non-obese female patients. So I do believe that this is independent risk factor of NAFL rather than just the obesity. It seems like the worse your NAFL, the more likely you're at risk to get malignancy. And lastly, it turns out NAFL is associated with lower quality of life. This is analysis of European NAFL registry. Well, they showed substantial burden of symptoms, including fatigue, emotional functioning, et cetera, in patients with NAFL. And after adjusting for a lot of confounding risk factors, it turns out that lobular inflammation is significantly associated with lower health-related quality of life. So if you have no lobular inflammation, you'll be happy. If you have significant lobular inflammation, it seems like it may affect quality of life. So in summary, NAFL recurrence and de novo NAFL after liver transplant, very common. The long-term impact, the long-term impact of NAFL on allograft survival post-transplant remains unclear. NAFL is independent risk factor for cardiovascular events and malignancy, the two most common causes of morbidity and mortality after transplant. So with that, the ball is in Dr. Watts. Great. Thank you.

NAFL post-liver transplant

NASH impact on young adult transplant cases

fibrosis progression in NASH patients

cardiovascular events and malignancy in NAFL patients

allograft survival in NAFL post-transplant