Good morning. Thank you very much, Rohit. I, too, would like to thank the organizers for the opportunity to teach you this morning about my favorite topic, liver fibrosis. Clicker doesn't work. I hope we don't have technical difficulties the rest of the morning. There we go. In the interest of full disclosure, we do participate in a number of industry-sponsored trials studying novel antifibrotics. I don't own any biomedical stock, and I don't accept money from industry, first speaking. What you can expect to learn today is to gain an understanding of the pathogenesis and, thus, an appreciation of the potential reversibility of liver fibrosis. This is a critical point, which I'm going to emphasize time and again. To be familiar with the expected fibrosis outcomes associated with different NASH treatment options and to recognize key clinical management issues in patients with fibrosis. This is an outline of what I'm going to cover. This is in your syllabus, and I would encourage you to follow along. We'll cover the clinical case and the questions. We'll talk about the pathogenesis of fibrosis, the reversibility of fibrosis. We'll cover the specific clinical questions that I was assigned, and I'll summarize with some key takeaways. So, our patient, the same patient we've had for the last two speakers, is our 52-year-old woman with type 2 diabetes and a BMI of 38. She now presents for bariatric surgery. We know that her diabetes is poorly controlled, and now she has gone on to have a liver biopsy, as was recommended, which shows a stage 3 liver fibrosis. So, the questions are, what is the likelihood of liver disease regression after bariatric surgery? Are there additional approaches, new drugs, to address her fibrosis, and should these be added to the surgical treatment? And if this patient is treated non-surgically for obesity and diabetes, are there antifibrotics that could be added to her regimen to treat her fibrosis? So, I think the first important thing to recognize in this space, which you've heard a little bit about, is that fibrosis is important. So, we really need to care about fibrosis. This is an elegant study from an Alaskan cohort of patients with hepatitis C who had liver biopsy at baseline and then were followed here for 10 years. You can see there the ISHAC fibrosis scores. Does my pointer work? There we go. So, in terms of the ISHAC fibrosis, patients with 0 to 1 fibrosis had a very high probability of being alive at 10 years, whereas patients with, excuse me, this is with complications of end-stage liver disease, the data are the same for mortality. But patients with advanced fibrosis here have a very high probability of having a complication of end-stage liver disease, and patients with intermediate degrees of fibrosis have intermediate outcomes. Another elegant study, this one from Sweden, studied patients for 40 years with liver biopsy proven fibrosis. Patients were then followed in Swedish registries for a mean of 20 years, and you can see this on the y-axis is the proportion of patients who were alive. And so, patients' controls in patients with F1 fibrosis were about the same. But if you've got F2, F3, or F4 fibrosis, your outcome is significantly altered. So, the first point, the first point is that fibrosis is bad. So, if you have a fibrosis, and even moderate fibrosis suggests progressive disease. Advanced fibrosis is associated with poor outcomes. So, we really need to understand how much fibrosis our patients have. Let's talk about pathogenesis. I think perhaps the most important point in the space of understanding pathogenesis of fibrosis and cirrhosis is that injury, regardless of type, whether it's NASH, hepatitis B, C, autoimmune disease, represents the liver's wound healing response to that injury. And the outcome is essentially the same, a fibrogenic response and ultimately cirrhosis with its complications. This is a cartoon that depicts the cell and molecular biology of the response to injury. So, in all parenchymal organs, there is injury typically to the epithelial cell in the liver of the hepatocyte. This injury to the epithelial cell then leads to recruitment of inflammatory cells, T-cells, macrophages, and K-cells, which then produce various molecules, which lead to activation of effector cells. The effector cell in the liver, of course, is the hepatic stellate cell, hopefully well known to all of us by now. And then the combination of these various molecules and cell-cell interactions, which are also abnormal in this wounding milieu, lead to activation. And I should also emphasize that in most forms of parenchymal injury, there is an autocrine loop in which effector cells self-stimulate. So fibrosis is dynamic, and the biology of this involves multiple different elements, cells, which I have shown you stellate cells are critical. Kupfer cells, endothelial cells, immune cells in the liver are also important. Multiple molecules in multiple different pathways. I would also emphasize that the matrix structure itself is not static. It is a dynamic one in which there are elements of deposition and degradation both. So perhaps some of the best evidence that emphasizes the dynamic nature of fibrosis comes from the hepatitis B literature. This is an old slide now that was given to me by Ian Wanlis, which is a trichrome stained liver of a patient who had cirrhosis. So I think you would agree this is high magnification here. This is nodular cirrhosis, low magnification of the same liver here in B. This patient then was treated with lamivudine for three and a half years and had, I'm not sure why, but had a follow-up liver biopsy, which is shown here. And I think we would all agree that that's a pretty normal looking biopsy. There are quantitative data in the hepatitis B space. These are data from Europe. In a randomized controlled trials of tenofovir and adefavir, patients received open label treatment for seven years and 348 patients had paired baseline and week 240 liver biopsies. And what you can see here are the proportion of patients who had different stages of fibrosis here, ISHAC stage 0 to ISHAC stage 6. And what I want to emphasize is that by year 5, the number of patients with advanced fibrosis is decreasing and there are even some patients whose fibrosis goes entirely away. In hepatitis B, there are even outstanding outcome data. This is an old study now, which hopefully you are all familiar with. This study was actually ended early because patients receiving antiviral treatment actually had reduced disease progression and reduced mortality compared to placebo. And I would submit to you that this was because their fibrosis improved. In hepatitis C, this is a very nice study from Italy that examined histamorphometrically livers in 38 consecutive patients with child's class A cirrhosis who had an SBR here after PEG interferon therapy. They had four year follow-ups and then they did picroserious red morphometric analysis of collagen, which is an outstanding way to quantitatively measure collagen. They did immunohistochemistry to detect smooth muscle alpha-actin, inflammatory cell CD34 and others. The bottom line is that there was a median reduction of 72% in the area of fibrosis. If you look at on the Y axis here, the area of fibrosis in pretreatment biopsies compared to post-treatment biopsies, you can see that the vast majority of these patients had a reduction in fibrosis. So outstanding evidence in hepatitis B and C after treatment. There actually are also data in autoimmune hepatitis if you relieve bile duct obstruction, fibrosis gets better. Probably the oldest data are in hemochromatosis in which if you deplete the liver of iron, fibrosis improves. Automatic hepatitis with abstinence and or steroids and then primary PBC with FXR agonist. So there's good evidence that suggests that fibrosis reverses. So let's turn to our specific clinical questions. So the first question is, what is the likelihood of liver disease regression after bariatric surgery? You've already heard a little bit of this from our previous speakers. So weight loss is effective. As little as 5% weight loss leads to reduction in hepatic fat as well as immunotransferases, reduces NASF score and histologic, meaningful histologic improvements are seen at 7-10% weight loss. Exercise, as you've heard, is also effective and likely improves histology as well as fibrosis. These are the data from the Cuban paper that you've already heard about. 293 patients with histologically proven NASH underwent lifestyle changes to reduce weight over 52 weeks. 88 subjects in this cohort lost greater than 5% weight. Weight loss was independently associated with improvements in NASH histologic parameters and all patients who lost greater than 10% total body weight had reductions in NASF. And as shown in this graph here, 81% of patients who had fibrosis at baseline had reduction in fibrosis stage. So massive changes in fibrosis with large increases or large decrements in weight. Perhaps the best evidence comes from a very recent meta-analysis, large meta-analysis of 32 studies which were retrospective in nature. They used variable methods and outcomes. These patients, there were paired liver biopsies in 619 patients which included 22 of the studies and fibrosis was assessed at the closest to one year interval as possible. The study included primarily women. BMI was very high at 49. Pre-surgery, post-surgery, 34. Most of these patients had Roux-en-Y gastric bypass surgeries. In this study there was complete, complete resolution of steatosis in 66% of patients, inflammation in 50% of patients and ballooning in 76% of patients. So what about fibrosis? The data are shown here in this forest plot. At the end of the day there was complete resolution of fibrosis in 40% of patients shown here. So remarkable results. There are some caveats with these data. One is that most of these studies were small. So the sample sizes were small. This was a retrospective set of studies and the overall quality of the evidence in the meta-analysis and systematic review was judged to be low. There were not a great number of patients with advanced fibrosis and cirrhosis. So in terms of obesity surgery, the data suggest that this clearly leads to improvement in steatosis, inflammation, hepatocyte ballooning and fibrosis. There is complete resolution of NASH in some patients. Evidence is largely in women with Roux-en-Y gastric bypass surgery and this has largely been shown in earlier stages of fibrosis. The data also suggest that there is an improvement in liver function in some of these studies. The current ASLD guidelines are shown here. Quote, it is premature to consider foregut bariatric surgery as an established option to specifically treat NASH and in compensated cirrhosis foregut surgery may be considered on a case-by-case basis. So I think there, although obesity surgery is clearly interesting and there are some intriguing data here, there are still many questions. So which type of obesity surgery? As you know, sleeve gastrectomy is gaining popularity and there are even now endoscopic approaches to obesity. What is the appropriate stage to intervene? Do we need to intervene early or do we need to wait until later? What is the appropriate BMI at which to intervene? And I think questions are going to ideally be answered with higher quality randomized controlled trials. So take home point number two is that it's alive and I think this patient has a substantial chance of having fibrosis regression and or reversal with obesity surgery. What we don't know is what are the predictors of a response and we really don't have long term data. So just a quick point about assessment of fibrosis. You've heard a little bit about this already. It is critically important that we assess fibrosis. Liver biopsy and histology has been the time honored and gold standard approach. However, this is largely a standard of tradition based on our founders in hepatology and I think we're now moving away from that. And you have seen the data in terms of serum markers as well as structural examinations of liver such as transient elastography. Regardless of what we use when we stage fibrosis it needs to be done longitudinally. We need to do this as non-invasively as possible. We need to use techniques that are widely available. My own bias is that a combination of blood tests and structural exams are probably going to be the most effective. I would remind you that physiologic measure of portal pressure is likely to be the best overall measure of outcome in patients with advanced fibrosis. Okay, are there additional approaches to address her fibrosis and should these be added to the surgical treatment? Couple of themes to keep in mind. So we may approach fibrosis at any of these various stages. We could eliminate inflammation. We might accelerate the reversion process by modifying the cells in the liver, stellate cells in particular. We might stimulate effector cell mediated matrix degradation which would be an attractive approach. We could block or inhibit effector cell function such as fibrogenesis, proliferation, contraction or motility and we might directly degrade matrix. There are a number of anti-fibrotic therapies with general, generally anti-inflammatory or anti-oxidative effects that have been studied in human liver disease and this table shows a number of these. Again, this is in your syllabus so I'm not going to go through all this in detail. The theme here is that these in general are not highly effective and although they're safe except for IL-10 and anti-TNF treatments, they just haven't been proven to be effective. What about stellate cell specific anti-fibrotic therapies? A number of these have been studied in human liver disease as well. So the ARBs we've heard a little bit about, farglitazar which is a PPAR gamma agonist, interferon gamma was studied in a large trial, profenadone, selimartin, statins. All of these appear to be safe but not very effective. Now when we think about NASH, I would encourage you to think about the different stages in the pathogenesis of the disease. So this is a bit of a complicated slide but really to simplify this, think about early disease, steatosis, lipogenesis, insulin resistance, hepatitis, the inflammatory portion of the disease, so inflammation, oxidative injury, activation of hepatic stellate cells, and then the fibrogenic component where there's active matrix deposition and turnover which involves stellate cells and other molecules. I've listed some specific drugs here that we might think about. I particularly like the ones that hit multiple levels of the pathogenic cascade and I've highlighted these here in color. The PPAR agonists are attractive, FXR agonists are attractive, statins and the ARBs. So, if this patient is treated non-surgically for herbesity and diabetes, are there antifibrotics that could be added to her regimen to treat her liver fibrosis? And I'll tell you at this point the answer is not clear. I do think there are some options, however. So this is a table that highlights a couple of compounds that I think would be attractive in this patient. The TZDs, you've heard a little about, but these are actually effective in reducing fibrosis but have significant side effects. The statins, I'll come back to in a second. Vitamin E, recent meta-analysis. I think the GLP-1 agonists are very attractive. They induce weight loss and really don't appear to have a lot of side effects. So what about the statins? So there is a meta-analysis performed two years ago, a very well done study, that examined 10 high quality individual studies, over 250,000 patients, over 50,000 statin users and 200,000 non-users in a variety of liver diseases, hep C, hep B or miscellaneous causes. They used various techniques to assess fibrosis, whether it was biopsy, serum tests or imaging. And you can see here in this forest plot, this is the effect on fibrosis in high quality studies and moderate quality studies is significant. So over time it appears that statins may be effective antifibrotic treatments. There are a number of large clinical trials now ongoing in the NASH liver fibrosis space. They're highlighted here. I'm not going to go through these in detail. We have data on a couple of these. Simtuzumab and Solanceratib have just been shown to not be effective. We're waiting on the data on these other three huge studies and hopefully one of these or more of these will be effective. I would also emphasize if you go to clinicaltrials.gov, there are over 100 clinical trials active in this space. So we're going to see in the next five to ten years multiple large well-designed studies to address antifibrotic treatment in NASH. So take home point number three is that single highly effective antifibrotics are not here yet. My own bias is that combinations will likely be needed. There are other options considered. In this specific patient, I think if she has, we didn't hear whether she was hypercholesterolemic or not, but I think if she is, she should be put on a statin. I think if she's a candidate for a TZD or a GLP-1 agonist, these should be added and I would talk to her endocrinologist. So our key takeaways are that advanced fibrosis marks patients for a poorer outcome, a very important prognostic indicator. Treatment of the underlying disease often leads to fibrosis regression. Much more data are required to better understand how to predict who is going to have fibrosis regression and why. Weight loss is probably currently the best therapy for NASH, whether it's obesity surgery induced or not, and there is hope for primary antifibrotic drugs in the future. Thank you very much.

liver fibrosis

reversibility

case study

type 2 diabetes

bariatric surgery

antifibrotic therapies