Well, good morning, everyone. I'd like to thank the AASLD and the organizers of this course for inviting me to speak to you all. So I'll be speaking about getting the patient with NASH and obesity to transplant. These are my disclosures. And also, I have another disclosure. I am not a surgeon, as I was introduced. Again, I'm an interventional gastroenterologist with a big interest in obesity medicine and bariatric endoscopy. So we are currently amidst an obesity pandemic. Worldwide, there are 700 million adults estimated to have obesity. In the United States alone, 2 thirds of our adult population is either overweight or have obesity. And a third of these people have obesity. So we know obesity is a chronic disease. But why is it so important to talk about? And it's because it is a major risk factor for cardiovascular disease and diabetes. And pertinent to this talk, chronic liver disease, including cirrhosis and hepatocellular carcinoma. We know that the risk of developing non-alcoholic fatty liver disease, or NAFLD, is five times greater for persons with obesity versus without obesity. And in patients with biopsy proven non-alcoholic steatohepatitis, or NASH, obesity is independently associated with the progression of fibrosis. And we all know that further weight gain further promotes more fibrosis progression and can result in cirrhosis. And these patients have an increased risk of decompensation over the next two to five years and a higher risk of developing HCC. The current situation with NASH and liver transplantation, well, NASH has now become the second most common indication for listing of liver transplantation in the United States after hepatitis C virus. And this, of course, is in parallel to the rising rates of obesity. Patients with NASH cirrhosis are less likely to undergo a liver transplant due to various reasons, including a slower progression of their disease as measured by their MELD score. These patients are also less likely to receive MELD exception points. And first and foremost, patients with NASH, obesity, and cirrhosis have other comorbidities, including cardiovascular diseases. And these can preclude them from undergoing a transplant. And more humbling data has shown that these patients are less likely to survive for 90 days on the wait list compared to patients on the wait list for other indications. When it comes to BMI, interestingly, there is no strict BMI cutoff that exists in order to list or not list a patient for a liver transplant. BMI really is an imperfect measure of a surgical risk in patients with cirrhosis. And BMI fluctuates due to the volume overload as well as the variable distribution of visceral and subcutaneous adiposity. Contrary to what I used to think and what many of us may or may not know, you know, patient and graft survival between liver transplant recipients with or without obesity is quite comparable. And this was shown in the US Liver Transplant Experience published in 2017. Well, then why are we making such a fuss? Why do we need to address weight loss and obesity management prior to liver transplant? Well, these patients have less access to available grafts, particularly living donor grafts, due to the graft-to-bodyweight restrictions. We also think there are increased technical difficulties during surgery, including mean operative time, perioperative issues such as wound infections, dehiscence, longer hospital stay, and incisional hernias. And we also worry about recurrence of NAFLD and NASH in the donor liver. And we know that pre-transplant overweight status is a strong predictor for recurrence of NAFLD and NASH in the post-transplant period. So the management of the patient with NASH and obesity before liver transplant is complex and challenging. I think we've heard the word complex in every talk so far because it is complex and it is challenging. But the goals of evaluating and managing our patients are multiple and they include a thorough evaluation, again, of an intense worker for cardiovascular disease because of the presence of metabolic syndrome. We need to help our patients lose weight under a strict supervision. We want to help reduce and improve metabolic comorbidities and reduce the liver fibrosis progression. Overall, our goal is to improve survival weight while waiting for a liver transplant and provide these patients with more access to available grafts. So when it comes to treatments for obesity, they really fall along a spectrum according to the risk of the intervention and the efficacy. At the lower left, I want to point you to diet and exercise and what we call lifestyle intervention. Lifestyle intervention is the least risky intervention but also the least efficacious. Weight loss requires a very intense and well-driven multidisciplinary approach. This cannot just be your patient coming in and saying, as of today, I'm just gonna stop eating so much and start exercising. That doesn't work, that has never shown to work. You need a comprehensive program and in these patients, you need the quarterback, the transplant hepatologist, the transplant dietician, a behavioral psychologist, and all the other support including an obesity medicine specialist or bariatrician from the bariatric clinic. It's not just one person, it takes a village. So lifestyle intervention is the cornerstone of all weight management and particularly in the management of NAFLD and NASH. We know, let me see if I can point or not, this is, okay, you see it there. We know that by reducing caloric intake and exercising or even following the isocaloric Mediterranean diet that people can achieve complete resolution of steatosis. In the middle box, in order to really achieve an improvement or even resolution of NASH and regression of fibrosis, people need to lose even more weight. And this was beautifully shown in a study published in 2015 by a group in Havana, Cuba. They took 293 patients who had biopsy proven NASH and enrolled them in intense lifestyle intervention over the course of 52 weeks and then repeated the liver biopsies. And what the author showed was that yes, any weight loss is good because it will help improve the NAFLD activity score, improve some of the NASH, a little bit of fibrosis improvement. But until patients lose greater than seven or really 10% of their total body weight loss, that's the kind of significant weight loss that we need to encourage our patients to lose to really see complete resolution of NASH, steatosis, and significant regression of fibrosis. However, the reality is that again, if you look over to the right, at 10% total body weight loss, we get that study showed 100% or complete resolution of steatosis, almost complete resolution of NASH, and an 81% regression of fibrosis. But look at the number of patients that actually achieved the weight loss. It was only 10% of the cohort. So regardless, lifestyle intervention is still the cornerstone, the starting point of weight loss, but it sometimes may not be enough. And furthermore, patients who have cirrhosis have specific challenges. Many have sarcopenia, protein calorie malnutrition, poor functional status. They may not be able to engage in an exercise program. And many throughout the course unfortunately decompensates. So these patients have a lower chance of achieving their weight loss goal. So moving along the spectrum, on the other end, the extreme end, is bariatric surgery. So the role of bariatric surgery is still being defined today. But for the purpose of this talk, we'll talk about pre-liver transplant surgery and simultaneous bariatric surgery with a liver transplant. So pre-transplant bariatric surgery is really an option for a very small and selective pool of candidates because of the mortality risk related to surgery, to bariatric surgery. This was a big study that compared patients who underwent bariatric surgery. And they were broken up into patients who had decompensated cirrhosis, compensated cirrhosis, and without cirrhosis. And you can see that the 30-day mortality was 16% in patients with decompensated cirrhosis. That is, you know, that's significant. When it comes to types of bariatric surgery, there are really two most common surgeries really being performed worldwide are the vertical sleeve gastrectomy and the room-wide gastric bypass. Adjustable gastric band has pretty much fallen out of favor due to multiple reasons. So which one would you choose? Which one would you recommend for your patient with cirrhosis? Well, let's compare the two. On the left, you have the vertical sleeve gastrectomy. Well, it requires less operative time. It is a purely restrictive procedure, and the weight loss is more gradual. And then you have to think, you know, these patients may need ongoing surveillance of their gastric varices, portal hypertensive gastropathy, and either pre or post at some point may need an ERCP. And so this procedure does not preclude access to the stomach or the second portion of the duodenum. In contrast, you have the room-wide gastric bypass, which, yes, is a longer operation, and it is both restrictive because of the gastric pouch created and malabsorptive because the pouch, the food content's emptied directly into the small intestine. The weight loss is quite rapid, but it results in difficult access to the stomach and duodenum. So patients who need ongoing surveillance of their gastroesophageal varices and are at some point may need an ERCP, you know, it proves quite challenging. So let's talk about the advantages of undergoing sleeve gastrectomy prior to liver transplant. Well, we do think that it could help target patients with lower MELD scores and well-controlled complications of liver disease. The sustained weight loss after the sleeve may reduce the risk for further hepatic decompensation. It could improve the liver function to the point where perhaps maybe the liver transplant may not be needed for some time. And maybe there's some question as to whether the sleeve may result in a lower risk of intolerance to oral intake compared to performing both the sleeve at the time of the transplant. So this is a nice study that was published out of the group at UC San Francisco. They looked at 32 patients retrospectively who underwent a laparoscopic sleeve gastrectomy. We saw the median age of 55 years, the majority were women, and half of the cohort had a child PUB with a prior history, but not current history of decompensation. And what we saw of the 32 patients that underwent a laparoscopic sleeve, that there were really very few complications including renal insufficiency, transient encephalopathy, and unfortunately one patient had a gastric staple line due to retention of an orogastric tube. However, no reoperations, no 0-30 day postoperative mortality, no liver-related morbidity in the preoperative period. Again, mostly had a stable or improved MELD score at six months. And we can see that over the course of 12 months that there was a mean reduction of 11 BMI points, and that's significant. This data I thought was very interesting. So how did they do after? Because that's really what we're focused on. Well, 28 of the 32 patients were then deemed eligible to be actively listed for a liver transplant. Of the four not eligible, three had transferred centers, and one patient, again, had the gastric leak and was excluded from undergoing liver transplant. Among the 28 eligible patients, 14 underwent a liver transplant, whereas seven were deferred because of a lower MELD score, quote, maybe being too well. So in summary, performing sleeve gastrectomy before the liver transplant is feasible. But again, it can only be offered to a very small selective group of patients. It does have acceptable complication rates, and it does promote significant and sustained weight loss that may improve obesity-related comorbidities, and may ultimately postpone or delay the need for liver transplant. So now let's talk about simultaneous bariatric surgery and liver transplant. This is a figure taken from the group in Mayo Rochester, and you can see the sleeve at the lower right corner adjacent to the liver. So what are the advantages of doing combined operations? Well, both liver diseases and obesity are addressed with one operation, one hospital recovery. It can reduce issues with adhesions found at a reoperative surgery. It could potentially eliminate barriers such as insurance approval for a second, i.e., bariatric surgery. And perhaps some patients may prefer to avoid a second operation. So two for the price of one. So this is the protocol that was adopted by the Mayo Clinic in Rochester in 2006. Again, all patients underwent lifestyle modification if they had BMIs greater than or equal to 35 at the time of listing. If the patients were successful with weight loss and got their BMI to under 35 and the MELD score was high enough, they underwent the liver transplant. However, those that could not achieve the BMI less than 35, but needed to undergo a liver transplant, they were offered a simultaneous liver transplant and sleeve gastrectomy. With the sleeve gastrectomy performed as soon as the liver was transplanted. And what we can see here, so on the right in total, since 2006, there have been 45 patients who underwent liver transplant and 29 who underwent simultaneously. But this analysis looked at patients who had at least three plus year follow-up data. And so it left to 36 with liver transplant and 13 that underwent simultaneous operations. We can see that there was a significantly higher percent total body weight loss at all time points for patients that underwent the simultaneous liver transplant and sleeve compared to just liver transplant. And that the entire cohort, so 100% of the group that underwent the simultaneous transplant and sleeve maintained greater than 10% of their total body weight loss compared to only a third of the cohort that just underwent liver transplant. So that's significant. Furthermore, the patients that underwent the combined operations had a lower prevalence of hypertension, insulin resistance, and hepatic steatosis. And these patients also required fewer antihypertensive medications than lipid agents at the last follow-up. Survival was also not statistically significant between the two groups. So in summary, intense lifestyle intervention to lose weight before liver transplant is feasible in some patients. But the ones who needed more help, we did, the study did show that sleeve gastrectomy at the time of liver transplant did result in more profound and sustainable weight loss. And furthermore, long term, these patients were able to maintain more than 10% of that total body weight loss. So we've talked about surgery. Is there something in the middle for patients that maybe do not want a bariatric surgery or maybe cannot tolerate it? Well, up until recently, our options were limited, but now we have endoscopic bariatric therapies, or EBTs. So endoscopic bariatric therapies have allowed us to now provide an effective and minimally invasive treatment approach to obesity. It has increased treatment options beyond surgery, medications, and lifestyle measures, and they may be suitable options for selected patients. Again, in this case, we're looking at a bridge to surgery, a bridge to transplantation. I'll be talking mainly about intragastric balloon therapy. Currently, there are eight IGBs in the world market, three that are currently approved in the United States, and we know that their mechanisms of action are twofold. They do result in delayed gastric emptying and also promote early satiety due to the effects of the space-occupying device. And most of the robust data has been shown, has been provided by the single, the BIB balloon, Orbera. So the balloon is placed, this is an outpatient procedure under anesthesia, after a diagnostic of endoscopy, we pass this catheter, the balloon looks like it's like a spring roll, it has a sheath around it. We inject anywhere from 400 to 700 milliliters of saline, and we sometimes add a few drops of methylene blue. And then the balloon sits there in the stomach for up to six months. And we add methylene blue because, you know, in the event that the balloon should slowly deflate, for example, some of the first signs that the patient may see would be discoloration of the urine, it turns like a greenish color. So then the patient comes back, can you play the second, no, here it is, I can do it. There we go, so then the patient comes back at the six-month period. Again, this is under endotracheal intubation. We aspirate all the gastric contents, and then there's a deflation kit that comes with it. You puncture the balloon with the needle, you aspirate all the fluid until it's flat like a pancake, and then we pull it out through the esophagus and through the mouth with dedicated forceps. And this takes under 20 minutes. So how effective is the balloon therapy? Well, this is data from the US Pivotal trial that showed that when combined with lifestyle intervention, patients that undergo placement of an intergastric balloon can achieve three times the weight loss at the six-month period compared to just lifestyle intervention alone. And we also know that the majority of the weight loss will occur in the first three months of therapy. So what about intragastric balloon therapy in patients with NASH and obesity? Well, the data is limited, but I do think it is encouraging. And this is a complex, again, population to manage because there are special considerations. Again, if patients have gastroesophageal varices, they need to be very well assessed. That may preclude them from undergoing balloon therapy. Also, the severity of the portal hypertensive gastropathy as well, the balloon can rub against the gastric mucosa and increase the risk of bleeding. So this was a small study based out of Singapore published in 2012 that looked at eight patients that underwent balloon therapy versus 10 that underwent a control group. And they obtained liver biopsies pre- and post-balloon placement. And we see that there was a significant decrease in BMI, the NAFLD activity score, and a trend towards improvement in steatosis. More recently, last year, this was published by the Mayo Rochester Group. This was an open-label study of 21 subjects. And they took liver biopsies at the time of balloon placement and removal. All these patients had NASH. And we can see that almost all patients had improvement points in their NAFLD activity score. And there was fibrosis regression in 20% of these subjects. And last but not least, there was a study that was published in India at a single center that looked at five patients who underwent a liver transplant who had balloons placed. There was most common signs and symptoms were nausea and vomiting as expected. There were no deaths. So is there a role for intragastral balloon therapy as a bridge to liver transplantation? What does the future hold? Well, we obviously need larger, more prospective studies. These protocols need to be tailored to the high-risk patients. Unfortunately, insurance companies are not covering the balloon in most parts. It is strictly out-of-pocket cash pay. And then you worry about post-liver transplant weight gain. We know that patients, after they have the balloon removed, they're also at high risk of losing weight. So what can we do to sustain the weight loss? So in summary, you know, obesity and NASH cirrhosis are on the rise. And management of this patient population must take into account both liver and cardiovascular-related comorbidities. Effective weight loss is effective in improving and possibly halting NASH progression. But the target goal, if you can get your patients to lose at least 10% of their total body weight loss, that's really what they need to achieve to really see significant regression or improvement in fibrosis. And last but not least, and most importantly, a multidisciplinary approach is required to help provide the best options for achieving and sustaining weight loss. This involves lifestyle intervention. This involves clear communication with the bariatric clinic, with the surgeons, the hepatology team. And perhaps there's a role for me to perform endoscopic bariatric therapies. I think it will be, it's coming. So thank you for your time and attention. Thank you. Thank you for your questions and answers. Dr. Gomez, thank you so much for, again, such a wonderful, engaging talk about how we're going to get our, really, our growing transplant indication, getting them to transplant. Now I'd like to open up the floor if anybody has any questions. Please don't be shy to ask our panelists here. I have a couple to start off with. Carolyn, one of the things that you had mentioned were essentially saving the kidneys. And one of the cornerstones of post-transplant management is calcineurin toxicity causing renal dysfunction. And there's many different ways that people have managed that. And I think that, over time, I think that we kind of need to reevaluate, particularly with newer therapies that have come out for management. What are you doing right now to help save the kidneys? It sounds like I have to save the whales and the kidneys and all of that. But I think, in terms of immunosuppression, your goal is to have enough immunosuppression to prevent rejection, but not enough to cause other harm. So having a constant look at what are they taking and when you can reduce it is beneficial. For a long time, we thought that sirolimus would be a really good tool to minimize damage to the kidney but perhaps it's not as good as we thought it was. And so many of the patients that, in the past, that got switched over to sirolimus were kind of switching them back if they develop severe proteinuria to a different regimen. I think it's an evolving, in terms of the immunosuppression, I think it's evolving but I also think it's very multifactorial. And you can't look at the immunosuppression alone without also considering all these other potential things that are affecting the kidney. Thank you. Thank you. I think you were first. Who's first? Go ahead. Oh, okay, sorry, over here. Thanks, those are both excellent talks. This is a question for Carolyn. How do you counsel patients, post-transplant patients, on recreational exposure to water, water sports, swimming in pools, that type of thing? So there is a risk and that risk can vary depending on where you are and the time of year that it is. They just need to know that they shouldn't go in if they have cuts, that they really need to, really try and minimize their exposure to lakes, to rivers, even at the ocean, if there's a risk of exposure. And there always is to some type of infection. They don't want to not go in. They just need to know what the risks are and then they can make a decision for themselves. But some people have developed very severe, life-threatening, and in some cases, infections that have killed them as a result of those exposures. Even non-intentional, even when they think, I'm just going down to the river for the weekend and it's not that big a deal. So I think it's just having the conversation with them because they don't think it's a risk. Swimming pools? Swimming pools are okay? Well, they should be, if they're well-maintained. I have a couple of questions for Dr. Driscoll. As far as calcium and vitamin D supplementation, do you recommend that for all your post-transplant patients? I think that you could, right? If you look at the risk of bone loss at the time of transplant and then think about it in terms of prevention for future bone loss. I mean, if you were really worried, you could measure their vitamin D levels, which I tend to do at an annual visit. But it's not a bad thing for them to take. And then the second question was regarding the new Shingrix vaccine. You know, we used to tell them, you obviously don't get the old Shingles vaccine because it's live. But the Shingrix, I think, is not a live virus. What are you doing at your center? So I'd actually talked to the transplant infectious disease provider. And what he shared with me is that there aren't any specific data in immunosuppressed patients regarding Shingrix. And then he said, if the PCP offers it, let them take it. And I don't know what you do with your patients. Do you do anything? We offer the Shingrix now. We do. Yeah. We're still not recommending it at our center, which is good since there's no data. Right. Thank you. Hi, Carolyn. I want to thank you. For those of us that have been doing this more than 20 years, we understand that the patients we saw 20 years ago are in that group that have now progressed to be serotics or undergoing liver transplant. What I want to ask you, because I've looked at the guidelines but don't recall anything to this degree, because I do general gastroenterology, I also do inflammatory bowel disease. And they have a one-page checklist. It's called Cornerstones. And it goes through vaccines and all the different things, pap smears, what you should be doing on a regular basis with these patients. And I'm just wondering if there's something that's been put together for us back in general practice to look at all of those guidelines that you put out. So in terms of the post-transplant patients? Yep. There are, AASLD does have guidelines for management of post-transplant patients. I understand that, but is there a one-page tear-off that has it all in one place? I haven't seen that. We gotta work on that. Yes, good morning. This question is for Dr. Gomez. You mentioned that the cost of the gastric balloon was all out of pocket. Can you give us some idea of what kind of price tag are you talking about? Sure. It will vary depending on where it's performed, in a hospital or an ASC. Some practices may even bundle payments to include a certain number of visits with the dieticians. But you could look anywhere between $7,000 and $12,000 for placement, I know, right, for placement and removal. We have been working with trying to solicit letters of medical necessity to the insurance companies. Hi, Dr. Gomez. Excellent talk, I really enjoyed it. Thank you. I have a question with the balloon. How often are you monitoring those patients post, I guess, the insertion of the balloon? And I understand, do you do a two-week liquid diet or what's their diet once the balloon's inserted? Sure, great question. It's progressive. So the day, protocols will vary, but the general thought is the day of and the day after the procedure are clear liquids. And then for the first two to four weeks, it's some type of a liquid diet. We tend to progress to a blenderized diet because it provides patients with more options than just drinking a Boost Shake a couple times a day. But again, it's a lot of intense education and counseling because they have to attend classes with the dieticians and the behavioral psychologists to make sure that, you know, the goal is not just to lose weight and become more sarcopenic. It's to lose weight, but the healthy way. They need to take in enough protein every day. I also have a question. What's the chances of migration of that balloon placement? And also, do you have any data as to the success? How many patients actually keep the weight off after the balloon is removed? Great question. So the risk of migration. So overall, the balloons are very safe. There have been a couple of letters that were published by the FDA in the past two years with some serious adverse events. However, when you take a look at the overall adverse events, including the risk of death with the balloon, you have a higher chance of dying from undergoing a colonoscopy than you do placement of an intragastric balloon. But with that being said, there have been a handful of cases of reported perforation and migration of the balloon, which can oftentimes necessitate surgery. Your second question was weight recidivism is the big concern with the intragastric balloon. All patients will regain some weight afterwards just because the bodies, the delayed gastric emptying is no longer delayed, and there are interactions between the gut and the brain that reset the brain. But the patients that will have the best chances of maintaining the majority of that weight loss are the ones that already go into the program implementing lifestyle intervention. And furthermore, face-to-face visitor accountability. That was shown in a study in the Spanish group that compared patients that just underwent balloon versus balloon and had frequent follow-up. And patients that have frequent follow-up, essentially they're just being held accountable for their weight loss success. Those patients will achieve and be able to maintain more weight loss. Dr. Gomez, what is your definition after that six-month time frame of success? Is there a certain amount of weight that definitely should have been lost at that point, or what defines success for you? Well, the studies have shown that the balloon can help people achieve between maybe 10 to 13% of their total body weight loss at six months. There are no clear definitions at this point to define successful weight loss after the balloon is removed. But we do see an increase of a few kilograms after the balloon is removed. But one study that showed that if patients are able to maintain at least 70% of that weight loss achieved, then that would be successful. Thank you very much.

NASH management

obesity challenges

liver transplant

fibrosis progression

weight loss interventions

bariatric surgery

endoscopic bariatric therapies