And now, to a hot topic, reflux and dysmotility in the bariatric setting. And for that, we have Barham Abudaye from the Mayo Clinic in Rochester, and he's going to talk to us about reflux, dysmotility in bariatric patients. Thank you. Thank you, moderators. Thank you, Vani and Pratik, for the kind invitation. As discussed, this is a hot topic. If I could get my slides. It's a new topic, so forgive me if we don't have all the answers, or if I'm not as facile as some of my brilliant colleagues in foregut physiology, I'm just a simple advanced endoscopist at the end of the day, but I'll try to do my best. So these are my disclosures, and also I'm going to be discussing some off-label therapeutics toward the end of the talk, and I will make sure to mention these off-label uses toward the end of this discussion. So we really have a huge unmet need, because we have a catch-22 phenomena here. The disease of obesity is a problem, and its treatment is a problem for reflux and foregut physiology, both dysphagia and reflux. So that is a perfect storm for no easy answers, and a lot more to learn to offer patients some solutions. Let's start by talking about the disease itself. We're approaching 50% of the U.S. population being classified as having obesity, and the rates of severe obesity, they're also increasing, and in response to that, we're seeing an increased number of bariatric procedures, with the predominant procedure being the laparoscopic sleeve gastrectomy in 80% of patients, which we know now has clear implication on foregut physiology and reflux. So obesity itself is a huge risk factor for affecting the foregut physiology and reflux, with symptomatically and objectively, and increased risk of cancer. You could see that obesity is associated with increased Demiester score, increased acid exposure time, correlation with erosive esophagitis, and increased risk of adenocarcinoma of the esophagus. The biggest risk factor for reflux, so if you look at the y-axis plotting the BMI of the patient, and here if they have a hiatal hernia, plus heartburn symptoms, you could see at the BMI of 30, there's a clear inflection point showing the risk of obesity on gastroesophageal reflux disease. So to understand the impact of obesity on foregut physiology and reflux, and the impact of treatment of obesity on this physiology, it's very important to understand that this is not a simple physiology, because it's really an orchestration between three different things. You have preload, so let's use analogy on the heart. You have the preload, which is esophageal clearance. You have afterload, which is gastric pressure. And then you have the antireflux barrier, and the antireflux barrier, I refer to it as a barrier because it's a conglomerate of three different things, not just the lower esophageal sphincter that we as gastroenterologists are very accustomed to. So here we're showing two components of this antireflux barrier, and I will introduce the third very shortly. But the lower esophageal sphincter is truly, it's not just a sphincter, it's mostly a sling plus clasp, which is accentuating this angle of HISS. So that's one component. An equally important component is the diaphragmatic hiatus, which also is suspending this complex anteriorly and creating this angle of HISS. And then the third one, which is not shown in this review, which we now understand it's quite important, which is the gastroesophageal flap valve. So these are the three components of the antireflux barrier, and we need to think about them equally when we're talking about obesity and we're talking about how the impact of treatment of obesity, like bariatric surgery, affects this physiology. This comes from Ning Nguyen and the UCI group. And these are the three components of the antireflux barrier, the diaphragmatic cross, this is the G-junction flap valve, and this is the lower esophageal sphincter with its clasp and sling fibers as shown here. Now when Dr. Hill defined this flap valve, in his initial experiments, if you go back to these old experiments, he did that on cadavers. And the reason this is important, because in cadavers, obviously, the lower esophageal sphincter is not functional. It's not a sphincter anymore. And you could see that this flap valve was sufficient to prevent reflux because of this phenomenon. So what did Dr. Hill do? He took cadavers. He obstructed the stomach and the esophagus, creating a closed system, and start putting liquid in the stomach and seeing at what pressure that liquid start escaping to the esophagus. And that was purely a function of this flap valve. That's why this flap valve is an important concept of the antireflux barrier. And simplistically defining this flap valve, if you go in a retroflex position, you have to do it in short retroflexion to get an idea. And as we discussed this morning, you have to put maximum insufflation because you want to try to open this hiatus. Because if you truly have reflux, you will likely have a hiatal hernia. So in a normal phenomenon, you could see that if you look in a short retroflexion at the depth of the fundus, you could see a flap valve that's measuring about 2 centimeters. And there is no gap between the scope and the lower esophageal sphincter, as shown here. In a situation where there is HG2, which we said is challenging, but you could get clues. The biggest clue is you start seeing effacement of that flap valve. You start seeing it shorter than in a HG1. And if you observe over a couple of inspiration-expiration cycles, you're going to see what I call a smiley face. You're going to see that there's a gap that intermittently appears between the complex and your scope. HG3, you have complete effacement, but you still do not have migration of the entire complex above the diaphragm. And then HG4, you have clear hiatal hernia, and you have migration of the complex above the diaphragm. And you could see that the more defects you have in this anterior reflux barrier correlates highly with pH scores, as shown on this figure from Shaheen and DeBeester. So show of hands, this is HG what? Or shout it out. Three. Yeah. So you're all experts in this. You see there's effacement in the flap valve, and you have a gap between the scope and your complex, and that's a HG3. And this is pathologic. There is no anterior reflux barrier here. So you could give the patient PPI, you'll treat the acid component of it, but the regurgitation component and the volume reflux is likely unaltered. Now we talked about the disease of obesity and its impact on foregut physiology. With the idea of the physiology I just gave you, clearly the solution of obesity, these are the two main surgeries, the laparoscopic sleeve gastrectomy and the rho-Y gastric bypass. Clearly they affect the foregut physiology and could be correlated with both dysphagia and reflux. Simplistically, why is that? Let's look at the phenomena. One is you're creating a restricted afterload. In sleeve, you have the sleeve that is dissected and does not accommodate. In the bypass, you have a restricted pouch that does not accommodate and relax. So the afterload on the esophagus is increased. So when you have a phenomena like in the heart where the afterload is increased, then eventually with time, the esophagus will tire out and you'll have some dysmotility of the esophagus. So you have an afterload on the esophagus. You have poor clearance of the esophagus eventually. And the third insult that happens with these surgeries is people lose a lot of weight with these surgeries. And if you do not have a hiatal hernia before, you will likely develop a hiatal hernia after because there is a phenomena where there is a fat pad that is wedged in the diaphragmatic hiatus before the weight loss. And that fat pad dissolves. And now you have a clear hiatal hernia that I will show you some nice videos of that to accentuate this situation. So let's look at bariatric surgery and its impact on foregut physiology. This is a meta-analysis of 27 studies, including 600 sleeve patients and 470 gastric bypass patients. And this is limited to the short term. These are studies limited where they did physiological testing, pH, and manometry before and a few months after surgery. Now, not a few years after surgery, a few months after surgery, but that gives us some inclination of what's happening to the foregut physiology with bariatric surgery. So let's start with the sleeve gastrectomy. To summarize this table in simplistic term, if you look at manometry, in the short term you'll have a decrease in lower esophageal sphincter pressure. You have this decrease in the esophageal amplitude of contraction. So you're already seeing this increase after load on the esophagus affecting the esophagus even a few months after surgery. And then you have increased incidence compared to baseline of ineffective peristalsis. On pH, as expected, you have increase in total acid exposure time, both in supine and recumbent. And you have increase in total number of reflux episodes. Now on row-wide gastric bypass, you obviously removed most of the parietal cell mass, but you're still seeing a similar impact on the esophagus. You're still seeing ineffective peristalsis. On pH, you have decrease in acid exposure time, but the number of refluxing episodes are not changing. That means you still could make some acid and reflux it after gastric bypass, or if you have a short limb, you could start refluxing bile as well. Now we started getting intrigued by the impact of these procedures on the forecut physiology, and we scope a lot of patients after these procedures. So we started doing endoflips on a lot of these patients with symptoms and without symptoms to see what's happening to this physiology when we're scoping these patients. In a normal endoflip phenomena, you could see that this is the endoflip probe, and you replace it across the GE junction. You have the distensibility index, and this 16-centimeter balloon gives you an inclination of secondary peristalsis, as John showed us earlier. So what do you expect to see in normal anatomy? You see these repetitive anti-grate contraction, and you see that there's relaxation of the lower esophageal sphincter here, and that's what you expect to see in normal physiology. What we start seeing is this is normal. What we start seeing in sleeve patients, even at one to two years after the operation, in some significant portion of them, not everybody, it's about 40% to 50%, is you start seeing that on endoscopy there is no stricture, so there's normal GE junction, but you start seeing that there's poor relaxation of the GE junction complex. Instead of having these repetitive anti-grate contraction, in percentage of patients you start seeing these clear repetitive retrograde contractions. So indicating an increased afterload on the esophagus, and this afterload, if left unchecked over years, and we've seen that now when we documented this phenomenon, you have a pseudo-Ecclesia type of picture, where you have a low distensibility index of the GE junction with normal endoscopy, and could be normal manometry, and then you see absence peristalsis in the esophagus, and that's a function of time. We could correlate the time from surgery with this changes in repetitive retrograde contractions and the absence peristalsis in these patients. So why this happens, we don't know. It's the increased afterload pressure on the esophagus, changes in nitric oxide, acetylcholine signaling, or nerve damage because of surgery, we do not know, but we define this entity as POSIT, or post-obesity surgery esophageal dysfunction, which is a new entity. We classified it on endoflip, and in endoflip you could see that the combination of normal EGD with low distensibility index of the GE junction, and either absent peristalsis or disorganized or repetitive retrograde peristalsis is what's defined as endoflip. A more rigorous diagnosis, which we defined here, comes from high-resolution manometry. We started the study with looking at 73 post-parietic patients and getting standardized dysphagia questionnaire. You could see high rates of dysphagia over time. There was no difference between sleeve or row-wide gastric bypass, and it was a time-dependent phenomenon. That means the more time goes after the surgery, the more likely that they develop these symptoms. When we looked at high-resolution manometry, this is laparoscopic sleeve, about 40 patients, 60 patients row-wide gastric bypass, and here are the presurgical controls. We saw these striking phenomenas. If you look at any Chicago classification, you could see that the incidence of abnormality is much higher than presurgical controls. If you start looking at a new accolade type picture, 1, 2, 3, you could see incidence in gastric bypass at 8.6, 5% in laparoscopic sleeve versus 0% in the presurgical control. When you look at this POSIT or post-obesity surgery esophageal dysfunction, you could see higher incidence, though this did not reach statistical significance. What's defined this post-obesity surgery esophageal dysfunction on high-resolution manometry? A-parastalsis, normal IRP, and increase in the intragastric pressure, indicating this increase after both phenomena. So this story got exaggerated. If you start now saying, OK, bariatric surgery is an insult, but how about if we take a cohort that they had an initial insult, which is an isomphen duplication, and now get converted to a row-wide gastric bypass? So we looked at this cohort, and surprisingly, we had significant number of these patients. We had 101 patients at the Mayo Clinic who had an innocent converted to a row-wide gastric bypass. And what happens after this? Nuanced dysphagia of about 45.7%, and persistent dysphagia was at 55.6%. So this is a real phenomenon. I mean, something is going on, and the more insults. So if you take a lab-banned patient and you convert them to gastric bypass, or you take a sleeve patient and convert them to a row-wide gastric bypass, or an innocent take down to gastric bypass, you're seeing this phenomenon, and this is real. So obviously now, we're decreasing clearance of the esophagus. We're increasing pressure. We're affecting the anti-reflex barrier. So GERD and sleeve gastrectomy are associated. To summarize the literature, as of 2019, there was about 46 studies looking at 10,000 patients who had a laparoscopic sleeve gastrectomy. Incidence of de novo reflux is 23%, long-term prevalence of esophagitis at 28%, incidence of birth esophagus is 8%, and conversion because of reflux to row-wide gastric bypass is 4%. But when we looked at conversion from sleeve to row-wide gastric bypass and divided by indication, you could see that the conversion because of GERD is up to 30% in the reports and literature based on this meta-analysis. So hiatal hernia is a big confounder. We talked about affecting esophageal clearance, increasing gastric afterload, but now patients losing weight, and again, that fat disappeared from the diaphragmatic hiatus, and now you have a small pouch that herniates and causes problems. And if here we looked at this cross-sectional cohort of patients who got endoscopy, and we look at sleeve gastrectomy patient versus row-wide gastric bypass, and we looked at the prevalence of erosive esophagitis, and you could see for both the sleeve gastrectomy and the row-wide gastric bypass, presence of hiatal hernia is a big confounder and contributor to the esophagitis in this phenomenon. And here's why. Here's a patient, LA-grade B esophagitis, and you could see the LA-grade B, and now you're retroflexing in the small pouch, and you could see that the hiatal hernia, and this was not present before the gastric bypass. That means this is a function of losing this fat pad, and now this small pouch is herniating in and out of this sliding hiatal hernia in a gastric bypass patient. Now be careful retroflexing in a gastric bypass, so you need a nice flexible instrument to do that, but we try to do that to illustrate that concept. So when we looked at that patient on endoflip, this is the phenomenon of increase after load. You could see that although you have a normal pouch, there is low distance stability of the pouch, and now you get a bolus, it does not go forward, it shoots backwards because of the hiatal hernia. So reflux gets accentuated because of this physiology and impact on foregut physiology. Now future directions, we talk about obesity being a problem. We talked about bariatric surgery having concerns as far as foregut physiology, both dysphagia and reflux, but then reflux or obesity is a risk factor for reflux, and patients come with refractory reflux, and they have obesity. What do you do with these patients? Because a BMI of 35 is a contraindication for a surgical front duplication. Your only option is a gastric bypass, and we discussed about issues with the gastric bypass, but in 2022, the answer is a gastric bypass for somebody with refractory reflux and obesity. But what future consideration is for this cohort of patients? And again, this is off-label use. There is a clear overlap between GERD and obesity and a huge, huge unmet need. So novel solutions that we're going to see, we'll take front and central over the next few years, hopefully, is using endoscopic management as an anatomy-preserving paradigm to treat both reflux and obesity. That means we're treating reflux in the setting of obesity, and this is a patient that we've done a TIF on, and then done an endoscopic sleeve gastroplasty at the same session. And you could see here, we went from a HELL-GRADE 3 to a HELL-GRADE 1, and we recreated this valve on CT scan. You could see this lip that's three centimeters that was absent from before. Then we did an endoscopic sleeve gastroplasty. We collaborate with our colleagues in surgery. This is a patient with a large hiatal hernia and obesity. They did a laparoscopic hiatal hernia repair and a toupee for duplication. As you can see, here's the toupee. And at the same session, in the same OR, we did an endoscopic sleeve gastroplasty, where we did an endoscopic implication of the greater curvature of the stomach for weight loss. If those who are not familiar with endoscopic sleeve gastroplasty, it's done with the overstitch device. Here's the device. The device is a full-thickness suturing device that uses a helical retractor. You start at the level of the incisora. You can see with the helical retractor, you acquire the entire wall of the stomach. You pull it into your suturing device, and you're able to acquire full-thickness sutures in a series of five sutures that are administered in an O-shaped configuration. From the anterior to the greater curvature of the posterior wall of the stomach, you're able to create a restricted stomach with a smaller volume and a shorter length of that stomach as shown here. So the incisionless operating platform is another device used to create this endoscopic sleeve gastroplasty. Instead of using sutures, it uses these plications that are made of nitinol and distributed by a suture. Each plication reduces the stomach by about 7 centimeters. So with the post-tube procedure, you create endoscopic sleeve gastroplasty by placing these plications in synchronized fashion from the level of the anterom body junction to the proximal stomach. And you can see you can take the stomach from before, about five vertebral bodies in length and big volume, to a two and a half vertebral body after. So the stomach accords him down, and you created a sleeve gastroplasty using this. This is the before and after. But the appeal of this platform is now you create an obesity procedure, which is then endoscopic sleeve gastroplasty. But this same platform could be used to create a fundoplication. And that's what we did in this experiment in dogs, is we used the same platform to create a sleeve and to do these plications at the G junction to create a flat bowel using these plications. So in the future, we might have a platform that could treat obesity and GERD at the same session. So to conclude, obesity impacts GERD and gastroesophageal physiology. That's clear. Obesity and GERD surgical therapeutics have limitations and potentially important negative consequences on GERD and esophageal function. Traditional anterior plexus surgery commonly fails in patients with concurrent untreated obesity. We need novel therapeutics. And this is an area of huge unmet need. And with that, I conclude. And thank you for your kind attention. Thank you.

reflux

dysmotility

bariatric patients

obesity

foregut physiology

laparoscopic sleeve gastrectomy