Presented by Ronnie Fass MD, Case Western Reserve University, Cleveland, OH.
So good afternoon and welcome to the diverse a tech webinar Syrians. Today's webinar reflects hypersensitivity and functional heartburn. All roads lead to Rome. We presented by Dr Rani Fast. Dr. Fast is the medical director of the Digestive Health Center, chairman of the Division of gastroenterology and hepatology and head of the esophageal and swallowing program at the Metro Health Medical Center in Cleveland, Ohio. And we won't say anything about the weather in Cleveland for right now is also a tenured professor of medicine at Case Western Reserve University. Dr. Fast is the editor in chief of the Journal of Clinical Gastroenterology. And he is the editor in chief of the Journal of Neurology, gastroenterology and motility. Without any further ado, I present Dr Rani Fast. Thank you very much. It's a great pleasure for me to present you, uh, topic that is very close to me, Aziz, uh, the chair off the functional esophageal disorders or from fourth I was heavily involved in the red definition off both functional heartburn and other functional esophageal disorders and was also involved in the introduction off reflux service sensitivity as a new functional lists of regional disorder. Now, because still limited me to Onley one hour, uh, to cover these two topics functional heartburn and reflux hypersensitivity in that short period of time was very difficult for me. So I will focus primarily on functional Harbor will mention, uh, the importance, uh, in the value off reflux service sensitivity. And we'll be very happy to answer any questions that you have a to conclusion off my presentation. So first of all, when you look at the Rome four, uh, there are several functional esophageal disorders that way have known also from our previous around criteria. And they include functional chest pain, functional dysplasia, globus, functional heartburn. What's unique about wrong four is the introduction off a new functional esophageal disorder that was not recognized as a separate, functional esophageal disordered in previous Rome's, although it was well studied for almost four decades but was positions in different types off Asafa Gld source. And this is reflux hypersensitivity. Now that generated a very interesting situation because based on wrong four, we have two different functional ISTAF agility disorder with the same predominant symptom which is Harper, something that hasn't bean entertained before by the previous Rome criteria. Now in general, when we talk about functional esophageal disorders. These are chronic. It's off a joe symptoms in the absence of identifiable structural, inflammatory motor or metabolic mechanisms as the ideology, I'd like to start with a case presentation. So there is a 52 year old female here who presents for a follow up visit. She reports harbor and symptoms for the last six years. Notice if Asia or dine aphasia, her appetite and weight are step are stable. She does not smoke, but occasional consumes alcohol. Currently, she is on on top. Result. 40 mg once daily with breakthrough symptoms about 4 to 5 times a week, primarily during daytime. She's very anxious and concerned about her residual symptoms and the need to take BP I long term. She's got no prior work up for Gaza's off a jewel reflux disease. Her medical history includes hypertension, hyper lipid, EMEA, mild asthma and anxiety. She said she's under a significant amount of stress. Medication wise, she's on Ponta Pers of 40 mg once a day, hydrochlorothiazide for blood pressure and flex rail for some muscle spasms. A physical examination reveals that she's mildly obese, with it being my 31 but otherwise unremarkable after seeing by her gastroenterology ease. Obviously she will undergo an upper endoscopy, and her on upper endoscopy was normal. Biopsies from the esophagus during the upper endoscopy came back on. Remarkable. The gastroenterologist ordered AH wireless pH capsule off treatment because she's never been evaluated before for gastroesophageal reflux disease. He asked her to stop her p p i for at least seven days 7 to 10 days and ask you to come back. And as you can see, her wireless pH capsule of treatment was completely normal. And when you look at the bottom, you conceived symptom association Probability and Symptom Index. Both of them were negative. So this is very suspicion for functional heartburn to complete her work up. She also underwent high resolution is Off the Jail Manama Tree, which demonstrated a normal media and I AARP normal Mean Elliott's resting pressure, D. C. I and D. L. A deal was normal. And when you look at her swallows, she had 10% failed swallows and 70% week swallows and as a result of diagnosis off, ineffective esophageal motility was made. You can see here a simple of one of her swallows on the left on the other side of the screen, you can see other swallows on, uh, most of them where week except one which was failed. So this is consistent with. In fact, there was off a jail motility and the presence off ineffective. It's off a general motility in patients with a negative work up for gastroesophageal reflux disease. Like in this case, which included a normal endoscopy. Normal pH test in this case, a wireless pH capsule and no evidence of correlation between her symptoms and reflux events still suggest functional heartburn. The presence of ineffective It's off the jail off ineffectiveness of a jail, maternity or fragmented prosthesis do not exclude a functional list of padilla disorder. So to understand where we're coming from in relation to functional heartburn then and reflux hypersensitivity, we need to look at Rome. Three. In the case of from three, if you had patients with troublesome heartburn, but they had a normal endoscopy and you did a pH test, then a subset of these patients had a normal pH test, and a subset of them had an abnormal pH test. If off those that had an abnormal ph test, um, they had uh, So if this patient had an abnormal pH test, then these are the patients with non erosive reflux disease. Now, if they had a normal PhDs, then Rome three suggested that we need to look at a Symptom Indices Symptom Index and Symptom Association probability. If they were positive, then this group was called the Hypersensitive esophagus and Perrone three. They were also included under the category of non erosive reflux disease. If the patient had a normal or no evidence off an association between the symptoms and reflux events, then these patients Barone three, should still go through PP. I treatment. It's not clear Peron three for how long and if they were responsive, then we have another group which is negative and ask API negative pH test No evidence of symptom associations but still responsive to PPR. And this group was suggested also to be honor the category off non arose if reflux disease. The patients did not respond to p p. I treatment Dan. A diagnosis of functional heartburn was made. So based on Rome three, there are three sub groups that fall under the category of non erosive reflux disease. One of them is the Classic one. These are the patients that have an abnormal pH test. The other one is what they call the hypersensitive esophagus. These are the patients that have and abnormal symptom Association indices. This is the group that later roam free, termed as reflux hypersensitivity its old name. It's previous name is hypersensitive esophagus. It was the feeling off the wrong four committee that the term hypersensitive esophagus is too close. Two determines off a jail hypersensitivity, which suggest an underlying mechanism, which can be seen in all functional esophageal disorders. A za result. The name was changed. In addition, Rome four decided to extricate the hypersensitive esophagus now reflux hypersensitivity group and make it a separate functional. So for Jill the soldier, So let's look now at functional heartburn and reflux Hypersensitivity Perrone four. And this comes actually from a publication off the room for Community Run four also recognized that most of the time we make the diagnosis or functional esophageal disorders while patients on treatment something that was not recognized by Rome three and all their algorithms was based on no treatment at all. If you have patients with heartburn and normal endoscopy and they don't have history of gastroesophageal reflux disease. Unproven. Good. You study them off pp I preferably by a ph test. If you don't have an access to eat, then by Ph. Impedance and then you have three groups of patients that you may find those that have normal acid exposure. Negative symptom reflects association. This is the functional heartburn group. Does it have normal acid exposure? Positive seemed to reflex association previously termed hypersensitive esophagus now are on four term. It reflects hypersensitivity and then you have those that have abnormal answered exposure, positive or negative Symptom Reflux Association. And these are the non erosive reflux disease group they in relation to Rome. Four. If you have patient with proven gas esophageal reflex disease and they failed treatment and failure here is defined by failure off PPE twice a day and you do and reflux testing. And you find out that these patients have normal Asafa jail acid exposure because if they do have an abnormal acid exposure on treatment, then these patients have gastroesophageal reflux disease. Although you don't know what is the final tip IQ presentation of these patients and baseline because these patients have proven good, it is recommended that their test that there there will be tested on treatment and preferably with pH impedance if they have normal acid exposure. But they have negative symptom reflects association. Then they have functional heartburn that overlap with gastroesophageal reflux disease. Remember, these patients have history of proven good. Either they have an abnormal pH test in the case of normal endoscopy or they have evidence of erosive esophagitis. So here we say that they have a functional heartburn did overlap with gastroesophageal reflux disease if they have normal acid exposure but positive symptoms reflects association, then they have reflux hypothesis activity that overlaps with gastroesophageal reflux disease. Again, this is something that was introduced by round four, which is that there is ah possibility that functional is official disorders may overlap with Gert and may drive symptoms inpatient that failed PP I treatment This is the definition of functional harbored per round four. What you see in yellow This is new. It wasn't there in when compared to round three. So functional Harbor Peron four burning retro sternal discomfort of pain. No symptom relief. Despite optimal anti secretary therapy, Absence of evidence that gas is off a geo reflux eyes down the line cause either they, you know, looking at abnormal acid exposure and our symptom reflects association or absence off evidence off. Using a Filic esophagitis is the cause of symptoms they should be. Also absence off Major's off jail model disorders unlike Rome. Three. We just asked to exclude Arkle. Asian Room four added several other major model disorders like E G outflow, obstruction, distal esophageal spasm, jackhammer esophagus and absent contracted ity. Criteria must be fulfilled for the last three months, with symptom answered at least six months before diagnosis and the frequency of a least twice a week. Sorry. Now how come in is functional heartburn and reflects hypersensitivity? And this is from a recent publication that we've had looking at patients that were not treated before So these air naive patients. When you look at patients that have harbored and undergo upper endoscopy, about 30% of them will have erosive esophagitis and 70% will have normal endoscopy. When you take the patient with normal endoscopy and you perform a pH test, about 50% of them will have abnormal pH tests and thus will fall under the category of non erosive reflux disease the other 50% will have normal pH test. And when you look at symptoms, indices in orderto separate the reflex hypersensitivity from those with functional harbor, and then you find out that about 40% of them have reflux, hypersensitivity and 60% functional harbor. So from the beginning, you can see the 21% off the patient's naive Patients that show up in our office have functional heartburn, and 14% reflects hypersensitivity. So these two functional lists off a Jill disorders account for more than third of the patients. The naive patients that present with heartburn tow our clinic if you use an impedance plus pH in order to test this patient. So now you take the same patient population that I discussed in my previous slide, and instead of study them just with a pH test, you study them with peach impeded. So you're looking also ATO presence off non acidic reflects that may correlate with patients symptoms, so you are increasing the likelihood that you will find patients with reflux hypersensitivity. And this study clearly shows that within this group of patients now, reflux hypersensitivity goes up to 36% and functional heartburn is 40% suggesting that the functional ISTAF a jail disorders account sorry and functional Harvard is 24% suggesting that functional esophageal disorders account for 60% of these patients. If you look at patients that fail, PP I twice a day, and now you try to find out what percentage of them have reflex deficits, activity and what percentage have functional heartburn. The reflux, heifer, sensitivity and studies ranged from 28 to 36% and functional heartburn between 52 to 56% suggesting that inpatient it failed pp twice a day. Thes two functional esophageal disorders account for more than 90% of these patients. That's very interesting that when you have patients that show up in your clinic and they have heartburn, it's very difficult to determine if they have gastroesophageal reflux disease or a function on the sofa jail disorder. And within each group, you cannot determine, for example, if they have non erosive reflux disease or erosive esophagitis or they have within the functional group. If they have reflects hypersensitivity or functional heartburn based on any symptom dimension, it is severity or a frequency duration or any combination off these symptoms. One cannot determine what is the underlying disorder there is responsible for patients harbored symptoms from a clinical characteristics of patient with functional harbor that also applies to reflux. I process activity. They tend to be females young and middle age. They tend to overlap with other functional about disorders. We have information about non Correa chest pain or functional description, and psychological calm ability is not uncommon, especially so monetization, depression and anxiety. This is a study that we've done where we compare patient with functional heartburn to those with non erosive reflux disease. And the two things that really stood out in the study was the fact that patient with functional heartburn had longer duration off heartburn symptoms as compared to non erosive reflux disease patients. And they tended to have also an overlap with non cardiac chest pain. When you look at psychological comparability in patients with functional harbor as compared to those with non erosive reflux cities using the symptom checklist, 90 are then one can see that there was a significant difference when it came to summon ization where the where the other psychological commodities were about the same when the two groups were compared. This is another study that looked at functional heartburn and functional dyspepsia, showing that patients and if you look at the top with non erosive reflux ese ph Negative Symptom association probability negative thes are patient with functional heartburn that these patients tended to have more postprandial fullness, early society, bloating and nausea as compared to the other groups of patients, including those with reflux up insensitivity. In this study, which are the patients mentioned as nerd ph Negative Positive Symptom Association probability, suggesting that patients with functional heartburn commonly have an overlap with functional dyspepsia, this is a typical situation off a functional heartburn patients. Using a regular pH test, these patients reported six episodes off Harbor during a 24 hour PH test. You can see it's marked by the letter H, and the patient also reported two episodes off chest pain marked by the Let Us See and this is Over appeared off 24 hours. But if you look very carefully at this pH strip, you can see that the patient did not have even one episodes off acid reflux event, suggesting that these non treated patients all these symptoms were not associate ID with any reflects events. The pH test was normal. The endoscopy was normal. All of it is suggestive of function of urban patients. But one would consider this patient as very symptomatic is the patient reported six episodes of heartburn during the day. First two episodes of Chester It's time to pause and make a few statements about heartburn. We have to remember that the recognition or functional esophageal disorders, especially those that are associated with harbor as the predominant symptoms, truly revolutionized our understanding off Asafa. Just symptom, specifically heartburn. First of all, we learned that a sofa Jill symptoms are not stimulus specific, so different stimuli may lead to the same symptoms in the past was the axiom no acid, no heartburn. Now we know that this is not the case and this is not true. Patients may not have ass. It may not have acid reflux and still have heartburn at the end of the day. The esophagus has a very limited repertoire of symptoms, and thus one cannot touch a specific stimulus to each symptom. Heartburn can result from different interests off a jail events and something that we also learn over time as it reflects or chemical stimulus can lead to harbor. But at the same time, balloon distension or mechanical stimulus can also lead to harbor. So two different types of stimuli with a similar and product, which is Harper. So the fact that we don't identify specific suffer just stimulus that lead to heartburn in our patient population does not mean that we don't have a disorder so functional heartburn Israel When we look at the mutated mechanisms off heartburn in patients with functional harbor, there's no question that the main underlying mechanism is esophageal hypersensitivity, which drives symptoms in these patients and all the other mechanism that are mentioned. All of them operate through modulation off esophageal hypersensitivity, for example, abnormal central processing office of radio signals, hypervigilance, emotionally related factors and, of course, psychological comparability. All of them, at the end of the day altered a super just sensitivity, leading to lower perception thresholds for pain, which falls under the category Officer for jail hypersensitivity. I like this definition of esophageal hypersensitivity. It's pretty simple, and it states that this is the perception off non painful esophagitis stimuli as being painful, and the perception off painful esophagitis stimuli as being more painful the end of the day. As I mentioned, it's all about perceptions. Thresholds for pain, clearly showing that patients with the so fragile hypersensitivity have lower perception threats off the pain as compared to normal controls. Now this underlying mechanism is not unique to functional harbor. We see it also in patients with the other functional esophageal disorders. You see it also in patients with reflux hypersensitivity, and there is some data showing that we see it in patients with non erosive reflux. Disease is well now. Here's an example. This is a study that looked at balloon distension, and the patients that are the functional harbored ones are defined here as symptomatic, meaning they have heartburn but now, but no excess reflux. These patients also had a normal endoscopy, and they were compared to those with excess reflux, which in this study included those with non erosive reflux disease, an asymptomatic health ethic controls and those with Barrett's esophagus. If you look at the patient with functional heartburn, they had the lowest threshold balloon volume threshold for pain, as compared to the other groups where the patients with Barrett's esophagus and the highest so in this case it was suggested patient with functional harbor and demonstrate a so fragile hypersensitivity as compared to the other groups. It's very interesting that there are studies like this is actually a case report where it was reported that if you place a wireless speech capsule the Bravo in patients with functional heartburn, then there are more likely to report retro standoff discomfort during the wireless pH monitoring to the point that in some patients one has to come in and remove the wireless pH capsule in order to, uh, discontinue patients discomfort suggesting or proposing, uh, that these patients have a suffered gel hypersensitivity. Okay, this is, ah, figure that came actually from the wrong for publication, and it looks at the four disorders with heartburn as the predominant symptoms. Two of them are two disorders that fall under the category off gastroesophageal reflux disease and the other to fall under the category off functional esophageal disorders. And if you move from erosive esophagitis to non erosive reflux disease to reflux, hypersensitivity and then functional harbor and you can see that on the left side, especially in the case of erosive esophagitis, acid exposure is the main underlying mechanism is you get to non erosive reflux disease, where acid exposure is still an important underlying mechanism. We started to see that the suffered jail hypersensitivity also plays any foreign war, and that increases as you move from reflex hypersensitivity to those with functional heartburn. Where there it is primarily, that's a for jail hypersensitivity. It's very important also to understand Theo importance off functional heartburn and reflux hypersensitivity in patients that failed pp twice a day, or what we call refractory heartburn patients or PP i non responders. This is actually the first study that was done using the room for criteria to evaluate patients who fell, PP I twice a day. All these patients had persistent heartburn symptoms despite the behind treatment, and they required further testing. And in this study, the authors found, 36% of these patients had reflux hypersensitivity when they studied with impedance plus pH and 55% of them had functional harbor, suggesting that more than 90% of these patients had one of the functional esophageal disorders in the reflux, hypersensitivity or functional harbor. So this was one of the first studies proposing that most of the patients that failed PPE twice a day have functional is off the jail disorder is the driving underlying mechanism for the residual symptoms Not true. When you look at, uh, the different underlying mechanism for refractory GERD or refractory heartburn and the two are different because in refractory GERD, these air patient that we have documented gastroesophageal reflux disease that still do not respond to P P I twice a day were in the case of refractory heartburn, we don't have documentation of girls. So we don't know if these patients are true girl patients that failed PP I twice a day or they just belonged to one of the functional esophageal disorders from the beginning. Are there many mechanisms that have been proposed to lead to failure of PPE twice a day and you can see them mentioned on this slide and some of them may overlap in the same patient. Our focus has been for a long period of time in identifying residual reflex as a driving force for these patients, symptoms like weakly acidic reflux with weekly alkaline reflux or persistent acid reflux. But based on the study that I showed you in my previous slide, as well as other studies that confirmed the results of that study, it appears that functional heartburn and reflux hypersensitivity probably drives most off these patients failure to respond to P. P I treatment, and they account for up to 90% off these patients. This is an opportunity also to discuss the definition of reflux hypersensitivity. It's retro Stendhal symptoms, including heartburn and chest pain, normal endoscopy and evidence of triggering of symptoms by reflux events. Despite normal acid exposure on PH. Or pH. Impedance monitoring and response to anti secretary therapy does not exclude the diagnosis again. The reflex I percents activity. It's the group that used to be called hypersensitive Esophagus and this group have been studied for almost four decades, and I'd like to emphasize again, none off The wrong committees have disputed the presence off the reflex hypersensitivity group. They just felt that this is not a separate, functional lists of jail disorder, but whether they fall under different categories. As I mentioned from three thought that they should fall under the category off non erosive reflux disease. This is a study that is already available on the website of clinical gastroenterology and hepatology. But this is the first study that looked at patients who with documented gasses off your reflux disease that failed PPE twice a day. Patients were studied within Penis plus pH as well as high resolution and suffer German on a tree on. The study found out that 62.5% of these patients demonstrated an overlap with functional harbor, and 12.5% of them demonstrating overlap with reflux ever sensitivity, suggesting something new and very important that in patients with gastroesophageal reflux disease who failed twice daily p. P i Most of these patients have an overlap with the functional list off a jail disorder, and it is likely that the functional esophageal disorder that drives thes patients symptoms at this point. Now, this is the diagnostic work up for patients with the current heartburn despite PPS therapy without previous evaluation for gastroesophageal reflux disease, as it was proposed by the wrong foundation or by the sorry by the Rome Committee. So in this patient population, uh, an upper endoscopy should be done first, preferably with biopsies to exclude use in the Philippines off vaginas. Okay, then, if abnormality was not identified, then this patient should undergo reflects testing off PPL therapy, preferably with a pH test, and it should be probably with a wireless pH capsule because it provides between 48 to 96 hours of measurement. If the patients don't demonstrate an abnormal itself, a jail acid exposure, then symptom association with acid reflux, specifically with their civil reflux, should be looked at. Rome four suggests that the focus should be on acid reflux in relation to association, not non acetic reflux. If there is a positive association with an acid reflux, then reflux hypersensitivity is diagnosed not before a high resolution ISTAF a jail Manama tree excluded the presence off a major Asafa jail model disorder. If there is no evidence off on association of symptoms with acid reflux, then functional harbor is likely. The diagnosis again after exclusion off a major ISTAF, a German model disorder by high resolution, is Super jail Manama Tree. Now, in case off patients with previously established gastroesophageal reflux disease, Then in this situation, the only difference in relation to the diagnostic algorithm is that their test that their reflux testing should be performed on treatment and preferably within Penis plus pH and the presence off reflux, hypersensitivity or functional heart burning. These patients suggests an overlap with gastroesophageal reflux disease. What about other diagnostic techniques? I will not spend too much time on them, for example, on magnification, endoscopy or narrow band imaging as well as others. Um, they have shown, uh, to demonstrate minimal changes in the sofa go Gasic junction, for example, like micro erosions, increased vascular parity or romping pattern. But the but the presence of these minimal changes have not been translated to correlation with clinical presentation. So we do not rely today on this minimal changes in order to change the diagnosis off a patient from functional heartburn to non erosive reflux disease, studies have shown that another way to determine the presence of patient with functional heartburn is assess baseline impedance values. Here, for example, it was shown that in patients who failed P p I twice a day, if they have acid reflux, the baseline a Penis was the lowest. And if they had functional Harvard, meaning that they don't have any evidence off any type of reflex, either acid or non S E. Then these patient demonstrated their highest baseline Europeans values. I think that concept has bean later, um, and used with other diagnostic techniques. For example, the concept off mean nocturnal baseline pins. This is similar to the previous concept is just that the measurement off maternal off impedance is done during night time when there is less swallowing activities, less eating. So there are less, uh, artifact that may affect impedance measurements. And so one can measure nocturnal based on impedance at one o'clock two o'clock or three o'clock in the morning for 10 minutes, used the average of it and then use that to determine what type off. Uh, Sophie Jill disorder the patient has This is, by the way, looking at impedance plus pH but adding acting graffiti, This is something that we dio and we use it in order to determine the exact time when the patient was asleep. When you look at the period between recumbent, awake and recumbent, the two periods of recumbent awake, this is the time that the patient was asleep. And there is much less, uh, disturbances, uh, to the impedance recording. This is sleep time, and this is usually the time where one want to get based on impedance values. And the study shows that if the m n b I values are high A t the area or at the level off about 3500 arms. You're looking at functional heartburn close to eat. About 2200 U. C. H E, which is the hypersensitive esophagus now terms as we flood surface sensitivity. Another way to dio measurements off mucosal in penance without exposing the patients to 24 hours. Measurements is spot measurement using because of impedance technique. Originally thes technique used through the scope. A probe with two impeding sensors at the bottom on measurement spot measurement. Off this offer, Germany Khoza allowed one to determine the presence off certain esophageal disorders. Thes technique has evolved over time, and right now, instead of using the to censor techniques, we have a balloon at the tip of the probe. And along the balloon, there are several lines off Indian censors, and so this time the balloon is inserted into the esophagus during endoscopy. Inflated. The sensors get in contact with the soft German because intent can provide a spot impedance measurement as and as you can see in the study, one can determine. Based on these measurements, the likelihood off San esophageal disorder, um, including different types of gastroesophageal reflux disease disorders like here in this case, erosive, esophagitis and non erosive reflux disease or patient with functional heartburn and then other disorders like Arkle Asia or use in the Philippines or vaginitis Easter Pathology can also help us to determine the presidents of functional heartburn. The presence off dilated interstellar space is, uh, exclude. Uh, functional heartburn can be seen in patient with gastroesophageal reflux disease. However, in patients with heartburn and normal, no evidence off dilated into cell space. A space is then one should consider functional heartburn. We don't have data about reflex hypersensitivity in relation to these dilated into cellular spaces. There are now some studies looking at a variety off history, morphological changes that can be determined in the esophagus off patients. Some of them are related to gastroesophageal reflux disease. And so the some score of these history morphological changes can determine if the patient have, for example, gastroesophageal reflux disease or functional hard graham. So what is the treatment off functional harbor? So here are some basic rules. First of all, we have very limited data. The main approach is with pain modulators, or now we use more. The term neuro modulators always address a psychological comparability of present on Do not shy away from comprehensive approach as well as alternative and complementary medicine. This is actually a table showing the, um showing the different neural modulators that have been studied in functional esophageal disorders. It includes Onley randomized controlled trials. As you can see, most of them were done in non cardiac chest span. There are a few of them that were done in functional harbor FH here or reflux separatist activity our age. One thing that I wanted to point out is the fact that way have here tricyclic antidepressants, accessorize and snr eyes. But if you look at the bottom, we haven't been re needed in that was studied in functional harbor and was shown toe work in these patients as a pain modulator as a neural modulator, not as a medication that reduces acid reflux. Um, how to use tricyclics in practice. The main principle no low and slow start 10 mg or 25 mg at bedtime increased by 10 to 25 mg increments weekly. The goal of treatment is between 50 to 75 mg. Once daily, remember, we're using non mood altering doses if side effects emerge, don't give up on a class or on the medication. Decrease to a lower dose of the same medication, or one can switch to another tricyclic, and one can combine them with the necessary. When you look at the hierarchy off anti depressants for so for Joe pain reduction and global health improvement, venal affection or effects her on SNL rye was considered to be the top or the best here. I would be very careful in giving it a bedtime, because in my experience it does affect patients sleep experience followed by sit trillion and necessary and then in Superman, in the pain reduction and in the global health improvement trace adult. We have some studies in functional heartburn. This is a study. For example, inpatient fell PPR once a day on, they were randomized to either pp I twice a day adding through oxytocin or placebo. And in this study, six weeks treatment off any of these editions through oxygen appeared to be, uh, to provide the best symptom improvement in this patient population eyes compared to the other, uh, therapeutic strategies, this is a negative study. This study looked at taking patients with reflux hypersensitivity here called the sofa jail hypersensitivity in this study, and then patients with functional harbor and randomize them to their any payment fixed those 25 mg versus placebo, showing that it doesn't matter how you look in relation to the percentage off. I wouldn't say good improvement like it says on the table on the figure, but heartburn improvement more than 50%. And regardless, if it's I t. T or protocol assessment, there was no difference between the two groups. The main limitation of this study is the fact that they fix those often in Permian was given, and usually it is recommended when it comes to try cycling treatment in patients with functional so fragility disorders is to titrate it and find what is the best dose that control patients symptoms. This is a study that randomized patients with functional heartburn to either melatonin 6 mg, no trickling 25 mg or placebo, three months randomized placebo controlled trial and those that received melatonin demonstrated the best improvement in heartburn symptoms even better than no tricked early. Interestingly, this study placebo did better. The no triple in improving patient symptoms Hypnotherapy. This is ah very small study that was published. We don't have any other studies that looked at other, uh, psychological interventions intentional with functional heartburn. But this was a positive study showing that hypnotherapy in this nine functional heartburn patient significantly improved symptoms. This is a study that we've done on this is in patients that fail PP I refractory heartburn patients. So most of these patients could have been in the reflux, hypersensitivity or functional heartburn patient, and they were randomized to either pp I double those or PPL plus acupuncture and those that we see PPR. Acupuncture did significantly better than those that receive PPE twice a day after four weeks of treatment. So always address psychological culpability in patients with functional heartburn. Variety off interventions should be considered. Many of them were studied in under other functional esophageal disorders, especially cognitive behavioral therapy. Onda, then the new kid on the block mindfulness should all be considered in this patient population. And I'd like to finish year with the management algorithm that myself and Dr Prakash rally we published last year in gastroenterology and one can look at the bottom off this management algorithm and see reflex hypersensitivity and functional our brand and look at the different therapeutic interventions that can be entertained in this patient population. One thing before I finished is that in the case of reflux hypersensitivity, because these patients still have evidence off positive association between the symptoms and acid reflux events is that one should consider, um, anti reflux medications like H two blockers. Backlog fan if the patients are naive from pump inhibitors and I would be very careful, though, but there are several studies showing even the value off anti reflux surgery in this patient population. Thank you very much, Dr Fast, thank you very much for out truly outstanding lecture on functional heartburn and reflux hypersensitivity. We just have a couple of questions, so I'm going to read them to you and look forward to your response. The first question is, I attended the lecture of Craig Sullivan, M D associate professor New York Medical College, during the American Academy a O. H. NSF 2018 diet based approach for reflux. He advocated that 90% plant based diet would lead to reduce gas Trinh Pepsi in and acid production. It would be very important in treating reflux. Any comment on that so there are a variety of recommendations for certain diets that haven't been really studied. Andi. It's very interesting that most of the lifestyle modifications that recommend, uh, that we recommend today almost all of them and and some of them clearly excessive. Eight good related symptoms. We don't have really, uh, studies that support our recommendations. In fact, when you look at lifestyle modifications with evidence based support, they include Onley, the following weight loss, nighttime lifestyle, life lifestyle changes, for example, not eating at least three hours before you go to sleep. Elevating and elevating the head of the bed. Um, even a simple, uh information like avoid spicy food or avoid fairy food while we have all the understanding that these are likely, uh, type off intervention that will markedly improved patient symptoms. We don't have any evidence. So while he recommended that, I would ask him, Where is the evidence to support that? And I can tell you there's a lot off recommendations today, uh, in the literature on, especially in the general media literature on the Web. And they're also websites that dedicated to the fact that they think that Gaza's of Poggio reflux disease eyes actually an acid deficiency disorder. And they recommended the patients will, um will treat themselves with asset as the as the underlying treatment. Thank you very much. Here's the next question. What's the reason or mechanism? How melatonin improves symptoms and functional heartburn? So that's a very good question. Well, one of the probably the possible mechanisms that it improves sleep, and we know that sleep good sleep eyes analgesic were poor. Sleep is hyper ologists. That's bean shown by many studies. In fact, good sleep eyes equivalent almost to an energetic medication that's being shown by studies. Now then, I would say, probably what drives study like that, Uh, But there is also evidence that melatonin, uh, improves also good related symptoms because there is evidence that melatonin also affect as its equation, and so melatonin can decrease as its equation in the stomach and potentially may improve good related symptoms during that mechanism. But because reflex is not really the mechanism behind functional heartburn, my belief that it works here through its effect on sleep and thus on ah, simple perception mhm very interesting. Here's the next question. Does the presence of a hiatus hernia play into your algorithm. Uh, and so when we look at patient with functional heartburn, thes patients don't have large al hernia that's being shown by studies that looked into this. Obviously, in my algorithm that I showed here and when you look at the on and I'm not sure if you're referring to the algorithm that is on the screen right now, that algorithm looks at patients who fell p p i who failed PP I. Obviously, if patients have largely al hernia and they fell PP, I then that large al hernia should be addressed. Uh, no question about that. While it's not mentioned here, Thesis is one of the reasons to in my mind to refer a patient for and to reflect surgery, which will include repair off the Johanna. Okay, we have time for just a couple of more eso. What are the differences in the ideology and path of physiology of functional heartburn and reflux hypersensitivity. So the the both of them have a sofa general hypersensitivity as the underlying mechanism. The main difference, though, is that patients with reflux hypersensitivity demonstrate clearly sensitivity to physiological amounts off the sofa. Jail answered exposure because they do demonstrate correlation between their symptoms and s e reflux events that's being demonstrated by almost four decades of research. So in this case, this is a group of patient with the sofa gel hypersensitivity that appears to be driven primarily by chemical stimuli on defined by a sofa. Jill acid reflux. Okay, what if impedance pH is not sufficiently sensitive for the reflux causes of functional heartburn or chest pain? Do you think that micro aspiration can cause functional symptoms and in that way can be erroneously diagnosed? So I'm not sure I understand the question because micro aspiration into the lungs. I assume this is a different story. I would go. I would go with the comment that the tools that we have today are not perfect. Absolutely. I agree with that. I will go with the comment that, um as's time goes by, maybe as we get mawr Azzawi get better diagnostic test We may cheap away from dysfunctional esophageal disorders on DSO we may find out other mechanisms that we haven't figured out before because our diagnostic tests have certain limitations. Do I think that in the future in the near future, we will get rid off functional heartburn or reflux hypersensitivity, I doubt it. I think it's time to get used to the fact that we have these patients and that they commonly show up in our in our clinic and that we need to know how to address them. Thank you. And here's our last question. Would you call regurgitation that does not respond to P. P I and Negative Bravo as functional regurgitation. And would you treat them the same way as functional heartburn? Excellent question. And I I would say now that has not trickled into the Rome definition. Remember, the focus in relation to reflect hypersensitivity and functional heartburn is the harbor and symptom. There's no mentioning off regurgitation. A regurgitation is a little bit more complex and per definition of the Montreal is that you have to feel fluid coming back to your throat. However, patients may feel regurgitation even though nothing comes into the back of their throat. They feel movement off off, off reflux throughout their Sophocles. And so my belief is, and there are actually several studies showing that during that period of time, they want may not document any reflex event that this is the same type off abnormal perception off interest off a jail event. So, personally, I do believe that functional regurgitation exists. And if there is functional regurgitation, then I would approach it like functional heartburn. But at this point, it hasn't established itself as a separate, functional esophageal disorder. Dr. Fast, do you have time for one more question? Absolutely. So if p p I therapy is not affected, is their surgical options. If p p I is not effective in s so it's not clear to me if BP is not effective in what patient Population in f e p. A is not effective in the functional esophageal disorders that we discussed. For example, if p p. A. Is not effective in reflux hypersensitivity, I would not consider surgery as an option. Um, uh, it is mentioned on my algorithm reflex. Entire reflects surgery is an option, but this is because there are certain studies that reported that in fact, there is a study and the title of the study. This is a surgical study that said that patients with hypersensitive esophagus do respond to anti reflects surgery. This is the title off the paper. But if you ask me in patients who felt pity I twice a day and I found out that they have reflux hypersensitivity. If I would consider anti reflux surgery, I would say that the likely that I would consider it is extremely small. And in fact, I would personally recommend not to refer those patients for surgery. Okay, thank you very much. On behalf of diverse take healthcare, we'd like to thank you very much, Doctor fest for wonderful lecture and thank you for taking the time for the questions and answers and for everyone. Thank you for your attendance. We appreciate it. This entire webinar will be recorded, has been recorded and will be posted on our diverse tech Healthcare university website in the coming days. So to everyone.