Gastro-esophageal reflux disorders

Chapter 15

Gastro-esophageal reflux disorders Sabine Roman Université de Lyon, Hospices Civils de Lyon, Digestive Physiology, E Herriot Hospital, Lyon, France, Université de Lyon, Lyon I University, Digestive Physiology, Lyon, France, Université de Lyon, Inserm U1032, LabTAU, Lyon, France

Key Points ●

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The clinical diagnosis of gastroesophageal reflux disease is based on the occurrence of heartburn and regurgitation in the absence of warning signs. Upper endoscopy is normal in two-thirds of patients, but if abnormal, grade C and grade D esophagitis, Barrett's mucosa, and peptic stricture are strong indicators of gastroesophageal reflux disease. Esophageal acid exposure time >6% during prolonged 24-hr pH study is strong evidence for gastroesophageal reflux disease. Treatment with proton pump inhibitors relieves symptoms and heal esophagitis whereas anti-reflux surgery is aimed at restoring the function of anti-reflux barrier.

Introduction According to the Montreal definition, gastro-esophageal reflux disease (GERD) is “a condition which develops when the reflux of gastric contents into the esophagus causes troublesome symptoms/and or complications” [1]. This common digestive disease is associated with esophageal symptoms such as heartburn and regurgitation, and also with other digestive (epigastric pain, dysphagia) or extra-digestive (chronic cough, hoarseness, throat clearing) symptoms [2]. The diagnosis is usually clinical in patients with typical presentation. However complementary examinations are necessary to rule out complications and to link gastro-esophageal reflux (GER) episodes with symptoms. Upper gastro-intestinal (GI) endoscopy is usually the first line examination and different reflux detection techniques can then be used depending on their availability and indications. The cornerstone treatment of this condition is proton pump inhibitors (PPI) along with lifestyle management. Anti-reflux surgery may be discussed in some cases.

Definitions and epidemiology GER episodes are reflux events of gastric content into the esophagus. They are physiological. They become pathological when they are associated with symptoms and/or mucosal injuries. GERD symptoms are either typical or atypical. Typical symptoms are heartburn and regurgitation. Atypical symptoms include dysphagia, epigastric pain and extra-esophageal symptoms such as chest pain, chronic cough, sore throat, pharyngitis, ear, nose and throat (ENT) symptoms and dental erosions. Typical and atypical symptoms may co-exist. However, the occurrence of extra-digestive symptoms alone is not uncommon and may cause diagnostic difficulties. Besides symptoms, reflux events of gastric content into the esophagus can induce esophageal mucosal lesions including esophagitis, peptic stricture, and or Barrett's mucosa. Esophagitis is defined as esophageal mucosal break (s) in the distal part of the esophagus while Barrett's mucosa is defined as the replacement of normal esophageal mucosa by intestinal metaplasia. This preneoplastic condition may lead to dysplasia and esophageal adenocarcinoma [1]. The prevalence of GERD is increasing in Western countries [3]. Around 25% of population complain about heartburn at least once a month and 12% at least once a week. The prevalence of GERD parallels the prevalence of obesity which is an important risk factor for GERD [4]. Men and women are equally affected.

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Pathophysiology GERD pathophysiology is multifactorial. Dysfunction of the esophago-gastric junction (EGJ), harmful content of the refluxate, esophageal sensitivity and impairment of protective mechanisms, all play a role in the occurrence of pathological GERD [4]. The EGJ is composed of the lower esophageal sphincter (LES) and the crural diaphragm that are normally superimposed. This forms an anti-reflux barrier. A proximal displacement of the LES above the crural diaphragm defines hiatal hernia and the resultant disruption of the barrier function facilitates reflux of gastric content into the esophagus. A hypotensive EGJ promotes occurrence of GER episodes. Acid pocket is an area near the EGJ that remains acidic after meals and is a mechanism for postprandial GERD through increases in short segment refluxes [5]. With disruption of the EGJ found in hiatus hernia, the acid pocket expands, and this worsens GERD. Transient lower esophageal sphincter relaxations (TLESRs) are spontaneous relaxations of the LES that occur in the absence of swallowing. They represent the physiological mechanism of belching. An increased number of TLESRs and/or an increased number of reflux episodes associated with TLESRs are encountered in patients with pathological GERD. Reflux content is an important determinant of GERD pathogenicity. Hydrochloric acid, the main component of gastric secretions, is harmful for the esophageal mucosa. It induces symptoms including heartburn and chest pain and/or mucosal lesions such as esophagitis and Barrett's esophagus. Pepsin, a proteolytic enzyme secreted by gastric mucosa, bile acids and pancreatic enzymes (e.g., trypsin) might also be present in the refluxate, especially if there is a duodeno-gastric reflux associated with GERD. These enzymes are toxic to the esophageal mucosa. Esophageal sensitivity might explain symptom perception, as patients with GERD frequently exhibit a hypersensitive esophagus with an increased perception of reflux episodes. Finally there are some physiological mechanisms to protect against the occurrence of reflux and/or its consequences. Esophageal contractions induced by swallowing or esophageal distension are responsible for esophageal clearance and thus decrease the contact time between reflux content and esophageal mucosa. Furthermore, saliva is rich in bicarbonates and its deglutition can neutralize reflux acidity and reduce its toxicity. An impairment of these defensive mechanisms (esophageal hypomotility, reduced secretion of saliva) might indirectly increase reflux pathogenicity. Different risk factors are associated with the occurrence of GERD. Obesity facilitates GERD occurrence by increasing abdominal pressure and inducing EGJ dysfunction (hiatal hernia is more frequent in case of obesity as well as decreased EGJ resting pressure) [6]. Older age is also a risk factor of GERD. Consumption of fatty and acidic foods, coffee, peppermint and some medications (example, for asthma) can decrease LES pressure.

Diagnosis The diagnosis of GERD is based on clinical presentation. Complementary examinations might be required to confirm the diagnosis of GERD, to look for GERD complications and/or to link symptoms with reflux episodes. The current algorithm for diagnosis of GERD is presented in Fig. 1.

Clinical diagnosis The occurrence of typical symptoms (heartburn, regurgitation) is usually sufficient to diagnose GERD, and no complementary examination is necessary in the absence of warning signs (bleeding, dysphagia, and weight loss). A first-line treatment, nowadays typically a proton pump inhibitor (PPI), is then prescribed. In case of atypical symptoms, complementary examinations are necessary to link symptoms to GERD. Standardized questionnaires have been developed to help physicians diagnose GERD. Their sensitivities and specificities were reported in studies at around 70% [7, 8] but they might not be more reliable than taking a careful history from the patient. These questionnaires are not sufficient alone to diagnose GERD but may provide indications that further investigations are needed to confirm GERD. In the absence of warning signs, therapeutic test with a PPI has been proposed to diagnose GERD. Its sensitivity was reported around 70% and its specificity around 44% [9]. While it may represent a pragmatic and reasonable approach in patients with typical symptoms and in absence of warning signs, it is not sufficient in patients with atypical symptoms to confirm the diagnosis of GERD.



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FIG. 1  Algorithm for the diagnosis of gastro-esophageal reflux disease (GERD). In case of symptoms suggestive of GERD, an upper gastro-intestinal endoscopy (GI) is recommended for patients older than 50 years or in the presence of warning signs. A therapeutic trial with proton pump inhibitors (PPI) can be proposed in patients with typical symptoms without previous reflux monitoring. In patients with persistent symptoms on PPI, reflux monitoring on PPI is helpful to determine if there is a persistent pathological acid exposure on PPI.

Upper gastro-intestinal endoscopy and esophageal biopsies When GERD is suspected, upper GI endoscopy is the first line examination in the presence of warning sign, when first-line treatment has failed, and in patients older than 50 years [10]. The warning signs are bleeding, dysphagia, and weight loss. It is important to search for these symptoms and if present, then an upper GI endoscopy should be performed to rule out GERD complications and to look for other possible diagnosis (esophageal or gastric tumor, infectious esophagitis, eosinophilic esophagitis (EoE), etc…). Esophagitis is a typical mucosal lesion of GERD. Based on endoscopic findings, esophagitis severity is classified into four grades using the Los Angeles classification [11]. Grade A esophagitis is defined as esophageal mucosal breaks no longer than 5 mm. Grade B corresponds to at least one mucosal break longer than 5 mm, confined to the mucosal fold but not continuous between two folds. Grade C is characterized by mucosal breaks that are continuous between the tops of mucosal folds but not circumferential. Finally, grade D is defined by extensive mucosal breaks that involve at least 75% of the esophageal circumference. While Los Angeles grade C and D esophagitis provide robust evidence of GERD and also predict the response to treatment [12], grade A and B esophagitis may be encountered in asymptomatic subjects [13]. Progression from grade A/B esophagitis to grade C/D and Barrett's esophagus was observed in 1–6% and 1–12% of cases respectively while it might regress to normal endoscopy in 20–60% [14]. Based on these different considerations, the recent Lyon consensus on GERD diagnosis defined grade C and D esophagitis as strong evidence for GERD while grade A was not sufficient for the diagnosis of GERD (Fig. 2) [15]. Regarding grade B esophagitis, the group of experts in the Lyon

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FIG. 2  Diagnosis of gastro-esophageal reflux disease (GERD) according to the Lyon Consensus. Pathological GERD is defined as grade C or D esophagitis, peptic stricture or Barrett's esophagus on upper gastro-intestinal endoscopy or acid exposure time >6% on pH-(impedance) monitoring. Additional tests are required in case of inconclusive diagnosis of GERD.

consensus acknowledged that it might be rarely observed in healthy controls and thus recommended to perform another test to confirm GERD when anti-reflux is considered in patients with grade B esophagitis. Other endoscopic findings, such as peptic stricture and Barrett's esophagus >1 cm are indicative of pathological GERD [15]. Barrett's mucosa is a preneoplastic condition where the normal esophageal mucosa is replaced by intestinal metaplasia that predisposes to dysplasia and esophageal adenocarcinoma. It is suspected by the presence of salmon pink mucosa above the EGJ (identified endoscopically as the zone above the gastric folds). Biopsies are required to search for intestinal metaplasia that confirms the diagnosis of Barrett's mucosa [16]. Overall endoscopic abnormalities are encountered in only 10–30% of patients with GERD [11, 17]. Thus a normal upper GI endoscopy does not rule out GERD and most patients with GERD symptoms have normal appearing mucosa on endoscopy. To improve the endoscopy yield, it has been proposed to perform systematic biopsies in the distal part of the esophagus [18]. Indeed reflux episodes might induce microscopic esophageal mucosal lesions. Increased dilated intercellular spaces, papillary elongation, and basal cell hyperplasia are more frequently encountered in patients with GERD than in patients with functional heartburn [19, 20]. But sensitivity and specificity are not optimal (e.g., 85% and 63%, respectively in the study by Kandulski et al.) limiting the diagnostic value of histological abnormalities [19]. It is important to note that performing esophageal biopsies is recommended in patients with refractory GERD symptoms in order to search for eosinophilic esophagitis. Indeed the Rome IV diagnostic criteria require an exclusion of eosinophilic esophagitis (by performing esophageal biopsies) to diagnose esophageal functional disorders [21].

Reflux monitoring Reflux monitoring consists of identifying reflux episodes into the esophagus. It can be considered as the gold standard to diagnose GERD. As the main component of reflux is acid, reflux episodes are usually identified by the presence of acid in the esophagus using esophageal pH monitoring. Another method of reflux detection is based on the detection of liquid and air in the esophagus using esophageal pH-impedance monitoring [22]. Reflux monitoring allows also assessment of relationship between reflux episodes and symptoms. It is indicated in patients with atypical symptoms or incomplete or absent responses to PPI therapy [15] with the aim to confirm GERD (Fig. 1). Different methods of reflux monitoring are compared in Table 1.

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TABLE 1  Comparison of reflux monitoring techniques: catheter-based pH monitoring, wireless pH monitoring, and pH-impedance monitoring

pH electrode location

Anesthesia for placement

Catheter-based pH monitoring

Wireless pH-monitoring

pH-impedance monitoring

pH electrode placed 5 cm above the proximal border of the EGJ

pH electrode clipped into the esophagus 6 cm above the squamocolumnar junction

pH electrode placed 5 cm above the proximal border of the EGJ

Esophageal manometry is usually performed before to localize the EGJ

Placement is usually performed during an upper GI endoscopy

Esophageal manometry is usually performed before to localize the EGJ

No anesthesia or local anesthesia

Usually under general anesthesia

No anesthesia or local anesthesia

But possible without anesthesia Performed off or on PPI

Off PPI (PPI should be stopped 7 days before recording)

Off PPI (PPI should be stopped 7 days before recording)

Off or on PPI

Recording duration

24 h

48–96 h

24 h

Reflux identification

Only acid reflux episodes

Only acid reflux episodes

Acid and weakly acid reflux episodes Characterization of liquid and/ or gas content

Tolerance

+/−

+++

+/−

Cost

+

+++

+++

Esophageal pH-monitoring Esophageal pH monitoring consists of measuring the pH in the distal esophagus. Reflux episodes are defined as an esophageal pH <4. The ambulatory recording is performed for 24 h. A catheter-based system can be used. It consists of a transnasal catheter connected to an external recorder. A pH sensor is located at the tip of the catheter inserted transnasally into the esophagus. It is placed 5 cm above the proximal border of the EGJ. A wireless system can be used for esophageal pH monitoring as an alternative. A capsule with a pH sensor is clipped into the distal esophagus, 6 cm proximal to the squamocolumnar junction (i.e., the transition zone between the esophageal and the gastric mucosa) identified during an upper GI endoscopy. pH data recorded by the capsule are transmitted to an external recorder through telemetry. Wireless pH monitoring has several advantages over the catheter-based system [23]. Patient tolerance is improved due to absence of a transnasal catheter and there are fewer dietary modifications and restrictions on activities using the wireless system compared to a catheter-based system. Recording with wireless pH monitoring can be extended to 48–96h. This results in a higher sensitivity for detection of both abnormal acid esophageal exposure and positive symptom-reflux association [24]. However, cost and availability limit its use in clinical practice in some countries. Esophageal pH monitoring is performed off PPI. It is indicated in patients without proven GERD (that is no esophagitis, no peptic stricture, no Barrett's esophagus on upper GI endoscopy, no previous positive pH monitoring) to assess symptoms refractory to PPI therapy and to confirm GERD prior to anti-reflux surgery. Based on pH-monitoring (catheter-based or wireless system), the Lyon consensus defined GERD as acid exposure time (AET, percentage of time with an esophageal pH <4) of >6% of the total time [15]. An AET <4% of the total time is considered as normal. Finally an AET between 4% and 6% is considered as a grey area where the diagnosis of GERD is uncertain and other complementary examinations are recommended.

Esophageal pH-impedance monitoring Esophageal intraluminal impedance consists of measuring the impedance of intra-esophageal bolus with a probe inserted transnasally. It allows the detection of liquid and gas into the esophagus. The impedance value is low in case of liquid and high in case of air. The distribution of impedance electrodes along a catheter allows the differentiation of ­swallowing

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(i.e., a change of impedance signal with anterograde propagation, from proximal to distal esophagus) from reflux episodes (i.e., a change of impedance signal with retrograde propagation, from distal to proximal esophagus). Combined with recording of pH, esophageal pH-impedance monitoring enables the detection and characterization of all types of reflux episodes (acid or weakly acid, liquid, gaseous or mixed) [25]. As for pH monitoring, the pH-impedance catheter is placed so that the pH electrode is located 5 cm above the proximal border of the EGJ and the impedance measurements are usually performed 3, 5, 7, 9, 15 and 17 cm above the EGJ. Ambulatory recording is performed for 24 h. Compared to pHmonitoring, pH-impedance has the advantage of detecting reflux episodes regardless of their pH values. It is of particular interest for patients on anti-secretory therapy (PPI); where reflux episodes are less acidic on PPI than off PPI. Thus, while pH monitoring alone is performed off anti secretory therapy (PPI, anti H2), pH-impedance monitoring can be performed either off or on PPI as it allows the detection of acid and weakly acid reflux episodes. According to the Lyon consensus, the same definition of GERD is proposed for pH alone and pH-impedance monitoring performed off or on PPI i.e., an AET (esophageal pH <4) >6% of the total time is considered as pathological, an AET <4% is normal and AET between 4% and 6% is an inconclusive diagnosis of GERD [15]. The total number of liquid and mixed reflux episodes (acid and weakly acid) identified from impedance is an adjunct test for diagnosis of GERD: a total number of reflux episodes >80 per 24h is considered as pathological while a total number <40 per 24h is normal. Post reflux swallow induced peristaltic wave (PSPW) index, a novel metric described in pH impedance monitoring, is useful to determine the percentage of reflux episodes that are followed by a swallow-induced esophageal contraction [26]. It might differentiate accurately patients with GERD from those with functional heartburn. So far, its calculation is manual thereby limiting its clinical use. The group of experts of the Lyon consensus considered PSPW index as an exploratory tool requiring further investigation to confirm its yield in GERD diagnosis [15]. The indications for esophageal pH-impedance monitoring off PPI are the same as esophageal pH-monitoring. Choice is driven by the availability and cost. Esophageal pH-monitoring is indicated on PPI in patients with prior evidence of reflux (esophagitis, Barrett's esophagus on upper GI endoscopy or positive reflux monitoring off PPI) and symptoms refractory to PPI therapy. Tips and tricks for pH and pH-impedance monitoring ● ●

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If the study is indicated off PPI, PPI should be stopped for at least 7days before recording. The pH or pH impedance catheter is inserted transnasally and the pH sensor is positioned 5 cm above the proximal border of the EGJ, previously determined by esophageal manometry. During the recording, patient should be instructed to eat normally and to have normal activities. Chewing gum should be avoided. In case of pH-impedance monitoring, sparkling drinks should be avoided to limit gas swallows that may alter impedance interpretation. A complete absence of esophageal acid exposure on a pH or pH-impedance study should not automatically lead to an exclusion of GERD diagnosis. Instead, PPI therapy, pH sensor misplacement and atrophic gastritis should be considered. Likewise, a very high acid exposure on a pH or pH-impedance study should not automatically lead to a diagnosis of GERD; pH sensor misplacement should be considered if this situation arises.

Symptom-reflux association During pH and pH-impedance monitoring, the patient can indicate the occurrence of symptoms either by pressing a button on the data recorder or by filling in a diary. A symptom is considered related to a reflux episode if the symptom occurred within 2 min following the reflux episode [25]. Different parameters are used to evaluate the reflux-symptom association, and these are described below. – Symptom index (SI) is defined as the percentage of symptom events that are related to reflux episodes, i.e., the number of reflux related symptom events divided by the total number of symptom events times 100%. A SI >50% is considered positive, i.e., a large proportion of the patient's symptoms are considered to be reflux-related. – Symptom Association Probability (SAP) is a statistical parameter that expresses the strength of relationship between symptom events and reflux episodes during the measurement. SAP value above 95% (corresponding to P <0.05 by applying the Fisher's exact test on a 2 × 2 table) is considered a positive relationship. SI and SAP are calculated automatically with a dedicated software used to analyze pH and pH-impedance monitoring. To interpret SI and SAP reliably, at least three symptom events should be reported by the patient. The likelihood of a positive relationship between reflux and symptoms is important if the two indices are positive. Based on the Rome IV criteria, these indices are used to define reflux hypersensitivity (normal AET and positive SI or SAP) and functional symptoms (normal AET and negative SI and SAP) [21].



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Other tests Esophageal high resolution manometry Esophageal high resolution manometry (HRM) allows the assessment of EGJ function (resting pressure, relaxation during swallowing) and esophageal body contractility. It consists of measuring intra-esophageal pressure variations using a transnasally inserted catheter that has several pressure sensors distributed along its length. Pressure variations reflect the contractile activity of the esophagus and are represented as esophageal pressure topography plots. It is the gold standard for assessing esophageal contractility. Esophageal manometry is indicated for suspicion of esophageal motility disorders in patients with dysphagia or chest pain after ruling out esophageal mucosal abnormality with upper GI endoscopy. It has no direct role in the diagnosis of GERD [27]. In patients with GERD, HRM is frequently used to accurately localize the EGJ before performing an esophageal pH-(impedance) monitoring. It is also mandatory before anti-reflux surgery to rule out major motility disorders (especially absence of esophageal contraction for example achalasia which is a condition characterized by impairment of EGJ relaxation and absence of normal esophageal contraction [28]) that may contraindicate anti-reflux surgery. Finally it may help identify causes that facilitate the reflux of gastric content into the esophagus, such as manometric hiatal hernia (separation of the LES and the crural diaphragm), hypotensive EGJ and esophageal hypocontractility (Fig. 3) [27]. A multiple rapid swallow (MRS) test can be performed during HRM; it consists of five 2 mL swallows of <2s apart; normally MRS is followed by an esophageal contraction more vigorous than the contraction observed after one single swallow. The absence

FIG. 3  Classification of esophageal motor patterns in gastro-esophageal reflux disease using esophageal high resolution manometry. Esophago-gastric junction can be normal (one single high pressure zone, the lower esophageal sphincter (LES) and t the crural diaphragm (CD) are superimposed), hypotensive or demonstrates a hiatal hernia (two high pressure zones, the upper one corresponds to LES and the lower one to the CD). Esophageal contractions can be normal, ineffective (contractile vigor as measured with distal contractile integral (DCI) <450 mmHgscm), fragmented (defect in the contractile front >5 cm) or absent. Finally a contractile reserve is present if multiple rapid swallow (MRS) test is followed by an esophageal contraction while the contractile reserve is absent if no contraction is observed after MRS.

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of esophageal contraction after MRS is considered as an absence of contractile reserve and can be more frequently encountered in GERD patients than in controls [27]. The combination of esophageal impedance and pressure measurements, called the esophageal high resolution impedance manometry (HRIM), might be performed to identify reflux episodes (using impedance measurements) and their mechanism (using pressure measurements). This is the gold standard to diagnose TLESRs [29]. It also allows ruling out some other differential diagnosis. For example, rumination syndrome can mimic GERD symptoms [30]. This functional gastrointestinal disorder is characterized by effortless and repetitive regurgitation of recently ingested food from the stomach to the oral cavity followed by either reswallowing or spitting. Esophageal HRIM confirms the diagnosis of rumination through reflux episodes that extend to the proximal esophagus and is closely associated with an abdominal pressure increase >30 mmHg and also esophageal pressure increase [30]. In a retrospective cohort of 94 highly selected patients with refractory GERD symptoms, different profiles were identified based on the results of esophageal HRIM, performed after a meal (post prandial study): reflux episodes with a majority of TLESRs was seen in 14%, rumination in 20%, supragastric belching (that is air movement into the esophagus where air is swallowed or aspirated into the esophagus and then immediately expulsed; this behavioral disorder can be associated with reflux hypersensitivity and functional symptoms) in 42% and normal pattern in 24% [31].

Barium esophagogram Barium esophagogram has no value to diagnose GERD [32]. However it may be performed to identify hiatal hernia, and it is routinely performed when anti-reflux surgery is considered.

Baseline and mucosal impedance Recently some authors have proposed to measure esophageal baseline impedance during 24-h pH-impedance monitoring to diagnose GERD [33–35]. Indeed, low baseline esophageal impedance might reflect an impaired esophageal mucosal integrity which is associated with GERD. Patients with GERD have lower average baseline impedance values than healthy subjects. A simplified method was proposed to measure baseline impedance. This measurement, called the mean nocturnal baseline impedance (MNBI), consists of measuring the baseline impedance 3 or 5 cm above the LES during overnight rest as the mean baseline impedance of three 10-min time periods during a period without swallowing [36]. MNBI is lower in GERD patients than in patients with functional heartburn and in patients who respond to PPI therapy compared to those who exhibit persistent GERD symptoms on PPI [36, 37]. An alternative is to measure mucosal impedance using a dedicated device during upper GI endoscopy [38, 39]. Mucosal impedance is lower in the distal esophagus in patients with GERD compared to controls. Patients with EoE have a unique pattern with a low mucosal impedance both in the proximal and the distal esophagus while patients with GERD have a low mucosal impedance only in the distal esophagus. Further studies are required to define the role of mucosal impedance measurement in the algorithm of GERD diagnosis.

Therapeutic management Lifestyle modifications are usually advised in patients with GERD but PPI remains the cornerstone of GERD treatment [40]. An alternative to medical treatment is surgery. It consists of restoring the integrity of the anti-reflux barrier by performing a fundoplication (the upper part of the stomach is wrapped around the EGJ). Finally, minimally invasive procedures are emerging but so far none of them are considered as first line treatment for GERD.

Lifestyle modifications As overweight and obesity are risk factors for GERD, it is logical to recommend weight loss as part of management. Avoidance of various foods (carbonated soft drink, coffee, fat food, chocolate, peppermint, citrus, spicy food) that may induce symptoms are usually recommended but the evidence is extremely limited [40]. Sleeping with the head; end of bed elevated may help to reduce nocturnal reflux episodes.

Medical treatment Proton pump inhibitors PPIs inhibit gastric acid secretion by irreversibly blocking the H+ K+ ATPase proton pumps. Thus with PPIs, the reflux content becomes less acidic, and thereby improving esophageal symptoms and healing esophagitis [40]. They are



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c­ ommonly prescribed as an empirical trial but also as first line treatment in patients with GERD symptoms, esophagitis and/or positive reflux monitoring. Overall PPIs are efficacious in up to 85% of patients with GERD (better response rates in patients with esophagitis than in those with pathological AET but normal esophageal mucosa). The recommended dose is the lowest one that provides symptom relief and/or esophagitis healing. A prescription for PPI ranges from on demand therapy to twice daily. PPIs should be taken 15–30 min before meals to optimize absorption and efficacy. There are no significant differences in efficacy between various types of PPI formulations although some provide longer acid suppression. Long term PPI therapy has been linked to different side effects including gastro-intestinal malabsorption, osteoporosis, dementia, heart and kidney diseases [41]. These side effects are usually limited and whether PPI is truly responsible has not been clearly demonstrated. Thus experts do not recommend specific monitoring of side effects of patients on PPI.

Histamine-2 receptors antagonists (H2RAs) H2RAs inhibit acid secretion by decreasing the stimulating effect of histamine on acid secretion. They induce esophagitis healing and symptom relief but are less powerful than PPIs [40]. They represent an alternative to PPI therapy in patients with mild symptoms and with poor tolerance to PPI therapy. These agents were also proposed as add on therapy in patients with incomplete response to PPIs to reduce acid nocturnal breakthrough. However, they are associated with tachyphylaxis limiting their effects to control acid secretion.

Potassium competitive acid blockers (PCAB) PCAB is a new class of acid suppressant agents that inhibit gastric H+ K+ ATPase with a faster onset of action than PPI [42]. It is non-inferior to PPI to heal esophagitis. PCAB may heal esophagitis and reduce symptoms in patients who failed to respond to PPI therapy. It is important to note that a majority of studies evaluating vonoprazan were conducted in Asia where the prevalence of patients with CYP2C19 extensive metabolizer genotype is high. Contrary to PPI, the elimination of P-CAB is independent of CYP2C19 and this may explain the stronger effect of PCAB on acid suppression among Asians.

Other medications Antacids might neutralize reflux content and alginates can form a protective film to limit the contact between reflux and the esophageal mucosa. These drugs have shown some efficacy in mild GERD symptoms. Indeed a meta-analysis on the efficacy of these OTC medications in relieving GERD symptoms found a relative benefit of 11% for simple antacids and up to 60% for alginate-antacid combinations when compared to placebo [43]. Reflux inhibitors TLESR are another promising avenue. However their development was stopped due to lack of efficacy or side effects. The only TLESR inhibitor still available is baclofen, a GABA B agonist. It has been shown to decrease the number of reflux episodes, but its clinical use has been limited by a number of neurologic side effects (somnolence, dizziness, drowsiness) [44]. Because hypersensitivity is an important determinant of symptoms perception, some antidepressant drugs (amitriptyline and citalopram) may be useful in patients with refractory GERD. [45]

Anti-reflux surgery The aims of surgical fundoplication are to restore the normal anatomy and to re-establish the competence of the anti-reflux barrier. The two most popular surgical procedures are the laparoscopic Nissen (360°) fundoplication and the Toupet (270°) fundoplication. The efficacy of surgical fundoplication is similar to that of medical treatment, with a good outcome in >80% of cases at 5 years, post fundoplication or PPI treatment in patients with typical GERD symptoms and pathological GERD confirmed by complementary examinations [46]. Patients with hiatal hernia and/or persistent regurgitation on PPI might be good candidates for surgery with the caveat that these patients have a proven GERD demonstrated by pH monitoring off PPI [44]. A recent randomized trial evaluated the efficacy of surgery in patients who failed to respond to PPI therapy [47]. The authors compared laparoscopic Nissen fundoplication, PPI and baclofen (omeprazole 20 mg BID and baclofen up to 20 mg TID), and PPI alone (omeprazole 20 mg BID) in patients with refractory heartburn and abnormal esophageal acid exposure and/or positive symptom association probability on pH-impedance monitoring performed on PPI. Surgery was significantly better at 12 months than PPI and baclofen (P=0.007) and PPI alone (P<0.0001), while no significant difference was observed between PPI and PPI+baclofen (P=0.17). It is important to note that this study was conducted in a group of wellselected refractory GERD patients, that comprised of a very small number of patients [47]. Thus, fundoplication is a valid option in patients with typical symptoms, who previously respond to PPI therapy and with proven GERD. It might be also indicated in patients refractory to PPI as long as they are well selected and exhibit

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proven GERD. These indications should be balanced with risks of surgical complications and of side effects (dysphagia, flatulence, inability to belch).

Minimally invasive procedures Transoral incisionless fundoplication (TIF) is an endoscopic treatment of GERD. It consists of a fundoplication but performed during an upper GI endoscopy. This procedure appears to be safe (2% adverse events) and effective with a significant decrease of esophageal symptoms [48]. 89% of patients have stopped their PPI after the procedure. However few long term studies are currently available. An observational study demonstrated a decrease of complete response over time (51% at 1 year vs 32% at 5 years) [49]. Magnetic sphincter augmentation (LINX®) consists of surgical implantation of a ring of magnetic beads around the LES. It has been shown to improve GERD in the short term [50]. 80% of patients are able to stop PPI. Device removal because of adverse events, mainly dysphagia, occurs in about 2% of implants. Electrical stimulation of the LES might increase LES resting pressure and induce a significant decrease of esophageal acid exposure in GERD patients [51, 52]. Electrodes are laparoscopically placed in the LES and is then connected to an implantable pulse generator. Around 2/3rd of GERD patients were able to stop PPI therapy based on studies. Further controlled studies are required to confirm the efficacy of electrical stimulation.

Conclusions Gastro-esophageal reflux disease is one of the most common digestive diseases seen in clinical practice. Its diagnosis is usually clinical based the presence of heartburn and regurgitation and absence of warning signs. Upper GI endoscopy is the first line examination even though it is normal in two-thirds of patients. The presence of a grade C or D esophagitis, Barrett's mucosa and peptic stricture are strong evidence for GERD. Reflux monitoring is indicated to confirm GERD in case of normal endoscopy, non-response to first line treatment or atypical symptoms, and to confirm the relationship between GERD episodes and symptoms. In case of unproven GERD (no previous esophagitis, no Barrett's mucosa, no peptic stricture), pH monitoring should be performed off PPI, using either catheter-based or wireless pH-monitoring or ­pH-impedance monitoring. In case of proven GERD, pH-impedance monitoring is preferred and performed on PPI. An esophageal acid exposure time >6%, over 24 hours is strong evidence for GERD. In case of uncertain diagnosis, adjunct tests may be considered (microscopic esophagitis, total number of reflux episodes detected on impedance, baseline impedance). PPI therapy is the first line treatment of GERD. Anti-reflux surgery can be an alternative in well selected patients. Minimally invasive procedures require further studies before it can be routinely recommended for GERD.

Acknowledgments SR has served as consultant for Medtronic and Diversatek Healthcare. She received research grant support from Crospon and Diversatek Healthcare.

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