Refractory Gastroesophageal Reflux Disease: Diagnosis and Management

Trevor A Davis,C Prakash Gyawali 대한소화기 기능성질환∙운동학회 2024 Journal of Neurogastroenterology and Motility (JNM Vol.30 No.1

Gastroesophageal reflux disease (GERD) is common, with increasing worldwide disease prevalence and high economic burden. A significant number of patients will remain symptomatic following an empiric proton pump inhibitor (PPI) trial. Persistent symptoms despite PPI therapy are often mislabeled as refractory GERD. For patients with no prior GERD evidence (unproven GERD), testing is performed off antisecretory therapy to identify objective evidence of pathologic reflux using criteria outlined by the Lyon consensus. In proven GERD, differentiation between refractory symptoms (persisting symptoms despite optimized antisecretory therapy) and refractory GERD (abnormal reflux metrics on ambulatory pH impedance monitoring and/or persistent erosive esophagitis on endoscopy while on optimized PPI therapy) can direct subsequent management. While refractory symptoms may arise from esophageal hypersensitivity or functional heartburn, proven refractory GERD requires personalization of the management approach, tapping from an array of non-pharmacologic, pharmacologic, endoscopic, and surgical interventions. Proper diagnosis and management of refractory GERD is critical to mitigate undesirable long-term complications such as strictures, Barrett’s esophagus, and esophageal adenocarcinoma. This review outlines the diagnostic workup of patients presenting with refractory GERD symptoms, describes the distinction between unproven and proven GERD, and provides a comprehensive review of the current treatment strategies available for the management of refractory GERD.

Screening for Barrett’s Esophagus: Balancing Clinical Value and Cost-effectiveness

Amit Patel,C Prakash Gyawali 대한소화기 기능성질환∙운동학회 2019 Journal of Neurogastroenterology and Motility (JNM Vol.25 No.2

In predisposed individuals with long standing gastroesophageal reflux disease (GERD), esophageal squamous mucosa can transform into columnar mucosa with intestinal metaplasia, commonly called Barrett’s esophagus (BE). Barrett’s mucosa can develop dysplasia, which can be a precursor for esophageal adenocarcinoma (EAC). However, most EAC cases are identified when esophageal symptoms develop, without prior BE or GERD diagnoses. While several gastrointestinal societies have published BE screening guidelines, these vary, and many recommendations are not based on high quality evidence. These guidelines are concordant in recommending targeted screening of predisposed individuals (eg, long standing GERD symptoms with age > 50 years, male sex, Caucasian race, obesity, and family history of BE or EAC), and against population based screening, or screening of GERD patients without risk factors. Targeted endoscopic screening programs provide earlier diagnosis of high grade dysplasia and EAC, and offer potential for endoscopic therapy, which can improve prognosis and outcome. On the other hand, endoscopic screening of the general population, unselected GERD patients, patients with significant comorbidities or patients with limited life expectancy is not cost-effective. New screening modalities, some of which do not require endoscopy, have the potential to reduce costs and expand access to screening for BE.

Nutrient Drink Test to Assess Gastric Accommodation in Cyclic Vomiting Syndrome: Single-blinded Parallel Grouped Prospective Study

Afrin N Kamal,Kevin B Harris,Shashank Sarvapalli,Gregory S Sayuk,C Prakash Gyawali,Scott Gabbard 대한소화기 기능성질환∙운동학회 2023 Journal of Neurogastroenterology and Motility (JNM Vol.29 No.1

Background/AimsCyclic vomiting syndrome (CVS) is characterized by episodes of nausea and vomiting, separated by symptom-free intervals. The pathogenesis of CVS is poorly understood. Limited data exist on evaluating impaired gastric accommodation as a mechanistic means for symptoms. We aim to determine if CVS patients demonstrate impaired gastric accommodation applying a nutrient drink test (NDT) protocol. MethodsThrough this single-blinded pilot clinical trial, patients with CVS per Rome IV critera and healthy controls were assessed for presence of impaired gastric accommodation by administering an established NDT protocol. Statistical analysis was performed, with data presented as medians and interquartile range. ResultsEleven CVS patients and 15 healthy controls participated in the study between January 2018 and October 2018. Median age was 42.0 years and 37.0 years; majority of subjects were female, 72.7% and 73.3%, respectively. Demographics were similar between CVS and healthy controls. Almost all healthy controls (93.3%) ingested the complete 500 mL protocol, whereas a smaller proportion (72.7%) were able to complete all 4 doses in the CVS group (P = 0.188). Post-prandial visual analogue scale scores of nausea and abdominal pain were found to be significantly higher in CVS patients compared to healthy controls. ConclusionsTo our knowledge, this is the first NDT protocol in CVS evaluating the role of impaired gastric accommodation and hypersensitivity as a possible pathophysiologic mechanism. Findings from this study suggest the presence of gastric hypersensitivity in a subset of CVS patients. These results provide the foundational data necessary for future larger testing of NDT and diagnostic accuracy in CVS.

Chronic Cough Is Associated With Long Breaks in Esophageal Peristaltic Integrity on Highresolution Manometry

( Michael C Bennett ),( Amit Patel ),( Nitin Sainani ),( Dan Wang ),( Gregory S Sayuk ),( C Prakash Gyawali ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2018 Journal of Neurogastroenterology and Motility (JNM Vol.24 No.3

Background/Aims Breaks in the peristaltic contour on esophageal high-resolution manometry (HRM) may be associated with bolus retention in the esophagus. We evaluated the relationship between peristaltic breaks and esophageal symptoms, reflux exposure, and symptom outcomes in a prospective patient cohort. Methods Two hundred and eighteen patients (53.2 ± 0.9 years, 68.3% female) undergoing both pH-impedance testing and HRM over a 5-year period were prospectively evaluated. Demographics, symptom presentation, acid exposure time, symptom association probability, and symptom burden scores were collected. Outcomes were assessed on follow-up using changes in symptom scores. Presence of long breaks (≥ 5 cm) on HRM was assessed by a blinded author. Relationships between breaks, reflux parameters, presenting symptoms, and outcomes were assessed. Results Patients with long breaks were more likely to have cough as a presenting symptom than those without (43.4% vs 28.6%, P = 0.024); statistical differences were not demonstrated with other symptoms (P ≥ 0.3). Numbers of swallows with long breaks were higher in patients with cough compared to those without (2.4 ± 0.3 vs 1.6 ± 0.2, P = 0.021); differences were not found with other symptoms (P ≥ 0.4). Long breaks were not associated with age, gender, race, reflux burden, symptom association, or changes in symptom metrics (P ≥ 0.1 for all comparisons). Among patients with cough, the presence of long breaks predicted suboptimal symptom improvement with antireflux therapy (P = 0.018); this difference did not hold true for other symptoms (P ≥ 0.2). Conclusions Long breaks in esophageal peristaltic integrity are associated with cough. The presence of long breaks is associated with suboptimal benefit from antireflux therapy. (J Neurogastroenterol Motil 2018;24:387-394)

Esophageal Baseline Impedance From High-resolution Impedance Manometry Correlates With Mean Nocturnal Baseline Impedance From pH-impedance Monitoring

( Anthony Horton ),( Brian Sullivan ),( Katie Charles ),( Thasha Mcintosh ),( Andrea Davis ),( Ziad Gellad ),( Rahul Shimpi ),( C Prakash Gyawali ),( Amit Patel ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2020 Journal of Neurogastroenterology and Motility (JNM Vol.26 No.4

Background/Aims Esophageal baseline impedance (BI) can be extracted from pH-impedance tracings as mean nocturnal baseline impedance (MNBI), and from high-resolution impedance manometry (HRIM), but it is unknown if values are similar between acquisition methods across HRIM manufacturers. We aim to assess correlations between MNBI and BI from HRIM (BI-HRIM) from 2 HRIM manufacturers in the setting of physiologic acid exposure time (AET). Methods HRIM and pH-impedance monitoring demonstrating physiologic AET (< 4%) off proton pump inhibitors were required. BI-HRIM was extracted as the average from 5 cm and 10 cm above the lower esophageal sphincter. Distal BI-HRIM (DBI-HRIM) was also extracted from the most distal channel (Medtronic studies). MNBI was extracted from 6 channels. Concordance between BI-HRIM across manufacturers with MNBI was analyzed. Results Thirty-six patients met the inclusion criteria (59.6 ± 1.7 years; 22% female; body mass index 30.5 ± 0.7; AET 1.6 ± 0.2%). Although MNBI was similar at all channels (P ≥ 0.18), Diversatek BI-HRIM was lower than Medtronic BI-HRIM (P = 0.003). Overall, BI-HRIM correlated with MNBI at corresponding recording sites, 7 cm and 9 cm (P < 0.05), but not at other sites (P ≥ 0.19). Pearson’s correlations > 0.5 were seen at MNBI at 7 cm for both systems, and at 9 cm for Medtronic. DBI-HRIM correlated with MNBI at 3 cm and 5 cm (P < 0.03), but not at other locations (P > 0.1). Conclusions While numeric differences exist between manufacturers, BI-HRIM correlates with MNBI from corresponding channels in patients with physiologic AET. Comparison with AET elevation is needed to determine correlations between pathologic MNBI with BI-HRIM across manufacturers. The optimal HRIM channels from which BI values should be extracted also warrants further study. (J Neurogastroenterol Motil 2020;26:455-462)

Patients With Definite and Inconclusive Evidence of Reflux According to Lyon Consensus Display Similar Motility and Esophagogastric Junction Characteristics

( Mentore Ribolsi ),( Edoardo Savarino ),( Benjamin Rogers ),( Arvind Rengarajan ),( Marco Della Coletta ),( Matteo Ghisa ),( Michele Cicala ),( C Prakash Gyawali ) 대한소화기기능성질환·운동학회 2021 Journal of Neurogastroenterology and Motility (JNM Vol.27 No.4

Background/Aims The role of esophageal high-resolution manometry (HRM) within Lyon consensus phenotypes, especially patients with inconclusive gastroesophageal reflux disease (GERD) evidence, has not been fully investigated. In this multicenter, observational study we aim to compare HRM parameters in patients with GERD stratified according to the Lyon consensus. Methods Clinical and endoscopic data, HRM and multichannel intraluminal impedance-pH (MII-pH) studies performed off proton pump inhibitor therapy in patients with esophageal GERD symptoms were reviewed. Lyon consensus criteria identified pathological GERD, reflux hypersensitivity, functional heartburn, and inconclusive GERD. Patients, with inconclusive GERD were further subdivided into 2 groups based on total reflux numbers (≤ 80 or > 80 reflux episodes) during the MII-pH recording time. Results A total of 264 patients formed the study cohort. Pathological GERD and inconclusive GERD patients were associated with higher numbers of reflux episodes, lower mean nocturnal baseline impedance (MNBI) values, and a higher proportion of patients with pathologic MNBI compared to functional heartburn (P < 0.05 for each comparison). On multivariate analysis, pathological GERD and inconclusive GERD patients, both with ≤ 80 or > 80 reflux episodes, were significantly associated with pathologic esophagogastric junction contractile integral values and with presence of hiatus hernia (type 2/3 esophagogastric junction). Patients with inconclusive GERD and > 80 reflux episodes were significantly associated with fragmented peristalsis and ineffective esophageal motility whilst inconclusive GERD with ≤ 80 reflux episodes were significantly associated with fragmented peristalsis. Conclusion Esophageal motor parameters on HRM are similar between pathologic and inconclusive GERD according to the Lyon consensus. (J Neurogastroenterol Motil 2021;27:565-573)

High-resolution Manometry Determinants of Refractoriness of Reflux Symptoms to Proton Pump Inhibitor Therapy

( Mentore Ribolsi ),( Edoardo Savarino ),( Benjamin Rogers ),( Arvind Rengarajan ),( Marco Della Coletta ),( Matteo Ghisa ),( Michele Cicala ),( C Prakash Gyawali ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2020 Journal of Neurogastroenterology and Motility (JNM Vol.26 No.4

Background/Aims Impaired esophageal motility and disrupted esophagogastric junction (EGJ) on high-resolution manometry (HRM) have been associated with increased reflux severity in gastroesophageal reflux disease (GERD) patients. However, there are limited data evaluating HRM parameters in proton pump inhibitors (PPI) non-responders. Methods Clinical and endoscopic data, HRM and multichannel intraluminal impedance-pH studies performed of PPI therapy in patients with typical GERD symptoms were reviewed from 3 international centers. Frequency of GERD symptoms was assessed on and off PPI therapy in both non-responders (< 50% symptom improvement on PPI therapy) and responders. Rome IV definitions identified non-erosive reflux disease, reflux hypersensitivity, and functional heartburn. Univariate and multivariate analyses were performed to determine predictors of non-response. Results Of 204 patients, 105 were PPI non-responders and 99 were responders. Non-responders showed higher EGJ contractile integral values, and a lower frequency of type II and III EGJ morphology (P ≤ 0.03 for each comparison). Esophageal body diagnoses on HRM (fragmented peristalsis, ineffective esophageal motility, or absent peristalsis) did not predict non-response. On multivariate analysis, non-pathological acid exposure time (OR, 2.5; 95% CI, 1.2-5.0; P < 0.001), normal mean nocturnal baseline impedance values (OR, 2.7-2.4; 95% CI, 1.0-6.1; P < 0.05), normal EGJ contractile integral values (OR, 3; 95% CI, 1.3-7.4; P = 0.012), and presence of type I EGJ morphology (OR, 1.9; 95% CI, 1.0-3.4; P = 0.044) were associated with an unfavorable response to PPIs. Conclusions Intact EGJ metrics on HRM complement normal reflux burden in predicting non-response to PPI therapy. HRM has value in the evaluation of PPI non-responders. (J Neurogastroenterol Motil 2020;26:447-454)

Transient Hiatal Separation During Straight Leg Raise Can Predict Reflux Burden in Gastroesophageal Reflux Disease Patients With Ineffective Esophageal Motility

Wei-Yi Lei,Shu-Wei Liang,Taher Omari,Wei-Chuan Chang,Ming-Wun Wong,Jui-Sheng Hung,Chih-Hsun Yi,Tso-Tsai Liu,Lin Lin,C Prakash Gyawali,Chien-Lin Chen 대한소화기 기능성질환∙운동학회 2022 Journal of Neurogastroenterology and Motility (JNM Vol.28 No.4

Background/Aims Straight leg raise (SLR) can be utilized to evaluate the integrity of the esophagogastric junction during high-resolution manometry (HRM). We aim to assess the value of transient hiatal separation during SLR in symptomatic reflux patients. Methods Consecutive reflux patients undergoing esophageal HRM and pH monitoring were included. Transient hiatal separation was defined by a ≥ 1 cm separation between the lower esophageal sphincter and crural diaphragm during SLR. We compared esophageal motor patterns and reflux monitoring parameters between patients with normal, transiently abnormal and consistently abnormal esophagogastric junction morphology during SLR. Results Of 85 (56.3% female, mean age: 46.7 ± 12.3 years) completed SLR, esophagogastric junction morphology was normal in 31 (36.5%), transient hiatal separation in 19 (22.3%), and consistently hiatal hernia in 35 (41.2%). The values of total acid exposure time (P = 0.016), longest acid reflux episodes (P = 0.024), and DeMeester scores (P = 0.016) were higher in hiatal hernia compared to patients with non-transient hiatal separation, but there were no differences between those with and without transient hiatal separation. Within ineffective esophageal motility, the presence of transient hiatal separation during SLR significantly associated with a higher total acid exposure time (P = 0.014), higher DeMeester scores (P = 0.019), higher total acid reflux events (P = 0.037), and higher longest acid reflux episodes (P = 0.006). Conclusion Our work suggests that SLR may have value as a provocative test during HRM, and future outcome studies are warranted to elucidate the clinical relevance of motor abnormalities depicted from SLR.