Identification of Different Phenotypes of Esophageal Reflux Hypersensitivity and Implications for Treatment

doi:10.1016/j.cgh.2020.03.063

Clinical Gastroenterology and Hepatology

Volume 19, Issue 4, April 2021, Pages 690-698.e2

https://doi.org/10.1016/j.cgh.2020.03.063 Get rights and content

Background & Aims

Reflux hypersensitivity (RH), a functional esophageal disorder, is detected in 14%–20% of patients who present with typical esophageal symptoms. As many as 40% of patients with RH do not respond to treatment with pain modulators or proton pump inhibitors (PPIs); behavior disorders might contribute to lack of treatment efficacy. We aimed to assess the prevalence of behavioral disorders and their effects on typical reflux symptoms in patients with RH.

Methods

We performed a retrospective study of 542 patients with PPI-refractory esophageal symptoms (heartburn, regurgitation, or chest pain) or with symptoms that responded to PPI therapy, evaluated for anti-reflux surgery from January 2016 through August 2019 at a single center in London, United Kingdom. We collected data on symptoms, motility, and impedance-pH monitoring and assigned patients to categories of RH (n = 116), functional heartburn (n = 126), or non-erosive reflux disease (n = 300).

Results

Of the 116 patients with a diagnosis of RH, 59 had only hypersensitivity, whereas 57 patients (49.2%) had either excessive supragastric belching (SGB, 39.7%), based on 24-hour impedance-pH monitoring, or rumination (9.5%), based on postprandial manometry combined with impedance. The prevalence of SGB and rumination in patients with RH was significantly higher than in patients with functional heartburn (22%; P < .001). Patients with RH and rumination were significantly younger (P = .005) and had the largest number of non-acid reflux episodes (P = .023). In patients with RH with SGB, SGB episodes were associated with 40.6% of marked reflux symptoms (heartburn, regurgitation, or chest pain), based on impedance-pH monitoring. In patients with RH and rumination, 40% of reflux-related symptoms (mostly regurgitation) were due to possible rumination episodes.

Conclusions

Almost half of patients with a diagnosis of RH have behavior disorders, including excessive SGB or rumination. Episodes of SGB or rumination are associated with typical reflux symptoms. Segregation of patients with diagnosis of RH into those with vs without behavioral disorders might have important therapeutic implications.

Section snippets

Study Subjects

We identified patients with PPI-refractory esophageal symptoms (heartburn, regurgitation, or chest pain) or PPI-responsive patients evaluated for antireflux surgery by interrogating the electronic database (January 2016–August 2019) at the Royal London Hospital GI Physiology Unit. Patients were included if they were older than 16 years and underwent high-resolution manometry (HRM) and off-PPI impedance-pH monitoring. Patients were excluded if they had (1) endoscopic esophagitis, Barrett’s

Patients

Of 597 patients, 55 were excluded (38 had a major motility disorder, 10 had technical problems with impedance-pH tracings, and 7 had very low MNBI [<1000 ohms] from significantly impaired mucosal integrity). The final study cohort included 116 patients with RH, 126 patients with FH, and 300 patients with NERD. Demographics and clinical characteristics are described in Supplementary Table 1.

Prevalence of Supragastric Belching and Rumination

The proportion of patients with excessive SGB in the RH group (39.7%) was significantly higher than in the

Discussion

On the basis of recent emphasis on behavioral disorders in PPI-refractory states,¹⁴ we hypothesized that undiagnosed behavioral disorders might account for some of the 40% reported refractoriness to RH management.7, 8, 9 We found that 21% of patients with PPI-refractory reflux symptoms investigated with endoscopy/reflux monitoring are initially diagnosed as having RH, and 49% of these patients have pathologic SGB or rumination. Furthermore, in RH-SGB patients, SGB triggered 34% of symptomatic

CRediT Authorship Contributions

Akinari Sawada, MD, PhD (Conceptualization: Equal; Formal analysis: Lead; Investigation: Lead; Writing – original draft: Lead; Writing – review & editing: Equal),

Mauricio Guzman, MD (Data curation: Equal; Formal analysis: Equal; Investigation: Equal),

Kornilia Nikaki, MD (Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Writing – review & editing: Equal),

Shirley Sonmez, MRS (Data curation: Equal; Investigation: Equal),

Etsuro Yazaki, PhD (Formal analysis: Equal; Methodology:

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Dysphagia
2023, Primary Care - Clinics in Office Practice
AGA Clinical Practice Update on the Personalized Approach to the Evaluation and Management of GERD: Expert Review
2022, Clinical Gastroenterology and Hepatology
Citation Excerpt :
Conversely, an empiric PPI trial is not optimal for isolated extra-esophageal symptoms because mechanisms other than GERD frequently contribute to symptom generation, making likelihood of PPI non-response high.9,10 Additional clinical factors that can explain symptom generation include central obesity and/or a known hiatal hernia pointing to a mechanical etiology of gastro-esophageal reflux, anxiety, or stress-induced symptoms suggesting visceral hypersensitivity and/or hypervigilance, behavioral disorders including rumination and supragastric belching, or mixed connective tissue disorder raising suspicion for esophageal dysmotility and reduced refluxate clearance.11-13 During the initial clinic visit, it is essential that clinicians provide standardized educational material on GERD mechanisms, weight management, lifestyle and dietary behaviors, relaxation strategies, and awareness about the brain-gut axis relationship to patients with reflux symptoms (BPA 2).
As many as one-half of all patients with suspected gastroesophageal reflux disease (GERD) do not derive benefit from acid suppression. This review outlines a personalized diagnostic and therapeutic approach to GERD symptoms.
The Best Practice Advice statements presented here were developed from expert review of existing literature combined with extensive discussion and expert opinion to provide practical advice. Formal rating of the quality of evidence or strength of recommendations was not the intent of this clinical practice update.
Clinicians should develop a care plan for investigation of symptoms suggestive of GERD, selection of therapy (with explanation of potential risks and benefits), and long-term management, including possible de-escalation, in a shared-decision making model with the patient.
Clinicians should provide standardized educational material on GERD mechanisms, weight management, lifestyle and dietary behaviors, relaxation strategies, and awareness about the brain-gut axis relationship to patients with reflux symptoms.
Clinicians should emphasize safety of proton pump inhibitors (PPIs) for the treatment of GERD.
Clinicians should provide patients presenting with troublesome heartburn, regurgitation, and/or non-cardiac chest pain without alarm symptoms a 4- to 8-week trial of single-dose PPI therapy. With inadequate response, dosing can be increased to twice a day or switched to a more effective acid suppressive agent once a day. When there is adequate response, PPI should be tapered to the lowest effective dose.
If PPI therapy is continued in a patient with unproven GERD, clinicians should evaluate the appropriateness and dosing within 12 months after initiation, and offer endoscopy with prolonged wireless reflux monitoring off PPI therapy to establish appropriateness of long-term PPI therapy.
If troublesome heartburn, regurgitation, and/or non-cardiac chest pain do not respond adequately to a PPI trial or when alarm symptoms exist, clinicians should investigate with endoscopy and, in the absence of erosive reflux disease (Los Angeles B or greater) or long-segment (≥3 cm) Barrett’s esophagus, perform prolonged wireless pH monitoring off medication (96-hour preferred if available) to confirm and phenotype GERD or to rule out GERD.
Complete endoscopic evaluation of GERD symptoms includes inspection for erosive esophagitis (graded according to the Los Angeles classification when present), diaphragmatic hiatus (Hill grade of flap valve), axial hiatus hernia length, and inspection for Barrett’s esophagus (graded according to the Prague classification and biopsied when present).
Clinicians should perform upfront objective reflux testing off medication (rather than an empiric PPI trial) in patients with isolated extra-esophageal symptoms and suspicion for reflux etiology.
In symptomatic patients with proven GERD, clinicians should consider ambulatory 24-hour pH-impedance monitoring on PPI as an option to determine the mechanism of persisting esophageal symptoms despite therapy (if adequate expertise exists for interpretation).
Clinicians should personalize adjunctive pharmacotherapy to the GERD phenotype, in contrast to empiric use of these agents. Adjunctive agents include alginate antacids for breakthrough symptoms, nighttime H2 receptor antagonists for nocturnal symptoms, baclofen for regurgitation or belch predominant symptoms, and prokinetics for coexistent gastroparesis.
Clinicians should provide pharmacologic neuromodulation, and/or referral to a behavioral therapist for hypnotherapy, cognitive behavioral therapy, diaphragmatic breathing, and relaxation strategies in patients with functional heartburn or reflux disease associated with esophageal hypervigilance reflux hypersensitivity and/or behavioral disorders.
In patients with proven GERD, laparoscopic fundoplication and magnetic sphincter augmentation are effective surgical options, and transoral incisionless fundoplication is an effective endoscopic option in carefully selected patients.
In patients with proven GERD, Roux-en-Y gastric bypass is an effective primary anti-reflux intervention in obese patients, and a salvage option in non-obese patients, whereas sleeve gastrectomy has potential to worsen GERD.
Candidacy for invasive anti-reflux procedures includes confirmatory evidence of pathologic GERD, exclusion of achalasia, and assessment of esophageal peristaltic function.
Distinct Clinical Physiologic Phenotypes of Patients With Laryngeal Symptoms Referred for Reflux Evaluation
2022, Clinical Gastroenterology and Hepatology
Citation Excerpt :
Patients with LPR and pathologic GERD with hiatal hernia (group A) would be the optimal candidates for escalated antireflux therapy, including potential surgical intervention.8 Patients with LPR and mild reflux or reflux hypersensitivity (group B) and those with reflux-induced reflex cough (group D) may benefit from “mild” antireflux management with acid suppression or alginates.21 Invasive interventions such as antireflux surgery should generally be avoided due to unclear benefits in these groups.
Heterogeneous presentations and disease mechanisms among patients with laryngeal symptoms account for misdiagnosis of laryngopharyngeal reflux (LPR), variations in testing, and suboptimal outcomes. We aimed to derive phenotypes of patients with laryngeal symptoms based on clinical and physiologic data and to compare characteristics across phenotypes.
A total of 302 adult patients with chronic laryngeal symptoms were prospectively enrolled at 3 centers between January 2018 to October 2020 (age 57.2 ± 15.2 years; 30% male; body mass index 27.2 ± 6.0 kg/m²). Discriminant analysis of principal components (DAPC) was applied to 12 clinical and 11 physiologic variables collected in stable condition to derive phenotypic groups.
DAPC identified 5 groups, with significant differences across symptoms, hiatal hernia size, and number of reflux events (P < .01). Group A had the greatest hiatal hernia size (3.1 ± 1.0 cm; P < .001) and reflux events (37.5 ± 51; P < .001), with frequent cough, laryngeal symptoms, heartburn, and regurgitation. Group B had the highest body mass index (28.2 ± 4.6 kg/m²; P < .001) and salivary pepsin (150 ± 157 ng/mL; P = .03), with frequent cough, laryngeal symptoms, globus, heartburn, and regurgitation. Group C frequently reported laryngeal symptoms (93%; P < .001), and had fewest esophageal symptoms (9.6%; P < .001) and reflux events (10.7 ± 11.0; P < .001). Group D commonly reported cough (88%; P < .001) and heartburn. Group E (18%) was oldest (62.9 ± 14.3 years; P < .001) and distinguished by highest integrated relaxation pressure.
DAPC identified distinct clinicophysiologic phenotypes of patients with laryngeal symptoms referred for reflux evaluation: group A, LPR and gastroesophageal reflux disease (GERD) with hiatal hernia; group B, mild LPR/GERD; group C, no LPR/No GERD; group D, reflex cough; and group E, mixed/possible obstructive esophagogastric junction. Phenotypic differences may inform targeted clinical trials design and improve outcomes.
Rumination Syndrome “Real Prevalence”: A Need to Increase Awareness, Early Recognition, and Specific Management
2022, Gastroenterology
Reply
2021, Clinical Gastroenterology and Hepatology
Refractoriness to Treatment Suggests That Clinical Evaluation Should Go Beyond the Diagnosis of Reflux Disease
2021, Clinical Gastroenterology and Hepatology

View all citing articles on Scopus

: Conflicts of interest These authors disclose the following: Daniel Sifrim receives research grants from Reckitt Benckiser UK, Jinshan Technology China, and Alfa Sigma, Italy. C. Prakash Gyawali consults for Medtronic, Diversatek, Ironwood, IsoThrive, and Quintiles. The remaining authors disclose no conflicts.

: Funding The study was conducted with financial support from Research Grant DDCH1A3R, Queen Mary University of London.

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Original ArticleAlimentary TractIdentification of Different Phenotypes of Esophageal Reflux Hypersensitivity and Implications for Treatment

Background & Aims

Methods

Results

Conclusions

Section snippets

Study Subjects

Patients

Prevalence of Supragastric Belching and Rumination

Discussion

CRediT Authorship Contributions

Gastroenterology

Clin Gastroenterol Hepatol

Am J Gastroenterol

Gastroenterology

Am J Gastroenterol

Best Pract Res Clin Gastroenterol

Clin Gastroenterol Hepatol

The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus

Am J Gastroenterol

Reflux related symptoms in patients with normal oesophageal exposure to acid

Gut

The role of nonacid reflux in NERD: lessons learned from impedance-pH monitoring in 150 patients off therapy

Am J Gastroenterol

Non-erosive reflux disease (NERD): acid reflux and symptom patterns

Aliment Pharmacol Ther

Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review

Gut

Patients with refractory reflux symptoms often do not have GERD

Neurogastroenterol Motil

Prevalence, characteristics, and treatment outcomes of reflux hypersensitivity detected on pH-impedance monitoring

Neurogastroenterol Motil

Proton pump inhibitor responders who are not confirmed as GERD patients with impedance and pH monitoring: who are they?

Neurogastroenterol Motil

Double blind cross-over placebo controlled study of omeprazole in the treatment of patients with reflux symptoms and physiological levels of acid reflux: the "sensitive oesophagus"

Gut

GERD phenotypes from pH-impedance monitoring predict symptomatic outcomes on prospective evaluation

Neurogastroenterol Motil

Selective serotonin reuptake inhibitors for the treatment of hypersensitive esophagus: a randomized, double-blind, placebo-controlled study

Am J Gastroenterol

Original Article
Alimentary Tract
Identification of Different Phenotypes of Esophageal Reflux Hypersensitivity and Implications for Treatment