Gastro-esophageal reflux disease in primary care practice: a narrative review

Introduction

Gastroesophageal reflux disease (GERD) is currently one of the most common gastrointestinal (GI) diagnoses in patients, presenting to primary care physicians (PCP). This condition has a substantial impact on patients’ quality of life and is associated with high healthcare resource utilization. Diagnosis of GERD is convoluted and management is complex, especially in cases where initial interventions fail. PCP are frequently faced with challenges of choosing appropriate care strategies.

We aimed to review the current state and significance of GERD for PCP, including prevalence, pathophysiology, complications, initial presentation and diagnosis, treatment strategies and subsequent steps in cases of failure of initial management. We present the following article in accordance with the Narrative Review reporting checklist (available at https://aoe.amegroups.com/article/view/10.21037/aoe-21-62/rc).

Methods

Literature search was conducted of the PubMed database of publications with relevant search terms for each section of the presented article. Generally, articles written in English language and published after 2000 were considered and reviewed (Table 1). Manual review of references from retrieved literature was conducted to supplement the search results. Older sources were included if considered a landmark paper or lacked a newer publication on the subject. Thorough review of relevant guidelines and authoritative sources were also conducted to produce this review.

History of gastro-esophageal reflux disease

GERD is one of the most common chronic conditions of the GI tract, affecting nearly 60 million Americans and over a billion people worldwide (1). It is the second most common GI-related diagnosis, preceded only by abdominal pain and accounts for over 5.25 million office and 325 thousand emergency room (ER) visits annually (2). The expenditures on the prescribed acid suppression medication have grown substantially from $7.9 billion dollars in 2001 to $12.4 billion in 2015 in the US alone (2). Currently two of the top five selling drugs in the United States are proton pump inhibitors (PPI) (1). A considerable increase in PPI use occurred worldwide over the last two decades as well. Such, in the UK general practice PPI use increased from 0.2% in 1990 to 15% in 2014 (3).

GERD emerged as a separate entity in the 1960s and 1970s, initially led by surgeons and then gastroenterologists, interested in this pathology (4). The term “gastroesophageal reflux disease (GERD)” was first introduced in the English literature by Krejs et al. in 1976 (5). Since that time GERD has become a well-recognized entity with increased burden of the disease in the population and a high health care resource utilization (6). Numerous medications and various surgical interventions have been introduced for the treatment of this condition. Currently, it is the most common chronic disease with an estimated direct and indirect cost exceeding 75 billion dollars annually and expenditures continue to increase (7). The disease has significant impact on patient quality of life and leads to substantial morbidity in the general population (8).

Definition of GERD

According to the Montreal Definition and Classification, GERD is defined as a condition, that develops when the reflux of stomach contents causes troublesome symptoms and/or complications (9). It has been postulated that symptoms become troublesome when they affect patient quality of life. All symptoms are subdivided into esophageal and extra esophageal syndromes. Esophageal syndromes include such symptomatic syndromes as typical reflux syndrome, reflux chest pain syndrome and syndromes with esophageal injury, particularly reflux esophagitis, stricture, Barrett’s esophagus and adenocarcinoma. Extraesophageal syndromes include those with well-established associations with GRED, such as reflux-associated cough, laryngitis, asthma, dental erosion and proposed associations such as pharyngitis, sinusitis, idiopathic pulmonary fibrosis (IPF) and recurrent otitis media (9). Whereas it remains in the hands of the patients to determine the degree of affliction by the condition, diagnosis is sometimes difficult and convoluted even with the typical esophageal syndromes. In an analysis of 308 patient with GERD, neither assessment with the Reflux Disease Questionnaire (RDQ) by PCP, endoscopy by gastroenterologist, or a trial of esomeprazole therapy were sensitive or specific enough for the diagnosis of GERD (8).

Pathophysiology

Imbalance between aggressiveness of the gastric refluxate on the one hand and antireflux mechanism on the other leads to the development of symptoms of GERD (10). Anatomical structures, such as circular muscle thickening at the low esophageal sphincter (LES), the diaphragmatic crura and valve mechanism of the angle of His and functional mechanisms, such as esophageal peristalsis, saliva production and epithelial integrity play a protective role in the development of GERD. Western diet with high volume meals leads to chronic over distention of the stomach and shortening of the LES, similar to the shortening of the neck of an air balloon, resulting in stretching of the phrenoesophageal membrane and development of the hiatal hernia (11,12). Hiatal hernia leads to separation of the LES from diaphragmatic crura and its proximal displacement, transposing it into the negative pressure environment of the chest, decreasing its effective strength (13-15).

Certain foods that cause either an increase in the acidity of the gastric content or relaxation of the LES, as well as an inhibition of gastric motility and gastric stasis contribute to the reflux (16). Incidence and severity of GERD are likely related to the degree of anatomical derangements of the gastroesophageal junction (GEJ) in patient with hiatal hernias. Analyzing a group of 175 patients with GERD diagnosed based on the 24-hour pH-metry, Schlottman et al. identified a direct relationship between size of the hiatal hernia and severity of GERD, including frequency of cough, wheezing, decrease of the LES pressure and peristalsis as well as severity of the acid reflux on the pH-metry and degree of the esophagitis on endoscopy (17). However, silent GERD prevalence, assessed by the presence of esophageal injury in the patient with absent GERD symptoms, ranges from 2% to 23% (18,19). Many different factors were implemented in the development of GERD. Obesity is one of the most prominent risk factors for GERD (20,21). Obesity, leading to a rise in intraabdominal pressure and chronic lung diseases with decreased in intrathoracic pressure, result in increase of the transdiaphragmatic pressure gradient, promoting the development of the GERD (10,22). Data from The National Health and Examination Survey (NHANES) estimated a prevalence of obesity at 42.8% and severe obesity at 9.2% in adults with no difference among men and women and it had progressively increased over the last two decades (23). Baik et al. have demonstrated a statistically significant increase in the prevalence of Barrett’s esophagus in patients with obesity, defined by the abdominal diameter index. These findings have been corroborated by numerous other authors especially for the development of the GEJ adenocarcinoma (20,24,25).

Prevalence of GERD

GERD is one of the most common conditions of the GI tract affecting over 60 million people in the United States (1). It has a profound impact on patient’s quality of life and comprises a significant proportion of patient concerns at many primary care practices (7,10). Unfortunately, the significance of the problem is universally underestimated (26).

True prevalence of the GERD is hard to determine, however it is estimated to affect approximately 11–14% of the population world-wide, with rising prevalence with increase in body mass index (BMI) and abdominal diameter (7). In the systematic review, El-Serag et al. analyzed 30 studies addressing prevalence and incidence of GERD in the general population from various parts of the world. Astonishingly, GERD prevalence was estimated at 18–28% in North America, 9–26% in Europe, 3–8% in East Asia, 9–33% in the Middle East, 12% in Australia and 23.0% in South America (27). There has also been a steady statistically significant increase in the prevalence of GERD since 1995 worldwide (3).

The prevalence of GERD is also increasing with age. In a survey of 1,859 employees and their families in Japan, Okimoto et al. identified an increasing prevalence of GERD in adults compared to children. Defining the presence of GERD on the GERD calculator questionnaire (GerdQ) as a score >8, GERD was present in 4.4% of subjects under 20 years of age compared to 11.6% of adults. Moreover, the prevalence continued to increase with age and reached 18.4% at age of 60 and 21.1% at the age of 80. Again, the authors noted an increasing incidence of GERD with a rise in BMI. The prevalence of GERD in adults with BMI ≥25 was 18.7%, compared to 9.3% in those with the BMI <25 (28). Risk factors have significant implications in the development of GERD. In the surveillance of over a thousand subjects in Russia with a validated 72-point questionnaire, Bor et al. identified a total GERD prevalence at 23.6%. Notably, it was higher in females (29.5% vs. 15.4%) and also increased with age. Particularly, GERD was present in 20.4% of smokers, 24.2% of coffee drinkers, 21.5% of alcohol consumers and 45.9% of stressed participants (29).

Meta-analysis, including 102 published reports and almost half a million patients, revealed various incidence of the GERD throughout the world, ranging from 2.5% in China to 51.2% in Greece. Pooled prevalence was 13.3% with an increase with age (OR 1.26), in smokers (OR 1.32), nonsteroidal anti-inflammatory drugs (NSAIDs) users (OR 1.44) and in obese individuals (OR 1.73) (30). In another meta-analysis of 102 papers, representing 37 countries and all regions of the UN geoscheme, the global pooled prevalence of GERD was 13.98%. This prevalence varied greatly according to a region (12.88% in Latin America and the Caribbean to 19.55% in North America) and a country (4.16% in China to 22.40% in Turkey) with an estimated prevalence of GERD globally at 1.03 billion (31). The prevalence of GERD in the USA adult population in one study was estimated as high as 45% (32).

Presentation and symptoms

Classic symptoms of GERD, also known as “typical” are heartburn, retrosternal chest pain and regurgitation. Development of dysphagia in patient with GERD might signify development of reflux related stricture and should rise a concern for malignancy. These symptoms are described as an esophageal syndromes. Other, less common, “atypical” symptoms are part of so called extraesophageal syndromes and may include reflux related chronic cough, laryngitis, asthma, dental erosions, pharyngitis, sinusitis, IPF and recurrent otitis media (9).

Classic symptoms of GERD, also known as “typical” are heartburn, retrosternal chest pain and regurgitation. Development of dysphagia in patient with GERD might signify development of reflux related stricture and should rise a concern for malignancy. These symptoms are described as an “esophageal syndromes”. Other, less common, “atypical” symptoms are part of so called “extraesophageal syndromes” and may include reflux related chronic cough, laryngitis, asthma, dental erosions, pharyngitis, sinusitis, IPF and recurrent otitis media (9).

GERD can have a profound impact on a patient’s quality of life. In a systematic review Liker et al. analyzed 23 papers, assessing the impact of GERD on a patient’s quality of life. Analysis of the results of the short form 36 (SF-36) survey of GERD patients demonstrated significant impairment in the domains of vitality, bodily pain, general health, physical and emotional role, mental health and physical and social functioning (26). In a mail survey of over 130 thousand respondents, the majority of GERD patients reported reduced enjoyment of food (more than 80%), disturbed sleep (more than 60%) and difficulties concentrating at work (over 40%). Heartburn affected a wide range of daily activities, including exercise, playing with children, hobbies and enjoying intimacy and sex. Nearly half of GERD patients avoided physical activities that might precipitate heartburn symptoms, one third reported restrictions in some activities, and 16% limited sporting activities and exercise (26). Sleep disturbances were observed in over 55% of patients with severe GERD. Even in the well-controlled symptoms group, up to 25% of patient reported waking up at night and up to 65% of patient with GERD reported an inability to get a good night sleep (26). Additionally, 40% reported that their daily activities were compromised by their symptoms (26).

Functional esophageal disorders (functional heartburn, chest pain and dysphagia, globus and reflux hypersensitivity) are defined by Rome IV criteria as conditions with typical symptoms in the absence of objective evidence of corresponding abnormalities (33,34). Frequently, patients with functional esophageal disorders fail to respond to initial medical treatment and careful evaluation is required to distinguish these individuals from typical GERD patients (35).

Risk of GERD complications

GERD can lead to the development of numerous esophageal and extraesophageal complications. Esophagitis, esophageal ulcers, Barrett’s esophagus and esophageal cancer are well established GERD related complications (18,36). Other, less acknowledged conditions are cough, chronic sinusitis, laryngitis, bronchitis, asthma and IPF, pneumonia, dental caries and others (9,37-39). Large population-based studies from Europe have demonstrated five to eight-fold increase in the rate of adenocarcinoma in patients with GERD (40,41). Among over a million patients in Europe, absence of GERD on endoscopy was associated with 55% reduction in incidence of upper GI malignancy and 61% decrease in mortality (42). A group of authors analyzed 13 studies with nearly 40 thousand patients, focusing on the risk of head and neck cancers in patient with GERD. There was a statistically significant increase in the rate of malignancies, especially laryngeal carcinoma in these patients (OR =1.86, 95% CI: 1.27–2.74) (43). In a recent study, medical therapy and surgical interventions for reflux led to a decreased risk of esophageal adenocarcinomas in patients with GERD, especially those with Barrett’s esophagus, although the risk still remained about 10 times elevated compared to the general population (44). Various pulmonary complications can develop due to “reflux”, including direct aspiration of the acidic gastric secretions or “reflex” (refluxate-triggered, vagally mediated airway spasm) mechanisms. This may lead to restrictive pulmonary disease and altered respiratory mechanics that can contribute to a worsening of the reflux (45).

Management of GERD

Initial management of the patient with a typical presentation of GERD starts with diet and lifestyle modification. Avoidance of the foods, that can precipitate reflux symptoms can improve patient quality of life. Citrus and other acidic foods, such as fruits, tomatoes, juices, coffee and carbonated drinks trigger reflux symptoms, by having slower distal esophageal transit than neutral fluids, leading to worsening of reflux symptoms (16,46). Predominantly non-vegetarian diet, greasy food and chocolate have been associated with increased GERD symptoms, possibly by causing low esophageal sphincter pressure (LESP) relaxation (46-48). Fruits and vegetables have a protective effect on the GERD and Barrett’s esophagus development (36). Use of alcohol and tobacco was associated with increased risk of GERD and Barrett’s esophagus (36). In a cross-sectional study of 817 participants, the Mediterranean diet (composite/traditional dishes, fresh fruit and vegetables, olive oil, and fish) was associated with a statistically significant 57% decrease of the risk of GERD, even after adjustment for age, sex, socioeconomic factors, lifestyle and eating habits (49). Increased fiber intake (psyllium 5 g TID) led to a significant increase in the minimal resting LES pressure, decrease in the number of reflux episodes and heartburn symptoms in a study group of 36 patients (50).

Lifestyle modifications have also enjoyed increased scientific attention since the recognition of a side effects profile of medical therapy. Several studies have demonstrated that weight loss leads to decrease in the severity and duration of reflux episodes (51). In a trial of 332 patients enrolled in a supervised weight management program, average weight loss of 13±7.7 kg resulted in the decrease of overall prevalence of GERD from 37% to 15% (P<0.01) with the mean GERD symptom score decreasing from 5.5 to 1.8 (P<0.01). The authors reported an overall 81% reduction, including 65% complete resolution of reflux symptoms with significant correlation between the degree of weight loss and a reduction in GERD symptom scores (52). In a large Norwegian population-based study involving nearly 30,000 individuals, a decrease in BMI of over 3.5 points or more resulted in a significant reduction of (50–70%) of GERD symptoms (53).

Abdominal, or diaphragmatic breathing exercise is a simple office-based intervention that has been shown to decrease acid exposure in GERD patients and improve quality of life. It is postulated that this intervention actively trains diaphragmatic crura, contributing to the competency of the LES, directly affecting severity of GERD. In one RCT, published by Eherer et al., acid exposure was shown to decrease by nearly 50% after just 4 weeks of training, improving Quality of Life (QoL) scores. After 9 months of ongoing training, QoL scores improved by 36% and PPI usages decreased by 75% (54). In another RCT, Halland et al showed that postprandial esophageal acid exposure reduced by 56% in patients randomized to diaphragmatic breathing (55).

Tobacco cessation has been shown to lead to decrease in symptoms of GERD. However, the effect was more prominent in normal weight individuals. In obese patients it did not result in a meaningful outcome, probably due to more significant role of obesity in the pathogenesis of GERD (51). A randomized controlled study of 30 patients revealed significantly higher supine reflux symptoms in those who had late evening meals, obese individuals and those with presence of a hiatal hernia (56). Elevating the head of bed during sleep was shown to be an effective method of decreasing distal esophageal exposure to reflux and shortening the acid clearance time compared to a flatbed position (57).

Medical therapy

Medical therapy is a mainstay in the management of the majority of GERD cases. In a typical GERD presentation empiric therapy with a PPI is frequently initiated first without additional confirmatory studies. In cases where symptoms are not improved over a course of several weeks, patients are referred for additional studies and evaluation by specialists.

PPI have been shown to be the most effective agents in the treatment of GERD (58). In the Cochrane database systematic review including 134 trials with over 35,000 patients with esophagitis, Khan et al. unequivocally demonstrated superiority of PPI treatment over other agents in healing erosive esophagitis (EE) (59). Five randomized controlled trials (RCTs) with a total of 965 patients demonstrated a statistically significant improvement in healing of esophagitis over placebo (RR =0.22; 95% CI: 0.15–0.31). Ten RCTs, including 1,241 participants reported a statistically significant benefit of H2 receptor antagonist (H2RA) over placebo (RR =0.74, 95% CI: 0.66–0.84). There was no statistically significant benefit to prokinetic therapy versus placebo in three RCTs, involving 198 participants (RR =0.71, 95% CI: 0.46–1.10). Twenty-six RCTs, involving 4,032 participants reported on outcomes of PPI versus H2RA with or without prokinetic agents and demonstrated a statistically significant benefit of PPI therapy (RR =0.51, 95% CI: 0.44–0.59) (59). However, therapeutic gain of PPI over placebo was only 30–50% in reflux control and was higher in patient with EE than in non-erosive reflux disease (NERD) (37% vs. 56%) (58). As many as 45% of patient with GERD do not respond to PPI therapy (35). Even lower response rates are observed in controlling regurgitation (25–60%) or atypical symptoms (60,61). Functional esophageal disorders may play a role in failure of standard medical antireflux therapy (33-35).

Side effects of PPI

PPI have become a “go to” therapy in the current practice of GERD management and are now widely available without a prescription. As a result, over-prescription and over-utilization of the PPI has taken a significant prevalence in the current medical practice. Continued overprescribing and over-the-counter use of PPI medications is ubiquitous worldwide. In the analysis of over 1,800 patients, Jones et al. demonstrated that only half of them were formally diagnosed with GERD. Of these, 65% were taking over the counter medications. Among patients undiagnosed with GERD, 97% were taking over the counter PPI medications (62).

This is a concerning trend, as these medications carry significant side effect risk and complications. Numerous studies have called attention to various adverse health outcomes of the chronic use of PPI. These include acute nephritis and chronic kidney injury, dementia, along with an increased mortality in patient with dementia, fatal hypomagnesemia, clostridium difficile infection, osteoporosis and fractures, community acquired pneumonia and cardiovascular events (63-69). However, in the recent metanalysis including over three hundred thousand patients Desai et al. failed to show association of PPI use and dementia or Alzheimer’s disease (70). In the metanalysis of 24 observational studies involving over 2 million patients taking PPI from 1990 to 2018, Poly et al. demonstrated an increased risk of 20 % for hip fractures (71). The risk of prosthetic joint infection was 2.4 times higher in PPI users (72). The risk was further increased in patients with high dose PPI (30%) or long-term therapy (24%). In the analysis of over six million patient records from the US Department of Veterans Affairs administrative database with 5.7 years of follow up, Xie and co-authors demonstrated a statistically significant 25% increase in mortality in PPI users vs. H2 blocker users (HR 1.25, 95% CI: 1.23–1.28) (73). Recently, PPIs were associated with increased severity and mortality in patients with COVID-19 infection (74,75). To the contrary, in the large placebo controlled randomized trial Moayyedi et al. found that pantoprazole was not associated with any adverse events, except for enteric infections during a three-year therapy (76). Analyzing published data on PPI complications Vaezi et al. pointed out to predominantly observational nature of these studies. Acknowledging the problem with universal over prescription of PPI, minimal absolute risk increase of complications and enormous benefit for patient with GERD, authors called for pragmatic, “common sense” approach to PPI prescribing at the lowest effective dose (77).

De-escalation of PPI therapy

De-escalation of PPI therapy might be considered in clinical practice. In response to the formulary changes in the Tennessee Medicaid program, attempt at tailoring PPI use was undertaken in 129 patients of internal medicine clinic. Eighteen (14%) of patient discontinued the PPI therapy, 40 (31%) continued it and 71 (55%) were switched to H2 blockers. At eight months follow-up, 81% of these patients remained on H2 blockers or were completely off acid suppression therapy (78). Experience of another family medicine clinic in the underserved area of rural Minnesota demonstrated success in the discontinuation of PPI therapy. Of the 126 patients, 21% were willing to undergo the trial. Of these, 86% successfully discontinued PPI use, 9% decreased the dose and 5% remained on the current dose (79). However, in the metanalysis of six trials involving 1,758 subjects aimed at discontinuation of the PPI therapy either abruptly, or to “on demand” use, lack of symptom control favored continuation of the PPI therapy in five of those trials (80).

Failure of initial therapy and escalation of care

Whereas PPI hold a dominant role in the management of the GERD, they do not affect anatomical relationship and pathophysiological mechanisms of reflux. By decreasing acidity of the gastric refluxate and alleviating heartburn they simply mask the ongoing problem of continued reflux (81). Various anti-reflux interventions, on the other hand, address the anatomic basis of the disease and have shown promise in the management of GERD (13,82,83). Further refinements of the technology in the field brought to the forefront numerous less invasive surgical and endoscopic options. Laparoscopic and robotic procedures are now a standard of care (14). Magnetic sphincter augmentation procedure (LINX) is a new device aimed at reflux control that is implanted laparoscopically (84). Endoscopic interventions such as transoral incisionless fundoplication (TIF), Stretta, Medigus Ultrasonic Surgical Endostapler (MUSE), antireflux mucosectomy (ARMS) and others are designed to address GERD completely via endoscopic approach without surgical incisions (85,86). These procedures reduce the magnitude of the intervention and facilitate patient’s recovery and return to normal activities after anatomically corrective intervention.

Conclusions

GERD is a ubiquitous condition, affecting over a billion of adult population across the globe and its prevalence is steadily increasing as a result of the western diet and rising rates of obesity. It has a profound impact on patients’ quality of life and is associated with high healthcare resource utilization and societal cost. Diagnosis and management of the condition is convoluted. First line interventions, such as diet and lifestyle modifications, carry limited success. PPI are the most effective medical agents and commonly are a mainstay of the initial medical therapy. However, they are frequently over prescribed and overutilized, especially with over-the-counter availability. Chronic use of PPI is associated with a wide range of complications. De-escalation of PPI therapy might be successful in some patients. In cases of failure of initial intervention and medical therapy, early referral to specialist with expertise in the management of GERD is indicated for selection of appropriate management strategy and improvement of patients’ outcomes.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Abbas E. Abbas and Roman V. Petrov) for the series “New Technologies in Esophageal Surgery and Endoscopy” published in Annals of Esophagus. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aoe.amegroups.com/article/view/10.21037/aoe-21-62/rc

Peer Review File: available at https://aoe.amegroups.com/article/view/10.21037/aoe-21-62/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-21-62/coif). The series “New Technologies in Esophageal Surgery and Endoscopy” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Shaheen NJ, Hansen RA, Morgan DR, et al. The burden of gastrointestinal and liver diseases, 2006. Am J Gastroenterol 2006;101:2128-38. [Crossref] [PubMed]
2. Peery AF, Crockett SD, Murphy CC, et al. Burden and Cost of Gastrointestinal, Liver, and Pancreatic Diseases in the United States: Update 2018. Gastroenterology 2019;156:254-272.e11. [Crossref] [PubMed]
3. Othman F, Card TR, Crooks CJ. Proton pump inhibitor prescribing patterns in the UK: a primary care database study. Pharmacoepidemiol Drug Saf 2016;25:1079-87. [Crossref] [PubMed]
4. Rameau A, Mudry A. When did gastro-esophageal reflux become a disease? A historical perspective on GER(D) nomenclature. Int J Pediatr Otorhinolaryngol 2020;137:110214. [Crossref] [PubMed]
5. Krejs GJ, Seefeld U, Brändli HH, et al. Gastro-oesophageal reflux disease: correlation of subjective symptoms with 7 objective oesophageal function tests. Acta Hepatogastroenterol (Stuttg) 1976;23:130-40. [PubMed]
6. Dent J, El-Serag HB, Wallander MA, et al. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 2005;54:710-7. [Crossref] [PubMed]
7. Corley DA, Kubo A, Levin TR, et al. Abdominal obesity and body mass index as risk factors for Barrett's esophagus. Gastroenterology 2007;133:34-41; quiz 311. [Crossref] [PubMed]
8. Dent J, Vakil N, Jones R, et al. Accuracy of the diagnosis of GORD by questionnaire, physicians and a trial of proton pump inhibitor treatment: the Diamond Study. Gut 2010;59:714-21. [Crossref] [PubMed]
9. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:1900-20; quiz 1943. [Crossref] [PubMed]
10. Menezes MA, Herbella FAM. Pathophysiology of Gastroesophageal Reflux Disease. World J Surg 2017;41:1666-71. [Crossref] [PubMed]
11. Crookes PF. Physiology of reflux disease: role of the lower esophageal sphincter. Surg Endosc 2006;20:S462-6. [Crossref] [PubMed]
12. Jobe BA, Hunter JG, Watson DI. Esophagus and Diaphragmatic Hernia. In: Brunicardi FC, Andersen DK, Billiar TR, et al. editors. Schwartz's Principles of Surgery, 10e. New York, NY: McGraw-Hill Education; 2014.
13. Petrov RV, Su S, Bakhos CT, et al. Surgical Anatomy of Paraesophageal Hernias. Thorac Surg Clin 2019;29:359-68. [Crossref] [PubMed]
14. Bakhos CT, Petrov RV, Parkman HP, et al. Role and safety of fundoplication in esophageal disease and dysmotility syndromes. J Thorac Dis 2019;11:S1610-7. [Crossref] [PubMed]
15. van Herwaarden MA, Samsom M, Smout AJ. The role of hiatus hernia in gastro-oesophageal reflux disease. Eur J Gastroenterol Hepatol 2004;16:831-5. [Crossref] [PubMed]
16. Sethi S, Richter JE. Diet and gastroesophageal reflux disease: role in pathogenesis and management. Curr Opin Gastroenterol 2017;33:107-11. [Crossref] [PubMed]
17. Schlottmann F, Andolfi C, Herbella FA, et al. GERD: Presence and Size of Hiatal Hernia Influence Clinical Presentation, Esophageal Function, Reflux Profile, and Degree of Mucosal Injury. Am Surg 2018;84:978-82. [Crossref] [PubMed]
18. Fass R, Dickman R. Clinical consequences of silent gastroesophageal reflux disease. Curr Gastroenterol Rep 2006;8:195-201. [Crossref] [PubMed]
19. Naik RD, Vaezi MF. Outcomes Data on Surgical Therapies for Silent Reflux. JAMA Otolaryngol Head Neck Surg 2019;145:667-8. [Crossref] [PubMed]
20. Schlottmann F, Dreifuss NH, Patti MG. Obesity and esophageal cancer: GERD, Barrett’s esophagus, and molecular carcinogenic pathways. Expert Rev Gastroenterol Hepatol 2020;14:425-33. [Crossref] [PubMed]
21. Bakhos CT, Patel SP, Petrov RV, et al. Management of Paraesophageal Hernia in the Morbidly Obese Patient. Thorac Surg Clin 2019;29:379-86. [Crossref] [PubMed]
22. Chatila AT, Nguyen MTT, Krill T, et al. Natural history, pathophysiology and evaluation of gastroesophageal reflux disease. Dis Mon 2020;66:100848. [Crossref] [PubMed]
23. Hales CM, Carroll MD, Fryar CD, et al. Prevalence of Obesity and Severe Obesity Among Adults: United States, 2017-2018. NCHS Data Brief 2020;1-8. [PubMed]
24. Baik D, Sheng J, Schlaffer K, et al. Abdominal diameter index is a stronger predictor of prevalent Barrett's esophagus than BMI or waist-to-hip ratio. Dis Esophagus 2017;30:1-6. [Crossref] [PubMed]
25. Lynch KL. Is Obesity Associated with Barrett's Esophagus and Esophageal Adenocarcinoma? Gastroenterol Clin North Am 2016;45:615-24. [Crossref] [PubMed]
26. Liker H, Hungin P, Wiklund I. Managing gastroesophageal reflux disease in primary care: the patient perspective. J Am Board Fam Pract 2005;18:393-400. [Crossref] [PubMed]
27. El-Serag HB, Sweet S, Winchester CC, et al. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 2014;63:871-80. [Crossref] [PubMed]
28. Okimoto E, Ishimura N, Morito Y, et al. Prevalence of gastroesophageal reflux disease in children, adults, and elderly in the same community. J Gastroenterol Hepatol 2015;30:1140-6. [Crossref] [PubMed]
29. Bor S, Lazebnik LB, Kitapcioglu G, et al. Prevalence of gastroesophageal reflux disease in Moscow. Dis Esophagus 2016;29:159-65. [Crossref] [PubMed]
30. Eusebi LH, Ratnakumaran R, Yuan Y, et al. Global prevalence of, and risk factors for, gastro-oesophageal reflux symptoms: a meta-analysis. Gut 2018;67:430-40. [Crossref] [PubMed]
31. Nirwan JS, Hasan SS, Babar ZU, et al. Global Prevalence and Risk Factors of Gastro-oesophageal Reflux Disease (GORD): Systematic Review with Meta-analysis. Sci Rep 2020;10:5814. [Crossref] [PubMed]
32. Delshad SD, Almario CV, Chey WD, et al. Prevalence of Gastroesophageal Reflux Disease and Proton Pump Inhibitor-Refractory Symptoms. Gastroenterology 2020;158:1250-1261.e2. [Crossref] [PubMed]
33. Bhardwaj R, Knotts R, Khan A. Functional Chest Pain and Esophageal Hypersensitivity: A Clinical Approach. Gastroenterol Clin North Am 2021;50:843-57. [Crossref] [PubMed]
34. Losa M, Manz SM, Schindler V, et al. Increased visceral sensitivity, elevated anxiety, and depression levels in patients with functional esophageal disorders and non-erosive reflux disease. Neurogastroenterol Motil 2021;33:e14177. [Crossref] [PubMed]
35. Abdallah J, George N, Yamasaki T, et al. Most Patients With Gastroesophageal Reflux Disease Who Failed Proton Pump Inhibitor Therapy Also Have Functional Esophageal Disorders. Clin Gastroenterol Hepatol 2019;17:1073-1080.e1. [Crossref] [PubMed]
36. Ireland CJ, Thompson SK, Laws TA, et al. Risk factors for Barrett's esophagus: a scoping review. Cancer Causes Control 2016;27:301-23. [Crossref] [PubMed]
37. Barrett CM, Patel D, Vaezi MF. Laryngopharyngeal Reflux and Atypical Gastroesophageal Reflux Disease. Gastrointest Endosc Clin N Am 2020;30:361-76. [Crossref] [PubMed]
38. Ghisa M, Della Coletta M, Barbuscio I, et al. Updates in the field of non-esophageal gastroesophageal reflux disorder. Expert Rev Gastroenterol Hepatol 2019;13:827-38. [Crossref] [PubMed]
39. Madanick RD. Extraesophageal presentations of GERD: where is the science? Gastroenterol Clin North Am 2014;43:105-20. [Crossref] [PubMed]
40. Lagergren J, Bergström R, Lindgren A, et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340:825-31. [Crossref] [PubMed]
41. Olsen CM, Pandeya N, Green AC, et al. Population attributable fractions of adenocarcinoma of the esophagus and gastroesophageal junction. Am J Epidemiol 2011;174:582-90. [Crossref] [PubMed]
42. Holmberg D, Santoni G, von Euler-Chelpin MC, et al. Incidence and Mortality in Upper Gastrointestinal Cancer After Negative Endoscopy for Gastroesophageal Reflux Disease. Gastroenterology 2022;162:431-8.e4. [Crossref] [PubMed]
43. Eells AC, Mackintosh C, Marks L, et al. Gastroesophageal reflux disease and head and neck cancers: A systematic review and meta-analysis. Am J Otolaryngol 2020;41:102653. [Crossref] [PubMed]
44. Maret-Ouda J, Konings P, Lagergren J, et al. Antireflux Surgery and Risk of Esophageal Adenocarcinoma: A Systematic Review and Meta-analysis. Ann Surg 2016;263:251-7. [Crossref] [PubMed]
45. Chan WW, Ahuja N, Fisichella PM, et al. Extraesophageal syndrome of gastroesophageal reflux: relationships with lung disease and transplantation outcome. Ann N Y Acad Sci 2020;1482:95-105. [Crossref] [PubMed]
46. Newberry C, Lynch K. The role of diet in the development and management of gastroesophageal reflux disease: why we feel the burn. J Thorac Dis 2019;11:S1594-601. [Crossref] [PubMed]
47. Chirila I, Morariu ID, Barboi OB, et al. The role of diet in the overlap between gastroesophageal reflux disease and functional dyspepsia. Turk J Gastroenterol 2016;27:73-80. [Crossref] [PubMed]
48. Surdea-Blaga T, Negrutiu DE, Palage M, et al. Food and Gastroesophageal Reflux Disease. Curr Med Chem 2019;26:3497-511. [Crossref] [PubMed]
49. Mone I, Kraja B, Bregu A, et al. Adherence to a predominantly Mediterranean diet decreases the risk of gastroesophageal reflux disease: a cross-sectional study in a South Eastern European population. Dis Esophagus 2016;29:794-800. [Crossref] [PubMed]
50. Morozov S, Isakov V, Konovalova M. Fiber-enriched diet helps to control symptoms and improves esophageal motility in patients with non-erosive gastroesophageal reflux disease. World J Gastroenterol 2018;24:2291-9. [Crossref] [PubMed]
51. Ness-Jensen E, Hveem K, El-Serag H, et al. Lifestyle Intervention in Gastroesophageal Reflux Disease. Clin Gastroenterol Hepatol 2016;14:175-82.e1-3.
52. Singh M, Lee J, Gupta N, et al. Weight loss can lead to resolution of gastroesophageal reflux disease symptoms: a prospective intervention trial. Obesity (Silver Spring) 2013;21:284-90. [Crossref] [PubMed]
53. Ness-Jensen E, Lindam A, Lagergren J, et al. Weight loss and reduction in gastroesophageal reflux. A prospective population-based cohort study: the HUNT study. Am J Gastroenterol 2013;108:376-82. [Crossref] [PubMed]
54. Eherer AJ, Netolitzky F, Högenauer C, et al. Positive effect of abdominal breathing exercise on gastroesophageal reflux disease: a randomized, controlled study. Am J Gastroenterol 2012;107:372-8. [Crossref] [PubMed]
55. Halland M, Bharucha AE, Crowell MD, et al. Effects of Diaphragmatic Breathing on the Pathophysiology and Treatment of Upright Gastroesophageal Reflux: A Randomized Controlled Trial. Am J Gastroenterol 2021;116:86-94. [Crossref] [PubMed]
56. Piesman M, Hwang I, Maydonovitch C, et al. Nocturnal reflux episodes following the administration of a standardized meal. Does timing matter? Am J Gastroenterol 2007;102:2128-34. [Crossref] [PubMed]
57. Villamil Morales IM, Gallego Ospina DM, Otero Regino WA. Impact of head of bed elevation in symptoms of patients with gastroesophageal reflux disease: a randomized single-blind study (IBELGA). Gastroenterol Hepatol 2020;43:310-21. [Crossref] [PubMed]
58. Dean BB, Gano AD Jr, Knight K, et al. Effectiveness of proton pump inhibitors in nonerosive reflux disease. Clin Gastroenterol Hepatol 2004;2:656-64. [Crossref] [PubMed]
59. Khan M, Santana J, Donnellan C, et al. Medical treatments in the short term management of reflux oesophagitis. Cochrane Database Syst Rev 2007;CD003244. [PubMed]
60. Bell RCW. Management of regurgitation in patients with gastroesophageal reflux disease. Curr Opin Gastroenterol 2020;36:336-43. [Crossref] [PubMed]
61. Kahrilas PJ, Jonsson A, Denison H, et al. Regurgitation is less responsive to acid suppression than heartburn in patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2012;10:612-9. [Crossref] [PubMed]
62. Jones R, Liker HR, Ducrotté P. Relationship between symptoms, subjective well-being and medication use in gastro-oesophageal reflux disease. Int J Clin Pract 2007;61:1301-7. [Crossref] [PubMed]
63. Gomm W, von Holt K, Thomé F, et al. Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis. JAMA Neurol 2016;73:410-6. [Crossref] [PubMed]
64. Cetin H, Wurm R, Reichardt B, et al. Increased risk of death associated with the use of proton-pump inhibitors in patients with dementia and controls - a pharmacoepidemiological claims data analysis. Eur J Neurol 2020;27:1422-8. [Crossref] [PubMed]
65. Recart DA, Ferraris A, Petriglieri CI, et al. Prevalence and risk factors of long-term proton pump inhibitors-associated hypomagnesemia: a cross-sectional study in hospitalized patients. Intern Emerg Med 2021;16:711-7. [Crossref] [PubMed]
66. Tawam D, Baladi M, Jungsuwadee P, et al. The Positive Association between Proton Pump Inhibitors and Clostridium Difficile Infection. Innov Pharm 2021; [Crossref] [PubMed]
67. Zhou B, Huang Y, Li H, et al. Proton-pump inhibitors and risk of fractures: an update meta-analysis. Osteoporos Int 2016;27:339-47. [Crossref] [PubMed]
68. Xie Y, Bowe B, Li T, et al. Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD. J Am Soc Nephrol 2016;27:3153-63. [Crossref] [PubMed]
69. Nguyen PA, Islam M, Galvin CJ, et al. Meta-analysis of proton pump inhibitors induced risk of community-acquired pneumonia. Int J Qual Health Care 2020;32:292-9. [Crossref] [PubMed]
70. Desai M, Nutalapati V, Srinivasan S, et al. Proton pump inhibitors do not increase the risk of dementia: a systematic review and meta-analysis of prospective studies. Dis Esophagus 2020;33:doaa041. [Crossref] [PubMed]
71. Poly TN, Islam MM, Yang HC, et al. Proton pump inhibitors and risk of hip fracture: a meta-analysis of observational studies. Osteoporos Int 2019;30:103-14. [Crossref] [PubMed]
72. Bruin MM, Deijkers RLM, Bazuin R, et al. Proton-pump inhibitors are associated with increased risk of prosthetic joint infection in patients with total hip arthroplasty: a case-cohort study. Acta Orthop 2021;92:431-5. [Crossref] [PubMed]
73. Xie Y, Bowe B, Li T, et al. Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans. BMJ Open 2017;7:e015735. [Crossref] [PubMed]
74. Hariyanto TI, Prasetya IB, Kurniawan A. Proton pump inhibitor use is associated with increased risk of severity and mortality from coronavirus disease 2019 (COVID-19) infection. Dig Liver Dis 2020;52:1410-2. [Crossref] [PubMed]
75. Price E, Treacher DF. Reduced gastric acidity, proton pump inhibitors and increased severity of COVID-19 infections. Crit Care 2021;25:73. [Crossref] [PubMed]
76. Moayyedi P, Eikelboom JW, Bosch J, et al. Safety of Proton Pump Inhibitors Based on a Large, Multi-Year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin. Gastroenterology 2019;157:682-691.e2. [Crossref] [PubMed]
77. Vaezi MF, Yang YX, Howden CW. Complications of Proton Pump Inhibitor Therapy. Gastroenterology 2017;153:35-48. [Crossref] [PubMed]
78. Ramser KL, Sprabery LR, Hamann GL, et al. Results of an intervention in an academic Internal Medicine Clinic to continue, step-down, or discontinue proton pump inhibitor therapy related to a tennessee medicaid formulary change. J Manag Care Pharm 2009;15:344-50. [Crossref] [PubMed]
79. Odenthal DR, Philbrick AM, Harris IM. Successful deprescribing of unnecessary proton pump inhibitors in a primary care clinic. J Am Pharm Assoc (2003) 2020;60:100-4. [Crossref] [PubMed]
80. Boghossian TA, Rashid FJ, Thompson W, et al. Deprescribing versus continuation of chronic proton pump inhibitor use in adults. Cochrane Database Syst Rev 2017;3:CD011969. [Crossref] [PubMed]
81. Gyawali CP, Fass R. Management of Gastroesophageal Reflux Disease. Gastroenterology 2018;154:302-18. [Crossref] [PubMed]
82. Luketich JD, Nason KS, Christie NA, et al. Outcomes after a decade of laparoscopic giant paraesophageal hernia repair. J Thorac Cardiovasc Surg 2010;139:395-404, 404.e1.
83. Terry M, Smith CD, Branum GD, et al. Outcomes of laparoscopic fundoplication for gastroesophageal reflux disease and paraesophageal hernia. Surg Endosc 2001;15:691-9. [Crossref] [PubMed]
84. Dunn C, Bildzukewicz N, Lipham J. Magnetic Sphincter Augmentation for Gastroesophageal Reflux Disease. Gastrointest Endosc Clin N Am 2020;30:325-42. [Crossref] [PubMed]
85. Mayor MA, Fernando HC. Endoluminal Approaches to Gastroesophageal Reflux Disease. Thorac Surg Clin 2018;28:527-32. [Crossref] [PubMed]
86. Akcelik A, Miller C, Bakhos C, et al. Endoscopic interventions in the management of the gastroesophageal reflux: a narrative review. Ann Esophagus 2023;6:10.