Unveiling the intricacies: Insight into gastroesophageal reflux disease

Abstract

Gastroesophageal reflux disease (GERD) poses a substantial global health challenge, with prevalence rates exhibiting geographical variation. Despite its widespread recognition, the exact prevalence and associated risk factors remain elusive. This article comprehensively analyzed the global burden of GERD, shedding light on its risk factors, underlying pathophysiological mechanisms, current diagnostic modalities, evolving management strategies tailored to diverse patient profiles, and complex determinants contributing to treatment failures. A deeper comprehension of GERD is achieved by dissecting these intricate facets, paving the way for enhanced clinical management and improved patient outcomes.

Key Words: Gastroesophageal reflux disease; Risk factors; Pathophysiological mechanisms; Diagnosis; Management

Core Tip: To enhance physicians' understanding of gastroesophageal reflux disease (GERD), it is crucial to comprehensively examine its risk factors, underlying pathophysiological mechanisms, current diagnostic modalities, and diverse management strategies tailored to various patient profiles. Additionally, identifying the determinants contributing to treatment failures is essential. By delving into these aspects, healthcare providers can better address GERD, a significant global health challenge.

INTRODUCTION

Gastroesophageal reflux (GER) is defined as the effortless passage of gastric contents into the esophagus, and it is a normal physiological process. According to the American College of Gastroenterology (ACG) guidelines, when GER leads to troublesome symptoms such as frequent heartburn, regurgitation, chest pain, burping, cough, dysphagia, or complications such as esophagitis or stricture formation, it is referred to as GER disease (GERD)[1,2].

EPIDEMIOLOGY OF GERD

The global prevalence of GERD, despite its widespread discussion, remains uncertain due to several factors. Chief among these is the absence of a universally accepted definition of GERD. The gold standard for diagnosing GERD is combined pH impedance testing, which is invasive and often not widely available, posing challenges for widespread use in epidemiological studies. Procedures like endoscopy and multichannel intraluminal impedance-pH monitoring are labor-intensive and impractical for determining community prevalence. Although endoscopy is more commonly used than ambulatory pH tests, it cannot detect non-erosive reflux disease (NERD), further complicating accurate prevalence estimation. Consequently, various symptom questionnaires and definitions have been utilized as screening tools in much of the research on GERD epidemiology, leading to wide variation in prevalence estimates.

After reviewing research around the globe, many experts have employed heartburn and/or regurgitation occurring at least once a week as a threshold for GERD[3,4]. Nirwan et al[3] conducted the most recent systematic review and meta-analysis on GERD in 2020[3]. “Having heartburn and/or regurgitation at least once weekly” was the definition that was applied. However, this definition overlooks a significant portion of patients with GERD who may be asymptomatic or present with symptoms other than reflux or heartburn. It also fails to distinguish between gastrointestinal disorders like reflux hypersensitivity and functional heartburn, which can manifest with similar symptoms. Figure 1 looks at the pooled prevalence of GERD according to geographical location based on data from Nirwan et al[3].

Figure 1  Pooled prevalence of gastroesophageal reflux disease according to geographical location.

PATHOPHYSIOLOGY OF GERD

The pathophysiology of GERD is complex as it is a multifactorial disease condition with many genetic and environmental risk factors[5]. Underlying pathophysiological mechanisms of GERD are many[6]. According to Herregods et al[7], certain factors can either cause or worsen GER, while other factors may amplify the severity of GERD symptoms[7]. According to Miller et al[8] and Nandurkar and Talley[9], the main causes of increased GER include transient lower esophageal sphincter relaxations (TLESRs) and other irregularities in lower esophageal sphincter (LES) pressure[8,9]. Figure 2A summarizes the pathophysiological factors causing GERD.

Figure 2 Gastroesophageal reflux disease. A: Factors causing gastroesophageal reflux disease (GERD); B: Factors associated with GERD symptoms; C: Symptoms/conditions associated with GERD. LES: Lower esophageal sphincter; NSAIDS: Nonsteroidal anti-inflammatory drugs; TLESR: Transient lower esophageal sphincter relaxation.

Motor abnormalities and anatomical factors implicated in the pathogenesis of GERD are believed to have a genetic basis, supported by studies showing approximately 31% heritability of GERD. Single nucleotide polymorphisms in genes such as FOXF1, CCND1, MHC, DNA repair genes, and specific genetic loci on chromosomes 3, 15, and 19, among others, have been identified[10]. Additionally, genes like CRTC1, BARX1, and FOXP1, are identified as susceptibility loci associated with the development of esophageal adenocarcinoma and Barrett’s esophagus (BE)[10-12].

Overall, GERD is said to be caused by a malfunctioning LES triggered by risk factors such as obesity, smoking, family history, pregnancy, hiatus hernia, reduced gastric motility, and medications[12-17]. Figure 2B summarizes the recognized risk factors/associated factors of GERD.

CLASSIFICATION OF GERD

GERD can result in erosive reflux disease or NERD. When reflux induces inflammation or ulceration of the esophagus, it is defined as erosive reflux disease. Meanwhile, patients whose endoscopy does not show erosive changes but still produces abnormal acid reflux on 24-hour pH monitoring recordings are labeled as having NERD. NERD is the most common presentation of GERD, with around 78%-93% of all reflux diseases being labelled as NERD in the Asia-Pacific region[18]. There is another subset of patients with reflux sensitivity who have GER within the normal range but in whom esophageal hypersensitivity results in the generation of symptoms[19]. The main differential diagnosis for GERD is functional heartburn, which presents with similar symptoms, but there is no evidence of either increased GER on ambulatory pH monitoring or esophageal mucosal damage on endoscopy[20].

CLINICAL PROFILE OF GERD

GERD is among the most prevalent gastrointestinal motility disorders affecting individuals of all ages and is characterized by a range of uncomfortable symptoms, including chest pain, heartburn, sour taste in the mouth, bad breath (halitosis), vomiting, difficulty swallowing (dysphagia), and respiratory issues[1]. The common GERD symptoms are shown in Figure 2C.

COMPLICATIONS OF GERD

GERD leads to a range of complications such as reflux esophagitis, BE, strictures, and extra-esophageal manifestations, such as asthma, chronic cough, and laryngitis[21,22].

Reflux esophagitis

Reflux esophagitis, characterized by inflammation of the esophageal mucosa and encountered by gastroenterologists during endoscopy, is the most common complication of GERD[23]. According to the Los Angeles classification system as seen in Figure 3, reflux esophagitis is graded into Grades A, B, C, and D based on endoscopic findings[24]. Of them, only Grades C and D are considered diagnostic of GERD[25].

Figure 3 Los Angeles classification of esophagitis. Grades C and D are diagnostic of gastroesophageal reflux disease. LA: Los Angeles.

BE

BE is characterized by the transformation of the normal stratified squamous epithelium of the esophagus into a metaplastic columnar epithelium. Diagnosis of BE requires the presence of columnar epithelium extending more than 1 cm proximal to the gastroesophageal junction, confirmed by biopsy[26]. BE is of concern because it can progress from metaplastic epithelium to dysplasia and potentially to carcinoma[26].

Esophageal stricture

An esophageal stricture or narrowing of the esophageal lumen can occur in GERD due to acid-induced mucosal damage, chronic inflammatory changes, fibrosis, scarring, and loss of distensibility. Patients with esophageal strictures commonly present with dysphagia[27].

DIAGNOSIS OF GERD

The diagnosis of GERD is usually symptom-based, but certain investigations, such as esophageal-gastro-duodenoscopy and ambulatory esophageal pH impedance monitoring, are useful in confirming the diagnosis[2]. Figure 4A summarizes the various diagnostic methods used in the management of GERD.

Figure 4 Diagnosis and management of gastroesophageal reflux. A: Investigations used in gastroesophageal reflux disease (GERD) diagnosis; B: Options available for the management of GERD. FSSG: Frequency scale for the symptoms of gastroesophageal reflux disease; GERDQ: Gastroesophageal reflux disease questionnaire; GERD-X: Endoscopic full thickness plication; H2RB: Histamine 2 receptor blocker; MI: Mucosal impedance; MNBI: Mean nocturnal baseline impedance; MSA: Magnetic sphincter augmentation; P-CAB: Potassium-competitive acid blocker; PPI: Proton pump inhibitor; PSPW: Post-reflux swallow-induced peristaltic wave; RDQ: Reflux disease questionnaire; RYGB: Roux-en-Y gastric bypass; TIF: Transoral incisionless fundoplication; UGI: Upper gastrointestinal.

Symptom-based diagnosis

Symptom-based diagnosis can be optimized by using validated, country-specific GERD screening tools with credible sensitivities and specificities. Many countries have validated country-specific symptom-based screening tools with high sensitivity and specificity, which can be applied to diagnose GERD in community settings[28].

Investigation of GERD

The investigations most useful to confirm the diagnosis of GERD are upper gastrointestinal (UGI) endoscopy and 24-h ambulatory combined pH impedance studies. Twenty-four-hour pH-metry and pH capsules have not shown significant diagnostic value in GERD. Other investigations performed to exclude common differential diagnoses include barium contrast studies, high-resolution manometry, endoluminal functional lumen imaging probe and gastric scintigraphy[29].

UGI endoscopy

UGI endoscopy is useful in identifying erosive esophagitis and its complications[24]. Endoscopy has a limitation since patients with NERD do not have visible lesions. If there are visible mucosal lesions, a biopsy can help differentiate erosive esophagitis and BE from eosinophilic esophagitis and carcinoma, which are not directly related to GERD[30].

Twenty-four hour combined pH impedance testing

Intraluminal impedance, combined with pH monitoring, enables the identification of retrograde bolus movement and provides detailed information about reflux events, including their frequency, duration, acidic nature, and relationship with symptoms. Thus, when recorded for 24 h, it is helpful to quantify the GER and detect its association with symptoms. Therefore, pH impedance is more sensitive and specific in confirming the diagnosis of GERD[31]. It is also useful in differentiating NERD from functional heartburn and reflux hypersensitivity. Without the combination of impedance, isolated pH monitoring is not useful in diagnosing GERD, especially in the pediatric age group and those on regular acid-lowering drugs[30,32].

Gastrointestinal motility assessment

Gastrointestinal motility studies are not commonly performed as first-line investigations in patients with GERD. However, high-resolution manometry is useful in diagnosing hiatus hernia and ruling out esophageal motor disorders such as achalasia[33]. This technology utilizes multiple closely spaced sensors to measure intraluminal pressure along the entire length of the esophagus.

Delayed gastric emptying is a recognized pathophysiological mechanism of GERD. Gastric emptying studies are sometimes recommended in treatment-refractory GERD to identify gastroparesis, which may benefit from prokinetic medications[34].

MANAGEMENT

Management of GERD includes lifestyle modifications/non-pharmacological treatment, medical treatment, and surgical/endoscopic interventions[35]. Figure 4B summarizes these arms.

Lifestyle modifications

Habit modifications: As large meals[36], sleeping soon after eating a meal[37], eating a meal fast[38], midnight snacking[39], irregular mealtimes[39], and smoking[40] are recognized risk factors for GERD, it might be prudent to modify these or avoid these habits[41].

Positioning: Many trials have been done demonstrating that elevation of the head end of the bed improves GERD symptoms[42,43]. A systematic review done in 2006 showed the same[44]. However, a recent systematic review conducted on the same topic failed to show conclusive evidence to prove such an association[45].

Sleeping in the left lateral position is recommended for patients with GERD because it reduces acid reflux. This position is believed to be effective because it positions the esophagogastric junction above the level of gastric juice[46]. The right lateral position, meanwhile, predisposes to reflux, as shown by experiments with prolonged acid exposure times and acid clearance durations[46,47].

A study conducted by Kapur et al[48] on 15 patients with GERD revealed no significant difference in TLESRs and LES pressure between the left and right lateral sleeping positions. However, they observed that postprandial reflux occurred twice as frequently in the right lateral position[48]. In a trial led by Allampati et al[49], a positional therapy device designed to position subjects in a left lateral sleeping position with head elevation was found to improve nocturnal GERD symptoms[49].

Dietary interventions: (1) Avoidance of the trigger food: While patients often avoid foods that trigger GERD symptoms and receive advice from medical professionals to do so, further studies are needed to better understand the role of dietary modifications in managing GERD[50,51]. Common trigger foods of GERD are listed in Figure 2B, and they include common culprits such as spices[52], fried food[53], carbonated beverages[54], bread[55], tea[56], coffee[57], acidic food[58], alcohol[59], and chocolate[60];

(2) Low-fat diet: Oily food is a common culprit for heartburn, with a significant association found between high fat intake and symptoms of GERD[53]. Of 32.8% of Sri Lankans were found to suffer from heartburn following the consumption of oily food in our research[55]. Oily food is shown to delay gastric emptying[61], increase the rate of TLESRs[62] and is said to reduce LES pressure[63]. A systematic review was done in 2024[64] that analyzed the findings of two randomized cross-over studies evaluating the effect of a high-fat diet vs a low-fat diet in patients with GERD with no conclusive evidence. Of the two studies, only one study noted a significantly high esophageal acid exposure percentage in those following a high-fat meal compared to a standard meal[53]. The other study did not note such a difference[65].

A randomized control study not included in the review, which analyzed the symptoms of GERD in patients with metabolic syndrome, comparing a diet of low-fat vs full-fat dairy food, did not note a difference[66]. Meanwhile, another cross-sectional study not included in the systematic review analysis showed that it was not the amount of fat, but the type (higher saturated-to-unsaturated fat intake) that was associated with higher acid exposure time (AET) and number of reflux episodes[67];

(3) Low carbohydrate diet: The same systematic review in 2024 also analyzed the findings of studies on the effect of three studies[67-69] that demonstrated reduced GERD symptoms and distal esophageal acid exposure following low-carbohydrate diets[64]. One of these studies, a cross-sectional study analyzing objective and subjective GERD testing, noted that it is the type and not the amount of carbohydrate e.g., simple sugars, that was associated with GERD[67];

(4) Low fermentable, oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet: A randomized controlled trial involving 8 patients with GERD symptoms compared the acute effects of a low FODMAP diet vs a high FODMAP diet, revealing reduced symptoms of regurgitation after meals with the low FODMAP diet. Nevertheless, further research is necessary to explore this area more comprehensively[70]; and

(5) Probiotics and prebiotics: Probiotics or live microorganisms administered for health benefits for humans are also thought to alleviate GERD symptoms. Analyzing 14 studies assessing the health effects of probiotics in patients with GERD, a systematic review (2020) reported that 11 (79%) of the studies had positive benefits. However, due to significant heterogeneity among the studies and the fact that only five of them were of good quality, quantitative evaluation of the results was not feasible[71].

Meanwhile, studies on prebiotics are quite rare, with only a case series suggesting that a soluble fiber named maltosyl-isomaltooligosaccharide might have an improvement of GERD symptoms[72].

Weight loss: Obesity is one of the strongest predictors of GERD. A significant association has been reported between body mass index, waist circumference, weight gain, and GERD symptoms and complications[73-76].

The underlying pathophysiology mechanisms of obesity-induced GERD are multifactorial and include increased intragastric pressure, increased TLESRs, esophageal dysmotility, hiatal hernia, and reduced LES tone[76]. Weight loss has been consistently shown to be a beneficial lifestyle modification across multiple studies[77,78].

Since the association between obesity and GERD is so strong, ACG guidelines recommend weight loss as part of the management of GERD[35]. The HUNT study also showed that a decrease in body mass index had a dose-dependent effect on reducing GERD symptoms[77].

Psychological interventions

Mental stress and other psychological/psychiatric conditions are important and well-recognized risk factors for developing symptoms of GERD[13,79]. These conditions could also lower the effectiveness of pharmacological and surgical therapies[80]. Mental stress is a recognized etiological factor for functional disorders such as functional dyspepsia and functional heartburn, which are major differential diagnoses of GERD as well as potential sources for treatment resistance[81]. Thus, stress relief could play an important role in the management of GERD[82].

Some interventions such as hypnotherapy, mindfulness training, relaxation techniques, biofeedback, breathing exercises, cognitive behavior therapy, and drugs such as anxiolytics can be considered in the treatment of GERD despite varying levels of evidence[83-86].

Hypnotherapy: Hypnotherapy is an established intervention for symptoms of functional gastrointestinal disorders[87,88]. This can be helpful in the management of GERD symptoms as functional heartburn is one of the main differential diagnoses of GERD and can coexist with GERD[20]. Hypnotherapy promotes a state of relaxation with focused attention targeted at reducing visceral hypersensitivity and symptom hypervigilance[88].

Mindfulness training: Psychological comorbidities increase GERD symptoms[89]. Interventional studies on patients with GERD symptoms have shown that anxiety, depression, and associated GERD symptoms reduce with mindfulness-based stress reduction techniques[85].

Relaxation: Similarly, a controlled study showed that patients who received relaxation training had significantly lower reflux symptom numbers and a reduced AET than those receiving a placebo[90].

Breathing exercises: The main goal of breathing exercises/respiratory physiotherapy is to improve diaphragmatic function and change the breathing pattern from thoracic to abdominal breathing pattern, which is ideal[91].

A systematic review was done in 2023 on 11 studies conducting breathing training. While the results were inconclusive due to the heterogenicity of different studies, the review noted that breathing does have a potential benefit and needs to be studied further[92]. A similar sentiment was expressed in a review conducted in 2020[93].

Cognitive behavior therapy: Cognitive behavior therapy focuses on recognizing GERD symptoms and warning signs and conducting behavioral exercises to prevent them. It is more in line with belching-associated reflux and is shown to reduce esophageal acid exposure in patients with GERD symptoms associated with supra gastric belching[94].

Biofeedback: Reflux and its symptoms are said to occur due to abdominal muscle contractions during gastroesophageal pressure equilibration. Biofeedback therapy involves relaxing these abdominal muscles and thus decreasing reflux[95]. A case-control study investigating the effectiveness of diaphragm biofeedback training in patients noted that crural diaphragm tension and gastroesophageal junction pressure, but not LES pressure, were significantly elevated following treatment. Acid suppression usage decreased significantly compared to controls[96]. Meanwhile, yet another study analyzing esophageal manometry testing following biofeedback sessions in a single subject showed that even LES pressure increased after the sessions, reducing symptomatic reflux episodes[97].

Anxiolytics: Anxiety and depression are psychological factors found at higher levels in subjects with GERD symptoms than in controls[98]. A systematic review conducted in 2015 showed that antidepressants help modulate esophageal sensation and can reduce functional chest pain[86].

Pain modulators such as selective serotonin reuptake inhibitors and tricyclic antidepressants in low doses are used for the management of functional heartburn, though some may have limited data regarding efficacy[86,99]. While patients with reflux hypersensitivity might benefit from medical treatment given for GERD due to esophageal hypersensitivity, the functional nature of the disease warrants the use of tricyclic antidepressants and selective serotonin reuptake inhibitors as the cornerstones of treatment[81].

Pharmacological management

Proton pump inhibitors (PPIs) are the most prescribed first-line drug for GERD. Other drugs prescribed are histamine receptor antagonists, gamma-aminobutyric acid (GABA) agonists (e.g., baclofen), and potassium-competitive acid blockers (P-CAB) (e.g., soraprazan, linaprazan)[35,100,101].

PPIs: PPIs irreversibly inhibit the H+/K+ adenosine triphosphatase pump (proton pump) of the parietal cell and are superior in reducing the secretion of gastric acid compared to H2 receptor blockers[102,103]. PPIs are not only the most prescribed drug for GERD but are also frequently overused[104]. While there are several types of PPIs available with varying degrees of acid suppression potency[105], meta-analyses have indicated that their effectiveness in healing and relieving symptoms differs only marginally[106].

Patients are advised to take PPIs 30 to 60 minutes before a meal because these medications bind specifically to active acid-secreting proton pumps[35]. PPIs, which cause significant acid suppression, are noted to be better at controlling typical GERD symptoms, such as heartburn, than other symptoms[107]. Previously, it was thought that patients with ERD responded better to PPIs than patients with NERD, but a new meta-analysis has shown that they are equally effective in both ERD and well-defined NERD[108]. A full-dose PPI therapy of 4 weeks to 8 weeks is recommended in patients with GERD symptoms[109]. If the response is not satisfactory with once-daily dosing, PPIs can be taken twice daily[110]. Patients not responding to PPIs should be investigated further[110]. If the symptoms recur after a satisfactory initial treatment, PPIs should be restarted at the lowest possible dose to control symptoms and can also be used on a need-to-use basis if there is no endoscopic evidence of GERD[35,109].

Those with endoscopic evidence of GERD, such as esophagitis, BE, and strictures, are advised to be on long-term PPI therapy to promote healing[35,109]. PPIs can be switched or a higher dose can be given if esophagitis is not healing satisfactorily[109]. While there are side effects of PPIs, experts agree that the benefits outweigh the risks[35]. Switching between classes of PPIs can be considered for those who experience minor side effects[35].

Long-term use of PPI is reported to be associated with multiple rare and devastating complications. They include nutritional deficiencies (e.g., calcium deficiency and risk of fracture and vitamin B12 deficiency)[111,112], increased risk of infection (e.g., Clostridioides difficile and respiratory infections)[113,114], kidney disease (e.g., acute intestinal nephritis and chronic kidney disease)[115,116], gastrointestinal problems (e.g., small intestinal bacterial overgrowth, rebound acid hypersecretion on discontinuation, increased risk of gastric cancer)[117-119], cardiovascular problems (e.g., impairing effectiveness of certain cardiovascular medications)[120], and cognitive decline (e.g., increased risk of dementia)[121]. However, despite theoretical concerns regarding the potential consequences, there is no current recommendation to initiate long-term PPI therapy with calcium, vitamin D, or vitamin B₁₂ supplementation or routine monitoring of mineral density, serum B₁₂ levels, magnesium levels, or creatinine levels[35].

Histamine 2 receptor blockers: Though histamine 2 receptor blockers (H2RB) are less potent at blocking gastric acid secretion[122], they are recommended in controlling nocturnal GERD symptoms[35]. While the NICE guidelines recommend administering H2RBs if the PPI response is inadequate[109], the ACG guidelines have no such recommendation[35]. Though H2RB may have a place as a step-down management option following PPI therapy[123], continuous use of H2RBs can cause tolerance to them, limiting their efficacy[124].

P-CAB: P-CABs, like vonoprazan, are a relatively new class of drugs used in some Asian countries for GERD treatment[125]. They reversibly bind to the H+/K+ adenosine triphosphatase pumps and offer several advantages over PPIs, including rapid onset of action, longer half-life, and the ability to be taken independently of meals[100]. In a preliminary trial, P-CAB has shown a higher therapeutic benefit than PPIs in the management of GERD[125]. Given these advantages over PPIs, P-CABs are likely to become more commonly used for GERD treatment globally once they are established.

Prokinetics: Prokinetics that increase gastric motility reduce GER by improving gastric emptying and reducing intragastric pressure. Several systematic reviews on the role of prokinetic drugs in the treatment of GERD revealed that the pooled estimates of symptom resolution and endoscopic healing are better in patients on prokinetic agents[126,127]. However, they did not give conclusive evidence on which oral prokinetic agent is superior. Due to their central nervous system side effects, prokinetics such as metoclopramide and domperidone are not recommended solely for the use of GERD, except when delayed gastric emptying has been proven[35].

Baclofen: GABA class B receptors are found in the neurons of the motor nucleus of the vagus and nucleus tract solitarious and play an important role in TLESRs[101]. Thus, baclofen, a GABA-B agonist, is efficacious in reducing TLESRs, reflux episodes, and related symptoms. It can be used as a treatment for PPI-refractory, proven GERD. However, caution should be used due to side effects such as drowsiness and dizziness[35,128].

Sucralfate: Sucralfate binds to both normal and eroded mucosa by forming polyvalent bridges between positively charged proteins found in the mucosa (present in high concentrations in mucosal lesions) and the negatively charged sucralfate polyanions[129]. However, due to its limited documented efficacy in GERD, it is not recommended for the use of treatment for GERD except when pregnant[35].

Antacids: Antacids, composed of magnesium, calcium, aluminum, sodium, or combinations thereof, are generally well tolerated and can alleviate heartburn symptoms effectively. However, their efficacy in treating non-acid reflux and regurgitation is limited, making them primarily useful for symptom relief. Antacids are used exclusively for on-demand symptom relief, with little evidence to favor one type over another[35,110].

Alginates: Alginates or alginic acid derivatives precipitate into a gel-raft-like layer in the presence of gastric acid, creating a mechanical barrier and displacing the postprandial acid pockets[130]. According to a recent meta-analysis, alginates show higher effectiveness than antacids and placebos[131].

SURGICAL THERAPIES

Criteria for those who warrant anti-reflux surgery are listed in Table 1[110]. The surgical options are discussed below.

Table 1 Criteria for those who warrant anti-reflux surgery.

Criteria[110]
Having typical GERD symptoms; at least a year-long history
Response to PPI; need for PPI dosage to increase
Hiatal hernia
Documented esophagitis
Documented acid reflux
Documented symptom reflux correlation
Proven LES incompetence

GERD: Gastroesophageal reflux disease; LES: Lower esophageal sphincter; PPI: Proton pump inhibitor.

Fundoplication with or without hernia repair

Anti-reflux surgery is intended to create a functional anti-reflux barrier. The fundoplication strengthens the LES, regains the normal anatomy through a crural repair, and reinstates the needed intra-abdominal esophagus length[110]. Fundoplication can be performed via open surgery, laparoscopy, or robotic-assisted surgery. Since its introduction in 1991, laparoscopic anti-reflux surgery has almost replaced open surgery and is now the standard approach for fundoplication[132]. Fundoplication can be “complete”, or it can have various stages of “partial fundoplication”, as subsequently demonstrated by Toupet, Belsey, Dor, Hill, and Collis[133].

Fundoplication, which creates a comprehensive barrier against both acidic and non-acidic reflux, demonstrates superior efficacy compared to PPIs in terms of reducing acid exposure time and improving symptoms. However, the procedure can be associated with surgical complications and occasional recurrence of symptoms in some patients[134,135]. Though a considerable number of patients require pharmacotherapy even after anti-reflux surgery, the patient satisfaction rates are significantly higher, and heartburn and regurgitation are lower compared to those under PPI treatment only[136]. When compared, both complete and partial fundoplication have similar efficacy, though each can give rise to complications such as dysphagia, bloating, and vomiting. The inability to belch is a complication of complete fundoplication, while a higher incidence of GERD recurrence is seen in partial fundoplication[137,138].

The decision to undergo anti-reflux surgery should be carefully considered, weighing the potential benefits of symptom relief and freedom from medication against the risks of surgery and the potential for symptom recurrence. This evaluation should take account of the variability in surgical outcomes, an individual’s overall health, and preferences[35].

Magnetic sphincter augmentation

Magnetic sphincter augmentation (MSA) (LINX reflux management system) is a procedure where an interlinked, flexible ring of magnetic beads coated with titanium is inserted laparoscopically around the LES to prevent reflux[139]. The ring allows the LES to open during swallows and keeps it closed at other times preventing reflux[139]. Manometric investigations have shown that this procedure restores loose LES pressures to normal pressures[140].

This procedure has rare complications, such as post-surgical dysphagia and erosion of the ring into the esophagus[141]. A follow-up study of post-MSA patients for 5 years showed good symptom improvement and long-term acid reduction[142]. Compared with fundoplication, patients undergoing MSA showed no significant difference in control of GERD symptoms but had shorter surgery times, shorter hospital stays, less bloating, and a better ability to belch[35,143].

Roux-en-Y gastric bypass

The outcomes of anti-reflux surgery, including fundoplication, are often poorer in patients with obesity. This may be attributed to increased intra-abdominal pressure, which can lead to disruptions of the fundoplication and other surgical complications[144]. Roux-en-Y gastric bypass (RYGB), meanwhile, is a surgical option in patients with GERD with obesity to reduce gastric acid and prevent bile reflux[35]. Studies have shown that RYGB and fundoplication have comparable results[145]. RYGB should be considered for its combined effect of weight reduction and acid control. The patients being considered for it should be counselled about the risks and lifestyle modifications needed to make the surgery a success[35].

Endoscopic anti-reflux procedures

Despite the development of various endoscopic anti-reflux procedures such as Endocinch suturing, Stretta, Enteryx injection, and endoscopic full-thickness plication (GERD-X), their adoption remains limited due to factors like sparse clinical studies, modest effectiveness, high costs, and associated complications. As a result, these procedures are only available at a few specialized centers[110]. Of the endoscopic procedures, transoral incisionless fundoplication (TIF), GERD-X, and Stretta have shown more promising results, and they are discussed below.

TIF

TIF, using the EsophyX device and T-fasteners, creates a flap valve covering 180° to 270° of the circumferences of the esophagogastric junction by plicating portions of the proximal stomach wall[146]. Meta-analyses showed a satisfactory reduction in symptoms and AET, and TIF is shown to be a safe and effective option for patients with GERD[147,148] ACG guidelines recommend TIF as well as fundoplication surgery for patients with refractory, proven GERD. TIF can be recommended if the patient is unwilling to undergo open surgery, has a small hiatus hernia of less than 2 cm, or has no severe erosive esophagitis[35].

GERD-X

This is a newer endoscopic plication device. Compared to EsophyX devices, it is a simpler and quicker surgical procedure with proven efficacy[149].

Stretta procedure

Stretta involves the application of thermal heat in the form of radiofrequency energy using a flexible transoral catheter and needle electrodes[150]. The mechanism of action of Stretta is not exactly clear, and the postulated mechanism includes the radiofrequency energy causing structural rearrangements of smooth muscles and interstitial cells of Cajal in the LES[150]. Stretta is considered a treatment option for patients with PPI-refractory GERD who are unwilling or not suitable for surgery[151]. However, according to the latest ACG guidelines, Stretta is not recommended as an alternative for medical or surgical treatment due to controversial data regarding its efficacy[35].

EMERGING TREATMENTS

Neuromodulation therapies present newer avenues for the treatment of GERD. Examples of neuromodulation therapies for GERD, include transcutaneous electrical acustimulation (TEA), implantable LES electrical stimulation (LES-ES), electroacupuncture, and manual acupuncture. Systematic reviews have provided evidence supporting LES-ES and TEA as effective therapeutic options[85].

In TEA, bipolar electrical stimulation is delivered transcutaneously through two skin surface electrodes at acupuncture sites at the leg and wrist. A small study of 30 subjects showed an improvement in reflux-related symptoms and esophageal manometry metrics[152].

Electroacupuncture and manual acupuncture have somewhat similar methodologies involving electrical stimulation and manual stimulation at acupuncture sites in the body. The evidence related to these is poor[153,154]. The physiological basis of how these interventions work is unclear and could involve a placebo effect or even pain gaiting or modulation.

LES-ES meanwhile involves delivering bipolar electrical stimulation via two electrodes implanted in the LES submucosa approximately 1 cm apart. These leads are connected to a pulse generator implanted in the subcutaneous layer in the anterior abdominal wall. The electrical pulses were delivered at intervals in 12 sessions of 30-min durations per day. A study following 25 patients implanted with this device for over 2 years showed significant improvement in symptom scores and pH impedance metrics[155].

PROGNOSIS

GERD left untreated can give rise to complications such as BE and esophageal cancer, though the estimated number is unclear[156].

If correctly identified as GERD through objective diagnostic tests and treated appropriately, the prognosis related to symptoms and complications with pharmacological treatment is positive[108]. However, most patients require long-term therapy as stopping medical treatment can bring about a symptom relapse[2].

Meanwhile, in a considerable number of patients, pharmacological treatment might prove fruitless due to many reasons. Such cases are called refractory GERD[157,158]. In these patients and those with complications, surgical options can offer a better prognosis[136].

REFRACTORY GERD

Refractory GERD is defined as the failure of GERD symptoms to respond to 8 weeks of double doses of PPIs. This definition has some controversy as to whether it should be the standard once-daily dose or twice-daily PPI dose[159]. Common causes of refractory GERD include misdiagnosis, poor patient compliance, non-adherence to prescribed timing, hypersensitivity, rumination syndrome, supra-gastric belching, altered esophageal motility, and delayed gastric emptying[157,158]. The phenotype is also important, as systematic reviews showed that patients with NERD have less symptom relief than patients with erosive esophagitis on the same dose of PPI, are more likely to be treatment-resistant, and thus require further investigations[160]. Misdiagnosis is a cause of concern as symptoms of non-GERD disorders such as reflux like dyspepsia, gastroparesis, achalasia, and eosinophilic esophagitis overlap with GERD symptoms and reduce the odds of responding to PPIs.

As per ACG guidelines, the first step in the management of treatment refractive GERD is to improve treatment compliance and proper timing[157]. Doubling the dose of PPIs is also practiced, but studies have shown mixed results[161]. Typical GERD symptoms, obesity, and male sex were found to be positive predictors of increased relief when the PPI dose was increased[162]. One can switch to another PPI in the case of failure of treatment, but older PPIs, such as omeprazole, were found to have similar efficacy compared to the newer PPIs[163].

One of the main concerns regarding the treatment of refractory GERD is that it severely affects the quality of life of patients, leading to sleep disturbances, decreased work performance, and emotional stress[157].

CONCLUSION

Globally, GERD is a highly prevalent disorder, yet its true impact remains unclear due to a lack of comprehensive research and variations in diagnostic procedures and screening tools across different regions. GERD significantly diminishes quality of life, increases healthcare costs, and leads to several complications. It presents with a spectrum of symptoms other than the typical symptoms of heartburn, regurgitation, and chest pain and can progress to more severe conditions like BE and carcinoma. Early diagnosis and effective treatment strategies are essential to mitigate the burden of the disease on healthcare systems and improve patient outcomes. This underscores the need for standardized diagnostic criteria and more extensive epidemiological studies to determine the exact disease burden. Additionally, therapeutic trials are essential to evaluate emerging treatment options, ultimately enhancing healthcare outcomes for patients with GERD.