Gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is a chronic digestive disorder characterized by the recurrent retrograde flow of gastric contents into the esophagus, leading to symptoms such as heartburn and regurgitation, and potentially causing esophageal inflammation or more severe complications.^[1][2] It affects approximately 10-20% of adults in Western populations and about 5% in Asian countries, with equal prevalence among men and women, though complications like Barrett's esophagus occur more frequently in men.^[1][3] The primary symptoms of GERD include a burning sensation in the chest known as heartburn, often worsening after meals, at night, or when lying down; regurgitation of sour or bitter liquid into the throat or mouth; and noncardiac chest pain.^[2][1] Additional atypical symptoms may involve chronic cough, hoarseness, sore throat, or exacerbation of asthma, which can mimic other conditions and complicate diagnosis.^[3][4] GERD arises primarily from dysfunction of the lower esophageal sphincter (LES), which normally prevents reflux, often due to transient relaxations, hiatal hernia, obesity, or delayed gastric emptying.^[1][2] Risk factors include pregnancy, smoking, consumption of trigger foods like fatty or spicy items, alcohol, and certain medications such as NSAIDs or calcium channel blockers.^[3][2] Pathophysiologically, this reflux exposes the esophageal mucosa to acid and pepsin, triggering inflammation via cytokine-mediated responses and impairing natural defenses like saliva production or esophageal motility.^[1] Diagnosis typically relies on clinical history and response to proton pump inhibitors (PPIs), with confirmatory tests such as upper endoscopy, esophageal pH monitoring, or manometry used for refractory cases or to assess complications.^[4][1] Initial treatment emphasizes lifestyle modifications, including weight loss, elevated head during sleep, and avoiding late meals, alongside medications like antacids, H2-receptor antagonists, or PPIs such as omeprazole.^[3][4] For persistent symptoms, surgical options like Nissen fundoplication may be considered to reinforce the LES.^[1] Untreated GERD can lead to erosive esophagitis, strictures, Barrett's esophagus—a precancerous condition—and rarely esophageal adenocarcinoma.^[2][1]

Pathophysiology

Reflux mechanisms

Gastroesophageal reflux disease (GERD) primarily arises from the retrograde flow of gastric contents into the esophagus due to impaired anti-reflux barriers. The predominant mechanism facilitating this reflux is transient lower esophageal sphincter (LES) relaxation (TLESR), defined as a spontaneous relaxation of the LES lasting more than 10 seconds without associated swallowing or pharyngeal peristalsis.^[5] TLESR accounts for approximately 70% of acid reflux episodes in GERD patients and is triggered by gastric distension, such as from meals or air accumulation, which activates vagal mechanoreceptors in the proximal stomach.^[5] This reflex-mediated relaxation, combined with temporary inhibition of the crural diaphragm and longitudinal esophageal shortening, generates a positive pressure gradient that propels stomach contents upward.^[5] Hiatal hernia exacerbates reflux by compromising LES integrity and altering pressure dynamics at the esophagogastric junction. In sliding hiatal hernia, the most common type associated with GERD, the gastroesophageal junction migrates proximally through the diaphragmatic hiatus, separating the LES from the supportive crural diaphragm and reducing overall LES pressure and length.^[6] This displacement increases LES compliance, allowing greater opening during relaxation events and facilitating reflux, particularly under conditions of elevated intra-abdominal pressure such as straining or coughing.^[6] Larger hernias (>3 cm) further impair the "pinchcock" mechanism of the crural diaphragm, prolonging acid exposure by hindering esophageal clearance.^[6] Reflux episodes vary by body position, influencing their frequency and duration. Upright reflux predominates in most GERD patients, occurring during daily activities and postprandially, while supine reflux is less common but often more damaging in severe disease, such as erosive esophagitis, due to gravity effects impairing esophageal clearance and prolonging acid exposure during nocturnal recumbent periods. In uncomplicated cases, upright acid exposure exceeds supine exposure (p < 0.0001), correlating with daytime symptoms, whereas bipositional reflux in advanced GERD reflects lower LES pressure and heightens nocturnal risk.^[7] The injurious potential of refluxate stems from its composition, with reflux episodes being acid or non-acid, including hydrochloric acid, bile acids, and pepsin, which synergistically damage the esophageal mucosa. Acid lowers esophageal pH, inducing cellular edema, inflammation via cytokines like IL-8, and reactive oxygen species production.^[8] Bile acids, often from duodenogastric reflux, solubilize cell membranes and promote DNA damage, with cytotoxicity amplified in acidic conditions and linked to severe esophagitis and Barrett's esophagus.^[8][9] Pepsin, a proteolytic enzyme activated below pH 4.5, degrades epithelial proteins and intercellular junctions, causing direct cytotoxicity and oxidative stress even in non-acidic environments upon reactivation.^[8][9]

Esophageal defense factors

The lower esophageal sphincter (LES) serves as the primary mechanical barrier preventing gastroesophageal reflux, consisting of intrinsic smooth muscle fibers (clasp and sling fibers) and extrinsic support from the diaphragmatic crura and phrenoesophageal ligament.^[10] It maintains a tonic contraction with a resting pressure of 15 to 30 mmHg above intragastric pressure, generated by myogenic tone and modulated by cholinergic excitatory and nitrergic inhibitory neural inputs.^[10] During swallowing, the LES relaxes for approximately 5 seconds to allow bolus passage, while transient LES relaxations (TLESRs), lasting 10 to 45 seconds and often triggered by gastric distention, permit gas venting but can facilitate reflux if prolonged.^[10] In GERD, reduced LES pressure below 6 mmHg or frequent TLESRs compromise this barrier, allowing gastric contents to enter the esophagus more readily.^[11] Esophageal peristalsis provides a secondary defense by clearing refluxate from the esophagus, with primary peristalsis initiating bolus transport during swallowing and secondary peristalsis responding to esophageal distention by reflux to eliminate residual volume.^[12] This coordinated wave of contraction, propagating at 2 to 4 cm/s, removes up to 90% of refluxed material within seconds, minimizing contact time with the mucosa.^[13] Ineffective esophageal motility, characterized by weak peristaltic amplitude (distal contractile integral <450 mmHg·s·cm), disrupts this clearance, particularly in patients with reflux esophagitis where prevalence reaches 29% compared to 15% in non-erosive reflux disease.^[12] Chemical defenses further protect the esophagus through salivary bicarbonate secretion and inherent mucosal barriers. Saliva, produced at 0.5 to 1.5 L/day, contains bicarbonate (up to 50 mM during acid stimulation) that neutralizes refluxed acid, raising esophageal pH from below 2 to above 5 within minutes, while growth factors like epidermal growth factor promote repair.^[9] The esophageal mucosa comprises a pre-epithelial mucus layer rich in mucins (MUC5AC, MUC3), non-bicarbonate buffers, and prostaglandins; an epithelial layer with tight junctions (claudins, occludins) and desmosomes forming a selective permeability barrier; and a post-epithelial component involving blood flow and H⁺ transporters for ion removal.^[14] These elements collectively buffer acid, limit diffusion of pepsin and bile acids, and facilitate rapid restitution of damaged cells.^[14] Impairments in these defense factors culminate in prolonged esophageal acid exposure, a hallmark of GERD progression. Hypotensive LES, ineffective peristalsis, and reduced salivary bicarbonate (e.g., threefold lower secretion in severe cases) extend acid contact time beyond 5% of the day, fostering mucosal inflammation and erosions.^[9] In refractory GERD, secondary peristalsis failure rates exceed 50%, correlating with increased symptom severity and esophageal pH exposure indices above 14.7 on DeMeester scoring.^[12] Such deficits often coexist, amplifying refluxate retention and transitioning physiologic reflux to pathologic disease.^[15]

Signs and symptoms

Typical symptoms in adults

The hallmark symptom of gastroesophageal reflux disease (GERD) in adults is heartburn, a burning sensation in the chest that often radiates upward toward the throat or neck. Heartburn from GERD is the most frequent cause of non-cardiac chest pain overall; this pain can manifest as burning, squeezing, or sharp sensations, potentially on the left side, resembling cardiac ischemia, and often intensifies after meals, when lying down, or following consumption of spicy, fatty, or acidic foods.^[16][2][17] Heartburn and regurgitation after fatty meals can have a delayed onset, typically appearing within 30 minutes to 3 hours after eating. Fatty foods slow gastric emptying and promote transient lower esophageal sphincter relaxations (TLESRs), leading to reflux symptoms that are not immediate but occur later, often when lying down or several hours post-meal. The exact timing varies by individual, but delayed symptoms (beyond 1 hour) are common with high-fat meals. This discomfort typically arises from the reflux of acidic stomach contents into the esophagus and is frequently triggered by meals, particularly large or fatty ones, with symptoms persisting for 30 minutes to several hours.^[18][19] Regurgitation, another prevalent symptom, involves the effortless return of sour or bitter-tasting fluid—often gastric acid mixed with food—into the mouth or hypopharynx, sometimes leading to a sour taste or the sensation of food "coming back up."^[2][18] This occurs due to the passive flow of refluxate beyond the esophagus and can provoke nausea or a globus sensation in the throat; in severe cases, reflux irritation of the esophagus and throat may escalate nausea to vomiting, though vomiting is not the most common symptom and differs from the passive nature of regurgitation, despite subjective similarities.^[19][3] Water brash and hypersalivation are also recognized symptoms in adults with GERD, often occurring in association with heartburn or regurgitation. Water brash involves a sudden rush of saliva filling the mouth, often with a sour, bitter, or salty taste, causing the patient to swallow a lot or spit it out. Patients may describe it to their doctor as: "I get a sudden rush of saliva filling my mouth, often with a sour, bitter, or salty taste, causing me to swallow a lot or spit it out. It usually happens with heartburn or regurgitation." Hypersalivation refers to excessive saliva production, where the mouth feels constantly full, leading to frequent swallowing, drooling, or difficulty speaking or eating. Patients may describe it as: "I produce too much saliva, my mouth feels constantly full, leading to frequent swallowing, drooling, or difficulty speaking/eating." These symptoms are often triggered by factors such as eating or lying down. To aid in accurate diagnosis of potential causes like GERD, patients should be specific about triggers (e.g., after eating, lying down), frequency, duration, taste, and associated symptoms like heartburn or regurgitation.^[20][3] Dysphagia, defined as difficulty swallowing, and odynophagia, or painful swallowing, may develop in adults with GERD as a result of esophageal inflammation (esophagitis) caused by repeated acid exposure.^[17][19] These symptoms reflect mucosal irritation or narrowing and can make eating challenging, though they are less common than heartburn or regurgitation in uncomplicated cases.^[2][1] Nocturnal symptoms, including intensified heartburn and regurgitation, frequently occur when lying down due to reduced gravity's effect on keeping stomach contents in place, leading to significant sleep disruption and daytime fatigue.^[2][17] Such episodes can awaken individuals multiple times per night, impairing overall quality of life and productivity by contributing to chronic tiredness and reduced concentration.^[19][18] Less commonly, adults with GERD may experience early satiety (feeling full soon after starting a meal), secondary anorexia (loss of appetite), or dysgeusia (altered taste perception). Early satiety can result from reflux-associated nausea, discomfort, or overlap with functional dyspepsia. Anorexia may develop secondarily from persistent queasiness or aversion to eating due to symptoms. Dysgeusia often manifests as a persistent sour, bitter, or occasionally metallic taste, attributed to acid reflux reaching the mouth or throat. These are not classic GERD symptoms—typical ones include heartburn, regurgitation, and related complaints—but can occur secondarily or in cases overlapping with dyspeptic conditions.^{[21][18][22][23]}

Symptoms in children and infants

In infants, gastroesophageal reflux disease (GERD) most commonly manifests as frequent regurgitation or spitting up of stomach contents, often occurring after feeding and affecting up to 50% of infants in the first few months of life.^[24][25] This is typically physiologic gastroesophageal reflux (GER) but can progress to GERD if accompanied by complications such as poor weight gain. Vomiting may also occur, ranging from effortless regurgitation to more forceful episodes, and is reported in about 66% of 4-month-olds, though it decreases significantly by age 1 year.^[26] Regurgitation (also known as spitting up) in infants and young children is often a physiological phenomenon due to the immaturity of the digestive system, particularly the lower esophageal sphincter, and is usually benign. It does not require medical consultation if the infant is gaining weight appropriately, remains calm and content, and feeds well.^[25][24] However, consultation with a pediatrician is warranted in the presence of alarm symptoms that may indicate GERD, complications, or alternative conditions requiring evaluation:

• Failure to gain weight or weight loss (failure to thrive)
• Projectile (forceful, fountain-like) vomiting
• Presence of blood, bile (green or yellow fluid), or coffee-ground material in regurgitated contents
• Excessive irritability, crying, arching of the back, or refusal to feed
• Respiratory difficulties (choking, gagging, apnea, wheezing, stridor, hoarseness, recurrent infections, or cyanosis)
• Onset of regurgitation after 6 months of age or persistence or intensification beyond 12 months
• Other signs such as fever, diarrhea, abdominal distension, or lethargy

^[25][24][27] Beyond gastrointestinal signs, infants with GERD often exhibit irritability, excessive crying, and refusal to feed, which can contribute to dehydration or inadequate nutrition.^[24] Arching of the back, known as Sandifer syndrome, is a distinctive paroxysmal dystonia associated with GERD, characterized by abnormal head, neck, and trunk posturing that typically occurs post-feeding and resolves with GERD treatment; it affects approximately 1% of infants with GERD symptoms.^[28] Failure to thrive, marked by poor weight gain or growth faltering, arises from chronic feeding difficulties and is a key indicator requiring medical evaluation.^[25][24] Respiratory symptoms are particularly prevalent in pediatric GERD due to the shorter esophagus and closer proximity of the airway to the esophagus, facilitating aspiration of refluxate. These include wheezing, chronic cough, stridor, hoarseness, and recurrent respiratory infections, with wheezing noted in up to 25% of affected infants.^[29][26] Choking, gagging, or apnea may also occur during episodes, heightening the risk in non-verbal patients where diagnosis relies on observing these non-specific cues.^[24] In older children, GERD symptoms overlap with those in infants but may include more pronounced feeding refusal leading to weight loss, as well as abdominal discomfort or dysphagia.^[29] Most cases of physiologic regurgitation resolve spontaneously by 12–18 months of age as the lower esophageal sphincter matures and with dietary transitions to solids, though persistent cases warrant monitoring for complications.^[25][27]

Extraesophageal symptoms

Extraesophageal symptoms of gastroesophageal reflux disease (GERD) refer to manifestations occurring outside the esophagus, primarily affecting the respiratory tract, larynx, and oral cavity due to reflux of gastric contents. These symptoms arise from mechanisms such as direct microaspiration of acid and pepsin or vagally mediated reflexes that trigger irritation in distant sites. Unlike typical esophageal symptoms, extraesophageal ones often occur without heartburn or regurgitation, complicating diagnosis.^[30] Chronic cough is a prominent respiratory symptom, affecting 10–56% of GERD patients and accounting for approximately 20% of chronic cough cases lasting over eight weeks. It is typically non-productive and may worsen with posture, eating, or talking, resulting from microaspiration of refluxate irritating the airways or a reflex arc via the vagus nerve that sensitizes cough receptors. Asthma exacerbations are similarly linked, with up to 50% of difficult-to-control asthma cases showing evidence of distal esophageal reflux and 35–55% exhibiting proximal reflux events. Microaspiration of gastric acid can provoke bronchospasm, while vagal reflexes may heighten airway hyperresponsiveness, leading to wheezing and shortness of breath. Laryngitis, observed in 10–15% of otolaryngology visits, presents as hoarseness, vocal fatigue, or throat clearing due to laryngeal edema and erythema from direct acid-peptic contact or neural reflexes.^[30][31] Laryngopharyngeal reflux (LPR), also known as silent reflux, is a form of extraesophageal GERD in which refluxed gastric contents reach the larynx and pharynx, frequently without prominent heartburn or regurgitation. This condition commonly presents with hoarseness, chronic throat clearing, persistent cough, globus sensation (feeling of a lump in the throat), sore throat, and a sensation of excess mucus or postnasal drip. Symptoms arise from direct mucosal exposure to acid, pepsin, and other gastric components or through vagally mediated reflexes. LPR is particularly prevalent in patients presenting to otolaryngologists with chronic laryngeal complaints and may require targeted diagnostic evaluation including laryngoscopy and pH-impedance monitoring.^[32][33] Laryngeal manifestations include globus sensation—a persistent feeling of a lump in the throat—and sore throat, which affect up to 60% of chronic laryngitis cases associated with GERD. These symptoms stem from irritation of the pharyngeal and laryngeal mucosa by refluxed material, often without visible esophageal damage. Dental erosions and enamel loss represent oral involvement, with prevalence ranging from 10.6% to 42% in GERD patients, significantly higher than in controls (mean 48.81% vs. 20.48%). Gastric acid with a pH below 5.5 demineralizes tooth enamel by dissolving hydroxyapatite, exacerbated by reduced salivary buffering in some patients; this erosion leads to increased tooth sensitivity from exposed dentin, higher risk of cavities due to compromised enamel integrity allowing bacterial proliferation, and bad breath (halitosis), which can manifest as a fecal-like odor due to reflux of stomach acid and partially digested food carrying rotten, acidic, and fecal-like odors from gastric contents—often triggered by eating before bed, lying flat, or consuming spicy or fatty foods—in addition to chronic acid exposure altering oral pH and promoting anaerobic bacteria or direct regurgitation; palatal and lingual surfaces of upper teeth are commonly affected. In children, oral symptoms like dental erosions occur at higher rates (up to 98.1%), highlighting vulnerability in developing dentition.^{[30][31][34][35]} Attributing extraesophageal symptoms solely to GERD poses significant challenges, as they frequently lack accompanying typical GERD features and overlap with other conditions like allergies, postnasal drip, or smoking-related issues. Diagnostic tests such as 24-hour pH monitoring or laryngoscopy show low specificity (around 66% for cough), and response to proton pump inhibitors is inconsistent, further obscuring causality. Co-existing comorbidities often confound attribution, necessitating multidisciplinary evaluation to rule out alternative etiologies.^[30][31]

Complications

Untreated or severe gastroesophageal reflux disease (GERD) can lead to erosive esophagitis, characterized by inflammation and mucosal breaks in the esophagus due to repeated acid exposure.^[1] The severity of erosive esophagitis is commonly assessed using the Los Angeles (LA) classification system, which grades lesions based on the number, length, and circumferential extent of mucosal breaks observed endoscopically.^[36] Grade A involves one or more mucosal breaks no longer than 5 mm that do not extend between the tops of two mucosal folds; Grade B features one or more breaks longer than 5 mm but still not extending between folds; Grade C includes breaks that are continuous between the tops of two or more folds and involve less than 75% of the esophageal circumference; and Grade D encompasses breaks involving 75% or more of the circumference.^[37] Progression from lower to higher grades, particularly C and D, correlates with increased risk of complications and poorer healing response to therapy.^[1] A significant long-term consequence of chronic GERD is Barrett's esophagus, a metaplastic transformation where the normal stratified squamous epithelium of the distal esophagus is replaced by columnar epithelium resembling intestinal tissue, serving as an adaptive response to ongoing acid and bile injury.^[38] This condition affects approximately 3% of individuals with GERD and markedly elevates the risk of progressing to esophageal adenocarcinoma, a type of cancer with poor prognosis if advanced.^[38] The annual incidence of adenocarcinoma in patients with Barrett's esophagus is about 0.12% to 0.5%, though this risk increases with factors such as segment length greater than 3 cm, low-grade dysplasia, or obesity.^[39] Endoscopic surveillance is recommended to detect dysplasia early, as it can be identified during routine evaluation of GERD complications.^[40] Esophageal strictures represent another structural complication, arising from fibrosis and scarring following prolonged inflammation, often as a sequela of healing peptic ulcers or severe erosive esophagitis.^[41] These benign narrowings, which account for up to 90% of non-malignant esophageal strictures, can cause progressive dysphagia and obstruction by reducing the esophageal lumen diameter to less than 13 mm.^[42] Peptic ulcers in the esophagus, formed by acid erosion of the mucosa, contribute to stricture development through cycles of ulceration and repair, particularly in patients with long-standing GERD and hiatal hernia.^[43] Esophageal strictures may also rarely develop as a postpartum complication of severe GERD during pregnancy. Pregnancy-related GERD is typically mild and transient, resolving after delivery, but in rare severe cases—such as persistent reflux esophagitis or hyperemesis gravidarum with recurrent vomiting—chronic acid exposure can lead to esophagitis, scarring, and stricture formation that may become symptomatic postpartum.^[44][45][46] Rare complications of GERD include esophageal perforation, a life-threatening tear in the esophageal wall resulting from deep ulceration or severe inflammation, which can lead to mediastinitis if untreated.^[47] Additionally, chronic GERD-mediated changes, especially via Barrett's esophagus, confer an increased risk for esophageal adenocarcinoma, though associations with other cancers such as squamous cell carcinoma are less direct and primarily linked to confounding factors like smoking.^[48]

Causes and risk factors

Physiological causes

Dysfunction of the lower esophageal sphincter (LES), characterized by reduced basal pressure or inappropriate transient relaxations, serves as the primary physiological cause of gastroesophageal reflux disease (GERD) by failing to maintain a competent barrier against gastric reflux. Hiatal hernias, characterized by the protrusion of the stomach through the diaphragmatic hiatus, represent a primary physiological cause of gastroesophageal reflux disease (GERD) by compromising the integrity of the lower esophageal sphincter (LES). Type I, or sliding hiatal hernias, account for over 95% of cases and involve the displacement of the gastroesophageal junction into the thoracic cavity, which disrupts the LES's barrier function and facilitates acid reflux into the esophagus.^[49] In contrast, type II paraesophageal hernias, comprising about 5% of cases, occur when a portion of the stomach migrates alongside the esophagus while the LES remains in place, potentially leading to mechanical obstruction and secondary reflux due to altered intra-abdominal pressure dynamics.^[49] These anatomical abnormalities inherently weaken LES competence, independent of external influences.^[50] Delayed gastric emptying, often associated with gastroparesis, contributes to GERD by increasing the volume of refluxate through prolonged retention of gastric contents. This delay heightens gastric distension, which triggers transient LES relaxations and elevates intragastric pressure, thereby promoting the upward migration of acid and food into the esophagus.^[51] In patients with GERD, such physiological delays correlate with worsened symptom severity, including higher heartburn scores, though direct correlations with acid exposure time may vary.^[51] Gastroparesis thus exacerbates reflux volume by sustaining a reservoir of potentially acidic material in the stomach.^[52] Esophageal motility disorders, particularly ineffective esophageal motility (IEM), predispose individuals to GERD by impairing the esophagus's ability to clear refluxed material. IEM, the most common esophageal motility disorder observed in GERD patients, is defined by the Chicago Classification version 4.0 as more than 70% ineffective swallows (distal contractile integral <450 mmHg·cm·s) or 50% or more failed swallows (distal contractile integral = 0 mmHg·cm·s), leading to prolonged acid contact with the esophageal mucosa.^[53] This hypocontractility reduces bolus propulsion and acid neutralization, increasing mucosal injury and symptom persistence in GERD patients, with prevalence rising in severe cases such as erosive esophagitis.^[54][53] Such inherent peristaltic inefficiencies thus perpetuate reflux episodes.^[55] Genetic predispositions play a significant role in GERD susceptibility, with twin studies estimating heritability at 43% (95% confidence interval: 32–55%) after adjusting for age and body mass index, attributing variance primarily to additive genetic factors.^[56] Monozygotic twins exhibit higher concordance rates (42%) compared to dizygotic twins (26%), underscoring a familial aggregation driven by shared genetics rather than environment alone.^[56] Family history of upper gastrointestinal disorders further elevates risk, with an odds ratio of 1.46 (95% confidence interval: 1.22–1.74), highlighting inherited vulnerabilities in esophageal and gastric function.^[56]

Lifestyle and environmental factors

Obesity, particularly central adiposity, is a significant modifiable risk factor for gastroesophageal reflux disease (GERD), as it elevates intra-abdominal pressure through the mechanical effects of excess visceral fat on the abdominal cavity. This increased pressure promotes transient relaxations of the lower esophageal sphincter (LES) and facilitates acid reflux into the esophagus. Studies indicate that individuals with abdominal obesity face a 1.5- to 2-fold higher risk of developing GERD symptoms and erosive esophagitis compared to those with normal weight distribution.^[57] Central obesity independently contributes to non-erosive reflux disease, underscoring its role beyond overall body mass index.^[58] Pregnancy increases GERD risk primarily through hormonal influences, such as elevated progesterone relaxing the LES, and mechanical compression from the enlarging uterus on the stomach. GERD symptoms occur in 30 to 50 percent of pregnancies, often worsening in the third trimester due to these combined effects.^[59] Smoking and alcohol consumption further exacerbate GERD risk by impairing LES function and esophageal mucosal defenses. Nicotine from smoking induces relaxation of the LES circular muscle, reducing its basal tone and increasing the likelihood of reflux episodes.^[60] Alcohol, meanwhile, directly damages the esophageal mucosa and may weaken LES pressure, leading to heightened symptom severity upon consumption or withdrawal.^[61] Both habits are established risk factors, with epidemiological data linking them to greater GERD prevalence across populations.^[1] Certain dietary patterns and specific food triggers heighten GERD susceptibility by altering gastric acidity, LES tone, or gastric emptying. High-fat meals, including fried and greasy foods, delay gastric emptying and promote LES relaxation, which can lead to reflux symptoms with a delayed onset, typically appearing within 30 minutes to 3 hours after eating. These delayed symptoms are often more pronounced when lying down or several hours post-meal due to prolonged gastric distension and increased transient LES relaxations.^[62][63] Spicy foods, citrus fruits, caffeine, and chocolate act as stimulants or irritants that relax the LES, boost acid production, or directly damage the mucosa, often precipitating symptoms in susceptible individuals. Studies indicate that intake of coffee, tea, and carbonated drinks is associated with slightly increased GERD symptoms.^[62][63][64] Consuming large meals overloads the stomach, elevating intragastric pressure and facilitating reflux, particularly when combined with other triggers.^[63] Postural behaviors, such as bending forward or lying down shortly after eating, including before bedtime, mechanically aggravate GERD by increasing intra-abdominal pressure and allowing gravitational facilitation of reflux. These positions compress the stomach, pushing contents toward the esophagus, especially in the presence of a weakened LES.^[65] Activities involving forward bending or recumbency post-meal are associated with symptom exacerbation, highlighting the role of body positioning in daily reflux events.^[66]

Associated medical conditions

Gastroesophageal reflux disease (GERD) is frequently associated with connective tissue disorders, particularly systemic sclerosis (scleroderma), where esophageal involvement is common due to impaired motility and fibrosis of the esophageal smooth muscle. In patients with systemic sclerosis, nearly 90 percent exhibit some degree of gastrointestinal involvement, with the esophagus being the most affected organ, leading to reduced peristalsis and lower esophageal sphincter (LES) dysfunction that promotes acid reflux.^[67] This motility impairment exacerbates GERD symptoms, contributing to complications such as esophagitis and strictures in up to 50 percent of affected individuals.^[68] Post-bariatric surgery, particularly laparoscopic sleeve gastrectomy, can precipitate or worsen GERD through anatomical changes that increase intragastric pressure and disrupt the anti-reflux barrier. Approximately 30 percent of patients develop new-onset GERD following sleeve gastrectomy, attributed to the removal of the gastric fundus, which normally helps maintain LES integrity.^[69] In contrast, Roux-en-Y gastric bypass may improve preexisting GERD in many cases but can lead to persistent symptoms in about 35 to 49 percent of patients over long-term follow-up due to altered anatomy.^[70] Certain medications are known to exacerbate GERD by weakening the LES or irritating the esophageal mucosa. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, can directly damage the esophageal lining and promote inflammation, increasing reflux risk in susceptible individuals.^[71] Calcium channel blockers, used for hypertension and angina, reduce LES pressure, thereby facilitating acid reflux.^[72] Anticholinergic agents, including those for overactive bladder or irritable bowel syndrome, further impair esophageal clearance and LES tone, worsening GERD symptoms.^[73] GERD frequently co-occurs with irritable bowel syndrome (IBS), with comorbidity rates reported around 30-40% in clinical populations. Shared pathophysiological factors include altered gastrointestinal motility, visceral hypersensitivity, and brain-gut axis dysregulation.^[74][75] Functional constipation is frequently associated with gastroesophageal reflux disease (GERD), with studies demonstrating significant overlap between the two conditions. Straining and difficulty with evacuation in constipation can increase intra-abdominal pressure, which may reduce lower esophageal sphincter competence and promote reflux.^[76] Individuals with overlapping constipation and GERD tend to experience worsened symptom severity and reduced quality of life.^[77] Treating functional constipation can alleviate GERD symptoms in affected patients. A randomized controlled trial found that psyllium seed, used to treat functional constipation, achieved similar initial treatment response rates to omeprazole (89.2% versus 94%) in patients with concomitant GERD and functional constipation, but resulted in significantly lower recurrence rates after treatment discontinuation (24.1% versus 69.8%).^[78]

Microbial influences

Recent research has highlighted the role of microbial dysbiosis in the esophageal and gastric microbiota as a contributing factor to gastroesophageal reflux disease (GERD) pathogenesis, shifting focus from solely acid-mediated damage to microbiome-driven inflammation.^[79] In GERD patients, the esophageal microbiome exhibits an imbalance characterized by an increase in Gram-negative bacteria, such as Prevotella and Campylobacter, alongside a relative decrease in Gram-positive bacteria like certain Streptococcus species.^[79] Similarly, the gastric and intestinal microbiota in these individuals show reduced abundance of beneficial genera, including Lactobacillus and Bifidobacterium, coupled with elevations in pathogenic species such as Escherichia coli and Enterococcus.^[80] These shifts in microbial composition can precede overt inflammation, activating Toll-like receptors (e.g., TLR4) on esophageal epithelial cells and promoting cytokine release that weakens the mucosal barrier.^[81] A 2023 study demonstrated that certain Lactobacillus species facilitate the repair of DNA damage in esophageal epithelial cells induced by bile acids, a common refluxate in GERD, by enhancing recruitment of repair proteins like γH2AX and RAD51 while suppressing NF-κB-mediated inflammation.^[82] This suggests that microbial deficiencies in protective bacteria may exacerbate DNA repair impairments and chronic esophageal inflammation in GERD, potentially accelerating progression to more severe conditions like Barrett's esophagus.^[83] Dysbiotic microbiota may promote reflux through altered bile acid metabolism, where imbalances in bacterial deconjugation lead to increased secondary bile acids that irritate the esophageal mucosa and impair lower esophageal sphincter function.^[84] For instance, elevated levels of deconjugated bile acids, facilitated by overgrowth of bile salt hydrolase-producing pathogens, can heighten mucosal permeability and inflammatory responses, creating a feedback loop that sustains GERD symptoms.^[85] Proton pump inhibitors (PPIs), a cornerstone of GERD therapy, can further disrupt the microbiota by elevating gastric pH, which favors proliferation of Gram-positive bacteria like Streptococcaceae while diminishing Gram-negative taxa, potentially worsening dysbiosis and esophageal inflammation over long-term use.^[79] This alteration may contribute to PPI-refractory GERD in some patients by promoting bacterial overgrowth that enhances bile acid toxicity and mucosal injury.^[86] Preliminary probiotic trials, such as those involving Lactobacillus supplementation, have shown promise in restoring microbial balance and alleviating symptoms, though larger studies are needed.^[82]

Diagnosis

History and physical examination

The diagnosis of gastroesophageal reflux disease (GERD) begins with a thorough patient history to identify characteristic symptoms such as heartburn and regurgitation, which are the most reliable indicators for presuming the condition.^[87] These symptoms, often exacerbated by meals or recumbency, provide high specificity (up to 96%) for GERD when present.^[87] Other characteristic symptoms include water brash (a sudden rush of saliva filling the mouth, often with a sour, bitter, or salty taste, causing frequent swallowing or spitting) and hypersalivation (excessive saliva production leading to a constantly full mouth, frequent swallowing, drooling, or difficulty speaking or eating).^[1] Patients should describe these symptoms specifically to their doctor, noting details such as triggers (e.g., after eating or lying down), frequency, duration, taste, and associated symptoms like heartburn or regurgitation to facilitate accurate diagnosis and differentiation from other conditions. Validated symptom questionnaires, such as the GERD-Q, assist in assessing probability by scoring the frequency of heartburn, regurgitation, and associated symptoms like nausea or sleep disruption over the past week; a score of 8 or higher suggests GERD with 65% sensitivity and 71% specificity in primary care settings. Alarm symptoms in the history, including unintentional weight loss, progressive dysphagia, or iron-deficiency anemia, signal potential complications like esophageal stricture or malignancy and necessitate prompt endoscopic evaluation rather than empiric therapy.^[87] Odynophagia or hematemesis further heightens concern for erosive disease or bleeding.^[87] Physical examination in GERD is typically unremarkable and nonspecific, serving primarily to identify comorbidities or alternative causes rather than confirming the diagnosis.^[1] Findings may include epigastric tenderness on abdominal palpation, reflecting possible esophagitis or hiatal hernia, and assessment of body mass index to evaluate obesity as a risk factor.^[1] Respiratory signs like wheezing or rhonchi can occasionally appear if aspiration complicates GERD.^[1] The history and physical examination play a crucial role in ruling out mimics, particularly cardiac conditions causing chest pain or pulmonary disorders like asthma exacerbating cough, by eliciting symptom timing, triggers, and relieving factors that differentiate GERD from ischemic or bronchospastic events.^[88] For instance, exertional onset or radiation to the arm suggests cardiac etiology, prompting electrocardiography before attributing symptoms to reflux.^[87]

Endoscopic evaluation

Upper endoscopy, also known as esophagogastroduodenoscopy (EGD), serves as the primary visual diagnostic tool for confirming gastroesophageal reflux disease (GERD) by directly examining the esophageal mucosa for signs of injury, classifying GERD as erosive reflux disease (ERD) when mucosal damage is visible or non-erosive reflux disease (NERD) when the mucosa appears normal.^[89][90] The procedure involves inserting a flexible endoscope—a thin tube equipped with a light and camera—through the mouth into the esophagus, stomach, and duodenum to visualize abnormalities such as erosions, ulcers, or strictures.^[91] It is typically recommended for patients with alarm symptoms like dysphagia, weight loss, or anemia, or those with refractory symptoms despite therapy, to rule out complications.^[92] Preparation for upper endoscopy requires fasting for at least 6 to 8 hours beforehand to ensure a clear view of the gastrointestinal tract, with patients advised to avoid solid foods and most liquids.^[93] For optimal detection of erosive esophagitis in GERD evaluation, proton pump inhibitors (PPIs) should ideally be discontinued for 2 to 4 weeks prior to the procedure, as ongoing therapy can mask mucosal changes.^[92][90] During the procedure, moderate or deep sedation is commonly administered via intravenous agents like propofol to minimize discomfort, allowing the patient to remain relaxed while the endoscope advances.^[94] Biopsies are routinely obtained if suspicious lesions such as irregular ulcers, masses, or columnar epithelium suggestive of Barrett's esophagus are identified; the Seattle protocol recommends four-quadrant biopsies every 1 to 2 cm in the affected area to confirm intestinal metaplasia histologically.^[91] Endoscopic findings in GERD are graded using the Los Angeles (LA) classification system, which categorizes erosive esophagitis based on the size and extent of mucosal breaks.^[95] Per the Lyon Consensus 2.0, LA grades B, C, and D provide conclusive evidence of GERD, while grade A is borderline and supportive only with additional evidence.^[90] Grade A includes one or more erosions ≤5 mm limited to a mucosal fold; grade B features erosions >5 mm still confined to folds; grade C involves erosions extending over folds but covering <75% of the esophageal circumference; and grade D denotes confluent erosions involving >75% of the circumference.^[95] This system aids in assessing disease severity and guiding management, with grades C or D indicating higher risk for complications like Barrett's esophagus—a metaplastic change that may predispose to esophageal adenocarcinoma.^[96] Ulcers, if present, are deeper mucosal defects often linked to severe reflux, while Barrett's esophagus is identified by salmon-colored tongues of epithelium extending proximally from the gastroesophageal junction.^[91] In non-erosive reflux disease (NERD), which accounts for the majority of GERD cases, upper endoscopy typically reveals normal esophageal mucosa despite typical symptoms, highlighting the procedure's limited sensitivity for this subtype.^[89] Normal findings do not exclude GERD but help differentiate it from other conditions, prompting further functional testing if needed.^[91] Although generally safe, upper endoscopy carries risks including perforation of the esophagus or stomach, occurring in approximately 0.01% to 0.04% of diagnostic procedures, with higher rates in patients with strictures or prior interventions.^[97] Other potential complications include bleeding (rare, <0.5%), infection from transient bacteremia, and cardiopulmonary events related to sedation.^[97]

Physiological testing

Physiological testing in gastroesophageal reflux disease (GERD) involves functional assessments to quantify acid exposure, motility, and symptom-reflux associations, particularly for refractory or atypical cases where endoscopy is nondiagnostic. These tests provide objective measures of esophageal function, helping to confirm GERD mechanisms such as excessive reflux events or impaired clearance.^[98] Ambulatory 24-hour esophageal pH monitoring serves as the gold standard for diagnosing GERD by measuring the frequency and duration of acid reflux episodes in the distal esophagus. A transnasal catheter with a pH sensor positioned 5 cm above the lower esophageal sphincter records pH drops below 4, indicating acidic gastric content reflux, over a full day of normal activities to correlate symptoms like heartburn with reflux events. This test detects abnormal esophageal acid exposure; according to the Lyon Consensus 2.0, acid exposure time (AET) <4% excludes GERD, >6% confirms it, and <40 reflux episodes per 24 hours is physiological (40-80 inconclusive, >80 pathological).^{[98][90][99][100]} Multichannel intraluminal impedance-pH (MII-pH) monitoring enhances 24-hour pH assessment by combining pH measurement with impedance to detect both acid and non-acid or weakly acidic reflux episodes, regardless of pH level. This is particularly useful when standard pH monitoring is normal but symptoms persist, as it can identify non-acid reflux as a cause. Impedance electrodes along the catheter track retrograde bolus movement through conductivity changes in the esophageal lumen, allowing characterization of reflux composition and proximal extent; in healthy adults, total reflux episodes average around 40 over 24 hours, with acid reflux being twice as common as nonacid.^{[101][100][102]} This modality is particularly valuable for evaluating patients on proton pump inhibitors (PPIs), where nonacid reflux may predominate, and it improves symptom association analysis by linking reflux to reported symptoms via metrics like the symptom association probability. Per Lyon Consensus 2.0, on therapy, AET >4% with >80 episodes supports refractory GERD.^[90] Esophageal manometry evaluates motility disorders contributing to GERD by measuring lower esophageal sphincter (LES) pressure and peristaltic function using a catheter with multiple sensors. High-resolution manometry, the preferred modern approach, generates spatiotemporal pressure topography to assess LES resting pressure (normally 10–30 mmHg) and esophageal body contractions; in GERD, hypotensive LES (below 10 mmHg) and ineffective esophageal motility, characterized by failed or weak peristalsis in over 50% of swallows, are common findings that impair reflux clearance. This test is often performed prior to pH monitoring to ensure accurate sensor placement and identifies motility abnormalities in up to 60% of GERD patients.^{[103][104][54]} The Bravo pH capsule offers a wireless alternative to traditional catheter-based monitoring, attached endoscopically to the esophageal mucosa 6 cm above the squamocolumnar junction for up to 96 hours of recording. Advantages include improved patient tolerance due to the absence of a transnasal catheter, which reduces discomfort and gagging, allowing more natural daily activities and higher compliance; studies show it detects abnormal acid exposure in similar proportions to catheter methods but with extended monitoring yielding up to 20–30% more GERD diagnoses in equivocal cases. Data are transmitted to an external receiver, providing comparable accuracy for symptom correlation without the artifacts from catheter dislodgement.^{[105][106][107]} Lyon Consensus 2.0 recommends prolonged (96-hour) wireless pH for unproven GERD cases off therapy.^[90] Interpretation of pH monitoring results may use the DeMeester score, a composite metric that integrates six parameters—including percentage time pH <4 (total, upright, and supine), longest reflux episode, and number of episodes >5 minutes—to quantify abnormal acid exposure. A score exceeding 14.7 indicates pathological GERD with high sensitivity and specificity for predicting response to therapy; for instance, elevated scores correlate with erosive esophagitis and guide decisions for surgical intervention in PPI-refractory patients. However, the Lyon Consensus 2.0 provides updated criteria, with AET >6% (off therapy) or >80 reflux episodes confirming GERD, standardizing and refining diagnosis as of 2023.^{[108][109][110][90]}

Differential diagnosis

Gastroesophageal reflux disease (GERD) often presents with symptoms such as heartburn and regurgitation that can overlap with other conditions, necessitating a careful differential diagnosis to avoid misattribution and ensure appropriate management.^[1] Common mimics include cardiac, pulmonary, and gastrointestinal disorders, where distinguishing features guide further evaluation.^[87] Cardiac causes, such as angina pectoris, must be excluded in patients with chest pain resembling GERD symptoms, as cardiac ischemia can present similarly without typical exertional features.^[111] Distinguishing characteristics include lack of relief with antacids and association with risk factors like coronary artery disease; electrocardiography or stress testing is essential to differentiate, as proton pump inhibitors (PPIs) do not alleviate ischemic pain.^[1] Alarm symptoms, such as radiation to the arm or jaw, further prompt cardiac assessment.^[112] Esophageal motility disorders, notably achalasia, mimic GERD through dysphagia and regurgitation but involve impaired esophageal peristalsis and lower esophageal sphincter relaxation.^[87] Key differentiators include regurgitation of undigested food and absence of response to antacids or PPIs, with high-resolution manometry revealing aperistalsis for confirmation.^[1] Eosinophilic esophagitis (EoE) also overlaps with refractory GERD symptoms like dysphagia, but endoscopy with biopsies demonstrates >15 eosinophils per high-power field, and partial PPI response may occur before steroid therapy is needed.^[112] Pulmonary disorders, including asthma, can be exacerbated by or confused with GERD due to chronic cough or wheezing from microaspiration or vagal reflexes.^[111] Distinguishing features encompass respiratory triggers and poor or inconsistent PPI efficacy (response in only about 30-50% of cases), often requiring pulmonary function tests to clarify the relationship.^[87] Upper gastrointestinal mimics like functional dyspepsia present with epigastric discomfort and bloating without erosive esophagitis, showing limited PPI response and normal endoscopy findings.^[1] Biliary colic, associated with gallstones, causes postprandial right upper quadrant pain unrelated to posture or meals typical of GERD, with no improvement from antacids or PPIs and ultrasound revealing cholelithiasis.^[112]

Treatment

Lifestyle and dietary modifications

Lifestyle and dietary modifications serve as the cornerstone of initial management for gastroesophageal reflux disease (GERD), offering evidence-based strategies to alleviate symptoms by addressing factors that promote reflux without relying on medications. These interventions target mechanical and physiological contributors to reflux, such as increased intra-abdominal pressure and transient lower esophageal sphincter (LES) relaxations, and are particularly beneficial for patients with mild to moderate symptoms, including an acidic sensation in the back of the mouth from regurgitation. Systematic reviews indicate that adherence to these changes can significantly reduce reflux frequency and severity, with weight loss and positional adjustments showing the strongest supportive data among non-pharmacologic approaches.^[113][114] For patients with obesity, a body mass index (BMI) greater than 25 kg/m², weight loss is strongly recommended as it directly correlates with improved GERD outcomes. Clinical studies demonstrate that achieving even modest weight reduction—such as 5-10% of body weight—leads to decreased esophageal acid exposure and symptom relief, with one cohort reporting a reduction in upright pH less than 4 from 8.0% to 5.5% (P < 0.05) after an average loss of 12.4 kg over 13 weeks. Obesity contributes to reduced LES pressure via elevated intra-abdominal pressure and hiatal hernia formation, and weight loss mitigates these effects by lowering overall pressure on the LES, thereby enhancing its competency and reducing reflux episodes, though direct manometric improvements in LES pressure are not consistently observed. Guidelines from gastroenterology societies endorse structured weight loss programs, including caloric restriction and exercise, as a first-line intervention for overweight individuals with GERD.^{[113][115][116][117]} Modifying meal patterns is another critical strategy to minimize reflux provocation. Consuming smaller, more frequent meals rather than large ones helps prevent excessive gastric distension, which can trigger LES relaxation and acid backflow. Remaining upright for at least 2–3 hours after eating aids digestion, leverages gravity to retain stomach contents, and reduces the risk of acid reflux symptoms. Additionally, avoiding meals within 3 hours of bedtime significantly reduces nocturnal symptoms, as evidenced by case-control studies showing an odds ratio of 7.45 (95% CI 3.38–16.4) for GERD in those with shorter dinner-to-bed intervals. This timing adjustment allows gastric emptying to progress before recumbency, decreasing the likelihood of acid pooling in the esophagus during sleep. Staying hydrated by drinking water throughout the day can also help dilute gastric acid and promote clearance of refluxate.^{[118][119][120][121]} Elevating the head of the bed by 6-8 inches provides substantial relief for nocturnal GERD by leveraging gravity to keep acid in the stomach. Randomized trials confirm this reduces total esophageal acid exposure time and reflux episode frequency, with one high-quality crossover study reporting symptom improvement in participants using elevation compared to flat positioning. This simple modification is more effective than medications alone for nighttime symptoms and is recommended for patients experiencing heartburn upon lying down.^[113][122] For acute relief of GERD-related symptoms such as chest tightness, immediate non-pharmacological measures include sitting upright or standing to utilize gravity and prevent reflux; practicing diaphragmatic breathing (e.g., inhaling for 4 seconds, holding for 2 seconds, exhaling for 6 seconds, repeated several times) to reduce esophageal pressure and belching; slowly sipping warm water or dilute salt water to dilute and clear acid; loosening tight clothing to alleviate intra-abdominal pressure; and chewing sugar-free gum to stimulate saliva production and enhance esophageal acid clearance. These techniques can provide relief within minutes and complement long-term strategies such as elevating the bed head by 15-20 cm, avoiding meals 3 hours before bedtime, and limiting intake of spicy, oily, or caffeinated foods.^[123][124] Management of concomitant constipation is recommended for patients in whom it contributes to GERD symptoms, as constipation increases intra-abdominal pressure and can exacerbate reflux. Lifestyle measures include increased dietary fiber intake, adequate hydration, regular physical activity, and, when necessary, bulk-forming laxatives such as psyllium. A randomized clinical trial in patients with functional constipation and GERD demonstrated that treatment with psyllium seed achieved similar initial symptom response rates to omeprazole (89.2% vs 94%) but resulted in significantly lower recurrence rates (24.1% vs 69.8%, P < 0.001).^[125] Dietary trigger avoidance focuses on limiting foods that impair LES function or increase acid production. A low-fat diet is advised, as high-fat intake decreases LES pressure and delays gastric emptying, exacerbating reflux in susceptible individuals. Carbonated beverages promote gastric distension and belching, which can precipitate transient LES relaxations, while common triggers such as fatty or fried foods, spicy foods, citrus, tomatoes, mint, garlic, onions, caffeine, chocolate, and alcohol irritate the esophageal mucosa or relax the LES and are linked to heightened symptom perception, including acidic sensations in the mouth.^[126] Systematic analyses associate these triggers with elevated GERD risk, and their restriction—such as opting for lean proteins, non-citrus fruits, and whole grains—can lead to notable symptom reduction, though individual responses vary. Soothing herbal teas such as ginger or chamomile may provide relief for some patients.^[127] Patients are encouraged to maintain a food diary to identify personal triggers while prioritizing balanced nutrition.^{[128][129][113]}

Pharmacologic therapy

Pharmacologic therapy for gastroesophageal reflux disease (GERD) primarily involves acid-suppressing and symptom-relieving agents, with proton-pump inhibitors (PPIs) serving as the cornerstone of treatment due to their superior efficacy in symptom control and mucosal healing. Selection of medications, doses, and durations should be determined by a healthcare provider, and self-treatment is not recommended.^[130] PPIs, such as omeprazole, pantoprazole, esomeprazole, and rabeprazole, irreversibly inhibit the H+/K+ ATPase proton pump in gastric parietal cells, thereby suppressing acid secretion by up to 99% when administered appropriately, and can provide short-term relief for symptoms like acidic mouth sensation when used over-the-counter.^[130] They are typically dosed once daily before breakfast for mild to moderate GERD, or twice daily (before breakfast and dinner) for severe cases or erosive esophagitis, with full-dose treatment for 4 to 8 weeks for initial healing followed by maintenance at half-dose for 6-12 months or longer for ongoing symptom control.^[130] In patients with erosive esophagitis, PPIs achieve endoscopic healing rates of 80-90% after 8 weeks of therapy, significantly outperforming other acid-suppressive agents.^[131] Potassium-competitive acid blockers (P-CABs), such as vonoprazan (VOQUEZNA), represent a newer class of acid-suppressing agents approved by the FDA in 2023 for healing and maintenance of erosive esophagitis and in 2024 for heartburn relief in non-erosive GERD. Unlike PPIs, P-CABs competitively block the potassium-binding site of the H+/K+ ATPase, providing faster onset and more potent acid suppression independent of meal timing, with clinical trials showing superior healing rates (e.g., up to 93% at 8 weeks for erosive esophagitis) and efficacy in PPI-refractory cases. They are dosed once daily, typically 20 mg, and may be considered for patients with inadequate response to PPIs, though long-term safety data are still emerging as of 2025.^[132][133] H2-receptor antagonists (H2RAs), such as famotidine or cimetidine, are reversible inhibitors of histamine H2 receptors on parietal cells, reducing acid production by approximately 50-70% and providing relief for mild GERD symptoms or nocturnal acid breakthrough when added to PPI therapy; examples include ranitidine as an alternative when PPIs are unsuitable.^[134] They are indicated for short-term use in uncomplicated GERD, with dosing typically 20 mg twice daily for famotidine, and are less effective than PPIs for healing erosive esophagitis, achieving rates of only 50-60% at 8 weeks.^[134] Common side effects include headache, dizziness, and gastrointestinal upset, though tolerance to their acid-suppressive effects can develop within 1-2 weeks.^[134] Antacids and alginate-based formulations offer rapid, on-demand symptomatic relief for intermittent GERD episodes by neutralizing existing gastric acid or forming a protective raft over stomach contents to prevent reflux, including for short-term relief of acidic feelings in the mouth; antacid examples include Maalox and Rennie for quick relief of heartburn or belching, while alginates such as Gaviscon create a protective barrier.^[135] Antacids, such as Tums (calcium carbonate), Maalox (aluminum hydroxide or magnesium hydroxide combinations), act within minutes but provide short-lived effects lasting 30-60 minutes, making them suitable for mild, occasional heartburn rather than maintenance therapy.^[135] Alginates, derived from seaweed, demonstrate superior efficacy over antacids alone, with odds ratios of 4.42 for symptom resolution in non-erosive GERD compared to placebo.^[135] Side effects are minimal, primarily limited to constipation or diarrhea depending on the formulation.^[135] Prokinetic agents, such as metoclopramide, domperidone, or itopride, enhance gastrointestinal motility and increase lower esophageal sphincter tone to reduce reflux episodes, particularly for symptoms like belching or fullness in GERD patients with delayed gastric emptying.^[136] Metoclopramide is dosed at 10 mg up to four times daily before meals, but its use is limited to short-term due to risks including tardive dyskinesia, extrapyramidal symptoms, and neuroleptic malignant syndrome, with black-box warnings for long-term administration.^[136] Efficacy in GERD is modest, often as an adjunct rather than monotherapy, and prokinetics are not first-line due to these safety concerns.^[136] Long-term PPI use, while effective for maintenance in chronic GERD, is associated with potential risks including increased fracture incidence due to impaired calcium absorption and elevated susceptibility to enteric infections such as Clostridium difficile.^[137] These concerns, supported by observational studies showing a 20-30% higher hip fracture risk with prolonged high-dose therapy, necessitate periodic reassessment and deprescribing when possible.^[137] Additionally, PPIs may alter the gut microbiome, potentially contributing to infection risks, though this effect requires further elucidation.^[130]

Surgical and endoscopic treatments

Surgical treatments for gastroesophageal reflux disease (GERD) are primarily indicated for patients with refractory symptoms unresponsive to medical management, often confirmed through physiological testing such as pH monitoring. The Nissen fundoplication remains the gold standard surgical procedure, involving the creation of a 360-degree wrap of the gastric fundus around the distal esophagus to reinforce the lower esophageal sphincter and prevent reflux.^[138] This operation is most commonly performed via a laparoscopic approach, often including repair of concomitant hiatal hernias if present, which minimizes invasiveness, reduces postoperative pain, and shortens hospital stays compared to open surgery.^[139][140] Variations include complete (Nissen) wraps for optimal reflux control and partial wraps, such as the Toupet (270-degree posterior), which may lower the incidence of swallowing difficulties while providing comparable long-term symptom relief.^[141] Another surgical option is magnetic sphincter augmentation using the LINX device, a ring of titanium beads with magnetic cores implanted laparoscopically around the lower esophageal sphincter. This mechanism permits bolus passage during swallowing by separating the beads under pressure while closing to resist gastric reflux in the resting state. Long-term studies demonstrate sustained efficacy, with over 85% of patients achieving symptom improvement and independence from proton pump inhibitors at 5-year follow-up.^[142] Endoscopic therapies offer less invasive alternatives for select patients with mild-to-moderate GERD. The Stretta procedure delivers radiofrequency energy endoscopically to the lower esophageal sphincter and gastric cardia, inducing collagen contraction to strengthen the antireflux barrier and reduce transient relaxations. Clinical data indicate durable symptom reduction and decreased esophageal acid exposure, with benefits persisting up to 10 years in responsive patients.^[143] Transoral incisionless fundoplication (TIF) uses a specialized device to create a partial fundoplication by fastening the gastric fundus to the esophagus without abdominal incisions, effectively restoring the gastroesophageal junction flap valve. This approach improves quality of life and proton pump inhibitor use in patients with small hiatal hernias, showing significant reflux control at 5- to 6-year follow-up.^[144] Postoperative complications from these interventions include transient dysphagia, which affects up to 40% of patients early after fundoplication but often resolves within months, and gas bloat syndrome due to impaired belching. Recurrence of GERD symptoms occurs in 10-20% of cases, sometimes necessitating revision surgery.^[145][146]

Management in special populations

In pregnant individuals, gastroesophageal reflux disease (GERD) is typically mild and transient, with symptoms usually resolving after delivery. However, in rare severe cases—such as persistent reflux esophagitis or hyperemesis gravidarum with recurrent vomiting—chronic acid exposure can lead to esophagitis, scarring, and esophageal stricture formation, which may become symptomatic postpartum.^[147][45] This rare potential long-term complication informs the need for prompt and effective management in severe presentations to mitigate chronic esophageal injury. Management prioritizes non-pharmacologic interventions due to potential fetal risks, with antacids such as aluminum or magnesium hydroxide serving as first-line therapy for mild symptoms because of their established safety profile.^[148] Proton pump inhibitors (PPIs), which studies have shown to be safe during pregnancy with no significant increase in congenital malformations or other adverse outcomes across all trimesters, including omeprazole as a preferred option, are considered when symptoms persist.^[149] Emphasis is placed on positional therapy, such as elevating the head of the bed and avoiding supine positioning after meals, to reduce reflux episodes without medication.^[150] For infants and children, conservative measures form the cornerstone of GERD management to minimize intervention risks. Thickened feeds, achieved by adding rice cereal to formula or using antiregurgitant formulas, can reduce regurgitation frequency, though evidence indicates only moderate efficacy in healthy infants.^[151] Upright positioning for 20 to 30 minutes post-feeding, combined with frequent burping during meals, helps gravity aid esophageal clearance and is recommended as a low-risk strategy.^[152] Surgical options like fundoplication are reserved for severe, refractory cases with complications such as failure to thrive or respiratory issues, as most pediatric GERD resolves spontaneously by age 12 to 18 months.^[153] In elderly patients, GERD treatment requires cautious dosing of PPIs due to age-related physiological changes, with no routine adjustment needed for mild to moderate renal impairment but close monitoring recommended for those with severe kidney disease to avoid accumulation and potential toxicity.^[154] Long-term PPI use warrants vigilance for neuropsychiatric effects, including an elevated risk of delirium in hospitalized geriatric populations, prompting periodic reassessment and consideration of deprescribing when symptoms are controlled.^[155] Post-bariatric surgery patients face a heightened risk of de novo or worsened GERD, particularly after sleeve gastrectomy, necessitating early endoscopic evaluation for any new-onset symptoms to identify anatomical complications like hiatal hernia or esophagitis.^[156] Upper gastrointestinal endoscopy is the preferred initial diagnostic tool, as it allows direct visualization and biopsy to guide tailored interventions, such as conversion to Roux-en-Y gastric bypass for refractory cases.^[157]

Epidemiology

Global prevalence

Gastroesophageal reflux disease (GERD) affects approximately 14% of the global adult population, equating to over 890 million individuals based on recent estimates.^[158] This prevalence is derived primarily from symptom-based assessments, such as weekly heartburn or regurgitation, which serve as reliable proxies for the condition in large-scale epidemiological studies. Regional variations are notable, with rates ranging from 18-20% in Western countries like North America and parts of Europe to 5-10% in Asian populations, reflecting differences in diagnostic criteria, lifestyle factors, and healthcare reporting.^[158] In 2021, the global burden included about 826 million prevalent cases, underscoring GERD's status as a major public health concern.^[159] Incidence and prevalence trends indicate a steady global rise, with prevalent cases increasing by approximately 83% from 451 million in 1990 to 826 million in 2021, driven largely by the obesity epidemic that heightens intra-abdominal pressure and impairs esophageal clearance.^[159] This escalation corresponds to an approximate 1-2% annual increase in affected populations in many regions, though age-standardized rates have remained relatively stable when adjusted for population growth.^[159] Obesity, as a key modifiable risk factor, contributes significantly to this upward trajectory, with higher body mass indices correlating strongly with GERD onset.^[160] Underreporting remains a challenge in low-resource settings, where limited access to diagnostic tools like endoscopy and primary care exacerbates the gap between true burden and documented cases.^[161] In such areas, particularly in parts of Africa and South Asia, socioeconomic barriers and low health-seeking behavior lead to underdiagnosis, potentially masking the full scale of GERD's impact.^[161] The COVID-19 pandemic has introduced additional complexities, with post-2020 data showing potential increases in GERD prevalence linked to viral effects on gastrointestinal motility and lockdown-related lifestyle changes. COVID-19 survivors exhibit a 35% higher risk of developing GERD (HR 1.35), with the risk increasing stepwise with disease severity, possibly due to inflammation, dysbiosis, or ventilator use in critical cases that can promote reflux through impaired lower esophageal sphincter function.^[162] These trends highlight the need for enhanced surveillance in vulnerable populations.^[163] Projections from the Global Burden of Disease study suggest that GERD cases may exceed 1 billion globally by 2050, driven by population aging, growth, and rising obesity rates.^[164]

Demographic patterns

Gastroesophageal reflux disease (GERD) exhibits similar overall prevalence between men and women, though some population-based studies report slightly higher rates in women.^[165] In particular, the prevalence increases significantly in women after menopause, attributed to hormonal changes such as reduced estrogen levels that may impair esophageal motility and lower esophageal sphincter function.^[166] Conversely, men face a greater risk of severe complications from GERD, including erosive esophagitis and Barrett's esophagus, which are more frequently diagnosed in male patients.^[167] Age-related patterns show that GERD prevalence typically peaks between 40 and 60 years, reflecting cumulative exposure to risk factors over time.^[168] However, recent trends indicate a rising incidence among younger adults, particularly those aged 30-39, linked to modern lifestyle factors such as increased obesity and dietary changes.^[169] Ethnic differences in GERD prevalence are evident, with higher rates observed among Caucasians compared to African and Asian populations.^[170] For instance, Caucasians demonstrate elevated risks for symptomatic GERD and related complications, while Asians and African Americans tend to report lower frequencies of heartburn and reflux symptoms.^[171] Socioeconomic status also influences GERD distribution, as lower income and education levels correlate with higher prevalence, often due to limited access to healthcare and diets high in processed foods.^[172] Certain special populations experience disproportionately high GERD rates, including those with obesity, where prevalence can reach up to 70% in severely obese individuals.^[173] Similarly, diabetic patients show elevated GERD risk, with studies reporting rates around 45% in this group, potentially exacerbated by autonomic neuropathy affecting gastrointestinal motility.^[174]

History

Early observations

The earliest known descriptions of symptoms akin to gastroesophageal reflux disease (GERD) appear in ancient medical texts. Hippocrates (c. 460–370 BCE), often regarded as the father of Western medicine, documented a condition termed cardialgia in his Aphorisms and Epidemics, portraying it as a painful burning sensation rising from the stomach to the chest, accompanied by heat, nausea, and bitter eructations—features consistent with modern heartburn. This observation reflected the humoral theory prevalent in ancient Greece, where such discomfort was attributed to an excess of acidic or hot humors irritating the upper digestive tract, though without recognition of reflux as a mechanical process.^[175] By the 17th and 18th centuries, European physicians began linking gastric acid more explicitly to esophageal irritation, moving beyond purely humoral explanations. This insight gained traction in the 19th century, when pathologist Carl von Rokitansky (1804–1878) firmly established the connection between peptic acid exposure and esophagitis through systematic autopsy studies, describing chronic inflammation as a direct result of regurgitated gastric juices.^[176] Concurrently, William Heberden (1710–1801) highlighted the mimicry of GERD symptoms in his 1772 description of angina pectoris, observing that postprandial chest pain and tightness could resemble cardiac distress.^[177] Pre-20th century surgical efforts to address presumed esophageal disorders were rudimentary and frequently confounded GERD with related conditions like achalasia, leading to misguided interventions. Attempts at dilation or incision of the esophageal sphincter in the late 19th century, inspired by observations of motility issues, aimed to relieve dysphagia and regurgitation but often failed due to incomplete understanding of reflux mechanics; these procedures prefigured later techniques like the Heller myotomy (1913), underscoring the diagnostic overlap.^[178] Throughout this era, misconceptions persisted, with symptoms frequently dismissed as manifestations of hysteria—especially among women—or as mere consequences of intemperate diet and lifestyle, delaying recognition of GERD as a distinct pathophysiological entity.^[179]

Development of treatments

The development of treatments for gastroesophageal reflux disease (GERD) began in the early 20th century with symptomatic relief strategies focused on neutralizing gastric acid. Antacids, such as preparations containing magnesium and aluminum hydroxides, emerged as initial therapies around the 1910s to 1950s, providing temporary neutralization of stomach acid to alleviate heartburn and regurgitation associated with reflux esophagitis.^[180] These agents offered modest efficacy but required frequent dosing and were limited by short duration of action, serving primarily as first-line options before more targeted interventions.^[181] Surgical approaches gained prominence in the mid-20th century, with the introduction of the Nissen fundoplication in 1956 marking a key milestone. Developed by Rudolph Nissen, this procedure involved wrapping the fundus of the stomach around the lower esophagus to reinforce the lower esophageal sphincter and prevent reflux, initially performed via open surgery for patients with severe, refractory symptoms.^[182] By the 1970s, pharmacological advancements shifted focus to histamine-2 (H2) receptor antagonists, exemplified by cimetidine, which was synthesized in the early 1970s and approved for clinical use in 1976.^[183] These drugs inhibited acid secretion more effectively than antacids by blocking histamine-mediated parietal cell activity, significantly reducing ulcer recurrence and reflux symptoms, and establishing a new standard for acid-related disorders including GERD.^[184] The 1980s brought a revolutionary leap with the discovery and introduction of proton pump inhibitors (PPIs), starting with omeprazole, which was identified in 1979 and first approved for medical use in 1988.^[185] Omeprazole irreversibly inhibited the H+/K+-ATPase proton pump in parietal cells, achieving profound and sustained acid suppression that surpassed H2 blockers in healing esophagitis and controlling GERD symptoms, thus transforming medical management into a more reliable, once-daily regimen.^[186] Surgical techniques evolved further in the 1990s with the adoption of laparoscopic Nissen fundoplication, first reported in 1991, which minimized invasiveness, reduced recovery time, and expanded access to antireflux surgery for medically refractory GERD patients.^[187] Standardization of GERD treatment accelerated in the 21st century through international consensus guidelines. The 2006 Montreal Consensus defined GERD as a condition arising when reflux of stomach contents causes troublesome symptoms and/or complications, providing a unified framework for diagnosis and management that emphasized symptom-based and objective criteria to guide therapy selection.^[188] This was refined by the Lyon Consensus in 2018, with the 2023 update (Lyon 2.0) enhancing diagnostic precision by establishing thresholds for esophageal testing—such as acid exposure time and impedance metrics—and classifying Los Angeles grade B esophagitis as conclusive evidence of GERD, thereby improving treatment personalization and outcomes.^[189] In 2024, the U.S. Food and Drug Administration approved vonoprazan, a potassium-competitive acid blocker, for the relief of heartburn in non-erosive gastroesophageal reflux disease.^[190] In 2025, the American Society for Gastrointestinal Endoscopy (ASGE) published guidelines on the diagnosis and management of GERD, emphasizing endoscopic evaluation for patients with alarm symptoms and personalized therapy approaches.^[191]

Research

Current investigations

Recent clinical studies have investigated the impact of COVID-19 on gastroesophageal reflux disease (GERD), revealing an increased prevalence linked to factors such as infection-related esophageal inflammation, psychological stress, and procedural interventions like intubation in severe cases. A 2025 prospective cohort study reported significant elevations in heartburn and acid reflux symptoms among post-COVID-19 patients, with Gastrointestinal Symptom Rating Scale (GSRS) scores indicating a higher incidence compared to pre-infection baselines, attributed to viral effects on esophageal motility and barrier function.^[192] Similarly, a 2024 analysis of over 9,800 participants in Indonesia demonstrated that the COVID-19 pandemic correlated with a GERD prevalence rise from 61.8% pre-pandemic to 67.9%, with odds ratio of 1.31 (95% CI: 1.17-1.46), primarily due to heightened stress and disrupted dietary habits during lockdowns.^[193] Advancements in endoscopic imaging techniques are enhancing GERD diagnostics, with high-definition endoscopy combined with artificial intelligence (AI) enabling more precise lesion detection and severity assessment. High-definition white-light endoscopy, often integrated with narrow-band imaging, improves visualization of mucosal breaks and erosions, achieving diagnostic sensitivities of 80-90% for Los Angeles grade A/B esophagitis when paired with AI algorithms.^[194] AI-assisted systems, such as convolutional neural networks trained on endoscopic datasets, classify GERD severity using the Los Angeles grading system with accuracies ranging from 87.9% to 95.7%, outperforming junior endoscopists (71.5-77.4% accuracy) by segmenting lesions in real-time via models like Attention U-Net (intersection over union: 0.9007).^[194] A 2024 study validated an uncertainty-aware deep learning network for fine-grained GERD grading, reporting 90.2% accuracy on high-resolution images, which aids in early detection of subtle reflux-related changes and reduces interobserver variability.^[195] These tools are particularly effective in identifying non-erosive reflux disease features, though challenges remain in datasets underrepresented for severe grades (C/D).^[196] Ongoing genetic and biomarker research is advancing personalized risk stratification for GERD, identifying variants and serum markers that predict susceptibility and progression. A 2025 genome-wide association study (GWAS) pinpointed serum metabolites, such as branched-chain amino acids and bile acids, as biomarkers associated with GERD risk, enabling stratification models with potential to guide preventive interventions in high-risk individuals.^[197] Mendelian randomization analyses from 2025 have established causal genetic links between GERD predisposition and conditions like pancreatic cancer (odds ratio: 1.15 per SD increase in GERD polygenic score) and age-related frailty (shared heritability: 0.12-0.25), supporting polygenic risk scores for tailored screening.^[198][199] Additionally, pharmacogenomic studies in 2025 highlight CYP2C19 and SLCO1B1 gene variants influencing proton pump inhibitor response, with variant carriers showing 20-30% reduced efficacy, paving the way for biomarker-driven dosing adjustments.^[200] Randomized controlled trials and meta-analyses are evaluating long-term outcomes of endoscopic therapies for GERD, focusing on durability beyond five years. A 2024 meta-analysis of anti-reflux mucosal interventions, including radiofrequency ablation and plication techniques, reported sustained symptom relief in 70-85% of patients at 5-10 years, with GERD-HRQL score reductions of ≥50% and low complication rates (adverse events: 5-10%). For Stretta radiofrequency therapy, a 2024 long-term follow-up of a randomized trial showed 72% of patients achieving normalized health-related quality of life (HRQOL) at 10 years, alongside 64% reducing proton pump inhibitor use by ≥50% and 41% discontinuing it entirely, with no serious adverse events.^[143] A 2024 meta-analysis on endoscopic cardia submucosal full-thickness plication confirmed efficacy in refractory GERD, with DeMeester scores improving by 15-20 points at 3-5 years and esophagitis healing in 80% of cases, though relapse occurred in 15-20% after 5 years.^[201] The 2024 American Society for Gastrointestinal Endoscopy guideline synthesizes these trials, recommending endoscopic options for select patients based on 5-year remission rates of 60-80% for symptom control.^[191]

Emerging therapies

Emerging research into microbiome-targeted therapies for gastroesophageal reflux disease (GERD) focuses on modulating the gut-esophageal axis to alleviate symptoms in refractory cases. Probiotics, particularly Lactobacillus strains, have shown promise in preclinical models by facilitating DNA repair and reducing inflammation induced by bile acids, key contributors to GERD-related esophageal damage. A 2023 study demonstrated that Lactobacillus species exhibit anti-genotoxic and anti-inflammatory effects in experimental GERD models, suggesting potential for preventing complications like Barrett's esophagus.^[83] Fecal microbiota transplantation (FMT) represents another investigational approach, aiming to restore microbial balance and reduce proton pump inhibitor dependency in patients with refractory GERD. A randomized, double-blind, placebo-controlled trial involving washed microbiota transplantation delivered via gastroscopy reported significant symptom improvement and decreased medication reliance after 24 weeks, with sustained benefits observed at one-year follow-up.^[202] Ongoing clinical evaluations, including phase II-like protocols, explore FMT's role in addressing dysbiosis-linked GERD pathophysiology, though larger trials are needed to confirm long-term efficacy and safety. Advancements in endoscopic devices target both GERD complications and anti-reflux mechanisms. Endoscopic mucosal resection (EMR) techniques have evolved for managing Barrett's esophagus, a GERD sequela, with improved precision in removing dysplastic tissue while preserving esophageal function. The 2024 American Gastroenterological Association guideline endorses EMR combined with ablation for nodular dysplasia, highlighting higher complete eradication rates (up to 90%) compared to earlier methods, based on meta-analyses of over 2,000 patients.^[203] Next-generation iterations of the LINX Reflux Management System, a magnetic sphincter augmentation device, incorporate enhanced biocompatibility and MRI compatibility up to 1.5 Tesla, expanding applicability for GERD patients requiring imaging follow-up. These updates build on the original device's laparoscopic implantation around the lower esophageal sphincter to mimic natural barrier function, with five-year data showing 99% elimination of regurgitation in treated cohorts.^[204] Potassium-competitive acid blockers (P-CABs), such as vonoprazan, offer faster acid suppression onset—achieving peak inhibition within hours versus days for traditional therapies—addressing limitations in non-erosive GERD management. The U.S. Food and Drug Administration approved vonoprazan tablets in July 2024 for heartburn relief in non-erosive GERD adults, following phase III trials demonstrating superior symptom control over placebo at 20 mg daily dosing.^[205] This approval extends prior 2023 endorsement for erosive esophagitis healing, positioning P-CABs as a bridge for refractory cases. Preclinical investigations into neuromodulation target lower esophageal sphincter dysfunction directly. A 2023 study developed a battery-free, deformable electronic stent for wireless LES stimulation in porcine models, resulting in increased sphincter pressure and reduced reflux episodes without mucosal injury.^[206] Anti-reflux peptides, such as bombesin, are also in early stages, with rat models of GERD showing reduced epigastric pain and restored antioxidant markers after administration, indicating potential modulation of inflammation and motility.^[207] Gene therapy approaches aim to enhance lower esophageal sphincter integrity by addressing genetic vulnerabilities in GERD. Preclinical efforts, including NIH-funded models, overexpress ion transporters like Na+,K+-ATPase in esophageal cells to repair acid-induced barrier defects, demonstrating restored epithelial resistance in vitro and rodent GERD simulations.^[208] Emerging trends also explore gene editing for LES muscle reinforcement, though human translation remains distant.^[209]