Clinical manifestations and diagnosis of gastroesophageal reflux in adults

INTRODUCTION — 

Gastroesophageal reflux disease (GERD) is notable for its high prevalence, variety of clinical presentations, underrecognized morbidity, and substantial economic consequences.

This topic will review the clinical manifestations and diagnosis of GERD. The pathophysiology and management of GERD are discussed in detail separately. (See "Pathophysiology of gastroesophageal reflux disease" and "Initial management of gastroesophageal reflux disease in adults" and "Surgical treatment of gastroesophageal reflux in adults".)

TERMINOLOGY — 

We classify gastroesophageal reflux disease (GERD) based either on the appearance of the esophageal mucosa on upper endoscopy or the correlation between pH-metry results and patient-reported symptoms. Varied definitions exist for GERD and include those based on symptoms, endoscopy findings, physiologic testing with pH-metry, or even response to antisecretory therapy [1-3].

●Erosive esophagitis – Erosive esophagitis is the unequivocal finding of GERD. It is characterized by endoscopically visible breaks in the distal esophageal mucosa with or without symptoms of GERD. (See 'Endoscopic findings' below.)

●True nonerosive reflux disease (NERD) – True NERD is defined by quantifiably excessive esophageal acid exposure based on testing with pH-metry in the absence of erosive esophagitis.

●Reflux hypersensitivity or functional heartburn – Reflux hypersensitivity or functional heartburn occurs when the patient experiences typical reflux symptoms with normal results on upper endoscopy and esophageal acid exposure within the normal range on pH-metry [4]. These conditions are disorders of gut-brain interaction dysregulation that are often accompanied by hypervigilance and anxiety [5,6].

According to Rome IV criteria, reflux hypersensitivity is defined by patient-reported symptoms that correlate with reflux events during reflux monitoring. By contrast, functional heartburn is defined by a lack of correlation between patient symptoms and reflux events [4]. The management of these two entities is the same.

As measured by esophageal pH-metry, some degree of reflux is physiologic. However, individuals vary widely in their sensitivity to acid reflux, and reflux-like symptoms do not consistently correlate with abnormalities on endoscopy or pH-metry. This makes it impossible to establish a dichotomous cutoff between normal and abnormal and has led to qualifiers to the definition of GERD, including "true nonerosive reflux disease (NERD)," "proven GERD," and "actionable GERD."

EPIDEMIOLOGY — 

The prevalence of gastroesophageal reflux disease (GERD) varies by geographic region and depends on the criteria used to define it. In a systematic review of 31 epidemiologic studies, the prevalence of GERD ranged from 15 to 30 percent in Western countries and 5 to 10 percent in Asia [7]. The incidence in the Western world was approximately five per 1000 person-years or 0.5 percent per year.

Epidemiologic estimates are usually based on questionnaire data that equate self-reported heartburn and/or regurgitation with GERD. These data likely overestimate the prevalence of GERD compared with estimates based on endoscopic findings or abnormal esophageal acid exposure on pH-metry.

CLINICAL FEATURES

Clinical manifestations — Classic symptoms of gastroesophageal reflux disease (GERD) are heartburn (pyrosis) and regurgitation.

●Heartburn is typically described as a burning sensation in the retrosternal area that is usually postprandial. Heartburn that can potentially impair quality of life includes frequent (≥2 days/week), mild episodes or less frequent (<2 days/week) episodes that are moderate to severe.

●Regurgitation is defined as the perception of flow of refluxed gastric content into the mouth or hypopharynx. Patients typically regurgitate acidic material mixed with small amounts of undigested food.

Other symptoms of GERD include dysphagia, chest pain, water brash, globus sensation, odynophagia, extraesophageal symptoms (eg, chronic cough, hoarseness, wheezing), and, infrequently, nausea.

●Dysphagia is common in the setting of longstanding heartburn and is often attributable to reflux esophagitis but can be indicative of an esophageal stricture [8]. Odynophagia is an unusual symptom of GERD but, when present, usually indicates an esophageal ulcer. (See "Approach to the evaluation of dysphagia in adults".)

●GERD-related chest pain can mimic angina pectoris. It is typically described as substernal, squeezing, or burning pain that radiates to the back, neck, jaw, or arms. The pain usually occurs after meals and can awaken patients from sleep. It can last minutes to hours, be exacerbated by emotional stress, and resolve spontaneously or with antacids. Although individuals with reflux-induced chest pain may also have typical reflux symptoms, the presence of heartburn in such patients does not accurately predict objective evidence of GERD (ie, abnormal esophageal pH monitoring) [9].

●Water brash or hypersalivation is a relatively unusual symptom in which patients can foam at the mouth, secreting as much as 10 mL of saliva per minute in response to reflux.

●Globus sensation is the almost constant perception of a lump in the throat (irrespective of swallowing). Although some authors suggest a relationship between globus sensation and GERD, this is unproven. (See "Globus sensation".)

●Nausea is infrequently reported with GERD, but a diagnosis of GERD should be considered in patients with otherwise unexplained nausea. (See "Approach to the adult with nausea and vomiting".)

Radiographic findings — Double-contrast barium swallow examination has limited utility in the diagnosis of GERD. It is less sensitive than upper endoscopy and has variable reproducibility [10,11]. It is also less specific, with a significant proportion of asymptomatic individuals experiencing barium reflux during testing.

Radiography is more sensitive than endoscopy in the detection of subtle strictures (image 1) and in characterizing the morphology of hiatal hernias [12]. Although it is less sensitive than endoscopy, double-contrast barium radiography can reveal mucosal changes associated with esophagitis, such as a granular appearance or shallow collections of barium indicative of erosions.

Complications — Complications from GERD can arise even in patients who lack typical esophageal symptoms. These complications may be esophageal (eg, Barrett's esophagus, esophageal stricture, esophageal adenocarcinoma) or extraesophageal (eg, chronic laryngitis, exacerbation of asthma). (See "Complications of gastroesophageal reflux in adults".)

DIAGNOSIS

Patients with classic symptoms — In individuals with typical symptoms of heartburn and/or regurgitation, the diagnosis of gastroesophageal reflux disease (GERD) is often based on clinical symptoms alone [13]. However, patients may require additional evaluation if they have alarm features, risk factors for Barrett's esophagus, poor response to treatment, or abnormal gastrointestinal imaging studies [14]. (See 'Evaluation in selected patients' below.)

A response to antisecretory therapy is not a diagnostic criterion for GERD. Although 40 to 90 percent of patients with symptoms suggestive of GERD have a good symptomatic response to proton pump inhibitors (PPIs), a response to PPIs correlates poorly with objective measures of GERD. In a diagnostic meta-analysis, the symptomatic response to PPI therapy had a pooled sensitivity and specificity of 78 and 54 percent, respectively, compared with the reference standard of 24-hour pH monitoring [15].

Patients without classic symptoms — Other symptoms (eg, chest pain, globus sensation, chronic cough, hoarseness, wheezing, and nausea) may be seen in the setting of GERD but are not sufficient to make a clinical diagnosis of GERD in the absence of classic symptoms of heartburn and regurgitation. Alternative disorders need to be excluded before attributing such symptoms to GERD. As an example, individuals with unexplained chest pain should undergo risk stratification and assessment for cardiac causes of chest pain prior to a gastrointestinal evaluation.

EVALUATION IN SELECTED PATIENTS — 

Additional evaluation is required in selected patients with suspected gastroesophageal reflux disease (GERD) to rule out alternative etiologies, confirm the diagnosis of GERD, and assess for complications (eg, Barrett's esophagus). (See "Complications of gastroesophageal reflux in adults".)

Upper gastrointestinal endoscopy

Indications — Upper endoscopy is indicated in patients with suspected GERD to evaluate alarm features or abnormal imaging if not performed within the last three months. Upper endoscopy should also be performed to screen for Barrett's esophagus in patients with risk factors. On upper endoscopy, biopsies should target any areas of suspected metaplasia or dysplasia and, in the evaluation of dysphagia, test for eosinophilic esophagitis.

Patients should discontinue proton pump inhibitors (PPIs) or potassium-competitive acid blockers at least two to four weeks prior to endoscopy. Acid suppression medications can mask findings of erosive and eosinophilic esophagitis and potentially result in missed diagnoses [1,10]. (See 'Alarm features' below and 'Risk factors for Barrett's esophagus' below and 'Abnormal upper gastrointestinal tract imaging' below.)

Upper endoscopy is not required to make a diagnosis of GERD. However, upper endoscopy can rule out an upper gastrointestinal malignancy and detect esophageal manifestations of GERD, such as Barrett's metaplasia, erosive esophagitis, stricture, or hiatus hernia. Upper endoscopy can also rule out other etiologies in patients with GERD symptoms that are refractory to a trial of PPI therapy. (See "Approach to refractory gastroesophageal reflux disease in adults", section on 'Diagnostic strategies and initial management' and "Initial management of gastroesophageal reflux disease in adults", section on 'Pretreatment evaluation'.)

Alarm features — Alarm features that are suggestive of a gastrointestinal malignancy include:

●New onset of dyspepsia in patient ≥60 years

●Evidence of gastrointestinal bleeding (hematemesis, melena, hematochezia, occult blood in stool)

●Iron deficiency anemia

●Anorexia

●Unexplained weight loss

●Dysphagia

●Odynophagia

●Persistent vomiting

●Gastrointestinal cancer in a first-degree relative

Risk factors for Barrett's esophagus — Screening for Barrett's esophagus is typically recommended for patients with multiple risk factors (one of which must be duration of GERD of at least 5 to 10 years).

Risk factors for Barrett's esophagus include:

●Duration of GERD of at least 5 to 10 years

●Age 50 years or older

●Male sex

●White individuals

●Hiatal hernia

●Obesity

●Nocturnal reflux

●Tobacco use (past or current)

●First-degree relative with Barrett's esophagus and/or adenocarcinoma

Multiple societies have issued guidelines regarding screening patients for Barrett's esophagus with varying recommendations. These are discussed in detail separately. (See "Barrett's esophagus: Epidemiology, clinical manifestations, and diagnosis", section on 'Screening patients for Barrett's esophagus'.)

Abnormal upper gastrointestinal tract imaging — Abdominal imaging is not required to establish the diagnosis of GERD but may have been performed for evaluation of concurrent symptoms. In such cases, luminal imaging abnormalities in the upper gastrointestinal tract may warrant diagnostic evaluation with upper endoscopy.

Endoscopic findings — Upper endoscopy may be normal in patients with GERD or may reveal evidence of esophagitis of varying severity. Among individuals with untreated reflux-like symptoms, approximately 34 percent of those older than 65 years and 18 percent of those younger than 65 years of age will have significant endoscopic esophagitis (Los Angeles grade B, C, or D) [16]. The severity and duration of symptoms correlate poorly with the presence or severity of esophagitis.

In contrast to infectious and medication-induced esophagitis, which tend to be in the mid-esophagus, the ulcerations seen in peptic esophagitis are usually irregularly shaped or linear, multiple, and located in the very distal esophagus. (See "Pill esophagitis", section on 'Upper endoscopy and biopsy in selected patients' and "Approach to the evaluation of dysphagia in adults", section on 'Infectious esophagitis'.)

Other endoscopic findings in patients with longstanding GERD include peptic strictures, Barrett's metaplasia, and esophageal adenocarcinoma. (See "Complications of gastroesophageal reflux in adults".)

●Grading the severity of esophagitis – Erosive esophagitis is graded according to its severity to guide management. Several endoscopic grading schemes have been devised to decrease interoperator variability of endoscopy in assessing the severity of peptic esophagitis. Of these, the Los Angeles classification is the most thoroughly evaluated classification for esophagitis and is the most widely used [17]. (See "Initial management of gastroesophageal reflux disease in adults", section on 'Manage recurrent symptoms'.)

•Los Angeles classification – The Los Angeles classification grades esophagitis severity by the extent of mucosal abnormality, with complications recorded separately. In this grading scheme, a mucosal break refers to an area of slough adjacent to more normal mucosa in the squamous epithelium with or without overlying exudate. Los Angeles A esophagitis is not considered diagnostic of GERD as this is found in 5 percent of asymptomatic individuals [1].

-Grade A – One or more mucosal breaks each ≤5 mm in length (picture 1)

-Grade B – At least one mucosal break >5 mm long, but not continuous between the tops of adjacent mucosal folds (picture 2)

-Grade C – At least one mucosal break that is continuous between the tops of adjacent mucosal folds, but which is not circumferential (picture 3)

-Grade D – Mucosal break that involves at least three-fourths of the luminal circumference (picture 4)

Histology — Histologic changes suggestive of GERD frequently occur in those with reflux-like symptoms and no visible endoscopic findings. However, histologic findings are not specific to GERD; they can also be seen in those with eosinophilic esophagitis. In a large, European, multicenter trial (the histoGERD trial) involving 1071 patients, the presence of histologic esophagitis was associated with male sex, reflux symptoms, a history of PPI use, and concomitant endoscopic esophagitis. Notably, among the 450 patients with no endoscopic signs of esophagitis, 42 and 17 percent had mild and severe histologic esophagitis, respectively [18].

The most consistently observed histologic finding of GERD is the dilatation of the intercellular spaces seen on transmission electron microscopy. Other histologic features include the presence of neutrophils, mononuclear cells, and eosinophils; dilated vascular channels in papillae of the lamina propria; thickening of the basal cell layer with pale, distended squamous ("balloon") cells; and elongation of the papillae of the epithelium (picture 5).

Histologic studies suggest that reflux initiates cytokine-triggered inflammation rather than causing a direct chemical (acid, pepsin, and bile) burn of the esophageal epithelium. In a unique experiment, investigators evaluated patients with high-grade esophagitis whose esophageal erosions had been successfully treated by PPI therapy. PPI therapy was then withdrawn to observe the histopathologic sequence of events leading to acute (recurrent) peptic esophagitis [19]. Lymphocytic inflammation and dilated intercellular spaces first occurred deep in the epithelium, not at the luminal surface, and regenerative changes (basal cell hyperplasia, papillary elongation) were initiated prior to the development of surface necrosis. (See "Pathophysiology of gastroesophageal reflux disease", section on 'Mechanisms of gastroesophageal reflux disease'.)

Esophageal manometry — In patients with suspected GERD with chest pain and/or dysphagia and a normal upper endoscopy, we perform esophageal manometry to exclude an esophageal motility disorder [11]. Manometry cannot diagnose GERD. However, it can ensure the correct placement of ambulatory pH probes and evaluate peristaltic function before antireflux surgery [1]. (See "Surgical treatment of gastroesophageal reflux in adults" and "Approach to refractory gastroesophageal reflux disease in adults", section on 'Residual acid reflux' and "Approach to refractory gastroesophageal reflux disease in adults".)

Ambulatory esophageal pH monitoring — In patients with persistent symptoms, we use ambulatory pH or pH-impedance monitoring to assess the adequacy of treatment and confirm the diagnosis of GERD, particularly if a trial of twice-daily PPI has failed [1,14]. The approach to the management of patients with refractory GERD is discussed separately. (See "Approach to refractory gastroesophageal reflux disease in adults", section on 'Esophageal impedance pH testing'.)

Methods for ambulatory pH monitoring include transnasal and wireless pH monitoring and esophageal pH monitoring with impedance. Each approach couples a pH sensor with compact, portable data recorders and computerized data analysis.

●Transnasal pH monitoring – Transnasal pH monitoring involves the placement of a catheter-type pH electrode 5 cm above the manometrically defined upper limit of the lower esophageal sphincter. The patient wears the monitor for 24 hours and is advised to consume an unrestricted diet.

●Wireless pH monitoring – Wireless pH monitoring involves affixing a capsule-shaped device to the distal esophageal mucosa [20,21]. The pH capsule is attached 6 cm proximal to the endoscopically defined squamocolumnar junction. Monitoring occurs for two to four days. The longer monitoring period may increase the study's sensitivity for detecting reflux episodes, facilitate the correlation of symptoms with reflux events, and allow for varying dietary and/or therapeutic circumstances and evaluating their impact on reflux [21,22]. (See "Esophageal multichannel intraluminal impedance testing".)

●Esophageal pH monitoring with impedance – Esophageal pH monitoring with impedance detects weakly acidic reflux, not simply acid reflux. It can consequently ascertain the correlation between symptoms and reflux events in patients who are on acid-suppressive therapy.

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of gastroesophageal reflux disease (GERD) includes infectious esophagitis, pill esophagitis, and eosinophilic esophagitis. Other causes of dysphagia include esophageal rings/webs, and impaired peristalsis due to an esophageal motility disorder. Slowly progressive dysphagia for solids with episodic esophageal obstruction is suggestive of a stricture or an esophageal cancer. Odynophagia may be due to infectious or medication-induced esophagitis. GERD can be distinguished from these conditions by esophageal manometry and upper endoscopy with biopsies of the esophagus. The differential diagnosis and evaluation of patients with dysphagia is discussed in detail separately. (See "Approach to the evaluation of dysphagia in adults", section on 'Symptom-based differential diagnosis'.)

Frequent heartburn may also be due to reflux hypersensitivity or functional heartburn. GERD can be distinguished from these conditions by pH or pH-impedance testing. Patients with reflux hypersensitivity have normal acid exposure but a positive symptom association with acid or weakly acidic reflux. Patients with functional heartburn have normal acid exposure and a negative symptom reflux association. Patients with functional dyspepsia have heartburn in one third of cases, but early satiety and postprandial fullness are the predominant symptoms. (See "Approach to refractory gastroesophageal reflux disease in adults", section on 'Functional heartburn' and "Functional dyspepsia in adults", section on 'Clinical manifestations and comorbidities'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gastroesophageal reflux in adults".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Acid reflux and GERD in adults (The Basics)" and "Patient education: Upper endoscopy (The Basics)" and "Patient education: Esophagitis (The Basics)")

●Beyond the Basics topics (see "Patient education: Gastroesophageal reflux disease in adults (Beyond the Basics)" and "Patient education: Upper endoscopy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Terminology – We classify gastroesophageal reflux disease (GERD) based either on the appearance of the esophageal mucosa on upper endoscopy or the results of pH-metry and patient-reported symptoms. Varied definitions exist for GERD and include those based on symptoms, endoscopy findings, physiologic testing with pH-metry, or response to antisecretory therapy. (See 'Terminology' above.)

●Epidemiology – The estimated prevalence of GERD is approximately 15 to 30 percent in Western countries and 5 to 10 percent in Asia. The accuracy of prevalence estimates is limited by epidemiologic studies that equate self-reported heartburn and/or regurgitation with a diagnosis of GERD. (See 'Epidemiology' above.)

●Clinical features – Classic symptoms of GERD are heartburn (pyrosis) and regurgitation. Other symptoms of GERD include dysphagia, chest pain, water brash, globus sensation, odynophagia, extraesophageal symptoms (eg, chronic cough, hoarseness, wheezing), and, infrequently, nausea. (See 'Clinical manifestations' above.)

●Diagnosis – In patients with classic symptoms, the diagnosis of GERD can be based on clinical symptoms alone. In patients without classic symptoms, alternative disorders need to be excluded before attributing the symptoms to GERD. (See 'Patients with classic symptoms' above and 'Patients without classic symptoms' above.)

●Additional evaluation in selected patients – Additional evaluation is required in selected patients with suspected GERD to rule out alternative etiologies, confirm the diagnosis of GERD, and assess for complications (eg, Barrett's esophagus).

•Indications for upper endoscopy – Upper endoscopy with biopsy should be performed at presentation for patients with an esophageal GERD syndrome who have any of the following:

-Alarm features suggestive of a gastrointestinal malignancy

-Abnormal upper GI tract imaging

-Risk factors for Barrett's esophagus

Suspected GERD that has not responded to an empirical trial of twice-daily proton pump inhibitor (PPI) therapy (see 'Evaluation in selected patients' above)

Alarm features that are suggestive of a gastrointestinal malignancy include:

-New onset of dyspepsia in a patient ≥60 years

-Evidence of gastrointestinal bleeding (hematemesis, melena, hematochezia, occult blood in stool)

-Iron deficiency anemia

-Anorexia

-Unexplained weight loss

-Dysphagia

-Odynophagia

-Persistent vomiting

-Gastrointestinal cancer in a first-degree relative

•Ambulatory pH monitoring for persistent symptoms despite PPI therapy – Ambulatory pH monitoring is also used to confirm the diagnosis of GERD in those with persistent symptoms (whether typical or atypical, particularly if a trial of twice-daily PPI has failed) or to monitor the adequacy of treatment in those with continued symptoms. (See 'Ambulatory esophageal pH monitoring' above.)

•Esophageal manometry in patients with chest pain and/or dysphagia – We perform an esophageal manometry to exclude an esophageal motility disorder in patients with chest pain and a normal upper endoscopy. Manometry is also performed to evaluate esophageal peristaltic function prior to antireflux surgery. (See 'Esophageal manometry' above.)