Gastroesophageal Reflux Disease (GERD)

01Pathophysiology

GERD occurs when the normal anti-reflux barrier at the esophagogastric junction (EGJ) fails, allowing gastric contents to flow back into the esophagus, oropharynx, and/or respiratory tract, producing troublesome symptoms and/or complications.

The anti-reflux barrier consists of two main components: the lower esophageal sphincter (LES), a 3 to 4 cm segment of tonically contracted smooth muscle, and the crural diaphragm, which provides extrinsic compression. Together they maintain a high-pressure zone that exceeds intragastric pressure and prevents reflux.

Transient lower esophageal sphincter relaxations (TLESRs) are the dominant mechanism behind reflux episodes, accounting for approximately 70% of all reflux events. TLESRs are a physiological mechanism for venting gas from the stomach. In GERD patients, TLESRs occur without a swallowing trigger, leading to inappropriate opening of the EGJ and acid reflux. The dominant stimulus for TLESRs is proximal gastric distension, which activates intraganglionic lamellar endings of the vagal afferent nerve. Key neurotransmitters involved include gamma-aminobutyric acid (GABA), glutamate, and endocannabinoids.

Beyond TLESRs, reflux also occurs via two additional mechanisms. Strain-induced reflux happens when a hypotensive LES opens during sudden increases in intra-abdominal pressure (e.g., coughing, straining). Free reflux occurs when the LES-to-intragastric pressure gradient falls to 0 to 4 mmHg, allowing passive backflow without any change in abdominal pressure.

The acid pocket is a physiological phenomenon that occurs postprandially. After a meal, a layer of unbuffered acid forms on top of the ingested food near the EGJ. In patients with a hiatal hernia or shortened LES, this acid pocket extends above the squamocolumnar junction, providing a ready source of acid for reflux and promoting inflammation and metaplasia at the EGJ.

Hiatal hernia is present in nearly 94% of patients with reflux esophagitis. When the proximal stomach herniates above the diaphragm, the LES becomes shorter and weaker, the crural diaphragm contribution is lost, and the acid pocket is displaced above the diaphragm, all of which increase reflux episodes.

Once reflux occurs, the severity of mucosal injury depends on esophageal clearance. Normal peristalsis clears refluxed acid, and salivary bicarbonate neutralizes residual acid. In GERD, peristaltic dysfunction impairs this clearance. The correlation between dysmotility severity and esophagitis severity is well established; reflux decreases when the patient is upright because gravity assists clearance.

The mucosal defense of the esophagus has three layers: a pre-epithelial bicarbonate-rich layer (derived partly from saliva), the epithelial barrier (tight junctions and intercellular junctional complexes that limit hydrogen ion penetration), and intracellular buffer systems (bicarbonate, protein, phosphate). Chronic reflux overwhelms these defenses. The damaging agents include both acidic gastric contents (hydrochloric acid, pepsin) and alkaline duodenal contents (bile salts, pancreatic enzymes).

In non-erosive reflux disease (NERD), the predominant mechanism is visceral hypersensitivity rather than gross mucosal damage. NERD patients show increased sensitivity to esophageal balloon distension and heightened responses to thermal, mechanical, and chemical stimuli. This involves both peripheral sensitization (upregulation of esophageal sensory afferents) and central sensitization (hyperexcitability of dorsal horn neurons and higher processing centers). This mechanism also explains why NERD patients often respond poorly to acid suppression alone, contributing to refractory GERD.

Extraesophageal manifestations are explained by two hypotheses: (1) direct contact through microaspiration of refluxed material into the upper airway, and (2) a vago-vagal reflex triggered by acidification of the distal esophagus, which induces bronchospasm and bronchial hyperresponsiveness. The laryngeal mucosa is thought to be more vulnerable than esophageal mucosa because it contains less bicarbonate buffering capacity.

Obesity contributes through increased intra-abdominal pressure, increased gastric capacity, higher frequency of TLESRs, esophageal dysmotility, decreased LES pressure, and a tendency toward hiatal hernia formation. Smoking increases gastric acid secretion, decreases salivary bicarbonate, lowers LES pressure, and damages the esophageal mucosal epithelium. Psychological factors (depression, anxiety) increase visceral hypersensitivity through autonomic nervous system activation and cortisol release via the hypothalamic-pituitary-adrenal axis. Genetic factors contribute up to 31% heritability and also influence PPI response through CYP2C19 polymorphism: rapid metabolizers tend to have lower PPI levels and are more prone to refractory GERD.

02Classification and Clinical Manifestation

Phenotypic Classification

Classification of Erosive Esophagitis (Los Angeles)

In Asian and Indonesian populations, LA grade A dominates (50 to 90% of erosive cases). Indonesian data from Miftahussurur et al. showed 89.3% LA grade A, 7.1% grade B, and 3.6% grade C among GERD patients in Surabaya.

Clinical Manifestations

Symptom Severity Definition

Alarm Symptoms (Red Flags)

03Diagnostic Workup

Diagnostic Approach in Detail

Step 1: Clinical Assessment and GerdQ.
The GerdQ is a validated 6-item questionnaire evaluating symptoms over the preceding 7 days. A score of 8 or above out of 18 identifies individuals with a high likelihood of GERD. In Indonesia, the GerdQ has been validated with a Cronbach alpha of 0.834. A study in Bandung showed that 65.2% of patients scoring 8 or above on GerdQ had esophagitis on endoscopy (p=0.004). The GerdQ also helps monitor treatment response over time.

Step 2: PPI Test (Best Initial Diagnostic Strategy for Typical Symptoms Without Alarm Features).
This is the most practical initial step for patients presenting with heartburn and/or regurgitation without alarm features. The test involves giving double-dose PPI for 2 weeks. If symptoms resolve, GERD is diagnosed. The test is considered positive when clinical improvement exceeds 50% within the first week. However, the PPI test has limited specificity (54 to 65%), meaning a positive result does not definitively confirm GERD because acid-sensitive functional conditions (e.g., functional dyspepsia) may also respond to acid suppression.

Step 3: Upper GI Endoscopy (First-Line for Alarm Symptoms; Gold Standard for Erosive Disease).
Endoscopy is the first-line investigation when alarm symptoms are present (dysphagia, weight loss, GI bleeding, anemia). It is also recommended for patients with non-cardiac chest pain after cardiac causes have been excluded, and for patients with inadequate PPI response after stopping PPI for 2 weeks. The LA classification system is used to grade erosive esophagitis. It is important to note that clinical symptoms do not correlate with endoscopic severity. Approximately 80% of symptomatic patients may have no visible erosions, meaning they have NERD. Every patient with chronic GERD symptoms should undergo endoscopy at least once in their lifetime.

Step 4: Ambulatory Reflux Monitoring (pH-metry and Impedance) for Refractory or Unclear Cases.
This is not performed routinely. Indications include refractory GERD, atypical symptoms, unclear diagnosis, and pre-operative evaluation. The primary outcome is the acid exposure time (AET). Per the Seoul consensus for Asian populations, AET of 4% or above is considered abnormal. The Lyon consensus uses a cutoff of >6%. Total reflux episodes exceeding 80 per 24 hours are also abnormal. Off-therapy monitoring helps determine disease severity, while on-therapy monitoring (while on twice-daily PPI) is used for patients with inadequate response to evaluate persistent acid exposure. Off-therapy monitoring alone is not recommended for severe erosive esophagitis (LA C or D) or long-segment Barrett's esophagus.

Step 5: High-Resolution Manometry
This is not a standalone diagnostic tool for GERD. Its primary role is pre-operative evaluation before anti-reflux surgery or endoscopic therapy (such as ARMS) to rule out esophageal motility disorders like achalasia. It also helps determine accurate catheter placement for pH-impedance testing. HRM may reveal LES hypotension, hiatal hernia, and esophageal hypomotility in GERD patients.

04Management and Treatment

Non-Pharmacological Therapy

Pharmacological Therapy

For typical GERD without alarm features

Start with double-dose PPI (e.g., esomeprazole 40 mg twice daily, taken 30 to 60 minutes before meals) for 2 weeks as a diagnostic trial. A positive result is defined as more than 50% symptom improvement within the first week, which confirms the diagnosis of GERD.

If the response is adequate, continue the same double-dose PPI regimen for a total of 8 weeks. Do not reduce the dose during this treatment phase.

After completing the full 8-week course, step down to the lowest effective dose for maintenance (e.g., esomeprazole 20 mg once daily). For NERD patients, two maintenance strategies are acceptable: continuous low-dose PPI (esomeprazole 20 mg daily) or on-demand PPI (esomeprazole 40 mg only when symptoms occur). Both strategies show comparable patient satisfaction. Do not attempt dose reduction in patients with LA grade C/D, Barrett's esophagus, or peptic stricture.

If the response to the initial 2-week trial is inadequate, consider the following options: increase PPI to twice daily if the patient was started on single dose, switch to a more potent PPI (esomeprazole has the highest efficacy ranking based on meta-analysis), or replace the PPI with a P-CAB such as tegoprazan 50 mg once daily.

For patients with alarm features

Proceed directly to upper GI endoscopy. Do not give empirical PPI without investigation.

For erosive esophagitis

PPI is the preferred therapy for both healing and maintenance. The healing rate with PPI is far superior to H2RA (12% vs. 6% per week). Esomeprazole 40 mg once daily has a 5% higher probability of healing compared to other PPIs. For LA grade C and D, do not attempt dose reduction or PPI discontinuation because the relapse rate approaches 100% within 6 months.

For non-cardiac chest pain (NCCP)

After excluding cardiovascular causes, give PPI at high dose (e.g., omeprazole 20 mg twice daily or esomeprazole 40 mg once daily) for a minimum of 8 to 12 weeks before considering further workup.

For refractory GERD (persistent symptoms despite double-dose PPI for 8 to 12 weeks)

Optimize PPI adherence and timing (30 to 60 min before meals). Switch PPI type or increase dose. Add bedtime H2RA for nocturnal acid breakthrough. Consider adding alginate, baclofen (for belching/regurgitation), prokinetics (if dysmotility is documented), or a neuromodulator. Replace PPI with a P-CAB (tegoprazan). If pharmacotherapy fails with objective evidence of reflux, consider endoscopic therapy (ARMS, TIF, Stretta) for patients without hiatal hernia >2 cm, or anti-reflux surgery (laparoscopic fundoplication) for LA grade C/D, large hiatal hernia, or severely symptomatic patients. Avoid surgery in patients with gastroparesis (risk of severe nausea, vomiting, bloating, and poor outcomes). For obese patients with GERD, Roux-en-Y gastric bypass (RYGB) is recommended over fundoplication (100% symptom resolution rate, heartburn dropped from 87% to 22%).

For pregnancy

First-line agents are antacids, alginate, and sucralfate. If symptoms persist, use H2RA (except nizatidine due to teratogenicity). PPI is category B (except omeprazole which is category C).

For extraesophageal manifestations

Do not initiate empirical PPI if there are no concomitant typical GERD symptoms. If typical symptoms are present, trial PPI twice daily for 8 to 12 weeks before further investigation. Endoscopy is not recommended solely for diagnosing asthma, chronic cough, or laryngopharyngeal reflux related to GERD. Adding prokinetics, baclofen, gabapentin, or alginate is not recommended if there is no response to PPI for extraesophageal symptoms.

Helicobacter pylori considerations

Routine screening and eradication of H. pylori are not recommended in GERD patients. The exception is patients requiring long-term PPI, where eradication may prevent progression to gastric corpus atrophy or intestinal metaplasia. In Indonesia, H. pylori prevalence in GERD patients is very low (1.9% in the Miftahussurur study).

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The single most common trap with GERD questions is assuming that heartburn always equals erosive esophagitis. In reality, 60 to 70% of GERD patients have NERD with a completely normal endoscopy. The exam frequently tests this concept by presenting a patient with classic heartburn and regurgitation, then revealing a normal endoscopy, and asking for the next step. The answer is not to repeat the endoscopy or order CT imaging; it is to continue PPI therapy or proceed to ambulatory reflux monitoring if the diagnosis remains in doubt.

A second major trap is the chest pain question. When a vignette describes substernal burning or chest tightness, the instinct to jump to GERD must be suppressed until cardiac causes are excluded first. The correct sequence is always: rule out cardiac disease first, then evaluate for GERD. Endoscopy and/or reflux monitoring for GERD-related chest pain is appropriate only after the cardiac workup is negative.

Third, watch for the refractory GERD question. Before labeling a patient as having refractory GERD, the exam expects you to verify PPI adherence and timing (must be taken 30 to 60 minutes before meals, not at bedtime or with food). Many "refractory" cases are actually due to incorrect PPI administration. Once true refractory GERD is established after at least 8 to 12 weeks of optimized double-dose PPI, the next step is endoscopy (if not already done) followed by ambulatory pH-impedance monitoring on therapy.

Fourth, do not confuse barium swallow with endoscopy for GERD diagnosis. Barium esophagography has very low sensitivity and specificity for GERD and is not recommended for diagnosis. It is only useful for evaluating dysphagia and anatomical abnormalities. The exam may offer it as a distractor answer.

Fifth, remember the pregnancy treatment hierarchy: antacids, alginate, and sucralfate are first-line. H2RA (except nizatidine) is second-line. PPI (category B, except omeprazole which is category C) is third-line. The exam frequently tests which agents are safe in pregnancy.

Sixth, the LA classification grades are a favorite testing target. Grade A (mucosal break 5 mm or shorter, not extending between folds) and grade B (longer than 5 mm but not extending between folds) represent mild disease. Grades C and D represent severe disease that requires long-term PPI without dose reduction and may warrant surgical evaluation. Do not attempt PPI weaning in LA C/D or Barrett's esophagus.

Finally, regarding H. pylori and GERD: the exam may try to get you to reflexively eradicate H. pylori in a GERD patient. The correct answer is that routine H. pylori screening and treatment is not recommended in GERD, because atrophic gastritis from H. pylori infection actually serves as a protective factor against GERD by reducing acid secretion. The only exception is patients requiring long-term PPI, where eradication is performed to prevent progression to corpus atrophy or intestinal metaplasia.

The core competency being tested across all GERD questions is the ability to sequence the diagnostic and therapeutic approach correctly: clinical assessment and GerdQ first, then PPI trial for uncomplicated disease, endoscopy for alarm features or refractory symptoms, and reflux monitoring reserved for cases where the diagnosis remains uncertain despite initial workup.