Experiencing persistent gastro-oesophageal reflux symptoms despite receiving a “normal” endoscopy result can be profoundly frustrating for patients and clinically challenging for healthcare providers. This scenario occurs more frequently than many realise, affecting approximately 60-70% of individuals presenting with typical reflux symptoms. The apparent contradiction between subjective symptom experience and objective endoscopic findings highlights the complexity of gastro-oesophageal reflux disease (GORD) and the limitations of conventional diagnostic approaches. Understanding why this discrepancy exists requires exploring the sophisticated mechanisms underlying oesophageal function, the various pathophysiological processes that can produce reflux-like symptoms, and the advanced diagnostic techniques that may reveal abnormalities invisible to standard endoscopy.
Understanding Non-Erosive reflux disease (NERD) and endoscopic limitations
Defining NERD: when oesophageal mucosa appears normal despite symptomatic GORD
Non-erosive reflux disease represents the most common presentation of GORD in clinical practice, accounting for approximately 60-70% of all reflux cases. Unlike erosive oesophagitis, where visible mucosal breaks, erosions, or ulcerations are apparent during endoscopy, NERD presents with typical reflux symptoms in the absence of endoscopically visible oesophageal damage. This condition challenges the traditional understanding that reflux symptoms necessarily correlate with visible mucosal injury.
The pathophysiology of NERD involves subtle molecular and microscopic changes within the oesophageal epithelium that remain invisible to standard endoscopic examination. Patients with NERD experience genuine acid exposure , but the duration, frequency, and pH levels may be insufficient to produce macroscopic mucosal lesions. Research demonstrates that individuals with NERD often have normal oesophageal acid exposure times on 24-hour pH monitoring, yet still experience significant symptom burden due to heightened visceral sensitivity and altered pain perception pathways.
Endoscopic detection thresholds and microscopic mucosal changes
Standard white-light endoscopy operates within specific detection thresholds that may miss early-stage mucosal alterations characteristic of reflux disease. The human eye, even when aided by high-definition endoscopic imaging, cannot detect microscopic changes such as dilated intercellular spaces, basal cell hyperplasia, or papillary elongation that occur in the initial stages of acid-induced oesophageal injury. These histological changes represent the earliest manifestations of reflux disease and can be present for months or years before visible erosions develop.
Microscopic examination of oesophageal biopsies from patients with normal-appearing mucosa frequently reveals inflammatory infiltrates, particularly eosinophils and lymphocytes, along with structural alterations in the epithelial architecture. These changes indicate ongoing tissue remodelling processes that contribute to symptom generation despite the absence of visible mucosal damage. The threshold for symptom development appears to be significantly lower than the threshold for endoscopically detectable mucosal injury.
Los angeles classification system limitations in early reflux disease
The Los Angeles Classification System, developed to standardise the grading of reflux oesophagitis, focuses exclusively on visible mucosal breaks and their dimensions. This classification system, while valuable for categorising established erosive disease, inherently excludes patients with early-stage reflux disease who have not yet developed macroscopic lesions. Grade A oesophagitis, the mildest category, requires mucosal breaks of at least 5mm in length, meaning that smaller erosions or subtle inflammatory changes remain unclassified.
This classification gap creates a diagnostic blind spot where patients experience genuine reflux-related symptoms but receive normal endoscopy reports. The system’s reliance on visible pathology overlooks the spectrum of NERD presentations and may inadvertently minimise the clinical significance of patients’ symptoms. Recent proposals for modified classification systems attempt to address these limitations by incorporating subtle mucosal changes and inflammatory markers visible with advanced imaging techniques.
Prevalence rates of NERD amongst GORD patients in clinical practice
Epidemiological studies consistently demonstrate that NERD represents the predominant form of GORD in both primary care and specialist gastroenterology settings. Population-based research indicates that approximately 60-70% of individuals with typical reflux symptoms have normal endoscopic findings, with this proportion rising to 80% in certain demographic groups, particularly younger patients and women. These statistics underscore the clinical importance of recognising and appropriately managing endoscopy-negative reflux disease.
The prevalence of NERD varies significantly across different healthcare settings and patient populations. Tertiary referral centres may see higher proportions of erosive disease due to selection bias, while community-based studies reveal the true dominance of non-erosive presentations. Understanding these prevalence patterns helps clinicians adjust their diagnostic approach and treatment strategies accordingly, recognising that normal endoscopy findings do not exclude clinically significant reflux disease.
Functional oesophageal disorders mimicking classical reflux symptoms
Functional heartburn: rome IV criteria and diagnostic challenges
Functional heartburn, as defined by the Rome IV criteria, represents a distinct clinical entity characterised by burning retrosternal discomfort that resembles gastro-oesophageal reflux but lacks objective evidence of pathological acid exposure or symptom-reflux association on ambulatory monitoring. This condition affects approximately 22-25% of patients presenting with heartburn symptoms and poses significant diagnostic challenges due to its symptomatic overlap with classical GORD.
The pathophysiology of functional heartburn involves altered central pain processing and visceral hypersensitivity rather than excessive acid exposure. Patients with this condition demonstrate normal oesophageal acid exposure times on 24-hour pH monitoring but exhibit heightened sensitivity to physiological levels of acid reflux. This hypersensitivity may result from central sensitisation, altered neurotransmitter pathways, or psychological factors that amplify normal physiological sensations into symptomatic experiences.
Diagnosing functional heartburn requires comprehensive evaluation including symptom assessment, endoscopy, and ambulatory pH-impedance monitoring. The Rome IV criteria specify that symptoms must be present for at least 3 months with onset at least 6 months prior to diagnosis, normal endoscopy findings, and absence of pathological reflux on objective testing. However, distinguishing functional heartburn from NERD remains challenging, as both conditions can present with similar symptoms and normal endoscopic appearances.
Reflux hypersensitivity syndrome and visceral pain pathways
Reflux hypersensitivity syndrome represents another functional oesophageal disorder where patients experience typical reflux symptoms in association with physiological levels of oesophageal acid exposure. Unlike functional heartburn, this condition demonstrates a temporal relationship between symptoms and reflux episodes on ambulatory monitoring, but the total acid exposure time remains within normal limits. This suggests that symptom generation occurs due to heightened sensitivity rather than excessive acid production or reflux frequency.
The underlying mechanisms involve alterations in peripheral nociceptor sensitivity, spinal cord processing, and central pain modulation pathways. Research indicates that patients with reflux hypersensitivity demonstrate increased expression of acid-sensing ion channels and transient receptor potential vanilloid receptors in oesophageal mucosa. These molecular changes enhance the detection threshold for acid stimuli, causing normal physiological reflux events to trigger symptomatic responses.
The distinction between normal physiological reflux and pathological reflux lies not only in the quantity of acid exposure but also in the individual’s sensitivity to that exposure.
Oesophageal motility disorders: ineffective oesophageal motility and delayed clearance
Primary oesophageal motility disorders can produce symptoms that closely mimic gastro-oesophageal reflux disease, particularly when they involve ineffective oesophageal motility (IEM) or delayed acid clearance mechanisms. IEM, characterised by weak or failed peristaltic waves, occurs in approximately 25-30% of patients with reflux symptoms and normal endoscopy findings. This condition impairs the oesophagus’s ability to clear refluxed material effectively, leading to prolonged mucosal contact time with gastric contents.
The relationship between motility disorders and reflux symptoms is bidirectional and complex. Poor oesophageal clearance can exacerbate the effects of normal amounts of reflux by increasing contact time between acid and oesophageal mucosa. Conversely, chronic acid exposure can damage oesophageal smooth muscle and neural pathways, leading to secondary motility dysfunction. This creates a self-perpetuating cycle where motility problems worsen reflux, and reflux further impairs motility.
High-resolution manometry studies in patients with normal endoscopy findings frequently reveal subtle motility abnormalities that may not meet criteria for major motility disorders but still contribute to symptom generation. These include borderline ineffective motility, fragmented peristalsis, and reduced lower oesophageal sphincter pressure that falls within the normal range but may be inadequate for individual patients’ anatomical or physiological characteristics.
Supragastric belching and Aerophagia-Related symptoms
Supragastric belching and aerophagia represent underrecognised causes of reflux-like symptoms that can occur with normal endoscopic findings. Supragastric belching involves the rapid ingestion and subsequent expulsion of air through the oesophagus without the air reaching the stomach, creating symptoms that patients often interpret as heartburn or acid regurgitation. This behavioural phenomenon affects approximately 10-15% of patients presenting with reflux-like symptoms.
The mechanism involves voluntary or involuntary air swallowing followed by immediate retrograde air movement through the oesophagus. During this process, small amounts of gastric contents may be drawn upward, creating genuine reflux symptoms despite the absence of primary gastro-oesophageal reflux disease. Patients often describe these episodes as burping or belching , but may also report burning sensations or regurgitation that mimics classical GORD symptoms.
Advanced diagnostic techniques beyond standard endoscopy
24-hour ambulatory ph monitoring and DeMeester score interpretation
Ambulatory pH monitoring remains the gold standard for quantifying oesophageal acid exposure in patients with normal endoscopy findings and persistent reflux symptoms. This technique involves placing a pH probe 5cm above the lower oesophageal sphincter to continuously monitor acid exposure over a 24-hour period. The DeMeester score, a composite scoring system incorporating multiple pH parameters, provides objective quantification of pathological reflux with a threshold score of 14.72 distinguishing normal from abnormal acid exposure.
However, traditional pH monitoring has limitations that may explain persistent symptoms despite normal results. The technique only detects acid reflux (pH < 4) and may miss weakly acidic or non-acid reflux episodes that can still trigger symptoms in sensitive individuals. Additionally, day-to-day variability in reflux patterns means that a single 24-hour study may not capture the full spectrum of an individual’s reflux disease. Studies suggest that up to 20% of patients with typical GORD symptoms have normal 24-hour pH monitoring results.
Recent advances in pH monitoring technology include wireless pH capsules that extend monitoring periods to 48-96 hours, potentially capturing episodic reflux that might be missed during shorter recording periods. These extended studies often reveal pathological acid exposure in patients who had normal 24-hour testing, highlighting the importance of adequate monitoring duration in selected cases.
Multichannel intraluminal Impedance-pH testing for Non-Acid reflux detection
Multichannel intraluminal impedance-pH (MII-pH) monitoring represents a significant advancement in reflux diagnosis, combining traditional pH measurement with impedance technology to detect all types of reflux episodes regardless of pH level. This technique measures changes in electrical resistance across multiple oesophageal levels, enabling detection of liquid, gas, and mixed reflux episodes with pH values ranging from highly acidic to alkaline.
MII-pH monitoring is particularly valuable for patients with normal endoscopy and normal conventional pH studies who continue to experience symptoms. The technique can identify weakly acidic reflux (pH 4-7) and non-acid reflux (pH > 7) that may trigger symptoms in hypersensitive individuals. Research demonstrates that approximately 30-40% of reflux episodes in patients on proton pump inhibitor therapy are non-acidic, potentially explaining persistent symptoms despite acid suppression.
The ability to correlate symptoms with specific reflux episodes (symptom index and symptom association probability) provides crucial diagnostic information for patients with functional oesophageal disorders. A positive symptom correlation with non-acid reflux episodes may guide alternative treatment strategies beyond acid suppression, such as anti-reflux surgery or prokinetic medications that address the mechanical aspects of reflux disease.
High-resolution manometry assessment of lower oesophageal sphincter function
High-resolution manometry (HRM) provides detailed assessment of oesophageal motor function and lower oesophageal sphincter characteristics that may contribute to reflux symptoms despite normal endoscopic findings. This technique uses closely spaced pressure sensors to create detailed topographic representations of oesophageal pressure patterns during swallowing and at rest. HRM can identify subtle motility abnormalities that may not be apparent on conventional manometry or endoscopy.
Parameters of particular relevance include lower oesophageal sphincter pressure, relaxation completeness, and the presence of hiatal hernia or anatomical disruption of the gastro-oesophageal junction. Even within the normal range, lower sphincter pressures at the low end of normal (10-15 mmHg) may be insufficient to prevent reflux in patients with other predisposing factors such as increased intra-abdominal pressure or delayed gastric emptying.
HRM also evaluates oesophageal body function, identifying patterns of ineffective motility, premature contractions, or spatial discoordination that may impair acid clearance. The Chicago Classification system for motility disorders has evolved to incorporate subtle abnormalities that may contribute to reflux symptoms, including borderline motility patterns that fall between normal and clearly pathological findings.
Narrow-band imaging and chromoendoscopy for subtle mucosal changes
Advanced endoscopic imaging techniques, including narrow-band imaging (NBI) and chromoendoscopy, enhance visualisation of subtle mucosal changes that may be invisible during standard white-light endoscopy. NBI uses specific wavelengths of light to highlight vascular patterns and surface structures, potentially revealing early inflammatory changes or microerosions in patients with normal-appearing oesophageal mucosa.
Studies using NBI in patients with reflux symptoms and normal conventional endoscopy demonstrate increased detection rates of minimal mucosal changes, including increased vascularity, subtle colour changes, and micro-erosions. These findings may help explain persistent symptoms in patients with otherwise normal endoscopic examinations. The clinical significance of these minimal changes continues to be investigated, but they may represent early stages of reflux disease progression.
Advanced imaging techniques are revealing that the oesophageal response to acid exposure exists on a spectrum, with subtle changes occurring long before visible erosions develop.
Pathophysiological mechanisms in Normal-Appearing oesophageal mucosa
The pathophysiological mechanisms underlying persistent reflux symptoms in patients with normal endoscopy findings involve complex interactions between acid exposure, mucosal sensitivity, neural pathways, and central pain processing. Even in the absence of visible mucosal damage, molecular and cellular changes occur within the oesophageal epithelium that can trigger symptom generation through various mechanistic pathways.
Microscopic examination of apparently normal oesophageal mucosa from symptomatic patients frequently reveals dilated intercellular spaces, a hallmark of early acid-induced tissue damage. These spaces allow increased penetration of hydrogen ions and other luminal contents into deeper epithelial layers, potentially activating nociceptors and inflammatory cascades. The process occurs through disruption of tight junctions between epithelial cells, mediated by acid-induced alterations in claudin and zonula occludens protein expression.
Inflammatory mediators, including interleukins, prostaglandins, and nerve growth factor, become upregulated in response to even minimal acid exposure. These substances sensitise pain pathways and lower the threshold for symptom generation, explaining how physiological levels of reflux can produce significant symptoms in certain
patients. The upregulation of substance P and calcitonin gene-related peptide in oesophageal sensory neurons further amplifies pain signalling, creating a hypersensitive state where minimal stimuli produce disproportionate symptom responses.
Genetic polymorphisms affecting acid-sensing ion channels (ASICs) and transient receptor potential vanilloid 1 (TRPV1) receptors contribute to individual variation in acid sensitivity. Patients carrying specific genetic variants demonstrate increased channel expression and enhanced responsiveness to acid stimulation, potentially explaining why some individuals develop symptoms with minimal reflux exposure while others remain asymptomatic despite significant acid contact. These genetic factors may influence both symptom severity and treatment responsiveness in patients with endoscopy-negative reflux disease.
Central sensitisation mechanisms involve alterations in spinal cord and brainstem processing of visceral pain signals. Repeated acid exposure, even at subclinical levels, can induce long-term potentiation in dorsal horn neurons, lowering the activation threshold for pain transmission. This process, similar to chronic pain syndromes in other organs, may explain why symptoms persist even after successful acid suppression and why some patients require multimodal treatment approaches addressing both peripheral and central pain mechanisms.
Treatment strategies for Endoscopy-Negative reflux disease
Managing patients with persistent reflux symptoms despite normal endoscopy findings requires a comprehensive approach that addresses multiple potential pathophysiological mechanisms. The heterogeneous nature of endoscopy-negative reflux disease necessitates individualised treatment strategies based on symptom patterns, response to initial therapy, and findings from advanced diagnostic testing when available.
Proton pump inhibitor (PPI) therapy remains the first-line treatment approach, with approximately 60-70% of patients with endoscopy-negative reflux disease achieving symptom improvement with standard-dose therapy. However, the response rate is lower than in erosive oesophagitis, and many patients require dose optimisation or alternative acid-suppression strategies. The timing of PPI administration becomes particularly important, with optimal dosing occurring 30-60 minutes before the largest meal to ensure peak acid suppression during postprandial reflux episodes.
For patients with inadequate response to standard PPI therapy, several modification strategies may improve efficacy. Twice-daily dosing can provide more complete 24-hour acid suppression, particularly beneficial for patients with nocturnal symptoms or those with rapid PPI metabolism. Alternative PPI formulations, including delayed-release capsules or immediate-release suspensions, may offer advantages in specific patient populations with altered gastric pH or rapid gastric emptying.
Histamine-2 receptor antagonists (H2RAs) may be added to PPI therapy for patients with breakthrough nocturnal symptoms, as these medications can provide additional acid suppression during periods when PPI efficacy wanes. The combination approach addresses the pharmacokinetic limitations of PPIs and may be particularly useful for patients with delayed gastric emptying or those requiring bedtime acid suppression.
Beyond acid suppression, prokinetic agents targeting oesophageal and gastric motility disorders can provide symptom relief in selected patients. Baclofen, a gamma-aminobutyric acid-B receptor agonist, reduces transient lower oesophageal sphincter relaxations and may be particularly beneficial for patients with non-acid reflux or those with normal acid exposure times on ambulatory monitoring. Domperidone or metoclopramide may improve gastric emptying and reduce reflux frequency, though their use requires careful consideration of potential side effects.
Psychological interventions, including cognitive behavioural therapy and hypnotherapy, address the central sensitisation and anxiety components that often accompany functional oesophageal disorders. These approaches can be particularly valuable for patients with functional heartburn or reflux hypersensitivity syndrome, where symptom generation involves altered central pain processing rather than excessive acid exposure.
Successful management of endoscopy-negative reflux disease often requires addressing both the peripheral mechanisms of symptom generation and the central processing of visceral pain signals.
Lifestyle modifications remain important adjunctive treatments, with particular emphasis on weight management, dietary modifications, and behavioural interventions. Elevation of the head of the bed, avoidance of late evening meals, and identification of individual dietary triggers can significantly improve symptom control when combined with pharmacological therapy. The effectiveness of these interventions may be enhanced when patients understand the rationale behind recommendations and actively participate in symptom monitoring.
Differential diagnosis and alternative causes of Reflux-Like symptoms
Establishing an accurate differential diagnosis for patients presenting with reflux-like symptoms but normal endoscopy findings requires systematic consideration of various cardiac, pulmonary, biliary, and psychological conditions that can mimic gastro-oesophageal reflux disease. This diagnostic process becomes particularly challenging when symptoms are atypical or when multiple conditions coexist, requiring careful clinical assessment and selective use of appropriate diagnostic tests.
Cardiac conditions, particularly coronary artery disease and oesophageal spasm, frequently present with chest pain that patients describe as heartburn or indigestion. The anatomical proximity of the heart and oesophagus, combined with shared neural pathways, creates significant symptomatic overlap. Exercise stress testing or cardiac catheterisation may be necessary to exclude coronary disease in patients with chest pain, particularly those with cardiovascular risk factors. Microvascular angina and coronary spasm can produce symptoms identical to reflux disease but require entirely different treatment approaches.
Pulmonary conditions, including asthma, chronic cough, and laryngopharyngeal reflux, can create a complex interplay of symptoms that challenges diagnostic accuracy. Asthma and reflux disease frequently coexist, with each condition potentially exacerbating the other through shared neural reflexes and inflammatory pathways. Differentiating primary pulmonary disease from reflux-induced respiratory symptoms requires careful assessment of symptom timing, triggers, and response to specific therapies.
Biliary disorders, particularly gallbladder dysfunction and biliary dyskinesia, can produce epigastric pain and nausea that patients interpret as reflux symptoms. The postprandial timing of biliary pain often overlaps with reflux symptoms, making clinical differentiation challenging. Hepatobiliary scintigraphy or magnetic resonance cholangiopancreatography may be necessary to evaluate biliary function in selected patients with atypical presentations.
Medication-induced oesophageal injury represents an important but often overlooked cause of reflux-like symptoms in patients with normal endoscopy findings. Bisphosphonates, doxycycline, potassium supplements, and nonsteroidal anti-inflammatory drugs can cause oesophageal irritation and inflammation that produces symptoms identical to acid reflux. The temporal relationship between medication initiation and symptom onset provides important diagnostic clues, though chronic low-grade irritation may develop insidiously over months or years.
Eosinophilic oesophagitis presents particular diagnostic challenges, as early-stage disease may not produce visible endoscopic abnormalities but can cause dysphagia, chest pain, and food bolus impaction that patients describe as reflux symptoms. The increasing recognition of this condition has highlighted the importance of obtaining oesophageal biopsies in selected patients with normal-appearing mucosa but suggestive clinical features, particularly younger patients with atopy or food allergies.
Psychological factors, including anxiety, depression, and somatisation disorders, can significantly influence symptom perception and reporting in patients with reflux-like complaints. The gut-brain axis involves bidirectional communication between the central nervous system and enteric nervous system, with psychological stress capable of altering gastric acid secretion, oesophageal motility, and visceral sensitivity. Patients with underlying psychological conditions may experience genuine physical symptoms that respond poorly to conventional acid suppression therapy but improve with appropriate psychological intervention.
Infectious oesophagitis, though uncommon in immunocompetent patients, can occasionally present with reflux-like symptoms despite normal initial endoscopic appearance. Viral oesophagitis, particularly cytomegalovirus or herpes simplex virus, may cause subtle mucosal changes that develop into visible lesions over time. Fungal oesophagitis, primarily candida species, can occur in patients with diabetes, immunosuppression, or prolonged antibiotic use.
The diagnostic approach for patients with persistent symptoms despite normal endoscopy should be systematic and evidence-based, beginning with careful reassessment of symptom characteristics, medication history, and response to initial therapy. Advanced testing, including ambulatory pH-impedance monitoring, high-resolution manometry, or cross-sectional imaging, should be considered based on specific clinical indications rather than routine screening. The goal is to identify treatable conditions while avoiding unnecessary testing that may increase healthcare costs without improving patient outcomes.