Table of Contents  

Kristo and Schoppmann: Diagnosis of gastro-oesophageal reflux disease and its associated conditions


Gastro-oesophageal reflux disease (GORD) is a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications.1 Observational longitudinal studies have shown a dramatic increase in individuals experiencing symptoms of GORD – some reporting an increase of 50% – which can be attributed to modern working conditions and Western lifestyle.2 Importantly, GORD can cause major complications and may lead to oesophageal adenocarcinoma.3 Worryingly, the incidence of oesophageal adenocarcinoma is rising and the condition is not always accompanied by typical symptoms, often presents in advanced stages and increasingly affects the young.4 Therefore, special emphasis must be placed on accurate, timely diagnosis.

Modern diagnostic approaches involve a variety of procedures that differ in specificity and sensitivity. First and foremost, GORD may be suggested by clinical presentation.5 Endoscopic investigation can substantiate the presumed diagnosis. High-resolution manometry (HRM) and 24- or 48-hour pH monitoring form part of modern patient-adapted strategies against GORD and can confirm the need for anti-reflux intervention. If diagnosis is established too late or therapeutic treatments fail, reflux can cause erythema, erosion and ulceration, with subsequent peptic stricture or Barrett’s oesophagus (BO), a widely known preneoplastic condition.69 In such cases, endoscopic evaluation is typical, allowing prompt diagnosis and treatment.

Recently, a novel oesophageal motility disorder – jackhammer oesophagus (JO) – has been reported to be associated with the reflux of gastric contents.10 Patients with JO often present with intense symptoms that overlap with GORD, which complicates diagnosis and subsequent therapy. Again, accurate testing with modern diagnostic instruments is required.

This article focuses on the diagnostic instruments that can assist in the diagnosis of GORD and aid in differentiating the disease from overlapping conditions.

Diagnosis of gastro-oesophageal reflux disease

Currently, combinations of clinical presentation, therapeutic response to medical therapy, endoscopy, HRM and ambulatory pH monitoring are utilized to diagnose and initiate treatment of GORD.

It is possible to distinguish between typical, atypical and alarming symptoms of the disease (Table 1). Klauser et al.11 evaluated 304 patients who were referred for ambulatory pH monitoring to assess typical symptoms. Interestingly, of several symptoms that were believed to be associated with GORD, only heartburn and acid regurgitation were frequent in patients with pathological pH levels. Heartburn and acid regurgitation demonstrated a high specificity (90%) but low sensitivity (38% and 6%, respectively) for GORD. The disease may also be present in patients presenting with chronic coughing, nausea and epigastric pressure or pain, which can be considered to be atypical signs.12 Additionally, manifestations such as asthma, dental erosions and laryngitis should raise suspicion of GORD and suggest the reflux of gastric contents as a possible aetiological factor. Giannini et al.13 investigated whether patients with typical symptoms of GORD should undergo empirical treatment or treatment according to endoscopic findings. After randomizing 612 patients, they observed that therapeutic response rates did not differ between groups, whereas empirical medication was more cost-effective than endoscopic treatment. Taken together, presumptive diagnosis can be established in the presence of heartburn and acid regurgitation, whereas empirical proton pump inhibitor (PPI) therapy and therapeutic response are needed to substantiate the diagnosis. Nevertheless, physicians should be aware of a potential placebo effect, low sensitivity of reported symptoms and the fact that antisecretory therapy may interfere with subsequent endoscopic screening.


Presentation and symptoms of gastro-oesophageal reflux disease

Presentation Symptoms
Typical Heartburn, acid regurgitation
Atypical Nausea, epigastric pain, dental erosion, chronic cough, laryngitis
Alarming Dysphagia, odynophagia, haematemesis

Consequently, there are situations that should warrant further evaluation by endoscopic means. If patients do not respond to medical interventions, present with alarm symptoms such as dysphagia or odynophagia, or carry risk factors for BO or oesophageal adenocarcinoma, further evaluation by endoscopy is recommended.14 Endoscopic visualization of mucosal breaks – areas of reflux-damaged mucosa that are distinct from the healthy mucosal surface – is proof of GORD. Lundell et al.15 analysed endoscopic oesophageal changes and revealed that the severity of visible oesophagitis is significantly associated with the grade of pathological acid exposure, severity of heartburn, outcome of PPI therapy and risk of symptom relapse.

Two classification systems predominate for grading the extent of endoscopically visible mucosal defects, namely the Los Angeles (LA) classification system and the Savary–Miller (SM) scale. The LA system comprises grades A–D and classifies mucosal breaks from ≤ 5 mm to breaks that extend to at least 75% of the oesophageal circumference.16 The SM scale comprises grades 0–4, with normal mucosa classified as grade 0 and complicated disease classified as grade 4.17 Interestingly, Rath et al.18 compared classification systems for reflux oesophagitis and analysed interobserver agreement: the SM scale showed moderate performance in terms of agreement between observers but performed poorly when inexperienced physicians were questioned. In contrast, LA grading was the most reproducible in all subgroups and unaffected by level of experience. Therefore, grading by the LA system represents the more powerful tool in the detection and comparison of reflux oesophagitis.

If endoscopic evaluation fails to detect lesions induced by the reflux of gastric contents, ambulatory 24-hour impedance pH monitoring offers the highest sensitivity and specificity by recording total time pH < 4 with a probe placed 5 cm proximal to the lower oesophageal sphincter.19 Jamieson et al.20 evaluated the normal values, threshold and accuracy of 24-hour pH monitoring and concluded that specificity and sensitivity for total time pH < 4 and a composite score were nearly 100%. These outcomes are very significant as accurate diagnosis is achieved in an outpatient setting. Catheter-free, transnasally inserted pH monitoring systems are also available and can record over longer periods.21 Wireless pH monitoring seems to offer comparable outcomes to 24-hour catheter-based systems, but there seems to be no need for a prolonged observational period.22

It is apparent that there are several available steps in the diagnosis of GORD. At our centre, we emphasize intensive patient-orientated investigation that involves medical history and symptom assessment in particular. For patients with atypical or alarming symptoms, existing risk factors for oesophageal adenocarcinoma or scheduled surgical anti-reflux interventions, we strongly recommend endoscopic visualization and grading using the LA classification system. We also advocate ambulatory pH monitoring in routine preoperative testing and unclear cases, which forms part of our individualized anti-reflux strategy.

Diagnosis of Barrett’s oesophagus

Barrett’s oesophagus is a condition named after Norman Rupert Barrett, the first to describe the appearance of columnar lined mucosa in the distal oesophagus, which he initially believed to be a failure of the embryonic epithelial lining.23 Today we know that BO is a metaplastic pre-malignant condition caused by the reflux of gastric contents that affects nearly 6% of the population in the Western world.24 Moreover, it is the most important risk factor for the development of oesophageal adenocarcinoma, the incidence of which has risen dramatically in recent years.25 Hvid-Jensen et al.26 conducted a nationwide cohort study to investigate the incidence of adenocarcinoma among patients with BO. They found that the annual risk of developing adenocarcinoma was 0.12% in this group; even higher risk has been described elsewhere.27

Endoscopy with biopsy sampling is the modality of choice to detect BO (Figure 1). Screening should target the distal oesophagus above the gastric folds. The metaplastic epithelium appears salmon coloured, differs from the normal, pale, glossy squamous oesophageal mucosa and can be described as a short (≤ 3 cm) or long (> 3 cm) segment.28,29 Today, the Prague C&M criteria are utilized for interobserver communication and the classification of BO.30 Here, the circumferential and maximum extent of endoscopically visible BO segments are delineated, offering high overall validity. After visualization of the salmon-coloured areas, standardized biopsies should be obtained. The Seattle protocol, named after the institution responsible for its development, recommends biopsies in BO at 2-cm levels and 1 cm distance when BO is dysplastic.31 Here, the pathologist is screening for intestinal metaplasia with goblet cells and dysplastic areas within the BO to establish final diagnosis. Nevertheless, a second expert opinion is mandatory in the management of dysplastic BO.32


Salmon-coloured area above the proximal gastric folds in a 49-year-old patient with chronic GORD. Histopathology of biopsies obtained from the distal oesophagus revealed the presence of non-dysplastic BO.


Diagnosis of BO is dominated by endoscopic screening and biopsy sampling. A metaplastic columnar lined oesophagus should be examined by standardized biopsies in accordance with the Seattle protocol. In cases of dysplasia, a second expert pathologist should confirm diagnosis.

Diagnosis of eosinophilic oesophagitis

Eosinophilic oesophagitis (EO) represents a chronic allergen-driven immunological disease in which type 2 T-helper cells infiltrate and remodel the oesophageal wall.33 EO overlaps with GORD in clinical presentation and diagnostic processes. Interestingly, the reflux of gastric contents induces eotaxin expression, which in turn leads to eosinophilic infiltration and hinders diagnosis.34 A large Chinese endoscopic study of more than 1000 participants found that oesophageal eosinophilia was present in nearly 6.6% of the general population, whereas EO could be established in only 0.4%.35

Eosinophilic oesophagitis has typically been understood to be caused by GORD and was not described as a distinct condition until 1993.36,37 Currently, diagnosis relies on clinical presentation, HRM and endoscopy and biopsy sampling. It is of significant clinical importance to understand that symptoms overlap with GORD and differ depending on age. For example, children are often incorrectly treated as they commonly present with symptoms of reflux disease. Liacouras et al.38 reviewed 381 children with EO and observed that 81.9% presented with symptoms of reflux, whereas only 18.1% presented with dysphagia. Furthermore, half of the children had hypersensitivity at different locations and 43% reported first-degree family members who were allergic to certain foods or had asthma. EO presents differently in adults. Sqouros et al.39 conducted a meta-analysis of 24 studies involving 325 patients: EO predominantly presented as dysphagia (93%) and food impaction (62%) in adults. Moreover, typical symptoms of GORD were noted in only 23.6% of patients.

Keeping these implications in mind, when EO is suspected it seems reasonable to start PPI therapy to differentiate the disorder from reflux-induced eosinophilia, commonly referred to today as PPI-responsive oesophageal eosinophilia (PPI-REE). Proof of concept was demonstrated by Ngo et al.,40 who presented a case series of three patients with oesophageal eosinophilia in whom PPI therapy decreased eosinophil numbers. Dellon et al.41 conducted a prospective trial in which patients who experienced dysphagia underwent an 8-week, twice-daily PPI treatment. Again, rates of eosinophilic infiltration were reduced, with over one-third of patients exhibiting PPI-REE.

Importantly, endoscopy and biopsy sampling play a major role in the detection of EO. As disease is not continuously infiltrating the oesophagus but rather has a patchy distribution, current guidelines recommend obtaining two to four biopsies from at least two oesophageal levels.42 A total of > 15 eosinophils per high-power field are needed to diagnose EO.43 Interestingly, there are some endoscopic transformations that can be visualized and support the diagnosis of EO (Figure 2). Micro-abscesses, mucosal oedema, rings, furrows and stenosis can be present but are not pathognomonic.44,45 Additionally, HRM offers a potent tool to rule out achalasia, hypercontractile oesophagus and spasmodic dysphagia.


A 57-year-old patient clinically presenting with dysphagia and concomitant asthma. After an initial 8-week course of double-dose PPI, endoscopic visualization revealed the presence of oedema, oesophegeal ring formation and longitudinal furrows. Histopathology revealed a count of > 15 eosinophils per high-power field, which established the diagnosis of EO.


At our centre, if clinical signs suggest that EO may be the cause of symptoms presented by a patient, we perform a PPI trial to exclude the presence of PPI-REE. Subsequently, we perform endoscopy to check for oesophageal changes and obtain samples from different oesophageal levels to establish diagnosis. As part of the diagnostic process, all patients undergo HRM to exclude potential coincidence of another dysphagia-inducing disorder.

Diagnosis of jackhammer oesophagus

Jackhammer oesophagus is a novel hypercontractile oesophageal motility disorder that was initially described using HRM. Swallows that exceeded a distal contractile integral (DCI) of 8000 mmHg/s/cm were originally regarded as pathological as they did not occur in healthy volunteers. Nevertheless, as the number of HRM studies grew, single hypercontractile swallows were also observed in control subjects.46 Therefore, the disease-defining criteria were changed to ≥ 20% of swallows with a DCI of > 8000 mmHg/s/cm in the context of normal contractile propagation (normal distal latency and contractile front velocity).46 Patients who fulfil these prerequisites usually present with dysphagia, non-cardiac chest pain and regurgitation (Figure 3), which clearly overlap with symptoms of GORD.


A 53-year-old patient presented in our outpatient clinic with intermittent chest pain and dysphagia. High-resolution manometry revealed that all swallows had elevated DCIs with a multipeaked appearance. This confirmed the clinical suspicion of JO.


Accurate medical history, symptom assessment and HRM represent diagnostic cornerstones for JO. Unresponsiveness to PPI therapy may be suggestive of hypercontractility. Importantly, cardiac pathologies have to be excluded before declaring chest pain as non-cardiac.

Interestingly, different pathophysiological mechanisms have been suggested for the development of JO. JO may be present as a primary motility disorder or it may be induced by GORD or by an outflow obstruction, expressed by an elevated integrated relaxation pressure. These various aetiological factors have to be acknowledged in the interpretation of JO and subsequent therapy.

In conclusion, patients with JO typically present with dysphagia, non-cardiac chest pain, regurgitation and exhibit ≥ 20% of swallows with a DCI of > 8000 mmHg/s/cm while failing to meet the HRM criteria for achalasia or oesophageal spasm. The identification of aetiological factors may be helpful in therapeutic considerations, but these factors have an unclear effect on the course of a patient’s disease.



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