Recent Advances in Diagnostic Testing for Gastroesophageal Reflux DiseaseThe purpose of this review is to present the recent advances in Gastroesophageal Reflux Disease (GERD) diagnostic approach and testing, and their use in clinical practice.
In general, the modern approach considers GERD as a syndrome rather than a disease, consequently constituting a diagnostic challenge in some cases. In the last decade, the diagnostic approach and methodology have changed as will be presented in this review.
GERD Diagnostic MethodologyThe Montreal definition of GERD mandates that troublesome symptoms and/or complications are present regardless of syndromes present and that those syndromes are caused by reflux .
Figure 1 The Montreal definition of GERD
It is widely accepted  that the diagnostic criteria for GERD syndromes are:
• Symptom complex is attributable to gastro esophageal reflux and of sufficient severity to compromise quality of life.
• Endoscopic findings of erosive esophagitis, stricture, or Barrett's metaplasia.
In the simplest case, when symptoms are typical and the patient responds to therapy trial designated to address those symptoms, no diagnostic tests are necessary. Diagnostic testing is required in the following scenarios: (1) To avoid misdiagnosis. (2) To identify complications of reflux disease. (3) In an evaluation of empirical treatment failures.
Hence, typical symptoms combined with vomiting, evidence of gastrointestinal blood loss, involuntary weight loss, dysphagia, anemia, chest pain or epigastric mass, should lead to further evaluation by endoscopy, thus avoiding misdiagnosis.
Diagnostic of dysphagia merits special consideration as it can be indicative of a stricture or malignancy. Dysphagia is a very common symptom among GERD patients: 37% of 11,945 patients who participated in esophagitis clinical trials, reported suffering from esophagitis without stricture or Barrett's esophagus. 83% of the cases were resolved with PPI therapy. . The discrepancy led the Montreal consensus group to suggest that only "troublesome" dysphagia warrants endoscopic investigation. The term "Troublesome" dysphagia is used when patients need to alter their eating habits, have symptoms of solid food getting impacted, in case there is a worsening pattern, or when dysphagia does not resolve with PPI therapy, which is significantly associated with failed esophagitis healing.
It is accepted that during endoscopic evaluation of dysphagia, multiple esophageal mucosal biopsy specimens should be obtained (preferably 5) in order to rule out eosinophilic esophagitis (EE / EoE), an allergic inflammatory condition of the esophagus expressed with dysphagia and heartburn. In the past, patients with EE were incorrectly diagnosed as GERD patients and were typically prescribed PPI, assuming that the problem was caused by excess exposure to stomach acid. However, it was since discovered that EE patients often have a normal esophageal pH exposure. Since symptoms of GERD and EE are often very similar, and pH monitoring test is not sufficient, differential diagnosis between GERD and EE is more complicated .
The increasing recognition of eosinophilic esophagitis as a confounding clinical entity has increased the potential value of biopsies when performing upper endoscopy for GERD. Traditional teaching claiming that histologic assessment of mucosa in the setting of GERD is of limited value due to poor specificity of histologic findings for GERD has been tempered by the need to differentiate eosinophilic esophagitis from GERD.
A recent systematic review ofeosinophilic esophagitis suggested that mucosal pinch biopsy specimens should be obtained from all patients who suffer from EE in the differential diagnosis. Biopsy specimens should be obtained regardless of the gross appearance of the mucosa, and multiple biopsy specimens should be obtained from different esophageal locations along the length of the esophagus. Given the high rate of eosinophilic disease in the setting of dysphagia without an obvious obstructing lesion, such subjects may benefit from mucosal biopsies. No evidence demonstrates the usefulness of routine esophageal biopsies in the setting of reflux symptoms without dysphagia .
Treatment failure is an important factor in GERD management, leading to further diagnostic testing that evaluates the cause of the troublesome symptoms that did not respond to empirical twice-daily PPI therapy. Did therapy fail due to troublesome symptoms attributable to reflux that were not resolved via PPI therapy or because the symptoms under consideration are not attributable to reflux? In current practice, this dilemma is usually faced when the patient has already been treated with twice-daily PPI therapy for a significant period and it is unlikely that endoscopy will reveal esophagitis .
This diagnostic technique is still considered the most useful initial diagnostic test conducted for GERD and/or other upper GI tract pathologies (USPSTF grade B, quality fair). Use of endoscopy is more important than mere direct visualization of the esophageal tissue appearance (esophagitis) as it includes a biopsy and a histopathology evaluation of the esophageal epithelium.
Esophageal pH monitoring
1. Catheter-based 24h pH monitoring test
A pH sensor is inserted through a catheter into the subject's esophageal lumen, located 5 cm above the LES, for a period of 24 hours. The probe is connected to a monitoring device which records the pH level in the esophagus.
2. Wireless capsule pH monitoring
A significant advance in pH recording has been the incorporation of an antimony electrode into a wireless capsule that transmits pH data to an external receiver via radiofrequency telemetry [5, 6]. The capsule is placed in the esophageal mucosa by endoscopy at 6 cm above the squamocolumnar junction (SCJ). Major advantages of the wireless system include patient tolerability and capability of performing extended recording for periods of 2-4 days. Discomfort associated with conventional catheter electrodes can lead patients to minimize or avoid reflux-provoking stimuli such as meals and physical activity, thus decreasing the detection of abnormal acid exposure. As a result of improved patient tolerability, the wireless pH system may provide a more accurate picture of an individual's acid exposure profile under more realistic conditions. The capsule system was better tolerated and preferred by patients, although a failure rate of approximate 15% was reported due to failure or premature detachment.
Extended pH monitoring using wireless technology improves the detection of reflux and increases the sensitivity of testing. Several studies have demonstrated that increasing the recording period from 24 to 48 hours increases the sensitivity of pH monitoring by 10%-26%.
Another advantage of a prolonged monitoring period is the ability to perform testing, both on and off PPI therapy, in a single study. The off-therapy testing reveals the presence and duration of abnormal acid reflux episodes and maximizes symptom-reflux association owing to the greater number of symptom and reflux episodes. It is used to document the presence of acid reflux in patients with non-erosive reflux disease (NERD) who are being considered for anti-reflux endoscopic or surgical therapy. Off-therapy testing is also used for patients with a low index of suspicion for having reflux disease, such as those showing no symptomatic response to empiric trials of PPI therapy, or those with atypical symptoms. In contrast, pH testing for patients receiving PPI therapy can provide documentation of the effectiveness of PPI therapy.
pH Impedance Testing
1. Multichannel Intraluminal Impedance
Multichannel intraluminal impedance (MII), a method of detecting intraesophageal bolus movement, based on measuring the resistance to alternating electrical current (i.e., impedance) of the content of the esophageal lumen was first described by Silny in 1991. Multiple electrodes positioned along the axial length of the impedance catheter determine the proximal extent of a reflux event.
The conductivity of the empty esophageal lumen is relatively stable, with the electrical circuit registering values 2000 to 4000 ohm. The appearance of a liquid bolus in the impedance-measuring segment is recognized as a rapid drop in impedance as the increased ionic content of the bolus improves the electrical conductivity between the two electrodes. The impedance remains low as long as the bolus is present between the two electrodes and starts rising once the bolus is cleared from the segment by the esophageal peristalsis.
It is capable of differentiating ante grade from retrograde bolus movement, as well as liquid from gas reflux.
a - Drops in impedance starting proximally and moving distally are indicative of antegrade bolus movement as seen during swallowing.
b - Drops in impedance starting distally and moving proximally are indicative of retrograde bolus movement as seen during reflux.
The presence of gas in the impedance-measuring segment is recognized by a rise in impedance typically above 5000 ohm. Since there are no electrical charges to close the circuit when the two electrodes are suspended in air, impedance will return to the baseline values once the air bolus has passed and the electrodes are back in contact with the esophageal mucosa.
A pH electrode incorporated into the recording assembly allows for simultaneous detection and 24 hours recording of acid content. Patient tolerability is similar to conventional pH monitoring as this is a catheter-based system.
Currently, there is a definite role of pH-impedance testing in clinical practice . As PPI use for GERD has increased and is being used as a clinical trial, patients suffering from typical or atypical reflux symptoms in spite of PPI therapy and without erosive esophagitis, often pose a diagnostic and management challenge. The association of non-acid reflux events with symptoms, which has been demonstrated in several studies, turned Impedance-pH monitoring to be the most sensitive technique for the detection of reflux events. Since pH-impedance testing is able to detect, localize and classify reflux events as acidic, weakly-acidic or alkaline, simultaneously, it has been posited as the future standard for reflux detection and monitoring . The more comprehensive reflux detection, the more individualized therapy in patients based on their reflux profile as well as predict response to medical or surgical treatment.
Despite the pH monitoring superiority, theoretically, the clinical utility of combined pH-impedance monitoring is still being investigated and the conventional pH testing has demonstrated high sensitivity and specificity in patients with GERD and erosive esophagitis. However, symptom association for regurgitation on PPI therapy is better detected by impedance testing than pH testing alone as well as NERD diagnosis.
2. Esophageal Mucosal Impedance (MI)
Single-channel esophageal mucosal impedance catheters are designed to diagnose chronic GERD more quickly and efficiently than impedance or pH monitoring .
The MI device consists of two circumferential sensing rings with a length and separation of 2 mm mounted on a soft, 2-mm diameter catheter that is advanced through an upper endoscope. Electrodes along its length are wired to an impedance voltage transducer.
New data recently presented at the DDW 2013 shows mucosal impedance to be a reliable indication for reflux diagnosis and a naval technology for better GERD diagnosis (David Armstrong, "State of the Art Lecture: Improving the Diagnosis of GERD: Which Test and When?"; Michael F. Vaezi "Esophageal Mucosal Impedance Measurement: Time to Move Beyond pH Monitoring for GERD Diagnosis" )..
Narrow-Band Imaging (NBI) refers to an imaging technique for endoscopic diagnostic medical tests, where light of specific blue and green wavelengths is used to enhance the detail of certain aspects of the surface of the mucosa. A special filter is electronically activated by a switch in the endoscope leading to the use of ambient light of wavelengths of 440 to 460 nm (blue) and 540 to 560 nm (green). As peak light absorption of hemoglobin occurs at these wavelengths, blood vessels appear very dark, allowing improved visibility and identification of other surface structure.
The use of NBI to enhance the contrast between esophageal and gastric mucosa and improve visualization of the SCJ has been studied in GERD patients. NBI has been shown to increase reproducibility in grading esophagitis . A prospective study has evaluated the use of NBI to differentiate erosive esophagitis from NERD and controls , in which a total of 107 patients underwent endoscopy with NBI.
Compared to conventional endoscopy, NBI allowed for an increased detection of micro-erosions, vascularity, and mucosal islands ("pit patterns"). In terms of differentiating patients using these criteria, erosive esophagitis and NERD patients had a higher prevalence of micro-erosions and vascularity compared to controls. Erosive esophagitis and NERD patients were only differentiated by an increased vascular surface in the absence of pit patterns (sensitivity 86.1%, specificity 83.3%). Although NBI with endoscopy is unlikely to serve as a standard for the diagnosis of GERD, it could serve as an adjunct in the classification of erosive and non-erosive disease.
Salivary Pepsin Test
Pepsin is an enzyme produced and secreted by chief cells in the stomach.
Some of the patients with gastroesophageal reflux disease (GERD) suffer from laryngopharyngeal reflux (LPR), However, there is no reliable diagnostic test for LPR as there is for GERD.
Detection of pepsin in laryngeal epithelium or sputum (rapid salivary pepsin test or no-invasive pepsin test) should provide an evidence for reflux of gastric contents to the larynx, and serve as diagnostic test of LPR. It was tested in a prospective study in patients with LPR symptoms undergoing antireflux surgery .
A pilot study by Nicola de Bortoli showed high saliva pepsin level in 71% of GERD patients ("Use of a Non-Invasive Pepsin Diagnostic Test to Detect GERD: Correlation with MII-pH Evaluation in a series of suspected NERD patients", DDW 2013 conference).
The use of histological characteristics can assist in the diagnosis of GERD, and more specifically NERD.
Dilation of the intracellular space (DIS) has emerged as a promising diagnostic marker of NERD [13, 14]. Moreover, there is also evidence that DIS can be affected by PPI treatment, potentially serving as a clinical endpoint in therapy. However, definitive histological parameters of DIS have yet to be defined for reflux disease. Histological parameters such as basal cell hyperplasia and papillae elongation have proven less sensitive or specific for GERD, but might ultimately play a role when used in combination with DIS . Ultimately, histopathological characteristics will likely be used in concert with other modalities to better diagnose and characterize GERD.
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