Vaezi M.F., Sifrim D. Assessing Old and New Diagnostic Tests for Gastroesophageal Reflux Disease / Gastroenterology. 2018;154:289–301.

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Авторы: Vaezi M.F. / Sifrim D.

Assessing Old and New Diagnostic Tests for Gastroesophageal Reflux Disease

Michael F. Vaezi1, Daniel Sifrim2

1 Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee; and
2 Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Аннотация на русском языке

A detailed critique of objective measurements of gastroesophageal reflux disease (GERD) would improve management of patients suspecting of having reflux, leading to rational selection of treatment and better outcomes. Many diagnostic tests for GERD have been developed over the past decades. We analyze their development, positive- and negative-predictive values, and ability to predict response to treatment. These features are important for development of medical, surgical, and endoscopic therapies for GERD. We discuss the value of available diagnostic tests and review their role in management of patients with persistent reflux symptoms despite adequate medical or surgical treatment. This is becoming a significant health economic problem, due to the widespread use of proton pump inhibitors. GERD is believed to cause nonesophageal symptoms, such as those provoked by ear, nose, throat, or respiratory disorders. We analyze the value of GERD diagnostic tests in evaluation of these troublesome, nonesophageal symptoms.

Keywords: GERD; Mucosal Impedance; Reflux Monitoring.

Abbreviations used in this paper: DGER, duodenogastroesophageal reflux; EoE, eosinophilic esophagitis; GERD, gastroesophageal reflux disease; MI, mucosal impedance; NBI, narrow-band imaging; NERD, nonerosive reflux disease; PPI, proton pump inhibitor; PSPW, postreflux swallow-induced peristaltic wave; SAP, symptom association probability; SI, symptom index.

Conflicts of interest. The authors disclose the following: Vanderbilt and Sandhill co-own the patent on MI technology.

Funding. Michael F. Vaezi has a research grant from Sandhill Scientific Inc. (Denver, Colorado). Daniel Sifrim has research grants from Sandhill Scientific (Denver, Colorado) and Reckitt Benckiser (Hull, UK).

Gastroesophageal reflux disease (GERD) is a common condition affecting up to 20% of the Western world.1 It is a challenge to identify patients with GERD, because of suboptimal performance of diagnosis tests. Patients suspected of having GERD are first tested for a response to acid-suppressive therapy, often with a proton pump inhibitor (PPI). This approach, known as the PPI trial, is used based on symptoms believed to be caused by GERD. Heartburn and regurgitation are the 2 cardinal symptoms of GERD, although the disease can cause other symptoms, such as chest pain or pulmonary, ear, nose, or throat symptoms.2

However, neither patients’ symptoms nor response to PPI are strongly associated with a final diagnosis of GERD. Heartburn and regurgitation have suboptimal sensitivity (30%–76%) and specificity (62%–96%) in identification of patients with GERD.3,4 GERD is found in only 54% of patients with a dominant symptom of heartburn and in only 29% of patients with a predominant symptom of regurgitation.5 This is likely due to the significant overlap among GERD, gastroparesis, functional dyspepsia, and eosinophilic esophagitis, which all cause symptoms of heartburn and regurgitation. Symptoms alone are therefore not adequately sensitive or specific to guide therapeutic strategies. Alternatively, response or lack of response to an initial trial of PPI therapy does not rule in or out GERD as the possible etiology of continued symptoms.

Figure 1. Diagnostic tests for GERD.

Diagnostic tests for GERD are used in presurgical or endoscopic interventions (to ensure that patients have GERD) and for patients with continued symptoms despite an initial PPI trial. Continued symptoms with PPI use is the most common and the most challenging indication for a diagnosis of GERD. Given the complexity of patient presentations and technical advances in the field of GERD research, it is important yet challenging to determine whether reflux contributes to symptoms in patients who do not respond to aggressive acid suppression. Optimizing strategies to improve appropriate GERD diagnosis is critical to improve patient outcomes and reduce unnecessary cost from suboptimal diagnostic testing and a greater understanding of the pathophysiology and treatment of GERD symptoms in the presence of normal esophageal acid exposure.

We review technical developments in tests in for GERD over the past decades (Figure 1), and analyze their ability to identify or exclude GERD and adequately predict response to treatment (Table 1). These abilities are important for development of medical (new acid blockers and antireflux drugs), surgical, and endoscopic therapies in GERD.

Table 1. Advantages and Disadvantages of Diagnostic Methods for GERD

GERD questionnaires- Useful for primary care physicians and gastroenterologists-Unable to discriminate true NERD from reflux hypersensitivity and functional heartburn
- Sensitivity 65%, specificity 70%
PPI test- Good in primary care for patients without alarm symptoms- Positive in peptic ulcer disease and functional dyspepsia
- Specificity 24%–65%
Endoscopy- Enables diagnosis of esophagitis, Barrett esophagus, EoE, and GERD complications
- Excellent specificity
- Poor sensitivity; 70% of patients have normal mucosa
- High cost but most patients undergo testing as part of evaluation
Narrow-band imaging- Distinguishes normal from NERD and reflux esophagitis
- Correlates with esophageal acid exposure
- Unclear effects for patient management and/or response to treatment
- Not readily available in all centers
Biopsies- Enables the diagnosis of microscopic esophagitis and rules out EoE
- Normal in functional heartburn
- 15% of healthy individuals may have microscopic esophagitis
- Requires an experienced pathologist
Catheter-based pHmetry- Easy to perform
- Relatively noninvasive
- Enables detection of increased acid exposure and different locations along the esophagus and proximal stomach
- Accurate automatic analysis
- Unpleasant for patients, which might lead to behavior modification
- Day-to-day variability
- Sensitivity values below 71% in patients with normal findings from endoscopy
- Requires manometry
Wireless pHmetry- Enables prolonged monitoring (48–96 hours)
- Overcomes day-to-day variability and patients’ behavioral modification
- Better tolerated by patients
- Accurate automatic analysis
- Expensive
- Requires endoscopy
- Some patients have odynophagia requiring removal
- Capsule may detach prematurely leading to inaccurate/suboptimal results
pH-impedance- Enables detection of nonacid reflux, aerophagia, and supragastric belching
- Enables assessment of proximal reflux
- Best distinction between patients with GERD versus functional heartburn
- Unpleasant for patients
- Day-to-day variability
- Inaccurate automatic analysis (requires time-consuming manual editing)
- Requires manometry
- Unknown clinical relevance of non–acid reflux in the setting of aggressive acid suppression
MI- Decreased in esophagitis, NERD, Barrett esophagus and EoE
- Data acquired in short period, eliminating the need for ambulatory tests
- Can measure MI values all along esophageal axis and radial distribution
- Normal in healthy individuals and functional heartburn
- Requires endoscopy but most patients will need endoscopy as part of workup
- Liquid and air esophagus may confound the results
- Cost unknown
- Undergoing validation studies
PSPW and mean nocturnal baseline impedance- Decreased in esophagitis, NERD, Barrett’s esophagus, and EoE and normal in functional heartburn- Requires catheter-based pH-impedance
- Requires manometry
- Uncomfortable for patients
- Uncertainty that impedance electrodes in contact with esophageal epithelium
- Requires time-consuming manual calculations (research only)
Salivary pepsin concentration- Noninvasive
- Detected in high proportion of patients with GERD, and in high concentrations
- Moderate sensitivity and specificity
- Requires further validation
Endoscopy and Biopsies
In patients with symptoms of GERD, an early endoscopy should be considered if their symptoms provide evidence for complicated disease (ie, dysphagia, weight loss, hematemesis), eosinophilic esophagitis, infection, or pill-induced injury.6 Failure to respond to appropriate antisecretory medical therapy should also prompt evaluation with esophagogastroduodenoscopy. Furthermore, endoscopy should be used to diagnose Barrett’s esophagus in high-risk patients (white men with a high body mass index, 50 years or older, with chronic GERD symptoms).7 Additionally, endoscopy is often performed as part of the preoperative evaluation of patients being considered for antireflux surgery or for the placement of wireless esophageal pH monitoring devices. GERD can be diagnosed with confidence when endoscopy reveals esophagitis, but endoscopy may be normal in approximately two-thirds of untreated patients with heartburn and regurgitation. There can be significant interobserver variations in mild esophagitis (Los Angeles Classification of GERD grade A). Therefore, many experts consider only grades B or higher as objective evidence of GERD.8

In patients with typical reflux symptoms, endoscopic findings may include esophagitis, strictures, Barrett’s esophagus, and typical features of eosinophilic esophagitis (EoE). Endoscopy identifies these disorders with high levels of specificity.9 However, endoscopy detects GERD with a low level of sensitivity and diagnostic yield, because most patients do not have esophageal erosions, either because of nonerosive reflux disease (NERD) or recent PPI treatment.10

The role of biopsies for diagnosis of reflux disease in adults is controversial. Clinicians who are against the use of biopsies for diagnosis of GERD claim that this method is time consuming, expensive, requires expert pathologists, and has poor sensitivity. Proponents of use of biopsies suggest that clinicians should consider obtaining histology when the pretest probability for GERD is high and endoscopy does not reveal erosions11 or in patients with NERD and some degree of dysphagia to exclude EoE or other mimics of GERD.

In patients with NERD, histologic assessment of mucosal biopsies can demonstrate elongated papillae, basal cell hyperplasia, dilated intercellular spaces, and infiltration by neutrophils and/or eosinophils.12 A histologic global score that included all these findings differentiated patients with NERD from those with functional heartburn and healthy individuals. This study used impedance-pH monitoring as standard.13 Individual parameters or global scores identify patients with microscopic esophagitis with moderate levels of sensitivity; this is because 20% of patients have normal biopsies, and microscopic esophagitis is present in 15% of healthy individuals and in some patients with functional heartburn.14,15 The location of esophageal biopsies might be important, in that abnormalities might be more likely in the esophageal quadrant that follows the gastric small curvature.16 Ideally, a simple, reproducible, and sensitive histologic biomarker that does not require detection by an expert pathologist or expensive technology could be of great help in clinical practice.

Recent studies proposed that total epithelial thickness of at least 430 mm in the distal esophagus might be a marker of GERD, diagnosed via endoscopy and esophageal pH monitoring.11,17 This marker, and new histologic parameters, should be tested for its ability to identify patients with GERD who have normal symptoms and findings from endoscopy.
Barium Studies
Fluoroscopy tracking of barium swallows (and it is still performed in many centers) can detect spontaneous or provoked gastroesophageal reflux. With this method, reflux is provoked by maneuvers such as straight leg raises, coughing, Valsalva maneuver, and a water siphon test. Barium esophagrams with double contrast can detect signs of esophagitis, but identify esophagitis itself with a low level of sensitivity.18

On the other hand, detection of reflux during barium tests identifies patients with GERD with low sensitivity and specificity values. Spontaneous or induced reflux of barium can be seen in healthy subjects and can be absent from patients with GERD. Although previous studies reported that barium tests detect GERD with sensitivity and specificity values of approximately 70%,19 a more recent study, which used impedance-pHmetry as a standard, found barium tests to identify patients with GERD with lower levels of sensitivity (67%) and specificity (47%); barium tests could not properly identify patients with increased acid exposure or positive reflux symptom association. The authors concluded that the presence or absence of reflux during barium esophagography is not a predictor of the frequency of gastroesophageal reflux and does not have any value for the diagnosis of GERD.20
Ambulatory Reflux Monitoring

The original role of ambulatory pH testing was to determine the presence of reflux in symptomatic patients with normal upper endoscopy. Patients with classic symptoms of reflux, such as heartburn and regurgitation, with normal endoscopy findings, underwent 24-hour ambulatory pH tests to determine if their symptoms were caused by abnormal esophageal acid exposure before starting therapy. This was in the era of less-optimal acid-suppressive therapy, necessitating the added physiologic confirmation of GERD. However, over time and with the use of more aggressive acid-suppression methods (PPIs), pH tests have begun to detect GERD with lower levels of specificity. Today, esophageal reflux monitoring is reserved for patients with symptoms that are refractory to PPIs.7,21 This is accomplished with either catheter-based pH or impedance-pH monitoring or wireless pH monitoring techniques. Wireless pH monitoring is often performed for patients off PPI therapy.

Ambulatory reflux monitoring is used to document the presence of reflux (in patients who have not undergone endoscopy and are being considered for surgical or endoscopic therapies), to determine if reflux might be the cause of symptoms in patients who have undergone surgical or endoscopic therapies yet have continued symptoms, to assess adequacy of reflux control in patients with complications of GERD (such as Barrett’s esophagus), and to evaluate symptoms in patients refractory to PPIs (the most commonly reason for diagnostic testing in patients with GERD).

Indications for ambulatory reflux monitoring:
  • To document abnormal esophageal acid exposure in endoscopy-negative patients considered for endoscopic or surgical antireflux procedures
  • For patients who have undergone endoscopic or surgical reflux therapy who continue to have GERD symptoms
  • To assess the adequacy of acid control in patients with complicated GERD, such as Barrett’s esophagus
  • For evaluation of PPI-refractory patients (most common indication)
pH Monitoring Methods

Standard catheter-based pH monitoring measures distal esophageal acid exposure using a single pH electrode catheter that is passed through the nose and positioned 5 cm above the superior margin of the lower esophageal sphincter, determined by manometry. Multiple-probe catheters have additional pH electrodes located more proximally in the esophagus or the hypopharynx with or without gastric pH electrode. These electrodes allow detection of proximal esophageal and/or pharyngeal acid reflux events and assess degree of gastric acid suppression, which may be useful in the evaluation of extraesophageal GERD symptoms, particularly laryngitis, chronic cough, and asthma. However, proximal22 and hypopharyngeal23,24 pH electrodes are no longer commonly used because they detect esophageal acid exposure with low levels of sensitivity.

Posterior oropharyngeal pH monitors have a teardrop tip with a colored light-emitting diode and do not require manometry.25 This device is used for patients with laryngeal findings that are believed to be related to GERD. In-depth in vitro and in vivo validation studies compared this device to current standard pH catheters, and showed it to be superior in time to reach equilibrium pH, but found no difference in its ability to detect vaporized liquids, as initially believed possible.26 There was initial excitement about the ability of posterior oropharyngeal pH monitoring to predict response to acid-suppressive therapy,27 based on a small uncontrolled study. However, enthusiasm decreased after a larger study found that this technique did not predict response to PPI therapy in 34 patients with suspected GERD-related laryngeal symptoms.28

Due to inherent limitations of catheter-based pH monitoring, a wireless capsule pH probe was developed in 2003. A capsule was positioned in the distal esophagus that wirelessly transmitted pH measurements to a recording device on patients’ belts.29 In addition to being wireless, this device records pH measurements for 48 or 96 hours (Figure 2A).30 Patients tolerate it better than the catheter systems, and report less interference in their daily activities and higher overall satisfaction.31 The capsule pH probe also detects reflux events with higher levels of sensitivity, due to prolonged monitoring, improved patient compliance, reduced impairment of patients’ daily activity, and decreased likelihood of catheter movement. One limiting factor for its use is its higher cost than the catheter system; cost limits the availability of the capsule pH probe worldwide.

The rationale for performing pH testing before surgical or endoscopic therapy is to ensure objective evidence of pathologic reflux. Earlier studies had associated abnormal pH findings before surgical fundoplication with favorable outcomes after treatment.32,33 For example, in a study of 199 patients undergoing laparoscopic Nissen fundoplication, abnormal 24-hour pH scores (odds ratio 5.4), typical GERD symptoms (odds ratio 5.2), and response to acidsuppressive therapy (odds ratio 3.3) increased odds of reduced symptoms after surgery; however, the ability of pH monitoring to predict outcomes of surgery has been recently questioned.34–36 A study evaluating surgical outcomes of 115 patients (79 with typical GERD and 36 with extraesophageal GERD symptoms) found that only full or partial response to acid-suppressive therapy was associated with a good outcome after surgery. Severity of acid reflux, based on pH tests, symptom indices, degrees of esophagitis, and hiatal hernia size were not associated with symptom response35; however, given likelihood of placebo response to empiric PPI therapy, it would be wise to combine presence of abnormal reflux parameters with response to PPI therapy as factors that predict outcome of surgery.

Bile Monitoring

Duodenogastroesophageal reflux (DGER) is due to regurgitation of duodenal contents (bile acids trypsin and bilirubin) into the stomach with subsequent reflux in to the esophagus. Measurement of DGER may be important because factors other than acid and pepsin could contribute to mucosal injury and symptoms in patients with GERD.37,38 The fiberoptic spectrophotometer Bilitec 2000 (Synectics, Stockholm, Sweden) was used in the 1990s and early 2000s to study the role of duodenal contents in GERD; it measured bilirubin as a marker of bile reflux. These studies showed that DGER can cause esophageal mucosal damage, especially when mixed with gastric acid and pepsin, and cause symptoms, especially in patients who are on PPI therapy or have undergone gastrectomy.38–40 Although Bilitec was an important advancement in the assessment of DGER, it was replaced by impedance-pH monitoring in the clinic. There is a resurgence of interest in Bilitec, given the increasing prevalence of refractory GERD and symptomatic reflux in patients who have undergone gastrectomy or bariatric surgery.

Monitoring for Weak or Nonacidic Episodes

After meals or during PPI treatment, most reflux episodes are weakly acidic or nonacidic; these episodes can provoke typical or atypical reflux symptoms.41 Nonacidic reflux is difficult to detect with pHmetry. Esophageal impedance monitoring allows detection of reflux events regardless of the pH. Impedance and pH monitoring are usually performed in combination, and a distinction can be made between acid (pH <4), weakly acidic (pH 4–7), and alkaline (pH >7) reflux episodes. This technique also allows distinction of reflux composition (air, liquid, or mixed), proximal extent, and clearance times (Figure 2B and C). Impedance-pH monitoring provides identical information as catheter-based pHmetry and offers the additional possibility of detecting patients with a positive association between symptoms and weakly acidic and/or gas reflux (although the clinical value of reflux symptom association is recently questioned). Furthermore, impedance-pH monitoring is much more sensitive than pHmetry in detecting rumination and belching disorders.42,43

Figure 2. Tracking reflux. (A) pH Tracing of a 4-day wireless pH study showing pathologic reflux. Days 1 and 2 shown in top and days 3 and 4 in the bottom tracings. This study illustrates the day-to-day variation in gastroesophageal reflux, particularly that there is no abnormal reflux during the first 24 hours. Pathologic acid exposure is evident on the second and fourth nights in the supine position (green shaded areas) as well as in the upright positions in 3 of the 4 study periods. (B) Multichannel impedancepH tracing showing 2 episodes of non- and weakly acidic material as well as 2 episodes of swallows of liquids. The bottom channel (channel 7 in red) indicates the pH of the refluxate, whereas channels 1 to 6 measure the extent of decrease or increase in baseline impedance values due to reflux or swallows. (C) ImpedancepH tracing showing supragastric belching events associated with acid gastroesophageal reflux.

Impedance-pH monitoring is considered the most accurate and detailed method to assess gastroesophageal reflux44 and increases the diagnostic yield of reflux monitoring in patients with GERD.45,46 Impedance-pH tracings should be analyzed in a quantitative fashion, as in pHmetry, by searching for increased numbers of reflux episodes (acid and nonacid), prolonged acid or volume exposures, or increased numbers of proximal reflux events. The impedance-pH parameters that best predict response to therapy are a matter of debate. On the one hand, studies have shown that acid exposure time, rather than impedancebased measurements, better predict response to PPI therapy in patients with typical symptoms,47 or to fundoplication for atypical presentations.48 On the other hand, good outcomes after antireflux surgery have been reported for patients with an abnormal number of reflux episodes (acid and nonacid combined) as detected by impedance-pH.49 However, these studies lacked control groups; there is also no information on whether patients with low total number of reflux episodes have poor outcomes after antireflux surgery.

Antireflux medical or surgical therapy, therefore, cannot be recommended based solely on an increased number of impedance-detected reflux episodes.50 A recent large cohort study of medically and surgically managed patients who underwent pH-impedance monitoring identified increased esophageal acid exposure, and a correlation between symptoms and reflux episodes detected by impedance, as factors associated with symptom reduction after therapy.51

Clinicians debate whether to perform reflux monitoring on or off PPI therapy. Most patients are referred for reflux monitoring because they did not respond to PPI treatment. If the pretest probability of GERD is low, reflux monitoring off PPI therapy can help rule out GERD if the tests results are normal. Recent data (unpublished; 2017) indicate that “low pretest probability” requires better definition for patients with esophageal and extraesophageal syndromes, and the normal pH cutoff value (4.2% or 5.5%) might be adjusted to include only patients with moderate to severe reflux. Patients without esophagitis who are considered for a surgical or endoscopic antireflux procedure also should be tested off PPI therapy, which modestly increases the diagnostic yield of impedance monitoring, compared with pH monitoring alone.52 If a patient has a high pretest probability of GERD (due to positive findings from endoscopy or reflux monitoring) with typical symptoms that are refractory to PPI treatment, it is useful to perform pH-impedance monitoring on PPI, to determine if he or she received an insufficient PPI dose or has reflux-related residual symptoms.50,53 For patients with refractory reflux symptoms, pH-impedance studies performed while patients were on PPI therapy have shown that many persistent symptoms can be time-related to reflux. In most cases, the number of reflux episodes is not increased, but patients have enhanced perception of these reflux episodes. Therefore, impedance-pH monitoring has significantly contributed to the concept of hypersensitivity as an important factor in treatment-resistant GERD.54

Symptom Association Analysis

In addition to quantitative measurement of esophageal acid or nonacid exposure, pH and impedance monitoring allow measurement of association between reported symptoms and acid or nonacid reflux events. Symptom index (SI) and symptom association probability (SAP) are the 2 most commonly used indices.55,56 The SI calculates the percentage of reflux-related symptom episodes during the study period.55 This approach has been criticized because it does not incorporate the total number of reflux events in its calculation. The SAP was subsequently developed to overcome this limitation.56 The SAP is calculated based on constructing a 2 х 2 contingency table of symptom and reflux events. SAP is now the metric commonly used in research and clinical practice despite limited information about its accuracy.

The SAP is superior to SI (leading to frequent use of SAP) based on its statistical analysis, despite limited outcome metrics. Rome IV therefore recommends use of SAP to differentiate reflux hypersensitivity from functional disorders, despite lack of response to PPI therapy, and normal physiologic reflux parameters in both groups.57 This distinction is problematic given the lack of association between SAP scores and treatment outcome in patients with GERD, poor reporting of symptoms during ambulatory reflux monitoring by most patients, and high level of variation in symptom association among patients with mild to no reflux; SAP is commonly used to assess all these patients.35,48,58,59 Therefore, positive SAP scores in patients who do not respond to PPI therapy and have normal results from esophageal ambulatory reflux monitoring should not be used to escalate GERD therapy. Positive results from SAP analysis alone should never be an indication for antireflux surgery.

Novel Impedance Parameters

Other impedance parameters (apart from number of reflux episodes or volume exposure), such as gas movement, impedance baseline, and the postreflux swallow-induced peristaltic wave (PSPW), were recently proposed to increase the diagnostic yield for reflux disease. Impedance allows a precise tracking of intraesophageal air movement and distinction between typical gastric belching from supragastric belching.60 In patients with GERD, supragastric belching is common. Moreover, in many patients with GERD, supragastric belching also can provoke acid reflux and contribute to the total esophageal acid exposure.61,62

Analysis of impedance-pH monitoring tracings allows measurements of baseline impedance (stable impedance values in the absence of swallow, belching, or reflux-induced impedance changes). Impedance baseline values correlate with esophageal mucosal integrity status.63 Low baseline impedance is associated with increased acid exposure64 and sensitivity to acid.65 From the diagnostic viewpoint, baseline impedance is normal in patients with functional heartburn.66 Low baseline impedance is observed in patients with erosive esophagitis, Barrett’s esophagus, eosinophilic esophagitis, or bolus stasis secondary to severe esophageal motility disorders. The mean nocturnal baseline impedance consists of measuring baseline impedance during the overnight rest period without swallowing.67 Mean nocturnal baseline impedance was lower in patients with GERD and typical symptoms who responded to PPI therapy or antireflux surgery compared with those who did not respond, so this parameter might be used to predict response to treatment.68,69

Impedance changes also can be used as a measure of peristalsis-associated esophageal clearance.70 Gastroesophageal reflux is followed by reflex swallow-induced or secondary peristalsis. The clearance effect of such peristaltic activity can be measured as changes in impedance after reflux. The PSPW index was designed to assess the clearance abilities in patients with different GERD phenotypes. Similar to impedance baseline, the PSPW index is low in patients with GERD and NERD but normal in patients with functional heartburn.71 The PSPW index might have diagnostic and prognostic complementary value, particularly when pH-impedance is performed on PPI. However, calculation of PSPW is tedious, with significant interobserver variability; as such, it is difficult to recommend for use outside of research.50
Novel Techniques
Salivary Pepsin Measurement

Pepsin is a proteolytic enzyme whose precursor pepsinogen is released solely by gastric chief cells. The measurement of pepsin levels in saliva was proposed as a noninvasive method to detect GERD.72 Different assays can be used to measure salivary pepsin. Immunologic assays are considered superior to enzymatic assays, which are difficult to obtain and standardize and lose sensitivity under certain conditions.73 Researchers performed a pilot study of an immunologic assay, with a lateral flow device, in 58 patients with GERD and 51 controls. All patients with GERD underwent esophagogastroduodenoscopy and wireless 48-hour pH monitoring. The salivary pepsin test identified patients with GERD (based on abnormal pH and/or esophagitis) with a positive-predictive value of 81% and negative-predictive value of 78%.74 A study of an improved immunologic assay found that up to one-third of healthy asymptomatic individuals had low concentrations of pepsin in their saliva. A higher proportion of patients with GERD symptoms (with pathological acid exposure and/or a correlation between reflux and symptoms in pH-impedance tests) tested positive for salivary pepsin, and had higher concentrations, than asymptomatic healthy individuals (controls).

These findings did not allow differentiation between patients with GERD vs patients with hypersensitive esophagus. However, patients with functional heartburn had low salivary levels of pepsin (similar to controls). The assay for salivary pepsin identified patients with reflux-related symptoms, vs patients with functional heartburn, with moderate levels of sensitivity and specificity, similar to questionnaires and reflux monitoring.75 This technique might be best suited for patients with proximal reflux and extraesophageal symptoms. Likewise, the noninvasive nature of the method would greatly facilitate diagnosis of pediatric GERD.

Several studies measured salivary pepsin (using immunologic and enzymatic assays) in patients with extraesophageal GERD symptoms. Results of these studies were not conclusive. Whereas some studies suggested that salivary pepsin can help diagnosis of laryngopharyngeal reflux,76–79 recent studies80,81 failed to show clinical benefit for this test. One study examined the ability of salivary pepsin to discriminate between asymptomatic volunteers (controls) and subjects with a combination of laryngeal and reflux symptoms (laryngeal, with or without reflux). Although the group with a combination of laryngeal and reflux symptoms had a higher concentration of salivary pepsin, the test failed to distinguish between controls and subjects with the combination of laryngeal and reflux symptoms with good levels of sensitivity or specificity.

An assay that measures salivary pepsin levels would be an ideal noninvasive diagnostic test for children suspected of having GERD. Unfortunately, studies found that this test was not useful in diagnosis of GERD, either with typical or extraesophageal symptoms.82,83 Studies of the salivary pepsin assay in adults with typical GERD symptoms have reported promising results, comparable to those from pHmetry or pH-impedance monitoring. Unfortunately, studies in patients with extraesophageal symptoms or suspicion of pediatric GERD (the most interesting applications for this technique) have yielded either inconclusive or negative results. The lack of standardized sampling protocols and changing reference normal values (due to manufacturing modifications of antibodies and lateral flow device) has hampered our ability to translate initial promising results into clinical practice. Concentration of salivary pepsin may not be the best measure of severity of reflux because of the wide range observed in individuals over 24 hours. Defining a regimen for optimal saliva collection may help to improve this test as a biomarker for GERD. In the meantime, promising results obtained in adult patients with typical GERD symptoms, need to be reproduced by different centers before clinical application.

Mucosal Impedance

An important clinical observation in catheter-based impedance-pH monitoring was that in patients with severe reflux disease (esophagitis and Barrett’s esophagus), analysis of ambulatory impedance measurement was not reliable, because the baseline values were too low to be accurately interpreted. This observation indicated that (true) GERD may result in chronic changes on the esophageal epithelium that might be difficult to detect by impedance during prolonged reflux monitoring.

This concept sparked the development of mucosal impedance (MI) (Figure 3). MI involves endoscopic placement of a probe that goes through the working channel of the endoscope and makes direct contact with the mucosa. The probe is used to measure impedance along the mucosa84 without the need for a cumbersome overnight catheter. Initial studies with this device correlated MI values with epithelial changes due to GERD or EoE.84–86 MI allows differentiation of GERD (both erosive and nonerosive GERD) from EoE, achalasia, and a healthy esophagus84 (Figure 3). MI measurements correlate inversely with eosinophil counts (lower impedance correlates with higher eosinophil counts). A prospective double-blinded study showed that the MI pattern along the esophageal axis identifies patients with EoE with a 91% positive-predictive value and high levels of sensitivity and specificity, without a need for histologic assessment.86,87 Validation studies showed that MI was lower at the sites of erosive GERD than nonerosive areas, and that impedance values gradually increased from the distal to proximal esophagus in patients with GERD but not individuals without GERD85 (Figure 3B). Furthermore, MI detects GERD with higher specificity than pH monitoring (95% vs 64%) and a higher positive-predictive value (96% vs 40%).84

Figure 3. Schematic and endoscopic representation of MI catheter. (A) A 2-mm impedance-sensing electrode, positioned 1mm from the tip of a 2-mm soft catheter, advanced through an upper endoscope. MI measurements obtained by direct mucosal contact of sensors at the site of esophagitis (if present) and 2, 5, and 10 cm above the squamocolumnar junction (SCJ). (B) Median (and interquartile range) MI measurements at 2, 5, and 10 cm above the SCJ for 5 patient groups. MI measurements were significantly lower for patients with GERD (E+, E-/pH+) or EoE than patients without GERD (achalasia or E-/pH-). Patients with and without GERD had lower MI values in the distal esophagus, with a progressive increase along the esophagus. Patients with GERD had lower MI values at all levels than patients without GERD. Patients with EoE have a distinct MI pattern from patients with GERD, who have low MI values all along the esophagus. (Reproduced with permission from Ates et al.84)

Mucosal impedance normalizes in patients with GERD on acid-suppressive therapy, so MI measurements represent changes caused by GERD that are reversed with therapy. The role of MI in evaluation of changes is progressing. Studies are under way to determine whether MI can be used to assess patients with PPI-refractory symptoms of GERD or PPI-responsive esophageal eosinophilia. Recent data (unpublished; 2017) indicate that MI can be used to distinguish between patients with NERD vs functional heartburn. Researchers have developed a balloon with various impedance sensors to measure epithelial changes along the esophagus. It is too early to propose that this technology be used as a definitive tool for diagnosis of GERD. Outcome studies are needed to determine whether results from MI can predict response to PPI or surgery in patients with GERD.

Narrow-Band Imaging

Narrow-band imaging (NBI) uses a spectral narrowband filter for visualization of mucosal patterns and microvasculature. NBI increases contrast and allows for detection of changes in the microvasculature in the mucosa in patients with GERD. Endoscopic NBI has enabled identification of small changes, such as villous mucosal surface, mucosal islands, microerosions, and increased vascularity at the squamocolumnar junction.88 NBI is therefore used to detect GERD and determine improvement of GERD after PPI therapy. However, findings from NBI analysis do not always correlate with findings from histologic analysis.88,89 NBI has increased the reproducibility of grading esophagitis.90,91 In a study of 82 patients, NBI allowed for detection of small inflammatory foci in the esophagus, which correlated with positive responses to PPI therapy.92 Although NBI is not the first-line modality for diagnosis of GERD, due to the cost of endoscopy, it can be used in diagnosis and to response to PPI therapy.
Future Directions
Current diagnostic tests for GERD allow for determination of different phenotypes in patients with reflux symptoms, such as erosive reflux disease, NERD, hypersensitive esophagus, and functional heartburn. These classifications are based on findings from endoscopic and reflux monitoring. The distinction between hypersensitive esophagus and functional heartburn depends on findings from reflux/ symptom association analyses (SI and SAP indices). These parameters are frequently used despite their lack of validation. Symptom indices are subjective and depend entirely on patients pushing the event marker at the exact time of their symptom onset. Some studies have questioned the use of these indices, especially for patients with refractory symptoms and minimal reflux measured by pH or impedance testing.

We need to improve techniques for determining phenotypes of patients with NERD and to confirm diagnosis of GERD related to extraesophageal symptoms. Prolonged wireless pHmetry, the global histologic score, new impedance parameters, such as impedance baseline and PSPW, or other biomarkers should improve discrimination of patients with NERD from those with functional heartburn. Identifying the correct phenotype greatly affects the treatment options for patients. Reflux hypersensitivity could produce the same phenotype as functional heartburn; we treat both with pain modulators. Antireflux surgery should be reserved for patients with erosive esophagitis and patients with true NERD. Likewise, medical or surgical antireflux treatment should be provided only to patients with extraesophageal symptoms, if reflux is objectively identified as the cause of such symptoms, without other potential identifiable causes, especially for patients who respond to PPI therapy.
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