Mucosal Impedance: A New Way To Diagnose Reflux Disease and How It Could Change Your Practice

WHAT IS IMPEDANCE?

Evaluation of gastroesophageal reflux disease (GERD) has expanded over time from pH testing (wireless or ambulatory) to include multichannel intraluminal impedance which permits differentiation of the refluxate as either acid, weakly acid, or nonacid. Impedance is a measure of the total opposition to current flow between adjacent electrodes mounted on a catheter placed along the esophagus. Intra-esophageal impedance depends on the conductivity of the material through which current must travel. By placing a series of conducting rings in a catheter spanning the length of the esophagus, changes in impedance can be recorded in response to the movement of intraluminal material. Liquids (reflux or oral intake) result in a drop in baseline impedance measurements, whereas gas (burping or air swallow) shows a rise in baseline impedance measurements. The directionality to the flow (anterograde or retrograde) is determined based on timing of the change in impedance along the esophagus (1).

The use of combined multichannel intraluminal impedance and pH (MII-pH) was an important advancement in gastroesophageal reflux testing because it enabled detection of gastroesophageal reflux at all pH levels (both acid and nonacid). It was considered the most sensitive tool for measuring reflux. However, a recognized limitation of this device is that in patients with esophagitis, severe reflux, and Barrett’s esophagus the baseline impedance values are too low to provide accurate and meaningful results. In addition, the catheter nature of the device results in potential confounding of baseline impedance values due to intraluminal contents (i.e. air, liquid, solids). Finally, patients often complain of discomfort and reduced oral intake with trans-nasally positioned catheters resulting in reduced sensitivity and patient compliance. Thus, there is need for a simple and efficient method for diagnosing reflux disease without the prolonged and uncomfortable catheter-based systems.

WHAT IS MUCOSAL IMPEDANCE?

In response to these limitations, we have developed an endoscopically placed probe (Figure 1a) to measure conductivity of the esophageal epithelium directly in a matter of seconds during endoscopy (2). During upper endoscopy, an mucosal impedance (MI) catheter is placed through the working channel of the endo-scope and direct contact mucosal impedance measurements are obtained. This whole process adds ~1 min to the procedure, and each MI measurement takes 5 s.

Figure 1.

Schematic representation of MI and MII catheter. (a) Two 2-mm–long impedance sensing electrodes positioned 1 mm from the tip of a 2-mm soft catheter were advanced through the working channel of an upper endoscope. Mucosal impedance (MI) measurements were obtained by direct mucosal contact of sensors for 5 s at the site of esophagitis (if present) and 2, 5, and 10 cm above the squamocolumnar junction (SCJ). (b) Photograph of the MI catheter (inset) and schematic comparison of the MI catheter to the traditional multichannel impedance pH catheter along the esophageal lumen. Measurements represent distances from the SCJ.

This technology represents an improvement in design over the prior intraluminal impedance technology (Figure 1b) because it uses direct as opposed to indirect conductivity, utilizes a more optimal sensory array and impedance rings that are closer together, and minimizes measurement error due to the presence of intraluminal contents. Importantly, the design has undergone extensive validation to determine these specifications so that they provide optimal sensitivity and specificity (3,4). Moreover, it is comfortable for the patient (i.e., performed when the patient is sedated).

Adoption of any new technology must undergo validation and reproducibility testing in the population for which it will be employed. Below we present data on some preliminary encouraging results employing MI in patients with GERD and eosinophilic esophagitis (EoE) which will need future validation studies.

MUCOSAL IMPEDANCE EASILY DISTINGUISHES VARIOUS ESOPHAGEAL DISORDERS

MI is affected by the presence of dilated intercellular spaces (DIS), or spongiosis, which affects paracellular permeability of the esophageal lumen. DIS is an important histologic feature in GERD and EoE which inversely correlates with MI measurements (i.e., lower impedance values with increasing DIS, Figure 2a (4)).

Figure 2.

MI correlates inversely with spongiosis, differentiates esophageal disorders, and monitors treatment response in GERD. (a) Correlation of impedance (ohms) to corresponding biopsy specimens for dilated intercellular spaces (DIS). The horizontal line represents an impedance cut-off value of 2,300Ω. (b) Median (interquartile range, IQR) Mucosal impedance (MI) values in an axial distribution along the esophagus for achalasia, gastroesophageal reflux disease (GERD; E+, E−/pH+), E−/pH−, and eosinophilic esophagitis (EoE). GERD and non-GERD patients showed lower MI values at the distal esophagus with a progressive increase along the esophagus, with the former group having lower MI values at all levels than the latter group. The MI pattern in EoE was distinct from GERD in showing low MI values all along the esophagus. (c) Median (IQR) MI values at 2, 5, and 10 cm above the squamocolumnar junction (SCJ) in patients with esophagitis (E+) before and after proton-pump inhibitor (PPI) therapy. At all sites in the esophagus, the MI values increased significantly after PPI therapy.

We have recently shown that MI can differentiate GERD-related conditions (esophagitis, non-erosive GERD) from EoE and from non-GERD-related conditions (normal, achalasia, Figure 2b; (ref. 3)).

There are advantages to MI over pH testing. The latter assumes chronic reflux based on a 1- or 2-day study whereas the former assesses impact of chronic esophageal epithelial exposure to refluxates. As compared with pH monitoring, MI has superior specificity (95% vs. 64%) and positive-predictive value (96% vs. 40%), with similar sensitivity and negative predictive value (3). Both esophagitis and non-erosive disease demonstrate a low MI pattern in the distal esophagus 2 cm from the squamocolumnar junction (SCJ) but higher proximally (5 and 10 cm from the SCJ). The impedance values recover to normal values post proton-pump inhibitor (PPI) therapy restoring the epithelium to normal function (Figure 2c), implying that MI can be used to monitor treatment response.

With respect to EoE, studies from the Mayo Clinic showed that impedance correlates inversely with eosinophil counts (i.e. lower impedance correlates with higher eosinophil counts; (3)). MI measurements in EoE have a distinct pattern compared with GERD or normal. Unlike GERD where the values are lower in the distal esophagus and recover in the mid and proximal regions, in EoE the values are low all along the esophagus. Our studies confirmed that MI measurements are low at 2 cm from the SCJ and stay low along the esophageal axis at 5 and 10 cm from the SCJ. Active EoE is signified by a cut-off value of <2,300 Ω. Just as with treatment of GERD, successful treatment of EoE (i.e., improvement in eosinophil count) with steroids or dietary therapy resulted in improvement of impedance measurements (4). A recent study demonstrated in a prospective double-blinded study that the MI pattern along the esophageal axis can accurately predict EoE with 91% positive-predictive value and high sensitivity and specificity without the need for histologic assessment (Figure 3; (ref. 5)).

Figure 3.

Mucosal impedance (MI) predicts eosinophilic esophagitis (EoE; >15 eosinophils on histology) versus non-EoE (<15 eosinophils on histology) with 91% positive-predictive value by observing MI pattern along the esophageal axis without knowledge of diagnosis. Yellow line represents diagnosis based on MI, and red line represents diagnosis by histology.

MI measurement at 5 cm can differentiate normal from abnormal (cut-off3,700 Ω) with sensitivity 83% and specificity 79% and GERD and EoE (cut-off 1,400 Ω) with sensitivity of 84% and specificity of 70% (ref. 6). With respect to Barrett’s esophagus, one study determined that MI measurements can determine whether or not a patient is compliant with PPI therapy (7). Barrett’s patients on PPI had similar MI measurements to patients with normal endoscopy and pH testing, whereas those off PPI had measurements similar to GERD patients.

THE FUTURE OF MUCOSAL IMPEDANCE TECHNOLOGY

In order to reduce variability in measurements and confounding by air or liquids around the sensors we have recently devised the next generation of MI catheter whereby the impedance electrodes are mounted on a balloon which can be inflated in the esophagus allowing direct sensor contact onto the epithelium. Instead of one sensor, this advanced technology will have a total of 40 sensors measuring esophageal epithelial impedance along a 10 cm length of esophagus both radially and axially (Figure 4).

Figure 4.

Mucosal impedance (MI) balloon with 40 sensors measuring esophageal epithelial impedance along a 10 cm length of esophagus both radially and axially. Left picture shows the balloon deflated; right picture shows the balloon inflated.

HOW ELSE CAN MUCOSAL IMPEDANCE BE USED?

There are still several clinical scenarios for which MI may be employed as a potentially useful tool. It may predict which patients respond to anti-reflux surgery as a component of pre-fundoplication work up. MI may also help delineate whether patients’ extra-esophageal symptoms are reflux related, an area which is in dire need of a robust testing modality.

This test could also be used to help predict which EoE patients are PPI responsive. Furthermore, EoE patients undergo many endoscopies with biopsies in order to assess response to various treatment modalities. MI could help eliminate this need with potential cost savings. Finally, it may also be employed to assess the effectiveness of acid suppressive therapy in eliminating acid reflux in those with Barrett’s esophagus who undergo radiofrequency ablative therapies.

This novel technology may help guide therapy in clinically difficult situations with improvement in MI as a treatment endpoint, especially when symptoms have improved but pathology hasn’t. MI may have impact in other disease processes where barrier dys-function is prominent, including inflammatory bowel disease and celiac disease. However, the role of this device in these disorders is conjecture and will need several future studies.

CONCLUSIONS

MI measures conductivity across the esophageal epithelium, correlates with level of DIS, can distinguish esophageal disorders, and can monitor treatment response in GERD and EoE. The ability of this new test to assess barrier function in real time in a way that adds little time to endoscopy and without discomfort to the patient is novel. At this time we have much to learn about its role in the management of the aforementioned esophageal disorders and are just beginning to assess its potential in other intestinal disorders. We have hopes that future designs will allow outpatient MI measurements similar to currently performed manometry. This will allow a more efficient and less costly means of monitoring treatment response in various esophageal and possibly non-esophageal diseases.

Study Highlights.

WHAT IS CURRENT KNOWLEDGE

• pH testing requires 24–48 h.

• pH testing does not necessarily reflect chronicity of reflux.

• Intraluminal impedance measures indirect conductivity of the epithelium and as such is subject to error.

WHAT IS NEW HERE

• Mucosal impedance (MI) measures direct conductivity of the esophageal epithelium.

• MI measures chronicity of reflux in seconds.

• MI has superior positive-predictive value and specificity versus pH monitoring.

• MI can differentiate esophageal disorders.

• MI can measure treatment response in gastroesophageal reflux disease and eosinophillic esophagitis.