Novel Diagnostic Technologies: Mucosal Impedance, Optical Coherence Tomography, Endomicroscopy

Mucosal Impedance

Impedance is a measure of resistance to flow of current. Impedance of the esophageal mucosa can be measured by placing a specialized multichannel catheter with a series of conducting rings into the lumen of the esophagus. When there is movement of intraluminal material between these conducting rings, changes in impedance occur, and can be recorded in terms of amplitude of impedance change over time. Presence of intraluminal liquids as a result of oral intake or reflux results in a drop in impedance from the baseline, while gas due to burping or swallowing of air results in a rise in impedance above the baseline. The directionality of change in impedance allows us to determine if the flow is anterograde or retrograde. When there is no measurable movement of liquid or gas through the esophagus, the catheter is in direct contact with the esophageal mucosa. The mucosal impedance measured under such conditions is termed the esophageal baseline impedance value. This baseline impedance correlates with transepithelial resistance (TER), which is reflective of the structural integrity of the esophageal mucosa. The TER is significantly influenced by the structural integrity of the intercellular junction complex, a critical element in the maintenance of epithelial barrier function. These tight junctions function to seal off paracellular pathways, form paracellular ion channels, and act as transporters. In the presence of reflux, both acid and nonacid, structural alterations in the mucosa occur, critical among which is the appearance of dilated intercellular spaces (DISs) with resultant impairment in esophageal mucosal integrity and a decrease in TER, and as a consequence, a lowered baseline impedance value.

Currently, preliminary studies demonstrate a potential for using measures of baseline mucosal impedance in the clinical evaluation of patients with GERD, assessing adequacy of acid suppression therapy in patients with Barrett esophagus, and in the diagnosis and response to treatment with fluticasone for eosinophilic esophagitis.

Baseline impedance can be measured using a specialized multichannel intraluminal impedance/pH catheter (ComfortTec, Sandhill Scientific, Inc, Highlands Ranch, Colorado). The length of the catheter selected for use is based on the height of the patient; each catheter has specialized circumferential electrodes located at 3, 5, 7, 9, 15, and 17 cm from the tip. The pH probe is placed 5 cm above the upper margin of the manometrically defined lower esophageal sphincter (LES). Impedance and pH signals are collected at a sampling rate resolution of 50 Hz. Data recorded over a 24-hour period are analyzed using a dedicated software program (BioView analysis; Sandhill Scientific, Inc, Highlands Ranch, Colorado). Distal baseline impedance is calculated using data obtained from the sensor at 3 cm, while proximal baseline impedance is calculated from data obtained at the sensor 17 cm above the LES. Measurements are made during four different periods of time over the 24 hours of recording. The first interval is the time between breakfast and lunch, the second interval is between lunch and dinner, the third interval is between dinner and going to sleep, and the fourth interval is during sleep. During each of these four time intervals, three different time periods are selected, each of 1-minute duration, where a constantly stable impedance tracing is noted without alterations due to swallowing or reflux events. Impedance during each of these intervals is calculated by averaging the three impedance readings obtained, and then overall baseline impedance at a particular site is calculated by averaging the measurements made at the four time intervals ( Fig. 10.1 ).

Farré and colleagues placed impedance catheters in rabbits, and after obtaining baseline values, perfused a control solution with a pH of 7.2. During perfusion of the liquid solution, impedance dropped dramatically, and on cessation of perfusion the impedance recovered immediately. In contrast, when perfusion was performed using saline with a pH of 1.5 and 1.0, impedance values persistently remained lower at 39.1 ± 7.0% and 63.9 ± 6.5% ( P < .05) respectively. The in vivo basal impedance correlated positively with the TER obtained in vitro ( r = 0.72; P = .0021). Histologic evaluation of the mucosa demonstrated induction of the DIS even though the tissue showed no gross evidence of erosions. Similarly, in healthy volunteers, infusion with saline of pH 2.0 and 1.0 resulted in the baseline impedance remaining lower at 21.9 ± 6.5% and 52.7 ± 5.0% ( P < .0001) respectively.

Kessing et al. studied esophageal baseline impedance levels in patients with GERD both on and off therapy, and in normal controls. They found a negative correlation between esophageal acid exposure time and distal baseline impedance, suggesting that acid reflux lowers baseline impedance levels. Further, use of proton pump inhibitors resulted in increases in baseline impedance, suggesting the role of acid exposure in altering mucosal integrity in lowering baseline impedance. In addition to median baseline impedance values being lower at 2 cm above the squamocolumnar junction in patients with GERD as compared to those without GERD, baseline impedance is decreased even further at sites of erosive esophagitis compared to those without erosion. Further, a graded increase in baseline impedance along the axis of the esophagus from distal to proximal is seen in patients with GERD. A similar gradient is not seen in individuals without reflux.

Wright et al. performed a prospective observational study to determine if mucosal impedance values could help determine if patients with Barrett esophagus were compliant with their acid suppression regimen. All patients had histologically confirmed intestinal metaplasia. Measurements of mucosal impedance were made using a customized single-channel mucosal impedance catheter with unique sensors that was passed through the working channel of a standard endoscope. Mucosal impedance was measured at the site of Barrett epithelium as well as 2, 5, and 10 cm above the squamocolumnar junction. Mucosal impedance values in patients with Barrett esophagus who were not compliant with their acid suppression therapy were lower and similar to the values in patients with GERD. In contrast, mucosal impedance values in patients who were compliant with the acid suppression therapy were higher and similar to values found in patients without GERD ( Fig. 10.2 ).

In addition, a number of small studies have investigated the role of changes in baseline impedance of the esophageal mucosa in the diagnosis and management of a variety of esophageal pathology. These studies can at best be considered exploratory and further validation is needed before they can be applied clinically. Fukahori et al. evaluated the role of baseline impedance measurements as a parameter to assess the condition of the esophageal mucosa, with the ultimate aim being to replace the need for endoscopic examinations in patients where the procedure would be challenging, in this case neurologically impaired children. In the study, a cutoff value of 1500 ohms represented the baseline impedance that suggested the presence of reflux esophagitis. Other investigators have noted a linear correlation between lower baseline impedance values and acid hypersensitivity, suggesting that lower mucosal baseline impedance is a surrogate marker for impaired mucosal integrity, with an increased sensitivity to acid exposure. Studies on the role of mucosal impedance to diagnose functional heartburn have shown mixed results. Weijenborg et al. evaluated 12 patients with nonerosive reflux disease (NERD) and 9 patients with functional heartburn. Subjects underwent an acid perfusion test, assessment of mucosal integrity by measurement of tissue impedance, and upper endoscopy with biopsy. Obtained specimens were analyzed in Ussing chambers for transepithelial electrical resistance and transepithelial permeability. No difference in baseline impedance, transepithelial resistance, or permeability was found between the two groups, concluding thereby that alterations in baseline impedance were not helpful in distinguishing patients with NERD from those with functional heartburn. Kandulski et al. performed a prospective study in which 52 patients (19 with NERD, 16 with erosive reflux disease, and 17 with functional heartburn) were studied using endoscopy and multichannel intraluminal impedance studies after discontinuation of proton pump inhibitor therapy. Baseline impedance was assessed at 3, 5, 7, 9, 15, and 17 cm proximal to the LES. Biopsies were also taken 3 cm above the gastroesophageal junction and histologic assessment was performed to semiquantitatively assess the presence of dilated intercellular spaces. They found that baseline impedance was significantly lower in both forms of reflux disease when compared to that of functional heartburn. When a cutoff value of less than 2100 ohms was used, baseline impedance had 78% sensitivity and 71% specificity with positive and negative predictive values of 75% in distinguishing patients with reflux disease versus those with functional heartburn. Although promising, the studies need further validation and more defined establishment of cutoff points, and they are not yet ready for clinical use.

Eosinophilic Esophagitis

Over the last decade, much progress has been made in understanding the eosinophilic esophagitis, a chronic inflammatory disorder of the esophagus. Eosinophilic esophagitis is believed to be primarily mediated by penetration of the esophageal epithelium by food antigens, which induces a T-helper type 2 cell allergy and results in eosinophil predominant inflammation, decreased barrier function of the esophagus, and dilation in the cellular spaces. Clinically it is characterized by symptoms of esophageal dysfunction, presenting predominantly as feeding difficulties in children, and dysphagia or food impaction in adults. Diagnosis is established when one or more biopsy specimens obtained from the proximal and distal esophagus demonstrate eosinophilic predominant inflammation, with more than 15 eosinophils per high-power field (HPF), representing the minimum threshold value. However, using histologic criteria alone may result in diagnostic error. In up to one-third of patients who did not meet the criteria for eosinophilic esophagitis (<15 eosinophils per HPF) on initial biopsy, subsequent biopsy at repeat endoscopy demonstrated more than 15 eosinophils per HPF, fulfilling the criteria for diagnosis. Further, a proportion of patients with GERD may meet the criteria for eosinophilic esophagitis with 15 or more eosinophils per HPF in the absence of eosinophilic esophagitis. Hence, there is great interest in diagnostic modalities that may help establish/support the diagnosis and monitor response to treatment. Because the cardinal pathophysiologic feature of eosinophilic esophagitis is impaired mucosal integrity with DIS and decreased barrier function, measurements of alterations in mucosal impedance have attracted significant attention.

Katzka and colleagues measured mucosal impedance in 10 patients with active eosinophilic esophagitis (>15 eosinophils per HPF), 10 patients with inactive eosinophilic esophagitis (<15 eosinophilic per HPF) following treatment of histologically confirmed eosinophilic esophagitis, and in 10 controls without esophageal symptoms. Mucosal impedance was significantly lower in patients with active eosinophilic esophagitis (1909 Ohms) than subjects with inactive disease (4349 Ohms) or in controls (5530 Ohms). There was a significant inverse correlation between mucosal impedance and the number of eosinophils per HPF on histology ( RS = −0.584). When a mucosal impedance cutoff value of 2300 Ohms was used to define active eosinophilic esophagitis, test characteristics demonstrated 90% sensitivity and 91% specificity. The low baseline impedance levels are apparent over the entire esophagus including the proximal, mid, and distal portions ( Fig. 10.3 ). Serial changes in baseline impedance can also be used to determine response to therapy. Van Rhijn and colleagues in a prospective study of 15 patients with eosinophilic esophagitis, assessed esophageal mucosal barrier integrity before and after the 8-week course of swallowed fluticasone propionate (500 µg twice daily [BID]). Substantial increases in esophageal mucosal integrity were noted following treatment with increase in mucosal impedance and transepithelial electrical resistance, and decrease in transit epithelial molecular flux.

The role of acid suppression therapy with proton pump inhibitors in patients with the eosinophilic esophagitis is unclear. Although some patients clearly benefit from being placed on acid suppression therapy, others do not. Studies of mucosal impedance suggest that eosinophilic esophagitis may not represent a single disease entity but rather represent a heterogeneous group of disorders. One such subgroup has been termed proton pump inhibitor responsive eosinophilia (PPI-REE). Although parameters of mucosal integrity (electrical tissue impedance, transepithelial electrical resistance, transit epithelial molecule flux) are reduced at baseline in both classic eosinophilic esophagitis and PPI-REE, treatment with high-dose acid suppression therapy using proton pump inhibitors partially restores mucosal integrity in patients with PPI-REE. Measurement of mucosal impedance before and after an 8-week course of acid suppression using proton pump inhibitors may therefore help identify the subset of patients who may benefit from continued treatment, and allow the discontinuation of these medications in patients who do not show any improvement in mucosal impedance, thereby reducing the exposure to the potential toxicities resulting from the long-term use of proton pump inhibitors.