Abstract
Eosinophilic esophagitis (EoE) is the second most common cause of chronic esophageal inflammation after GERD, with increasing incidence and prevalence across all age groups. Since current diagnosis and follow up of EoE require endoscopy with biopsies, there is an increased interest in non or less invasive tests for its diagnosis and follow up. Baseline mucosal impedance measurement allows evaluation of mucosal barrier properties and is widely accepted as an adjunct method in GERD diagnosis. As EoE is associated with increased mucosal permeability, the use of baseline impedance to evaluate mucosal integrity has been investigated in several studies. It was found that baseline mucosal impedance, measured either during 24 h reflux monitoring or during endoscopy, was significantly lower in all parts of the esophagus in EoE patients. Impedance measurement correlated with eosinophil counts on biopsies, offering a tool to monitor treatment response. Additionally, baseline impedance patterns differed between those responding to proton pump inhibitor (PPI) treatment and those resistant to PPI, potentially allowing to tailor future treatment to the individual patient. In summary, baseline impedance measurement offers a potential tool for diagnosis and follow up in EoE. Its exact place in EoE treatment is yet to be determined and requires further future studies.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Eosinophilic esophagitis (EoE) is a chronic, immune-mediated or antigen-mediated esophageal disease, second only to GERD as a cause of chronic esophageal inflammation. Incidence and prevalence of EoE is increasing in both children and adults [1]. The exact cause of EoE is currently unknown, but a strong association with atopic diseases such as asthma and atopic dermatitis is well established [2]. In fact, a similar inflammatory pattern involving a local T-helper 2 type inflammation is present in the esophagus of patients with EoE, patients with asthma and those with atopic dermatitis [3]. The diagnosis is based on the presence of increased number of eosinophils in esophageal mucosal biopsies. Patients with EoE can be either asymptomatic, or present with dysphagia, food impaction or refractory GERD, and can progress to esophageal fibrosis and stricture formation if left untreated [4]. Thus, surveillance is paramount to prevent long term complications. As both the diagnosis and the treatment response assessment in EoE require an endoscopic procedure with biopsies, there is an increased interest in non or less invasive for its diagnosis and follow up.
Intraluminal impedance monitoring measures changes in conductivity to an alternating electrical current along electrodes mounted on a catheter, which in a tubular organ such as the esophagus, in the absence of swallowing or reflux, are in close contact with the mucosa. The electrical impedance, expressed in ohms, is the equivalent to the resistance to the electrical current [5]. Multichannel intraluminal impedance (MII) can thus detect bolus movement by measuring the direction of changes in electrical resistance, caused by fluid or gas: liquid bolus with more ions will have lower impedance than the baseline, while gas with fewer ions will have a higher value [6]. Between bolus movement the impedance levels return to a baseline level, which is dependent on mucosal characteristics of the collapsed esophageal wall [7](Fig. 1).
Low baseline impedance measurements have been used as a marker for impaired mucosal integrity, a finding initially demonstrated in acid-induced heartburn in healthy volunteers and in GERD patients [7]. Moreover, lower baseline esophageal impedance in GERD patients was found to correlate with higher acid exposure time (AET), and increase in impedance following proton pump inhibitor (PPI) treatment was noted in those patients [8]. Woodland et al [9] found that mean baseline mucosal impedance levels could help differentiate between non-erosive reflux disease (NERD) and those with functional heartburn. Similar results were found in a study by Kandulski et al [10], demonstrating that baseline impedance in lower esophagus can differentiate between functional heartburn, GERD and NERD. Likewise, patients with Barrett’s mucosa were found to have significantly lower baseline impedance compared to patients with normal mucosa [11].Initially, baseline impedance was calculated manually for a 6-h period, excluding reflux episodes and swallow events. The concept of Mean Nocturnal Baseline Impedance (MNBI) was introduced by Martinucci et al. [12]. While still requiring manual calculations, MNBI measurement consisted of evaluating 10-min periods at 3 different timepoints during night, and gave results similar to traditional baseline impedance measurements. Frazzoni et al. demonstrated that the use of MNBI and additional measure of post-swallow peristaltic wave index (PSPW) increased the diagnostic yield of impedance pH monitoring of patients with reflux disease, especially NERD [13]. In another study, the same group demonstrated the ability of MNBI and PSPW index to distinguish between reflux and functional heartburn patients in PPI-refractory patients [14]. Further studies demonstrated that MNBI correlated with reflux burden [13, 15] and both symptomatic relief [15, 16]and endoscopic healing [16] following therapy. The normal values for mucosal impedance were found to have significant regional variability, possibly influenced by various factors such as genetics, BMI and meal composition [17]. Recently, a simplified method for MNBI measurement was introduced, allowing fast and accurate mucosal impedance assessment [18](Fig. 2). In the Lyon consensus published in 2018 [19], the use of MNBI was endorsed as an adjunct for GERD diagnosis in borderline cases.
Several previous studies demonstrated specific mucosal alterations in EoE that result in increased mucosal permeability. The dilation of the intercellular space in EoE is well documented and is considered one of the histologic hallmarks for the disease [20]. Previous studies demonstrated reduced expression of intercellular junction proteins [21, 22] and adhesion molecules [23], with inverse correlation between junction protein expression and dilation of the intercellular space [24]. In addition, higher expression of proteases with lower expression of protease inhibitors was demonstrated in EoE mucosa [22], potentially weakening the tight junctions between cells and increasing permeability. Using Ussing chambers in vitro, Warnes et al [25] demonstrated lower transepithelial resistance and increased mucosal permeability in EoE patients.
In their study in 2013, Van Rhijn et al [26] investigated baseline impedance in EoE patients and its relationship with acid exposure. Ambulatory 24 h pH-impedance was performed in EoE and healthy controls with matched acid exposure, and impedance levels in proximal, middle and distal esophagus were compared between cohorts. Reflux characteristics including proximal reflux extent were similar between cohorts as per study design. Baseline impedance levels in EoE patients were markedly lower compared to healthy controls in the distal, middle and proximal esophagus. Baseline impedance decreased from proximal to distal in healthy subjects. However, EoE patients had decreased baseline impedance throughout the esophagus, without such gradient (Fig. 3).
As high prevalence of EoE in patients with esophageal atresia was reported, Pesce et al. [27] investigated the use of MNBI in pediatric patients with esophageal atresia. The diagnosis of EoE in those patients is often challenging due to symptom overlap with GERD and presence of dysphagia due to esophageal dysmotility secondary to atresia and its repair. The delay in diagnosis might put the children in risk for EoE complications. It was found that patients with both esophageal atresia and EoE had lower impedance values compared with GERD patients or EoE patients without history of atresia repair. The authors suggested that MII-pH could be valuable in selecting which patients with esophageal atresia should undergo endoscopic examination.
In addition to the measurement of MNBI during MII-pH monitoring, other methods for impedance measurement have been investigated in EoE. The question whether direct mucosal impedance could differentiate between GERD and non-GERD patients has been explored by Ates et al [28], using a method of direct mucosal impedance measurement using a specific probe during endoscopy. The authors were able to demonstrate characteristic impedance patterns for GERD, non-GERD and EoE patients, allowing discrimination between these conditions. In another study, Katzka et al [29] demonstrated a correlation between mucosal impedance and eosinophil count on biopsies, potentially allowing to differentiate between active and non-active EoE patients. A similar ability to distinguish between active and in-remission EoE patents based on mucosal impedance was demonstrated by Warners et al [25]. In their study, both mucosal integrity measured by electrical tissue spectroscopy (ETIS) in vivo, and by transepithelial electrical resistance and transepithelial molecule-flux in vitro, correlated with esophageal eosinophilia. Mucosal impedance was similar between patients treated with diet and those treated with fluticasone.
Investigating the influence of reflux on EoE, Frazzoni et al. [30] demonstrated that off-PPI MNBI was able to distinguish between PPI responsive to PPI-refractory EoE. Those with PPI refractory EoE had significantly lower MNBI gradients between mid and lower esophagus and had lower MNBI improvement following PPI treatment. In a follow up study, greater mucosal damage, as measured by lower MNBI, was found in lower esophagus of PPI responsive patients, when compared to PPI-refractory ones [31].
In conclusion, measurement of mucosal baseline impedance during 24 h reflux monitoring or instant mucosal impedance during endoscopy offers a potential tool for diagnosis and follow up in EoE. Its exact place in EoE treatment is yet to be determined and requires further future studies.
References
Navarro P, Arias Á, Arias-González L, Laserna-Mendieta EJ, Ruiz-Ponce M, Lucendo AJ (2019) Systematic review with meta-analysis: the growing incidence and prevalence of eosinophilic oesophagitis in children and adults in population-based studies. Aliment Pharmacol Ther 49(9):1116–1125. https://doi.org/10.1111/apt.15231
Blanchard C, Wang N, Rothenberg ME (2006) Eosinophilic esophagitis: pathogenesis, genetics, and therapy. J Allergy Clin Immunol 118(5):1054–1059. https://doi.org/10.1016/j.jaci.2006.07.038
Straumann A, Bauer M, Fischer B, Blaser K, Simon HU (2001) Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response. J Allergy Clin Immunol 108(6):954–961. https://doi.org/10.1067/mai.2001.119917
Chang NC, Thakkar KP, Ketchem CJ, Eluri S, Reed CC, Dellon ES (2021) A gap in care leads to progression of fibrosis in Eosinophilic esophagitis patients. Clin Gastroenterol Hepatol. https://doi.org/10.1016/j.cgh.2021.10.028
van Wijk MP, Sifrim D, Rommel N, Benninga MA, Davidson GP, Omari TI (2009) Characterization of intraluminal impedance patterns associated with gas reflux in healthy volunteers. Neurogastroenterol Motil 21(8):825-e55. https://doi.org/10.1111/j.1365-2982.2009.01289.x
Bredenoord AJ, Tutuian R, Smout AJPM, Castell DO (2007) Technology review: Esophageal impedance monitoring. Am J Gastroenterol 102(1):187–194. https://doi.org/10.1111/j.1572-0241.2006.00966.x
Farré R, Blondeau K, Clement D et al (2011) Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique. Gut 60(7):885–892. https://doi.org/10.1136/gut.2010.233049
Kessing BF, Bredenoord AJ, Weijenborg PW, Hemmink GJM, Loots CM, Smout AJPM (2011) Esophageal acid exposure decreases intraluminal baseline impedance levels. Am J Gastroenterol 106(12):2093–2097. https://doi.org/10.1038/ajg.2011.276
Woodland P, Al-Zinaty M, Yazaki E, Sifrim D (2013) In vivo evaluation of acid-induced changes in oesophageal mucosa integrity and sensitivity in non-erosive reflux disease. Gut 62(9):1256–1261. https://doi.org/10.1136/gutjnl-2012-302645
Kandulski A, Weigt J, Caro C, Jechorek D, Wex T, Malfertheiner P (2015) Esophageal intraluminal baseline impedance differentiates gastroesophageal reflux disease from functional heartburn. Clin Gastroenterol Hepatol 13(6):1075–1081. https://doi.org/10.1016/j.cgh.2014.11.033
Waśko-Czopnik D, Błoński W, Paradowski L (2007) Diagnostic difficulties during combined multichannel intraluminal impedance and pH monitoring in patients with esophagitis or Barrett’s esophagus. Adv Med Sci 52:196–198
Martinucci I, de Bortoli N, Savarino E et al (2014) Esophageal baseline impedance levels in patients with pathophysiological characteristics of functional heartburn. Neurogastroenterol Motil 26(4):546–555. https://doi.org/10.1111/nmo.12299
Frazzoni M, Savarino E, de Bortoli N et al (2016) Analyses of the post-reflux swallow-induced peristaltic wave index and nocturnal baseline impedance parameters increase the diagnostic yield of impedance-pH monitoring of patients with reflux disease. Clin Gastroenterol Hepatol 14(1):40–46. https://doi.org/10.1016/j.cgh.2015.06.026
Frazzoni M, de Bortoli N, Frazzoni L et al (2017) The added diagnostic value of postreflux swallow-induced peristaltic wave index and nocturnal baseline impedance in refractory reflux disease studied with on-therapy impedance-pH monitoring. Neurogastroenterol Motil. https://doi.org/10.1111/nmo.12947
Patel A, Wang D, Sainani N, Sayuk GS, Gyawali CP (2016) Distal mean nocturnal baseline impedance on pH-impedance monitoring predicts reflux burden and symptomatic outcome in gastro-oesophageal reflux disease. Aliment Pharmacol Ther 44(8):890–898. https://doi.org/10.1111/apt.13777
Xie C, Sifrim D, Li Y, Chen M, Xiao Y (2018) Esophageal baseline impedance reflects mucosal integrity and predicts symptomatic outcome with proton pump inhibitor treatment. J Neurogastroenterol Motil 24(1):43–50. https://doi.org/10.5056/jnm17032
Sifrim D, Roman S, Savarino E et al (2020) Normal values and regional differences in oesophageal impedance-pH metrics: a consensus analysis of impedance-pH studies from around the world. Gut. https://doi.org/10.1136/gutjnl-2020-322627
Hoshikawa Y, Sawada A, Sonmez S et al (2020) Measurement of Esophageal nocturnal baseline impedance: a simplified method. J Neurogastroenterol Motil 26(2):241–247. https://doi.org/10.5056/jnm19183
Gyawali CP, Kahrilas PJ, Savarino E et al (2018) Modern diagnosis of GERD: the Lyon Consensus. Gut. https://doi.org/10.1136/gutjnl-2017-314722
Ravelli A, Villanacci V, Cadei M, Fuoti M, Gennati G, Salemme M (2014) Dilated intercellular spaces in eosinophilic esophagitis. J Pediatr Gastroenterol Nutr 59(5):589–593. https://doi.org/10.1097/MPG.0000000000000491
Abdulnour-Nakhoul SM, Al-Tawil Y, Gyftopoulos AA et al (2013) Alterations in junctional proteins, inflammatory mediators and extracellular matrix molecules in eosinophilic esophagitis. Clinical immunology (Orlando, Fla) 148(2):265–278. https://doi.org/10.1016/j.clim.2013.05.004
Simon D, Page B, Vogel M et al (2018) Evidence of an abnormal epithelial barrier in active, untreated and corticosteroid-treated eosinophilic esophagitis. Allergy 73(1):239–247. https://doi.org/10.1111/all.13244
Sherrill JD, Kc K, Wu D et al (2014) Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis. Mucosal Immunol 7(3):718–729. https://doi.org/10.1038/mi.2013.90
Katzka DA, Tadi R, Smyrk TC et al (2014) Effects of topical steroids on tight junction proteins and spongiosis in esophageal epithelia of patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol 12(11):1824–9.e1. https://doi.org/10.1016/j.cgh.2014.02.039
Warners MJ, van Rhijn BD, Verheij J, Smout AJPM, Bredenoord AJ (2017) Disease activity in eosinophilic esophagitis is associated with impaired esophageal barrier integrity. Am J Physiol Gastrointest Liver Physiol 313(3):G230–G238. https://doi.org/10.1152/ajpgi.00058.2017
van Rhijn BD, Kessing BF, Smout AJ, Bredenoord AJ (2013) Oesophageal baseline impedance values are decreased in patients with eosinophilic oesophagitis. United Eur Gastroenterol J 1(4):242–248. https://doi.org/10.1177/2050640613496411
Pesce M, Krishnan U, Saliakellis E et al (2019) Is there a role for pH impedance monitoring in identifying Eosinophilic esophagitis in children with Esophageal atresia? J Pediatr 210:134–140. https://doi.org/10.1016/j.jpeds.2019.03.015
Ates F, Yuksel ES, Higginbotham T et al (2015) Mucosal impedance discriminates GERD from non-GERD conditions. Gastroenterology 148(2):334–343. https://doi.org/10.1053/j.gastro.2014.10.010
Katzka DA, Ravi K, Geno DM et al (2015) Endoscopic mucosal impedance measurements correlate with eosinophilia and dilation of intercellular spaces in patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol 13(7):1242-1248.e1. https://doi.org/10.1016/j.cgh.2014.12.032
Frazzoni M, Penagini R, Frazzoni L et al (2019) Role of reflux in the pathogenesis of eosinophilic esophagitis: comprehensive appraisal with off- and on PPI impedance-pH monitoring. Am J Gastroenterol 114(10):1606–1613. https://doi.org/10.14309/ajg.0000000000000379
Frazzoni M, Frazzoni L, de Bortoli N et al (2021) Response of eosinophilic oesophagitis to proton pump inhibitors is associated with impedance-pH parameters implying anti-reflux mechanism of action. Aliment Pharmacol Ther 53(11):1183–1189. https://doi.org/10.1111/apt.16371
Funding
The authors did not receive support from any organization for the submitted work.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors have no relevant financial or non-financial interests to disclose.
Research involving human and animal partcipants
As a review article, no have human or animal participants were involved, and therefore no ethical committee approval nor informed consent were sought.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Ilia, S., Monica, V. & Daniel, S. Mean nocturnal baseline impedance and endoscopic mucosal impedance measurements in patients with eosinophilic esophagitis: a new tool for follow up and management?. Updates Surg 75, 389–393 (2023). https://doi.org/10.1007/s13304-022-01331-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13304-022-01331-4