Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 license 
http://creativecommons.org/licenses/by-nc-nd/4.0

Fox, Mark R

Omari, Taher

Rommel, Nathalie

Gastroenterology

Flinders Academic Commons

Archived at the Flinders Academic Commons: http://dspace.flinders.edu.au/dspace/ ‘This is the peer reviewed version of the following article: Fox M, Omari T, Rommel N. Supraesophageal Reflux Disease: Solving a Riddle Wrapped in a Mystery Inside an Enigma. Gastroenterology. 2015 Nov;149(6):1318-20. which has been published in final form at http://dx.doi.org/10.1053/j.gastro.2015.09.033Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ Gastro editorial  Fox, Omari, Rommel 1/9 23.03.2017 Supra-Esophageal Reflux Disease: Solving a riddle wrapped in a mystery inside an enigma Mark Fox 1,2, Taher Omari 3, Nathalie Rommel 5,6 1 Abdominal Center, Department of Gastroenterology, St. Claraspital, Basel, Switzerland 2 Zürich Neurogastroenterology and Motility Research Group, Division of Gastroenterology and Hepatology, University Hospital Zurich, Switzerland 3 Human Physiology, Medical Science and Technology, School of Medicine  Flinders University, Adelaide, South Australia 5 KU Leuven, Neurosciences, ExpORL, Leuven, Belgium 6 KU Leuven, Translational Research Center for Gastrointestinal Diseases (TARGID), Leuven, Belgium7 University Hospital Leuven, Leuven, Gastroenterology (Neurogastroenterology and Motility), University Hospital Leuven, Leuven, Belgium. Correspondence Address Mark Fox, Abdominal Center, Department of Gastroenterology, Claraspital, Basel, Switzerland  dr.mark.fox@gmail.com  Tel. +41 (0)791934795Gastro editorial  Fox, Omari, Rommel 2/9 23.03.2017 Symptoms referable to irritation and inflammation of the pharynx, larynx and bronchi are very common in the community. Hoarseness, persistent sore throat, globus and chronic cough are present in up to 25% of the primary care population and account for a large number of referrals to gastroenterologists, respiratory physicians and ear, nose and throat (ENT) specialists.1 Epidemiological research has documented an association between gastro-esophageal reflux disease (GERD) and a range of “supra-esophageal” symptoms and diseases (Table 1). Further clinical studies report a high prevalence of typical reflux symptoms in patients with signs of laryngo-pharyngeal disease 2 and, also, a high frequency of throat and respiratory symptoms among patients with pathological esophageal acid exposure.3 Based on this evidence, the Montreal classification included so called laryngo-pharyngeal or supra-esophageal reflux disease (SERD) as a subcategory of GERD,4 and clinical reviews have proposed gastric acid and reflux suppression as empirical treatment for these “atypical” manifestations of GERD.5 Notwithstanding this broad based agreement, if reflux of gastric contents is a common cause of supra-esophageal symptoms and disease, then many issues remain unresolved. In many cases the mechanism of disease is a riddle. The inability of current investigations to establish an association between reflux events and symptoms is a mystery. The failure of proton pump inhibitors (PPI) to treat laryngo-pharyngeal symptoms or heal mucosal disease in well-designed clinical trials is an enigma. In this issue of Gastroenterology, Babaei and colleagues applied state-of-the-art physiological measurements to study the pharyngo-esophageal response to simulated reflux events.6 Their findings identified specific abnormalities in patients with symptoms suggestive of SERD. Moreover their approach to investigation could point the way to promising new clinical diagnostic tests for this condition. Mechanism of disease The simplest mechanism proposed for SERD is microaspiration of gastric contents into the pharynx and larynx.7 In vivo experiments suggest that minute amounts of acid are sufficient to cause mucosal damage, especially in the Gastro editorial  Fox, Omari, Rommel 3/9 23.03.2017 presence of pepsin.8 However, in most cases, ambulatory pH-impedance monitoring detects very few pharyngeal reflux events and this direct mechanism alone cannot explain the frequent symptoms reported by many patients. Other proposals include the possibility that distal esophageal reflux causes laryngo-pharyngeal symptoms by an indirect mechanism either by triggering an antedromic vasovagal reflex and neurogenic inflammation, or by prompting repetitive swallowing behavior.7 An additional consideration is that acid exposure to the distal esophagus heightens visceral sensitivity of the whole organ through a central mechanism.9 If this effect extends to the larynx and pharynx, then this would lower the sensory threshold not only to further reflux events but also to a range of other potential stimuli such as temperature change, cigarette smoke, airborne allergens and ingestion of alcohol or other irritants.7   Physiological Measurement In patients with heartburn, acid regurgitation and reflux esophagitis the cause of laryngo-pharyngeal symptoms and disease may be obvious. However, the majority of patients with suspected SERD do not have typical reflux symptoms or mucosal disease.10 In this group, physiological measurements that detect reflux events at, or close to, the site of pathology provide objective evidence to support of the diagnosis. Studies that include pharyngeal pH sensors in addition to esophageal sensors may be more discriminatory of SERD patients.11 The current standard is ambulatory pH-impedance reflux monitoring.12 This technology can detect both acid and non-acid reflux and, in principle, establish a causal association between these events and symptoms. Unfortunately, there is little consensus regarding the optimal acquisition, analysis or interpretation of this data. Moreover, in practice, if isolated pharyngeal reflux events are sufficient to cause disease, if symptoms are present all the time, or if there is only an indirect link between reflux and symptoms, then even the most accurate ambulatory reflux monitoring will not establish a definitive SERD diagnosis. These issues are compounded by the fact that symptoms such as hoarseness and chronic cough are very common and have multiple potential causes that may coexist with Gastro editorial  Fox, Omari, Rommel 4/9 23.03.2017 GERD by chance. These are real and important concerns because treatment decisions, including referral for anti-reflux surgery, are based on this information. Given the limitations of existing tests, new methods to detect SERD are of interest. Measurement of pepsin and bile acids in the saliva have been proposed as an 'office-based' method for detecting reflux. Recent studies indicate that high levels of pepsin provide a specific marker of GERD.13 The presence of this gastric enzyme in the throat can be explained only by supra-esophageal reflux and, therefore, this approach may be particularly value for SERD diagnosis.14 The same concept can be applied by nuclear imaging. Scintigraphy is used to detect reflux to the pharynx after ingestion of a radio-labelled drink, with late studies of the lungs obtained to detect aspiration.15 Both these investigations are well-tolerated and require less expertise to interpret than pH-impedance studies; however, neither provides insight into the mechanism of disease.   To address this issue, the current study applied high-resolution impedance manometry (HRiM) to obtain a detailed description of sensory-motor mechanisms that control upper esophageal sphincter (UES) function and how this is disrupted in patients with typical symptoms of GERD and SERD.6 It is known from the previous work by Reza Shaker’s group,16 that both relaxation and contractile UES responses are present in health, each governed by independent neural circuits that are activated in relation to the rate, magnitude and physical properties of distending stimuli. Relaxation enables venting of gas (“belching”). Contraction guards against reflux of gastric contents into the pharynx. The authors identified the UES relaxation reflex (RR) and contraction reflex (CR) by HRM and SER events using impedance data. These observations revealed that some patients with SERD symptoms have aberrant UES responses to rapid esophageal infusion of liquid (i.e. simulated reflux) that were not seen in patients with GERD symptoms or healthy controls. Specifically, rather than an effective contraction of the UES and proximal esophagus to clear “refluxate” away from the sensitive laryngo-pharyngeal region, some patients had an inappropriate Gastro editorial  Fox, Omari, Rommel 5/9 23.03.2017 UESRR and / or ineffective UES and esophageal CR during liquid reflux. The absolute frequency of SER during individual studies and how often SER was associated with each form of dysfunction was not reported and therefore the overall extent to which these aberrant responses are permissive of reflux is unknown; nevertheless, the unique abnormality in patients with SERD symptoms were inappropriate UESRRs. Although failure to initiate UES and esophageal CR also occurred in this group, the latter abnormality was seen also in GERD, and SER was never reported following “isolated” failure of the protective response.  This study provides new insight into the pathophysiology of SERD. The presence of inappropriate UESRR in patients with laryngo-pharyngeal symptoms is consistent with microaspiration as a mechanism of disease. In addition, the technology and methodology used by this group is of interest to clinicians looking for a new, more informative diagnostic test for SERD. HRiM provides a comprehensive, non-radiological assessment of pharyngo-esophageal function. High resolution manometry with spatiotemporal “Clouse” plots delivers a continuous representation of motor activity from the pharynx to the stomach. Intraluminal impedance detects bolus movement by measuring changes in resistance between multiple pairs of electrodes. To date, this combined technology has been applied most often to study patients with pharyngeal swallowing problems and to assess the risk of aspiration.17 The findings reported here suggest that HRiM could be applied also to assess the risk of supra-esophageal reflux in patients with laryngo-pharyngeal symptoms. Importantly, the HRiM methodology is different to ambulatory pH-impedance monitoring or stationary observations after a test meal because, rather than relying on the detection of spontaneous SER events, a standardized challenge designed to simulate gastro-esophageal reflux (i.e. esophageal infusion) is applied to identify patients at risk of SERD.   Further validation is required before HRiM could be used for SERD diagnosis. Surprisingly, the current study did not apply standardized questionnaires, Gastro editorial  Fox, Omari, Rommel 6/9 23.03.2017 laryngoscopic assessment or physiological studies to define study groups. Not one of these investigations represents a “gold standard"; however, symptoms are non-specific and the differential diagnosis for patients with “troublesome regurgitation along with at least one supra-esophageal manifestation” (the entry criterion used in the study) includes motility disorders, rumination syndrome and a number of ENT or respiratory diseases.18 This could explain why only 5/19 patients with “typical” SERD symptoms had the “characteristic” UESRR abnormality after rapid esophageal saline infusion. Future studies should apply standardized inclusion criteria with either pathological acid exposure or a positive reflux-symptom association on pH-impedance monitoring. Additionally, HRiM data analysis could be optimized. In this paper assessment of impedance was subjective and considered separately to the pressure measurements. Pressure Flow Analysis (PFA) is a semi-automated method which integrates high resolution pressure and impedance signals to obtain objective metrics that cannot be determined by either method alone.19 Application of PFA in patients with pharyngeal dysfunction identifies biomechanical factors that determine the success or failure of the swallow and defines the risk of aspiration.19, 20 This includes not only UES relaxation, but also UES opening and the efficacy of pharyngeal clearance.20 Adapting this approach, UES responses to esophageal infusion could be quantified in terms of “flow permissive characteristics” to detect factors that determine the risk of supra-esophageal reflux.  The success of scientific medicine is based on the identification and treatment of the pathophysiological basis of disease. To date, the diagnosis of SERD has been based as much on subjective assessment as objective physiology. Now, as with the introduction of HRM and the Chicago Classification of esophageal motility disorders a few years ago, new technology and methods is driving progress in the pharyngo-esophageal region. HRiM combined with analysis that utilizes all the information acquired, are now available to describe the causes of SERD, identify individual patients that can benefit from anti-reflux treatment and, in the process, solve this riddle wrapped in a mystery inside an enigma.  Gastro editorial  Fox, Omari, Rommel 7/9 23.03.2017 Table 1 Extraesophageal conditions linked to SERD Symptoms Diseases  Acid Regurgitation ▪ Dental erosions Voice change ▪ Sinusitis Hoarseness ▪ Posterior Laryngitis Chronic sore throat ▪ Vocal cord ulceration Repetitive throat clearing ▪ Laryngeal polyps Globus sensation ▪ Cancer of pharynx / larynx Chronic cough ▪ Bronchiectasis Recurrent aspiration ▪ Non-atopic asthmaGastro editorial  Fox, Omari, Rommel 8/9 23.03.2017 References 1. Lowden M, McGlashan JA, Steel A, et al. Prevalence of symptoms suggestive ofextra-oesophageal reflux in a general practice population in the UK. LogopedPhoniatr Vocol 2009;34:32-5.2. Champion GL, Richter JE. Atypical presentation of gastroesophageal refluxdisease: chest pain, pulmonary, and ear, nose, throat manifestations.Gastroenterologist 1993;1:18-33.3. Theodoropoulos DS, Ledford DK, Lockey RF, et al. Prevalence of upperrespiratory symptoms in patients with symptomatic gastroesophageal refluxdisease. Am J Respir Crit Care Med 2001;164:72-6.4. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition andclassification of gastroesophageal reflux disease: a global evidence-basedconsensus. Am J Gastroenterol 2006;101:1900-20; quiz 1943.5. Fox M, Forgacs I. Gastro-oesophageal reflux disease. BMJ 2006;332:88-936. Babaei A, Venu M, Naini SR, et al. Impaired Upper Esophageal Sphincter (UES)Reflexes in Patients with Supra-Esophageal Reflux Disease (SERD).Gastroenterology 2015.7. Pearson JP, Parikh S, Orlando RC, et al. Review article: reflux and itsconsequences--the laryngeal, pulmonary and oesophageal manifestations.Conference held in conjunction with the 9th International Symposium on HumanPepsin (ISHP) Kingston-upon-Hull, UK, 21-23 April 2010. Aliment PharmacolTher 2011;33 Suppl 1:1-71.8. Bulmer DM, Ali MS, Brownlee IA, et al. Laryngeal mucosa: its susceptibility todamage by acid and pepsin. Laryngoscope 2010;120:777-82.9. Sarkar S, Aziz Q, Woolf CJ, et al. Contribution of central sensitisation to thedevelopment of non-cardiac chest pain. Lancet 2000;356:1154-9.10. Koufman JA. The otolaryngologic manifestations of gastroesophageal refluxdisease (GERD): a clinical investigation of 225 patients using ambulatory 24-hourpH monitoring and an experimental investigation of the role of acid and pepsin inthe development of laryngeal injury. Laryngoscope 1991;101:1-78.11. Merati AL, Lim HJ, Ulualp SO, et al. Meta-analysis of upper probe measurementsin normal subjects and patients with laryngopharyngeal reflux. Ann Otol RhinolLaryngol 2005;114:177-82.12. Sifrim D, Dupont L, Blondeau K, et al. Weakly acidic reflux in patients withchronic unexplained cough during 24 hour pressure, pH, and impedancemonitoring. Gut 2005;54:449-54.13. Hayat JO, Gabieta-Somnez S, Yazaki E, et al. Pepsin in saliva for the diagnosis ofgastro-oesophageal reflux disease. Gut 2015;64:373-80.14. Sereg-Bahar M, Jerin A, Jansa R, et al. Pepsin and bile acids in saliva in patientswith laryngopharyngeal reflux - a prospective comparative study. ClinOtolaryngol 2015;40:234-9.15. Falk GL, Beattie J, Ing A, et al. Scintigraphy in laryngopharyngeal andgastroesophageal reflux disease: a definitive diagnostic test? World JGastroenterol 2015;21:3619-27.Gastro editorial                                                                  Fox, Omari, Rommel  9/9 23.03.2017 16. Jadcherla S, Hogan W, Shaker R. Physiology and pathophysiology of glottic reflexes and pulmonary aspiration: from neonates to adults. Semin Respir Crit Care Med 2010;31:554-60. 17. Omari TI, Dejaeger E, van Beckevoort D, et al. A method to objectively assess swallow function in adults with suspected aspiration. Gastroenterology 2011;140:1454-63. 18. Vardar R, Sweis R, Anggiansah A, et al. Upper esophageal sphincter and esophageal motility in patients with chronic cough and reflux: assessment by high-resolution manometry. Dis Esophagus 2013;26:219-25. 19. Omari TI, Papathanasopoulos A, Dejaeger E, et al. Reproducibility and Agreement of Pharyngeal Automated Impedance Manometry With Videofluoroscopy. Clin Gastroenterol Hepatol 2011. 20. Omari T, Wiklendt L, Dinning P, et al. Upper esophageal sphincter mechanical states analysis: a novel methodology to describe UES relaxation and opening. Front Syst Neurosci 2015;8:241.    

Supraesophageal Reflux Disease: Solving a Riddle Wrapped in a Mystery Inside an Enigma

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