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Proton Pump Inhibitor-Refractory Gastroesophageal Reflux Disease: Challenges and Solutions

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Proton Pump Inhibitor-Refractory Gastroesophageal Reflux Disease: Challenges and Solutions Journal name: Clinical and Experimental Gastroenterology Article Designation: Review Year: 2018 Volume: 11 Clinical and Experimental Gastroenterology Dovepress Running head verso: Mermelstein et al Running head recto: PPI-refractory GERD open access to scientific and medical research DOI: http://dx.doi.org/10.2147/CEG.S121056 Open Access Full Text Article REVIEW Proton pump inhibitor-refractory gastroesophageal reflux disease: challenges and solutions Joseph Mermelstein1 Abstract: A significant percentage of patients with gastroesophageal reflux disease (GERD) will not Alanna Chait Mermelstein2 respond to proton pump inhibitor (PPI) therapy. The causes of PPI-refractory GERD are numerous Maxwell M Chait3 and diverse, and include adherence, persistent acid, functional disorders, nonacid reflux, and PPI bioavailability. The evaluation should start with a symptom assessment and may progress to imag- 1Gasteroenterology and Nutrition Service, Department of Medicine, ing, endoscopy, and monitoring of esophageal pH, impedance, and bilirubin. There are a variety Memorial Sloan Kettering Cancer of pharmacologic and procedural interventions that should be selected based on the underlying Center, New York, NY, USA; mechanism of PPI failure. Pharmacologic treatments can include antacids, prokinetics, alginates, 2Department of Psychiatry and Behavioral Sciences, Memorial Sloan bile acid binders, reflux inhibitors, and antidepressants. Procedural options include laparoscopic Kettering Cancer Center, New York, fundoplication and LINX as well as endoscopic procedures, such as transoral incisionless fundopli- NY, USA; 3Department of Medicine, For personal use only. cation and Stretta. Several alternative and complementary treatments of possible benefit also exist. Columbia University College of Physicians and Surgeons, New York, Keywords: PPI failure, resistant GERD, acid-related diseases, gastroesophageal reflux disease, NY, USA acid reflux, proton pump inhibitors Introduction Gastroesophageal reflux disease (GERD), the most common upper gastrointestinal (GI) disorder in the US,1 is defined as symptoms or lesions that result from the retrograde flow of gastric contents into the esophagus.2 Proton pump inhibitors (PPIs), after acid activation to sulfonamides, covalently bind to cysteine residues on the luminal surface of H+/K+ ATPase proton pumps in the parietal cells, blocking ion transport and acid secretion. Chemically, all PPIs consist of a benzimidazole ring and a pyridine ring but vary in side ring substitution.1 Although PPIs are currently the most effective 3 Clinical and Experimental Gastroenterology downloaded from https://www.dovepress.com/ by 197.83.196.45 on 26-Jun-2019 treatment for GERD and its complications, up to 40% of patients with nonerosive reflux disease (NERD) remain symptomatic on standard therapy, and approximately 10–15% of patients with erosive esophagitis (EE) do not achieve full remission after 8 weeks of treatment.4,5 Patients with continued symptoms despite PPI treatment are considered to have refractory GERD, which is generally defined as the persistence of typical symptoms that do not respond to stable, twice-daily PPI dosing during at least 12 weeks of treat- ment.6–8 Up to 30% of GERD patients experience refractory GERD.2 Correspondence: Maxwell M Chait Columbia Doctors Medical Group, 180 East Hartsdale Avenue, Hartsdale, Causes of refractory GERD NY 10530, USA There are many potential causes of refractory GERD that vary in incidence, clinical Tel +1 914 725 2010 importance, and symptom severity and frequency. Poor compliance and adherence Fax +1 914 725 6488 Email [email protected] should first be assessed before further evaluation is pursued. The most common submit your manuscript | www.dovepress.com Clinical and Experimental Gastroenterology 2018:11 119–134 119 Dovepress © 2018 Mermelstein et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work http://dx.doi.org/10.2147/CEG.S121056 you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Mermelstein et al Dovepress mechanisms for refractory GERD include functional bowel regarding mealtime dosing of PPIs, 26% give no instructions disorders, weakly acidic reflux, and residual acid. Factors or say that timing is unimportant, and 10% incorrectly advise related to metabolism and bioavailability play a limited role their patients to take them with or after food.15 in PPI failure. GERD-like symptoms may also be due to a variety of other disorders, such as eosinophilic esophagitis Choice of agent (EoE), pill-induced esophagitis, infectious esophagitis, and Limited data directly compares the efficacy of different PPIs. achalasia, which should be considered in the differential Although some studies suggest that certain PPIs may be more diagnosis of patients with unremitting symptoms (Table 1). effective for GERD, this is not supported by a meta-analysis of pooled data.16 Therefore, choice of agent is an unlikely Factors related to medication cause of refractory GERD. administration PPI adherence and compliance Factors associated with functional An important initial consideration for all patients not fully esophageal disorders responding to PPI therapy is to evaluate medication adher- Functional GI disorders have traditionally been defined as ence, as regular medication administration is crucial for symptomatic disorders without known structural, metabolic, maximal efficacy. Several studies indicate poor medication or infectious cause.17 Functional disorders likely result from a adherence among PPI users, with two reports finding that diverse group of underlying mechanisms, which may include only 53.8% and 67.7% of patients filled their monthly PPI increased mucosal sensitivity to mechanical and chemical prescription more than 80% of the time.9,10 Moreover, many stimulation or worsened central perception of pain.18 patients discontinue PPIs when their symptoms resolve, as demonstrated by a large population-based survey in which Functional heartburn only 55% of patients took a PPI once daily for 4 weeks as Rome IV defines functional heartburn as 3 months of burn- For personal use only. prescribed, with 37% taking it for 12 or fewer days out of ing retrosternal pain without evidence of continued reflux or the month.11,12 underlying motility disorder that is not relieved by optimal Medication compliance is also important to investigate, antisecretory therapy.18 As many as 58% of patients with as several studies show that patients do not use PPIs at the refractory GERD fall into this category.19,20 appropriate time. One study of 100 patients with persistent GERD symptoms found that only 8% of patients reported Esophageal hypersensitivity dosing at the optimal 30–60 minutes prior to meal.13 Com- Esophageal hypersensitivity, which is defined as the height- mon reasons for nonadherence and noncompliance include ened perception of various stimuli, including acid, tempera- absence of symptoms, personal preference, side effects, and ture, mechanical distention, and electrical stimulation,21 may lack of knowledge or misinformation about medication,14 contribute to persistent GERD symptoms despite PPI therapy. as demonstrated by one national survey that 36% of physi- The mechanism of esophageal hypersensitivity is unclear but cians give their patients no directions or incorrect directions likely involves both peripheral and central sensitization via dilated intracellular spaces (DISs) and exposure of subepithe- Clinical and Experimental Gastroenterology downloaded from https://www.dovepress.com/ by 197.83.196.45 on 26-Jun-2019 Table 1 Causes of refractory GERD lial nerves to acid.22–24 Esophageal hypersensitivity may also • PPI adherence and compliance be influenced by stress, which can alter brain processing of • Functional esophageal disorders sensation, autonomic nervous activity, cortisol release, and Functional heart burn, esophageal hypersensitivity, IBS pathways involved in the spinal transmission of nociceptive • Weakly acidic or nonacid reflux signals.22 Weakly acid reflux, duodenogastroesophageal reflux • Residual acid Although the role of esophageal hypersensitivity in PPI NAB, acid pocket failure has not been well studied, most treatment-refractory • Delayed gastric emptying patients demonstrate a lower threshold for pain perception • Rapid PPI metabolism with esophageal balloon distention or electrical stimulation.25 • Eosinophilic esophagitis Studies of patients with GERD who have been exposed to • Causes unrelated to GERD anxiety induction or acute auditory stress show increased Abbreviations: GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor; IBS, irritable bowel syndrome; NAB, nocturnal acid breakthrough. perceptual response to acid exposure and exacerbation of 120 submit your manuscript | www.dovepress.com Clinical and Experimental Gastroenterology 2018:11 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress PPI-refractory GERD symptoms.26,27 Further supporting the contribution
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