Dysphagia lusoria: utility of high-resolution impedance manometry to identify true disease.

Dysphagia lusoria is a rare cause of dysphagia due to impingement of the esophagus by an aberrant right subclavian artery. Although most remain asymptomatic, this aberrant vessel can lead to progressive dysphagia in childhood or even later in life as a result of arteriosclerotic burden and attenuation of esophageal compliance that led to esophageal compression. We present a 56-year-old man with a 3-year history of progressively worsening dysphagia to solids and liquids and globus sensation. Videofluoroscopic swallowing study (modified barium esophagram) and barium esophagram showed delayed barium tablet transit in the upper esophagus and focal smooth narrowing of the upper esophagus caused by external compression, respectively. Computed tomography imaging demonstrated external compression of proximal esophagus from an aberrant right subclavian artery with high atherosclerotic burden. In addition, high-resolution impedance manometry (HRiM) revealed a striking high-pressure pulsatile vascular band in the proximal esophagus (108 mmHg) associated with poor bolus transit, demonstrating the utility of HRiM in strengthening the diagnoses of true dysphagia lusoria.

Development of quality indicators for the diagnosis and management of achalasia.

BACKGROUND: The management of achalasia has improved due to diagnostic and therapeutic innovations. However, variability in care delivery remains and no established measures defining quality of care for this population exist. We aimed to use formal methodology to establish quality indicators for achalasia patients. METHODS: Quality indicator concepts were identified from the literature, consensus guidelines and clinical experts. Using RAND/University of California, Los Angeles (UCLA) Appropriateness Method, experts in achalasia independently ranked proposed concepts in a two-round modified Delphi process based on 1) importance, 2) scientific acceptability, 3) usability, and 4) feasibility. Highly valid measures required strict agreement (≧ 80% of panelists) in the range of 7-9 for across all four categories. KEY RESULTS: There were 17 experts who rated 26 proposed quality indicator topics. In round one, 2 (8%) quality measures were rated valid. In round two, 19 measures were modified based on panel suggestions, and experts rated 10 (53%) of these measures as valid, resulting in a total of 12 quality indicators. Two measures pertained to patient education and five to diagnosis, including discussing treatment options with risk and benefits and using the most recent version of the Chicago Classification to define achalasia phenotypes, respectively. Other indicators pertained to treatment options, such as the use of botulinum toxin for those not considered surgical candidates and management of reflux following achalasia treatment. CONCLUSIONS & INFERENCES: Using a robust methodology, achalasia quality indicators were identified, which can form the basis for establishing quality gaps and generating fully specified quality measures.

Normal values and regional differences in oesophageal impedance-pH metrics: a consensus analysis of impedance-pH studies from around the world.

OBJECTIVE: Limitations of existing impedance-pH thresholds include small sample size of normative studies, inclusion of artefactual pH drops and incorrect identification of impedance reflux events. We aimed to obtain new impedance-pH thresholds from expert consensus analysis of tracings from a large number of healthy subjects. DESIGN: Of 541 studies performed worldwide using two different systems (Diversatek, USA, and Laborie, Netherlands), 150 tracings with oesophageal diagnoses, behavioural disorders and study-related artefacts were excluded. The remainder studies were subject to two reviewer consensus analysis, in-person or through video conference, consisting of editing meals and pH drops, identification of impedance reflux and postreflux swallow-induced peristaltic wave (PSPW) using strict pre-established criteria and measurement of distal mean nocturnal baseline impedance (MNBI). RESULTS: Consensus analysis was performed in 391 tracings (age 32.7 years, range 18-71, 54.2% female). Normative thresholds were significantly different between Diversatek and Laborie (total acid exposure time: 2.8% and 5%; reflux episodes: 55 and 78; MNBI at 3 cm: 1400 and 1500 ohms, at 5 cm: 1400 and 1800 ohms). Males had higher acid exposure, more reflux episodes and lower MNBI. Significant regional differences were identified, including higher PSPW scores in Western countries, and higher MNBI in Asia using Diversatek, and higher acid exposure in the Netherlands, higher MNBI in Asia and South Africa, and lower MNBI in Turkey using Laborie. CONCLUSION: Normal impedance-pH monitoring thresholds have regional and system-related differences. Clinical interpretation needs to use normal thresholds valid for the system used and world region, following careful editing of the tracings.

Spectrum of esophageal motility disorders in patients with liver cirrhosis.

Disorders of esophageal motility have been described in patients with cirrhosis in a small number of studies. In this review, we aim to provide an overview of the available evidence on esophageal motility disorders in cirrhosis and their clinical implications. This review delves into the following concepts: (1) Gastroesophageal reflux disease is common in liver cirrhosis due to many mechanisms; however, when symptomatic it is usually nocturnal and has an atypical presentation; (2) Endoscopic band ligation is better than sclerotherapy in terms of its effect on esophageal motility and seems to correct dysmotilities resulting from the mechanical effect of esophageal varices; (3) Chronic alcoholism has no major effects on esophageal motility activity other than lower esophageal sphincter hypertension among those with alcoholic autonomic neuropathy; (4) An association between primary biliary cholangitis and scleroderma can be present and esophageal hypomotility is not uncommon in this scenario; and (5) Cyclosporin-based immunosuppression in liver transplant patients can have a neurotoxic effect on the esophageal myenteric plexus leading to reversible achalasia-like manifestations.

Durability of pneumatic dilation monotherapy in treatment-naive achalasia patients.

BACKGROUND: Pneumatic dilation (PD) is often billed as a "short term" treatment for achalasia but anecdotally can last years. This study sought to explore how long a single pneumatic dilation may induce symptom remission in a treatment-naïve achalasia patient. METHODS: A single center, retrospective chart review of patients with an ICD-9 or - 10 code of achalasia between 2005 and 2017 was performed. Treatment naïve patients with manometric diagnosis of primary achalasia were included. Outcomes (success or failure); single vs multiple PD; age; and estimated duration of effect were evaluated. Each patient underwent a single PD unless re-intervention was required for relapse. RESULTS: 83 patients (52% female, median 51.6 ± 3.6 years) were included. 43% underwent 2 PD and 13% underwent 3 PD. There was no significant relation between age, gender, and number of PDs. After 1 PD, 87.5% of patients reported > 1 year of symptom remission. 80.5% of relapsed patients reported success after a 2nd dilation. 1 PD was more likely to result in success than multiple PDs (p < 0.001). The measured median duration of remission after 1 PD was 4.23 years, and for 2 PDs, 3.71 years. The median estimated remission time after 1 PD was 8.5 years (CI 7.3-9.7, p = 0.03). CONCLUSIONS: PD is a safe, durable treatment for achalasia. A single PD is likely to last years. A second PD, if required, also has a high likelihood of success.

Randomized Trial of Medical versus Surgical Treatment for Refractory Heartburn.

BACKGROUND: Heartburn that persists despite proton-pump inhibitor (PPI) treatment is a frequent clinical problem with multiple potential causes. Treatments for PPI-refractory heartburn are of unproven efficacy and focus on controlling gastroesophageal reflux with reflux-reducing medication (e.g., baclofen) or antireflux surgery or on dampening visceral hypersensitivity with neuromodulators (e.g., desipramine). METHODS: Patients who were referred to Veterans Affairs (VA) gastroenterology clinics for PPI-refractory heartburn received 20 mg of omeprazole twice daily for 2 weeks, and those with persistent heartburn underwent endoscopy, esophageal biopsy, esophageal manometry, and multichannel intraluminal impedance-pH monitoring. If patients were found to have reflux-related heartburn, we randomly assigned them to receive surgical treatment (laparoscopic Nissen fundoplication), active medical treatment (omeprazole plus baclofen, with desipramine added depending on symptoms), or control medical treatment (omeprazole plus placebo). The primary outcome was treatment success, defined as a decrease of 50% or more in the Gastroesophageal Reflux Disease (GERD)-Health Related Quality of Life score (range, 0 to 50, with higher scores indicating worse symptoms) at 1 year. RESULTS: A total of 366 patients (mean age, 48.5 years; 280 men) were enrolled. Prerandomization procedures excluded 288 patients: 42 had relief of their heartburn during the 2-week omeprazole trial, 70 did not complete trial procedures, 54 were excluded for other reasons, 23 had non-GERD esophageal disorders, and 99 had functional heartburn (not due to GERD or other histopathologic, motility, or structural abnormality). The remaining 78 patients underwent randomization. The incidence of treatment success with surgery (18 of 27 patients, 67%) was significantly superior to that with active medical treatment (7 of 25 patients, 28%; P = 0.007) or control medical treatment (3 of 26 patients, 12%; P<0.001). The difference in the incidence of treatment success between the active medical group and the control medical group was 16 percentage points (95% confidence interval, -5 to 38; P = 0.17). CONCLUSIONS: Among patients referred to VA gastroenterology clinics for PPI-refractory heartburn, systematic workup revealed truly PPI-refractory and reflux-related heartburn in a minority of patients. For that highly selected subgroup, surgery was superior to medical treatment. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT01265550.).

Plasma levels of TNF-α, IL-6, IFN-γ, IL-12, IL-17, IL-22, and IL-23 in achalasia, eosinophilic esophagitis (EoE), and gastroesophageal reflux disease (GERD).

An elevation of serum inflammatory biomarkers in achalasia patients compared with controls recently was demonstrated. It has not been determined whether the elevation of inflammatory cytokines is unique to achalasia or occurs with other diseases involving the esophagus. The primary aim of our study was to compare the differences in plasma immunological profiles (TNF- α receptor, IL-6, IFN-γ, IL-12, IL-17, IL-22, and IL-23) of patients with achalasia, eosinophilic esophagitis (EoE), and gastroesophageal reflux disease (GERD). A secondary aim of this study was to classify these same plasma cytokine profiles in the three achalasia subtypes. METHODS: Plasma from 53 patients with achalasia, 22 with EoE, and 20 with GERD (symptoms plus esophagitis or + reflux study) were analyzed. EXCLUSION CRITERIA: malignancy, autoimmune condition, immunodeficiency disorder, and treatment with steroids/immune modulating drugs. Cytokine levels were assayed via multiplex enzyme-linked immunosorbent assay (ELISA). RESULTS: Our key finding revealed significant elevations in IL- 6 (p = 0.0158) in achalasia patients compared with EoE patients. Overall, plasma inflammatory biomarker patterns were not different in the three subtypes of achalasia. CONCLUSION: There were no differences between the cytokine levels of any of the measured biomarkers between the achalasia and GERD groups suggesting that luminal stasis does increase biomarker levels for any of the cytokines examined in our study. While these results are an early first step towards clarifying some aspects of the pathogenesis of achalasia, they bring about many more questions that require further investigation and expansion. Further investigation with a larger cohort and a broader panel of biomarkers is needed.

Impact of Peppermint Therapy on Dysphagia and Non-cardiac Chest Pain: A Pilot Study.

BACKGROUND: Due to its smooth muscle relaxing properties, peppermint oil (PO) may relieve dysphagia and chest pain due to esophageal motility disorders. AIM: To explore the impact of PO on dysphagia and/or chest pain in patients referred for motility testing. METHODS: Patients initiated on PO for dysphagia and/or chest pain from 2013 to 2016 were identified. We excluded patients with obstructing esophageal lesions, patients lost to follow-up, and those with preexisting cardiac conditions. Concentrated PO was given as commercially available dissolvable peppermint tablets; two tablets before meals were prescribed to patients with dysphagia and on an as-needed basis for patients with chest pain. Patient-reported symptom response was assessed using a modified five-point Likert scale. RESULTS: Thirty-eight patients were included. Twenty-four patients (63%) reported improvement; 12 were much better and 12 were slightly better. Fourteen experienced no change and none reported feeling worse. Based on pre-treatment HRM, patients with distal esophageal spasm (DES) (n = 10) and esophagogastric junction outflow obstruction (EGJOO) (n = 8) appeared to demonstrate the best subjective improvement (83% and 100%, respectively) (P < 0.05). CONCLUSION: PO appears to provide symptomatic relief in some patients with dysphagia and CP. Presence of a well-defined manometric disorder, particularly DES or EGJOO, appeared to predict response.

Improving High-resolution Impedance Manometry Using Novel Viscous and Super-viscous Substrates in the Supine and Upright Positions: A Pilot Study.

BACKGROUND/AIMS: Swallows with viscous or solid boluses in different body positions alter esophageal manometry patterns. Limitations of previous studies include lack of standardized viscous substrates and the need for chewing prior to swallowing solid boluses. We hypothesize that high-resolution impedance manometry (HRiM) using standardized viscous and super-viscous swallows in supine and upright positions improves sensitivity for detecting esophageal motility abnormalities when compared with traditional saline swallows. To establish normative values for these novel substrates, we recruited healthy volunteers and performed HRiM. METHODS: Standardized viscous and super-viscous substrates were prepared using "Thick-It" food thickener and a rotational viscometer. All swallows were administered in 5-mL increments in both supine and upright positions. HRiM metrics and impedance (bolus transit) were calculated. We used a paired two-tailed t test to compare all metrics by position and substrate. RESULTS: The 5-g, 7-g, and 10-g substrates measured 5000, 36 200, and 64 700 mPa∙sec, respectively. In 18 volunteers, we observed that the integrated relaxation pressure was lower when upright than when supine for all substrates (P < 0.01). The 10-g substrate significantly increased integrated relaxation pressure when compared to saline in the supine position (P < 0.01). Substrates and positions also affected distal contractile integral, distal latency, and impedance values. CONCLUSIONS: We examined HRiM values using novel standardized viscous and super-viscous substrates in healthy subjects for both supine and upright positions. We found that viscosity and position affected HRiM Chicago metrics and have potential to increase the sensitivity of esophageal manometry.

Alternative therapies for GERD: a way to personalized antireflux surgery.

Gastroesophageal reflux disease (GERD) is a common disorder, known to affect about 20% of the Western population. Although conventional medical or surgical treatment has proven effective, there is certainly room for improvements. As only 10% of GERD patients are finally treated by antireflux surgery, a large therapeutic window exists. This treatment gap consists of patients who are not effectively treated with proton pump inhibitor but do not want to run the potential risks of conventional surgery. During the last two decades, several novel and intriguing options for the surgical treatment of GERD have been introduced and found their way into clinical use. The following summary will give an update of certain alternative therapeutic options to treat GERD or its pathological consequences.

Management options for patients with GERD and persistent symptoms on proton pump inhibitors: recommendations from an expert panel.

BACKGROUND: The aim of this study was to assess expert gastroenterologists' opinion on treatment for distinct gastroesophageal reflux disease (GERD) profiles characterized by proton pump inhibitor (PPI) unresponsive symptoms. METHODS: Fourteen esophagologists applied the RAND/UCLA Appropriateness Method to hypothetical scenarios with previously demonstrated GERD (positive pH-metry or endoscopy) and persistent symptoms despite double-dose PPI therapy undergoing pH-impedance monitoring on therapy. A priori thresholds included: esophageal acid exposure (EAE) time >6.0%; symptom-reflux association: symptom index >50% and symptom association probability >95%; >80 reflux events; large hiatal hernia: >3 cm. Primary outcomes were appropriateness of four invasive procedures (laparoscopic fundoplication, magnetic sphincter augmentation, transoral incisionless fundoplication, radiofrequency energy delivery) and preference for pharmacologic/behavioral therapy. RESULTS: Laparoscopic fundoplication was deemed appropriate for elevated EAE, and moderately appropriate for positive symptom-reflux association for regurgitation and a large hiatal hernia with normal EAE. Magnetic sphincter augmentation was deemed moderately appropriate for elevated EAE without a large hiatal hernia. Transoral incisionless fundoplication and radiofrequency energy delivery were not judged appropriate in any scenario. Preference for non-invasive options was as follows: H2RA for elevated EAE, transient lower esophageal sphincter relaxation inhibitors for elevated reflux episodes, and neuromodulation/behavioral therapy for positive symptom-reflux association. CONCLUSION: For treatment of PPI unresponsive symptoms in proven GERD, expert esophagologists recommend invasive therapy only in the presence of abnormal reflux burden, with or without hiatal hernia, or regurgitation with positive symptom-reflux association and a large hiatus hernia. Non-invasive pharmacologic or behavioral therapies are preferred for all other scenarios.

Distal Esophageal Spasm: A Review.

Distal esophageal spasm is a rare motility disorder presenting principally with nonobstructive dysphagia and noncardiac chest pain. In symptomatic patients, the manometric diagnosis is made when >10% of the wet swallows have simultaneous and/or premature contractions intermixed with normal peristalsis. We characterize manometry and barium as complementary diagnostic approaches, and given the intermittent nature of the disorder, one should be always aware that it is almost impossible to rule out spasm. Treatment is difficult; we propose an approach beginning with the least invasive intervention.

Throat Clearing, Frequently Reported, But is it GERD Related?

GOALS: To identify the association of throat clearing (TC) with gastroesophageal reflux disease (GERD) during objective reflux monitoring in a large number of patients studied in our esophageal testing laboratory. BACKGROUND: TC is frequently reported and considered to be an atypical symptom of GERD. Atypical GERD symptoms have been widely investigated and empirically treated with proton pump inhibitors. STUDY: We reviewed ambulatory impedance-pH studies of 186 patients referred for evaluation of possible GERD from January 2011 to December 2015 to evaluate the symptom association (SA) of TC with both an abnormal number of reflux episodes and also abnormal esophageal acid exposure (EAE). Patients were divided into 2 groups; group 1: TC is the only reported symptom, group 2: TC is one of the symptoms. All patients were studied off proton pump inhibitors therapy. RESULTS: Group 1 where TC was the only symptom in 27/186 (14.5%) patients. There was no significant difference in positive SA between this group (6/27; 22%) and group 2 (43/159; 27%) (Z score P=0.59). There was also no significant association between SA and abnormal EAE whether TC was the only presenting symptom (χ, P=0.7) or one of the reported symptoms (χ, P=0.10). None of the 6/27 had abnormal EAE. CONCLUSION: Although TC is often considered a possible GERD-related symptom, we found a low probability of objective association. TC is not likely to be the only presenting symptom, and if it happens, it is unlikely to be associated with GERD. Perhaps, TC should not be considered as a GERD symptom, even as an atypical one.

Symptom Index or Symptom Association Probability?: A Closer Look at Symptom Association in Suspected GERD Patients.

BACKGROUND: Symptom index (SI) and symptom association probability (SAP) are popular methods used to measure symptom association in patients with gastroesophageal reflux disease (GERD). AIM: To investigate whether these 2 methods yield similar results in analysis of both typical and atypical GERD symptoms. MATERIALS AND METHODS: Combined impedance-pH reflux studies of 1471 patients tested for possible GERD symptoms from January 2010 to May 2015 were reviewed. SI and SAP were analyzed for typical and atypical GERD symptoms including heartburn, regurgitation, indigestion, chest pain, cough, and throat clearing (TC). Patients who reported <3 symptom events during the 24-hour monitoring period were excluded. ON and OFF proton pump inhibitor (PPI) groups were reviewed. Kappa coefficient (κ) rather than simple percentage was used to measure the agreement rate. Simple percentage agreement is a less reliable method compared with κ. RESULTS: On PPI therapy, there was a good κ between SI and SAP for regurgitation (0.68) and indigestion (0.64), moderate for heartburn (0.48) and chest pain (0.51), and poor for cough (0.33) and TC (0.29). There was a lower κ OFF PPI therapy for heartburn (0.36), regurgitation (0.44), and indigestion (0.50). But there was no difference in κ for chest pain (0.61), cough (0.29), and TC (0.33). CONCLUSIONS: SI and SAP showed better agreement for patients with typical GERD symptoms and even better when tested ON PPI. A better symptom association method is needed for patients with atypical GERD symptoms.

Sporadic Fundic Gland Polyps and Gastric Acid Suppression Level.

BACKGROUND: Fundic gland polyps (FGPs) are a common endoscopic finding and are known to be associated with proton pump inhibitors (PPIs) use. It is not known if their prevalence is affected by gastric acidity levels. This study aimed to assess whether there is a correlation between FGPs and gastric acidity levels as identified on 24-hour ambulatory impedance-pH studies in patients on PPI therapy. METHODS: We performed a review of 402 consecutive patients who take at least once daily PPI and underwent esophagogastroduodenoscopy with combined impedance-pH studies in the same setting (time and place) between January 2010 and December 2014. Patients were classified into 2 groups based on the presence or absence of biopsy-confirmed FGPs during endoscopy. RESULTS: Of the 402 patients, 30 (7%) had FGPs. One of these polyps was found with low-grade dysplasia. There was no significant difference of the distributions of the [H+] in the FGPs versus the nonpolyp groups (P = 0.741). There was no significant difference between the 2 groups regarding PPI dose frequency regimens (once and twice) (P = 0.074). However, we found weak ordinal association with PPI duration (P = 0.01) (Spearman = 0.1). CONCLUSIONS: FGPs are common endoscopic lesions. Incidence of dysplasia in FGPs is not only rare, but also of unknown clinical significance. Although they seem to be associated with PPIs, the mechanism remains unclear, as we found no correlation between the presence of FGPs and gastric acid control or PPI dose. Future studies would be useful to elucidate an alternate mechanism.

Manometric Subtypes of Ineffective Esophageal Motility.

OBJECTIVES: Ineffective esophageal motility (IEM) is characterized by well-defined manometric criteria. However, much variation exists within the diagnosis: Some patients exhibit exactly the required five weak swallows to make the diagnosis. Others show consistently ineffective swallows with total absence of any normal swallow. "We hypothesize" there are two different manometric subtypes of IEM; IEM Alternans (IEM-A) and IEM Persistens (IEM-P). METHODS: A total of 231 IEM patients were identified by high-resolution manometry (HRM). IEM defined by distal contractile integral (DCI) <450 mm Hg/s/cm in ≥50% of test swallows. Abnormal reflux study was defined by excess total number of reflux episodes, abnormal esophageal acid exposure, or positive symptom association. RESULTS: A total of 195 (84%) patients had IEM-A and 36 (16%) had IEM-P. A striking gender difference with 34% of IEM-A being males compared to 53% of IEM-P. (P=0.03). Mean age of IEM-P (59.6 years+/-13.1) was greater than IEM-A (55.5 years+/-13.6) (P=0.04). Mean lower esophageal sphincter (LES) resting pressure was significantly lower in IEM-P (20.8 mm Hg+/-1.4) than IEM-A (29 mm Hg+/-1.2) (P=0.002). There was no difference in LES-integrated relaxation pressure (IRP), bolus transit, or manometric presence of hiatal hernia between the two groups. Out of 146, 89 (61%) patients had abnormal reflux study. Esophageal acid exposure in upright position was significantly higher in IEM-P than IEM-A (3.5 vs. 1.7%, P=0.04). Poor gastric acid control on proton pump inhibitor (PPI) was more prevalent among IEM-P patients (58%) than IEM-A (27%) (P=0.007). In subgroup analysis of 41 IEM patients with dysphagia, DCI for liquid swallows was significantly lower in IEM-P (111+/-142 mm Hg/s/cm) compared to IEM-A (421+/-502 mm Hg/s/cm) (P=0.04), lower mean LES resting pressure in IEM-P (16.6+/-9 mm Hg) than IEM-A (31.7+/-18 mm Hg) (P=0.01). CONCLUSIONS: There are two distinct manometric IEM subtypes; IEM-P with an older male predominance, more advanced reflux disease, weaker LES, and worse response to PPI; likely a more advanced manifestation than IEM-A. However, the question if there are different etiologies underlying the two subtypes remains to be answered.

The Safety of Appropriate Use of Over-the-Counter Proton Pump Inhibitors: An Evidence-Based Review and Delphi Consensus.

The availability of over-the-counter (OTC) proton pump inhibitors (PPIs) for the short-term (2 weeks) management of frequent heartburn (≥2 days/week) has increased markedly, yet evidence-based recommendations have not been developed. A panel of nine international experts in gastroesophageal reflux disease developed consensus statements regarding the risks and benefits of OTC PPIs using a modified Delphi process. Consensus (based on ≥80% approval) was reached through multiple rounds of remote voting and a final round of live voting. To identify relevant data, the available literature was searched and summarized. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system terminology was used to rate the quality of evidence and strength of recommendations; consensus was based on ≥2/3 agreement. After 4 rounds of review, consensus was achieved for 18 statements. Notably, the available data did not directly reflect OTC use, but instead, prescription use; therefore, extrapolations to the OTC setting were often necessary. This limitation is regrettable, but it justifies performing this exercise to provide evidence-based expert opinion on a widely used class of drugs. The panel determined that using OTC PPIs according to label instructions is unlikely to mask the symptoms of esophageal or gastric cancer or adversely impact the natural history of related precursor conditions. OTC PPIs are not expected to substantially affect micronutrient absorption or bone mineral density or cause community-acquired pneumonia, Clostridium difficile infection, or cardiovascular adverse events. However, OTC PPI use may be associated with slightly increased risks for infectious diarrhea, certain idiosyncratic reactions, and cirrhosis-related spontaneous bacterial peritonitis. The available evidence does not suggest that OTC PPI use consistent with label instructions is associated with substantial health risks. To minimize potential risks, healthcare professionals and consumers must actively participate in decision making when managing reflux-related symptoms in the self-care setting.