Targeting ATP12A, a Nongastric Proton Pump α Subunit, for Idiopathic Pulmonary Fibrosis Treatment.

Idiopathic pulmonary fibrosis (IPF) is a pathological condition of unknown etiology that results from injury to the lung and an ensuing fibrotic response that leads to the thickening of the alveolar walls and obliteration of the alveolar space. The pathogenesis is not clear, and there are currently no effective therapies for IPF. Small airway disease and mucus accumulation are prominent features in IPF lungs, similar to cystic fibrosis lung disease. The ATP12A gene encodes the α-subunit of the nongastric H+, K+-ATPase, which functions to acidify the airway surface fluid and impairs mucociliary transport function in patients with cystic fibrosis. It is hypothesized that the ATP12A protein may play a role in the pathogenesis of IPF. The authors' studies demonstrate that ATP12A protein is overexpressed in distal small airways from the lungs of patients with IPF compared with normal human lungs. In addition, overexpression of the ATP12A protein in mouse lungs worsened bleomycin induced experimental pulmonary fibrosis. This was prevented by a potassium competitive proton pump blocker, vonoprazan. These data support the concept that the ATP12A protein plays an important role in the pathogenesis of lung fibrosis. Inhibition of the ATP12A protein has potential as a novel therapeutic strategy in IPF treatment.

[Multicenter study of gastroesophageal reflux disease symptoms prevalence in outpatients in Russia].

BACKGROUND: Recently, there has been an increase in the prevalence of gastroesophageal reflux disease (GERD) in Northern Europe, North America and East Asia. However data on GERD prevalence in Russian population are very limited. AIM: To determine the prevalence of GERD among the population of Russia, the clinical spectrum of GERD symptoms, the main drugs used for GERD treatment, and the rate of their administration. MATERIALS AND METHODS: The study was conducted from November 2015 to January 2017 in 8 cities of Russia. A survey of patients over the age of 18 years old visiting outpatient medical institutions for any reason, including patients without gastrointestinal complaints was carried out using a short version of the Mayo Clinic questionnaire. RESULTS: In total, 6132 questionnaires of patients aged 1890 years were analyzed [2456 men (40.1%) and 3676 women (59.9%), mean age 46.615.4 years]. The GERD prevalence among the interviewed patients was 34.2%. The incidence of GERD increased depending on body mass index and the age of the patients. Medications used by the patients for heartburn relief included proton pump inhibitors 59.96%, antacids 67.92%, H2-histamine receptor blockers 11.42%, alginates 18.41% of patients. CONCLUSION: The results of this study indicate a high prevalence of GERD among residents of Russian cities applying for primary health care (34.2%). In comparison with previous studies, an increase in the proportion of GERD patients taking proton pump inhibitors was noted; in most cases the regimen of their intake was in accordance with the recommendations.

Proton pump inhibition for secondary hemochromatosis in hereditary anemia: a phase III placebo-controlled randomized cross-over clinical trial.

Iron overload is a severe general complication of hereditary anemias. Treatment with iron chelators is hampered by important side-effects, high costs, and the lack of availability in many countries with a high prevalence of hereditary anemias. In this phase III randomized placebo-controlled trial, we assigned adults with non-transfusion-dependent hereditary anemias with mild-to-moderate iron overload to receive esomeprazole (at a dose of 40 mg twice daily) or placebo for 12 months in a cross-over design. The primary end point was change of liver iron content measured by MRI. A total of 30 participants were enrolled in the trial. Treatment with esomeprazole resulted in a statistically significant reduction in liver iron content that was 0.55 mg Fe/g dw larger than after treatment with placebo (95%CI [0.05 to 1.06]; p = 0.03). Median baseline liver iron content at the start of esomeprazole was 4.99 versus 4.49 mg Fe/g dw at start of placebo. Mean delta liver iron content after esomeprazole treatment was -0.57 (SD 1.20) versus -0.11 mg Fe/g dw (SD 0.75) after placebo treatment. Esomeprazole was well tolerated, reported adverse events were mild and none of the patients withdrew from the study due to side effects. In summary, esomeprazole resulted in a significant reduction in liver iron content when compared to placebo in a heterogeneous group of patients with non-transfusion-dependent hereditary anemias. From an international perspective this result can have major implications given the fact that proton pump inhibitors may frequently be the only realistic therapy for many patients without access to or not tolerating iron chelators.

Applying Lyon Consensus criteria in the work-up of patients with proton pump inhibitory-refractory heartburn.

BACKGROUND: A hierarchical approach for gastro-oesophageal reflux disease (GERD) diagnosis by impedance-pH monitoring was proposed by the Lyon Consensus, based on acid exposure time (AET) and supportive impedance metrics. AIMS: To establish the clinical value of Lyon Consensus criteria in the work-up of patients with proton pump inhibitory (PPI)-refractory heartburn. METHODS: Expert review of off-therapy impedance-pH tracings from unproven GERD patients with PPI-refractory heartburn prospectively evaluated at referral centers. Impedance metrics, namely total reflux episodes, postreflux swallow-induced peristaltic wave index, and mean nocturnal baseline impedance, were assessed. Expert review of on-therapy preoperative impedance-pH tracings from a separate cohort of surgically treated erosive/nonerosive GERD cases. RESULTS: Off-therapy, normal, inconclusive, and abnormal AET was found in 59%, 17%, and 23% of 317 cases. Supportive evidence of GERD was provided by abnormal impedance metrics in up to 22% and 62% of cases in the normal and inconclusive AET groups, respectively. Adding the cases with inconclusive AET and abnormal impedance metrics to the abnormal AET group, a significant increase in GERD evidence was observed (from 23% to 37% of cases, p < 0.0002). At the on-therapy presurgical evaluation, abnormal/inconclusive AET and supraphysiological values of impedance metrics showed ongoing reflux in 21% and 90% of 96 cases, respectively (p < 0.00001); a relationship between on-therapy ongoing reflux and PPI-refractory heartburn was confirmed by the favorable surgical outcome at 3-year follow-up, 88% of cases being in persistent off-PPI heartburn remission. CONCLUSIONS: Impedance-pH monitoring, off- and on-therapy, is of high clinical value in the work-up of patients with PPI-refractory heartburn.

Interplay of potassium channel, gastric parietal cell and proton pump in gastrointestinal physiology, pathology and pharmacology.

Gastric acid secretion plays a pivotal role in the physiology of gastrointestinal tract. The functioning of the system encompasses a P2 ATPase pump (which shuttles electroneutral function at low pH) along with different voltage sensitive/neutral ion channels, cytosolic proteins, acid sensor receptors as well hormonal regulators. The increased acid secretion is a pathological marker of several diseases like peptic ulcer, gastroesophageal reflux disease (GERD), chronic gastritis, and the bug Helicobacter pylori (H. pylori) has also a critical role, which altogether affects the patient's quality of life. This review comprehensively described the nature of potassium ion channel and its mediators, the different clinical strategy to control acid rebound, and some basic experimental observations performed to study the interplay of ion channels, pumps, as well as mediators during acid secretion. Different aspects of regulation of gastric acid secretion have been focused either in terms of physiology of secretion or molecular interactions. The importance of H pylori infection and its treatment has also been discussed. Furthermore, the relevance of calcium signaling during acid secretion has been reviewed. The entire theme will make anyone understand in detail the gastric secretion machinery in general.

Upper Esophageal Sphincter Compression Device as an Adjunct to Proton Pump Inhibition for Laryngopharyngeal Reflux.

BACKGROUND: The Reflux Band, an external upper esophageal sphincter (UES) compression device, reduces esophago-pharyngeal reflux events. This study aimed to assess device efficacy as an adjunct to proton pump inhibitor (PPI) therapy in patients with laryngopharyngeal reflux (LPR). METHODS: This two-phase prospective clinical trial enrolled adults with at least 8 weeks of laryngeal symptoms (sore throat, throat clearing, dysphonia) not using PPI therapy at two tertiary care centers over 26 months. Participants used double dose PPI for 4 weeks in Phase 1 and the external UES compression device nightly along with PPI for 4 weeks in Phase 2. Questionnaire scores and salivary pepsin concentration were measured throughout the study. The primary endpoint of symptom response was defined as reflux symptom index (RSI) score ≤ 13 and/or > 50% reduction in RSI. RESULTS: Thirty-one participants completed the study: 52% male, mean age 47.9 years (SD 14.0), and mean body mass index (BMI) 26.2 kg/m2 (5.1). Primary endpoint was met in 11 (35%) participants after Phase 1 (PPI alone) and 17 (55%) after Phase 2 (Device + PPI). Compared to baseline, mean RSI score (24.1 (10.9)) decreased at end of Phase 1 (PPI alone) (21.9 (9.7); p = 0.06) and significantly decreased at end of Phase 2 (Device + PPI) (15.5 (10.3); p < 0.01). Compared to non-responders, responders to Device + PPI had a significantly lower BMI (p = 0.02) and higher salivary pepsin concentration (p = 0.01). CONCLUSION: This clinical trial highlights the potential efficacy of the external UES compression device (Reflux Band) as an adjunct to PPI for patients with LPR (ClinicalTrials.Gov NCT03619811).

Gastroesophageal reflux disease and Barrett esophagus: an overview of evidence-based guidelines.

Gastroesophageal reflux disease is an extremely common condition worldwide, with the published prevalence rates varying from 2.5% in China to 51.2% in Greece. Its economic and morbidity burden is vast, and optimizing care for this condition carries huge financial and patient­related benefits. The disease can be complicated by progression to Barrett esophagus (BE), a precancerous condition that affects approximately 2% of the population and remains undiagnosed in many individuals. The National Institute of Clinical Excellence has produced guidelines on cost­effective management of gastroesophageal reflux disease in patients in the United Kingdom, and the Benign Barrett's and Cancer Taskforce consensus was the largest international review of evidence known on the management of benign BE complications. This paper is a review of these guidelines with updates on new evidence. Areas for future development involve risk­stratifying patients to surveillance, chemoprevention agents, and genetic biomarkers to help decide who will be at highest risk of malignant progression. Evidence supports the safety of proton pump inhibitors for symptom control in the medium term (ie, 9 years) and reducing the risk of progression of BE, while surgical options are cost­effective treatments for certain patients. Barrett esophagus surveillance should be directed towards high­risk groups, while those at lower risk may benefit from chemoprevention strategies.

Laryngopharyngeal reflux: A confounding cause of aerodigestive dysfunction.

BACKGROUND: Laryngopharyngeal reflux (LPR) is one of the most common and important disorders of upper airway inflammation. It causes significant impairment to quality of life, and can predict serious laryngeal and oesophageal pathology, yet it remains under-diagnosed and under-treated. OBJECTIVE: This paper attempts to unravel the diagnostic dilemma of LPR and provide a practical, discriminating approach to managing this common condition. DISCUSSION: Historical red flags mandating early referral for specialist review are identified, and pathophysiology, symptomatology and common signs are reviewed. In addition, a comprehensive treatment plan consisting of lifestyle modifications, counselling aids and empirical medical therapy is proposed. A strategy for tracking clinical improvement using Belfasky's validated symptom index is included to aid counselling, compliance and follow-up.

Diagnosing gastro-oesophageal reflux disease or lactose intolerance in babies who cry a lot in the first few months overlooks feeding problems.

This paper explores two areas in which the translation of research into practice may be improved in the management of cry-fuss behaviours in the first few months of life. Firstly, babies who cry excessively are often prescribed proton pump inhibitors, despite evidence that gastro-oesophageal reflux disease is very rarely a cause. The inaccuracy of commonly used explanatory mechanisms, the side-effects of acid-suppressive medications, and the failure to identify treatable problems, including feeding difficulty when the diagnosis of 'reflux' is applied, are discussed. Secondly, crying breastfed babies are still prescribed lactase or lactose-free formula, despite evidence that the problem of functional lactose overload is one of breastfeeding management. The mechanisms and management of functional lactose overload are discussed. These two problems of research translation need to be addressed because failure to identify and manage other causes of cry-fuss problems, including feeding difficulty, may have adverse outcomes for a small but significant minority of families.

Cost-utility of laparoscopic Nissen fundoplication versus proton pump inhibitors for chronic and controlled gastroesophageal reflux disease: a 3-year prospective randomized controlled trial and economic evaluation.

BACKGROUND: Very few randomized controlled trials (RCTs) have compared laparoscopic Nissen fundoplication (LNF) to proton pump inhibitors (PPI) medical management for patients with chronic gastroesophageal reflux disease (GERD). Larger RCTs have been relatively short in duration, and have reported mixed results regarding symptom control and effect on quality of life (QOL). Economic evaluations have reported conflicting results. OBJECTIVES: To determine the incremental cost-utility of LNF versus PPI for treating patients with chronic and controlled GERD over 3 years from the societal perspective. METHODS: Economic evaluation was conducted alongside a RCT that enrolled 104 patients from October 2000 to September 2004. Primary study outcome was GERD symptoms (secondary outcomes included QOL and cost-utility). Resource utilization and QOL data collected at regular follow-up intervals determined incremental cost/QALY gained. Stochastic uncertainty was assessed using bootstrapping and methodologic assumptions were assessed using sensitivity analysis. RESULTS: No statistically significant differences in GERD symptom scores, but LNF did result in fewer heartburn days and improved QOL. Costs were higher for LNF patients by $3205/patient over 3 years but QOL was also higher as measured by either QOL instrument. Based on total costs, incremental cost-utility of LNF was $29,404/QALY gained using the Health Utility Index 3. Cost-utility results were sensitive to the utility instrument used ($29,404/QALY for Health Utility Index 3, $31,117/QALY for the Short Form 6D, and $76,310/QALY for EuroQol 5D) and if current lower prices for PPIs were used in the analysis. CONCLUSIONS: Results varied depending on resource use/costs included in the analysis, the QOL instrument used, and the cost of PPIs; however, LNF was generally found to be a cost-effective treatment for patients with symptomatic controlled GERD requiring long-term management.

Medical and nutrition management of eosinophilic esophagitis in children.

Eosinophilic esophagitis (EoE), esophageal inflammation that occurs in the absence of acidification, is characterized by mucosal eosinophilia and epithelial proliferative changes. Depending on the patient's age, EoE may present as a feeding disorder, vomiting, abdominal pain, dysphagia, or food impaction. In the absence of a well-delineated natural history, case reports suggest that in some individuals with EoE, the disease progresses to esophageal fibrosis and then presumably irreversible esophageal dysfunction. Successful management of EoE in children requires (1) identifying the causative agents for a given patient, (2) implementing effective medical and/or nutrition therapies, and (3) establishing a continuum of long-term care that delivers the child to adulthood without esophageal dysfunction.

[General practitioners' management of gastroesophageal reflux in France in 2005: a pharmacoeconomic study]. / Etude pharmaco-économique sur la prise en charge du reflux gastro-oesophagien en France en 2005 en médecine générale.

AIMS: Proton pump inhibitors (PPIs) rank third among drug classes in the amount they cost the French health care system annually (more than a billion euros, i.e., 5.7% of community pharmaceutical expenditures, 50% prescribed for gastroesophageal reflux disease (GERD)). METHODS: Data for a representative sample of patients aged 20 years and older, who visited their GP at least once in 2005 for uncomplicated symptomatic GERD came from the Thales database (1200 representative general practitioners (GP) connected to a computerized network) a. RESULTS: In 2005, 122 571 patients (mean age, 56 years, 45% male, 2.6 consultations for GERD) met the inclusion criteria. Extrapolated to the French population, this sample corresponds to 5.7 million people, i.e., 13% of the adult population who visited a GP during the year. PPIs were prescribed as first-line treatment for GERD in 84% of the consultations. Omeprazole, as a proprietary or generic drug, was prescribed most often (79%) and at a full dose (20mg), while other compounds (lansoprazole, pantoprazole, rabeprazole and esomeprazole) were prescribed at half dose in 64% of cases. The extrapolated annual cost of PPIs reimbursed for this indication was 465 million euros (Meuro) at a mean reimbursement level of 73%. Brand-name omeprazole still accounts for 11% of the total cost reimbursed. Complete replacement of brand-name omeprazole by its generic counterpart would reduce costs by 18.35Meuro (-4.3% reimbursed expenditure). The switch from generic full-dose omeprazole to a half dose of other PPIs would allow a further saving of 2.6 (with lansoprazole) to 13.2 Meuro (with pantoprazole). CONCLUSION: A substantial saving in reimbursed pharmaceutical spending in uncomplicated GERD and full compliance with clinical practice recommendations could be achieved by the substitution of less expensive PPIs.

The influence of co-morbid IBS and psychological distress on outcomes and quality of life following PPI therapy in patients with gastro-oesophageal reflux disease.

BACKGROUND: A subset of patients with gastro-oesophageal reflux disease (GERD) does not achieve complete symptom resolution with proton pump inhibitor (PPI) therapy. The factors which affect response to PPI therapy in GERD patients remain unclear. AIMS: To determine the prevalence and impact of irritable bowel syndrome (IBS) and psychological distress (PD) on GERD symptoms and disease-specific quality of life (QoL) before and after PPI therapy and to assess the same outcomes before and after PPI therapy in non-erosive reflux disease (NERD) and erosive oesophagitis (EO) GERD patients. METHODS: Patients undergoing oesophago-gastroduodenoscopy (OGD) for heartburn were recruited. Participants completed validated surveys: Digestive Health Symptom Index, Reflux Disease Questionnaire, Quality of Life in Reflux and Dyspepsia and Brief Symptom Inventory (BSI). IBS was defined as >3 Manning criteria and PD as BSI score >63. At OGD, patients were classified as NERD or EO. Patients were treated with rabeprazole 20 mg/day for 8 weeks before completing follow-up surveys. RESULTS: Of 132 GERD patients enrolled, 101 completed the study. The prevalence rates of IBS and PD were 36% and 41%, respectively. IBS independently predicted worse QoL before and after PPI therapy. PD independently predicted worse GERD symptoms and QoL before and after PPI therapy. There were no differences in symptoms or QoL between NERD and EO patients before or after PPI therapy. CONCLUSIONS: IBS and PD impacted GERD symptoms and QoL before and after PPI therapy. Symptoms and QoL before and after PPI therapy were similar in NERD and EO patients.

Approach to managing undiagnosed chest pain: could gastroesophageal reflux disease be the cause?

OBJECTIVE: To highlight gastroesophageal reflux disease as a common cause of undiagnosed chest pain. SOURCES OF INFORMATION: Diagnostic considerations are based on information in peer-reviewed articles retrieved from MEDLINE. Studies had to be in English and involve at least 30 subjects. Population-based studies had to have a sample size of at least 300 and a response rate of at least 60%. Thirty-seven relevant articles were found. MAIN MESSAGE: Clinical management of patients presenting with diagnostically challenging chest pain starts with a careful search for coronary artery disease and other potentially life-threatening causes. Investigations must continue until the underlying disease is identified and symptoms have been effectively controlled. Ongoing symptoms of undiagnosed chest pain cause considerable suffering, impair quality of life, and add unnecessary costs to the health care system. In more than half the patients with undiagnosed chest pain, symptoms are caused by gastroesophageal disease. Empirical acid-suppressive therapy with a proton pump inhibitor can assist clinicians in identifying patients whose symptoms are acid-related. CONCLUSION: Many patients with undiagnosed chest pain can be managed in primary care, minimizing the need for referrals and costly investigations.

The view of gastroenterologists on non-cardiac chest pain in Asia.

BACKGROUND: Non-cardiac chest pain is an important disorder in Asia. The practice and views of gastroenterologists on non-cardiac chest pain in this region are not known. AIMS: To determine the current understanding, diagnostic practice and treatment strategies among gastroenterologists on the management of non-cardiac chest pain in Asia. METHODS: A 24-item questionnaire was sent to gastroenterologists in Mainland China, Hong Kong, Malaysia, Indonesia, Philippines, Singapore, Taiwan and Thailand. RESULTS: 186 gastroenterologists participated with a response rate of 74%. 98% of gastroenterologists managed patients with non-cardiac chest pain over the last 6 months. 64% felt that the number of non-cardiac chest pain patients was increasing and 85% believed that the most common cause of non-cardiac chest pain was GERD. 94% of the gastroenterologists believed that they should manage non-cardiac chest pain patients, but only 41% were comfortable in diagnosing non-cardiac chest pain. The average number of investigations performed was four in non-cardiac chest pain patients, and oesophago-gastro-duodenoscopy was the most commonly used initial test. A proton pump inhibitor was considered the first-line treatment in non-cardiac chest pain and was reported as the most effective treatment by the gastroenterologists. CONCLUSION: Most gastroenterologists were practicing evidence-based medicine, but frequent use of investigations and a lack of awareness of the role of visceral hypersensitivity in non-cardiac chest pain patients were noted.

Extra-esophageal GERD: clinical dilemma of epidemiology versus clinical practice.

Gastroesophageal reflux disease (GERD) is a common disorder. A significant percentage of patients with GERD may experience extra-esophageal manifestations, such as asthma, cough, and laryngitis. Epidemiologic studies consistently demonstrate strong associations between GERD and potential extra-esophageal manifestations. However, randomized controlled studies evaluating the use of proton-pump inhibitors for treatment of extra-esophageal GERD have inconsistent results. In asthma, few randomized controlled studies have shown improvement in objective measures, such as forced expiratory volume or peak flow. For chronic cough, studies are all small and have not demonstrated consistent improvement with acid suppression. Even a recent well-designed large randomized controlled study in laryngitis demonstrated no difference in resolution of symptoms with acid suppression. Given the examples from the literature, the current treatment of extra-esophageal symptoms with acid suppression is controversial. Although improvement in symptoms has been shown in case series, it has not been consistent in randomized controlled studies. We offer potential explanations for the discrepancy between the epidemiologic associations and the lack of response to therapy in clinical trials.

Temporal trends in new and recurrent oesophageal strictures in a Medicare population.

BACKGROUND: The widespread use of proton pump inhibitors for gastro-oesophageal reflux disease could result in a decline in new as well as recurrent gastro-oesophageal reflux disease-related oesophageal strictures. The temporal trends of strictures have not been examined in population-based studies. METHODS: To examine the temporal trends in strictures, we calculated the age-adjusted incidence rates of new oesophageal strictures with or without oesophageal dilation in a sample of Medicare beneficiaries between 1992 and 2000. We also examined recurrent dilations recorded at least 3 months after a new stricture or the preceding recurrent stricture. RESULTS: The age-adjusted rates for strictures accompanied with dilation declined by approximately 11% from 215 per million to 192 per million. New oesophageal strictures with dilation declined as a proportion of all upper endoscopies procedures (from 2.6% to 1.9%). Recurrent dilation within 1 year declined dramatically from 16% (9.5% CI: 12.5-20.3) in 1992 to 8% (95% CI: 4.43-10.62) in 2000. In multivariable proportional hazards model, there was a 30% risk reduction of recurrent oesophageal strictures. CONCLUSIONS: This population-based study indicates that the incidence of new as well as recurrent oesophageal strictures has been declining. In the face of rising incidence of other gastro-oesophageal reflux disease-related complications, it is important to understand the explanation of the present observations.