Proton pump inhibitor resistance,the real challenge in gastro-esophageal reflux disease

Gastro-esophageal reflux disease(GERD)is one of the most prevalent chronic diseases.Although proton pump inhibitors(PPIs)represent the mainstay of treatment both for healing erosive esophagitis and for symptom relief,several studies have shown that up to 40%of GERD patients reported either partial or complete lack of response of their symptoms to a standard PPI dose once daily.Several mechanisms have been proposed as involved in PPIs resistance,including ineffective control of gastric acid secretion,esophageal hypersensitivity,ultrastructural and functional changes in the esophageal epithelium.The diagnostic evaluation of a refractory GERD patients should include an accurate clinical evaluation,upper endoscopy,esophageal manometry and ambulatory pH-impedance monitoring,which allows to discriminate non-erosive reflux disease patients from those presenting esophageal hypersensitivity or functional heartburn.Treatment has been primarily based on doubling the PPI dose or switching to another PPI.Patients with proven disease,not responding to PPI twice daily,are eligible for anti-reflux surgery.     

Combined multichannel intraluminal impedance and pH monitoring is helpful in managing children with suspected gastro-oesophageal reflux disease

BackgroundGastro-oesophageal reflux is very common in the paediatric age group. There is no single and reliable test to distinguish between physiologic and pathological gastro-oesophageal reflux, and this lack of clear distinction between disease and normal can have a negative impact on the management of children.AimsTo evaluate the usefulness of 24-h oesophageal pH-impedance study in infants and children with suspected gastro-oesophageal reflux disease.MethodsPatients were classified by age groups (A–C) and reflux-related symptoms (typical and atypical). All underwent pH-impedance study. If the latter suggested an abnormal reflux, patients received therapy in accordance with NASPGHAN/ESPGHAN recommendations, while those with normal study had an additional diagnostic work-up. The efficacy of therapy was evaluated with a specific standardized questionnaire for different ages.ResultsThe study was abnormal in 203/428 patients (47%) while normal in 225/428 (53%). Of those with abnormal study, 109 exhibited typical symptoms (54%), and 94 atypical (46%). The great majority of the patients with abnormal study were responsive to medical anti-reflux therapy.ConclusionsWe confirm the utility of prolonged oesophageal pH-impedance study in detecting gastro-oesophageal reflux disease in children and in guiding therapy. Performing oesophageal pH-impedance monitoring in children with suspected gastro-oesophageal reflux disease is helpful to establish the diagnosis and avoid unnecessary therapy.     

Addition of prokinetics to PPI therapy in gastroesophageal reflux disease: A meta-analysis

AIM: To investigate the efficacy of adding prokinetics to proton pump inhibitors (PPIs) for the treatment of gastroesophageal reflux disease (GERD).METHODS: PubMed, Cochrane Library, and Web of Knowledge databases (prior to October 2013) were systematically searched for randomized controlled trials (RCTs) that compared therapeutic efficacy of PPI alone (single therapy) or PPI plus prokinetics (combined therapy) for GERD. The primary outcome of those selected trials was complete or partial relief of non-erosive reflux disease symptoms or mucosal healing in erosive reflux esophagitis. Using the test of heterogeneity, we established a fixed or random effects model where the risk ratio was the primary readout for measuring efficacy.RESULTS: Twelve RCTs including 2403 patients in total were enrolled in this study. Combined therapy was not associated with significant relief of symptoms or alterations in endoscopic response relative to single therapy (95%CI: 1.0-1.2, P = 0.05; 95%CI: 0.66-2.61, P = 0.44). However, combined therapy was associated with a greater symptom score change (95%CI: 2.14-3.02, P < 0.00001). Although there was a reduction in the number of reflux episodes in GERD [95%CI: -5.96-(-1.78), P = 0.0003] with the combined therapy, there was no significant effect on acid exposure time (95%CI: -0.37-0.60, P = 0.65). The proportion of patients with adverse effects undergoing combined therapy was significantly higher than for PPI therapy alone (95%CI: 1.06-1.36, P = 0.005) when the difference between 5-HT receptor agonist and PPI combined therapy and single therapy (95%CI: 0.84-1.39, P = 0.53) was excluded.CONCLUSION: Combined therapy may partially improve patient quality of life, but has no significant effect on symptom or endoscopic response of GERD.     

Positive predictors for gastroesophageal reflux disease and the therapeutic response to proton-pump inhibitors

AIM:To identify objective and subjective predictors for the reliable diagnosis of gastroesophageal reflux disease(GERD)and the response to proton pump inhibitor(PPI)therapy.METHODS:Retrospectively,683 consecutive patients suspected for GERD who underwent pH-metry/impedance measurement(pH/MII)were analyzed.All patients had previously undergone standard PPI treatment(e.g.,pantoprazole 40 mg/d or comparable).Four hundred sixty patients were at least 10 d off PPIs(group A),whereas 223 patients were analyzed during their ongoing PPI therapy(group B).In addition,all patients completed a standardized symptom-and lifestyle-based questionnaire,including the therapeutic response to previous PPI trials on a 10-point scale.Uniand multivariance analyses were performed to identify criteria associated with positive therapeutic response to PPIs.RESULTS:In group A,positive predictors(PPs)for response in empirical PPI trials were typical GERD symptoms(heartburn and regurgitation),a positive symptom index(SI)and pathological results in pH/MII,along with atypical symptoms,including hoarseness and fullness.In group B,regular alcohol consumption was associated with the therapeutic response.The PPs for pathological results in pH/MII in group A included positive SI,male gender,obesity,heartburn and regurgitation.In group B,the PPs were positive SI and vomiting.Analyzing for positive SI,the PPs were pathological pH and/or MII,heartburn regurgitation,fullness,nausea and vomiting in group A and pathological pH and/or MII in group B.CONCLUSION:Anamnestic parameters(gender,obesity,alcohol)can predict PPI responses.In non-obese,female patients with non-typical reflux symptoms,pH/MII should be considered instead of empirical PPIs.     

Yield of 24-Hour Esophageal pH and Bilitec Monitoring in Patients with Persisting Symptoms on PPI Therapy

Current management algorithms propose pH monitoring under proton pump inhibitors (PPIs) in suspected gastroesophageal reflux disease (GERD) with insufficient treatment response, but recent observations challenge this approach because of its low yield. AIM: To perform an audit of the outcomes of pH monitoring under PPI therapy in our unit, and to study the yield of additional nonacid reflux monitoring. METHODS: All pH monitoring studies under antireflux therapy since 1997, with or without simultaneous Bilitec monitoring, were analyzed. RESULTS: From 1997 to 2003, 347 patients (157 men, mean age 49.4 +/- 0.8 years) underwent pH studies on PPI therapy (28% half-, 67% full-, and 5% double-dose PPI) for persisting typical (53%) or atypical (75%) symptoms. In 184 patients, simultaneous Bilitec monitoring was performed. Esophageal pH monitoring on PPI was pathological in 105 (30%) patients. Pathological pH monitoring on PPI was associated with typical reflux symptoms (64 versus 52%, P = 0.03), and a higher prevalence of persisting esophagitis (54 versus 36%, P < 0.005) and of hiatal hernia (58 versus 27%, P < 0.005). Bilitec monitoring on PPI therapy was pathological in 114 (62%) patients, of which 74 (40%) had normal pH monitoring. Adding Bilitec increased the rate of abnormal results over pH monitoring alone, from 38% to 69% on half-dose, from 27% to 69% on full-dose, and from 0% to 38% on double-dose PPI. CONCLUSIONS: The rate of abnormal pH monitoring in symptomatic GERD patients while on PPI therapy is relatively low, especially in those on double-dose PPI. Combined pH and Bilitec monitoring significantly increased the rate of ongoing pathological reflux compared to pH alone in refractory to PPI therapy GERD patients.     

难治性胃食管反流病的诊疗

难治性胃食管反流病目前已成为临床上的棘手问题。其发生机制尚未完全阐明。上消化道内镜、食管内动态pH监测以及食管多通道腔内阻抗-pH值监测等技术能够对难治性胃食管反流病的诊断提供帮助。通过改善患者的服药依从性以及调整质子泵抑制剂的剂量、种类和服药时间,配合促胃肠动力药、一过性下食管括约肌松弛抑制剂、疼痛调节剂或抗反流手术均有助于改善患者的顽固症状。     

Therapeutic efficacy of baclofen in refractory gastroesophageal reflux-induced chronic cough

AIM:To evaluate the efficacy and safety of baclofen for treatment of refractory gastroesophageal reflux-induced chronic cough (GERC) unresponsive to standard anti-reflux therapy. METHODS:Sixteen patients with refractory GERC were given an 8-wk course of baclofen 20 mg three times a day as an add-on therapy to omeprazole. Changes in the cough symptom score, cough threshold to capsaicin, reflux symptom score and possible adverse effects were determined after treatment. The variables of multi-channel intraluminal impedance combined with pH monitoring were compared between responders and non-responders to baclofen. RESULTS:Twelve of 16 patients completed treatment. Cough disappeared or improved in 56.3% (9/16)of patients, including 6 patients with acid refluxinduced cough (66.7%) and 3 patients with non-acid reflux-induced cough (33.3%). With baclofen treatment, the cough symptom score began to decrease at week 2, was clearly decreased at week 6 and reached a minimum at week 8. At the end of therapy, the lowest concentration of capsaicin required for induction of ≥ 2 and ≥ 5 coughs increased from 0.98 (1.46) to 1.95 (6.82) μmol/L (Z = -2.281, P = 0.024) and from 1.95 (7.31) to 7.8 (13.65) μmol/L (Z = -2.433, P = 0.014), respectively, and the reflux symptom score decreased from 8.0 ± 1.6 to 6.8 ± 0.8 (t = 2.454, P = 0.023). The number of acid reflux episodes was significantly lower in responders than in non-responders. The main adverse effects were somnolence, dizziness and fatigue. CONCLUSION:Baclofen is a useful, but suboptimal treatment option for refractory GERC.     

正常人和胃食管反流病人的昼夜食管pH和动力变化

目的:为探讨正常人和胃食管反流病(gastroesophageal reflux disease,GERD)病人昼夜食管运动规律以及食管运动与酸反流的关系。方法:45例GERD病人和10名正常人均接受食管测压和动态食管pH及压力同步监测。结果:(1)下食管括约肌压、远端食管蠕动压及有效食管蠕动百分比在酸反流DeMeester高计分组明显低于低计分组(P<0.05),在反流性食管炎组也明显低于非反流性食管炎组(P<0.05)。(2)有GERD症状或食管炎的卧位有效蠕动百分比明显低于立位(P<0.05)。反流性食管炎组80％有夜间或伴有夜间反流,而不伴反流性食管炎的GERD无1例出现夜间反流。结论:昼夜食管pH和压力动态监测有利于进一步探讨GERD的运动病理,除LES功能外,食管清除功能在GERD发病中起重要作用。     

胃食管反流病埃索美拉唑治疗长期随访研究

目的 研究埃索美拉唑长期维持或间歇治疗胃食管反流病(GERD)的疗效及安全性.方法 28例GERD患者先以每日2次每次20 mg埃索美拉唑为基础进行综合治疗2周,之后按治疗方式分为长期维持治疗组和间歇治疗组.维持治疗组患者为服用缓解症状所需最小剂量半年以上者.间歇治疗组患者每日1次口服埃索美拉唑20 mg维持至症状完全消失后停药,若症状复发则再以相同方案进行治疗.统计分析两组患者的用药剂量、复发情况及长期服用埃索美拉唑的不良反应.结果 13例患者需长期维持治疗(维持时间7～44个月),15例患者可通过间歇治疗达到症状缓解,均未见与埃索美拉唑相关的不良反应.13例长期维持治疗者中,缓解症状所需埃索美拉唑剂量7例为每日1次每次20 mg,5例为每日2次每次20 mg,1例为隔日1次每次20 mg.随访间歇治疗组患者10～57个月,发现服药时间越长,患者缓解时间越长,Pearson相关系数为0.447,差异有统计学意义(P=0.008).结论 GERD患者可通过埃索美拉唑长期维持治疗和间歇治疗两种方式缓解症状,且安全性较好.     

埃索美拉唑治疗老年胃食管反流相关性哮喘69例临床观察

目的 观察埃索美拉唑抗反流治疗对胃食管反流相关性哮喘的疗效.方法 69例胃食管反流相关性哮喘患者,在常规哮喘治疗基础上均给予每日1次每次埃索美拉唑40 mg+每日3次每次莫沙必利5 mg抗反流控制治疗8周,之后每日1次每次埃索美拉唑20 mg+每日临睡前莫沙必利5 mg维持治疗.按中华医学会呼吸病学分会哮喘组制定的支气管哮喘防治指南哮喘控制水平分级标准来观察疗效.随访2年.结果 哮喘完全控制39例、部分控制25例,有效率92.8%.完全停用哮喘治疗药物42例、用量减半18例、继续用药9例.随访2年,哮喘完全控制58例、偶有发作11例,但发作次数减少、程度减轻.结论 埃索美拉唑抗反流治疗胃食管反流相关性哮喘可明显改善患者症状,提高生活质量.     

The Effect of Gastroesophageal Flap Valve Appearance on the Management of Patients with Symptoms of Gastroesophageal Reflux Disease

Purpose To assess the effectiveness of anti-reflux treatment in gastroesophageal reflux disease patients classified according to esophagogastric junction morphology (Hill classification). Results A symptom score and endoscopic grading of gastrooesophageal flap valve appearance were determined in 49 symptomatic patients (female 26, male 23; mean age 49 years, range 21–76 years). Patients received 8 weeks of continuous rabeprazole at a daily dose of 20 mg and, upon symptom control, continued with on-demand treatment for 3 months. The mean symptom score at 8 weeks was significantly reduced in all groups. However, at the end of the on-demand therapy, patients with Hill grade IV had used more rabeprazole tablets than those in the two other groups (II: 10.86 ± 14.52, III: 14.73 ± 14.58, IV: 25.78 ± 15.85; P = 0.002). Conclusions Continuous treatment is effective in all groups of patients with reflux disease. Grading patients according to the gastroesophageal flap valve appearance is useful as a prognostic factor, especially when on-demand therapy is considered to be an option. The authors who have taken part in this study declare that they have no relationship with the manufacturers of the drugs involved and did not receive funding from the manufacturers to carry out their research. The authors did not receive money from any source to carry out this study.     

Gastroesophageal reflux disease related asthma: From preliminary studies to clinical practice

The diagnosis of asthma requires the presence of episodic respiratory difficulties characterized by variable and reversible airway obstruction. It has a high prevalence worldwide and is traditionally considered to be an allergic disease. Most cases are responsive to treatment with bronchodilators and anti-inflammatories, as recommended by national and international guidelines; however, approximately 10% of asthmatic patients are refractory even to optimal therapy. Gastroesophageal reflux disease (GERD) is a common disorder in asthmatic patients and the two disorders may be linked pathophysiologically. Here we review data from preliminary studies that suggest asthma could be induced or exacerbated by gastroesophageal reflux. The optimal strategies for the diagnosis of GERD-related asthma and its therapy are still debated. However, there is evidence to suggest that antireflux treatment is effective and practical for asthmatic patients with well-defined reflux disease.     

Laparoscopic fundoplication for gastroesophageal reflux disease

Gastroesophageal reflux disease(GERD) is a condition that develops when the reflux of gastric contents into the esophagus leads to troublesome symptoms and/or complications. Heartburn is the cardinal symptom, often associated with regurgitation. In patients with endoscopy-negative heartburn refractory to proton pump inhibitor(PPI) therapy and when the diagnosis of GERD is in question, direct reflux testing by impedance-pH monitoring is warranted. Laparoscopic fundoplication is the standard surgical treatment for GERD. It is highly effective in curing GERD with a 80% success rate at 20-year follow-up. The Nissen fundoplication, consisting of a total(360°) wrap, is the most commonly performed antireflux operation. To reduce postoperative dysphagia and gas bloating, partial fundoplications are also used, including the posterior(Toupet) fundoplication, and the anterior(Dor) fundoplication. Currently, there is consensus to advise laparoscopic fundoplication in PPI-responsive GERD only for those patients who develop untoward side-effects or complications from PPI therapy. PPI resistance is the real challenge in GERD. There is consensus that carefully selected GERD patients refractory to PPI therapy are eligible for laparoscopic fundoplication, provided that objective evidence of reflux as the cause of ongoing symptoms has been obtained. For this purpose, impedance-pH monitoring is regarded as the diagnostic gold standard.     

质子泵抑制剂治疗胃食管反流性咽喉炎的Meta分析

目的探讨质子泵抑制剂对胃食管反流性咽喉炎的治疗作用及其安全性,为胃食管反流性咽喉炎的临床治疗提供指导依据。方法计算机检索PubMed、CENTRAL、EMbase、the ISI Web of Knowledge databases、VIP、CNKI、CBM和WANFANG数据库,查找所有探讨质子泵抑制剂对胃食管反流性咽喉炎治疗作用的随机对照试验,检索时限均为建库至2012年3月2日。同时手检纳入文献的参考文献。按纳入排除标准由3名研究者独立进行RCT的筛选、资料提取和质量评价后,采用RevMan 5.1软件进行Meta分析,并采用GRADE系统进行证据质量评价。结果共纳入8个研究,591例患者。Meta分析结果显示:质子泵抑制剂治疗胃食管反流性咽喉炎的总体有效率[OR=7.79,95%CI(2.20,27.51),P<0.05]高于对照组,咳嗽症状缓解效率[OR=2.29,95%CI(0.83,6.35),P>0.05],与对照组比较差异不显著,内镜检查好转率[OR=18.83,95%CI(1.86,190.60),P<0.05],高于对照组。结论质子泵抑制剂对胃食管反流性咽喉炎的治疗作用较对照组明显;但因纳入研究较少、质量参差不齐、样本含量小、各研究方法变异性大,建议临床上审慎选择使用;需要更多高质量、大样本、多中心的随机对照试验进一步论证。     

难治性胃食管反流病诊断方法的研究进展

众多学者把质子泵抑制剂(proton pump inhibitors,PPIs)治疗不应答的胃食管反流病(gastroesophageal reflux disease,GERD)称为难治性胃食管反流病,本病是当前消化系统疾病谱中最为顽固的治疗难题之一.近年来众多研究者运用多种诊察手段来研究本病,希望找到该病的发病机制.本文就最近国内外有关难治性GERD的诊断方案,发病机制及相关研究结果等内容作一综述.     

Proton pump inhibitor treatment of patients with gastroesophageal reflux-related chronic cough： A comparison between two different daily doses of lansoprazole

AIM:To compare two different daily doses oflansoprazole given for 12 weeks and to assess the roleof gastrointestinal (GI) investigations as criteria forselecting patients.METHODS:Out of 45 patients referred for unexplainedchronic persistent cough,36 had at least one of theGI investigations (endoscopy,24-h esophageal pH-metry and a 4-week trial of proton pump inhibitor (PPI)therapy) positive and were randomly assigned to receiveeither 30 mg lansoprazole o.d.or 30 mg lansoprazoleb.i.d,for 12 weeks.Symptoms were evaluated atbaseline (visit 1) after the PPI test (visit 2) and after the12-week lansoprazole treatment period (visit 3).RESULTS:Thirty-five patients completed the studyprotocol.Twenty-one patients (60.0%) reportedcomplete relief from their cough with no differencebetween the two treatment groups (58.8% and 61.1%had no cough in 30 mg lansoprazole and 60 mglansoprazole groups,respectively).More than 80% ofthe patients who had complete relief from their cough atthe end of the treatment showed a positive response tothe PPI test.CONCLUSION:Twelve weeks of lansoprazole treatmenteven at a standard daily dose,is effective in patientswith chronic persistent cough.A positive response to aninitial PPI test seems to be the best criterion for selectingpatients who respond to therapy.     

Appropriateness in prescribing PPIs: A position paper of the Italian Society of Gastroenterology (SIGE) — Study section “Digestive Diseases in Primary Care”

The introduction of proton pump inhibitors (PPIs) into clinical practice about thirty years ago has greatly improved our therapeutic approach to acid-related diseases for their well-recognized efficacy and safety.Despite the well-defined indications, however, the use of PPIs continues to grow every year in both western and eastern countries and this phenomenon poses serious queries that include the onset of potential adverse effects and the increase in health care costs. The major reason explaining this worrying market expansion is the inappropriate use of PPIs. In order to re-establish a correct use of these effective drugs in daily clinical practice, the Italian Society of Gastroenterology (SIGE), nominated a panel of experts who reviewed the available clinical literature and produced a series of updated position statements on the use of PPIs in clinical practice.