治疗的主要目标是控制症状和预防并发症。基础治疗是抑酸。[1]Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013 Mar;108(3):308-28.http://gi.org/guideline/diagnosis-and-managemen-of-gastroesophageal-reflux-disease/http://www.ncbi.nlm.nih.gov/pubmed/23419381?tool=bestpractice.com 大多数 GORD 患者需要使用酸抑制剂进行长期药物治疗。质子泵抑制剂是这类药物中最有效的,且目前是治疗 GORD 的主要药物。几项研究表明,长期使用这些药物具有风险;因此,应以尝试停药或将剂量减至控制症状所需的最低剂量为目标进行治疗。[43]Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology. 2017 Mar;152(4):706-15.http://www.ncbi.nlm.nih.gov/pubmed/28257716?tool=bestpractice.com像内镜检查这样的诊断策略有助于选择适当的治疗方法。相反,质子泵抑制剂治疗本身也具有诊断意义。
轻度的典型的胃食管反流病的管理
轻度的或偶尔发病的胃食管反流病患者经常在自我治疗后寻求帮助。以患者为导向的治疗包括抑酸剂、胃食管反流病和食管炎患者的症状和治疗:有低质量的证据表明抗酸药治疗 8 周可以减轻症状,但在 4~8 周并没有达到内镜下治愈。低质量的观察性(队列)研究或者受试者<200名且方法学存在缺陷的随机对照临床试验(RCT)。 H2 受体拮抗剂预防持续性食管炎:有中等质量的证据表明,对胃食管反流病的患者,初始治疗使用 H2 受体拮抗剂比安慰剂可降低持续性食管炎的风险。但是,有高质量的证据表明,H2 受体拮抗剂在降低持续性食管炎的风险方面不如质子泵抑制剂有效。受试者<200名的随机对照临床试验(RCT)、受试者>200名且方法学存在缺陷的随机对照临床试验(RCT)、方法学存在缺陷的系统评价或者高质量的观察性(队列)研究。 和生活方式的改变。症状减轻:有低质量的证据支持生活方式改变(如抬高床头或减肥)的初始治疗可以影响反流症状。低质量的观察性(队列)研究或者受试者<200名且方法学存在缺陷的随机对照临床试验(RCT)。 尽管有效性证据强度不足,但仍然推荐所有患者都进行生活方式改变,[1]Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013 Mar;108(3):308-28.http://gi.org/guideline/diagnosis-and-managemen-of-gastroesophageal-reflux-disease/http://www.ncbi.nlm.nih.gov/pubmed/23419381?tool=bestpractice.com 其中包括:超重患者减肥;吸烟者戒烟;[44]Ness-Jensen E, Hveem K, El-Serag H, et al. Lifestyle intervention in gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2016 Feb;14(2):175-82.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636482/http://www.ncbi.nlm.nih.gov/pubmed/25956834?tool=bestpractice.com 抬高床头;以及(如有夜间症状)避免深夜进食。[1]Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013 Mar;108(3):308-28.http://gi.org/guideline/diagnosis-and-managemen-of-gastroesophageal-reflux-disease/http://www.ncbi.nlm.nih.gov/pubmed/23419381?tool=bestpractice.com[44]Ness-Jensen E, Hveem K, El-Serag H, et al. Lifestyle intervention in gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2016 Feb;14(2):175-82.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636482/http://www.ncbi.nlm.nih.gov/pubmed/25956834?tool=bestpractice.com一般不需要常规禁食特定的食物(例如巧克力、咖啡因、酒精、酸性的和/或辛辣的食物),除非能给个体带来益处。
对于需要治疗的胃食管反流病患者而言,质子泵抑制剂加生活方式改变通常是一线治疗。持续性食管炎的预防:有高质量的证据表明,对胃食管反流病患者,质子泵抑制剂比安慰剂更能够预防持续性食管炎的发生,而且比 H2 受体拮抗剂也更有效。系统评价或者受试者>200名的随机对照临床试验(RCT)。 对于年龄小于 40 岁、有典型而规律的烧心症状且没有警示症状的患者,起始治疗应该用标准剂量的质子泵抑制剂治疗 8 周。[1]Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013 Mar;108(3):308-28.http://gi.org/guideline/diagnosis-and-managemen-of-gastroesophageal-reflux-disease/http://www.ncbi.nlm.nih.gov/pubmed/23419381?tool=bestpractice.com 建议以 PPI 的最低有效剂量开始治疗。[8]World Gastroenterology Organisation. Global perspective on gastroesophageal reflux disease. October 2015 [internet publication].http://www.worldgastroenterology.org/UserFiles/file/guidelines/gastroesophagel-reflux-disease-english-2015.pdf 如果无效或疗效出充分,可以用高剂量质子泵抑制剂和内镜进行治疗。如果不能使用高剂量质子泵抑制剂(例如经济原因),可选择更换质子泵抑制剂。如果内镜没有发现糜烂性食管炎或 Barrett 食管,应当考虑进一步行诊断性检查。难治性胃食管反流病患者应被转诊至消化科医生处进行诊断性检查。注意寻找难治性原因;例如:功能性胃食管反流病/高敏感性(根据标准 pH 值定义患者没有胃食管反流病)、治疗依从性差、非酸性反流、酸控制不充分或存在诸如卓艾综合征等少见情况、或患者具有细胞色素 P450 2C19 多态性(CYP2C19;可导致质子泵抑制剂的快速代谢)。[45]Ichikawa H, Sugimoto M, Sugimoto K, et al. Rapid metabolizer genotype of CYP2C19 is a risk factor of being refractory to proton pump inhibitor therapy for reflux esophagitis. J Gastroenterol Hepatol. 2016 Apr;31(4):716-26.http://www.ncbi.nlm.nih.gov/pubmed/26580676?tool=bestpractice.com
当质子泵抑制剂不能取得充分效果时,对夜间有症状或 pH 值监测发现有食管酸反流的患者,应该考虑在睡前加用 H2 受体拮抗剂。[1]Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013 Mar;108(3):308-28.http://gi.org/guideline/diagnosis-and-managemen-of-gastroesophageal-reflux-disease/http://www.ncbi.nlm.nih.gov/pubmed/23419381?tool=bestpractice.com 但可能发生快速耐受。
不典型和复杂症状的管理
表现为复杂的或非典型的胃食管反流病(例如,吞咽困难或有消化道出血的证据)的患者通常要立即进行内镜检查。症状持续 5 年以上或年龄超过 40 岁的患者通常也要行内镜检查。这些患者也应该用质子泵抑制剂治疗但不是经验性治疗。
相关的动力障碍
唯一有证据支持的促动力药是西沙比利,但因为可能出现的严重心律失常而退市。唯一可用的促动力药甲氧氯普胺在治疗胃食管反流病中的作用尚不确定,而且与诸如永久性的锥体外系反应、运动障碍和精神后遗症等副作用相关。因此,不推荐使用促动力药。
治疗持续时间
对治疗有效的患者经常需要长期服用质子泵抑制剂以维持治疗。复发率:有高质量的证据表明,对食管炎治愈 6 至 12 个月的患者,质子泵抑制剂可以降低其食管炎或反流症状的复发率,而且比 H2 受体拮抗剂更有效。系统评价或者受试者>200名的随机对照临床试验(RCT)。
推荐对停用质子泵抑制剂后症状复发的患者以及糜烂性食管炎和 Barrett 食管患者使用质子泵抑制剂维持治疗。[1]Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013 Mar;108(3):308-28.http://gi.org/guideline/diagnosis-and-managemen-of-gastroesophageal-reflux-disease/http://www.ncbi.nlm.nih.gov/pubmed/23419381?tool=bestpractice.com 大部分患者停用质子泵抑制剂治疗后复发。然而,长期使用这些药物具有风险;因此,应以尝试停药或将剂量减至控制症状所需的最低剂量为目标进行治疗。[43]Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology. 2017 Mar;152(4):706-15.http://www.ncbi.nlm.nih.gov/pubmed/28257716?tool=bestpractice.com
某些非糜烂性反流病患者可以按需或间断给予质子泵抑制剂治疗。[1]Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013 Mar;108(3):308-28.http://gi.org/guideline/diagnosis-and-managemen-of-gastroesophageal-reflux-disease/http://www.ncbi.nlm.nih.gov/pubmed/23419381?tool=bestpractice.com [
]What are the benefits and harms associated with de-prescribing long-term proton pump inhibitor therapy in adults?https://cochranelibrary.com/cca/doi/10.1002/cca.1754/full显示答案 一些专家推荐降级治疗试验,[46]Haastrup P, Paulsen MS, Begtrup LM, et al. Strategies for discontinuation of proton pump inhibitors: a systematic review. Fam Pract. 2014 Dec;31(6):625-30.http://fampra.oxfordjournals.org/content/31/6/625.longhttp://www.ncbi.nlm.nih.gov/pubmed/25192903?tool=bestpractice.com[47]Boghossian TA, Rashid FJ, Thompson W, et al. Deprescribing versus continuation of chronic proton pump inhibitor use in adults. Cochrane Database Syst Rev. 2017 Mar 16;(3):CD011969.http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011969.pub2/abstracthttp://www.ncbi.nlm.nih.gov/pubmed/28301676?tool=bestpractice.com但这不是常规治疗方法。
手术选择
手术(开腹在慢性胃食管反流病中,反流症状和食管炎的改善:有低质量的证据表明,在减少反流和改善慢性胃食管反流病和食管炎患者内镜下食管炎评级(时间表未特指)方面,开腹胃底折叠术可能比抗酸药或 H2 受体拮抗剂更有效,但在 10 年以后的内镜下改善没有差异。低质量的观察性(队列)研究或者受试者<200名且方法学存在缺陷的随机对照临床试验(RCT)。 或腹腔镜治疗症状的严重程度:有低质量的证据比较了腹腔镜胃底折叠术和质子泵抑制剂或开腹手术的差别。低质量的观察性(队列)研究或者受试者<200名且方法学存在缺陷的随机对照临床试验(RCT)。 胃底折叠术)主要用于对质子泵抑制剂疗效好但不愿意长期进行药物治疗的患者(例如,由于副作用或依从性差)。[1]Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013 Mar;108(3):308-28.http://gi.org/guideline/diagnosis-and-managemen-of-gastroesophageal-reflux-disease/http://www.ncbi.nlm.nih.gov/pubmed/23419381?tool=bestpractice.com腹腔镜 Nissen(总)与 Toupet (270º) 或前壁 (180º) 胃底折叠术对 GORD 症状的控制效果不相上下。[48]Du X, Hu Z, Yan C, et al. A meta-analysis of long follow-up outcomes of laparoscopic Nissen (total) versus Toupet (270°) fundoplication for gastro-esophageal reflux disease based on randomized controlled trials in adults. BMC Gastroenterol. 2016 Aug 2;16(1):88.https://bmcgastroenterol.biomedcentral.com/articles/10.1186/s12876-016-0502-8http://www.ncbi.nlm.nih.gov/pubmed/27484006?tool=bestpractice.com[49]Du X, Wu JM, Hu ZW, et al. Laparoscopic Nissen (total) versus anterior 180° fundoplication for gastro-esophageal reflux disease: a meta-analysis and systematic review. Medicine (Baltimore). 2017 Sep;96(37):e8085.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604681/http://www.ncbi.nlm.nih.gov/pubmed/28906412?tool=bestpractice.com指南推荐术前进行动态 pH 值监测和食管测压,动态 pH 值监测只针对没有糜烂性食管炎证据的患者。[1]Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013 Mar;108(3):308-28.http://gi.org/guideline/diagnosis-and-managemen-of-gastroesophageal-reflux-disease/http://www.ncbi.nlm.nih.gov/pubmed/23419381?tool=bestpractice.com 对质子泵抑制剂治疗无效的患者很可能手术也没有效果。术后并发症发生率最高可达 20%。[50]University of Michigan Health System. Gastroesophageal reflux disease (GERD). May 2012 [internet publication].http://www.med.umich.edu/1info/fhp/practiceguides/gerd/gerd.12.pdf
患者应参与到实施手术治疗的决定中去,因进行手术的证据仍有争议。 [
]In adults with gastro-esophageal reflux disease, is there randomized controlled trial evidence to support the use of laparoscopic fundoplication surgery instead of medical management?https://cochranelibrary.com/cca/doi/10.1002/cca.1188/full显示答案 瑞典的一项大型全国性人口研究针对抗反流手术的长期疗效进行了评估,该研究中 2655 例患者在腹腔镜手术后接受了随访,随访的中位时间为 5.6 年,其中 17.7% 的患者报告出现反流复发(定义为:需要酸抑制剂的时间>6 个月或需要再次进行抗反流手术)。反流复发的危险因素包括:性别为女性、年龄较大和存在合并症(通过 Charlson 合并症指数测量)。[51]Maret-Ouda J, Wahlin K, El-Serag HB, et al. Association between laparoscopic antireflux surgery and recurrence of gastroesophageal reflux. JAMA. 2017 Sep 12;318(10):939-46.http://www.ncbi.nlm.nih.gov/pubmed/28898377?tool=bestpractice.com 必须权衡获益与死亡及其他不良反应的风险。[52]Garg SK, Gurusamy KS. Laparoscopic fundoplication surgery versus medical management for gastro-oesophageal reflux disease (GORD) in adults. Cochrane Database Syst Rev. 2015 Nov 5;(11):CD003243.http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003243.pub3/fullhttp://www.ncbi.nlm.nih.gov/pubmed/26544951?tool=bestpractice.com
有人提出了 GORD 的微创手术疗法。在一些试验中,磁珠括约肌增强技术显示出具有和腹腔镜 Nissen 胃底折叠术类似的疗效。[53]Ganz RA, Peters JH, Horgan S, et al. Esophageal sphincter device for gastroesophageal reflux disease. N Engl J Med. 2013 Feb 21;368(8):719-27.http://www.nejm.org/doi/full/10.1056/NEJMoa1205544#t=articlehttp://www.ncbi.nlm.nih.gov/pubmed/23425164?tool=bestpractice.com[54]Saino G, Bonavina L, Lipham JC, et al. Magnetic sphincter augmentation for gastroesophageal reflux at 5 years: final results of a pilot study show long-term acid reduction and symptom improvement. J Laparoendosc Adv Surg Tech A. 2015 Oct;25(10):787-92.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624249/http://www.ncbi.nlm.nih.gov/pubmed/26437027?tool=bestpractice.com[55]Zhang H, Dong D, Liu Z, et al. Revaluation of the efficacy of magnetic sphincter augmentation for treating gastroesophageal reflux disease. Surg Endosc. 2016 Sep;30(9):3684-90.http://www.ncbi.nlm.nih.gov/pubmed/26659236?tool=bestpractice.com严格的患者选择对于这种新颖的手术很重要,小于 2 cm 的食管裂孔疝患者似乎从这种方法受益最大。吞咽困难是这种手术后可能发生的一种副作用。[56]Sheu EG, Nau P, Nath B, et al. A comparative trial of laparoscopic magnetic sphincter augmentation and Nissen fundoplication. Surg Endosc. 2015 Mar;29(3):505-9.http://www.ncbi.nlm.nih.gov/pubmed/25012804?tool=bestpractice.com
长期用质子泵抑制剂治疗的相关问题
理论上长期抑酸的临床后遗症并不是长期治疗的障碍。[3]Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American Gastroenterological Association medical position statement on the management of gastroesophageal reflux disease. Gastroenterology. 2008;135:1383-91.http://www.gastrojournal.org/article/S0016-5085%2808%2901606-5/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/18789939?tool=bestpractice.com[43]Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology. 2017 Mar;152(4):706-15.http://www.ncbi.nlm.nih.gov/pubmed/28257716?tool=bestpractice.com流行病学研究已经发现使用抑酸治疗与骨折风险增加相关,或短期应用时与社区获得性肺炎的患病风险增加有关。[57]Yang YX, Lewis JD, Epstein S, et al. Long-term proton-pump inhibitor therapy and risk of hip fracture. JAMA. 2006 Dec 27;296(24):2947-53.http://www.ncbi.nlm.nih.gov/pubmed/17190895?tool=bestpractice.com[58]Laheij RJ, Sturkenboom MC, Hassing RJ, et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. 2004 Oct 27;292(16):1955-60.http://www.ncbi.nlm.nih.gov/pubmed/15507580?tool=bestpractice.com[59]Herzig SJ, Howell MD, Ngo LH, et al. Acid-suppressive medication use and the risk for hospital-acquired pneumonia. JAMA. 2009 May 27;301(20):2120-8.http://www.ncbi.nlm.nih.gov/pubmed/19470989?tool=bestpractice.com 筛查可能的副作用或者因为副作用而避免抑酸治疗没有明确的依据。[3]Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American Gastroenterological Association medical position statement on the management of gastroesophageal reflux disease. Gastroenterology. 2008;135:1383-91.http://www.gastrojournal.org/article/S0016-5085%2808%2901606-5/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/18789939?tool=bestpractice.com[60]Chen J, Yuan YC, Leontiadis GI, et al. Recent safety concerns with proton pump inhibitors. J Clin Gastroenterol. 2012 Feb;46(2):93-114.http://www.ncbi.nlm.nih.gov/pubmed/22227731?tool=bestpractice.com 部分[61]Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009 Mar 31;180(7):713-8.http://www.cmaj.ca/cgi/content/full/180/7/713http://www.ncbi.nlm.nih.gov/pubmed/19176635?tool=bestpractice.com[62]Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009 Mar 4;301(9):937-44.http://www.ncbi.nlm.nih.gov/pubmed/19258584?tool=bestpractice.com 但非全部[63]O'Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet. 2009 Sep 19;374(9694):989-97.http://www.ncbi.nlm.nih.gov/pubmed/19726078?tool=bestpractice.com[64]Ray WA, Marray KT, Griffin MR, et al. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern Med. 2010 Mar 16;152(6):337-45.http://www.ncbi.nlm.nih.gov/pubmed/20231564?tool=bestpractice.com[65]Bhatt DL, Cryor BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. New Engl J Med. 2010 Nov 11;363(20):1909-17.http://www.ncbi.nlm.nih.gov/pubmed/20925534?tool=bestpractice.com 研究发现了当氯吡格雷与质子泵抑制剂合用时,氯吡格雷疗效减弱和可能发生不良后果的证据。[66]Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Am J Gastroenterol. 2010 Dec;105(12):2533-49.http://www.ncbi.nlm.nih.gov/pubmed/21131924?tool=bestpractice.com 不推荐同时使用氯吡格雷和奥美拉唑。长期使用质子泵抑制剂与低镁血症的发生有关。[60]Chen J, Yuan YC, Leontiadis GI, et al. Recent safety concerns with proton pump inhibitors. J Clin Gastroenterol. 2012 Feb;46(2):93-114.http://www.ncbi.nlm.nih.gov/pubmed/22227731?tool=bestpractice.com 使用质子泵抑制剂也是 难辨梭菌 相关腹泻的危险因素之一。[67]US Food and Drug Administration. FDA drug safety communication: Clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). February 2012 [internet publication].http://www.fda.gov/Drugs/DrugSafety/ucm290510.htm
一项观察性研究表明,PPI 可以增加老年患者发生痴呆的风险;[68]Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. 2016 Apr;73(4):410-6.http://www.ncbi.nlm.nih.gov/pubmed/26882076?tool=bestpractice.com 然而另一项研究发现并无此类关联。[69]Taipale H, Tolppanen AM, Tiihonen M, et al. No association between proton pump inhibitor use and risk of Alzheimer's disease. Am J Gastroenterol. 2017 Dec;112(12):1802-8.http://www.ncbi.nlm.nih.gov/pubmed/28695906?tool=bestpractice.com 类似的观察性队列研究发现,PPI 的使用与慢性肾脏疾病相关。[70]Lazarus B, Chen Y, Wilson FP, et al. Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med. 2016 Feb;176(2):238-46.http://www.ncbi.nlm.nih.gov/pubmed/26752337?tool=bestpractice.com 但是,这些数据尚未经过前瞻性试验的验证。