类消化不良疾病及药物治疗

I’m worried and concerned GI symptoms bother me! I’m worried and concerned Heartburn disturbs my sleep I cannot bend over or exercise I cannot eat and drink whatever I like My whole life is affected Illustrator: Eric Werner

临床病例 P: 医生，我总觉得胸口这里发烫,好象喝了开水一样。 D: 还有其他什么不舒服的吗? P: 有时还觉得喉咙象有什么东西堵住一样。

胃食管反流病 Gastroesophageal Reflux Disease GERD

定义 胃-十二指肠内容物反流入食管引起烧心等症状，可引起反流性食管炎,以及咽喉、气道等食管以外组织的化学性炎症性损害.

流行病学 西方国家 胃食管反流症状：7-15％ GERD：患病率 5％ 年龄：发病率随年龄增长而增加，以 40~60岁为高峰 性别：男女发病大致相当，但RE以男性为多（2~3：1）

流行病学 国内： 患病率较西方国家者为低，且病情较轻。 北京与上海： GERD患病率：5.77％ RE发生率：1.92％

病因和发病机制 抗反流防御 反流物的攻击 胃酸 胃蛋白酶 非结合胆盐 胰酶 抗反流屏障 食管清除作用 食管粘膜屏障

发病机制 食管清除 抗反流屏障 蠕动 下食管括约肌 (LES) 重力 TLESR 唾液 低张LES 食粘膜屏障 H+ and LES 上皮屏障 后上皮屏障 抗反流屏障 下食管括约肌 (LES) TLESR 低张LES H+ and LES 膈肌角 膈食管韧带 His角 HCl Pepsin Pancreatic enzymes 胃排空

发病机制 食管清除作用 下食管括约肌（LES） 膈脚作用 反流性食管炎 反流物的攻击作用 食管裂孔疝 食管粘膜屏障 胃运动功能

The role of H. pylori in GERD is questionable In general, infection with H. pylori causes gastric disease. But is H. pylori infection protective against GERD? 47. The role of H. pylori in GERD is questionable An additional factor to be considered when discussing the pathogenesis and course of GERD is infection with the bacterium Helicobacter pylori. Although infection with H. pylori is associated with a variety of gastric diseases, including chronic active gastritis, peptic ulcer disease, ulcer bleeding, mucosa-associated lymphoid tissue lymphoma and distal gastric cancer, it has been hypothesised that it may be protective against GERD.56 This hypothesis is based upon evidence that patients with GERD have a lower rate of infection than the general population, and that patients with esophagitis or Barrett’s esophagus have a lower rate of infection with the potent cag-A-positive strains than those with less severe forms of the disease. The findings from a retrospective study57 of patients with duodenal ulcer disease also support this hypothesis. Eradication of the organism was found to increase the risk of GERD, with the severity of corpus gastritis before eradication a significant risk factor. The interaction between this organism and the gastric mucosa is, however, unlikely to increase acid reflux into the esophagus. Indeed, in most North American or Western European individuals, H. pylori has little effect on acid secretion from the gastric mucosa, and in other ethnic groups and elderly individuals H. pylori infection has a net suppressive effect on acid secretion. Thus, as acid reflux is central to the pathogenesis of GERD, the aetiological role for H. pylori in GERD has been questioned. Two large, well-designed studies have addressed this question, and their main findings are described on the following two slides. 56. McColl K. Motion – Helicobacter pylori causes or worsens GERD: arguments against the motion. Can J Gastroenterol 2002;16:615–17. 57. Labenz J, Blum AL, Bayerdörffer E, Meining A, Stolte M, Börsch G. Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux esophagitis. Gastroenterology 1997; 112:1442–7.

临床表现－典型症状 烧 心 Heart burn 胸 痛 Chest pain 反酸 regurgitation

Patients do not always correctly identify the symptom of heartburn Describing heartburn as “a burning feeling rising from the stomach or lower chest up towards the neck” can help patients recognise this symptom. Reflux questionnaire Identified a burning feeling rising from the stomach or lower chest up towards the neck as their main symptom 42% 15. Patients do not always correctly identify the symptom of heartburn Despite being the symptom most closely associated with GERD, the symptom of heartburn is often not recognised by patients. This can lead to patients being misdiagnosed as suffering from dyspepsia. The use of a verbal description of this symptom may, however, help patients to correctly identify heartburn. In a study in which the presence of heartburn as the predominant symptom was used as an exclusion criterion, 42% of the patients enrolled subsequently identified a burning feeling rising from the stomach or lower chest up towards the neck as their main symptom.4 4. Carlsson R, Dent J, Bolling-Sternevald E, Johnsson F, Junghard O, Lauritsen K et al. The usefulness of a structured questionnaire in the assessment of symptomatic gastroesophageal reflux disease. Scand J Gastroenterol 1998a;33:1023–9. n=196 Carlsson et al 1998a

临床表现－不典型症状 食管以外的刺激症状 咽喉部症状 咽部异物感、发声困难、咳嗽、癔球症、喉痛、声嘶 肺部症状 呛咳、哮喘样发作、吸入性肺炎、肺不张、肺脓肿和肺间质纤维化

Cough can be caused by acid refluxate entering the lung and/or stimulating the vagus nerve Esophageal–bronchial transmission via cough centre Aspiration to lower respiratory tree Stimulation of vagus nerve Cough response 21. Cough can be caused by acid refluxate entering the lung and/or stimulating the vagus nerve Two mechanisms may explain the association between GERD and chronic cough. Firstly, cough receptors may be directly activated through micro- or macroaspiration of gastric refluxate into the respiratory tract.21,26 Aspiration of refluxate is not, however, a prerequisite for cough to occur. The second, most common, pathogenic mechanism by which reflux triggers cough is through an esophageal–bronchial reflex. Nerve efferents in the distal esophagus can be irritated by prolonged acid reflux, and the resultant stimulus transmitted to, and from, the cough centre via the vagus nerve. 21. Irwin RS, French CL, Curley FJ, Zawacki JK, Bennett FM. Chronic cough due to gastroesophageal reflux. Clinical, diagnostic, and pathogenic aspects. Chest 1993;104:1511–17. 26. Irwin RS, Richter JE. Gastroesophageal reflux and chronic cough. Am J Gastroenterol 2000;95 Suppl:S9–14. Gastric refluxate Gastric refluxate Irwin et al 1993; Irwin et al 2000

并发症 上消化道出血 食管狭窄 Barrett食管和Barrett溃疡 癌变

诊断方法 1.内镜检查： 是诊断RE最准确的方法 内镜阴性GERD （endoscopic negative reflux disease, ENRD） (非糜烂性GERD， non-erosive reflux disease, NERD) 内镜阳性GERD （糜烂性GERD）

GERD: two main categories Patients with GERD 100% Patients with ENRD 60% Patients with esophagitis 40% 3. GERD: two main categories The definition of GERD provided by participants at the Genval workshop encompasses two main categories of disease: GERD without esophagitis and GERD with esophagitis.1 The first category, known as endoscopy-negative reflux disease (ENRD), is the most common manifestation of GERD, and has been estimated to account for about 60% of all patients with this disease.2–4 ENRD is less commonly known as symptomatic GERD. The second category of GERD, known as erosive esophagitis, includes those patients who also satisfy the Genval definition but who have definite mucosal breaks or metaplasia of the esophagus that are visible using endoscopy.5 A proportion of these patients will also have complications indicative of more extensive mucosal injury; these include esophageal ulcerations or strictures of the mucosa.2 1. Dent J, Brun J, Fendrick AM, Fennerty MB, Janssens J, Kahrilas PJ et al. An evidence-based appraisal of reflux disease management – the Genval Workshop Report. Gut 1999;44 Suppl 2:S1–16. 2. Quigley EM. Non-erosive reflux disease: part of the spectrum of gastro-oesophageal reflux disease, a component of functional dyspepsia, or both? Eur J Gastroenterol Hepatol 2001;13 Suppl 1:S13–18. 3. Jones R, Hungin A, Phillips J, Mills J. Gastro-oesophageal reflux disease in primary care in Europe: clinical presentation and endoscopic findings. Eur J Gen Pract 1995;1:149–54. 4. Carlsson R, Dent J, Bolling-Sternevald E, Johnsson F, Junghard O, Lauritsen K et al. The usefulness of a structured questionnaire in the assessment of symptomatic gastroesophageal reflux disease. Scand J Gastroenterol 1998a;33:1023–9. 5. Lundell LR, Dent J, Bennett JR, Blum AL, Armstrong D, Galmiche JP et al. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut 1999;45:172–80. Patients without complications 35% Patients with complications 5% Adapted from Quigley 2001

诊断方法 2. 24h食管pH监测：是目前诊断有否胃食管反流最好的定性与定量的检查方法。 pH<4为确定反流存在的界限点。pH<4的时间称为反流时间，是临床应用最广泛的反流变量。

诊断方法 BRAVO pH胶囊 在内镜下将特制的无导管 pH 电极送达 LES 上缘之上 5 cm 处，并吸附于管壁

诊断方法 3. 食管吞钡X线检查 敏感性不高 排除食管癌等 钡餐检查，观察食管的运动情况，可注意到有无返流征象

诊断方法 Bernstein试验（酸滴注试验） 滴注0.1N盐酸时出现类同平时的症状（胸骨后疼痛或烧心）则认定本试验阳性

诊断方法 从记录图形可测出LES的压力、长度，以及位置 可同时检查食管的顺应性等 LES压<6 mmHg时，易导致返流 食管压力测定 食道 LES 3 cm 5 cm P1 P2 P3 P4 灌注系统 压力传感器 食道导管 食管压力测定

诊断方法 6.治疗试验（质子泵抑制剂试验） 对疑及GERD的患者，可服用奥美拉唑20mg，每日2次，连服1周，以确定是否为GERD。若症状消失或基本好转可诊断GERD。 对于有非典型症状患者亦可运用此作试验性治疗。

诊断方法 7. 食管内胆红素测定 酸与胆汁混合返流居多，对食管损伤较大 用 Bilitec 2000 来测定返流物中的胆红素

GERD诊断的评估 证明反流 食管钡餐检查 24 小时动态PH试验 确定GERD是症状的病因 Bernstein试验 食管损伤 内镜检查

诊断 有明显的反流症状 内镜下有食管炎的表现 食管过度酸反流的客观证据 食管腔内pH监测和胆红素监测

鉴别诊断 其他原因食管炎：药物性、感染性、放射性等 胸痛：心脏疾病、胆道疾病、弥漫性食管痉挛 泛酸：消化性溃疡、功能性消化不良等 吞咽困难：食管癌、贲门失弛缓症、硬皮病等 其他：出现其他系统表现时，须与该系统有关疾病进行鉴别

治 疗 一般治疗 药物治疗 维持治疗　 抗反流手术治疗 并发症的治疗

一般治疗 饮食：高蛋白低脂；少食多餐；避免烟酒、咖啡、浓茶等 生活习惯：抬高床头；衣着宽松；保持大便通畅 其他：咀嚼口香糖等

药物治疗 质子泵抑制剂 Omeprazole Lansoprazole Pentoprazole Rabeprazole Esomeprazole

药物治疗 H2受体阻断剂 Cimetidine Ranitidine Famotidine Nizatidine

药物治疗 粘膜保护剂 铝碳酸镁 硫 糖 铝

药物治疗 促动力剂 胃复安:中枢和周围多巴胺受体拮抗剂 多潘立酮:多巴胺受体拮抗剂 西沙必利:选择性5-HT4激动剂 红霉素类:胃动素受体激动剂

对胆汁返流的治疗 目前对于胆汁返流的治疗常用硫糖铝和铝碳酸镁，以吸附胆汁，以后者为佳 宜用促动力药，以减少返流

铝碳酸镁 中和胃酸 与80%胃蛋白酶原呈可逆性结合 能 100% 与胆酸盐和溶血性卵磷脂结合，在酸性环境下防止胆酸盐和溶血性卵磷脂对胃黏膜的破坏作用

硫 糖 铝 胃黏膜保护作用，加固胃黏膜屏障 有一定的胆汁吸附作用

GERD的心身治疗 常有忧郁、焦虑等心理障碍 黛安神 百忧解

是指胃内容物返流引起的一系列不适症状和/或并发症的一种疾病状态 胃食管反流病（GERD） 是指胃内容物返流引起的一系列不适症状和/或并发症的一种疾病状态 食管的症状 食管外的症状 症状 并发症 经典的返流症状 返流引起的胸痛症状 已经确立与返流相关的疾病 返流性咳嗽 返流性喉炎 返流性哮喘 牙齿侵蚀损伤 食管损伤 引起的症状 返流性食管炎 返流引起的狭窄 Barrett´s 食管 腺癌 推测与返流 相关的疾病 鼻窦炎 肺部纤维化 咽炎 反复发作的中耳炎 蒙特利尔GERD定义与分类 Vakil et al, Am J Gastroenterol 2006

症状是诊断GERD的重要工具 典型的不适症状 (烧心、返酸或胃内容物返流)有助于诊断GERD 典型的返流症状在诊断GERD的敏感度上是适中的 典型的返流综合征(烧心和返流)非常具有特异性 GERD的症状和内窥镜检查结果没有相关性 Vakil et al, Am J Gastroenterol 2006, Klauser et al, Lancet 1990

消化不良，是GERD常见的误诊疾病 病史 + 内窥镜检查: 诊断:功能性消化不良, 没有显著的烧心感 返流性疾病调查问卷: 一种来自胃部或者下胸部的烧灼感向上向颈部放射，这一症状是他们的主要的主要症状 42% n=196 Carlsson et al 1998

GERD治疗方法的主流选择 市售的质子泵 抑制剂之间有没有 意义较大的差异？ 最好疗效 最差疗效 推荐 目前 指南 或 应该舍弃 ? x2 每天质子泵抑制剂 + H2受体拮抗剂治疗 最好疗效 市售的质子泵 抑制剂之间有没有 意义较大的差异？ x2 daily PPI 推荐 应该舍弃 目前 指南 x1 daily PPI x1每天½剂量的 质子泵抑制剂治疗 胃肠道动力药物+ H2受体拮抗剂治疗 胃肠道动力药物* 或 H2受体拮抗剂* 抗酸治疗+生活方式 抗酸治疗 最差疗效 生活方式 *尚未建立明显的剂量和疗效之间的关系 after Dent et al 2002

未经调查的GERD的初始治疗 (循证医学回顾) 质子泵抑制剂是治疗的选择 抗酸剂、H2 受体拮抗剂和促进胃肠道动力药物较安慰剂没有明显优势

结论 GERD在亚洲越来越常见 这一地区的大多数患者有非糜烂性胃食管反流病或者轻度侵蚀性食管炎

结论 质子泵抑制剂抑酸作用的功效与侵蚀性食管炎患者的症状缓解的速度、食管炎愈合以及长期的症状上和内窥镜检查无异常密切相关 埃索美拉唑在任何剂量上抑制胃酸的功效都要强于第一代PPI

结论 对于未经调查的GERD、NERD和轻度侵蚀性食管炎患者的长期治疗选择上，需要根据其症状来确定药物治疗剂量方案 重度侵蚀性食管炎的患者须接受持续（足够剂量）的PPI治疗 被证实患有Barrett´s食管的患者必须严密监测随访

结论 抗返流手术必须限于严格加以选择的一些患者 内镜下进行治疗操作目前仍处于试验阶段