胃食管反流病临床和实验研究
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摘要
胃食管反流病(GERD)是指过多的胃内容物反流入食管、或十二指肠内容物反流入胃并和胃内容物一起反流至食管引起的反酸、反食、烧心等症状或组织损害，常合并反流性食管炎(RE)。北京、上海两地对5000例18～70岁普通人群的流行病学调查显示，胃食管反流(GER)症状发生率为8.97％，GERD的患病率为5.77％，反流性食管炎的发生率为1.92％。GERD已成为危害人们健康的最常见疾病之一，部分严重者可发展成为Barrett食管(BE)和食管腺癌(EA)。近年来BE和EA的发病率明显增高，已引起国内外广泛关注。有研究表明，GERD患者约10％合并BE，BE患者中约10％合并有EA。但目前对GERD、RE及其并发BE、EA的发病机制尚不明确，从一定程度上影响了对它们的诊断和治疗。
临床研究 在引起GERD和RE的反流物中，胃酸反流的监测技术比较成熟，对胃酸反流引起的损伤作用已得到证实：与此同时，由于受监测水平限制，在相当长的一段时间里，对十二指肠内容物反流的评估还不十分科学，国内以往多采用pH监测的方式，根据pH值的增高来判断有无十二指肠胃反流及十二指肠胃食管反流(DGR、DGER)。随着科学技术发展，目前已可采用监测十二指肠内容物胆汁中的胆红素来较准确判断有无DGR、DGER的发生。通过对慢性胃炎患者胃内进行24小时胆汁持续监测、反流性食管炎及胃术后患者食管内进行24小时酸及胆汁的同步监测来探讨DGR在慢性胃炎，GER和DGER在胃食管反流病发生中的地位以及胃术后患者食管内GER和DGER的发生情况；同时，对胃及食管内24小时pH及胆汁监测之间的关系进行了研究，以探讨单纯根据pH值的升高能否代替临床上对胆汁的监测。
实验研究 对正常人及RE、BE、EA患者从增殖细胞核抗原(PCNA)和p53基因的蛋白及mRNA表达两方面着手，通过免疫组化染色和地高辛标记原位杂交的检测方法，探讨PCNA和p53基因在RE、BE、EA发生中的作用。
一、慢性胃炎患者胃内24小时胆汁持续监测
研究不同类型慢性胃炎患者胃内胆汁反流情况以及胆汁反流与不同类型慢
第二军医大学大学 临床医学博士学位论文 胃食管反流病临床和实验研究
性胃炎的关系。45例慢性胃炎患者均因腹痛、反酸、恶心、上腹部饱胀不适等
症状就诊，无胃部手术史，无全身其他系统疾病：男性31例，女性14例，年龄
13—70岁，平均N3．9土 11．4）岁。根据 1996年慢性胃炎新的悉尼分类法，所有
患者均经胃镜证实有慢性胃炎，其中慢性浅表性胃炎17例，慢性糜烂性胃炎21
例，慢性萎缩性胃炎7例。
用 Bilitec 2000便携式胆汁监测仪行胃内 24 ’J＼时胆汁持续监测。探头经一侧
鼻腔缓慢置入下食管括约肌下方 10cm处胃腔内，导管团定丁臭侧，这按胆门c
录仪监测24小时，观测胃内24小时胆汁反流情况，获得胆汁反流指标。
结果发现，不同类型慢性胃炎组之间各项胆汁监测指标相差显著。胆汁反流
总时间百分比慢性萎缩性胃炎组门．2土18刀）和慢性糜烂性胃炎组门．2土12．l）
明显高于慢性浅表性胃炎组K．3士14．1）（P＜0刀1人
表明胆汁反流与慢性糜烂性胃炎及萎缩性胃炎的发生有关，随着胆汁反流量
的增加，胃猫膜损伤亦随之加重。
二、反流性食管炎患者食管内24小时酸及胆汁的同步监测
本部分主要研究RE患者酸和胆汁反流的发生情况。研究对象共105例，其
中正常人对照组 20例，男性 14例，女性 6例，年龄引～68岁，平均（43．1士
12．4）岁，均无胃食管反流症状，内镜证实无食管下段炎症，并排除消化道及严
重全身器质性疾病；RE组85例，男性48例，女性37例，年龄19～82岁，平
均门9．3土 13．2）岁，均有烧心、反酸、胸痛等较典型的胃食管反流症状，内镜
证实食管下段炎症。
用 Digitrapper MKlll型便携式 pH监狈仪及 BilitpC 2000便携式胆汁监狈
仪同步监测食管下端 24h PH值及胆汁。受试者于检查前 3d停用所有抑酸药及胃
肠动力药物。术前禁食 12h，检测当日停普通饮食，进胆汁检测饮食，可自由活
动及睡眠，但避免剧烈运动，将PH及胆汁监测探头置于下食管括约肌（LE）上
方 scm处，对每例受试者同时行食管下端 24h pH及胆汁监测，并做好检查日记。
结果发现，RE患者酸及胆汁反流均较对照组显著增加；62．4％的RE患者存
在酸及胆汁混合反流，单纯酸反流为6O．b％，单纯胆门反流为J．OW，人江t。J反洲
为3．5％：男女之间比较，各种反流无差别。
表明酸与胆汁混合反流为RE最常见的反流模式，胆汁反流同样常见于RE患
3
第二军医大学大学 临床医学博士学位论文 胃食管反流病临床和实验研究
者，在GBRD的发生中起着重要作用：同步动态监测食管洲值及胆汁对RE的诊
断有重要意义。
三、胃术后患者食管内24小时酸及胆汁的同步监测
本部分研究不同类型胃术后患者食管内酸及胆汁反流情况。胃术后患者57
例，男性39例，女性18例，年龄22～67岁，平均（52．1士11．4）岁，均因烧
心、反酸、胸痛、?
Gastroesophageal reflux disease(GERD) means the symptoms including heartburn and regurgitation, or histionic lesions caused by reflux of overmuch intragastric acid and duodenal juice's to esophagus, usually complicated with reflux esophagitis(RE), and sometimes leading to severe complications such as Barrett's esophagus(BE) and esophageal adcnocarcinoma. lipidemiological mxcstigution in Beijing and Shanghai showed that the symptomatic incidence of GER is 8.97%. the morbidity of GERD is 5.77%, and the incidence of RE is 1.92%. The incidence of BE and EA has been greatly increased over the past several decades. But the etiology and pathogenesis of GERD, RE, BE and EA remains unclear, which influenced the diagnosis of them to some degree.
Clinical Study We investigated the status of DGR in the occurrence of chronic gastritis, GER and DGER in the occurrence of RE, and investigated the occurrence of GER and DGER in the patients performed different kind of gastrectomies. At the same time, we studied the relationship between pH and bile reflux in the stomach and esophagus, in order to discuss whether the monitoring of bile reflux could be substituted by the monitoring of acid.
Experimental Study In this Experiment, in oder to find out the actions of the genes of PCNA and p53 in the genesis of RE, BE and EA, we studied the expression of the two genes in the level of protein synthesization by immunohistochemical staining and of mRNA transcription by digoxigenin labeling in situ hybridization technique. 1. To monitor bile reflux for patients with chronic gastritis
The aim of this part is to study the bile reflux in patients with different kind of chronic gastritis. Method Using ambulatory bilirubin monitoring techniques to
assess the changes of intragastic bile reflux during 24h in 45 subjects(including 17 patients with chronic superficial gastritis, 21 with chronic erosive gastritis and 7 with chronic atrophic gastritis). Result Total time of intragastric bile reflux(%) was significantly greater for patients with chronic atrophic gastritis (16.2 ± 18.0) and chronic erosive gastritis (14.2 ± 12.1) than that for patients with chronic superficial gastritis (5.3 ± 14.1) (73<0.01). Conclusion Inlragastrie bile reflux is correlated \ulh chronic erosive gastritis and atrophic gastritis.
2. Simultaneously monitoring acid and bile reflux for 85 patients with reflux esophagitis
The aim of this part is to study the incidence of acid and bile reflux in patients with reflux esophagitis(RE) and to evaluate the significance of detecting bile reflux in diagnosing RE. Methods Using ambulatory 24h pH monitoring bilirubin monitoring techniques, we simultaneously assessed the changes of intraesophgeal pH and bile reflux during 24h in 105 subjects(including 85 patients with RL and 21) volunteers;. Results The time of esophageal acid exposure(pH<4) for RF patients was significantly greater than that for controls. Bile reflux, represented by total percentage time of bilirubin absorbance>0.14, was significantly greater for RE patients than that for controls. Neither acid nor bile reflux had difference between male and female. 62.4% of RE patients had both acid and bile reflux, 30.6% only had acid reflux, 3.5% only had bile reflux, and 3.5% had no reflux. Conclusion Both acid and bile reflux were very common in RE patients and both may played a role in the development of RE. Simultaneously monito
ring acid and bile reflux is very important to diagnose RE.
3. Simultaneously monitoring acid and bile in esophagus for patients with total or partial gastrectomy
The aim of this part is to study the acid and bile reflux in patients performed different kind of gastrectomies. Methods Using ambulatory acid and bilirubin monitoring techniques to assess the changes of introesophageal acid and bile reflux during 24h in 57 subjects performed different kinds of gastrectomies(including A~D 4 groups, Group A had 15 patients with proximal partial gastrectomy, Group B had 9 patients with Billroth I gastrectomy. Group C had 24 patients with Bill
临床研究 在引起GERD和RE的反流物中，胃酸反流的监测技术比较成熟，对胃酸反流引起的损伤作用已得到证实：与此同时，由于受监测水平限制，在相当长的一段时间里，对十二指肠内容物反流的评估还不十分科学，国内以往多采用pH监测的方式，根据pH值的增高来判断有无十二指肠胃反流及十二指肠胃食管反流(DGR、DGER)。随着科学技术发展，目前已可采用监测十二指肠内容物胆汁中的胆红素来较准确判断有无DGR、DGER的发生。通过对慢性胃炎患者胃内进行24小时胆汁持续监测、反流性食管炎及胃术后患者食管内进行24小时酸及胆汁的同步监测来探讨DGR在慢性胃炎，GER和DGER在胃食管反流病发生中的地位以及胃术后患者食管内GER和DGER的发生情况；同时，对胃及食管内24小时pH及胆汁监测之间的关系进行了研究，以探讨单纯根据pH值的升高能否代替临床上对胆汁的监测。
实验研究 对正常人及RE、BE、EA患者从增殖细胞核抗原(PCNA)和p53基因的蛋白及mRNA表达两方面着手，通过免疫组化染色和地高辛标记原位杂交的检测方法，探讨PCNA和p53基因在RE、BE、EA发生中的作用。
一、慢性胃炎患者胃内24小时胆汁持续监测
研究不同类型慢性胃炎患者胃内胆汁反流情况以及胆汁反流与不同类型慢
第二军医大学大学 临床医学博士学位论文 胃食管反流病临床和实验研究
性胃炎的关系。45例慢性胃炎患者均因腹痛、反酸、恶心、上腹部饱胀不适等
症状就诊，无胃部手术史，无全身其他系统疾病：男性31例，女性14例，年龄
13—70岁，平均N3．9土 11．4）岁。根据 1996年慢性胃炎新的悉尼分类法，所有
患者均经胃镜证实有慢性胃炎，其中慢性浅表性胃炎17例，慢性糜烂性胃炎21
例，慢性萎缩性胃炎7例。
用 Bilitec 2000便携式胆汁监测仪行胃内 24 ’J＼时胆汁持续监测。探头经一侧
鼻腔缓慢置入下食管括约肌下方 10cm处胃腔内，导管团定丁臭侧，这按胆门c
录仪监测24小时，观测胃内24小时胆汁反流情况，获得胆汁反流指标。
结果发现，不同类型慢性胃炎组之间各项胆汁监测指标相差显著。胆汁反流
总时间百分比慢性萎缩性胃炎组门．2土18刀）和慢性糜烂性胃炎组门．2土12．l）
明显高于慢性浅表性胃炎组K．3士14．1）（P＜0刀1人
表明胆汁反流与慢性糜烂性胃炎及萎缩性胃炎的发生有关，随着胆汁反流量
的增加，胃猫膜损伤亦随之加重。
二、反流性食管炎患者食管内24小时酸及胆汁的同步监测
本部分主要研究RE患者酸和胆汁反流的发生情况。研究对象共105例，其
中正常人对照组 20例，男性 14例，女性 6例，年龄引～68岁，平均（43．1士
12．4）岁，均无胃食管反流症状，内镜证实无食管下段炎症，并排除消化道及严
重全身器质性疾病；RE组85例，男性48例，女性37例，年龄19～82岁，平
均门9．3土 13．2）岁，均有烧心、反酸、胸痛等较典型的胃食管反流症状，内镜
证实食管下段炎症。
用 Digitrapper MKlll型便携式 pH监狈仪及 BilitpC 2000便携式胆汁监狈
仪同步监测食管下端 24h PH值及胆汁。受试者于检查前 3d停用所有抑酸药及胃
肠动力药物。术前禁食 12h，检测当日停普通饮食，进胆汁检测饮食，可自由活
动及睡眠，但避免剧烈运动，将PH及胆汁监测探头置于下食管括约肌（LE）上
方 scm处，对每例受试者同时行食管下端 24h pH及胆汁监测，并做好检查日记。
结果发现，RE患者酸及胆汁反流均较对照组显著增加；62．4％的RE患者存
在酸及胆汁混合反流，单纯酸反流为6O．b％，单纯胆门反流为J．OW，人江t。J反洲
为3．5％：男女之间比较，各种反流无差别。
表明酸与胆汁混合反流为RE最常见的反流模式，胆汁反流同样常见于RE患
3
第二军医大学大学 临床医学博士学位论文 胃食管反流病临床和实验研究
者，在GBRD的发生中起着重要作用：同步动态监测食管洲值及胆汁对RE的诊
断有重要意义。
三、胃术后患者食管内24小时酸及胆汁的同步监测
本部分研究不同类型胃术后患者食管内酸及胆汁反流情况。胃术后患者57
例，男性39例，女性18例，年龄22～67岁，平均（52．1士11．4）岁，均因烧
心、反酸、胸痛、?
Gastroesophageal reflux disease(GERD) means the symptoms including heartburn and regurgitation, or histionic lesions caused by reflux of overmuch intragastric acid and duodenal juice's to esophagus, usually complicated with reflux esophagitis(RE), and sometimes leading to severe complications such as Barrett's esophagus(BE) and esophageal adcnocarcinoma. lipidemiological mxcstigution in Beijing and Shanghai showed that the symptomatic incidence of GER is 8.97%. the morbidity of GERD is 5.77%, and the incidence of RE is 1.92%. The incidence of BE and EA has been greatly increased over the past several decades. But the etiology and pathogenesis of GERD, RE, BE and EA remains unclear, which influenced the diagnosis of them to some degree.
Clinical Study We investigated the status of DGR in the occurrence of chronic gastritis, GER and DGER in the occurrence of RE, and investigated the occurrence of GER and DGER in the patients performed different kind of gastrectomies. At the same time, we studied the relationship between pH and bile reflux in the stomach and esophagus, in order to discuss whether the monitoring of bile reflux could be substituted by the monitoring of acid.
Experimental Study In this Experiment, in oder to find out the actions of the genes of PCNA and p53 in the genesis of RE, BE and EA, we studied the expression of the two genes in the level of protein synthesization by immunohistochemical staining and of mRNA transcription by digoxigenin labeling in situ hybridization technique. 1. To monitor bile reflux for patients with chronic gastritis
The aim of this part is to study the bile reflux in patients with different kind of chronic gastritis. Method Using ambulatory bilirubin monitoring techniques to
assess the changes of intragastic bile reflux during 24h in 45 subjects(including 17 patients with chronic superficial gastritis, 21 with chronic erosive gastritis and 7 with chronic atrophic gastritis). Result Total time of intragastric bile reflux(%) was significantly greater for patients with chronic atrophic gastritis (16.2 ± 18.0) and chronic erosive gastritis (14.2 ± 12.1) than that for patients with chronic superficial gastritis (5.3 ± 14.1) (73<0.01). Conclusion Inlragastrie bile reflux is correlated \ulh chronic erosive gastritis and atrophic gastritis.
2. Simultaneously monitoring acid and bile reflux for 85 patients with reflux esophagitis
The aim of this part is to study the incidence of acid and bile reflux in patients with reflux esophagitis(RE) and to evaluate the significance of detecting bile reflux in diagnosing RE. Methods Using ambulatory 24h pH monitoring bilirubin monitoring techniques, we simultaneously assessed the changes of intraesophgeal pH and bile reflux during 24h in 105 subjects(including 85 patients with RL and 21) volunteers;. Results The time of esophageal acid exposure(pH<4) for RF patients was significantly greater than that for controls. Bile reflux, represented by total percentage time of bilirubin absorbance>0.14, was significantly greater for RE patients than that for controls. Neither acid nor bile reflux had difference between male and female. 62.4% of RE patients had both acid and bile reflux, 30.6% only had acid reflux, 3.5% only had bile reflux, and 3.5% had no reflux. Conclusion Both acid and bile reflux were very common in RE patients and both may played a role in the development of RE. Simultaneously monito
ring acid and bile reflux is very important to diagnose RE.
3. Simultaneously monitoring acid and bile in esophagus for patients with total or partial gastrectomy
The aim of this part is to study the acid and bile reflux in patients performed different kind of gastrectomies. Methods Using ambulatory acid and bilirubin monitoring techniques to assess the changes of introesophageal acid and bile reflux during 24h in 57 subjects performed different kinds of gastrectomies(including A~D 4 groups, Group A had 15 patients with proximal partial gastrectomy, Group B had 9 patients with Billroth I gastrectomy. Group C had 24 patients with Bill
引文
1.Bechi P, Pucciani F, Baldini F, et al. Long-term ambulatory enterogastriic reflux monitoring[J]. Validation of a new fiberoptic technique. Dig Dis Sci, 1993,38:1297-1306
2.Champion GL, Richer JE, Vaezi MF, et al. Duodenaogastro-esophageal reflux:relationship to pH and importance in Barrett' s esophagus[J]. Gastroenterology,1994, 107:747-754
3.Bechi p,Amorosi A.Mazzanti R.et al.Reflux-related gastric mucosal injury is associated with increased mucosal histamine content in humans. Gastroenterology,1993,104:1057-1063
4.Kondo K,Kojima H,Akiyama S,et al. Pathogenesis of adenocarcinoma induced by gastrojejunostomy in wistar rats:role of duodenogastric reflux. Carcinogenesis,1995, 16:1747-1751
5.Ali SL. Comparative in-vitro studies of antalcids. Pharm Ztg, 1982,127:1482-1489
6．朱爱勇，许国铭，李兆申，等．铝碳酸镁和西沙必利对胆汁反流性胃炎的疗效及胃内胆汁的影响．中华消化杂志，2000，20：105-107
2.Champion GL, Richer JE, Vaezi MF, et al. Duodenaogastro-esophageal reflux:relationship to pH and importance in Barrett' s esophagus[J]. Gastroenterology,1994, 107:747-754
3.Bechi p,Amorosi A.Mazzanti R.et al.Reflux-related gastric mucosal injury is associated with increased mucosal histamine content in humans. Gastroenterology,1993,104:1057-1063
4.Kondo K,Kojima H,Akiyama S,et al. Pathogenesis of adenocarcinoma induced by gastrojejunostomy in wistar rats:role of duodenogastric reflux. Carcinogenesis,1995, 16:1747-1751
5.Ali SL. Comparative in-vitro studies of antalcids. Pharm Ztg, 1982,127:1482-1489
6．朱爱勇，许国铭，李兆申，等．铝碳酸镁和西沙必利对胆汁反流性胃炎的疗效及胃内胆汁的影响．中华消化杂志，2000，20：105-107