1、难治性胃食管反流病RGERDDefinition of RGERDRGERD:Patients who are unresponsive to 4-8 weeks treatment with PPIs twice daily or esophageal injury caused by RE cant to be healing.Richter JE Natl Clin Gastroenterol 2007;4:658Others suggest that lack of satisfactory symptomatic response to PPI once a day is suffi
2、cient to consider patients as PPI failures.Any attempt to narrow the definition of refractory GERD might exclude many true sufferers.Hershcovici T et al.Best Practice&Research Clinical Gastroenterology 2010(24)923-936 Remains an area of controversy2难治性胃食管反流病RGERDPPI failed in Each of the Gastrooesop
3、hageal Reflux Disease(GERD)GroupsGERDNERD60-70%EE 20-30%Barretts oesophagus6-10%Failure on PPI qd40-50%Failure on PPI qd6-15%Failure on PPI qd20%Fass et al.Aliment Pharmacol Ther 2005;22(2):79-94.3难治性胃食管反流病RGERD30%NERD fail to PPI treatment4难治性胃食管反流病RGERDNERD-acid,visceral sensitivity5难治性胃食管反流病RGERD
4、Potential causes of PPI refractoriness in GERDNeurogastroenterol Motil(2012)24,697704 6难治性胃食管反流病RGERD7难治性胃食管反流病RGERDWeakly Acid RefluxThe prevalence of weakly acidic reflux in refractory GERD is 30-40%.When the esophageal pH falls by 1 unit,but remains 4,it is considered“weakly acidic reflux”.Gut,20
5、04,53:1024-10318难治性胃食管反流病RGERDEsophageal HypersensitivityAM J Gastroenterol,2012,107,8-15.Esophageal receptor upregulation and/or enhanced signalingPhysiological stressors,sensitization of spinal sensory neurons.Potential factors contributing to the spectrum of reflux perception in patients with GER
6、D 9难治性胃食管反流病RGERDGastroparesisDelayed gastric emptying(gastroparesis)may be a factor associated with severe reflux,dyspepsia,or both.Gastroparesis,concomitant in 25%of patients with gastroesophageal reflux disease(GERD),has been shown to improve after Nissen fundoplication.SURGICAL ENDOSCOPY AND OTH
7、ER INTERVENTIONAL TECHNIQUES，2008，22 （11）:2440-244410难治性胃食管反流病RGERDPoor Compliance with PPI Treatment Compliance to treatment and proper dosing are important.Timing and frequency of dosing are critical for maximum efficacy of the medication.Patients dosed optimally the PPIs(%)Proper dosing timing 46
8、%Patients dosed suboptimally the PPIs(%)60 min before meals39%after meals30%at bedtime28%as-needed4%PPI dosing situation in 100 patients with persistent GERD symptomsAliment Pharmacol Ther 2006;23:1473711难治性胃食管反流病RGERDNocturnal Acid BreakthroughNAB:Gastric pH below 4 over 60 consecutive minutes at n
9、ight-time in subjects who take proton pump inhibitors twice daily.Aliment Pharmacol Ther,2002,16()7:1309-1316.12难治性胃食管反流病RGERDDilated intercellular spaces The dilation of esophageal intercellular spaces(ICS)is considered an early morphologic marker of acid damage in patients with GERD.ICS will be di
10、fficult to eliminated in RGERD patients who fail to PPI treament.13难治性胃食管反流病RGERDBile RefluxGastroenterol 2009 January 21;15(3):334-338 230 patients with hear tburn and regurgitation continued to report symptoms after 8 wk of high-dose PPI therapy(40 mg esomeprazole bid).14难治性胃食管反流病RGERDPsychologica
11、l ComorbiditiesALIMENTARY PHARMACOLOGY&THERAPEUTICS,2007,26 (3):443-452.Anxiety and depression have been shown to increase GERD-related symptoms report in population-based studies.15难治性胃食管反流病RGERD16难治性胃食管反流病RGERDAn inflammatory response occurs in the squamous epithelium,induced by the release of inf
12、lammatory mediatorsLeads to the subsequent chemoattraction and infiltration of immune cellsFollowed by the proliferative response of the rat epithelium.Immunity:Mucosal InflammationGastroesophageal reflux disease-from reflux episodes to mucosal inflammation.Nat.Rev.Gastroenterol.Hepatol.201217难治性胃食管
13、反流病RGERDProtease activated receptor 2(PAR2)Gastroesophageal reflux disease-from reflux episodes to mucosal inflammation.Nat.Rev.Gastroenterol.Hepatol.2012n Activated by serine proteases n Upregulated in patients with GERD and induced by acid conditions in cell culture modelsn PAR2 activation:p Leads
14、 to epithelial IL-8 release and contributes to the pathogenesis of GERDpImplicated in inflammatory and neuroinflammatory effects the modulation of visceral hypersensitivity and pain generation and increasing epithelial permeability.GERD is Immune-mediated esophageal mucosal damage(IL-8 A new targets
15、 for GERD drug development.18难治性胃食管反流病RGERDProinflammatory and Neuroinflammatory AspectsGastroenterol.Hepatol.2012nTRPV1(transient receptor potential cation channel subfamily V member 1)pTRPV1 is involved in the inflammatory epithelial response,that is supposed to be involved in GERD-related symptom
16、 generation.pEE or NERD patients with high expression level of TRPVnNuroinflammatory aspects in GERD patients p NGFpGNDF19难治性胃食管反流病RGERDEsophageal EosinophiliaAmerican Journal of Gastroenterology，2008，435-442High intraepithelial eosinophil counts in esophageal squamous epithelium are not specific fo
17、r eosinophilic esophagitis.Eos20/HPF in GERD patients suggest it may be RGERD.20/HPF20难治性胃食管反流病RGERDErosive esophagitis may be related to small intestinal bacterial overgrowth Scandinavian Journal of Gastroenterology.2012GERD and SIBOOverlap of GERD and IBSLactulose hydrogen breath test（LHBT）In Abno
18、rmal LHBT,67%in EE,37%in control（P=0.024）65%in EE,31%in control(without IBS)（P=0.032）Small Intestinal Bacterial Overgrowth 21难治性胃食管反流病RGERD22难治性胃食管反流病RGERDUpper Gastrointestinal EndoscopyGastrointest Endosc 2007;66:21924nCommonly used in clinical practice to evaluate patients with GERD who failed PP
19、I treatment.nThe value of endoscopy in patients with refractory GERD is very low Eosinophilic oesophagitis was found in only 0.9%of RGERD patients,and NERD and functional heartburn patients take a big part.23难治性胃食管反流病RGERDA new method in the diagnosis of reflux esophagitis:confocal laser endomicrosc
20、opy.GIE.2012 Confocal laser endomicroscopy，CLE A new method to test GERD The distance between the surface to papillary(S-P)tip can be measured by using CLE.S-P distance:0.19um/cm in RE,0.44um/cm in control.黏膜表面毛细血管袢24难治性胃食管反流病RGERD共聚焦激光显微内镜诊断NERDNERD patients had more intrapapillary capillary loops(
21、IPCLs)than control.a.IPCLs number increased;b.IPCLs diameter become bigger;c.IPCLs extended to mucosal surface;d.The intercellular spaces of squamous cells was enlarged.Am J Gastroenterol.2012 Mar 13.25难治性胃食管反流病RGERDNERD diagnosed by CLE-Dilated DIC Am J Gastroenterol.2012 Mar 13.;Control:figuer a,b
22、,e;NERD:figure c,d,f （DIS）26难治性胃食管反流病RGERDEsophageal pH monitoring allow the quantification of esophageal acid exposure and the assessment of the temporal relationship between symptoms and acid reflux events.PH monitoring can be performed off PPI to test if the initial diagnosis was correct(i.e.,hea
23、rtburn was due to acid reflux)or on PPI to test whether the symptoms are due to residual acid reflux.Remote proximalacid refluxRemote proximalacid refluxAmbulatory 24h Esophageal pH Monitoring27难治性胃食管反流病RGERDAmbulatory 24h Esophageal pH Monitoring-Graphs28难治性胃食管反流病RGERDEsophageal Bilitec Bilitec det
24、ects bilirubin in the refluxate that is used as a surrogate marker for bile reflux.One has to recall that non-acidic and bile reflux are two distinct phenomena.Esophageal exposure to bile acids can result in heartburn symptoms.Dig Dis Sci 2005;50:815.29难治性胃食管反流病RGERD30难治性胃食管反流病RGERDGERD and PPIPaul
25、Moayyedi et al,Lancet,2006,June 24(367):2086-210032难治性胃食管反流病RGERDNew PPIsDis.Esophagus 2005;18:3703.Gastroenterol，2010;105:23416 In Process 33难治性胃食管反流病RGERDHistamine 2 receptor antagonist(H2RA)Histamine 2 receptor antagonist given in divided doses may also be used and are effective treatment in many
26、 patients with less severe GERD.American guidelines for diagnosis and treatment of GERD34难治性胃食管反流病RGERDPromotility therapyuRegurgitation may be the main symtom of refractory GERD,compare with those who are without treatment.uGERD is a disorder of gastrointestinal motility Defects in esophagogastric
27、motility(LES incompetence,poor esophageal clearance,and delayed gastric emptying)are central to the pathogenesis of GERD.If these defects could be corrected,then GERD would be controlled,making suppression of normal amounts of gastric acid unnecessary.American guidelines for diagnosis and treatment
28、of GERD35难治性胃食管反流病RGERDTransient lower esophageal sphincterrelaxation(TLESR)reducersGamma-aminobutyric acid B(GABAB)receptor agonists(Baclofen)Metabotropic glutamate receptor 5(mGluR5)antagonists(ADX10059)Am J Physiol 2001;281:G3115.Gastroenterology 2005;129:9951004.36难治性胃食管反流病RGERDGastroesophageal
29、reflux disease-from reflux episodes to mucosal inflammation.Nat.Rev.Gastroenterol.Hepatol.2012Cannabinoids(CB1)antagonist:(rimonabant)Decreased meal-induced TLESR;The total number of postprandial TLESR episodes acid reflux episodes was markedly reduced in healthy volunteers after treatment with rimo
30、nabant.Drug Therapy-In Process 37难治性胃食管反流病RGERDGastroesophageal reflux disease-from reflux episodes to mucosal inflammation.Nat.Rev.Gastroenterol.Hepatol.2012mGluR5 antagonist（ADX10059）ADX10059 has a different pharmacodynamic approach to TLESR reduction than the above medications,and has been shown
31、to reduce both acidic and nonacidic reflux events.After an increase in abnormal laboratory test results(liver enzymes)and a few cases of hepatic failure,the further development of ADX10059 was also discontinued.Drug Therapy-In Process 38难治性胃食管反流病RGERD Aliment.Pharmacol.Ther.33,11131122(2011).TRPV1 a
32、ntagonist（AZD1386)：TRPV 1 channel is responsive to noxious heat and acid.TRPV 1 antagonist(AZD1386)increased oesophageal and skin heat pain thresholds.It is a potential drug class for GERD treatment.Drug Therapy-In Process 39难治性胃食管反流病RGERDVisceral pain modulatorsMost of the patients who fail PPI tre
33、atment originate from the NERD groupmore than 50%of the PPI failure(twice daily)subjects demonstrate lack of either weakly or acidic reflux,the usage of these agents is highly attractive.Tricyclic antidepressantsTrazodone(a tetracyclic antidepressants)Selective serotonin reuptake inhibitors(SSRIs)Gu
34、t，2006，55:139840240难治性胃食管反流病RGERDAntireflux SurgeryGastrointest Surg(2010)14:14341441Gut 2011;60:435e441.uRefractory GERD was the most common(88%)indication for antireflux surgery and the most common preoperative symptom reported under failure of medical antireflux treatment was regurgitation(54%).4
35、1难治性胃食管反流病RGERDEndoscopic therapyRadiofrequency therapy:Stretta procedure;Injection therapy:Enteryx,GK,Stem cell injection;Suturing/plication therapyLINX reflux management system 42难治性胃食管反流病RGERDLINX reflux management systemSurg Endosc，2012 AprilJ Gastrointest Surg(2008)The device consists of a seri
36、es of interlinked titanium beads containing a magnetic core,is placed laparoscopically around the external esophagus at the gastroesophageal junction(EGJ)Improve the reflux barrier (reduced esophageal acid exposure),improved GERD-related quality of life,and cessation of dependence on PPIs43难治性胃食管反流病RGERDManagement algorithm of GERD patient who failed PPI once daily Best Practice&Research Clinical Gastroenterology 24(2010)92393644难治性胃食管反流病RGERD45难治性胃食管反流病RGERD
