1、Refractory Gastroesophageal reflux diseaseDefinition 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 respons
2、e to PPI once a day is sufficient 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 Remains an area of controversyof contr
3、oversyPPI failed in Each of the Gastrooesophageal Reflux Disease(GERD)GroupsGERDNERD60-70%EE 20-30%Barretts oesophagus6-10%Failure on PPI qd40-50%40-50%Failure on PPI qd6-156-15%Failure on PPI qd2020%Fass et al.Aliment Pharmacol Ther 2005;22(2):79-94.30%NERD fail to PPI treatmentNERD-acid,visceral s
4、ensitivityPotential causes of PPI refractoriness in GERDNeurogastroenterol Motil(2012)24,697704 MechanismWeakly acid refluxNABDilated intercellular spaces DGEREsophageal hypersensitivityGastroparesisPoor compliance with PPI treatment Psychological Weakly Acid RefluxThe prevalence of weakly acidic re
5、flux in refractory GERD is 30-40%.When the esophageal pH falls by 1 unit,but remains 4,it is considered“weakly acidic reflux”.Gut,2004,53:1024-1031 Esophageal distension Persistent impaired mucosal integrity Esophageal hypersensitivityEsophageal HypersensitivityAM J Gastroenterol,2012,107,8-15.Esoph
6、ageal receptor upregulation and/or enhanced signalingPhysiological stressors,sensitization of spinal sensory neurons.Potential factors contributing to the spectrum of reflux perception in patients with GERD GastroparesisDelayed gastric emptying(gastroparesis)may be a factor associated with severe re
7、flux,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 OTHER INTERVENTIONAL TECHNIQUES，2008，22 （11）:2440-2444Poor Compliance with PPI Treatment Compliance to treatment
8、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%Patients dosed suboptimally the PPIs(%)60 min before meals39%after meals30%at bedtime28%as-needed4%PPI dosing situation in 10
9、0 patients with persistent GERD symptomsAliment Pharmacol Ther 2006;23:14737Nocturnal Acid BreakthroughNAB:Gastric pH below 4 over 60 consecutive minutes at night-time in subjects who take proton pump inhibitors twice daily.50%55%60%65%70%75%NABDaytime acid refluxBoth24h pH Study in GERD on PPIAlime
10、nt Pharmacol Ther,2002,16()7:1309-1316.Dilated 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 difficult to eliminated in RGERD patients who fail to PPI treament.Bile RefluxGastroenter
11、ol 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).Psychological ComorbiditiesALIMENTARY PHARMACOLOGY&THERAPEUTICS,2007,26 (3):443-452.Anxiety and depression have been shown to incre
12、ase GERD-related symptoms report in population-based studies.An inflammatory response occurs in the squamous epithelium,induced by the release of inflammatory mediatorsLeads to the subsequent chemoattraction and infiltration of immune cellsFollowed by the proliferative response of the rat epithelium
13、.Immunity:Mucosal InflammationGastroesophageal reflux disease-from reflux episodes to mucosal inflammation.Nat.Rev.Gastroenterol.Hepatol.2012Protease activated receptor 2(PAR2)Gastroesophageal reflux disease-from reflux episodes to mucosal inflammation.Nat.Rev.Gastroenterol.Hepatol.2012n Activated b
14、y serine proteases n Upregulated in patients with GERD and induced by acid conditions in cell culture modelsn PAR2 activation:p Leads to epithelial IL-8 release and contributes to the pathogenesis of GERDpImplicated in inflammatory and neuroinflammatory effects the modulation of visceral hypersensit
15、ivity and pain generation and increasing epithelial permeability.G GERD is Immune-mediated esophageal mucosal damage(IL-8 A new targets for GERD drug development.Proinflammatory and Neuroinflammatory AspectsGastroenterol.Hepatol.2012nTRPV1(transient receptor potential cation channel subfamily V memb
16、er 1)pTRPV1 is involved in the inflammatory epithelial response,that is supposed to be involved in GERD-related symptom generation.pEE or NERD patients with high expression level of TRPVnNuroinflammatory aspects in GERD patients p NGFpGNDFEsophageal EosinophiliaAmerican Journal of Gastroenterology，2
17、008，435-442High intraepithelial eosinophil counts in esophageal squamous epithelium are not specific for eosinophilic esophagitis.Eos20/HPF in GERD patients suggest it may be RGERD.20/HPFErosive esophagitis may be related to small intestinal bacterial overgrowth Scandinavian Journal of Gastroenterol
18、ogy.2012GERD and SIBOOverlap of GERD and IBSLactulose hydrogen breath test（LHBT）In Abnormal 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 Upper Gastrointestinal EndoscopyGastrointest Endosc 2007;66:21924nCommonly used in clinica
19、l practice to evaluate patients with GERD who failed PPI 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.A new method in the diagnosis of reflux
20、 esophagitis:confocal laser endomicroscopy.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共聚焦激光显微内镜诊断NERDNERD patients had more intrapap
21、illary capillary loops(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.NERD diagnosed by CLE-Dilated DIC Am J Gastroenterol.2012 Mar 13.;Control:fig
22、uer a,b,e;NERD:figure c,d,f （DIS）Esophageal 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.,heartburn wa
23、s 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 MonitoringAmbulatory 24h Esophageal pH Monitoring-GraphsEsophageal Bilitec Bilitec detects bilirubin in the refluxate that is u
24、sed 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.Therapeutic options for RGERD patients Gastroenterology and Hepatology 27(2012)Suppl.3;37G
25、ERD and PPIPaul Moayyedi et al,Lancet,2006,June 24(367):2086-2100New PPIsDis.Esophagus 2005;18:3703.Gastroenterol，2010;105:23416 In Process Histamine 2 receptor antagonist(H2RA)Histamine 2 receptor antagonist given in divided doses may also be used and are effective treatment in many patients with l
26、ess severe GERD.American guidelines for diagnosis and treatment of GERDPromotility 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 motility(LES incompetence,poor e
27、sophageal 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 of GERDTransient lower esophagea
28、l 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.Gastroesophageal reflux disease-from reflux episodes to mucosal inflammation.Nat.
29、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 rimonabant.Drug Therapy-In Process Gastroesophageal reflux disease-f
30、rom 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 to reduce both acidic and nonacidic reflux events.After an increase in abnormal
31、laboratory test results(liver enzymes)and a few cases of hepatic failure,the further development of ADX10059 was also discontinued.Drug Therapy-In Process Aliment.Pharmacol.Ther.33,11131122(2011).TRPV1 antagonist（AZD1386)：TRPV 1 channel is responsive to noxious heat and acid.TRPV 1 antagonist(AZD138
32、6)increased oesophageal and skin heat pain thresholds.It is a potential drug class for GERD treatment.Drug Therapy-In Process Visceral pain modulatorsMost of the patients who fail PPI treatment originate from the NERD groupmore than 50%of the PPI failure(twice daily)subjects demonstrate lack of eith
33、er weakly or acidic reflux,the usage of these agents is highly attractive.Tricyclic antidepressantsTrazodone(a tetracyclic antidepressants)Selective serotonin reuptake inhibitors(SSRIs)Gut，2006，55:1398402Antireflux SurgeryGastrointest Surg(2010)14:14341441Gut 2011;60:435e441.uRefractory GERD was the
34、 most common(88%)indication for antireflux surgery and the most common preoperative symptom reported under failure of medical antireflux treatment was regurgitation(54%).Endoscopic therapyRadiofrequency therapy:Stretta procedure;Injection therapy:Enteryx,GK,Stem cell injection;Suturing/plication the
35、rapyLINX reflux management system LINX reflux management systemSurg Endosc，2012 AprilJ Gastrointest Surg(2008)The device consists of a series 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 PPIsManagement algorithm of GERD patient who failed PPI once daily Best Practice&Research Clinical Gastroenterology 24(2010)923936
