难治性胃食管反流病RGERD培训课件

1、难治性胃食管反流病RGERD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

2、 a day is sufcient to consider patients as PPI failures. Any attempt to narrow the denition 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RGERDDefinition of RGERDRG

3、ERD:PatiePPI failed in Each of the Gastrooesophageal Reux Disease (GERD) GroupsGERDNERD60-70% EE 20-30% Barretts oesophagus6-10% PPI failure patients 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RGERDPPI failed in Ea

4、ch of the Gast30%NERD fail to PPI treatment4难治性胃食管反流病RGERD30%NERD fail to PPI treatment4NERD-acid,visceral sensitivity5难治性胃食管反流病RGERDNERD-acid,visceral sensitivityPotential causes of PPI refractoriness in GERDNeurogastroenterol Motil (2012) 24, 697704 6难治性胃食管反流病RGERDPotential causes of PPI refrac7难治

5、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,2004,53:1024-10318难治性胃食管反流病RGERDWeakly Acid RefluxThe prevalenEsophageal Hypersensitivi

6、tyAM 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 GERD 9难治性胃食管反流病RGERDEsophageal HypersensitivityAM Ga

7、stroparesisDelayed 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 OTHER INTERV

8、ENTIONAL TECHNIQUES，2008，22 （11）: 2440-244410难治性胃食管反流病RGERDGastroparesisSURGICAL ENDOSCOPPoor Compliance with PPI Treatment Compliance to treatment and proper dosing are important. Timing and frequency of dosing are critical for maximum efcacy of the medication.Patients dosed optimally the PPIs(%)Pr

9、oper dosing timing 46%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RGERDPoor Compliance with PPI TreatNocturnal Acid BreakthroughNAB:

10、 Gastric pH below 4 over 60 consecutive minutes at night-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RGERDNocturnal Acid BreakthroughNABDilated intercellular spaces The dilation of esophageal intercellular spaces (ICS) is consid

11、ered 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. 13难治性胃食管反流病RGERDDilated intercellular spaces TBile RefluxGastroenterol 2009 January 21; 15(3): 334-338 230 patients with hear tburn and regurgitation

12、 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RGERDBile RefluxGastroenterol 2009Psychological ComorbiditiesALIMENTARY PHARMACOLOGY & THERAPEUTICS,2007,26 (3): 443-452.Anxiety and depression have been shown to increase GERD-related symptoms repo

13、rt in population-based studies. 15难治性胃食管反流病RGERDPsychological ComorbiditiesALINew Mechanism16难治性胃食管反流病RGERDNew Mechanism16难治性胃食管反流病RGERDAn inflammatory response occurs in the squamous epithelium, induced by the release of inflammatory mediatorsLeads to the subsequent chemoattraction and infiltration

14、 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难治性胃食管反流病RGERDAn inflammatory response LeadsProtease activated receptor 2(PAR

15、2)Gastroesophageal reflux disease-from reflux episodes to mucosal inflammation. Nat. Rev. Gastroenterol. Hepatol.2012 Activated by serine proteases Upregulated in patients with GERD and induced by acid conditions in cell culture models PAR2 activation : Leads to epithelial IL - 8 release and contrib

16、utes to the pathogenesis of GERDImplicated 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 for GERD drug development.18难治性胃食管反流病R

17、GERDProtease activated receptor 2(Proinflammatory and Neuroinflammatory AspectsGastroenterol. Hepatol.2012TRPV1(transient receptor potential cation channel subfamily V member 1)TRPV1 is involved in the inflammatory epithelial response ,that is supposed to be involved in GERD- related symptom generat

18、ion.EE or NERD patients with high expression level of TRPVNuroinflammatory aspects in GERD patients NGFGNDF19难治性胃食管反流病RGERDProinflammatory and NeuroinflaEsophageal EosinophiliaAmerican Journal of Gastroenterology，2008，435-442High intraepithelial eosinophil counts in esophageal squamous epithelium ar

19、e not specific for eosinophilic esophagitis .Eos20/HPF in GERD patients suggest it may be RGERD. 20/HPF20难治性胃食管反流病RGERDEsophageal EosinophiliaAmericaErosive esophagitis may be related to small intestinal bacterial overgrowth Scandinavian Journal of Gastroenterology. 2012GERD and SIBOOverlap of GERD

20、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 21难治性胃食管反流病RGERDErosive esophagitis may be relDiagnosis tests22难治性胃食管反流病RGERDDiagnosis tests22难治性胃食管反流病RGERUpper Gastroin

21、testinal EndoscopyGastrointest Endosc 2007;66:21924Commonly used in clinical practice to evaluate patients with GERD who failed PPI treatment.The 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

22、 heartburn patients take a big part.23难治性胃食管反流病RGERDUpper Gastrointestinal EndoscoA new method in the diagnosis of reflux 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 me

23、asured 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RGERDA new method in the diagnosis 共聚焦激光显微内镜诊断NERDNERD patients had more intrapapillary capillary loops(IPCLs) than control.IPCLs number increased;IPCLs diameter become bigger;IPCLs extended to mucosal surf

24、ace;The intercellular spaces of squamous cells was enlarged.Am J Gastroenterol. 2012 Mar 13. 25难治性胃食管反流病RGERD共聚焦激光显微内镜诊断NERDNERD patients hNERD diagnosed by CLE-Dilated DIC Am J Gastroenterol. 2012 Mar 13. ;Control:figuer a, b,e;NERD:figure c,d,f （DIS）26难治性胃食管反流病RGERDNERD diagnosed by CLE-Dilated Es

25、ophageal pH monitoring allow the quantication of esophageal acid exposure and the assessment of the temporal relationship between symptoms and acid reux events. PH monitoring can be performed off PPI to test if the initial diagnosis was correct (i.e., heartburn was due to acid reux) or on PPI to tes

26、t whether the symptoms are due to residual acid reux.Remote proximalacid reuxRemote proximalacid reuxAmbulatory 24h Esophageal pH Monitoring27难治性胃食管反流病RGERDRemote proximalRemote Ambulatory 24h Esophageal pH Monitoring- Graphs28难治性胃食管反流病RGERDAmbulatory 24h Esophageal pH MEsophageal Bilitec Bilitec de

27、tects bilirubin in the reuxate that is used as a surrogate marker for bile reux. One has to recall that non-acidic and bile reux 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RGERDEsophageal Bilitec Dig Dis Treament

28、of RGERD30难治性胃食管反流病RGERDTreament of RGERD30难治性胃食管反流病RG难治性胃食管反流病RGERD培训课件GERD and PPIPaul Moayyedi et al, Lancet, 2006, June 24(367):2086-210032难治性胃食管反流病RGERDGERD and PPIPaul Moayyedi et aNew PPIsDis. Esophagus 2005; 18: 3703.Gastroenterol，2010; 105: 23416 In Process 33难治性胃食管反流病RGERDNew PPIsDis. Esop

29、hagus 2005; 1Histamine 2 receptor antagonist (H2RA)Histamine 2 receptor antagonist given in divided doses may also be used and are effective treatment in many patients with less severe GERD.American guidelines for diagnosis and treatment of GERD34难治性胃食管反流病RGERDHistamine 2 receptor antagonisPromotili

30、ty therapyRegurgitation may be the main symtom of refractory GERD ,compare with those who are without treatment.GERD is a disorder of gastrointestinal motility Defects in esophagogastric motility (LES incompetence, poor esophageal clearance, and delayed gastric emptying) are central to the pathogene

31、sis 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 GERD35难治性胃食管反流病RGERDPromotility therapyRegurgitatiTransient lower esophageal sphincterrelaxation (TLESR

32、) 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RGERDTransient lower esophageal sphGastroesophageal reflux disease-from reflux episodes to m

33、ucosal 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 rimonabant. Drug Therapy-In Proces

34、s 37难治性胃食管反流病RGERDGastroesophageal reflux diseasGastroesophageal 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 b

35、een shown 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RGERDGastroesophageal reflux diseas Ali

36、ment. Pharmacol. Ther. 33, 11131122 (2011).TRPV1 antagonist （ 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RGERD Ali

37、ment. Pharmacol. Ther. 33,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 either weakly or acidic reux, the usage of these agents is highly attractive. Tricyclic antidepressantsTrazodone (a tetracyclic antidepressants) Selective serotonin reuptake inhibitors (SSRIs)Gut ，2006，55:139840240难治性胃食管反流病RGE