难治性胃食管反流病 RGERD

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 respon

2、se to PPI once 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 controversyPPI failed in Each of

3、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. 30%NERD fail to PPI treatmentNERD-acid,visceral sensitivityPot

4、ential 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 reflux in re

5、fractory GERD is 30-40%. When the esophageal pH falls by 1 unit, but remains 4, it is considered “weakly acidic reflux”.Gut,2004,53:1024-1031Esophageal distension Persistent impaired mucosal integrity Esophageal hypersensitivityEsophageal HypersensitivityAM J Gastroenterol ,2012,107, 8-15. Esophagea

6、l 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 r

7、eflux, 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

8、treatment and proper dosing are important. Timing and frequency of dosing are critical for maximum efcacy 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 situat

9、ion in 100 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.Aliment Pharmacol Ther,2002,16()7:1309-1316.Dilated intercellular

10、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 RefluxGastroenterol 2009 January 21; 15(3): 334-338 230 patients with hear

11、 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 increase GERD-related symptoms report in population-base

12、d studies. New MechanismAn 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.Immunity:Mucosal InflammationGastro

13、esophageal 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.2012 Activated by serine proteases Upregulate

14、d in patients with GERD and induced by acid conditions in cell culture models PAR2 activation : Leads to epithelial IL - 8 release and contributes to the pathogenesis of GERDImplicated in inflammatory and neuroinflammatory effects the modulation of visceral hypersensitivity and pain generation and i

15、ncreasing epithelial permeability. GERD is Immune-mediated esophageal mucosal damage(IL-8 A new targets for GERD drug development.Proinflammatory and Neuroinflammatory AspectsGastroenterol. Hepatol.2012TRPV1(transient receptor potential cation channel subfamily V member 1)TRPV1 is involved in the in

16、flammatory epithelial response ,that is supposed to be involved in GERD- related symptom generation.EE or NERD patients with high expression level of TRPVNuroinflammatory aspects in GERD patients NGFGNDFEsophageal EosinophiliaAmerican Journal of Gastroenterology，2008，435-442High intraepithelial eosi

17、nophil 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 Gastroenterology. 2012GERD and SIBOOverlap of G

18、ERD 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 Diagnosis testsUpper Gastrointestinal EndoscopyGastrointest Endosc 2007;66:21924Commonly used in clinical practice to

19、 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 heartburn patients take a big part.A new method in the diagnosis of reflux esophagitis:

20、 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 intrapapillar

21、y capillary loops(IPCLs) than control.IPCLs number increased;IPCLs diameter become bigger;IPCLs extended to mucosal surface;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:figuer a, b

22、,e;NERD:figure c,d,f （DIS）Esophageal 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

23、 acid reux) or on PPI to test whether the symptoms are due to residual acid reux.Remote proximalacid reuxRemote proximalacid reuxAmbulatory 24h Esophageal pH MonitoringAmbulatory 24h Esophageal pH Monitoring- GraphsEsophageal Bilitec Bilitec detects bilirubin in the reuxate that is used as a surroga

24、te 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.Treament of RGERDTherapeutic options for RGERD patients Gastroenterology and Hepatology 27 (2012) Suppl. 3;

25、37GERD 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 pat

26、ients with less severe GERD.American guidelines for diagnosis and treatment of GERDPromotility 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 incompe

27、tence, 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 of GERDTransie

28、nt 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.Gastroesophageal reflux disease-from reflux episodes to m

29、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

30、s Gastroesophageal 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 to reduce both acidic and nonacidic

31、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 Aliment. Pharmacol. Ther. 33, 11131122 (2011).TRPV1 antagonist （ AZD1386 )： TRPV 1 channel is re

32、sponsive 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 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 (