1、1Definition of RGERD?RGERD: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;4:658?Others suggest that lack of satisfactory symptomatic response to PPI once a day is suf?cient to con
2、sider patients as PPI failures.?Any attempt to narrow the de?nition 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 controversy22020/2/14PPI failed in Each of the Gastrooesophageal Re?ux D
3、isease (GERD) GroupsGERDNERD60-70% EE 20-30% Barretts oesophagus6-10% Failure on PPI qd40-50%40-50%Failure on PPI qd6-15%Failure on PPI qd20%Fass et al. Aliment Pharmacol Ther 2005; 22(2):79-94. 32020/2/1430%NERD fail to PPI treatment42020/2/14NERD-acid,visceral sensitivity52020/2/14Potential causes
4、 of PPI refractoriness in GERDNeurogastroenterol Motil (2012) 24, 697704 62020/2/14MechanismWeakly acid refluxNABDilated intercellular spaces DGEREsophageal hypersensitivityGastroparesisPoor compliance with PPI treatment Psychological 7Weakly Acid Reflux?The prevalence of weakly acidic reflux in ref
5、ractory 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 hypersensitivity82020/2/14Esophageal HypersensitivityAM J Gastroenterol ,2012, 107
6、, 8-15. Esophageal receptor upregulation and/or enhanced signalingPhysiological stressors, sensitization of spinal sensory neuronsPotential factors contributing to the spectrum of reflux perception in patients with GERD 92020/2/14GastroparesisDelayed gastric emptying (gastroparesis) may be a factor
7、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 INTERVENTIONAL TECHNIQUES ，2008，22 （11）2440-2444102020/2/14Poor Compliance
8、 with PPI Treatment ?Compliance to treatment and proper dosing are important. ?Timing and frequency of dosing are critical for maximum ef?cacy of the medication.Patients dosed optimally the PPIs(%)Properdosing timing 46%Patientsdosed suboptimally the PPIs(%)60 min before meals39%after meals30%at bed
9、time28%as-needed4%PPI dosing situation in 100 patients with persistent GERD symptomsAliment Pharmacol Ther 2006;23:14737112020/2/14Nocturnal Acid Breakthrough?NAB: Gastric pH below 4 over 60 consecutive minutes at night-time in subjects who take proton pump inhibitors twice daily.Aliment Pharmacol T
10、her,2002,16()7:1309-1316.122020/2/14Dilated 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 eliminatedin RGERD patients who fail to PPI treament. 132020/2/14Bile Re
11、fluxGastroenterol 2009 January 21; 15(3): 334-338230 patients with hear tburn and regurgitation continued to report symptoms after 8 wk of high-dose PPI therapy (40 mg esomeprazole bid).142020/2/14Psychological ComorbiditiesALIMENTARY PHARMACOLOGY & THERAPEUTICS ,2007,26 (3): 443-Anxiety and depress
12、ion have been shown to increase GERD-related symptoms report in population-based studies. 152020/2/1416An 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 p
13、roliferative response of the rat epithelium.Immunity:Mucosal InflammationGastroesophageal reflux disease-from reflux episodes to mucosal inflammation. Nat. Rev. Gastroenterol. Hepatol.2012172020/2/14Protease activated receptor 2(PAR2)Gastroesophageal reflux disease-from reflux episodes to mucosal in
14、flammation. 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 contributes to the pathogenesis of GERD?Implicated in inflammatory and
15、 neuroinflammatory effects the modulation of visceral hypersensitivity and pain generation and increasing epithelial permeability.G GERD is Immune-mediated esophageal mucosal damage(IL-8 A new targets for GERD drug development.182020/2/14Proinflammatory and Neuroinflammatory AspectsGastroenterol. He
16、patol.2012?TRPV1(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 generation.?EE or NERD patients with high expression level of TRPV?Nuroinflammatory aspects in GERD p
17、atients ? NGF?GNDF192020/2/14Esophageal EosinophiliaAmerican Journal of Gastroenterology，2008，435-442?High intraepithelial eosinophil counts in esophageal squamous epithelium are not specific for eosinophilic esophagitis .?Eos20/HPF in GERD patients suggest it may be RGERD. 20/HPF202020/2/14Erosive
18、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 Abnormal LHBT,67% in EE,37% in control （P=0.024）65% in EE,31% in control(without IBS)（P=0.032）Small Intestinal
19、 Bacterial Overgrowth 212020/2/1422Upper Gastrointestinal EndoscopyGastrointest Endosc 2007;66:21924?Commonly used in clinical practice to evaluate patients with GERD who failed PPI treatment.?The value of endoscopy in patients with refractory GERD is very lowEosinophilic oesophagitis was found in o
20、nly 0.9% of RGERD patients,and NERD and functional heartburn patients take a big part.232020/2/14A new method in the diagnosis of reflux esophagitis: confocal laser endomicroscopy. GIE.2012Confocal laser endomicroscopy，CLE A new method to test GERDThe distance between the surface to papillary (S-P)
21、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242020/2/14共聚焦激光显微内镜诊断NERDNERD patients had moreintrapapillary capillary loops(IPCLs) than control.a. IPCLs number increased;b. IPCLs diameter become bigger;c.IPCLs extended to mucosal surface;d. The inte
22、rcellular spaces of squamous cells was enlarged.Am J Gastroenterol. 2012 Mar 13.252020/2/14NERD diagnosed by CLE-Dilated DIC Am J Gastroenterol. 2012 Mar 13.Control:figuer a, b,e;NERD:figure c,d,f （DIS）262020/2/14?Esophageal pH monitoring allow the quanti?cation of esophageal acid exposure and the a
23、ssessment of the temporal relationship between symptoms and acid re?ux events. ?PH monitoring can be performed off PPI to test if the initial diagnosis was correct (i.e., heartburn was due to acid re?ux) or on PPI to test whether the symptoms are due to residual acid re?ux.Remote proximalacid re?uxR
24、emote proximalacid re?uxAmbulatory 24h Esophageal pH Monitoring272020/2/14Ambulatory 24h Esophageal pH Monitoring- Graphs282020/2/14Esophageal BilitecBilitec detects bilirubin in the re?uxate that is used as a surrogate marker for bile re?ux. One has to recall that non-acidic and bile re?ux are two
25、distinct phenomena.Esophageal exposure to bile acids can result in heartburn symptoms. Dig Dis Sci 2005;50:815.292020/2/1430Therapeutic options for RGERD patientsGastroenterology and Hepatology 27 (2012) Suppl. 3; 37312020/2/14GERD and PPIPaul Moayyedi et al, Lancet, 2006, June 24(367):2086-21003220
26、20/2/14New PPIsDis. Esophagus 2005; 18: 3703.Gastroenterol，2010; 105: 23416In Process332020/2/14Histamine 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 di
27、agnosis and treatment of GERD342020/2/14Promotility therapy?Regurgitation 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 de
28、layed 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 GERD352020/2/14Transient lower esophageal sphincte
29、rrelaxation (TLESR) reducers?Gamma-aminobutyric acid B (GABAB) receptor agonists(Baclofen)?Metabotropic glutamate receptor 5(mGluR5) antagonists(ADX10059)Am J Physiol 2001;281:G3115.Gastroenterology 2005;129:9951004.362020/2/14Gastroesophageal reflux disease-from reflux episodes to mucosal inflammat
30、ion. 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 Process372020/2/14Gastroe
31、sophageal 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 reflux eve
32、nts.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 Process382020/2/14Aliment. Pharmacol. Ther. 33, 11131122 (2011).TRPV1 antagonist （ AZD1386 )：TRPV 1 channel is respo
33、nsive to noxious heatand acid.TRPV 1 antagonist(AZD1386)increased oesophageal and skin heat pain thresholds.It is a potential drug class for GERD treatment.Drug Therapy-In Process392020/2/14Visceral pain modulators?Most of the patients who fail PPI treatment originate from the NERD group?more than 5
34、0% of the PPI failure (twice daily) subjects demonstrate lack of either weakly or acidic re?ux, the usage of these agents is highly attractive. ?Tricyclic antidepressants?Trazodone (a tetracyclic antidepressants)?Selective serotonin reuptake inhibitors (SSRIs)Gut ，2006，55:1398402402020/2/14Antire?ux
35、 SurgeryGastrointest Surg (2010) 14:14341441Gut 2011;60:435e441.?Refractory GERD was the most common (88%) indication for antire?ux surgery and the most common preoperative symptom reported under failure of medical antire?ux treatment was regurgitation (54%).412020/2/14Endoscopic therapy?Radiofreque
36、ncy therapy : Stretta procedure;?Injection therapy:Enteryx ,GK, Stem cell injection;?Suturing/plication therapy?LINX re?ux management system 422020/2/14LINX re?ux management systemSurg Endosc， 2012 AprilJ Gastrointest Surg (2008)The device consists of a series of interlinked titanium beads containin
37、g a magnetic core, is placed laparoscopically around the external esophagus at the gastroesophageal junction (EGJ)Improve the re?ux barrier (reduced esophageal acid exposure), improved GERD-related quality of life, and cessation of dependence on PPIs432020/2/14Management algorithm of GERD patient who failed PPI once daily Best Practice & Research Clinical Gastroenterology 24 (2010) 923936442020/2/1445
