难治性胃食管反流病RGERD

Refractory Gastroesophageal reflux disease,Definition 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;4:658Others suggest that lack of satisfactory symptomatic response 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 controversy,PPI failed in Each of the Gastrooesophageal Reux Disease (GERD) Groups,Fass et al. Aliment Pharmacol Ther 2005; 22(2):79-94.,30%NERD fail to PPI treatment,NERD-acid,visceral sensitivity,Potential causes of PPI refractoriness in GERD,Neurogastroenterol Motil (2012) 24, 697704,Weakly Acid Reflux,The 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,2004,53:1024-1031,Esophageal Hypersensitivity,AM 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,Gastroparesis,Delayed 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 INTERVENTIONAL TECHNIQUES，2008，22 （11）: 2440-2444,Poor 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.,PPI dosing situation in 100 patients with persistent GERD symptoms,Aliment Pharmacol Ther 2006;23:14737,Nocturnal 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 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 Reflux,Gastroenterol 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 Comorbidities,ALIMENTARY PHARMACOLOGY & THERAPEUTICS,2007,26 (3): 443-452.,Anxiety and depression have been shown to increase GERD-related symptoms report in population-based studies.,New Mechanism,An inflammatory response occurs in the squamous epithelium, induced by the release of inflammatory mediators,Leads to the subsequent chemoattraction and infiltration of immune cells,Followed by the proliferative response of the rat epithelium.,Immunity:Mucosal Inflammation,Gastroesophageal reflux disease-from reflux episodes to mucosal inflammation. Nat. Rev. Gastroenterol. Hepatol.2012,Protease activated receptor 2(PAR2),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 contributes 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.,Proinflammatory and Neuroinflammatory Aspects,Gastroenterol. Hepatol.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 TRPVNuroinflammatory aspects in GERD patients NGFGNDF,Esophageal Eosinophilia,American 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/HPF,Erosive esophagitis may be related to small intestinal bacterial overgrowth Scandinavian Journal of Gastroenterology. 2012,GERD and SIBO,Overlap of GERD and IBS,Lactulose 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 tests,Upper Gastrointestinal Endoscopy,Gastrointest 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 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: 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NERD,NERD patients had more intrapapillary 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,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 acid reux) or on PPI to test whether the symptoms are due to residual acid reux.,Remote proximalacid reux,Remote proximalacid reux,Ambulatory 24h Esophageal pH Monitoring,Ambulatory 24h Esophageal pH Monitoring- Graphs,Esophageal Bilitec,Bilitec detects 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.,Treament of RGERD,Therapeutic options for RGERD patients,Gastroenterology and Hepatology 27 (2012) Suppl. 3; 37,GERD and PPI,Paul Moayyedi et al, Lancet, 2006, June 24(367):2086-2100,New PPIs,Dis. 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 less severe GERD.,American guidelines for diagnosis and treatment of GERD,Promotility 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 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 GERD,Transient lower esophageal sphincterrelaxation (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.,Gastroesophageal reflux disease-from reflux episodes to mucosal inflammation. Nat. Rev. Gastroenterol. Hepatol.2012,Cannabinoids (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-from reflux episodes to mucosal inflammation. Nat. Rev. Gastroenterol. Hepatol.2012,mGluR5 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 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(AZD1386)increased oesophageal and skin heat pain thresholds. It is a potential drug class for GERD treatment.,Drug Therapy-In Process,Visceral pain modulators,Most 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 reupt