NAB
Poor complቤተ መጻሕፍቲ ባይዱance with PPI treatment
Mechanism
Dilated intercellular spaces
Gastroparesis
Esophageal hypersensitivity
DGER
Weakly Acid Reflux
The prevalence of weakly acidic reflux in refractory GERD is
Immunity:Mucosal Inflammation
An inflammatory response
occurs in the squamous epithelium, induced by the release of inflammatory mediators
Leads to the subsequent
Protease activated receptor 2(PAR2)
Activated by serine proteases
Upregulated in patients with GERD and induced by acid conditions in cell culture models
• 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.
Poor Compliance with PPI Treatment
Compliance to treatment and proper dosing are important. Timing and frequency of dosing are critical for maximum
Definition of RGERD
RGERD:Patients who are unresponsive to 4-8 weeks'
treatment with PPIs twice daily or esophageal injury caused by RE can’t to be healing.
Failure on PPI qd 40-50%
Failure on PPI qd 6-15%
Failure on PPI qd 20%
——Fass et al. Aliment Pharmacol Ther 2005; 22(2):79-94.
30%NERD fail to PPI treatment
PAR2 activation : Leads to epithelial IL - 8 release and contributes to the pathogenesis of GERD Implicated in inflammatory and neuroinflammatory effects the modulation of visceral hypersensitivity and pain generation and increasing epithelial permeability.
Gastroenterol. Hepatol.2012
Esophageal Eosinophilia
High intraepithelial eosinophil counts in esophageal squamous epithelium are not specific for eosinophilic esophagitis . Eos＞20/HPF in GERD patients suggest it may be RGERD.＞ 20/HPF
efficacy of the medication.
PPI dosing situation in 100 patients with persistent GERD symptoms Patients dosed Proper dosing timing optimally the PPIs(%) Patients dosed suboptimally the PPIs(%) >60 min before meals after meals 46% 39% 30%
NERD-acid,visceral sensitivity
Potential causes of PPI refractoriness in GERD
Neurogastroenterol Motil (2012) 24, 697–704
Weakly acid reflux Psychological
Psychological Comorbidities
Anxiety and depression have been shown to increase GERD-related symptoms report in population-based studies.
ALIMENTARY PHARMACOLOGY & THERAPEUTICS ,2007,26 (3): 443-
American Journal of Gastroenterology，2008，435-442
chemoattraction and infiltration of immune cells
Followed by the
proliferative response of the rat epithelium.
Gastroesophageal reflux disease-from reflux episodes to mucosal inflammation. Nat. Rev. Gastroenterol. Hepatol.2012
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
24h pH Study in GERD on PPI
75%
70% 65% 60% 55% 50% NAB Daytime acid reflux Both
Aliment Pharmacol Ther,2002,16()7:1309-1316.
Dilated intercellular spaces
at bedtime as-needed
28% 4%
Aliment Pharmacol Ther 2006;23:1473–7
Nocturnal Acid Breakthrough
NAB: Gastric pH below 4 over 60 consecutive minutes at
night-time in subjects who take proton pump inhibitors twice daily.
30-40%. When the esophageal pH falls by ≥ 1 unit, but remains ＞4, it is considered “weakly acidic reflux”.
• Esophageal distension
• Persistent impaired mucosal integrity • Esophageal hypersensitivity
is Immunemediated esophageal mucosal damage(IL-8
GERD
A new targets for GERD drug development. Gastroesophageal reflux disease-from reflux episodes to mucosal inflammation. Nat. Rev. Gastroenterol. Hepatol.2012
Proinflammatory and Neuroinflammatory Aspects
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 TRPV１． Nuroinflammatory aspects in GERD patients NGF↑ GNDF↑
Bile Reflux
230 patients with hear tburn and regurgitation continued to report symptoms after 8 wk of high-dose PPI therapy (40 mg esomeprazole bid).
Gastroenterol 2009 January 21; 15(3): 334-338
Remains an area of controversy
PPI failed in Each of the Gastrooesophageal Reflux Disease (GERD) Groups