Ignite Creation Date:
2024-05-05 @ 10:36 PM
Last Modification Date:
2024-10-26 @ 10:21 AM
Study NCT ID:
NCT01149395
Status:
COMPLETED
Last Update Posted:
2016-12-19
First Post:
2010-06-22
Brief Title:
Can E-cadherin Found in TissueBlood be Valuable in Identifying Monitoring Patients With Post-proton Pump Inhibitor PPI-Responsive Heartburn
Sponsor:
University of North Carolina Chapel Hill
Organization:
University of North Carolina Chapel Hill
Study Overview
Official Title:
Can Detection of Fragments of Cleaved E-cadherin in Tissue andor Blood be of Value for Identifying and Monitoring Patients With PPI-responsive Heartburn
Status:
COMPLETED
Status Verified Date:
2016-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this research study is to determine in heartburn patients with nonerosive disease if detecting the presence of a fragment of the protein e-cadherin in esophageal epithelium or the amount of fragments of e-cadherin in blood can be used to monitor healing of esophagitis treated with a proton pump inhibitor PPI The hypothesis is that the presence of fragments of e-cadherin in esophageal epithelium or the amount of fragments of e-cadherin in blood can you useful as a biomarker for the healing of esophagitis in patients successfully treated with a PPI
Detailed Description:
The symptom of heartburn was once a reliable indicator of gastroesophageal reflux disease GERD and as such patients would predictably respond to acid inhibition In the post-proton pump inhibitor PPI world neither of these statements is true since many patients presenting with heartburn have symptoms mediated by mechanisms unrelated to esophageal luminal acidity eg functional disease visceral hypersensitivity or activation of esophageal stretch receptors Consequently these subjects fail to respond to PPIs1-3 Since PPI-responsive and PPI-refractory patients with heartburn are indistinguishable by history it is difficult to determine which PPI-unresponsive subjects may respond to higher doses of a PPI Additionally when subjects do respond to PPI therapy symptom response may not correlate with lesion healing making a systemic marker of healing highly desirable Lesion healing is particularly problematic since the histopathologic lesion that correlates best with heartburn is the presence of dilated intercellular spaces DIS within esophageal epithelium which cannot be detected by with standard endoscopy and is most reliably demonstrable by performing transmission electron microscopy4-7 Consequently it would be desirable to have an objective marker of acid-mediated injury to esophageal epithelium that could identify those with PPI-responsive heartburn and determine healing of acid-damaged epithelium non-invasively
DIS in esophageal epithelium has been established as an early histopathologic feature of gastroesophageal reflux disease GERD This electron microscopic lesion is present in both erosive and nonerosive forms of GERD and results from acid damage to the intercellular junctional complex that controls paracellular permeability within esophageal epithelium8 Further it is known that treatment with PPIs results in resolution of DIS along with that of heartburn in patients with both erosive and nonerosive types of GERD9 E-cadherin is a protein which forms the intercellular adhesive bridge of the zonula adherens ZA10 and the ZA plays an integral role in maintaining the integrity of the tight junction between cells such that loss of adhesion between bridging molecules of e-cadherin results in loss of barrier function and increased paracellular permeability1112 Therefore under conditions where an acidic refluxate is present within the esophageal lumen a leaky junctional barrier promotes excessive entry of hydrogen ions into and so acidification of the intercellular space which in turn triggers heartburn by activation of acid-sensitive neurons within the mucosa13
Recently my lab has found that DIS in non-erosive acid-damage to rabbit esophageal epithelium is associated on Western blots with cleavage of the intercellular portion of e-cadherin and that this cleavage occurs by acid activation of an endogenous proteolytic process unpublished observations Moreover this same phenomenon on Western blots is replicated in human esophagus of patients with GERD ie endoscopic biopsies of esophageal epithelium reveal cleavage of e-cadherin in those with both erosive and non-erosive forms of GERD but is not present within the esophageal epithelium of healthy subjects or subjects without signs or symptoms of esophageal disease14 - see Fig 4 of attached poster presentation Specifically cleavage of e-cadherin in GERD patients leaves behind within the esophageal epithelium a cytoplasmic C-terminal fragment CTF of the molecule and this CTF is readily detected on Western blot Interestingly the size of the CTF is consistent as in the rabbit model with cleavage of e-cadherin by an endogenous matrix metalloprotease Also noteworthy is that the other cleaved extracellular component of e-cadherin is an N-terminal fragment NTF and this fragment is absorbed into the blood stream resulting in higher serum levels of NTFs of e-cadherin than healthy subjects as detectable using a commercial ELISA assay14 - see Fig 6 of attached poster presentation Since CTFs on Western blot of endoscopic biopsies and elevated NTFs of e-cadherin by ELISA in serum are a reflection of acid-injured esophageal epithelium this suggests the tantalizing possibility of a sensitive minimally invasive serum test for esophageal mucosal damage in the GERD subject We hypothesize that determination of either of the cleaved fragments of e-cadherin serum or tissue-based can discriminate between patients with acid-mediated heartburn who are likely to be PPI-responsive and those whose heartburn symptoms are not mediated by acid and so are PPI-refractory
The hypothesis will be tested by determining the presence or absence of CTFs of e-cadherin on esophageal biopsy and by measuring the level of NTFs of e-cadherin in serum of endoscopy-negative patients with heartburn and correlating the findings with the patients heartburn response to Kapidex 30 mg for 4 weeks Based on effective heartburn control on Kapidex or lack thereof patients will be classified as having PPI-responsive or PPI-refractory disease respectively and these classifications correlated with presence or absence of CTFs on pretreatment biopsy and pretreatment serum level of NTFs of e-cadherin Also after 4 weeks of Kapidex repeat serum specimens for NTFs are obtained from all treated patients to determine as a marker of healing whether the serum level of NTFs post-treatment are significantly lower than pretreatment serum level of NTFs in those that have PPI-responsive heartburn but not in those that have PPI-refractory heartburn
The results of this study are expected to show that patients with PPI-responsive heartburn have CTFs of e-cadherin in tissue and higher levels of NTFs of e-cadherin in serum at baseline and that these levels decrease after successful PPI therapy In contrast because symptoms in PPI-refractory subjects are not acid-mediated these subjects are expected to lack CTFs in tissue and to have lower levels of NTFs in serum at baseline compared to PPI-responsive patients and these levels will remain unchanged after PPI therapy Consequently such findings would establish detection of cleaved fragments of e-cadherin in tissue and blood as useful biomarkers of disease that can identify those with heartburn that are responsive to standard doses of Kapidex The results are also expected to show that patients with PPI-responsive heartburn but not those with PPI-refractory heartburn have a significant decline in the level of NTFs in serum post-treatment and that this lower level of NTFs is expected to fall within the range of controls Consequently such findings would establish that detection of serum NTFs before and after treatment can be useful as a biomarker of microscopic lesion healing in those with PPI-responsive heartburn Such findings might help select sub-groups appropriate for more intensive higher dose or long term PPI therapy
DIS in esophageal epithelium has been established as an early histopathologic feature of gastroesophageal reflux disease GERD This electron microscopic lesion is present in both erosive and nonerosive forms of GERD and results from acid damage to the intercellular junctional complex that controls paracellular permeability within esophageal epithelium8 Further it is known that treatment with PPIs results in resolution of DIS along with that of heartburn in patients with both erosive and nonerosive types of GERD9 E-cadherin is a protein which forms the intercellular adhesive bridge of the zonula adherens ZA10 and the ZA plays an integral role in maintaining the integrity of the tight junction between cells such that loss of adhesion between bridging molecules of e-cadherin results in loss of barrier function and increased paracellular permeability1112 Therefore under conditions where an acidic refluxate is present within the esophageal lumen a leaky junctional barrier promotes excessive entry of hydrogen ions into and so acidification of the intercellular space which in turn triggers heartburn by activation of acid-sensitive neurons within the mucosa13
Recently my lab has found that DIS in non-erosive acid-damage to rabbit esophageal epithelium is associated on Western blots with cleavage of the intercellular portion of e-cadherin and that this cleavage occurs by acid activation of an endogenous proteolytic process unpublished observations Moreover this same phenomenon on Western blots is replicated in human esophagus of patients with GERD ie endoscopic biopsies of esophageal epithelium reveal cleavage of e-cadherin in those with both erosive and non-erosive forms of GERD but is not present within the esophageal epithelium of healthy subjects or subjects without signs or symptoms of esophageal disease14 - see Fig 4 of attached poster presentation Specifically cleavage of e-cadherin in GERD patients leaves behind within the esophageal epithelium a cytoplasmic C-terminal fragment CTF of the molecule and this CTF is readily detected on Western blot Interestingly the size of the CTF is consistent as in the rabbit model with cleavage of e-cadherin by an endogenous matrix metalloprotease Also noteworthy is that the other cleaved extracellular component of e-cadherin is an N-terminal fragment NTF and this fragment is absorbed into the blood stream resulting in higher serum levels of NTFs of e-cadherin than healthy subjects as detectable using a commercial ELISA assay14 - see Fig 6 of attached poster presentation Since CTFs on Western blot of endoscopic biopsies and elevated NTFs of e-cadherin by ELISA in serum are a reflection of acid-injured esophageal epithelium this suggests the tantalizing possibility of a sensitive minimally invasive serum test for esophageal mucosal damage in the GERD subject We hypothesize that determination of either of the cleaved fragments of e-cadherin serum or tissue-based can discriminate between patients with acid-mediated heartburn who are likely to be PPI-responsive and those whose heartburn symptoms are not mediated by acid and so are PPI-refractory
The hypothesis will be tested by determining the presence or absence of CTFs of e-cadherin on esophageal biopsy and by measuring the level of NTFs of e-cadherin in serum of endoscopy-negative patients with heartburn and correlating the findings with the patients heartburn response to Kapidex 30 mg for 4 weeks Based on effective heartburn control on Kapidex or lack thereof patients will be classified as having PPI-responsive or PPI-refractory disease respectively and these classifications correlated with presence or absence of CTFs on pretreatment biopsy and pretreatment serum level of NTFs of e-cadherin Also after 4 weeks of Kapidex repeat serum specimens for NTFs are obtained from all treated patients to determine as a marker of healing whether the serum level of NTFs post-treatment are significantly lower than pretreatment serum level of NTFs in those that have PPI-responsive heartburn but not in those that have PPI-refractory heartburn
The results of this study are expected to show that patients with PPI-responsive heartburn have CTFs of e-cadherin in tissue and higher levels of NTFs of e-cadherin in serum at baseline and that these levels decrease after successful PPI therapy In contrast because symptoms in PPI-refractory subjects are not acid-mediated these subjects are expected to lack CTFs in tissue and to have lower levels of NTFs in serum at baseline compared to PPI-responsive patients and these levels will remain unchanged after PPI therapy Consequently such findings would establish detection of cleaved fragments of e-cadherin in tissue and blood as useful biomarkers of disease that can identify those with heartburn that are responsive to standard doses of Kapidex The results are also expected to show that patients with PPI-responsive heartburn but not those with PPI-refractory heartburn have a significant decline in the level of NTFs in serum post-treatment and that this lower level of NTFs is expected to fall within the range of controls Consequently such findings would establish that detection of serum NTFs before and after treatment can be useful as a biomarker of microscopic lesion healing in those with PPI-responsive heartburn Such findings might help select sub-groups appropriate for more intensive higher dose or long term PPI therapy
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None