Can E-cadherin Found in Tissue/Blood be Valuable in Identifying & Monitoring Patients With Post-proton Pump Inhibitor (PPI)-Responsive Heartburn
Condition: Heartburn; Gastroesophageal Reflux Disease
MeSH terms: Gastroesophageal Reflux; Heartburn
Study type: Interventional
Phase: Phase 1

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, e.g. functional disease, visceral hypersensitivity or activation of
      esophageal stretch receptors. Consequently these subjects fail to respond to PPIs[1-3]. 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 microscopy[4-7]. 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 epithelium[8].
      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 GERD[9]. E-cadherin is a
      protein which forms the intercellular adhesive bridge of the zonula adherens (ZA)[10]; 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 permeability[11,12]. 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 mucosa[13].

      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, i.e. 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 disease[14] - 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
      assay[14] - 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 patient's
      (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.
    

Intervention name(s): Dexlansoprazole
Intervention type(s): Drug
Intervention description(s): Dosage: 30 mg once per day for 4 weeks by mouth
Other intervention name(s): Kapidex
Intervention MeSH terms: Dexlansoprazole; Lansoprazole
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Heartburn; Gastroesophageal Reflux Disease