Histology of Symptomatic Gastroesophageal Reflux Disease

Is It Predictive of Response to Proton Pump Inhibitors?

Hiroto Miwa; Kaiyo Takubo; Tomohiko Shimatani; Takahisa Furuta; Tadayuki Oshima; Junji Tanaka; Junko Aida; Masanori Ito; Susumu Kurosawa; Takashi Joh; Tsuneya Wada; Yasuki Habu; Yusuke Watanabe; Michio Hongo; Tsutomu Chiba; Yoshikazu Kinoshita


J Gastroenterol Hepatol. 2013;28(3):479-487. 

In This Article

Abstract and Introduction


Background and Aim: To examine the differences in esophageal histopathology between non-erosive reflux disease (NERD) and reflux esophagitis (RE), and to investigate whether baseline esophageal histopathology can predict the therapeutic response to proton pump inhibitors (PPIs).

Method: The subjects comprised 94 patients with NERD (n = 71) or mild RE (n = 23). Tissue was biopsied from 5 cm above the squamo-columnar junction (SCJ), and the degree or presence of nine histopathological markers was assessed. The patients were treated with rabeprazole (RPZ) 10 mg once daily for 4 weeks. If complete heartburn relief was not achieved, RPZ was increased to 10 mg twice daily for another 2 weeks, and then to 20 mg twice daily for another 2 weeks if heartburn remained.

Results: Features of esophageal histopathology 5 cm above the SCJ differed between NERD and RE patients. The esophageal histopathology in patients unresponsive to RPZ was characterized by Protein Gene Product (PGP) 9.5 negativity in those with NERD, and intraepithelial bleeding in those with RE. In addition, the combination of dilated intercellular spaces (DIS) (+)/PGP 9.5 (−) was indicative of strong resistance to PPI therapy in NERD patients.

Conclusion: The therapeutic efficacy of PPI can be predicted from the features of biopsied esophageal tissue. Factors predictive of resistance to treatment with PPI are negativity for PGP 9.5 in NERD patients and intraepithelial bleeding in RE patients.


Patients with gastroesophageal reflux disease (GERD) have been increasing in number in recent years.[1] GERD is commonly treated with proton pump inhibitors (PPIs), but a high proportion of patients show no response.[2,3] Cases of GERD in which the symptoms cannot be relieved by PPI therapy are an important medical concern. Because about 20% of patients with reflux esophagitis (RE) and about 50% of patients with non-erosive reflux disease (NERD) do not respond to PPI therapy,[4] it is desirable to obtain information on whether PPI therapy would be effective or ineffective in individual patients before the start of therapy, especially for those with NERD. In other words, it would be desirable to identify non-responders to PPI before starting the therapy. Nocturnal gastric acid breakthrough (NAB),[5] gene polymorphism of CYP2C19 (extensive metabolizer),[6] esophageal reflux of duodenal fluid,[2] female gender, and poor treatment compliance have been noted as factors associated with resistance to PPI therapy. However, no previous study has investigated whether histopathological findings in the esophagus are predictive of resistance to PPI treatment.

It has been reported that GERD patients show changes in various esophageal histopathological parameters,[7–9] and in recent years, consensus guidelines for histological recognition of microscopically evident esophagitis in patients with GERD have been formulated.[10] These parameters include an increased eosinophil count, intrapapillary blood vessel dilatation, intraepithelial bleeding, papillary extension, basal cell hyperplasia (thickening), dilated intercellular spaces (DIS), enhanced cellular proliferation, appearance of Langerhans cells, and hyperplasia of nerve fibers. However, no study has compared differences in esophageal histopathological findings between patients with NERD and those with RE. We therefore examined differences in esophageal histopathology between these patient groups, and investigated whether the pathological features of esophageal biopsy samples obtained before the start of treatment could predict the therapeutic efficacy of PPI.

This investigation was conducted as part of the TORNADO (Treatment with high dose Of Rabeprazole for NERD patients conducted by AciD-related symptOm research group) study.[11]