The Influence of CYP2C19 Genetic Polymorphism and Dosage of Rabeprazole on the Accuracy of Proton-Pump Inhibitor Testing in Chinese Patients With Gastroesophageal Reflux Disease

INTRODUCTION A broad spectrum of symptoms are commonly associated with gastroesophageal reflux disease (GERD), which has an incidence of roughly 20% in the general population.[1] Despite recent, substantial advances in understanding GERD's pathogenesis, diagnosis still presents many challenges. A rapid symptomatic response to proton pump inhibitors (PPIs) in patients with a presumptive diagnosis of GERD is useful to validate diagnosis, which is known as the PPI test. Studies addressing diagnostic PPI testing have produced valuable estimates for Western populations regarding prediction of GERD in individual patients.[2][3][4] Some population-specific features distinguish Asian patients from their Western counterparts. First, the majority (75-90%) of Asian reflux patients have endoscopy-negative reflux disease (ENRD).[1][5] Not all of them demonstrate a favorable response to PPI treatment because the pathogenesis of ENRD is in part associated with psychosomatic pathways.[6][7] Second, PPIs are eliminated by a hepatic route, with a polymorphically expressed cytochrome P (CYP) 2C19 primarily responsible for the rate of metabolism.[8] Compared with people who have a homozygous wild-type genotype, people with a variant CYP2C19 allele exhibit lower rates of PPI degradation, higher plasma PPI concentrations (3-to-13 times higher), and a lesser degree of gastric acid secretion.[9] The prevalence of people who are poor metabolizers (i.e., have a homozygous variant genotype) has been cited as 1.2% to 3.8% for Caucasian-European populations, but 12.6% to 22.5% for Asian populations.[10] Lower gastric parietal cell mass is also prevalent in Asians. These characteristics may augment the therapeutic effect of PPIs in Asian patients.

When considering the pros and cons of PPI testing in an Asian population, the major pro is that there will be a high prevalence of poor or intermediate metabolizers who may have an increased serum level of PPI, resulting in a higher sensitivity, lower required dose of PPI, and less cost in testing. The con is mainly related to the increased proportion of ENRD patients. Up to 50% of ENRD patients, whose condition is termed functional heartburn, report sufficient heartburn relief with PPI treatment.[6][11] Therefore, a higher proportion of false positive cases may occur, which can lead to a decrease in test specificity.

The prediction of intra-esophageal damage is of paramount importance because patients with erosive and non-erosive disease have distinctive manifestations and prognosis.[12] Therefore, in this study, we tested the hypothesis that the PPI test can be used as a valid tool for diagnosis of esophagitis in a Chinese population. Validation of the accuracy of PPI testing would provide important information for comparison of diagnosis with the traditional endoscopy-first approach. We selected rabeprazole as the PPI test agent because it is well tolerated and can effectively prevent pathological and symptomatic GERD relapse.[13][14] Another potential benefit is that a variable proportion of rabeprazole degradation proceeds through a non-enzymatic pathway.[15][16] Thus, a decrease in inter-individual variability in serum PPI level may prove the rabeprazole-based regimen to be a diagnostic test with stable accuracy.

PATIENTS & METHODS Patients A consecutive series of patients with symptoms suggestive of GERD were enrolled from the Gastroenterology outpatient clinic in our institution. The typical GERD symptom was defined as heartburn and/or acid regurgitation of at least three episodes per week for a minimum of three months. Patients who received concurrent PPI treatment, had a medical contraindication to rabeprazole therapy, reported a history of peptic ulcer disease or gastrointestinal surgery, peptic ulcer disease or malignancy proven by endoscopy, the presence of alarm features (e.g., dysphagia, weight loss, bleeding, abdominal mass, and/or anemia), or who were unwilling or unable to provide informed consent were excluded from the study. Participants provided informed consent, and the Ethics Committee of National Taiwan University Hospital approved the study protocol prior to implementation (no. 940711).

Study Protocol All enrolled patients underwent an initial diagnostic evaluation with upper endoscopy and were classified with erosive or non-erosive disease. After endoscopy, patients in the two groups were randomly assigned to receive either one tablet of rabeprazole 20mg before breakfast or two tablets of rabeprazole before breakfast and dinner for 2 weeks. The random allocation was performed by choosing cards in sealed envelopes. Patient response to PPI treatment was recorded in a diary (illustrated below). Patients were notified about endoscopy results only at study completion.