Prevalence of CYP2C19 polymorphisms in medically and surgically managed patients with GERD

The medical therapy of gastroesophageal reflux disease relies predominantly on proton pump inhibitors, with surgery recommended for patients refractory to medical therapy and/or those with symptomatic hiatal hernias. Proton pump inhibitor plasma concentration, and thus the effectiveness and safety of proton pump inhibitors, are dependent on metabolism by cytochrome P450 2C19 (CYP2C19) in the liver. CYP2C19 polymorphisms and resultant enzyme activity influence plasma concentrations of proton pump inhibitors. For patients who are rapid metabolizers (2%-27% of patients) or ultrarapid metabolizers (<1%-5%) of proton pump inhibitors, dose escalation is recommended to obtain therapeutic benefit. Poor (1%-8%) or intermediate (20%-46%) metabolizers of proton pump inhibitors have increased drug effectiveness at lower doses but are at a higher risk of experiencing side effects. This study aimed to determine the prevalence of CYP2C19 phenotypes in medically and surgically managed patients. We hypothesized that surgical patients would have a higher prevalence of rapid and ultrarapid metabolizer phenotype, making them resistant to proton pump inhibitors compared with the medical patients.

This was a multisite retrospective cohort study of adult patients with CYP2C19 test results identified in their electronic health record from 2012 to 2023. The medically managed group included gastroesophageal reflux disease patients with positive pH testing, whereas the surgically managed group included patients who underwent antireflux surgery. CYP2C19 phenotypes were categorized as poor/intermediate, normal, or rapid/ultrarapid metabolizer. A positive pH test was defined as acid exposure time >6% or DeMeester score >14.7. Hiatal hernia size was classified as small, medium, or large based on imaging, endoscopy, and intraoperative findings. Descriptive statistics were used to characterize the metabolization status.

A total of 138 patients were included in this study: 58 medical patients (female: 59%, median age 62 years [interquartile range 46-68], 84% White) and 80 surgical patients (female: 66%, median age 61 years [interquartile range 53-67], 90% White). In the medical cohort, the mean acid exposure time was 15.3% and the median DeMeester score was 33 (21-69). The majority of medical patients were normal metabolizers (54%, n = 31). In the surgical cohort, 27% (n = 22) were poor or intermediate metabolizers, 30% (n = 24) were normal metabolizers, and 43% (n = 34) were rapid/ultrarapid metabolizers. Surgical patients had a higher prevalence of CYP2C19 rapid/ultrarapid metabolizer phenotypes compared with medical patients, 43% (n = 34) vs 24% (n = 14) (P = .02). Among patients with small- (n = 41) and medium-sized (n = 21) hiatal hernias, the majority were classified as rapid or ultrarapid metabolizer (39% and 57% with small and medium hernias, respectively), suggesting resistance to proton pump inhibitors. Additionally, surgical patients were significantly more likely to have medium- and large-sized hiatal hernias compared with medical patients (P < .01).

Surgical patients who underwent antireflux surgery had a higher prevalence of rapid/ultrarapid metabolizer CYP2C19 phenotypes compared with medical patients. These data suggest that proton pump inhibitor dose should be escalated in medical patients with these phenotypes, and if ineffective, a timely referral should be made for surgical management. This is one of the first studies assessing the pharmacogenomic CYP2C19 test in adult patients with gastroesophageal reflux disease. CYP2C19 testing has immense potential to optimize medical and surgical management of patients with gastroesophageal reflux disease, and prospective multisite studies are needed to confirm utility of the test.