Pathogenesis of gastro-oesophageal reflux disease and novel options for its therapy

The definitive version may be found at www.wiley.comBetter understanding of the mechanisms that lead to reflux disease is an important area for future research, given the very high prevalence of this problem. During the lifetime of this journal, much has been learnt about the pathophysiology of reflux disease. Abnormally, frequent acid reflux plays a key role in pathogenesis: this reflux occurs predominantly during transient lower oesophageal sphincter relaxations. Analysis of the literature suggests that the importance of transient relaxations as the major permissive event for occurrence of acid reflux is currently substantially underestimated. 'Transient relaxation' is an inexact descriptor, as this motor programme includes inhibition of the diaphragmatic hiatus and distal oesophageal body circular muscle and contraction of the oesophageal longitudinal muscle. Laxity of the diaphragmatic hiatus and hiatus hernia are probably important factors that increase the probability for acid reflux to occur during transient relaxations and in allowing strain-induced reflux episodes. The importance of straining and low basal tone of the lower oesophageal sphincter in causing abnormal reflux has probably been overestimated, but these need more investigation. High resolution manometry is the key method for acquisition of important new insights into the normal and disordered mechanics of the antireflux function of the gastro-oesophageal junction, but as yet, the potential of this technique has been tapped relatively little. In the future, improved understanding of the mechanics of the gastro-oesophageal junction should lead to improved physical antireflux procedures. Much progress has been made in defining the control of transient relaxations and this has been translated into several promising options for a new class of drug that treats reflux disease by inhibition of transient relaxations. Clinical trials on these agents appear imminent.J. Den

Transient lower esophageal sphincter relaxations (TLESRs) are the major mechanism of gastroesophageal reflux but are not the cause of reflux disease

In healthy subjects, the rate of acid reflux during transient lower esophageal sphincter relaxations (TLESRs) is more frequent at the proximal margin of the LES. In this study, we investigated the hypothesis that the rate of acid reflux at the proximal margin of LES during TLESRs is similar in reflux disease to that in healthy subjects. Concurrent esophageal manometry and pH monitoring were performed in the sitting position for 3 hr after a standard meal in 10 patients with reflux disease and 10 age-matched healthy controls. The rate of TLESRs in patients with reflux disease (5.0/hr [3.3-6.7]; median [interquartile range]) was similar to that of controls (4.5/hr [3.7-5.7]). The incidence of acid reflux 7 cm above the LES during TLESRs in patients (48.1% [27.2-71.4%]) was significantly higher than that in controls (10.9% [0.0-18.8%]) but there was no difference 2 cm above the LES (75.0 [69.2-87.5] vs. 74.3 [55.5-90.0%]). The rate of TLESRs and the incidence of acid reflux during TLESRs are not increased in reflux disease. These findings, therefore, indicate that reflux disease is not a disorder of TLESRs and relates more to the proximal extent of the refluxate