The relevance of transient lower oesophageal sphincter relaxations in the pathophysiology and treatment of GORD

Abstract

Gastro-oesophageal reflux disease (GORD) is associated with the passage of gastric contents into the oesophagus resulting in potential oesophageal damage and impaired quality of life. GORD is a frequently encountered problem in today's population, with 25% of people in western populations reporting such symptoms at least once a month. Proton pump inhibitors (PPI) are the drug of choice, with surgery being employed in refractory cases. Although acid suppression is often effective, some patients remain symptomatic despite maximal PPI therapy. By delving into the mechanisms of the disease, it is clear that transient lower oesophageal sphincter relaxations are a key component of its pathophysiology. Research has demonstrated various therapeutic targets for reducing the frequency of such relaxations through GABA and glutamate modulation, for instance. This review highlights such modulations and hopes to explore these mechanisms and therapeutic targets in an area that will no doubt see a change in its pharmacological management in the near future.TRANSIENT LOWER OESOPHAGEAL SPHINCTER RELAXATIONS-MECHANISMS Transient lower oesophageal sphincter relaxations (TLOSR) account for 65% of reflux episodes. 1 2 They are vagally mediated by stretch receptor activation following stomach distension.3 Evidence for this has been provided, courtesy of the 5-hydroxytryptamine 1 agonist sumatriptan, which results in a higher frequency of TLOSRs and reduced gastric emptying. 4 During such relaxations, diaphragmatic crural contraction inhibition hinders the crural diaphragm pinch-cock effect around the sphincter. 5A variety of dietary factors increase the rate of TLOSRs, including chocolate, fats, alcohol and peppermint. 6 A study by Piche et al 7 analysed the effect of carbohydrates on colonic fermentation, and demonstrated an increase in the rate of postprandial TLOSRs most likely due to excess release of glucagon-like peptide 1. Obesity is also implicated in the pathogenesis of reflux disease and TLOSRs. Schneider et al 8 concluded that obese individuals have two-thirds more TLOSRs per hour than non-obese patients with diffuse oesophageal spasm, with the majority of TLOSRs being complete and isolated in nature. Kahrilas et al 9 demonstrated that the presence of a hiatus hernia is also associated with TLOSRs with frequency being directly proportional to the size of hernia. Posture might also play a role with the right recumbent position increasing the frequency of TLOSRs. 10The relevance of TLOSRs has long been underestimated. Kawahara et al 11 showed that in children if swallow induced lower oesophageal sphincter (LOS) relaxation-associated reflux was reclassified as, in fact, due to TLOSR, the number of reflux episodes attributed to TLOSR would rise from 58% to 81%.The basal LOS pressure is also relevant. TLOSRs can occur even at low LOS pressures (less than 5 mm Hg) and certainly some reflux episodes in this setting are due to TLOSR rather than a low basal pressure. 12Studies have also shown that the refluxate associat...