GORD-GASTROESOPHAGEAL

Relevance Of Transient LOS Relaxations In The Pathophysiology And Treatment Of GORD



Relevance Of Transient LOS Relaxations In The Pathophysiology And Treatment Of GORD

Gastro-oesophageal reflux disease (GORD), defined as the presence of symptoms or lesions that can be attributed to the reflux of gastric contents into the oesophagus, is one of the most common disorders affecting the gastrointestinal tract. Gastric acid is essential in the development of GORD and the duration of oesophageal acid exposure is a major determinant of the severity of reflux oesophagitis. This is the reason why proton pump inhibitors, with their strong acid suppressing action, have brought relief to the majority of these patients, although most GORD patients do not have increased gastric acid secretion. (Mattioli 2003:1650-2)

The pathophysiology of GORD is multifactorial, including alterations in the volume, composition, or distribution of gastric contents, anatomical and/or motor dysfunction of the antireflux barrier at the gastro-oesophageal junction, impaired clearance mechanisms, and defective resistance to injury at the mucosal level. Acid suppressive therapy addresses one of the pathophysiological mechanisms—that is, gastric acid volume—without affecting others such as the non-acid component of the gastric contents or the function of the antireflux barrier. In spite of the efficacy of acid suppressive therapy, there have been many attempts to target other aspects of GORD pathophysiology, such as basal lower oesophageal sphincter (LOS) pressure, oesophageal body motility, or gastric emptying. Unfortunately, most of these approaches have been clinically disappointing. (Hurwitz 2007:509-14)

The prerequisite for the development of acid reflux events is the occurrence of functional and/or anatomical failure of the antireflux barrier at the gastro-oesophageal junction. In healthy subjects and in patients with mild to moderate GORD, reflux occurs mainly during transient LOS relaxations (TLOSRs). TLOSRs are LOS relaxations not induced by swallowing, which occur mainly during the first two postprandial hours. In patients with more severe GORD and in those with a hiatal hernia, although TLOSRs account for the majority of reflux episodes, a greater proportion occurs during absent basal LOS pressure and swallow induced LOS relaxations. Transient LOS relaxations are a neural reflex, triggered mainly by distention of the proximal stomach and organised in the brain stem, with efferent and afferent pathways travelling in the vagus nerve, activating an intramural inhibitory neurone which releases nitric oxide to relax the LOS.Pharmacological intervention to reduce TLOSRs has been proposed as a non-surgical strategy to improve the antireflux barrier in patients with GORD, and several agents that inhibit the occurrence of TLOSRs were identified, including atropine, cholecystokininA receptor antagonists, morphine, and nitric oxide synthase inhibitors. However, an unfavourable pharmacological profile precluded clinical application of these agents. More recently, the gamma aminobutyric acid (GABA) receptor type B agonist baclofen was shown to inhibit TLOSRs, thereby significantly decreasing acid reflux after a meal in healthy controls. Inhibitory GABAB receptors are present at many levels of the vago-vagal pathway that organises TLOSRs. (Micci 2001:757-66)

In this issue of Gut, Zhang and colleagues demonstrated that acute administration of baclofen reduced the rate of TLOSRs and reflux events by approximately 40% in ...