Heartburn – Underlying Mechanisms David Armstrong, MA, MB BChir, FRCPC, FRCP(UK) Division of Gastroenterology & Farncombe Family Digestive Health Research Institute, McMaster University Hamilton, Ontario Canada Heartburn is the cardinal symptom of GERD, particularly in developed, Western countries (1); however, heartburn is not synonymous with GERD (2). Heartburn can occur, for a variety of reasons, in the absence of gastroesophageal reflux (GER) or GERD and, conversely, GER or GERD may exist in the absence of heartburn or, indeed, other symptoms. To understand the mechanisms underlying heartburn, one must appreciate how the esophagus is exposed to refluxed gastric contents, how gastric refluxate may cause heartburn and other symptoms and how other mechanisms may cause reflux-like symptoms. Gastroesophageal Reflux In health, the reflux of gastric contents into the esophagus is prevented or minimized by the anti-reflux barrier which comprises the combined effects of the lower esophageal sphincter (LES), the crural diaphragm and the ‘flap valve’ effect of the angle of His at the gastroesophageal junction (3). It is worth noting that the reflux of gastric contents into the esophagus is a normal phenomenon in that esophageal acid exposure, measured 5 cm above the LES, is considered to be normal if esophageal pH is below 4 for less than 4% (55-60 minutes) of a 24-hour recording (4). Pathogenesis of Gastroesophageal Reflux Disruption of the anti-reflux barrier can occur if the neuromuscular function of the LES is impaired or if the anatomical location of the LES changes relative to the crural diaphragm. If LES function is impaired, the sphincter opens inappropriately or fails to close appropriately, allowing gastric contents to reflux into the esophagus. If the LES is located proximal to the crural diaphragm, the combined effects of the LES and the diaphragm are separated and, furthermore, the musculo-mucosal flap valve at the angle of His is effaced or reduced. The LES is a ring of smooth muscle that extends 3-4 cm across the gastro-esophageal junction (GEJ) at the level of the diaphragmatic hiatus, encircled by the crural diaphragm. The location of the LES, relative to the diaphragm, is maintained by the phrenoesophageal ligament which can accommodate positional changes that occur with swallow-induced esophageal shortening and with diaphragmatic movements during breathing, coughing and physical exertion. Disruption of the phreno-esophageal ligament allows the gastroesophageal junction to move proximally, into the chest, leading to formation of a hiatus hernia. Lower esophageal sphincter The LES is, normally, tonically-contracted with a resting pressure that is 10-30 mm Hg above intragastric pressure. Basal LES pressure (LESP) is dependent on both intrinsic, myogenic factors and extrinsic, neural factors; variations in LESP can be caused by a variety of factors including food, medications, gastric distension, raised intra-abdominal pressure and neuro-hormonal factors. Marked reductions in resting LESP may play a role in GER and GERD but reflux episodes are rare despite short duration increases in intra-abdominal pressure if the resting LESP is greater than 10 mm Hg and ‘free reflux’, that occurs in the absence of increased intragastric pressure, is rare if the resting LESP is greater than 5 mm Hg. The effect of reduced basal LESP is exacerbated if there is a co-existing hiatus hernia. Relaxations of the LES occur commonly and appropriately to allow transit of a swallowed bolus into the stomach; these relaxations are not, generally, associated with GER. In addition, swallowindependent, transient LES relaxations (TLESR), occur about 3 to 6 times per hour, triggered by gastric distension; TLESRs are thought to allow physiological venting or decompression of the stomach and may be associated with audible belching. TLESRs are identifiable by esophageal manometry as a rapid decrease in LES pressure that is not triggered by swallowing; they are mediated by a vago-vagal reflux starting with activation of proximal gastric receptors which relay signals, via afferent sensory vagal fibres to the nucleus tractus solitarius (NTS) and, thence, to the dorsal motor nucleus (DMN) of the vagus nerve. These areas coordinate activity of the LES and the crural diaphragm which are innervated by the vagus and phrenic nerves, via the myenteric plexus of the esophagus and LES. The modulation of TLESRs is affected by a variety of neurotransmitters including acetyl choline, CCK, opioids, cannabinoids, nitric oxide, gamma-aminobutyric acid (GABA) and glutamate. Especially when accompanied by inhibition of the crural diaphragm, TLESRs are the major mechanism associated with episodes of GER although TLESRs occur with comparable frequency in GERD patients and healthy subjects; this suggests that other factors, such as the pressure gradient across the LES or the compliance of the GEJ, are important in permitting the occurrence of GER. TLESRs terminate with the onset of secondary or, less commonly, primary esophageal peristalsis. Crural diaphragm The esophagus passes from the thorax to the abdomen via the esophageal hiatus in the diaphragm; the right crus of the diaphragm encircles the LES and, provided that there is no hiatus hernia, it contracts at the level of the LES to augment the anti-reflux barrier during inspiration. In health, the LES is maintained in position, relative to the diaphragm, by the phreno-esophageal ligament; disruption of the phreno-esophageal ligament predisposes to an esophageal hiatus hernia with migration of the LES proximally, into the thoracic cavity. Hiatus hernia The role of the hiatus hernia in facilitating GER has been recognized, anew, over the last 15-20 years as studies with newer manometric techniques have demonstrated two contributors to the GEJ pressure zone: the LES and the crural diaphragm. The contribution of the crural diaphragm and flap valve to the anti-reflux barrier is World Digestive Health Day WDHD May 29, 2015 WGO HANDBOOK HEARTBURN: A GLOBAL PERSPECTIVE 9
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