Heartburn – Underlying Mechanisms, continued impaired by the development of a hiatus hernia, consistent with research demonstrating that esophageal acid exposure, esophagitis severity and the prevalence of Barrett’s epithelium are all greater if a hiatus hernia is present. Impaired coordination or summation of the effects of the LES and the crural diaphragm are such that reflux in patients with hiatus hernia is associated, to a greater extent, with swallowing, straining and a low basal LES pressure. Gastric emptying Delayed gastric emptying does not appear to be a major etiological factor in GERD although a proportion of GERD patients demonstrated slow emptying of the proximal stomach, possibly in relation to dietary or obesity-related factors; it is speculated that this may predispose to an increased propensity for GER or to changes in the position of the ‘acid pocket’, an area of increased acidity located on top of other gastric luminal contents. Heartburn Heartburn was defined, in the Montreal Definition and Classification of GERD, as a ‘burning sensation in the retrosternal area (behind the breastbone)’ (1) because the term ‘heartburn’ has not been recognized or defined in a standard fashion across the world. Heartburn and regurgitation (the perception of flow of refluxed gastric content into the mouth or hypopharynx) were, further, defined as the characteristic symptoms of the typical reflux syndrome although it was acknowledged that other symptoms, such as epigastric pain or dyspepsia, are also, commonly, indicative of GERD. Furthermore, although GER is the most common cause of heartburn, refluxed gastric acid is not the only cause and, in addition to non-acid refluxate, other non-reflux-related causes have been implicated, including inflammation and dysmotility of the esophagus, ingested materials and esophageal hypersensitivity. Pathogenesis of Heartburn Heartburn, as the characteristic symptom of GER and GERD, is thought to occur because the esophageal epithelium is exposed to refluxed gastric content and, particularly, to refluxed gastric acid. In a high proportion of symptomatic individuals, heartburn is ameliorated by therapy that neutralize refluxed acid or reduce acid reflux by decreasing gastric acid secretion (5,6), suggesting that it is acid-mediated symptom. However, esophageal acid exposure, measured by intra-luminal pH-metry, is not as well-correlated with heartburn as it is with reflux-related esophageal injury such as erosive reflux esophagitis or Barrett’s esophagus. This may be due, in part, to the fact that the pH electrode is placed, by convention, 5 cm above the LES; in consequence, if the proximal extent of the refluxed gastric acid is distal to the electrode, the patient may report symptoms in the absence of any detectable reflux. In addition, symptoms are more common if the reflux episode extends more proximally, if it is longer or if there is a greater degree of prior acid exposure. These observations do not, however, prove that it is acid which causes symptoms; for example, GER includes pepsin which is active in an acidic environment, below pH 4, and it may be pepsin, rather than acid which causes symptoms. Regardless of what causes the symptoms, it is not clear how symptoms are generated. Intuitively, one might expect GER symptoms to occur the sub-epithelial layers are exposed to luminal acid because of ‘mucosal breaks’ or erosions; however, if this is the case, one must determine why at least half of individuals with GERD have NERD (non-erosive reflux disease) and why an appreciable proportion of patients with erosions do not report symptoms. It has been proposed that symptoms occur due to functional disruption of the epithelial barrier demonstrable as dilated intercellular spaces (DIS) which are a marker of compromised intercellular tight junctions and a consequent loss of a barrier which should, in health, prevent acid and other noxious molecules from activating chemosensitive nociceptors in the sub-epithelial layers (7,8). DIS are triggered, not only, by luminal acid but, also, by pepsin in an acidic environment, by bile acids and by other systemic factors such as cytokines; thus, DIS may be a non-specific response to injury that does not, necessarily, cause symptoms. As in other parts of the gastrointestinal tract, esophageal symptoms may indicate local, visceral hypersensitivity leading to a heightened perception of various luminal stimuli. The underlying mechanisms may be central or systemic, mediating the documented effect of stress on patients’ perception of heartburn. It is, also, possible that heartburn, whether reflux-related or functional, may be due to up-regulation of nociceptors such as TRPV1, a transient receptor potential (TRP) channel, acid-sensitive ion channels (ASIC) or ionotropic purinergic receptors (P2X) (8). Esophageal symptoms have also been linked to other abnormalities, including sustained esophageal contractions (SEC) observed in the longitudinal muscle layer (9) and esophageal inflammation, diagnosed increasingly commonly, in eosinophilic esophagitis. Summary There are multiple mechanisms underlying the pathogenesis of gastro-esophageal reflux disease and its characteristic symptom, heartburn. Heartburn is a symptomatic manifestation of refluxed gastric contents that elicit responses from esophageal nociceptors. The frequency, duration and severity of patients’ heartburn are correlated, to some extent, with esophageal acid exposure and, in a large proportion of GERD patients, therapeutic reduction in esophageal acid exposure is associated with a marked reduction in heartburn. However, it is possible that other refluxed gastric contents, in addition to acid, may cause heartburn just as some foods and drinks can cause retrosternal burning symptoms, en route to the stomach. Furthermore, there are other central and local mechanisms that may cause or contribute to heartburn, some by sensitizing the esophagus to apparently normal degrees of reflux and others by eliciting nociceptive responses in the absence of GER. An understanding of the multiple mechanisms underlying GER and heartburn is an important basis for managing GERD in view of the fact that symptom-based diagnosis of GERD has limited sensitivities and specificities of 62-67% and 63-70%, respectively (2). World Digestive Health Day WDHD May 29, 2015 WGO HANDBOOK HEARTBURN: A GLOBAL PERSPECTIVE 10
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