trigger gastro-esophageal reux; however, this does not occur in healthy individuals with an intact reux barrier because LES pressure increases during MMC III contractions [23].

ous mediates EGJ relaxation via the vagal efferent bres [10].

2. Swallow-induced LES relaxations. In health about 5–10% of reux episodes

4s before and 2s after the onset of LES relaxation and prolonged duration of LES relaxation lasting more than 10s with concurrent inhibition of the crural diaphragm. The introduction of combined high-resolution impedance manometry (HRiM) sup­ports this observation by direct detection of EGJ relaxation, opening and retrograde ow of gastric contents (i.e. reux) during TLESRs (and other events) [37, 38]. It is also possible to discriminate between reux of air (belching) and gastric secretions based on the impedance proles [37, 38].

After a reux episode occurs, the reuxate is cleared most often by a primary peri­staltic contraction that also neutralizes acid by bringing saliva from the mouth [41]. In many GERD patients, esophageal motor function is preserved; however, ineffec­tive esophageal motility (IEM) can impair esophageal clearance and is associated with increased likelihood of esophagitis [26, 42, 43]. The spectrum of IEM consists of fragmented peristalsis, hypotensive peristalsis and absent contractility (all can be observed in the same patients). Patients with more severe disease are characterized by a failure to respond to the physiologic challenge of multiple repeated swallows or the solid swallows (absent “contractile reserve”). It is the frequency of ineffective esophageal contractions after reux events that impacts on esophageal clearance and the severity of acid exposure [44, 45].

and crural diaphragm) which favors reux [4]. Other hypotheses include the release of metabolic and humoral mediators from visceral adipose tissue that have effects on vagal activity and may well impact on the frequency of TLESRs and other key aspects of EGJ function [50–52]. Of interest, although obese subjects complain of heartburn and acid regurgitation more frequently than normal weight controls, [46] this effect is weaker than that expected and many obese subjects with GERD have only mild or occasional reux symptoms. This lack of sensitivity and failure to seek treatment could, in part, explain the relatively high risk of GERD complications, including adenocarcinoma, in this group.

In patients with a small hiatus hernia, separation of the LES and crural diaphragm results in a twofold increase in reux events [19] and the risk of GERD increases with the size of the hiatus hernia [3, 53, 54]. The presence of a hiatus hernia has multiple effects on EGJ structure and function.First, the wide esophageal hiatus impairs the ability of the crural diaphragm to contribute to reux protection [55]. Indeed, in HRM studies, reduced augmentation of EGJ pressure during inspiration is an independent risk factor for GERD [56]. Second, contraction of the crural dia­phragm can trap gastric contents in the hiatal sac that can then pass into the esopha­gus through the (weak) LES due to negative thoracic pressure during inspiration [55]. Third, the frequency of reux events of all kinds is increased in patients with hiatus hernia [53, 54] due to mechanical effects on EGJ and proximal gastric func­tion. Whilst TLESR remains an important cause of reux events in this patient group, other mechanisms appear to be more important in the presence of a hiatus hernia [57]. Additionally, once reux has occurred, ineffective esophageal motility and impaired esophageal clearance are common in patients with a large hiatus her­nia [58, 59]. This results in prolonged exposure of the distal esophagus with acid gastric secretions that are thought to be a major cause of reux esophagitis, Barrett esophagus and other complications; all of which are more common in GERD patients with hiatus hernia than those without.

In health and in many patients with mild-moderate GERD separation of the intrinsic (LES) and extrinsic (crural diaphragm) components of the EGJ reux bar­rier is not constant but occurs intermittently [62]. HRM studies identify this spatial dissociation of the intrinsic LES and diaphragmatic sphincter, as a double peak pressure prole at the EGJ [63]. HRM provides a more prolonged and detailed analysis of EGJ pressure and this increased spatial and temporal resolution has excellent sensitivity and specicity for hiatus hernia [61]. Compared to barium uo­roscopy or endoscopy which each have a sensitivity of 73% for detection of a hiatus hernia, the sensitivity and specicity of HRM for hiatus hernia detection was 92% and 93% respectively [61].

Advances in esophageal motility diagnostic tests have provided further insights into the anatomy and function of the EGJ reux barrier [68–70]. Unlike “conven­tional” esophageal manometry systems with up to 12 pressure sensors, HRM sys­tems acquire pressure measurements from closely spaced sensors and display this information as topographic (Clouse) plots that integrate time, position and pressure data. Assessment of esophageal motility by the Chicago Classication for HRM is based on objective metrics derived from these measurements [64]. The intraluminal pressure at the EGJ is referenced to the intra-gastric pressure in clinical studies. The presence of adequate resting pressure provides an indication of resistance to retrograde ow of gastric content across the reux barrier. As discussed above, the intact EGJ barrier consists of superimposed LES and CD.The intrinsic LES can independently have a low resting tone, with values <8mmHg during the end expi­ratory phase consistently abnormal [56, 64]. Inspiratory augmentation of the CD provides adjunctive barrier function when intrathoracic pressures are at their low­est; [71] an element of the EGJ barrier that is not well assessed by basal and end expiratory LES pressure measurements. The EGJ contractile integral (EGJ-CI) may overcome these drawbacks by combining EGJ anatomy, basal tone, and varia­tion with respiration into a single metric assessing vigor of the EGJ [72, 73]. A further improvement can be achieved by calculating the “total-EGJ-CI”, a param­eter that summarizes EGJ barrier function during the entire HRM protocol compen­sating for variation in morphology and pressure over time [74]. Normative EGJ-CI and total EGJ-CI values have been described, and available data indicate that the risk of GERD is increased in the setting of abnormal results [74, 75]. Notwithstanding this nding, GERD has a complex aetiology and the ability of any measurement of EGJ function to provide a denitive GERD diagnosis is limited (although a robustly normal value may rule GERD out) [74]. Therefore, an abnormal EGJ barrier can be hypotensive (with reduced resting tone that can be overcome by events that increase intra-abdominal pressure), disrupted with separation of the two components of the EGJ barrier (i.e. hiatus hernia) or both. In the presence of a hiatus hernia, the rest­ing tone of the intrinsic LES is typically hypotensive, with esophageal reux bur­den higher than with either abnormality alone. Therefore, abnormalities of EGJ structure and function can coexist, and both can contribute to abnormal reux burden.

The metrics described above have been shown to predict reux outcome when testing is performed off PPI therapy in unproven GERD [91, 92]. In the clinical set­ting, the results provide guidance as to whether reux management should continue (if pathological reux is identied) or if alternate mechanisms should be sought for persisting symptoms. However, as discussed above, thresholds dening pathological from physiological reux burden are not precise, and a ‘grey area’ exists (“borderline reux burden”) where the clinical presentation and alternate evidence from physio­logical investigations (HRM, pH-impedance studies) could complement ambulatory reux monitoring ndings to support or reject GERD [85, 95] diagnosis. Reux hypersensitivity is dened by a positive symptom-reux association in the setting of physiologic reux, is part of the GERD spectrum and can respond to optimal acid and reux suppression therapy. In contrast, functional heartburn or functional chest pain is dened by normal ambulatory reux monitoring with negative symptom reux association and are functional conditions that are not caused by reux events.

There is limited research available describing prediction of outcomes of therapy based on manometry studies including EGJ morphology and esophageal motor func­tion; however, the purpose of this investigation is not to diagnose GERD but to exclude a major motility disorder, rumination syndrome and similar conditions. Using ambulatory reux monitoring, pathologic AET is a predictor of outcome from both medical and surgical antireux therapy [91, 92]. Within abnormal AET cohorts, those with positive symptom reux association have the highest likelihood of