Symptomatic reflux disease: the present, the past and the future

Abstract

The worldwide incidence of GORD and its complications is increasing along with the exponentially increasing problem of obesity. Of particular concern is the relationship between central adiposity and GORD complications, including oesophageal adenocarcinoma. Driven by progressive insight into the epidemiology and pathophysiology of GORD, the earlier belief that increased gastroesophageal reflux mainly results from one dominant mechanism has been replaced by acceptance that GORD is multifactorial. Instigating factors, such as obesity, age, genetics, pregnancy and trauma may all contribute to mechanical impairment of the oesophagogastric junction resulting in pathological reflux and accompanying syndromes. Progression of the disease by exacerbating and perpetuating factors such as obesity, neuromuscular dysfunction and oesophageal fibrosis ultimately lead to development of an overt hiatal hernia. The latter is now accepted as a central player, impacting on most mechanisms underlying gastroesophageal reflux (low sphincter pressure, transient lower oesophageal sphincter relaxation, oesophageal clearance and acid pocket position), explaining its association with more severe disease and mucosal damage. Since the introduction of proton pump inhibitors (PPI), clinical management of GORD has markedly changed, shifting the therapeutic challenge from mucosal healing to reduction of PPI-resistant symptoms. In parallel, it became clear that reflux symptoms may result from weakly acidic or non-acid reflux, insight that has triggered the search for new compounds or minimally invasive procedures to reduce all types of reflux. In summary, our view on GORD has evolved enormously compared to that of the past, and without doubt will impact on how to deal with GORD in the future.

Figure 1

Schematic presentation of epidemiological trends in GORD-related disorders. While typical GERD symptoms are balanced between comparator groups, the distribution of complications becomes progressively skewed in gender, geographic and racial distribution. *GORD symptoms are similar between Western and Middle Eastern countries, but are lower in Eastern countries.

Figure 2

Age-adjusted incidence rates of oesophageal adenocarcinoma for men and women in 1998–2002 in several regions. Reference population is world standard population (2000).

Figure 3

Model of GORD pathogenesis, conceptualising the progressive development of reflux manifestations with the progressive degradation of physiological defence mechanisms. With the accumulation of these ‘hits’ physiological reflux in transformed into pathological reflux manifest either symptomatically and/or with mucosal disease. Abdominal obesity plays a dominant role with its effect mediated through progressive degradation of the oesophagogastric junction (OGJ) culminating in the development of overt hiatus hernia.

Figure 4

Summary of proton pump inhibitor (PPI) efficacy for various GERD syndromes as assessed in randomised controlled trials. In each case, data among trials are averaged to derive estimates of placebo effect and therapeutic gain, defined as the degree to which PPI therapy improved upon the benefit seen with placebo. The blue segments represent the placebo effect and the green arrows the therapeutic gain beyond the placebo effect seen with PPIs. PPI data are grouped in terms of brand and dose, taking some liberties for simplification. However, it is imperative to recognise that the only disease manifestation in which a dose-response curve has been convincingly demonstrated by randomised controlled trial is in healing esophagitis. At the other extreme, in the case of asthma, controlled trial data are sparse and largest trial, in fact, showed the placebo response to be insignificantly better that the PPI. Modified from Kahrilas et al 2012.

Figure 5

pH-impedance monitoring allows identification of subgroups of patients with symptoms that are suspected to be caused by reflux. Based on presence or absence of excessive reflux and presence or absence of a temporal association between symptom events and reflux episodes four phenotypes can be identified. The likelihood of a favourable response to antireflux therapy, by inhibition of acid secretion or otherwise, differs among the groups. Patients whose symptoms are not reflux-related (phenotypes 3 and 4) are unlikely to respond to any type of antireflux treatment.