Pathophysiology and investigation of gastro-oesophageal reflux disease

The oesophagogastric junction

The OGJ is the principle antireflux barrier consisting of the lower oesophageal sphincter (LOS) and the crural diaphragm (CD), which are superimposed in health. The smooth muscles of the LOS are semi-circular fibres that form clasps around each other and bridge the gastric sling fibres, whereas the skeletal muscles of the CD form the external part of the antireflux barrier where the oesophagus passes through the right crus of the CD. Both the LOS and CD have an asymmetric pressure profile with inspiration producing a greater increase in OGJ pressure toward the greater curvature of the stomach, and the peak LOS pressure correlates with the maximum muscle thickness found on the greater curve where the gastric sling fibres are most dense.

Reflux can occur when intragastric pressure exceeds the resting LOS pressure, forcing gastric contents up into the oesophagus. A hypotensive LOS is common in patients with GORD, but paradoxically, a hypertensive LOS in GORD is not uncommon. Therefore, low LOS pressure cannot be the sole mechanism for reflux. When intragastric pressure increases, a ‘yield’ pressure is reached which triggers a transient lower oesophageal sphincter relaxation (TLOSR). This is a normal reflex mediated via vagal afferents, but if this reflex is hypersensitive, yield pressures are reduced and TLOSRs are triggered too frequently and are thought to have a stronger correlation with GORD than hypotensive LOS pressure. Both LOS pressure and TLOSRs can be defined on high-resolution manometry (HRM) where the LOS pressure is < 10 mmHg (software dependant), and TLOSRs are LOS relaxations lasting greater than 10 seconds in the absence of swallowing and are associated with CD inhibition.

TLOSRs are triggered by pharyngeal intubation, meal ingestion, upright posture, smoking, and hyperglycaemia, although the primary trigger for TLOSRs is thought to be gastric distension following meals or aerophagia (excessive air swallowing). Gastric accommodation is the physiological response to gastric distension, which serves to offset a rise in intragastric pressure during meal intake. In patients with GORD and healthy controls, smaller changes in intragastric pressure (i.e. poor gastric accommodation) lead to an overall increased presence of TLSORs. Hence, gastric accommodation likely plays a role in TLOSRs via mechanoreceptor signalling from the gastric wall. Moreover, this may explain why GORD frequently overlaps with conditions related to poor gastric accommodation, namely functional dyspepsia and gastroparesis.

Delayed gastric emptying may contribute to increased TLOSRs since prolonged retention of contents leads to prolonged distension. Other gastric factors include cholecystokinin (CCK), which has been shown to induce a period of partial relaxation followed complete lower oesophageal sphincter (LOS) relaxation along with CD inhibition. When nutrients enter the duodenum, CCK is released and prevents further emptying of the stomach. It should be noted that TLOSRs do have a physiological purpose, to allow gas venting from the stomach, whether that gas is ingested from air swallowing or carbonated drinks, or created by fermentation in the gut: excessive fermentation of poorly digested carbohydrates in the colon is associated with increased TLOSRs.

Hiatal hernia

The OGJ antireflux barrier may become jeopardized following separation of the LOS and CD, resulting in a hiatal hernia (HH). This is a fundamental finding in GORD, and HH is associated with the presence and severity of oesophagitis, increased oesophageal acid exposure, and reflux episodes, but not increased TLSORs. Instead, reflux episodes are increased during periods with low LOS pressure, straining, swallowing, and deep inspiration, which highlights the importance of the CD in protection against reflux. Impaired CD function can be assessed on HRM by inspiratory augmentation of OGJ pressure, and one study found that 37 out of 39 subjects with inspiratory augmentations of OGJ ≤ 0 mmHg had objectively pathological GORD. This was the strongest predictor of GORD, even more so than LOS pressure and LOS-CD separation.

The prevalence of a HH is associated with increased age but the aetiology remains unclear. It is thought that repetitive elevation of intragastric pressure may force the hiatus upwards, or alternatively, age-associated myopathy may play a role. HHs are seen in up to 40% of obese individuals, which supports the theory of increased gastric pressure. Furthermore, bariatric surgery can lead to increased intragastric pressure, namely sleeve gastrectomy and gastric band, for which worsening or new-onset GORD is more common compared to Roux-en-Y bypass.

A HH can also promote reflux via an acid pocket where part of the stomach is positioned above the diaphragm. This stomach portion generates acid, particularly following meals, which can then pool and reflux more easily into the oesophagus. Healthy controls were shown to also have an unbuffered acidic segment in the proximal stomach; however, this is typically below the squamocolumnar junction (SCJ) whereas the acid pocket in patients with GORD and HH lies above the diaphragm.

Oesophageal body

Defects in peristalsis may lead to impaired clearance of gastric refluxate and prolonged acid exposure. Indeed, hypomotility is common in GORD, but the cause and effect as to whether reflux causes hypomotility or vice versa is uncertain. Fundamentally, oesophageal peristalsis is required to counteract refluxate and this can be primary (swallow induced) or secondary (triggered by distension). Reflux elicits distension of the oesophageal lumen via activation of stretch receptors in the oesophageal wall, which triggers secondary peristalsis and volume clearance. However, this is not sufficient to neutralise acid. On the other hand, swallow-induced primary peristalsis contains bicarbonate saliva necessary to achieve chemical clearance and pH normalisation.

Reflux oesophagitis

The traditional paradigm of GORD complications is that acid directly erodes the oesophageal mucosa leading to inflammation, oesophagitis, and more rarely, dysplasia. Noxious refluxate containing acid, pepsin, and bile salts is thought to damage the tight junction proteins between cells, such as claudins, occludins, and E-cadherin. This leads to greater diametric separation between cells known as dilated intercellular spaces (DISs). DISs are seen in up to 100% of patients with erosive oesophagitis and up to 83% of patients with non-erosive reflux disease (NERD), and DISs reduce following proton pump inhibitor (PPI) therapy. However, up to 30% of healthy controls have DISs as well as patients with NERD who are refractory to PPI. Persistence of DISs may be consequent to bile acid or, indirectly, animal studies have shown that psychological stress induces DISs.

Overall, DISs appear to reflect reflux burden, but immune response presents an alternative paradigm for complications of GORD. This was first proposed by Souza and colleagues, who demonstrated in an in vitro model that oesophagitis developed several days after acidified bile salt exposure. Initial exposure triggered the increased presence of proinflammatory cytokines (interleukin-8 and interleukin-1β) that signal migration of T cells and neutrophils into the submucosa, which eventually progressed to the epithelial surface. More recently, biopsies from patients who discontinued PPIs 2 weeks before endoscopy showed T lymphocyte infiltration in areas without surface erosions. Furthermore, in patients with reflux oesophagitis, biopsies showed increased hypoxia-inducible factor 2a, a proinflammatory cytokine that is induced by bile salts.

Barrett’s oesophagus (BO) relates to the histological change from normal stratified squamous epithelium lining the oesophagus to a metaplastic columnar epithelium with goblet cells, typically more reflective of the duodenum than the stomach. ^, BO is thought to be an intermediate step between oesophagitis and oesophageal adenocarcinoma (OAC), and is more common in GORD than the general population. The risk of BO progressing to OAC is significantly reduced with adequate PPI therapy, which demonstrates the pathophysiology of gastric acid in BO progression, but there are likely immunological mechanisms akin to reflux oesophagitis. While these mechanisms remain unclear, FoxP3 , a gene associated with poor prognosis for oesophageal cancer, is greatly expressed in BO. ^,

Symptom perception

The means by which reflux triggers symptoms is still not well understood and highly paradoxical. First, patients with BO often report fewer symptoms compared to patients with no objective evidence of reflux. Second, symptoms respond variably to acid-suppression medications, which suggests other mechanisms than gastric acid alone. Indeed, pain receptors called transient receptor potential vanilloid-1 (TRPV1), present in oesophageal sensory afferents, are activated in response to several stimuli including heat, low pH, protons, lipid derivatives, and the principle compound in chilli peppers, capsaicin. In one study, researchers injected the oesophageal submucosa of healthy volunteers with acid and capsaicin, which only capsaicin triggered severe sensations of heartburn and chest pain. Patients will often report that spicy foods cause reflux, but capsaicin has not been shown to induce LOS dysfunction nor increase TLOSRs. Rather, enhanced symptom perception is likely due to direct effects on oesophageal sensation. TRPV1 may be the primary afferent pathway for reflux symptoms since it is upregulated in patients with erosive oesophagitis and NERD. Evidence to support this was objectively demonstrated in a study by Hobson et al. that showed that oesophageal afferent pathway sensitivity negatively correlated with acid exposure in NERD patients, meaning that equivalent symptoms could be generated by lower levels of acid exposure dependent on the sensitivity of oesophageal afferent nerves.

The advent of pH-impedance monitoring has revealed that symptom perception is multifactorial owing to acidity, composition (liquid, gas, or mixed), impaired reflux bolus clearance, and the proximal extent or volume of reflux. In NERD patients, spontaneous acid reflux enhances subsequent reflux perception regardless of activity or composition. Clearly, sensitization of the oesophagus from acidic and weakly acidic events primes the oesophagus. Additionally, mental fatigue may play a fundamental role in perception. Schey and colleagues showed that sleep deprivation led to heightened sensitivity and a greater intensity response to oesophageal acid exposure.

History, questionnaires, and an empiric proton pump inhibitor trial

Typical GORD symptoms (i.e. heartburn and regurgitation) respond better to medical and surgical treatment than atypical symptoms, which emphasises the value of a good clinical history. According to the Montreal Consensus, atypical symptoms include non-cardiac chest pain and extraoesophageal symptoms; i.e. laryngeal or pulmonary complaints, although chest pain, discomfort, and burning may be indistinguishable to some patients. In any case, an empiric trial of PPI therapy is often the first step, but up to 40% of patients will experience persistent symptoms despite PPI use. In addition, a large proportion of these patients do not demonstrate conclusive evidence of GORD on endoscopy or pH monitoring. ^,

When compared to endoscopy and pH monitoring, expert history by a gastroenterologist has only a sensitivity and specificity of 70% and 67%, respectively. Questionnaires share similarly limited sensitivity and specificity of 62% and 67% for the Reflux Disease Questionnaire (RDQ), and 65% and 71% for the GerdQ, respectively. Trial with PPIs is even more limited with a sensitivity of 71% and specificity of 44%, ^, yet PPI trials are cheap, pragmatic, and recommended by societal guidelines. This has undoubtedly led to the overuse of PPIs, which although they appear to be safe, may have detrimental consequences to the gut microbiome. ^, Ultimately, history, questionnaires, and PPI trials are of limited value in the diagnosis of GORD, highlighting the need for further investigation in most cases.