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Physiology and function in patients with complex gastrointestinal reflux disease

Learning points

  • The main role of endoscopy in patients with GORD is to investigate for complications
  • Upper gastrointestinal physiology testing can differentiate between patients with non-erosive reflux disease, hypersensitive oesophagus and functional heartburn, which have distinct phenotypes and require specific management strategies
  • Symptoms and laryngoscopic findings of LPR have low specificity for GORD and more research is needed in this area to improve diagnosis and treatment

Gastro-oesophageal reflux disease (GORD) is defined as excessive reflux of (usually acidic) gastric contents into the oesophagus that causes symptoms and/or complications[1]. GORD symptoms can be categorised as oesophageal or extra-oesophageal (Figure 1). Classic oesophageal symptoms are heartburn and regurgitation (the unpleasant retrosternal experience of material moving upwards into the oesophagus). Non-burning chest pain is also considered an oesophageal symptom of reflux. Extra-oesophageal symptoms are more nebulous and perhaps harder to identify as being definitely related to GORD, but can include hoarse voice, cough, sore throat and globus.

Figure 1: Classification of GORD (adapted from Vakil et al, 2006)

Investigation for GORD

Endoscopy
Upper gastrointestinal endoscopy is the most commonly performed investigation for GORD symptoms. However, a positive diagnosis of reflux often cannot be made by this method, and normal findings do not exclude reflux. Roughly 60% of endoscopies show normal results in people with true GORD, 30% show evidence of severe oesophagitis, and 10% show evidence of Barrett’s oesophagus. Consequently, the role of endoscopy in GORD should generally be to investigate complications and not to make a diagnosis. Risk factors for Barrett’s oesophagus (age, duration of reflux symptoms, white ethnicity, male sex, and obesity) should be key considerations when deciding whether to perform endoscopy.

Upper Gastrointestinal Physiology Studies
In patients with symptoms of GORD but without complications of reflux on endoscopy, a diagnosis can be made with ambulatory reflux monitoring. The most common indications for these studies are symptoms refractory to treatment with proton-pump inhibitors and anti-reflux surgery being considered.

The most common way to investigate is with a 24-hour pH catheter study, which is often combined with impedance measurements. Alternatively, a wireless pH capsule study can be used. In patients who do not yet have a diagnosis, proton-pump inhibitor therapy should be stopped before the test is performed to increase the sensitivity and specificity for GORD and to diagnose functional heartburn.

When reporting pH studies, two main factors are considered: the percentage of oesophageal acid exposure and the reflux–symptom association (calculated as a statistically significant temporal association between patient-reported symptoms on the receiver device and reflux episodes). This approach allows the clinician to follow a diagnostic algorithm (Figure 2).

Figure 2: Diagnostic algorithm for GORD

In patients with pathological oesophageal acid exposure, a diagnosis of non-erosive reflux disease can be made. This disorder should be treated by optimising reflux treatment with good adherence to and appropriate timing of proton-pump inhibitors (taken 15–30 minutes before meals) and ensuring appropriate lifestyle modifications, such as weight loss and reductions in alcohol intake and smoking. Patients might also be referred for anti-reflux surgery.

Where physiological acid exposure is found but there is a positive association between symptoms and reflux events (i.e., the patient perceives a normal amount of reflux symptomatically), the appropriate diagnosis is acid-hypersensitive oesophagus. Where physiological acid exposure is found and there is no reflux–symptom association, a diagnosis of functional heartburn can be made. In functional heartburn there is no benefit from escalating treatment with proton-pump inhibitors, and studies suggest that use of selective serotonin-reuptake inhibitors (eg, fluoxetine 20 mg) achieves better outcomes [2].

Thus, functional heartburn should be viewed as a specific diagnosis to be treated differently from true gastro-oesophageal reflux disease. Acid-hypersensitive oesophagus is less common, but again requires appropriate treatment with a selective serotonin-reuptake inhibitor or tricyclic antidepressant medications [3].

The “grey area”
On reflux studies, many patients have clearly abnormal oesophageal acid exposure (>6%), and many have clearly normal exposure (<4%). Those patients with exposure between 4% and 6% are in a “grey area” where the diagnosis is equivocal. In these patients, adjunctive measures, such as mean nocturnal baseline impedance, can be used. The basal impedance of the mucosa (which can be measured using a typical pH impedance catheter during rest at night) is proportional to the overall oesophageal acid burden. Baseline impedance values less than 2292 Ω might suggest non-erosive reflux disease rather than functional heartburn, but this differentiation needs to be assessed further in outcome studies [4].

Extra-oesophageal reflux syndromes
Patients are commonly referred to gastroenterologists with a diagnosis of laryngopharyngeal reflux, often after having been investigated by an ear, nose and throat doctor. Care needs to be taken with this diagnosis, as symptoms and laryngoscopic findings are neither sensitive nor specific for GORD [5]. Furthermore, placebo-controlled studies have demonstrated no benefit in treatment with proton-pump inhibitors when the diagnosis has been based on symptoms or laryngoscopic findings. Studies suggest that laryngopharyngeal reflux symptoms are more likely to respond to GORD therapy if they are associated with typical oesophageal symptoms. When considering anti-reflux surgery for patients with laryngopharyngeal reflux symptoms, these factors should be taken into account. Surgery should be considered only if pathological acid exposure is shown conclusively on objective conventional studies, and patients should be counselled that typical reflux symptoms are more likely to improve than extra-oesophageal reflux symptoms. Although newer technologies are being developed for the diagnosis of laryngopharyngeal reflux,  their use is not yet supported by evidence [6, 7].

Conclusions
A normal endoscopy cannot exclude GORD, but a positive endoscopy is diagnostic in only a few patients. Non-erosive reflux disease should be investigated with conventional wired pH impedance or wireless pH capsule studies in selected patients where management could be altered by the findings.

Extra-oesophageal reflux disease is a challenging area requiring more research. Based on current knowledge, any invasive intervention should be restricted to patients with positive results on objective (conventional) testing, ideally with concomitant typical reflux symptoms.


About the author

Dr Philip Woodland is a consultant gastroenterologist at the Royal London Hospital, where he leads the oesophageal service. He has active research programs in benign oesophageal disease, including gastro-oesophageal reflux disease. He is a member of the international GERD consensus group that publishes guidelines on upper gastrointestinal physiology testing.


References

1    Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:1900–20.
2    Ostovaneh MR, Saeidi B, Hajifathalian K, et al. Comparing omeprazole with fluoxetine for treatment of patients with heartburn and normal endoscopy who failed once daily proton pump inhibitors: double-blind placebo-controlled trial. Neurogastroenterol Motil 2014;26:670–78.
3    Viazis N, Keyoglou A, Kanellopoulos AK, et al. Selective serotonin reuptake inhibitors for the treatment of hypersensitive esophagus: a randomized, double-blind, placebo-controlled study. Am J Gastroenterol 2012;107:1662–67.
4    Gyawali CP, Kahrilas PJ, Savarino E, et al. Modern diagnosis of GERD: the Lyon Consensus. Gut 2018;67:1351–62.
5    Kotby MN, Hassan O, El-Makhzangy AM, Farahat M, Milad P. Gastroesophageal reflux/laryngopharyngeal reflux disease: a critical analysis of the literature. Eur Arch Otorhinolaryngol 2010;267:171–79.
6    Woodland P, Singendonk MMJ, Ooi J, et al. Measurement of salivary pepsin to detect gastroesophageal reflux disease is not ready for clinical application. Clin Gastroenterol Hepatol 2019;17:563–65..
7    Yadlapati R, Pandolfino JE, Lidder AK, et al. Oropharyngeal pH testing does not predict response to proton pump inhibitor therapy in patients with laryngeal symptoms. Am J Gastroenterol 2016;111:1517–24.