Pathophysiology and treatment of (functional) esophageal disorders

PART 1: Gastroesophageal reflux disease The retrograde movement of gastric contents into the esophagus or gastroesophageal reflux (GER), is a normal physiological phenomenon. When GER causes troublesome symptoms and/or lesions it is defined as gastroesophageal reflux disease (GERD). Symptoms can be divided into typical or esophageal manifestations such as heartburn and regurgitation, and atypical or extra-esophageal manifestations such as cough, non-cardiac chest pain, and ear-nose-throat pain. The first-line pharmacological treatment for patients with GERD is acid suppressive therapy such as proton pump inhibitors (PPIs). Although PPIs are highly effective in healing esophageal lesions, they are less effective in symptom control. Even up to 40% of GERD patients remain symptomatic despite adequately dosed PPI therapy and these patients are referred as having refractory GERD (rGERD). The pathophysiology of GERD is complex and multifactorial, with a wide range of possible clinical manifestations that remain incompletely understood. Therefore, the first objective of this PhD project was to obtain more insight in the association between psychological symptoms and the different GERD phenotypes. Historically psychological processes are associated with the GERD classifications of reflux hypersensitivity and functional heartburn, given the presumed role of brain-gut axis dysregulation in symptom generation in these patients. However, previous research suggested that psychological co-morbidities are potentially important across the GERD spectrum. Therefore, we investigated if psychological processes such as health anxiety, general psychological health, personality, pain coping and social functioning can discriminate between reflux classification categories, determined by the Lyon consensus, in a large cohort of refractory reflux patients using a traditional statistical and machine-learning approach. In this project, we observed that age and gender were the only variables significantly associated with reflux classification in the multinomial logistic regression and BMI was a significant factor in both regressions. Machine-learning analyses revealed poorly performing models with high misclassification rates in both models. Based on our research we suggest that psychological processes do not predict the GERD classification. The second objective of this PhD project was to explore a novel treatment option for patients with occasional GERD symptoms, as PPIs are more suitable for continued intake based on their pharmacokinetics. We investigated the effect of a complex with hyaluronic acid (HA) and chondroitin sulphate combined with the antacid magnesium trisilicate (MT) by analyzing its performance versus placebo treatment on mucosal integrity in GERD patients currently not treated with PPIs in a randomized, double-blind, placebo-controlled, cross-over trial. In this project, we observed no differences in the change from baseline for the average esophageal baseline impedance values measured at 3cm, 5cm and 15cm above the low esophageal sphincter (LES) in upright and recumbent body position were not significantly different between placebo and HA/CS/MT treatment. Furthermore, the investigational product resulted to be safe and well tolerated. Based on our research, we can conclude that the combination of HA/CS/MT did not alter esophageal permeability in or ex vivo and did not improve symptoms in a patient population with occasional GERD symptoms. The third objective of this PhD project was to investigate the potential role of MII-pH on PPI in the selection of patients with rGERD for anti-reflux surgery and to investigate the outcome of anti-reflux surgery in patients with rGERD. Therefore, we performed a prospective study, in which patient were selected for anti-reflux surgery according to currently established criteria, and an additional MII-pH measurement on PPI was added in combination with questionnaires. The interim analyses of this project revealed that after nine years or 108 months, the mean time after anti-reflux surgery, the group of patients with a negative SI or SAP had a higher proportion of patients classified as treatment successes compared with the group of patients with a positive SI or SAP. In our complete cohort at the last evaluation point, 66% of the patients scored their postoperative state as treatment success. Indeed, based on the Kaplan-Meier curve the probability of treatment success after nine years was estimated on 70.5%. Based on the result of our interim analyses, the symptom association indices on PPI cannot be used to select rGERD patients for anti-reflux surgery. PART 2: Functional globus Globus, defined as a persistent or intermittent non-painful sensation of a lump in the throat, foreign body sensation, tickling, itching or mucus accumulation in the throat. When no organic cause is found, functional globus is diagnosed. The pathophysiology behind functional globus remains unclear, although it is suggested that visceral hypersensitivity and sensory dysfunction play an important role. As the etiology of functional globus remains unclear, effective pharmacological treatment options are still lacking. The fourth objective of this PhD project was to investigate the presence of anxiety, multiple somatic complaints, depression, and fear of pain in a cohort of globus patients seen at a tertiary care center in comparison to a GERD population and a healthy control group. Additionally, we investigated the association between the psychological comorbidities and the severity of globus symptoms. This project showed that increased levels of psychological factors such as somatic complaints, depression and anxiety are present in globus patients seen at a tertiary care center, compared with healthy controls. Remarkably, the levels of somatic symptom severity were lower compared to patients with GERD. This study confirms the importance of screening for psychological comorbidities in globus patients as part of a holistic management approach for globus. As effective pharmacological treatment options are lacking for patients with globus, the fifth objective of this PhD project was to investigate the effect of pregabalin, an anti-epileptic drug, with established efficacy in the treatment of neuropathy, on globus sensation in a randomized, parallel, placebo-controlled, double-blinded trial in globus patients. No favorable treatment response at 8 weeks was observed after treatment with pregabalin, compared with placebo. Also, no improvement on the total GETS score and no favorable OTE was observed after pregabalin treatment. Furthermore, almost all the patients that received pregabalin experienced side effects (18/20) compared with placebo (7/18). These results suggest that pregabalin should not be further investigated as a therapeutic option in patient with globus. PART 3: Pharmacological effects of opioids on the pharynx, upper esophageal sphincter, and esophageal body during HRiM Opioids are one of the most prescribed classes of pain management drugs in Western society. However, less is known about the effects of opioids in acute settings and as non-prescription medications on the pharynx, UES and esophageal body. The last objective of this PhD project was to investigate the effect of an acute single dose of a non-prescription opioid on the contractile activity and the pressure flow parameters of the pharynx and esophageal body, assessed using HRiM and PFA in a randomized, double-blinded, placebo-controlled, cross-over study. After codeine administration, higher IRP4 values resulted in reduced deglutitive EGJ relaxation and shorter DL values. No effect of acute codeine administration was observed on the distal contractility. Bolus flow resistance at the EGJ and distention pressures was increased after codeine infusion. Based on CC v3.0, acute infusion of codeine induced EGJ-OO in six HV. However, codeine administration induced no significant alterations in any of the pharyngeal PFA metrics. Based on this project we can conclude that in healthy individuals, acute administration of codeine increased bolus resistance at the EGJ secondary to induced incomplete EGJ relaxation leading to major motility disorders in a subset of subjects including EGJ-OO. However, an acute single dose of codeine did not affect motility or bolus flow in pharynx and UES.

Publication year:2023

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