Pharmacologic treatment of GERD: Where we are now, and where are we going?

The introduction of acid inhibition in clinical practice has revolutionized the management of acid-related diseases, leading to the virtual abolition of elective surgery for ulcer disease and relegating antireflux surgery to patients with gastroesophageal reflux disease (GERD) not adequately managed by medical therapy. Proton pump inhibitors (PPIs) are the antisecretory drugs of choice for the treatment of reflux disease. However, these drugs still leave some unmet clinical needs in GERD. PPI-refractoriness is common, and persistent symptoms are observed in up to 40-55% of daily PPI users. Potassium-competitive acid blockers (P-CABs) clearly overcome many of the drawbacks and limitations of PPIs, achieving rapid, potent, and prolonged acid suppression, offering the opportunity to address many of the unmet needs. In recent years, it has been increasingly recognized that impaired mucosal integrity is involved in the pathogenesis of GERD. As a consequence, esophageal mucosal protection has emerged as a new, promising therapeutic avenue. When P-CABS are used as add-on medications to standard treatment, a growing body of evidence suggests a significant additional benefit, especially in the relief of symptoms not responding to PPI therapy. On the contrary, reflux inhibitors are considered a promise unfulfilled, and prokinetic agents should only be used on a case-by-case basis.

Esophageal physiology-an overview of esophageal disorders from a pathophysiological point of view.

The esophagus serves the principal purpose of transporting food from the pharynx into the stomach. A complex interplay between nerves and muscle fibers ensures that swallowing takes place as a finely coordinated event. Esophageal function can be tested by a variety of methods, endoscopy, manometry, and reflux monitoring being some of the most important. Regarding pathophysiology, motor disorders, such as achalasia, often cause dysphagia and/or chest pain. Functional esophageal disorders are a heterogeneous group with hypersensitivity as a dominant pathophysiological factor. Gastroesophageal reflux disease often causes symptoms, such as heartburn and regurgitation, and a spectrum of disease, ranging from minimal mucosal damage visible only in the microscope to esophageal ulcers and strictures in the most severe cases. Eosinophilic esophagitis is an immune-mediated condition that can result in significant dysphagia and associated luminal narrowing. In the following, we will provide an overview of the most common esophageal disorders from a combined pathophysiological and clinical view.

Axial Movements and Length Changes of the Human Lower Esophageal Sphincter During Respiration and Distension-induced Secondary Peristalsis Using Functional Luminal Imaging Probe.

BACKGROUND/AIMS: Efficient transport through the esophago-gastric junction (EGJ) requires synchronized circular and longitudinal muscle contraction of the esophagus including relaxation of the lower esophageal sphincter (LES). However, there is a scarcity of technology for measuring esophagus movements in the longitudinal (axial) direction. The aim of this study is to develop new analytical tools for dynamic evaluation of the length change and axial movement of the human LES based on the functional luminal imaging probe (FLIP) technology and to present normal signatures for the selected parameters. METHODS: Six healthy volunteers without hiatal hernia were included. Data were analyzed from stepwise LES distensions at 20, 30, and 40 mL bag volumes. The bag pressure and the diameter change were used for motion analysis in the LES. The cyclic bag pressure frequency was used to distinguish dynamic changes of the LES induced by respiration and secondary peristalsis. RESULTS: Cyclic fluctuations of the LES were evoked by respiration and isovolumetric distension, with phasic changes of bag pressure, diameter, length, and axial movement of the LES narrow zone. Compared to the respiration-induced LES fluctuations, peristaltic contractions increased the contraction pressure amplitude (P ＜ 0.001), shortening (P ＜ 0.001), axial movement (P ＜ 0.001), and diameter change (P ＜ 0.01) of the narrow zone. The length of the narrow zone shortened as function of the pressure increase. CONCLUSIONS: FLIP can be used for evaluation of dynamic length changes and axial movement of the human LES. The method may shed light on abnormal longitudinal muscle activity in esophageal disorders.

The sensory system of the esophagus--what do we know?

The nervous innervation and complex mechanical function of the esophagus make sensory evaluation difficult. However, during the last decades, several new techniques have made it possible to gain insight into pain processing of nociceptive signals. The current review highlights the sensory innervation and possibilities for quantitative sensory testing, the mechanosensory properties, the potential of high-resolution manometry and imaging, and the sensory system in special conditions, such as Barrett's esophagus. It is mandatory to understand the complex pathophysiology of the esophagus to enhance our understanding of esophageal disorders, but it also increases the complexity of future experimental and clinical studies. The new methods, as outlined in the current review, provide the possibility for researchers to enhance the quality of interdisciplinary research and to gain more knowledge about sensory symptoms and treatment possibilities.

Novel insights into esophageal diagnostic procedures.

The 21st century offers new advances in diagnostic procedures and protocols in the management of esophageal diseases. This review highlights the most recent advances in esophageal diagnostic technologies, including clinical applications of novel endoscopic devices, such as ultrathin endoscopy and confocal laser endomicroscopy for diagnosis and management of Barrett's esophagus; novel parameters and protocols in high-resolution esophageal manometry for the identification and better classification of motility abnormalities; innovative connections between esophageal motility disorder diagnosis and detection of gastroesophageal reflux disease (GERD); impedance-pH testing for detecting the various GERD phenotypes; performance of distensibility testing for better pathophysiological knowledge of the esophagus and other gastrointestinal abnormalities; and a modern view of positron emission tomography scanning in metastatic disease detection in the era of accountability as a model for examining other new technologies. We now have better tools than ever for the detection of esophageal diseases and disorders, and emerging data are helping to define how well these tools change management and provide value to clinicians. This review features novel insights from multidisciplinary perspectives, including both surgical and medical perspectives, into these new tools, and it offers guidance on the use of novel technologies in clinical practice and future directions for research.

Esophageal Acid Clearance During Random Swallowing Is Faster in Patients with Barrett's Esophagus Than in Healthy Controls.

BACKGROUND/AIMS: Impaired esophageal acid clearance may be a contributing factor in the pathogenesis of Barrett's esophagus. However, few studies have measured acid clearance as such in these patients. In this explorative, cross-sectional study, we aimed to compare esophageal acid clearance and swallowing rate in patients with Barrett's esophagus to that in healthy controls. METHODS: A total of 26 patients with histology-confirmed Barrett's esophagus and 12 healthy controls underwent (1) upper endoscopy, (2) an acid clearance test using a pH-impedance probe under controlled conditions including controlled and random swallowing, and (3) an ambulatory pH-impedance measurement. RESULTS: Compared with controls and when swallowing randomly, patients cleared acid 46% faster (P = 0.008). Furthermore, patients swallowed 60% more frequently (mean swallows/minute: 1.90 ± 0.74 vs 1.19 ± 0.58; P = 0.005), and acid clearance time decreased with greater random swallowing rate (P < 0.001). Swallowing rate increased with lower distal esophageal baseline impedance (P = 0.014). Ambulatory acid exposure was greater in patients (P = 0.033), but clearance times assessed from the ambulatory pH-measurement and acid clearance test were not correlated (all P > 0.3). CONCLUSIONS: More frequent swallowing and thus faster acid clearance in Barrett's esophagus may constitute a protective reflex due to impaired mucosal integrity and possibly acid hypersensitivity. Despite these reinforced mechanisms, acid clearance ability seems to be overthrown by repeated, retrograde acid reflux, thus resulting in increased esophageal acid exposure and consequently mucosal changes.

Understanding the sensory irregularities of esophageal disease.

Symptoms relating to esophageal sensory abnormalities can be encountered in the clinical environment. Such sensory abnormalities may be present in demonstrable disease, such as erosive esophagitis, and in the ostensibly normal esophagus, such as non-erosive reflux disease or functional chest pain. In this review, the authors discuss esophageal sensation and the esophageal pain system. In addition, the authors provide a primer concerning the techniques that are available for investigating the autonomic nervous system, neuroimaging and neurophysiology of esophageal sensory function. Such technological advances, whilst not readily available in the clinic may facilitate the stratification and individualization of therapy in disorders of esophageal sensation in the future.

Functional lumen imaging of the gastrointestinal tract.

This nonsystematic review aims to describe recent developments in the use of functional lumen imaging in the gastrointestinal tract stimulated by the introduction of the functional lumen imaging probe. When ingested food in liquid and solid form is transported along the gastrointestinal tract, sphincters provide an important role in the flow and control of these contents. Inadequate function of sphincters is the basis of many gastrointestinal diseases. Despite this, traditional methods of sphincter diagnosis and measurement such as fluoroscopy, manometry, and the barostat are limited in what they can tell us. It has long been thought that measurement of sphincter function through resistance to distension is a better approach, now more commonly known as distensibility testing. The functional lumen imaging probe is the first medical measurement device that purports in a practical way to provide geometric profiling and measurement of distensibility in sphincters. With use of impedance planimetry, an axial series of cross-sectional areas and pressure in a catheter-mounted allantoid bag are used for the calculation of distensibility parameters. The technique has been trialed in many valvular areas of the gastrointestinal tract, including the upper esophageal sphincter, the esophagogastric junction, and the anorectal region. It has shown potential in the biomechanical assessment of sphincter function and characterization of swallowing disorders, gastroesophageal reflux disease, eosinophilic esophagitis, achalasia, and fecal incontinence. From this early work, the functional lumen imaging technique has the potential to contribute to a better and more physiological understanding of narrowing regions in the gastrointestinal tract in general and sphincters in particular.

Neurophysiology of the esophagus.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the methods and characteristics of esophageal afferents in humans; the pitfalls in characterization of mechanosensitive afferents; the sensitization of esophageal afferents in human studies; the brain source modeling in the understanding of the esophagus-brain axis; the use of evoked brain potentials in the esophagus; and measuring descending inhibition in animal and human studies.

Pharmacologic treatments for esophageal disorders.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the role for ketamine and other alternative treatments in esophageal disorders; the use of linaclotide in the treatment of esophageal pain; the alginate test as a diagnostic criterion in gastroesophageal reflux disease (GERD); the use of baclofen in treatment of GERD; the effects of opioids on the esophagus; the use of antagonists on the receptor level in GERD; the effect of local formulation of drugs on the esophageal mucosa; and the use of electroencephalographic fingerprints to predict the effect of pharmacological treatment.

The neurophysiology of the esophagus.

This paper reports on the neurophysiology of the esophagus, including on the uneven distribution of innervation in the esophagus, reflected by the increased sensitivity and perception of gastroesophageal reflux disease (GERD) events in the proximal rather than distal esophagus; the role of the enteric nervous system (ENS) in swallowing; the role of the physiological stress-responsive systems, including the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis in mediating esophageal pain; the advances in understanding pain mechanisms and brain structure provided by technological imaging advances; investigations into the efficacy of the descending-pain control system, including diffuse noxious inhibitory control (DNIC); the role of abnormal nervous signaling in afferent pathways in the pathogenesis of Barrett's esophagus (BE); and the contribution of the esophageal mucosa to reflux symptoms.

Gastrointestinal sensitivity and gastroesophageal reflux disease.

This paper reports on gastrointestinal sensitivity, including on the role of refluxate volume on the perception of reflux symptoms; experimental pain models that mimic mechanisms and symptoms of pain associated with esophageal diseases; the potential role of the acid receptor TRPV1 in the genesis of gastroesophageal reflux disease (GERD) symptoms; and roles for ATP and the purine and pyrimidine receptor subfamilies P1, P2X, and P2Y in the pathogenesis of GERD symptoms.

Distensibility testing of the esophagus.

The following contains commentaries on distensibility testing using the functional lumen imaging probe (FLIP); the use of the distention test of the esophageal body in the clinic diagnosis of noncardiac chest pain; the functional lumen imaging in gastroesophageal reflux disease-impaired esophagogastric junction; a multimodal pain model for the esophagus; the rationale for distensibility testing; and further developments in standardized distension protocols.

Mechanism-based evaluation and treatment of esophageal disorders.

The following on mechanism-based evaluation and treatment of esophageal disordered contains commentaries on multimodal stimulation to study esophageal function, the neurophysiological and autonomous assessment of sensory abnormalities, and the clinical value of the novel diagnostic combinations to propose a mechanically targeted treatment.

The pain system in oesophageal disorders: mechanisms, clinical characteristics, and treatment.

Pain is common in gastroenterology. This review aims at giving an overview of pain mechanisms, clinical features, and treatment options in oesophageal disorders. The oesophagus has sensory receptors specific for different stimuli. Painful stimuli are encoded by nociceptors and communicated via afferent nerves to the central nervous system. The pain stimulus is further processed and modulated in specific pain centres in the brain, which may undergo plastic alterations. Hence, tissue inflammation and long-term exposure to pain can cause sensitisation and hypersensitivity. Oesophageal sensitivity can be evaluated ,for example, with the oesophageal multimodal probe. Treatment should target the cause of the patient's symptoms. In gastro-oesophageal reflux diseases, proton pump inhibitors are the primary treatment option, surgery being reserved for patients with severe disease resistant to drug therapy. Functional oesophageal disorders are treated with analgesics, antidepressants, and psychological therapy. Lifestyle changes are another option with less documentation.