Understanding the basic anatomy and physiology contributing to esophageal peristalsis can help with comprehension of esophageal disease states. Laryngopharyngeal reflux (LPR), an extraesophageal variant of gastroesophageal reflux disease, is retrograde movement of gastric contents into the laryngopharynx and is associated with hoarseness, chronic cough, throat clearing, sore throat, and dysphagia. Various direct and indirect mechanisms have been proposed to contribute to LPR. The current diagnostic tests for LPR have significant shortcomings. This article reviews the anatomy and physiology of upper esophageal sphincter, esophagus, and lower esophageal sphincter, and discusses current understanding of pathophysiology, evaluation, and management of LPR.
Key points
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Esophagus is a muscular tube with active peristalsis, which helps propel bolus into the stomach.
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Lower and upper esophageal sphincters act to prevent esophageal and laryngeal exposure to gastroduodenal contents.
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Dysfunction of esophageal peristalsis and/or LES and UES often results in symptoms of dysphagia, chest pain, and chronic pulmonary and laryngeal symptoms.
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Common clinical manifestations of LPR include dysphonia/hoarseness, cough, globus pharyngeus, throat clearing, and dysphagia.
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Laryngoscopic findings are often nonspecific for reflux-induced laryngitis and have high interrater variability.
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In the absence of risk factors for malignancy, empiric 2-month trial of PPI is considered a reasonable approach in patients suspected of having LPR.
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PPI therapy should be tapered in all patients with initial empiric therapy.
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Surgery is not recommended in patients whose symptoms do not respond to PPI unless regurgitation is an accompanying symptom.
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In nonresponders to empiric PPI therapy, other causes for chronic laryngeal inflammation should be entertained.
| EER | Extraesophageal reflux |
| GERD | Gastroesophageal reflux disease |
| LES | Lower esophageal sphincter |
| LPR | Laryngopharyngeal reflux |
| PPI | Proton pump inhibitor |
| TLESR | Transient lower esophageal sphincter relaxation |
| UES | Upper esophageal sphincter |
Introduction
Esophagus is a complex muscular tube connecting the pharynx to the stomach, which acts as a channel for the transport of food and prevents reflux of gastroduodenal contents. It is the only internal organ that traverses three body cavities. A thorough understanding of this anatomy and physiology is essential in understanding esophageal disease states.
Introduction
Esophagus is a complex muscular tube connecting the pharynx to the stomach, which acts as a channel for the transport of food and prevents reflux of gastroduodenal contents. It is the only internal organ that traverses three body cavities. A thorough understanding of this anatomy and physiology is essential in understanding esophageal disease states.
Anatomy
The proximal margin of the tubular esophagus is the upper esophageal sphincter (UES), the functional unit correlating anatomically with the junction of the inferior pharyngeal constrictor and cricopharyngeus. Although UES function is controlled by numerous muscles based on electromyographic signals, most studies indicate that the primary muscular element that generates tone in the sphincter at rest is the cricopharyngeus. It is innervated by the pharyngeal plexus and the recurrent laryngeal nerve. The esophagus extends distally 18 to 26 cm within the posterior mediastinum as a hollow muscular tube to the lower esophageal sphincter (LES) ( Fig. 1 ). The LES is a 2- to 4-cm long focus of tonically contracted thickened circular smooth muscle that lies within the diaphragmatic hiatus and is the major antireflux barrier protecting the esophagus from reflux of the gastric contents. The LES is innervated by parasympathetic (vagal) and sympathetic (splanchnic) nerves.
The esophageal wall is morphologically distinct compared with the rest of the gastrointestinal tract, because it has no serosa. It is comprised of four layers: (1) mucosa, (2) submucosa, (3) muscularis propria, and (4) the adventitia. The proximal 5% to 33% is skeletal muscle, the middle 35% to 40% mixed muscle, and the distal 50% to 60% smooth muscle. The muscles are arranged into inner circular and outer longitudinal layers. The smooth muscle portions of the esophageal body are innervated by the vagus nerve, which controls peristalsis under physiologic conditions. Neural innervation of the esophagus is from the myenteric or Auerbach plexus, located between the two muscle layers, and Meissner plexus located in the submucosa. The myenteric plexus is responsible for esophageal peristalsis, whereas the Meissner complex is the site of afferent sensory input ( Fig. 2 ). Excitatory stimulation from acetylcholine mediates contraction of the longitudinal and circular muscle layers. Inhibitory neurons predominately affect the circular muscle layer by nitric oxide. Excitatory stimulation from acetylcholine has its largest effect proximally, whereas inhibitory effect of nitric oxide is seen distally.
Physiology
Functionally, the UES, the esophageal body, and the LES act in coordinated manner to allow normal swallowing. Swallowing begins when a food bolus is propelled into the pharynx from the mouth. This oropharyngeal phase of swallowing is voluntary, whereas the esophageal phase that follows is involuntary. In rapid sequence and with precise coordination the larynx is elevated and the epiglottis seals the airway. A rapidly progressing pharyngeal contraction then transfers the bolus through the relaxed UES into the esophagus. The UES is opened by relaxation of its muscles, movement of the larynx anteriorly, and pulsation by the bolus. As the UES closes, a progressive circular contraction begins in the upper esophagus and proceeds distally along the esophageal body to propel the bolus through the relaxed LES ( Figs. 3 A and B ). Peristaltic pressures normally ranging from 30 to 180 mm Hg are generated. The LES subsequently closes with a prolonged contraction preventing movement back into the esophagus. The mechanical effect of peristalsis is a stripping wave that strips the esophagus clean from its proximal to distal end (see Fig. 3 B).
Secondary peristalsis is a progressive contraction in the esophageal body that is induced by stimulation of sensory receptors, rather than a swallow. This begins approximately at or above the level of the stimulus and resembles primary peristalsis. Its function is to clear the esophagus from food contents poorly cleared by the primary peristalsis and to push refluxed gastric contents back into the stomach.
The UES and LES are tonically contracted at rest. The closed state for the UES is a result of continuous neural excitation, with a small passive component to tone. The UES pressures are asymmetric being higher anteriorly and posteriorly. It is believed that the tonic contraction of the LES is a function of the muscle itself and not dependent on neural innervation. Stimulation of inhibitory fibers results in LES relaxation. LES relaxation occurs not only in response to swallowing, but may occur in response to esophageal distention (secondary peristalsis) or may occur without peristalsis. This is referred to as transient LES relaxation (TLESR), defined as periods lasting 10 to 60 seconds of spontaneous (not preceded by swallow), simultaneous relaxation of the LES and crural diaphragm. TLESR is thought to be a vagally mediated reflex that is part of normal digestion and triggered by gastric distention based on observations that it can be diminished with vagal cooling or vagotomy in dogs. TLESR is also absent in patients with achalasia, a condition in which the inhibitory innervation is defective. TLESR represents the primary mechanism for gastroesophageal reflux in normal individuals.
Gastroesophageal reflux disease
Approximately 25 to 75 million people in the United States are affected by gastroesophageal reflux disease (GERD), and 13% of Americans use medications for GERD at least twice weekly. GERD is a spectrum of disease usually producing symptoms of heartburn and acid regurgitation, which are considered to be part of the esophageal syndromes. Symptoms may also include chest pain or atypically may present as extraesophageal manifestations, such as dental erosion, laryngitis, asthma, chronic obstructive pulmonary disease, cough, hoarseness, postnasal drip disease, sinusitis, otitis media, and recurrent pneumonia, which are among the extraesophageal syndromes ( Fig. 4 ).
Extraesophageal reflux (EER) symptoms can occur concurrently with typical GERD symptoms or alone. The diagnosis of GERD is more difficult in those presenting solely with EER symptoms because it is not initially suspected. GERD has become an important public health problem because of the considerable economic burden, lack of productivity, medications, and required consultations. Annual direct cost for GERD management is reported at $971 per patient, with national expenditures ranging from $9.3 billion to $12.1 billion. However, the cost of treating EER is even more impressive. According to recent data, the cost of caring for patients with EER is five times that of GERD at approximately $50 billion ( Fig. 5 ).
Laryngopharyngeal reflux
Laryngopharyngeal reflux (LPR) is an extraesophageal variant of GERD, because the main symptomatic region involves the laryngopharynx. Although the hallmark symptoms of GERD include heartburn and regurgitation, symptoms of LPR often include hoarseness, chronic cough, sore throat, globus pharyngeus, and throat-clearing ( Box 1 ). Approximately 10% of all otolaryngologic clinic patients overall and 50% of patients with voice complaints have been diagnosed with LPR. However, the prevalence of LPR is difficult to determine because of lack of clear diagnostic gold standard and can certainly be exaggerated because even healthy individuals can have some findings consistent with LPR.
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Hoarseness
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Dysphonia
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Sore or burning throat
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Excessive throat clearing
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Chronic cough
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Globus
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Apnea
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Laryngospasm
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Dysphagia
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Postnasal drip
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Neoplasm
Pathophysiology
Laryngeal manifestation of GERD is thought to be related to direct acid-peptic injury to the larynx by esophagopharyngeal reflux (the microaspiration theory) or acidification of the distal esophagus through vagally mediated reflexes (the esophagealbrochial reflex theory) ( Fig. 6 ). Laryngeal tissue certainly lacks protective mechanisms of the esophagus (production of bicarbonate, physical barriers) and intrinsic acid clearance mechanism (peristalsis) and is highly vulnerable to any acid exposure. In addition to acidic pH levels, substances that can contribute to the noxious quality of the refluxate include pepsin, bile salts, and pancreatic enzymes. Earlier studies suggested that pepsin may be the main cause for LPR symptoms ; however, later studies suggested the coimportance of acid, pepsin, and bile acids. There is now a resurgence of publications on the role of pepsin in LPR. Some suggest that reflux of pepsin into the larynx with subsequent pepsin transfer into the cytoplasm of the laryngeal cells and later activation in the cell organelles with lower pH ranges than the lumen may be an important contributor to LPR. Dilation of intercellular spaces is reported to be an early morphologic marker in GERD; however, recent studies assessing dilation of intercellular spaces in patients suspected of LPR and GERD did not show a difference in epithelial space separation between patients and a group of control subjects.
