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The New England Journal of Medicine Review Articles Mechanisms of Disease F R A N K L I N H . E P S T E I N , M. D . , Editor ANATOMICAL CONSIDERATIONS T HE E SOPHAGOGASTRIC J UNCTION AND RAVINDER K. MITTAL, M.D., DAVID H. BALABAN, M.D. T HE lower esophageal sphincter regulates the flow of food between the esophagus and the stomach. It is now clear that both the intrinsic smooth muscle of the distal esophagus and the skeletal muscle of the crural diaphragm constitute the sphincter mechani
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   Review Articles  Mechanisms of Disease   F  RANKLIN  H. E  PSTEIN  , M.D.,  Editor   924    March 27, 1997  The New England Journal of Medicine  T  HE  E  SOPHAGOGASTRIC   J  UNCTION  R   AVINDER  K. M   ITTAL  , M.D.,   AND  D   AVID  H. B   ALABAN  , M.D.  From the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Box 10013, University of Virginia Health Sciences Cen-ter, Charlottesville, VA 22906-0013, where reprint requests should be ad-dressed to Dr. Mittal.©1997, Massachusetts Medical Society.  HE lower esophageal sphincter regulates theflow of food between the esophagus and thestomach. It is now clear that both the intrin-sic smooth muscle of the distal esophagus and theskeletal muscle of the crural diaphragm constitutethe sphincter mechanism at the lower end of theesophagus.  1  Furthermore, in normal subjects and pa-tients with reflux esophagitis, transient relaxation of both sphincters rather than diminished lower esoph-ageal sphincter pressure is the major mechanism of gastroesophageal reflux.  2  In this article we review the current understanding of the physiology of thesphincter mechanism at the esophagogastric junc-tion and its relation to esophageal disease.  HISTORICAL PERSPECTIVE   A person can stand upside down after eating alarge meal, yet there is no reflux of food into themouth or esophagus. Why is this so? It is intuitively clear that there must be a valve or sphincter mech-anism at the lower end of the esophagus. Whatconstitutes this valvular mechanism has been stud-ied intensely for many years. In 1958, Ingelfingerstated that the pinchcock action of the diaphragmis important in preventing gastroesophageal reflux.  3 Later investigators recorded an intraluminal zoneof high pressure between the esophagus and thestomach  4  and suggested that intrinsic muscles of the distal esophagus were entirely responsible formaintaining this pressure. Not until 1985 was thediaphragmatic hiatus proved to have a role in the valvular mechanism at the esophagogastric junc-tion.  1 T   ANATOMICAL CONSIDERATIONS  Several structures at the esophagogastric junctionare important in maintaining an antireflux barrier(Fig. 1). The intrinsic muscles of the distal esopha-gus, along with the sling fibers of the proximal stom-ach, constitute the internal mechanism of the loweresophageal sphincter, and the crural diaphragm con-stitutes the external mechanism. The phrenoesoph-ageal ligament anchors the distal esophagus to thecrural diaphragm.Under normal conditions, the lower esophagealsphincter is approximately 4 cm long. The crural di-aphragm, which forms the esophageal hiatus, encir-cles the proximal 2 cm of the sphincter.  5  Therefore,part of the sphincter lies in the esophageal hiatus,and part is intraabdominal. The distal esophagus hasbeen called the phrenic ampulla by radiologists, be-cause it has a bulbar shape on barium swallow.  6  Thephrenic ampulla most likely corresponds to the ana-tomical structures of the lower esophageal sphincter,along with a part of the proximal stomach.The muscles of the lower esophageal sphincter arethicker than those of the adjacent esophagus.  7,8  Themuscle thickness is not fixed, however, and is directly related to the sphincter pressure.  9  The sphincter hasa rich nerve supply, but the neuronal distributiondiffers from that in the rest of the esophagus.  10  Inthe sphincter, the myenteric plexus lies in severalmuscle planes, in contrast to the body of the esoph-agus, where the plexus lies between the layer of lon-gitudinal muscle and the layer of circular muscle.The sling, or oblique, fibers of the stomach, locat-ed below the lower esophageal sphincter, also con-tribute to the antireflux barrier. The sling fibers arearranged in a C  -shaped fashion, with the closed sideof the C  located on the greater curvature and theopen side oriented toward the lesser curvature.  11  This conformation of muscle fibers results in a “flap valve” mechanism by which pressure in the gastricfundus creates a flap that presses against the lowerend of the esophagus, augmenting the lower-esoph-ageal-sphincter pressure.  12  The diaphragm is composed of a costal part, whichsrcinates from the ribs, and a crural part, which is at-tached to the vertebral column. The two parts of thediaphragm have separate embryologic srcins; thecrural diaphragm develops from the dorsal mesen-tery of the esophagus, and the costal diaphragmfrom myoblasts srcinating in the lateral body wall.  13  The crural diaphragm forms a canal through whichthe esophagus enters the abdomen. In humans, thiscanal is formed primarily by the right crus of the di-aphragm.  14  The outer fibers in the canal are oriented Copyright © 1997 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org by DANIEL PONCE on April 3, 2007 .   MECHANISMS OF DISEASE   Volume 336Number 13    925  in a cranial-to-caudad direction, and the inner fibersare oriented obliquely. Contraction of the crural di-aphragm exerts a pinchcock-like action on the loweresophageal sphincter, thereby forming an extrinsicsphincter mechanism.  ESOPHAGOGASTRIC-JUNCTION PRESSUREUNDER VARIOUS PHYSIOLOGICCONDITIONS  The intraluminal pressure at the esophagogastric junction is a measure of the strength of the anti-reflux barrier and is typically quantified with refer-ence to the intragastric pressure. Both the loweresophageal sphincter and the crural diaphragm con-tribute to the esophagogastric-junction pressure.Since these two structures are anatomically super-imposed, the intraluminal pressure may be due tothe contraction of either muscle. To avoid confu-sion, the intraluminal pressure will be referred to asthe esophagogastric-junction pressure. The contri-bution from contraction of intrinsic smooth musclesof the distal esophagus will be called the lower-esophageal-sphincter pressure, and contributionsfrom contractions of the crural diaphragm will betermed the crural-diaphragm pressure. Distinguish-ing these pressures is important because it empha-sizes the individual contribution of each structure tothe esophagogastric-junction pressure.Continuous-pressure monitoring reveals that theesophagogastric-junction pressure varies over time.Minute-to-minute variations in pressure are attribut-able to contractions of the lower esophageal sphinc-ter. These fluctuations in pressure are usually small,ranging from 5 to 10 mm Hg. Large fluctuations inpressure due to contraction of the lower esophagealsphincter also occur, and these are coupled with theactivity of the migrating motor complex of the stom-ach. The frequency of these fluctuations in pressure isthe same as that of the migrating motor complex,usually three per minute. The pressure of the loweresophageal sphincter may exceed 80 mm Hg duringphase 3 of the migrating motor complex and typically peaks before the onset of gastric contraction.  15  Changes in the esophagogastric-junction pressureare also related to contractions of the crural dia-phragm. Normally, these contractions are linked withrespiration. Each inspiration increases the esophago-gastric-junction pressure.  16  This increase is abolishedby drugs, such as curare, that paralyze skeletal mus-cle.  1  The amplitude of the increase in pressure duringinspiration is directly proportional to the force of contraction of the crural diaphragm. During tidalinspiration, the esophagogastric-junction pressureincreases by 10 to 20 mm Hg, and with deep inspi-ration the increase ranges from 50 to 150 mm Hg.The crural diaphragm also contributes to the esoph-   Figure 1.   Anatomy of the Esophagogastric Junction.The lower esophageal sphincter and the crural diaphragm constitute the intrinsic and extrinsic sphinc-ters, respectively. The two sphincters are anatomically superimposed and are anchored to each otherby the phrenoesophageal ligament. Circular muscleLongitudinal muscleStomachLoweresophagealsphincterSquamocolumnar junctionPhrenoesophagealligamentDiaphragmSling fibers ExternalInternalCostal partCrural part Copyright © 1997 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org by DANIEL PONCE on April 3, 2007 .   926    March 27, 1997  The New England Journal of Medicine  agogastric-junction pressure during activities otherthan respiration, such as straight-leg raising and ab-dominal compression, because these activities inducesustained tonic contraction of the crural diaphragm.  17  The diaphragm also contracts during coughing, the Valsalva maneuver, and any physical activity thatincreases intraabdominal pressure. The crural dia-phragm alone can maintain a zone of high pressureat the abdominothoracic junction in patients whohave undergone surgical resection of the lower esoph-ageal sphincter.  18  NEURAL CONTROL OF CONTRACTILITY  Muscle tone in the lower esophageal sphincter isthe result of neurogenic and myogenic mechanisms. A substantial part of the neurogenic tone in humansis due to cholinergic innervation.  19   Although variousother excitatory and inhibitory neurotransmitters arepresent in the muscle of the sphincter, their physio-logic importance is unclear. Myogenic tone is medi-ated by shifts of intracellular stores of calcium in thesphincter muscle.  20  The modulation of lower-esophageal-sphinctertone that occurs with activity of the migrating mo-tor complex is largely mediated through the vagusnerve.  21  Relaxation of the sphincter induced by swal-lowing is mediated through the central nervous sys-tem (specifically, the dorsal nucleus of the vagusnerve). Efferent stimuli travel to the sphincter throughthe vagus nerve and the myenteric plexus (Fig. 2).The presynaptic neurotransmitter is acetylcholine,and the postsynaptic neurotransmitter is nitric oxide,although vasoactive intestinal peptide may also con-tribute.  22,23  The crural diaphragm, like the remainder of thediaphragm, is innervated by the phrenic nerves. Al-though the diaphragmatic hiatus is primarily com-posed of muscles from the right crus, it is innervatedby both the right and left phrenic nerves. The spon-taneous inspiratory activity of the crural diaphragmis due to the activity of inspiratory neurons whosecell bodies are located in the brain stem.  24  This ac-tivity is transmitted to the nucleus of the phrenicnerve, located in the cervical spinal cord. Voluntary control of the diaphragm srcinates with corticalneurons. The crural diaphragm contracts a fraction of a second earlier than the costal diaphragm, which may be physiologically important in relation to its functionas an antireflux barrier.  25  Sensory mechanisms in the esophagus can medi-ate reflex relaxation of the crural diaphragm. Esoph-ageal distention and swallowing induce relaxation of the lower esophageal sphincter and selective inhibi-tion of the crural diaphragm.  26  Transient relaxationof the sphincter, the principal mechanism of reflux,is also associated with simultaneous inhibition of thesphincter and the crural diaphragm.  27,28  PHYSIOLOGIC IMPORTANCE OF THE TWOLOWER ESOPHAGEAL SPHINCTERS   Why do we need two lower esophageal sphincters?The answer to this question lies in the observationthat the pressure gradient between the esophagusand the stomach is constantly changing. Because thisgradient is the driving force behind gastroesoph-ageal reflux, the esophagogastric-junction pressuremust constantly adapt to counteract these changes.This adaptive response is mediated through contrac-tion of either the lower esophageal sphincter or thecrural diaphragm. At end-expiration, the pressure gradient betweenthe stomach and esophagus is 4 to 6 mm Hg. There-fore, a normal lower-esophageal-sphincter pressureof 10 to 35 mm Hg at end-expiration suffices tocounteract the gradient. During activity of the mi-grating motor complex, gastric contractions increasethe gradient in favor of reflux. The lower-esophage-al-sphincter contraction linked with the gastric con-traction is thus important in preventing reflux.Changes in pressure in the thorax and abdomendue to the contraction of inspiratory and abdomi-nal-wall muscles induce pressure changes in theesophagus and stomach. Contraction of the inspira-tory muscles lowers intraesophageal pressure, andcontraction of the abdominal wall raises gastric pres-sure, thus increasing the pressure gradient in favorof gastroesophageal reflux. At such times, reflexcontractions of the crural diaphragm increase thepressure at the esophagogastric junction. The rapidchanges in esophageal and gastric pressure caused by contraction of the skeletal muscles of the chest andabdomen are thus counteracted by rapid contractionof the crural diaphragm. MECHANISMS OF GASTROESOPHAGEAL REFLUX   The movement of gastric contents into the esoph-agus, or gastroesophageal reflux, is due to a defectivesphincter mechanism at the esophagogastric junc-tion. An understanding of the two lower esophagealsphincters would lead one to expect weakness in ei-ther of the two to cause reflux. Indeed, some pa-tients with reflux disease have a weak lower esopha-geal sphincter, some have a weak crural diaphragm,and some have both. However, in patients with mild-to-moderate (nonerosive) reflux disease, the pres-sures exerted by the lower esophageal sphincter  29  and the crural diaphragm  30  are normal. In fact, somepatients with mild-to-moderate reflux disease have ahigher-than-normal pressure at the lower esophagealsphincter.  31   What, then, is the mechanism of gastroesophagealreflux? A large body of data indicates that in normalsubjects and patients with reflux disease, the condi-tion is primarily due to transient relaxation of the Copyright © 1997 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org by DANIEL PONCE on April 3, 2007 .   MECHANISMS OF DISEASE   Volume 336Number 13    927   Figure 2.   Neural Pathways to the Lower Esophageal Sphincter and Crural Diaphragm.Esophageal peristalsis and relaxation of the lower esophageal sphincter induced by swallowing result from the excitation of re-ceptors in the pharynx. The afferent stimulus travels to the sensory nucleus, the nucleus solitarius (small inset). A programmedset of events from the dorsal vagal nucleus and the nucleus ambiguus mediates esophageal peristalsis and sphincter relaxation.The vagal efferent fibers communicate with myenteric neurons that mediate relaxation (large inset). The postganglionic transmit-ters are nitric oxide (NO) and vasoactive intestinal peptide (VIP). Transient relaxation of the lower esophageal sphincter, the prin-cipal mechanism of reflux, appears to use the same neural pathway. The afferent signals for such relaxation may srcinate in thepharynx, the larynx, or the stomach. The efferent pathway is in the vagus nerve, and nitric oxide is the postganglionic neurotrans-mitter. Contraction of the crural diaphragm is controlled by the inspiratory center in the brain stem and the nucleus of the phrenicnerve. The crural diaphragm is innervated by the right and left phrenic nerves through nicotinic cholinergic receptors. Ach denotesacetylcholine, plus signs excitatory effects, and minus signs inhibitory effects.Smooth muscleStriated muscleSensory pathwaysMotor pathways Phrenic nervePhrenic nerveVagusnerveVagusnerve  Ach  Ach  Ach  VIP  NOCortical stimuliDorsal vagal nucleusNucleus ambiguusNucleus solitariusPhrenic nucleusMedullaInspiratory centerPharynxEsophagusCrural diaphragmLower esophageal sphincterMyenteric plexus Copyright © 1997 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org by DANIEL PONCE on April 3, 2007 .
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