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

T HE E SOPHAGOGASTRIC J UNCTION
RAVINDER K. MITTAL, M.D.,
DAVID H. BALABAN, M.D.

AND

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 mechanism at the lower end of the
esophagus.1 Furthermore, in normal subjects and patients with reflux esophagitis, transient relaxation of
both sphincters rather than diminished lower esophageal sphincter pressure is the major mechanism of
gastroesophageal reflux.2 In this article we review
the current understanding of the physiology of the
sphincter mechanism at the esophagogastric junction and its relation to esophageal disease.
HISTORICAL PERSPECTIVE

A person can stand upside down after eating a

large meal, yet there is no reflux of food into the
mouth or esophagus. Why is this so? It is intuitively
clear that there must be a valve or sphincter mechanism at the lower end of the esophagus. What
constitutes this valvular mechanism has been studied intensely for many years. In 1958, Ingelfinger
stated that the pinchcock action of the diaphragm
is important in preventing gastroesophageal reflux.3
Later investigators recorded an intraluminal zone
of high pressure between the esophagus and the
stomach4 and suggested that intrinsic muscles of
the distal esophagus were entirely responsible for
maintaining this pressure. Not until 1985 was the
diaphragmatic hiatus proved to have a role in the
valvular mechanism at the esophagogastric junction.1

From the Division of Gastroenterology and Hepatology, Department of

Internal Medicine, Box 10013, University of Virginia Health Sciences Center, Charlottesville, VA 22906-0013, where reprint requests should be addressed to Dr. Mittal.
1997, Massachusetts Medical Society.

924 

ANATOMICAL CONSIDERATIONS

Several structures at the esophagogastric junction

are important in maintaining an antireflux barrier
(Fig. 1). The intrinsic muscles of the distal esophagus, along with the sling fibers of the proximal stomach, constitute the internal mechanism of the lower
esophageal sphincter, and the crural diaphragm constitutes the external mechanism. The phrenoesophageal ligament anchors the distal esophagus to the
crural diaphragm.
Under normal conditions, the lower esophageal
sphincter is approximately 4 cm long. The crural diaphragm, which forms the esophageal hiatus, encircles 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 has
been called the phrenic ampulla by radiologists, because it has a bulbar shape on barium swallow.6 The
phrenic ampulla most likely corresponds to the anatomical structures of the lower esophageal sphincter,
along with a part of the proximal stomach.
The muscles of the lower esophageal sphincter are
thicker than those of the adjacent esophagus.7,8 The
muscle thickness is not fixed, however, and is directly
related to the sphincter pressure.9 The sphincter has
a rich nerve supply, but the neuronal distribution
differs from that in the rest of the esophagus.10 In
the sphincter, the myenteric plexus lies in several
muscle planes, in contrast to the body of the esophagus, where the plexus lies between the layer of longitudinal muscle and the layer of circular muscle.
The sling, or oblique, fibers of the stomach, located below the lower esophageal sphincter, also contribute to the antireflux barrier. The sling fibers are
arranged in a C-shaped fashion, with the closed side
of the C located on the greater curvature and the
open side oriented toward the lesser curvature.11
This conformation of muscle fibers results in a flap
valve mechanism by which pressure in the gastric
fundus creates a flap that presses against the lower
end of the esophagus, augmenting the lower-esophageal-sphincter pressure.12
The diaphragm is composed of a costal part, which
originates from the ribs, and a crural part, which is attached to the vertebral column. The two parts of the
diaphragm have separate embryologic origins; the
crural diaphragm develops from the dorsal mesentery of the esophagus, and the costal diaphragm
from myoblasts originating in the lateral body wall.13
The crural diaphragm forms a canal through which
the esophagus enters the abdomen. In humans, this
canal is formed primarily by the right crus of the diaphragm.14 The outer fibers in the canal are oriented

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MECH A NIS MS OF D IS EASE

Longitudinal muscle
Lower
esophageal
sphincter
External

Circular muscle

Internal

Diaphragm
Costal part
Crural part

Phrenoesophageal
ligament

Sling fibers
Squamocolumnar junction
Stomach

Figure 1. Anatomy of the Esophagogastric Junction.

The lower esophageal sphincter and the crural diaphragm constitute the intrinsic and extrinsic sphincters, respectively. The two sphincters are anatomically superimposed and are anchored to each other
by the phrenoesophageal ligament.

in a cranial-to-caudad direction, and the inner fibers

are oriented obliquely. Contraction of the crural diaphragm exerts a pinchcock-like action on the lower
esophageal sphincter, thereby forming an extrinsic
sphincter mechanism.
ESOPHAGOGASTRIC-JUNCTION PRESSURE
UNDER VARIOUS PHYSIOLOGIC
CONDITIONS

The intraluminal pressure at the esophagogastric

junction is a measure of the strength of the antireflux barrier and is typically quantified with reference to the intragastric pressure. Both the lower
esophageal sphincter and the crural diaphragm contribute to the esophagogastric-junction pressure.
Since these two structures are anatomically superimposed, the intraluminal pressure may be due to
the contraction of either muscle. To avoid confusion, the intraluminal pressure will be referred to as
the esophagogastric-junction pressure. The contribution from contraction of intrinsic smooth muscles
of the distal esophagus will be called the loweresophageal-sphincter pressure, and contributions
from contractions of the crural diaphragm will be
termed the crural-diaphragm pressure. Distinguishing these pressures is important because it emphasizes the individual contribution of each structure to
the esophagogastric-junction pressure.

Continuous-pressure monitoring reveals that the

esophagogastric-junction pressure varies over time.
Minute-to-minute variations in pressure are attributable to contractions of the lower esophageal sphincter. These fluctuations in pressure are usually small,
ranging from 5 to 10 mm Hg. Large fluctuations in
pressure due to contraction of the lower esophageal
sphincter also occur, and these are coupled with the
activity of the migrating motor complex of the stomach. The frequency of these fluctuations in pressure is
the same as that of the migrating motor complex,
usually three per minute. The pressure of the lower
esophageal sphincter may exceed 80 mm Hg during
phase 3 of the migrating motor complex and typically
peaks before the onset of gastric contraction.15
Changes in the esophagogastric-junction pressure
are also related to contractions of the crural diaphragm. Normally, these contractions are linked with
respiration. Each inspiration increases the esophagogastric-junction pressure.16 This increase is abolished
by drugs, such as curare, that paralyze skeletal muscle.1 The amplitude of the increase in pressure during
inspiration is directly proportional to the force of
contraction of the crural diaphragm. During tidal
inspiration, the esophagogastric-junction pressure
increases by 10 to 20 mm Hg, and with deep inspiration the increase ranges from 50 to 150 mm Hg.
The crural diaphragm also contributes to the esophVol ume 336

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The New England Journal of Medicine

agogastric-junction pressure during activities other

than respiration, such as straight-leg raising and abdominal compression, because these activities induce
sustained tonic contraction of the crural diaphragm.17
The diaphragm also contracts during coughing, the
Valsalva maneuver, and any physical activity that
increases intraabdominal pressure. The crural diaphragm alone can maintain a zone of high pressure
at the abdominothoracic junction in patients who
have undergone surgical resection of the lower esophageal sphincter.18
NEURAL CONTROL
OF CONTRACTILITY

Muscle tone in the lower esophageal sphincter is

the result of neurogenic and myogenic mechanisms.
A substantial part of the neurogenic tone in humans
is due to cholinergic innervation.19 Although various
other excitatory and inhibitory neurotransmitters are
present in the muscle of the sphincter, their physiologic importance is unclear. Myogenic tone is mediated by shifts of intracellular stores of calcium in the
sphincter muscle.20
The modulation of lower-esophageal-sphincter
tone that occurs with activity of the migrating motor complex is largely mediated through the vagus
nerve.21 Relaxation of the sphincter induced by swallowing is mediated through the central nervous system (specifically, the dorsal nucleus of the vagus
nerve). Efferent stimuli travel to the sphincter through
the 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 contribute.22,23
The crural diaphragm, like the remainder of the
diaphragm, is innervated by the phrenic nerves. Although the diaphragmatic hiatus is primarily composed of muscles from the right crus, it is innervated
by both the right and left phrenic nerves. The spontaneous inspiratory activity of the crural diaphragm
is due to the activity of inspiratory neurons whose
cell bodies are located in the brain stem.24 This activity is transmitted to the nucleus of the phrenic
nerve, located in the cervical spinal cord. Voluntary
control of the diaphragm originates with cortical
neurons. The crural diaphragm contracts a fraction of
a second earlier than the costal diaphragm, which may
be physiologically important in relation to its function
as an antireflux barrier.25
Sensory mechanisms in the esophagus can mediate reflex relaxation of the crural diaphragm. Esophageal distention and swallowing induce relaxation of
the lower esophageal sphincter and selective inhibition of the crural diaphragm.26 Transient relaxation
of the sphincter, the principal mechanism of reflux,
is also associated with simultaneous inhibition of the
sphincter and the crural diaphragm.27,28
926 

PHYSIOLOGIC IMPORTANCE OF THE TWO

LOWER ESOPHAGEAL SPHINCTERS

Why do we need two lower esophageal sphincters?

The answer to this question lies in the observation
that the pressure gradient between the esophagus
and the stomach is constantly changing. Because this
gradient is the driving force behind gastroesophageal reflux, the esophagogastric-junction pressure
must constantly adapt to counteract these changes.
This adaptive response is mediated through contraction of either the lower esophageal sphincter or the
crural diaphragm.
At end-expiration, the pressure gradient between
the stomach and esophagus is 4 to 6 mm Hg. Therefore, a normal lower-esophageal-sphincter pressure
of 10 to 35 mm Hg at end-expiration suffices to
counteract the gradient. During activity of the migrating motor complex, gastric contractions increase
the gradient in favor of reflux. The lower-esophageal-sphincter contraction linked with the gastric contraction is thus important in preventing reflux.
Changes in pressure in the thorax and abdomen
due to the contraction of inspiratory and abdominal-wall muscles induce pressure changes in the
esophagus and stomach. Contraction of the inspiratory muscles lowers intraesophageal pressure, and
contraction of the abdominal wall raises gastric pressure, thus increasing the pressure gradient in favor
of gastroesophageal reflux. At such times, reflex
contractions of the crural diaphragm increase the
pressure at the esophagogastric junction. The rapid
changes in esophageal and gastric pressure caused by
contraction of the skeletal muscles of the chest and
abdomen are thus counteracted by rapid contraction
of the crural diaphragm.
MECHANISMS OF GASTROESOPHAGEAL
REFLUX

The movement of gastric contents into the esophagus, or gastroesophageal reflux, is due to a defective
sphincter mechanism at the esophagogastric junction. An understanding of the two lower esophageal
sphincters would lead one to expect weakness in either of the two to cause reflux. Indeed, some patients with reflux disease have a weak lower esophageal sphincter, some have a weak crural diaphragm,
and some have both. However, in patients with mildto-moderate (nonerosive) reflux disease, the pressures exerted by the lower esophageal sphincter29
and the crural diaphragm30 are normal. In fact, some
patients with mild-to-moderate reflux disease have a
higher-than-normal pressure at the lower esophageal
sphincter.31
What, then, is the mechanism of gastroesophageal
reflux? A large body of data indicates that in normal
subjects and patients with reflux disease, the condition is primarily due to transient relaxation of the

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M ECH A NIS MS OF D IS EASE

Smooth muscle
Striated muscle

Cortical stimuli

Sensory pathways
Motor pathways

Nucleus solitarius
Dorsal vagal nucleus
Nucleus ambiguus
Inspiratory center
Medulla

Pharynx

Phrenic nucleus
Phrenic nerve
Vagus
nerve

Vagus
nerve
Phrenic nerve

Ach

Ach

Esophagus
VIP
NO
Crural diaphragm

Ach

Myenteric plexus
Lower esophageal sphincter

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 receptors in the pharynx. The afferent stimulus travels to the sensory nucleus, the nucleus solitarius (small inset). A programmed
set 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 transmitters are nitric oxide (NO) and vasoactive intestinal peptide (VIP). Transient relaxation of the lower esophageal sphincter, the principal mechanism of reflux, appears to use the same neural pathway. The afferent signals for such relaxation may originate in the
pharynx, the larynx, or the stomach. The efferent pathway is in the vagus nerve, and nitric oxide is the postganglionic neurotransmitter. Contraction of the crural diaphragm is controlled by the inspiratory center in the brain stem and the nucleus of the phrenic
nerve. The crural diaphragm is innervated by the right and left phrenic nerves through nicotinic cholinergic receptors. Ach denotes
acetylcholine, plus signs excitatory effects, and minus signs inhibitory effects.

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The New England Journal of Medicine

Lower
esophageal
sphincter
8

pH

60 sec
Crural
diaphragm

4
0

10 mm Hg

Electrode
catheter

Pharynx

10 mm Hg

Midesophagus
10 mm Hg

Distal
esophagus

Lower
esophageal
sphincter

mm Hg

40

10 arbitrary
units

DEMG

10 mm Hg

Stomach

928 

Figure 3. The Physiologic Record of

a Spontaneous, Transient Relaxation
of the Lower Esophageal Sphincter.
Manometric recordings were made
with an electrode inside a catheter
(inset) at various locations from the
pharynx to the stomach. The vertical
arrow indicates the onset of relaxation, which occurs in the absence
of swallowing, as shown by the absence of a pressure wave in the
pharynx. There is complete relaxation, sustained for more than 20
seconds, to the level of the intragastric pressure (horizontal line at the
bottom of the tracing for the lower
esophageal sphincter). Relaxation is
associated with inhibition of the crural diaphragm, as indicated by the
loss of inspiratory pressure oscillations at the level of the sphincter
and by inspiratory diaphragmatic
electromyography (DEMG). The contribution of the lower esophageal
sphincter is shown in pink, and that
of the crural diaphragm in brown.
Reflux (indicated by a decrease in
esophageal pH) occurs after complete relaxation of the sphincter and
the crural diaphragm and is associated with an increase in intraesophageal pressure.
Adapted from Mittal et al.32 with the
permission of the publisher.

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MEC H A NIS MS OF D IS EASE

sphincter.36 However, in patients with low-amplitude

contractions and erosive esophagitis, healing of the
esophagitis does not restore normal esophageal contractility. Patients with scleroderma and mixed connective-tissue disease have a similar defect that is due
to the replacement of esophageal muscle with fibrous connective tissue.37 Cisapride, a prokinetic drug
that facilitates the release of acetylcholine, increases
the amplitude of esophageal contractions and relieves
symptoms of reflux in some patients.38

lower esophageal sphincter and the crural diaphragm

(Fig. 3).2
Transient relaxation of the lower esophageal
sphincter is a long period (lasting 10 to 60 seconds)
of simultaneous relaxation of the lower esophageal
sphincter and crural diaphragm. In normal subjects
whose lower-esophageal-sphincter pressure was reduced to zero by either a pharmacologic agent (atropine)32 or stimulation of pharyngeal receptors,33 reflux
occurred only during periods of transient inhibition
of the crural diaphragm. These findings indicate that
the absence of lower-esophageal-sphincter pressure in
normal subjects does not induce reflux if contraction
of the crural diaphragm is preserved.
Transient relaxation of the lower esophageal sphincter is a neural reflex that is mediated through the brain
stem (Fig. 2). The efferent pathway for such relaxation
is in the vagus nerve, and nitric oxide is the postganglionic neurotransmitter.34 The mechanism of relaxation of the crural diaphragm is not known. Gastric
distention and pharyngeal stimulation are two possible mechanisms by which the afferent stimulus that
initiates transient relaxation of the lower esophageal
sphincter may originate.2 Gastric distention, upright
and right lateral decubitus postures, and meals high in
fat increase the frequency of such relaxation.2 The nature of the afferent dysfunction that increases the frequency of transient relaxation of the lower esophageal
sphincter in patients with reflux disease is not clear.
A subgroup of patients, usually with severe reflux
disease, have decreased lower-esophageal-sphincter
pressures and low-amplitude esophageal contractions.
The latter result in an impaired ability to clear an
acid bolus from the esophagus after an episode of reflux.35 Whether this is a primary defect or one due
to acid-induced esophagitis is not clear. There is
good experimental evidence to indicate that acidinduced injury to the esophagus can impair the contractility of the esophagus and the lower esophageal

HIATAL HERNIA AND REFLUX DISEASE

The majority of patients with moderate-to-severe

reflux disease have hiatal hernia, a condition in which
a portion of stomach herniates into the chest. Hiatal
hernia was once considered synonymous with gastroesophageal reflux disease. However, its importance
in relation to reflux was disputed in the 1970s, when
low pressure in the lower esophageal sphincter rather than the presence of a hernia was thought to be
correlated with reflux disease.39 Understanding the
two sphincter mechanisms has helped redefine the
importance of hiatal hernia.
There are a number of mechanisms by which a hiatal hernia may promote reflux. First, such a hernia
impairs the clearance of acid from the esophagus.40,41
During swallowing, the lower esophageal sphincter
immediately relaxes and remains relaxed for six to
eight seconds, the time needed for the esophageal
peristalsis induced by swallowing to traverse from
the upper end of the esophagus to the lower end.
Therefore, the distal esophagus is unprotected from
the time the lower esophageal sphincter relaxes to the
time the esophageal contraction arrives. When there
is a hiatal hernia, gastric acid is trapped in the hernial
sac in close proximity to the esophagus. After swallowing begins, as the lower esophageal sphincter relaxes, this acid can flow backward into the esophagus
(Fig. 4). This process may be repeated with subse-

Esophagus
Lower
esophageal
sphincter
Hiatal hernia
Crural
diaphragm
Stomach

Figure 4. Mechanism of Reflux Due to Hiatal Hernia.

A hiatal hernia is an acquired herniation of part of the stomach through the diaphragm (Panel A). After an episode of reflux (Panel
B), an esophageal peristaltic contraction clears the bolus of acid from the esophagus (Panel C) into the hiatal hernia (Panel D).
Subsequently, swallowing-induced relaxation of the lower esophageal sphincter results in reflux of acid from the hernial sac into
the esophagus (Panel E). This sequence can be repeated several times and results in markedly prolonged clearance of acid.

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The New England Journal of Medicine

quent swallows. Hiatal hernia may also cause reflux

when contraction of the crural diaphragm during inspiration and other physical maneuvers lead to a
compartmentalization of the stomach between the
lower esophageal sphincter and the diaphragm. Subsequently, acid trapped in the hernial sac may flow
into the esophagus through the lower esophageal
sphincter, which is either weak or forced open by
negative intrapleural pressure. Decreased pressure at
the sphincter in the presence of a hiatal hernia allows
the hernial contents to move easily into the esophagus.42 Third, a large hiatal hernia causes a widening
of the esophageal hiatus that may impair the ability
of the crural diaphragm to function as a sphincter.42
Several well-described mechanisms of reflux (deep
inspiration, swallowing, and increased intraabdominal pressure) in patients with large hiatal hernias29,43
could be related to either compartmentalization of
the stomach or weak sphincter function of the crural
diaphragm. Finally, in patients with hiatal hernias,
the absence of the flap-valve mechanism and the loss
of an intraabdominal portion of the esophagus could
be important factors contributing to reflux.14
A unifying hypothesis that incorporates the presence of a hiatal hernia, a decreased lower-esophageal-sphincter pressure, and transient relaxation of the
sphincter to account for reflux disease may now be
proposed. The initial event in such disease is most
likely to be frequent transient relaxation of the lower
esophageal sphincter and episodes of acid reflux. The
presence of acid in the esophagus causes esophagitis,
which reduces the sphincter pressure and impairs
esophageal contractility. In turn, esophagitis shortens the esophagus by causing acid-induced contraction of longitudinal muscles.44 Subsequently, fibrosis
develops in esophageal smooth muscle, leading to
permanent esophageal shortening and a sliding hiatal hernia. The hernia then enlarges the esophageal
hiatus, impairing the sphincter function of the crural
diaphragm. The presence of a hiatal hernia and a
weak diaphragmatic sphincter introduces additional
mechanisms of reflux, exacerbating the esophagitis.
Although this hypothesis is plausible, its proof awaits
further study.
TREATMENT OF REFLUX DISEASE

Current therapy for gastroesophageal reflux disease focuses on modifying risk factors, inhibiting the
production of gastric acid, and enhancing esophageal and gastric contractility. Patients should be counseled on lifestyle changes that decrease the incidence
of reflux, including stopping cigarette smoking, reducing fat in the diet, avoiding meals two hours before lying down, and sleeping with the head of the
bed elevated. Antisecretory drugs, such as histamine
H2-receptor antagonists and proton-pump inhibitors, may be offered to patients with persistent symptoms, with the choice of drug based on the severity
930 

of the disease. H2-receptor antagonists are effective

for mild-to-moderate disease, whereas proton-pump
inhibitors are usually reserved for patients with moderate-to-severe disease. Therapy with a prokinetic
drug such as cisapride may be effective in decreasing
symptoms in up to half of patients with mild-tomoderate reflux disease.38 Patients with severe disease and those who do not wish to take lifelong
medication may opt for surgical fundoplication of
the esophagus. Newer laparoscopic techniques have
shortened the hospital stay associated with this procedure.45
The optimal treatment of reflux disease is to reduce
the frequency of transient relaxation of the lower
esophageal sphincter, the underlying pathophysiologic derangement. Nitric oxide antagonists block transient lower-esophageal-sphincter relaxation,34 but nitric oxide is also important in swallowing-induced
relaxation of the sphincter, and blocking its action
can result in dysphagia and a condition resembling
achalasia. Atropine and morphine decrease the frequency of transient relaxation of the lower esophageal sphincter in normal subjects through an unknown
mechanism.32,46 Whether these or similar drugs are
safe and effective in treating reflux disease remains
to be determined.
ACHALASIA OF THE ESOPHAGUS

Achalasia, a major motor disorder of the esophagus, is characterized by impaired swallowing-induced

relaxation of the smooth muscle of the lower esophageal sphincter and the absence of esophageal peristalsis. In patients with achalasia, the region of the
sphincter shows degeneration of the myenteric plexus47 and a marked reduction in nitric oxide synthase.48 Because nitric oxide is the inhibitory neurotransmitter of the sphincter, relaxation in its absence
is impaired.
In patients with achalasia, nitric oxidecontaining
neurons are more sensitive than cholinergic nerves to
the pathologic insult (as yet unidentified). This may
explain the cholinergic hyperresponsiveness of achalasic esophageal smooth muscle.49 Electrical stimulation of the normal lower-esophageal-sphincter muscle
causes it to relax, whereas in patients with achalasia
such stimulation results in a paradoxical contraction.50 Experimental ablation of myenteric nerves in
the lower esophageal sphincters of opossums (with
benzyldimethyl tetradecyl ammonium chloride) causes nitric oxidecontaining neurons to disappear and
cholinergic nerve fibers (possibly extrinsic) to proliferate.51
Two thirds of patients with achalasia have autoantibodies52 against a 62-kd protein (DARPP-32), a
dopamine-carrying protein on the surface of cells in
the myenteric plexus. Binding of this antibody to its
antigen on myenteric neurons may initiate the degeneration of the myenteric plexus reported in these

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MEC H A NIS MS OF D IS EASE

patients (Pasricha PJ, Singaram C: personal communication).

Patients with achalasia present with dysphagia,
chest pain, and weight loss. The disease occurs in all
age groups, but most commonly in middle age. The
aperistalsis in the body of the esophagus is usually
irreversible, but in a few patients peristalsis is partially restored after the sphincter pressure is reduced.
The goal of treatment is to reduce the sphincter pressure. In some patients, nitrates and calcium-channel
blockers are effective in alleviating symptoms temporarily. Dilation of the lower esophageal sphincter
with large-diameter balloons (30 to 40 mm) and
surgical myotomy are effective therapies in the majority of patients.
Both surgical myotomy and balloon dilation carry substantial risk, however. Dilation can perforate
the esophagus, and surgical myotomy predisposes
patients to gastroesophageal reflux. The endoscopic
injection of botulinum toxin into the muscle of the
lower esophageal sphincter has proved to be an effective treatment for achalasia.53 Botulinum toxin reduces pressure at the sphincter by blocking the release of acetylcholine from the myenteric plexus.
The reduction in pressure is associated with symptomatic improvement and improved esophageal emptying of solid food. For reasons that are not clear,
the effects of a single treatment with botulinum
toxin can last six months or longer; in a recent
study, 11 of 21 patients had improvement in symptoms for six months after one injection.53 These results are similar to the results of pneumatic balloon
dilation in patients with achalasia. There are no important side effects of therapy with botulinum toxin. Whether it will replace pneumatic dilation, which
provides sustained improvement with a minimal risk
of esophageal perforation (5 percent),54 remains to
be seen.
CONCLUSIONS

The lower end of the esophagus is guarded by an

intrinsic smooth muscle, the lower esophageal sphincter, and an extrinsic skeletal muscle, the crural diaphragm. Functional or degenerative disorders of these
two sphincters result in esophageal disease. Gastroesophageal reflux is due to neurogenically mediated
transient relaxation of the sphincter mechanisms.
Achalasia is caused by degeneration of the myenteric
plexus and loss of nitric oxidecontaining nerves in
the lower esophageal sphincter. Future studies should
help to elucidate the afferent neuronal dysfunction
that leads to frequent episodes of transient relaxation of the lower esophageal sphincter in patients
with reflux disease and to identify the insult that
causes inhibitory nerves in the myenteric plexus to
be selectively lost in patients with achalasia. With a
clear understanding of the neurohumoral mechanisms underlying these diseases, treatment strategies

can be directed at the primary pathologic processes

responsible.
Supported in part by grants (R-29-DK-45027 and R-01-DK-51604)
from the National Institutes of Health and by a grant from the Jeffress
Trust of Virginia.

We are indebted to R.W. McCallum, M.D., for his support and to

Linda Berry for providing artwork.

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