The Sphincter of Oddi - Springer

Dig Dis Sci (2007) 52:1211–1218
DOI 10.1007/s10620-006-9171-8
REVIEW PAPER
The Sphincter of Oddi
Antonio Bosch · Luis R. Peña
Received: 24 October 2005 / Accepted: 21 November 2005 / Published online: 14 March 2007
C○ Springer Science+Business Media, Inc. 2006
Keywords Ampulla of Vater . Major papilla .
Choledochopancreatic junction . Bile flow regulation .
Sphincter dysfunction
Introduction
In the last decade and a half, much interest has been focused
on disturbances of the sphincter of Oddi as being
part of the functional bowel disorder syndrome. This has received
particular emphasis in postcholecystectomy patients
who have recurrent attacks of biliary or pancreatic type pain.
Many studies have shown that severing the musculature of
this sphincteric system may improve symptoms in a selected
population. Unfortunately, identifying this group of patients
has been a challenge. Anatomic and neurophysiologic studies
have uncovered an intricate muscular and neural network
between the sphincter of Oddi and its surroundings. This
may explain the difficulties in trying to propose a pathophysiologic
mechanism in the dysfunction of the sphincter
of Oddi, and in identifying patients who may benefit from
certain therapies.
In this paper, we will review the anatomy, physiology
and pharmacology of the sphincter of Oddi, paying special
attention to its seemingly complex intrinsic innervation. We
A. Bosch · L. R. Peña
University of Kentucky Chandler Medical Center, Division of
Digestive Diseases and Nutrition,
Lexington
A. Bosch ()
University of Kentucky Chandler Medical Center, Division of
Digestive Diseases and Nutrition,
800 Rose Street, Room MN 649, Lexington, KY 40536-0298
e-mail: abosc0@uky.edu
will also briefly discuss sphincter of Oddi dysfunction; its
definition, as well as its diagnosis and treatment.
Anatomy
The presence of a sphincter mechanism at the distal end of
the common bile duct was postulated as early as the 1600s
by anatomists such as Francisci Glissoni [1]. However, it
was not until 1887 that Rugero Oddi described the structure
that now bears his name, as a smooth muscle sphincter that
functions as a regulator of the flow of bile [2]. In the 1930s
Boyden, working with fetal material, was able to identify
a common bile duct and pancreatic duct sphincter musculature
that was distinct from the duodenal musculature [3].
Embryologically, the sphincter arises from the ventral floor
of the foregut and develops approximately 5 weeks after the
duodenal musculature.
Investigators looked at the morphology of the sphincter
of Oddi and separated this into distinct zones. In the 1950s,
Papalmitiades and Rettori described zones that made up the
sphincteric system: a specific common bile duct sphincter,
10 mm in length; a specific pancreatic duct sphincter, 6 mm
in length; and a common sphincter made up of thick, circular,
semicircular, longitudinal muscle fibers, and extending
approximately 6 mm [4]. In the 1960s, Barraya also divided
the sphincter into three parts, but in a somewhat different
fashion than Rettori et al. [5]. He described a superior occlusive
sphincter, a middle sphincter for both common bile
duct and pancreatic duct, and an inferior sphincter that took
part in the formation of the papilla. The superior occlusive
sphincter of each duct probably corresponded to the junction
point between the circular smooth muscle and the respective
duct, forming a notch that can often be seen in normal
cholangiogram images.
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1212 Dig Dis Sci (2007) 52:1211–1218
In the mid-1960s, Hand used cholangiogram images, duct
casting, as well as histologic studies in order to further describe
the anatomy of the sphincter of Oddi [6]. However, he
was unable to appreciate separate and distinct elements of the
sphinteric system as previously described. He observed that
before entering the duodenal wall, the common bile duct and
pancreatic duct become ensheathed together by connective
tissue, penetrating the duodenal wall through a muscular orifice
called the choledochal window. Outside the choledochal
window, both ducts become completely surrounded by circular
smooth muscle fibers, some in a figure-of-eight configuration
between both ducts. As both ducts pass through
the duodenal wall, the circular smooth muscle fibers of the
ducts and the duodenal wall musculature integrate via a network
of longitudinal muscle fibers. At this point, the lumen
of both ducts are not joined, but are separated by a thick
muscular septum. In the majority of cases, the two lumens
will become fused as they follow a variable course through
the submucosal layer of the duodenum to form the common
channel (Fig. 1). Throughout their course in the duodenal
submucosa the ducts and the common channel are further
surrounded by common circular smooth muscle. Columnar
epithelium with mucous-secreting glands lines the mucosa
of the sphincter. Mucosal valvules projecting from the orifice
of the papilla can often be seen, which represent longitudinal
mucosal folds emanating from the common channel.
Innervation
Intrinsic
The sphincter of Oddi intrinsic innervation appears to be
very complex. Two ganglionated plexuses have been described;
an outer myenteric plexus between the muscle layers
and a submucosal plexus. Various neurotransmitters and
hormones appear to have a regulatory effect in the neurons
of these plexuses. Most of the data regarding the intrinsic
innervation of the sphincter of Oddi and its interaction with
nearby structures come from animal studies. Talmage et al.,
using immunoassays, characterized distinct sub-populations
of neurons in the sphincter of Oddi of the guinea pig [7, 8].
The largest population of neurons was found to be immunoreactive
to choline acetyltransferase, as well as substance P and
enkephalin. These neurons are thought to be excitatory and
therefore increase SO tone in the guinea pig. The smaller
population of neurons was immunoreactive to nitric oxide
synthase, and was also found to express vasoactive intestinal
peptide (VIP) or neuropeptide Y. This population of neurons
was more likely inhibitory and cause relaxation of the SO
tone.
The most important hormone in the regulation of the SO
function appears to be cholecystokinin (CCK). Its effect on
Fig. 1 Anatomy of the papilla with the pancreatic duct (PD) and the
common bile duct (CBD) fused as they follow a variable course through
the submucosal layer of the duodenum to form the common channel
the SO is species dependent. In humans, cats, dogs and the
Australian brush-tailed possum, it decreases SO muscle tone,
while in the guinea pig and North American opossum it
causes alternating contraction and relaxation of the SO muscle
[9–13]. Regardless, its function is one of promoting flow
of bile and pancreatic juice into the duodenum. Animal studies
have suggested that neurons in the SO contain CCK
receptors that undergo prolonged depolarization and bursts
of action potential when stimulated with CCK octapeptide
(CCK-8) [14]. However, since the effect of CCK on the SO
may be inhibited by muscarinic blockade with atropine, and
the sensitivity of SO neurons may be inadequate at physiological
concentrations of CCK, its direct action is probably
on neurons providing input to the SO ganglia. A specific subpopulation
of neurons that project from the duodenum to the
SO ganglia has been shown in the possum and guinea pig by
retrograde labeling of SO neurons using carbocyanine. Immunoassay
studies on this sub-population of neurons have
demonstrated cholinergic or excitatory activity.
Kennedy and Mawe, in two separate studies, looked at the
sensitivity of these duodenal neurons to CCK in the guinea
pig and whether they provided any synaptic input to the SO
myenteric neurons [15, 16]. In the first study, published in
1998, they identified duodenal neurons projecting to the SO
by retrograde labeling with carbocyanine. These neurons
were then exposed to CCK-8, which elicited a prolonged
depolarization response. In their second study, published in
1999, the investigators isolated nerve bundles in the duodenal
mucosa which were then electrically stimulated while
a recording electrode was placed in the SO neurons. Fast
excitatory post-synaptic potentials (EPSP) were recorded in
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Dig Dis Sci (2007) 52:1211–1218 1213
Fig. 2 Blood supply to the
region of the sphincter of Oddi
54% of the SO neurons. Furthermore, this response was
completely inhibited by hexamethonium, suggesting a
cholinergic mediated response. A similar result was obtained
using intact duodenal mucosa, which localized first order
neurons of this response at the level of the duodenal villi.
In summary, it seems that the major intrinsic innervation
regulating the function of the SO comes from neurons that
originate in the duodenal mucosa and project into the SO
myenteric plexus. A smaller and still unclear contribution, at
least in humans, comes from a population of neurons in the
SO.
Extrinsic
Extrinsic innervation of the sphincter of Oddi is thought to be
similar to that of the rest of the biliary tract. Parasympathetic
input is mainly from cholinergic nerves originating from the
vagus. Sympathetic nerves travel via the superior mesenteric
ganglion by way of the inferior pancreatic duodenal artery.
However, the interaction of these nerves with the sphincter
of Oddi is not well understood.
Blood supply
In about half of the individuals an arterial plexus formed by
the ventral and dorsal branches of the retroduodenal artery
(also known as the posterior superior and anterior superior
pancreaticoduodenal artery) provides the major blood supply
to the region of the sphincter of Oddi (Fig. 2) [17].
The distance between the retroduodenal artery and the papillary
orifice is about 35 mm in the majority of individuals.
However, in about 5% of the population, this artery may be
located closer to the papillary orifice, placing it within the
range of an endoscopic sphincterotomy and increasing the
risk of severe hemorrhage during this therapeutic endoscopy
maneuver.
Sphincter of Oddi physiology
The function of the sphincter of Oddi is three-fold: (1) Regulates
the flow of bile and pancreatic juices into the duodenum,
(2) Diverts hepatic bile into the gallbladder reservoir,
(3) Prevents the reflux of duodenal contents into the pan-
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creaticobiliary system as well as keeps the bile duct free of
sludge and particulate matter. These functions are carried out
through a passive and an active component; the basal pressure,
and the phasic contraction, respectively. The basal pressure
component is responsible for minute-to-minute changes
with normal values ranging from 20 to 25 mm Hg (8–10 mm
Hg higher than the CBD). Phasic contractions are spontaneous
and rhythmic contractions that are important in the
“housekeeping” of the CBD. These are defined as the peak
SO pressure minus the basal SO pressure. Guelrud et al.
measured SO phasic contraction pressures in 50 healthy individuals
[18]. The average phasic pressure was 128 mm Hg
above the basal pressure; the average frequency of phasic
contractions was four/min, and the average contraction duration
was 6 s. Sixty percent of the phasic contractions were
antegrade, 14% retrograde, and 26% simultaneous. Toouli
et al. measured phasic wave propagation in 20 normal controls
and 15 patients with CBD stones [19]. Sixty percent
of normal controls had antegrade wave propagation, while
53% of patients with CBD stones had retrograde propagation.
Whether this finding was the result of a stone in the
CBD or the cause of stone formation is not entirely clear. Simultaneous
myoelectric recordings of the sphincter of Oddi
and the duodenal muscle have shown that phasic contractions
correspond to discrete electrical spike bursts independent
of duodenal electrical activity [20]. Furthermore, the
relation between SO activity and the migrating motor complex
(MMC) has been investigated [21, 22]. In contrast to
the MMC phase I, the activity of the sphincter of Oddi does
not have a period of total quiescence. Its frequency remains
constant until just the beginning of phase III of the duodenal
MMC, when it increases to approximately the same
frequency of the duodenal contractions. This increased activity
continues during the length of phase III of the duodenal
MMC, returning to normal after the end of phase III.
In addition to the “housekeeping” function, the phasic
contractions of the sphincter of Oddi promote flow into the
duodenum. The manner by which bile flows from the CBD
into the duodenal lumen varies from species to species. In
the opossum, there is a decrease in the basal pressure of the
SO, allowing bile to flow from the CBD to the SO segment
and then passively into the duodenum. However, the major
flow of bile is by an antegrade propulsive wave along the
SO segment [23]. In the fed state, the frequency of contractions
increases resulting in an increased bile flow across
the sphincter of Oddi. Conversely, in humans and dogs, the
majority of the bile flow into the duodenum occurs passively
between phasic contractions [22]. Actually, the main
function of the phasic contractions is to fill the distal duct
with bile, contributing very little to the expelling of bile
into the duodenum. During a meal there is no increase in
the frequency of contractions, but rather a decrease in the
amplitude, which increases the CBD filling interval. As the
Table 1 Effect on the motility of the sphincter of Oddi to a variety of
gastrointestinal hormones and drugs
Hormone/Drug Basal Pressure Phasic Pressure
CCK ↓ ↓
Secretin ↓ ↓
Glucagon ↔ ? ↓ ?
Octreotide ↑ ↑
Morphine ↑ ↑
Meperidine ↔ ↑
Atropine ↓ ↓
Nifedepine ↓ ↓
Amyl nitrate ↓ ↓
Midazolam ↔ ? ↔ ?
basal pressure of the SO decreases, passive flow of bile into
the duodenum increases. Other less well understood indirect
pathways can promote SO relaxation and bile flow. Examples
of these include increase gallbladder pressure and gastric
antrum distention.
Sphincter of Oddi pharmacology
The motility of the sphincter of Oddi can be influenced by
a variety of gastrointestinal hormones and drugs (Table 1).
As discussed previously, cholecystokin in (CCK) is the most
prominent hormone affecting SO motility. In humans, it inhibits
phasic contractions and reduces basal pressure, with an
overall effect of increasing bile flow into the duodenum [11].
CCK effects may be mediated directly through SO receptors
and/or indirectly by neural pathways between the duodenum
and the SO via non-adrenergic, non-cholinergic inhibitory
nerves. In animal studies, a direct excitatory action of CCK
on SO has been shown which is inhibited by the release of
an inhibitory non-adrenergic neurotransmitter. In cats, pharmacologic
denervation of the SO causes a paradoxical effect
in response to CCK [9]. This paradoxical response to CCK
has been observed in patients with suspected SO dyskinesia
[24].
Secretin, a well-known polypeptide hormone that is released
from the duodenal mucosal S-cells in response to
intraluminal acid, inhibits human SO motility [25, 26]. In
chronic alcohol abusers with no pancreatic disease, secretin
was found to induce a paradoxical spasmodic response in the
SO instead of the relaxation observed in controls [27].
The effect of glucagon on the human SO is controversial.
Several studies have shown a decrease in both the basal
and phasic pressures of the SO upon administration of intravenous
glucagon [28, 29]. Biliotti et al. showed no effect of
glucagon on the SO [30].
Octreotide acts at different sites in the human gastrointestinal
tract and generally inhibits the release of many gastrointestinal
hormones and neuropeptides, which has led
to its use in the treatment of acute pancreatitis. However,
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multi-center trials have failed to show a beneficial effect of
octreotide in the management of acute pancreatitis or the
prevention of post-ERCP pancreatitis [31–33]. In fact, cases
of octreotide-induced pancreatitis have been reported [34].
Morphine increases both the basal and phasic pressure of
the human SO and has been use in provocation studies to
diagnose SOD [35–37]. In contrast, meperidine is routinely
used in patients with biliary-type pain because of its lesser
effects on the SO. Elta et al. studied the effect of meperidine
on the sphincter of Oddi in 18 patients undergoing manometry
[38]. They found no difference in the baseline sphincter
pressure before and after meperidine in all patients. However,
the frequency of phasic contractions increased after
administration of meperidine.
Atropine, nifedipine and nitrates decrease both basal and
phasic pressure in the human SO. In both animal and human
studies, atropine has been found to antagonize the excitatory
effects of morphine and electrical stimulation on the
SO [35, 39]. This effect is thought to be mediated by M3
muscarinic receptors. Guelrud et al. investigated the effect
of nifedipine on the SO motor activity of healthy individuals
by performing endoscopic manometry after administration of
sublingual nifedipine [40]. The study concluded that 20 mg
of sublingual nifedipine produce a moderate but significant
decrease in basal SO pressure from 12.0 to 6.7 mm Hg as
well as in the amplitude, duration, and frequency of phasic
contractions. Glyceryl trinitrate (GTN), a nitric oxide donor,
relaxes the human SO when administered systemically [41].
In addition, both GTN and isosorbide dinitrate (ISND) can
evoke a profound inhibition of SO motility when administered
topically onto the papilla of Vater [42].
The effect of midazolam on the SO has been investigated
in four separate studies [43–46]. These studies concluded
that midazolam has a minimal effect on both the basal pressure
and phasic contractions in subjects with normal SO
manometry. However, in patients with elevated SO pressures
there was a significant decrease in the basal pressure and
phasic contractions.
Sphincter of Oddi dysfunction
Sphincter of Oddi dysfunction (SOD), also known as papillary
stenosis, sclerosing papillitis, biliary spasm and postcholecystectomy
syndrome, can be further subdivided into
two entities: (1) sphincter of Oddi stenosis and (2) sphincter
of Oddi dyskinesia.
Sphincter of Oddi stenosis
This entity encompasses any structural abnormality involving
the periampullary duodenal mucosa or the most distal
segments of the CBD or pancreatic duct associated with
narrowing of the sphincter of Oddi. Any pathological process
involving the SO which causes inflammation or scarring
can lead to SO stenosis. Such processes include pancreatitis,
passage of a CBD stone, intra-operative trauma, infection
and adenomyosis. The result of this stenosis is abnormal SO
motility and elevated basal pressures.
Sphincter of Oddi dyskinesia
In contrast to SO stenosis, SO dyskinesia is a functional
disorder which causes transient obstruction leading to the
typical symptoms associated with SOD. The pathological
disturbance of this entity is not well understood, but several
theories have been put forth. One proposed theory is a
malfunction in the neuronal pathway, intrinsic or extrinsic,
resulting in a paradoxical response to endogenous hormones.
A second theory is a disturbance of the smooth muscle of the
SO, at the hormone/neurotransmitter level.
Clinical features
The main clinical feature of SOD is recurrent bouts of epigastric/RUQ
pain which may radiate to the back and are often
precipitated by meals. The typical pain seen in SOD may be
associated with the following:
1. Transient increase of LFT’s or pancreatic enzymes at the
time of pain bouts.
2. Dilation of the CBD or PD demonstrated by radiological
imaging.
3. Delay in the emptying of contrast from the CBD or PD
while in the supine position.
However, the above features are not required for the diagnosis
of SOD, but are helpful for its classification into
different types.
Classification
Sphincter of Oddi dysfunction can be classified into biliary
SOD or pancreatic SOD, depending on the nature of the
abdominal pain. In addition, these two groups can be further
subdivided when the presence or absence of associated
clinical features are taken into account (Table 2).
Diagnosis
Diagnostic evaluation for SOD has included both noninvasive
and invasive tests. Imaging of the CBD and PD can
discover abnormally dilated ductal systems. Provocative
testing with CCK or morphine can induce dilation of both
the CBD and PD, and can reproduce the characteristic
pain associated with SOD. Hepatobiliary scintigraphy can
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1216 Dig Dis Sci (2007) 52:1211–1218
Table 2
Classification of biliary and pancreatic SOD
Biliary SOD
Pancreatic SOD
Type I (a) Pain associated with ↑ AST/ALT greater than 2 × normal on
at least two separate occasions
(a) Pain associated with elevation of pancreatic enzymes greater
than 1.5 × upper limit of normal
(b) Dilated CBD, >10 mm on U/S, 12 mm on ERCP (b) Dilated pancreatic duct by ERCP; >6 mm at the head or >
than 5 mm at the body
(c) Delayed drainage of contrast from CBD, >45 min in (c) Delayed drainage of contrast, >9 min
supine position
Type II Pain plus one or two of the above criteria (a, b, c) Pain plus one or two of the above criteria
Type III Pain only without any of the above criteria Pain without any of the above criteria
assess delayed biliary drainage in the case of biliary SOD.
However, these non-invasive tests are limited by their lack of
specificity. The gold standard for the diagnosis of SOD is invasive
testing using SO manometry. This involves retrograde
intubation of the SO with a pressure-transducing manometry
catheter during ERCP. The catheter, which is made of
polyethylene with a 5 Fr diameter and marked with circular
bands at 2-mm intervals, is deeply introduced into the CBD
or PD and slowly withdrawn to measure pressure along the
SO segment. The most important manometric feature in
the diagnosis of SOD is the basal SO pressure. Basal SO
pressures greater than 40 mm Hg are considered abnormal.
Differentiation between SO stenosis and dyskinesia can be
made by the response of the elevated basal SO pressure to
smooth muscle relaxants. If the elevated basal SO pressure
does not decrease with the administration of smooth muscle
relaxant, the most likely diagnosis is SO stenosis. The
relation between the different types of SOD and the findings
on SO manometry was first looked at by Sherman et al.
(Table 3)[47]. This study suggests that the diagnosis of SOD
becomes more accurate with the increasing number of objective
criteria as indicated by the higher number of abnormal
manometry found in patients classified as SOD type I.
Management of SOD
The basic premise in the therapy of SOD is that relaxation
of the SO should improve symptoms. This can be accomplished
pharmacologically, surgically or endoscopically.
Table 3 Percentage of abnormal SO manometry in patients with
biliary and pancreatic SOD
SOD Type
Biliary I 86
II 55
III 28
Pancreatic I 92
II 58
III 35
% Abnormal
Manometry
Pharmacologic agents that are known to relax the SO, and
therefore have been used in SOD, are dicyclomine, nitrates
and calcium-channel blockers [48–51]. However, response to
these agents has generally been disappointing. Surgical management
of SOD includes procedures to sever the sphincter
muscle such as sphincteroplasty, sphincterotomy and septectomy
[52–54]. These have been successful in the majority
of cases in providing long-term relief from symptoms of
SOD, but are limited by the invasiveness of the procedure
and related morbidity and mortality. The therapeutic modalities
described above have given way to the less-invasive
endoscopic therapy of endoscopic sphincterotomy (ES).
The most reliable finding predicting favorable response
to ES in patients with suspected SOD is elevated SO basal
pressure. Several studies have suggested a benefit from ES
in patients with SOD, having high SO basal pressures at the
time of manometry.
Geenen et al. looked at the improvement of symptoms
after ES in patients with suspected SOD type II and elevated
pressures in a prospective, double-blinded placebo controlled
study [55]. They randomized 24 patients with SOD type II
without elevated SO pressures into an ES group and a sham
sphincterotomy group. Twenty-three patients with SOD type
II and confirmed elevated SO pressures were randomized
into the different groups. Ten of 11 patients (91%) with elevated
SO pressures who underwent ES had improvement in
symptoms compared to three out of 12 (25%) in the sham
group. There was no statistically significant difference between
groups in patients with normal SO pressures, both
groups having a small percentage of patients with any improvement
of symptoms. Toouli et al. in a prospective randomized,
double-blinded study looked at 81 patients with
suspected SOD type I and II [56]. The patients were initially
divided into three manometric classifications: SO stenosis,
SO dyskinesia and normal manometry. Patients in each classification
were randomized to ES or sham sphincterotomy. A
statistically significant difference in symptom improvement
was found in the SO stenosis patients who underwent ES
compare with sham sphincterotomy. Patients in the biliary
dyskinesia group who underwent ES also had symptom improvement.
However, this was not statistically significant.
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The group with normal manometry did not show significant
improvement whether undergoing ES or sham sphincterotomy.
There are no up-to-date randomized studies looking at
the effect of sphincterotomy in patients with SOD type III
with or without abnormal SO manometry.
Conclusions
The sphincter of Oddi, although a small anatomical structure
when compared to the rest of the gastrointestinal tract,
is a very complex entity, the function of which is regulated
by both excitatory and inhibitory hormonal/neuronal signals.
Understanding of this sphincter mechanism can provide
some insight into the pathogenesis of biliary functional
disorders such as SOD. Currently, the best diagnostic modality
for the diagnosis of SOD is SO manometry and the most
successful therapeutic intervention is endoscopic sphincterotomy.
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