Choledocholithiasis, Ascending Cholangitis, and Gallstone Pancreatitis

Med Clin N Am 92 (2008) 925–960
Choledocholithiasis, Ascending
Cholangitis, and Gallstone Pancreatitis
Siriboon Attasaranya, MD, Evan L. Fogel, MD,
Glen A. Lehman, MD*
Division of Gastroenterology/Hepatology, Department of Medicine, Indiana University
Medical Center, 550 N. University Boulevard, UH 4100, Indianapolis, IN 46202, USA
Gallstone disease is one of the most common and most costly digestive
diseases that require hospitalization in the United States with an estimated
annual direct cost of $5.8 billion [1]. Gallstone disease is newly diagnosed in
more than 1 million people annually in the United States, and cholecystec-
tomy is performed in 700,000 cases [2]. The prevalence of gallstones has
ethnic variability, with prevalence rates of approximately 10% to 15% in
the United States and Europe [3].
The clinical spectrum of cholelithiasis ranges from an asymptomatic state
to fatal complications. Patients who have asymptomatic gallstones carry an
annual risk of approximately 1% for biliary colic [4,5], of 0.3% for acute
cholecystitis [4–6], of 0.2% for symptomatic choledocholithiasis [5,6], and
of 0.04% to 1.5% for gallstone pancreatitis (GSP) [7,8]. These small per-
centages, however, represent a large number of patients, given the overall
prevalence of gallstones.
Gallstone pathophysiology
Gallstones are classified into cholesterol stones and pigment stones.
Stones composed mostly of cholesterol account for 80% to 90% of patients
undergoing cholecystectomy in Western countries [9]. In normal bile, choles-
terol is soluble in the form of mixed micelles with an optimal concentration
of bile salts and phospholipids. With disproportionate concentrations, bile
becomes supersaturated, and the excess cholesterol precipitates as monohy-
drate crystals. These crystals embed in the gallbladder mucin gel with
* Corresponding author.
E-mail address: glehman@iupui.edu (G.A. Lehman).
0025-7125/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2008.03.001 medical.theclinics.com
926 ATTASARANYA et al
bilirubinate to form biliary sludge, which can aggregate eventually into

a gallbladder stone [10].
Black pigment stones make up a small proportion of gallstones. These
stones consist of polymerized calcium bilirubinate, precipitated as a result
of exceeding the solubility of calcium and unconjugated bilirubin.
Conditions that create excessive unconjugated bilirubin, such as chronic
hemolysis in hemoglobinopathies, cirrhosis [11], ineffective erythropoiesis,
and ileal diseases [12], predispose a patient to the formation of black
pigment stones. Brown pigment stones are formed primarily in the bile
duct. They result from bacterial infection that releases b-glucuronidase
to hydrolyze glucuronic acid from bilirubin. This process leads to
decreased solubility of deconjugated bilirubin and formation of brown
pigment stones.
Risk factors for gallstones

Risk factors for gallstone formation may be modifiable or nonmodifiable
(Box 1). Environmental factors and genetic predisposition probably play
interactive roles in gallstone formation. An inflammatory immune response
may contribute to a patient’s susceptibility to cholesterol stone formation
[13].
Box 1. Risk factors of gallstones

Nonmodifiable factors
Increasing age
Female gender
Ethnicity
Genetics, family history
Modifiable factors
Pregnancy and parity
Obesity
Low-fiber, high-calorie diet
Prolonged fasting
Drugs: clofibrate, ceftriaxone
Oral contraceptives
Low-level physical activities
Rapid weight loss (> 1.5 kg/wk)
Hypertriglyceridemia/low high-density lipoprotein
Metabolic syndrome
Gallbladder stasis
Specific diseases (ie, cirrhosis, Crohn’s disease with severe ileal
involvement/resection)
CHOLEDOCHOLITHIASIS AND GALLSTONE PANCREATITIS 927
Role of genetics
Geographic variations and ethnic differences in prevalence suggest
a genetic role in the formation of gallstones. The prevalence of gallstones
is increased in families and in identical twins of patients who have gallstones
[3]. The genes responsible for biliary lipid transport across the hepatic canal-
iculi [10,14] and for lipid metabolism [3] have been identified.
Role of gallbladder stasis

Impaired gallbladder contractility has been noted in some patients who
have gallbladder stones. Although gallbladder dysfunction can result from
gallstone disease or from excessive cholesterol infiltration into gallbladder
smooth muscle [10], gallbladder stasis, by itself, can contribute to gall-
bladder stone formation. Gallbladder stasis frequently is evident in
patients who have risk factors for cholelithiasis, including obesity, preg-
nancy, rapid weight loss, and prolonged fasting [15]. Furthermore, gall-
bladder dysmotility seems to be an independent risk factor for recurrent
gallstones in patients treated with extracorporeal shockwave lithotripsy
(ESWL) [16].
Prevention of gallstones
Moderate physical activity and dietary management (high fiber intake
and avoidance of saturated fatty acids) can lower the risk of cholelithiasis
[17]. Daily administration of cholecystokinin in patients receiving pro-
longed total parenteral nutrition was shown to prevent the formation
of gallbladder sludge in one small series [18]. Oral ursodeoxycholic acid
(UDCA) has been demonstrated to help prevent cholelithiasis during
rapid weight loss and in patients requiring long-term somatostatin ther-
apy [17]. For secondary prevention, there currently are insufficient data
to support the use of medical therapy, such as UDCA, for prevention
of biliary colic or for prevention of complications in patients who have
gallstones who are awaiting cholecystectomy or who are unfit for surgery
[17,19].
Choledocholithiasis: special consideration

Primary versus secondary bile duct stones
In the Western world, most stones in the common bile duct arise from the
passing of gallbladder stones into the common bile duct. Stones in the
common duct occur in 10% to 15% of people who have gallbladder stones.
Concomitant gallbladder stones and bile duct stones occur more frequently
in elderly, Asian patients and in patients who have chronic bile duct
inflammation (such as sclerosing cholangitis, parasitic infestation) and,

probably, hypothyroidism [20].
Primary bile duct stones are formed in the intrahepatic or extrahepatic
bile ducts. They are more prevalent in Asian populations. These stones usu-
ally are brown pigment stones. Bacterial colonization of bile and bile stasis
play important roles in the pathogenesis of these stones [21,22].
Clinical spectrum
Coexisting bile duct stones and gallbladder stones
Bile duct stones can be discovered incidentally during the evaluation of
gallbladder stones, with an estimated prevalence of 5% to 12% [23,24]. It
is difficult to determine whether the existing bile duct stones are asymptom-
atic in patients who present with biliary pain alone, because the pain can
originate from either the gallbladder stones or bile duct stones. Approxi-
mately one third of patients have spontaneous bile duct stone passage based
on stone disappearance 6 weeks after diagnosis, as determined in one study
by cholangiograms using an in situ cholangiogram catheter [25]. Given the
potential serious complications of bile duct stones, specific therapy generally
is indicated regardless of symptoms.
Symptomatic bile duct stones

Patients who have symptomatic bile duct stones are at high risk of expe-
riencing further symptoms or complications if left untreated. More than one
half of patients who had retained bile duct stones experienced recurrent
symptoms during a follow-up period of 6 months to 13 years [26], and
25% of patients developed serious complications [27].
Common clinical symptoms and signs include pain, fever, and jaundice.
Biliary pain confined to the epigastrium or right upper quadrant of the
abdomen is the most common presentation. Pain is variably mild to
severe at onset. Severe episodes commonly require emergency medical
visits and must be differentiated from cardiac or other potentially life-
threatening events. Infrequently, patients present with painless jaundice
and weight loss that mimics pancreatobiliary malignancy. Acute ascending
cholangitis and acute pancreatitis are two serious, life-threatening
complications.
Diagnosis of bile duct stones

Although advanced technologies have become more widely available,
a clinically oriented approach remains paramount. Atypical as well as typ-
ical clinical symptoms should be recognized. Newer techniques of biliary
imaging have simplified the diagnosis of bile duct stones. Noninvasive
methods have the lowest risk, whereas invasive techniques have the great-
est accuracy.
Blood tests
Patients who have cholangitis or pancreatitis associated with abnormal
serum liver function tests are at increased risk of having bile duct stones.
Elevations of serum alkaline phosphatase and gamma-glutamyl transpepti-
dase levels were detected in more than 90% of symptomatic patients [28].
The intensity of pain, degree of jaundice, and serum levels of these tests
can fluctuate over time. The serum bilirubin level typically is less than
15 mg/dL, because most bile duct stones cause intermittent and incomplete
biliary obstruction. Rarely, the serum transaminase levels can be elevated
profoundly (up to 2000 IU/L), mimicking acute viral hepatitis. With biliary
stones, however, these levels tend to decline rapidly over several days [29]
rather than slowly over several weeks, as occurs with viral syndromes. In
this clinical setting sequential follow-up of the pattern of liver function tests
may be helpful diagnostically.
Imaging studies for diagnosis of bile duct stones

Transabdominal ultrasound (TUS) is the most commonly used initial
diagnostic tool for suspected biliary stones. Gallbladder stones, if present,
generally are well visualized if the gallbladder is adequately distended and
not obscured by luminal gas or obesity. TUS has low sensitivity (25%–
60%) for the detection of bile duct stones , but it has a very high specific-
ity [30,31]. Indirect evidence, such as the presence of gallstones or biliary
ductal dilation, in the appropriate clinical setting is predictive of bile duct
stones, but the obstructed bile duct may not be dilated with acute obstruc-
tion. CT scanning has a similarly low sensitivity in the detection of bile
duct stones and is used primarily to document biliary dilation, to exclude
other causes of biliary obstruction (eg, a mass lesion), and to detect local
complications such as liver abscess. Magnetic resonance cholangiopancrea-
tography (MRCP) and endoscopic ultrasound (EUS) are less invasive than
endoscopic retrograde cholangiography (ERC) but can detect bile duct
stones with comparable accuracy. Recently, use of multidetector CT, in
conjunction with oral or intravenous contrast and with reconstruction of
axial and three-dimensional images, has been reported to have a sensitivity
of 85% to 97% and specificity of 88% to 96% in the diagnosis of bile duct
stones [43–46]. Although this accuracy is comparable to that of MRCP,
this method is limited by (1) relatively frequent allergic reactions to the
contrast agents, as high as 15% in one series using intravenous iotroxate
[45]; (2) suboptimal ductal contrast opacification in the presence of signif-
icant jaundice (bilirubin more than two or three times the upper limits of
normal) or in a patient who has undergone cholecystectomy [43,47]; and
(3) limited visualization of intrahepatic duct branches, particularly
when using oral contrast agents [45,48]. Table 1 summarizes the clinical
930
Table 1
Imaging studies for diagnosis of common bile duct stones
Characteristic TUS CT MRC EUS ERC
Sensitivity (%) 25–63 [30,31] 71–75 [30,31] 85 [32] 93–98 [32–34] 90–97 [35,36]
Specificity (%) 95–100 [30,31] 97 [30,31] 93 [32] 97–100 [32–34] 95–100 [35,36]
Advantages Inexpensive Safe Detection of concomitant High accuracy for duct High accuracy for duct High accuracy
Widely available intrahepatic duct stones, stone detection stone detection Therapeutic potential
Portable liver parenchymal lesions, Noninvasive intrahepatic Less invasive than ERC
and pancreatic lesions and extrahepatic duct Detects small stones in
ATTASARANYA
evaluation a nondilated duct [30]
Disadvantages Low sensitivity Radiation exposure Expensive Operator dependent Higher risk than EUS
Operator dependent Contrast allergy Time consuming High cost of equipment False positives (air bubbles)
Renal impairment Limited value in stones Insensitive for proximal False negatives with small
! 6 mm [37] common hepatic duct / stones in dilated duct
et al
Impacted stone at the intrahepatic duct stones Unsuccessful cannulation
ampulla [38], dilated bile
duct O 10 mm [39]
Claustrophobia
Ferromagnetic implant
Artifact interferencea
[40–42]
Abbreviations: ERC, endoscopic retrograde cholangiography; EUS, endoscopic ultrasound; MRC, magnetic resonance cholangiography; TUS, transab-
dominal ultrasound.
a
Including pneumobilia, flow artifact, duodenal diverticula.
applications and limitations of imaging studies in the diagnosis of bile duct

stones.
ERC is considered the reference standard for the diagnosis of bile duct
stones and provides an opportunity for therapy. Because of potential signif-
icant procedure-related risks and the availability of the other, less invasive,
accurate imaging modalities, ERC now is reserved for patients who have
confirmed bile duct stones or who are at high risk for bile duct stones
(Table 2) who probably will require therapeutic intervention [49].
Recurrent bile duct stones

Bile duct stones recur in about 4% to 24% of patients during a follow-up
period of 15 years [42]. Stones even can recur in patients after gallbladder
removal. It remains uncertain, however, what proportion of these recurrent
stones are, in fact, overlooked retained/residual stones from the prior ther-
apy. Recurrence is thought to be caused mainly by bile stasis and bacterobilia.
Main duct dilation (R 13 mm) and the presence of a periampullary divertic-
ulum are common risk factors for recurrent stones [42,50], perhaps resulting
from increased biliary stasis. Identification and treatment of correctable risk
factors, such as biliary strictures, papillary stenosis, and gallstones in patients
who have gallbladder in situ, is essential to prevent recurrence.
Detection of bile duct stones after endoscopic therapy

After biliary endoscopic sphincterotomy (BES), the biliary system
frequently is filled with air. The bile duct may be dilated persistently despite
removal of all bile duct stones. These two factors may decrease the accuracy
of imaging tests in detecting residual/recurrent stones after endoscopic ther-
apy. MRCP seems to have limited value in detecting stones in an air-filled
duct [51]. In this setting, intraductal EUS, in conjunction with ERC, has
been reported to detect stones in the dilated duct with a greater accuracy
than achieved with ERC alone [52].
Table 2
Risk classification of probability of bile duct stones based on clinical presentation and transab-
dominal ultrasound evaluation
High Risk Moderate Risk
Parameters (O 50%) (10%–50%) Low Risk (! 5%)
Jaundice Current History of jaundice No history of jaundice
Liver function tests Persistently elevated Declining Normal
Cholangitis Current History of fever No history of fever
Pancreatitis Current History of pancreatitis No history of pancreatitis
Common bile Dilated bile duct Borderline dilated Normal
duct diameter (R 10 mm)
Ductal stones seen Yes Questionable None (with large
(with small gallbladder stones)
gallbladder stones)
Therapy of bile duct stones

Biliary endoscopic sphincterotomy
Since its introduction in 1974, BES has supplanted surgery as the stan-
dard therapy for bile duct stones. About 85% to 90% of bile duct stones
can be removed by balloon/basket extraction following BES. In a large,
multicenter trial, the overall complication rate of BES was 9.8% in 2347 pa-
tients, including pancreatitis in 5.4%, bleeding in 2%, procedure-related
cholangitis in 1%, cholecystitis in 0.5%, and perforation in 0.3% [53]. In
the subgroup of 1600 patients who had common duct stones, the overall
complication rate was 8%.
Treatment of difficult bile duct stones

Approximately 10% to15% of patients have bile duct stones that cannot
be removed using standard BES and balloon/basket extraction techniques.
These stones generally are larger than 1.5 cm, are impacted, or are located
proximal to strictures [54]. Alternative therapies have been used to manage
these difficult bile stones.
Fragmentation of stones
Mechanical lithotripsy. Mechanical lithotripsy is the simplest and most
widely used technique for fragmenting stones. The lithotripter unit is
designed as either an integrated device or a salvage device that consists of
a metal sheath with a handle applicable to lithotripsy-compatible wire bas-
kets. In two studies, mechanical lithotripsy successfully removed 85% to
90% of ‘‘difficult’’ bile duct stones [55,56]. Mechanical lithotripsy usually
is successful only in stones smaller than 3 cm [55]. The most common reason
for unsuccessful mechanical lithotripsy is inability to capture the stones (eg,
inadequate space to open the basket).
Electrohydraulic lithotripsy. An electrohydraulic lithotripsy system consists

of a bipolar probe and a charge generator. Initiation of a spark causes ex-
pansion of the surrounding fluid that generates shock waves to fragment
stones. Electrohydraulic lithotripsy can be operated under either fluoro-
scopic or direct cholangioscopic guidance. Direct visualization is preferred
to permit deployment of the probe at the surface of the stone to ensure
the highest efficacy and to avoid ductal injury. This technique seems to be
helpful in patients who have concomitant intrahepatic duct stones or biliary
strictures [57]. A disadvantage of using cholangioscopy for electrohydraulic
lithotripsy is the need for two operators and the use of a fragile intraductal
miniscope. Recently, single-operator cholangioscopy has been used to direct
electrohydraulic lithotripsy therapy for bile duct stones; preliminary results
have been encouraging [58].
Extracorporeal shockwave lithotripsy. ESWL generates a shockwave origi-

nating outside the body using piezoelectric, electrohydraulic, or electromag-
netic systems. A liquid or tissue medium is required to prevent energy
attenuation. Because ESWL is painful, general anesthesia or, less frequently,
conscious sedation is required. Because most bile duct stones are not radi-
opaque and are not visualized by fluoroscopy before contrast injection at
endoscopic retrograde cholangiopancreatography (ERCP), a nasobiliary
tube may be required before ESWL. Complete stone clearance rates of
83% to 90% have been reported [59,60]. Most cases require several endo-
scopic procedures to remove the fragmented stones.
Laser lithotripsy. In laser lithotripsy, laser light at a particular wavelength is

focused on the surface of a stone to achieve stone fragmentation. An oscil-
lating plasma, consisting of a gaseous collection of ions and free electrons, is
created to induce wave-mediated fragmentation of stones. Laser lithotripsy
is performed under direct visualization using the cholangioscope or under
fluoroscopic guidance. A recent-generation device can differentiate between
the light reflection patterns of the bile duct wall and those of stones. The
laser beam is stopped immediately when bile ductal tissue is contacted to
prevent bile duct injury. Experience with this modality is limited, however.
The success rates of bile duct stone clearance with laser lithotripsy have been
reported at 64% to 97% [27].
Supplemental large-diameter biliary orifice balloon dilation

Endoscopic biliary orifice dilation (EBD) using a 6- to 8-mm diameter
balloon to remove bile duct stones has a reported success rate comparable
to that of BES. This success rate, however, seems to require more ERCP
sessions, more frequent use of mechanical lithotripsy, and, occasionally, res-
cue BES. Most importantly, two meta-analyses have shown that the rate of
pancreatitis is significantly higher with EBD than with BES [61,62].
Use of a large-diameter (12–20 mm) dilation balloon as an adjunctive
tool to enlarge an inadequate BES orifice can aid in the removal of large
or difficult bile duct stones. In a recent multicenter study of 103 patients,
this technique had a success rate of 92% and a complication rate of
7.6%, with a remarkably low rate of pancreatitis of 2.2% [63]. This low
rate of pancreatitis is attributed to the separate pancreatic and biliary ori-
fices following BES, so that the pancreatic orifice is avoided during biliary
balloon dilation. Although this combined technique seems to be attractive,
additional clinical experience is necessary.
Surgery
Laparoscopic bile duct exploration. Patients who have concomitant gallblad-
der and bile duct stones are treated ideally with a single procedure: laparo-
scopic cholecystectomy and laparoscopic bile duct exploration. In expert
hands, a single-stage laparoscopic procedure can achieve a stone clearance
rate comparable to that of ERCP. Either a transcystic approach (for stones

! 8–10 mm) or direct choledochostomy with choledoschoscopy (for larger
or multiple stones) can be performed. This procedure is technically demand-
ing, however, and only a minority of surgeons perform laparoscopic bile
duct exploration. The reported success rates range from 80% to 98%,
with complication rates of 4% to 16%, including bile duct injury, infection,
pancreatitis, and stricture [64].
Open common bile duct exploration. Open common bile duct exploration
generally is performed only if endoscopic and laparoscopic approaches
are unsuccessful. Additionally, choledochoenterostomy or sphincteroplasty
can be performed. The former procedure is preferable for stones larger
than 2 cm. Sump syndrome, which occurs when debris or food particles en-
ter a side-to-side choledochoduodenostomy and block the distal bile duct,
occurs in 1% of such cases and is managed by endoscopic therapy.
Long-term biliary stenting

Whenever stones cannot be removed completely endoscopically, biliary
stents should be placed to ensure adequate biliary drainage and to prevent
recurrent symptoms as well as biliary sepsis while awaiting further therapy.
Alternatively, long-term biliary stenting is used in patients who have severe
comorbid medical conditions that preclude surgery or who have had re-
peated endoscopic interventions for definitive therapy of bile duct stones
[65–68]. The main goal is to prevent the impaction of stones. Additionally,
long-term stenting can promote stone fragmentation, leading to decreased
stone size, and, occasionally, spontaneous passage of stones [65,69]. Internal
and external pigtail stents are preferred to straight stents because they mi-
grate less frequently and maintain the patency of the biliary orifice better.
Straight stents may be used selectively for stones associated with a biliary
stricture. Long-term biliary stenting, however, is associated with significant
mortality, ranging from 6% to 16%, mainly from cholangitis, and with mor-
bidity of up to 40% during 3 years of follow-up [70,71]. Moreover, new bile
duct stones can occur in patients who had inadvertent long-term stent place-
ment following therapy for bile duct stones [72]. In summary, long-term
stenting should be reserved as a definitive therapy for patients who are at
extremely high risk for endoscopic or surgical procedures or who have
a short life expectancy.
Acute ascending cholangitis

Acute cholangitis, or infection of the biliary tree, occurs as a consequence
of biliary tract obstruction. The clinical presentation ranges from a mild,
self-limited process to a serious, life-threatening condition requiring emer-
gent intervention. Bile duct stones are the most common cause of acute
cholangitis in Western countries [73]. Malignant obstruction rarely presents

with cholangitis do novo but can cause cholangitis after manipulation of
stent occlusion from the biliary tree. Indeed, previous therapy probably is
the second most common cause of acute cholangitis. Acute cholangitis is
occurring increasingly, secondary to biliary stricture from biliary surgery,
orthotopic liver transplantation, primary sclerosing cholangitis, or AIDS-
related cholangiopathy. These conditions are beyond the scope of this
discussion.
Pathophysiology
Bacterobilia occurs commonly in patients who have bile duct stones,
often in the absence of clinical cholangitis. Typically, the main entry route
of bacteria is ascending from the duodenum [73]; the portal venous and peri-
portal lymphatic systems serve as the portal of entry in a minority of cases
[74]. In the presence of bacterobilia, biliary obstruction plays a critical role
in the pathogenesis of cholangitis. Increasing intraductal pressure leads to
disruption of hepatocellular tight junctions, with subsequent translocation
(reflux) of bacteria and biliary toxins into the bloodstream. The occurrence
of bacteremia or endotoxemia is correlated directly with the intrabiliary
pressure [75,76]. Biliary obstruction promotes bile stasis and bacterial
growth and also may compromise host immune defense mechanisms [77].
Diagnosis and clinical manifestations

Charcot, in 1877, described a triad of fever, right upper abdominal pain,
and jaundice; this triad occurs in 56% to 70% of patients who have cholan-
gitis [78]. The more severe form, characterized by the additional clinical
features of hypotension and alteration of consciousness (Reynold’s pentad),
is uncommon and occurs in only 5% to 7% of cases [79,80]. Fever is the
most common presenting symptom, found in 90% of patients. The pain
in patients who have cholangitis, unlike the pain secondary to bile duct
stones in the absence of infection, is relatively mild and intermittent. Elderly
and immunocompromised patients can present with atypical symptoms and
signs. The presence of fever, leukocytosis, and abnormal liver function tests
is highly suggestive.
Laboratory tests
Leukocytosis and an elevated C-reactive protein level and erythrocyte
sedimentation rate are found commonly but are nonspecific. Liver function
tests invariably are elevated, with a widely variable range. Pancreatic
enzyme elevations suggest that bile duct stones caused the cholangitis,
with or without GSP [81].
Bile cultures are positive in 80% to 100% of patients who have chola-
ngitis, and blood cultures are positive in 21% to 71% [82,83]. Enteric
gram-negative organisms including Escherichia coli, Klebsiella, and Entero-

coccus are isolated from bile commonly; Staphylococcus and Streptococcus
are isolated infrequently. Anaerobic bacteria, such as Clostridium and Bac-
teroides, are isolated more commonly in polymicrobial infections in patients
who have had prior biliary-enteric surgery, are elderly [73], or have severe
disease [84,85]. Patients who have had recent biliary surgery or who have in-
dwelling stents are more likely to harbor Enterococcus or hospital-acquired
organisms such as Pseudomonas species, methicillin-resistant Staphylococcus
aureus, vancomycin-resistant Enterococcus, or fungi [86].
Imaging tests
The choices in imaging are the same as for the diagnosis of bile duct
stones but must be done more urgently in patients who have acute cholan-
gitis. An early CT scan is recommended to evaluate for biliary dilation and
simultaneous liver abscesses.
Management of cholangitis
Early diagnosis and prompt appropriate therapy are essential. Close
monitoring and reassessment of the treatment response are important to
guide the therapy. Patients who have mild disease are managed initially
with medical therapy, including antibiotics and supportive medical care.
Patients who respond promptly to medical therapy should undergo biliary
decompression and/or definitive therapy for bile duct stones as early as prac-
tical, preferably within 24 to 48 hours. Patients who have severe or progres-
sive disease require urgent biliary drainage in addition to medical therapy
[87]. Delay in securing biliary drainage in this subgroup may produce a fatal
outcome. A treatment algorithm is suggested in Fig. 1.
Medical therapy
Initially, antibiotics as well as supportive therapy, including adequate
hydration and correction of coagulopathy and metabolic derangements,
must be provided. Medical therapy alone is effective in approximately
80% of patients; prompt additional biliary drainage is required in the others
to control the clinical symptoms.
Antibiotic therapy
Antibiotics should be given early when acute cholangitis is suspected,
even before it is definitively established, to control bacteremia and sepsis.
The choice of empiric antibiotics is based on several considerations, includ-
ing host factors (renal function, allergic reactions), severity of disease, local
susceptibility pattern, community versus hospital-acquired infection, and
the presence of prior biliary intervention or surgery. Broad-spectrum
antibiotics with adequate biliary excretion such as ampicillin/sulbactam,
Acute cholangitis
Assess clinical status, prompt antibiotics, hydration, correct metabolic derangement
Mild Severe /unstable
Intensive care
Close monitoring/reassess in 6-12 hours altered anatomy (e.g.

gastric bypass surgery)
Favorable response Refractory/Progressive Urgent ERCP with
biliary decompression
Elective ERCP with ± definitive therapy

definitive therapy
of bile duct stones favorable response unfavorable response/
(within 24-48 hours)
technical failure
Elective ERCP Percutaneous drainage

with definitive therapy
(if not previously done)
Fig. 1. Algorithm for management of patients who have acute cholangitis.
piperacillin/tazobactam, third- or fourth-generation cephalosporins, quino-

lones, and carbapenems are preferred. Antibiotics with enterococcal and an-
aerobic coverage may be added in patients who have advanced age, severe
disease, a biliary stent in situ, or prior enterobiliary surgery. Biliary excre-
tion of most antibiotics is compromised in the presence of biliary obstruc-
tion, however [83]. Early biliary decompression is essential to restore good
biliary penetration of the antibiotics and to drain purulent bile, particularly
in patients who have severe disease. Once the micro-organisms have been
identified and their susceptibility has been determined, the antibiotics should
be adjusted to cover the identified micro-organism and to avoid the emer-
gence of antibiotic-resistant micro-organisms.
The duration of antibiotic therapy is based on the clinical response and the
presence of bacteremia. For mild disease, antibiotics generally are continued
for 5 to 7 days. For patients who have a positive blood culture, a 10- to 14-day
course of antibiotics is recommended. After a clinical response, switching
from intravenous to oral administration usually is appropriate. The optimal
duration of antibiotic therapy following biliary drainage has not been well
defined in prospective, randomized trials. One small retrospective study
reported that a 3-day duration of antibiotic therapy following biliary drain-
age seemed to be effective in selected patients who respond promptly (with
resolution of fever) to drainage procedures [88].
Biliary drainage
Biliary decompression is essential in patients who have cholangitis.
Decompression can be performed by endoscopic, percutaneous, or surgical
approaches or by multimodal therapy.
Endoscopic biliary decompression

An endoscopic approach offers several benefits, including defining ductal
anatomy, identifying simultaneous pathology (such as biliary strictures or
choledochal cysts), collecting bile for microbiologic study, providing tissue
sampling, and allowing definitive therapy in most cases. In severe cholangi-
tis biliary decompression and bile duct clearance by ERCP has lower
morbidity and mortality rates than open surgery with bile duct exploration
[89,90]; in one prospective, randomized trial, the morbidity of the endo-
scopic procedure was one half that of open surgery (34% versus 66%),
and the mortality with the endoscopic procedure was one third that of the
open approach (10% versus 32%) [90]. Similarly, morbidity and mortality
in elderly patients are lower with EBD than with percutaneous drainage
[91]. Endoscopic biliary decompression therefore is the procedure of choice,
and percutaneous or surgical drainage is reserved as an alternative when
endoscopic therapy is technically impossible or is unsuccessful.
Evaluation before endoscopic retrograde cholangiopancreatography. The

patient’s condition is stabilized as much as possible before the procedure.
Adequate hydration and prompt administration of systemic antibiotics are
essential. Details of prior surgeries that alter ERCP access should be iden-
tified. Appropriate periprocedural and intraprocedural monitoring is
needed. Critically ill patients may require emergency ERCP using a mobile
fluoroscopic unit at the bedside in the ICU. EBD without fluoroscopy has
been performed successfully in the ICU [92].
Endoscopic techniques of biliary drainage in acute cholangitis. When ERCP

is performed in the presence of active cholangitis and purulent bile, care
must be taken to avoid aggravating the existing high intraductal pressure.
Contrast injection during biliary cannulation should be minimized. Once
deep cannulation is successful, 20 to 40 mL of bile should be aspirated to
decompress the bile duct and to provide a sample of bile for microbiologic
analysis. Then limited contrast can be injected to fill only the extrahepatic
ductal system to define the cause and location of obstruction, unless intra-
hepatic bile duct pathology is suspected. Definitive therapy (BES with
removal of stones) is pursued in a stable patient who has confirmed bile
duct stones. In an unstable patient, every effort should be made to shorten
the procedure time while providing adequate biliary drainage; definitive
therapy can be performed subsequently once the patient is stable. Prolong-
ing the procedure to attempt definitive therapy in an unstable patient may
increase the morbidity and mortality.
In patients who have severe cholangitis, EBD can be achieved with plastic
biliary stents or with nasobiliary catheter drainage (NBD) with or without
BES. Concomitant BES facilitates the placement of a larger stent (10–11.5 F)
or multiple stents for more effective drainage and with a minimal risk of
stent migration. A large multicenter trial, however, noted that the risk
of postsphincterotomy bleeding is correlated significantly with the presence

of acute ascending cholangitis, even in the absence of coagulopathy [53].
Furthermore, one study comparing decompression by NBD alone (n ¼ 73)
versus NBD with BES (n ¼ 93) showed comparable success rates but
significantly more complications in the BES group (12% versus 2%),
mainly from bleeding or cholecystitis [93]. Overall, the decision whether
BES should be performed is tailored to the individual patient. If coagulop-
athy is present, or if the patient is unstable, placement of a biliary drainage
tube alone (preferably a 7-F biliary stent or NBD), without BES, generally
is recommended for short-term drainage and produces satisfactory results
[93,94]. BES may be performed when placement of a large (R 10 F) or
multiple stents is required. By separating the biliary and pancreatic
orifices, BES can avoid compression of the pancreatic orifice by the stents,
which otherwise could result in post-ERCP pancreatitis. In patients who
have a concomitant biliary stricture that requires dilation, BES also may
facilitate stent placement through the tight stricture. In patients who
have cholangitis in whom ERCP is performed but no bile duct stones
are identified, BES has been shown to improve outcomes compared with
no therapeutic intervention, with a faster recovery and shorter hospitaliza-
tion [95].
Two prospective studies demonstrated no difference in treatment out-
comes between biliary stenting and NBD in patients who had acute cholan-
gitis [96,97]. NBD provides the advantage of active decompression by
intermittent or continuous negative pressure suction and the opportunity
for sequential bacteriologic bile cultures. It is, however, less used frequently
because of patient discomfort, the possibility of inadvertent dislodgment of
the nasobiliary catheter, the risk of kinking with inadequate drainage, and
the potential for electrolyte disturbances secondary to the external diversion
of bile. No randomized, controlled trials have compared outcomes between
straight or pigtail biliary stents or among different stent sizes (7 F versus
larger size) in patients who have acute cholangitis. Theoretically, larger
stents should provide better drainage, particularly if thick, purulent bile
and stone debris are present. Because BES is needed for placement of larger
stents, the risk of BES-related bleeding needs to be weighed against the po-
tential benefit. Because most patients who have acute cholangitis undergo
definitive therapy for bile duct stones several days or weeks following suc-
cessful biliary decompression, the type or size of stent is likely to have no
effect on treatment outcomes. In patients who have debilitating comorbid
conditions, in whom the definitive therapy for bile duct stones is anticipated
to be delayed (ie, for months) or may be unsuccessful, BES with long-term
placement of multiple stents may be a reasonable alternative.
Percutaneous transhepatic biliary drainage

In percutaneous transhepatic biliary drainage a biliary drainage catheter
is placed under ultrasound or fluoroscopic guidance into an intrahepatic
duct and/or common bile duct, with the tip downstream in the duodenum.
In expert centers, the overall success rate of percutaneous drainage ap-
proaches 95% to 98% in patients who have biliary ductal dilation and is
70% to 80% in patients who do not have biliary dilation [98]. Potential se-
rious complications include sepsis, intraperitoneal hemorrhage, peritonitis,
and pancreatitis [98]. Percutaneous transhepatic biliary drainage generally
is reserved for patients in whom endoscopic biliary drainage is unsuccessful
or who have altered anatomy such as prior gastric bypass surgery.
Surgical drainage
Either open or laparoscopic common duct exploration may be per-
formed. In severely ill patients, the simplest procedure (eg, T-tube place-
ment) should be performed to shorten the procedure time. The option of
definitive therapy can be determined later, when appropriate. Because of
the operative risks, emergency surgical decompression rarely is performed;
it is reserved for patients in whom both endoscopic and percutaneous ap-
proaches have been unsuccessful or who have altered anatomy that pre-
cludes such approaches.
Gallstone pancreatitis
Gallstones are the most common cause of acute pancreatitis in Western
countries. The incidence of GSP is increased in women more than 60 years
old [99]. The pathogenesis is believed to be related to increased pancreatic
ductal pressure, possibly with biliopancreatic reflux, that occurred when
the bile duct stone passed or was impacted at the ampulla. Multiple small
gallstones (! 5 mm), a dilated cystic duct, and good postprandial gallblad-
der emptying are putative factors for GSP [100–102]. Anatomic variations
such as a long common channel [103] or a nonpatent accessory duct [104]
may be contributing risk factors.
Most stones pass spontaneously into the duodenum. Discovery of fecal
stones has been reported in about 90% of patients suspected of having
GSP, in comparison with 10% of controls [105]. The disease recurs, how-
ever, in approximately one third to two thirds of patients as early as 3
months after the initial episode if the underlying biliary stones are left un-
treated [106]. Although GSP usually is mild and self-limited, some patients
have a severe, complicated course that entails substantial mortality. Man-
agement of patients who have severe disease is complex and has been de-
bated for nearly a century.
Clinical presentation
Patients typically present with a sudden onset of unrelenting upper ab-
dominal pain, which radiates into the back in about 50% of cases. Nausea
and/or vomiting frequently occur. An elevated serum amylase and/or lipase
level three times the upper limit of normal or higher in the typical clinical
setting is diagnostic. When patients experience sudden severe abdominal
pain, other serious conditions should be considered and need to be excluded
(Box 2). Notably, other potentially life-threatening conditions, such as a per-
forated viscus or bowel ischemia, can produce modest elevation of the serum
amylase or lipase level.
Diagnosis
Recognition of GSP is crucial, because urgent endoscopic intervention
may prevent complications and mortality in selected cases, and specific ther-
apy of bile duct stones is essential to prevent recurrence. As noted earlier,
the diagnosis of acute pancreatitis is based on the characteristic pain and
elevated serum amylase or lipase levels. Suspicion of GSP is increased in
patients who have acute pancreatitis associated with abnormal liver function
tests, documented gallbladder stones, or biliary dilation in the absence of
other causes [107,108]. A history of excessive alcohol use, known gallstone
disease, previous/current medication use, abdominal trauma/surgery, previ-
ous episodes of pancreatitis, family history, and weight loss that suggests
a malignant process should be obtained. Liver function tests, triglyceride
levels, and the serum calcium level also should be obtained at presentation.
In selected cases, additional blood tests to exclude autoimmune pancreatitis
(anti-nuclear antibodies, IgG4) or genetically related pancreatitis (cystic
fibrosis, hereditary pancreatitis) should be considered.
Liver function tests

Elevation of alanine aminotransferase more than three times the upper
limit of normal within 1 to 2 days after onset is the single best predictor
of biliary pancreatitis, with a positive predictive value of 95% [109]. Any el-
evation of liver function tests in patients who have acute pancreatitis should
Box 2. Differential diagnosis of acute pancreatitis

Gastrointestinal diseases
Perforation of hollow viscus
Mesenteric ischemia/infarction
Intestinal obstruction
Acute cholecystitis
Acute cholangitis
Non-gastrointestinal diseases
Acute inferior wall myocardial infarction
Dissecting abdominal aortic aneurysm
Ectopic pregnancy
raise the possibility of GSP. A normal alanine aminotransferase level does

not exclude GSP, however, because the sensitivity rate is only 48% [109].
Moreover, liver function tests are entirely within the normal range in 10%
of cases [110].
Serum amylase/lipase
The serum amylase level rises within 2 to 12 hours after the onset of
symptoms and normalizes within 3 to 5 days [111]. Serum lipase, derived
mainly from pancreatic acinar cells, peaks at 24 hours and may remain ele-
vated for several days [112]. The serum amylase level tends to be higher with
GSP than with alcoholic pancreatitis [113]. Clinical use of the height of the
serum amylase/lipase is limited, however, because of overlapping values.
Furthermore, the amount of the serum amylase/lipase elevation is not
correlated with disease severity, and daily monitoring of these levels is of
limited value in predicting the progression or prognosis of acute pancreatitis
[114].
Imaging studies
In patients suspected of having acute pancreatitis, initial imaging studies
are useful mainly in confirming the diagnosis and in excluding other abdom-
inal emergencies. In patients who have a firm diagnosis, imaging studies may
be required to determine the potential cause (gallstones, bile duct dilation,
underlying chronic pancreatitis, or neoplastic process) and to detect local
complications (pancreatic necrosis, fluid collection) in patients who have
severe pancreatitis.
Abdominal plain roentgenograms

Abdominal plain roentgenograms contribute little to the diagnosis. The
‘‘sentinel loop’’ of distended small bowel is rare and does not affect manage-
ment. The primary value of plain roentgenograms is to exclude other
abdominal emergencies such as intestinal perforation or obstruction. Pan-
creatic calcifications, indicating underlying chronic pancreatitis, or opaque
gallbladder stones are detected rarely.
Transabdominal ultrasound
TUS is the first line of investigation for GSP because of its low cost, its
availability, and its portability for bedside examination of the critically ill
patient. The primary value of TUS for acute pancreatitis is to document
the presence of gallbladder stones and/or bile duct dilation, suggesting
GSP. Although TUS is highly accurate for the diagnosis of gallstones in
the absence of pancreatitis, it is only 60% to 80% sensitive in detecting
gallstones during an attack of acute pancreatitis, presumably because of
overlying bowel gas [114,115]. In particular, small gallstones (mean size,
! 4 mm) may be missed by TUS [116]. EUS or an interval TUS may
help in this situation.
CT scanning
A dynamic contrast-enhanced CT scan is the optimal tool for detecting
pancreatic parenchymal and peripancreatic inflammatory changes to con-
firm the diagnosis. Occasionally, certain causes of pancreatitis such as com-
mon duct stones, pancreatic calcifications indicating chronic pancreatitis, or
a pancreatic neoplasm can be discovered. In patients who have an uncertain
diagnosis, a CT scan is helpful to identify other abdominal emergencies such
as intestinal perforation, obstruction, or mesenteric infarction.
Balthazar and colleagues [117–119] have combined the extent of pancre-
atic/peripancreatic inflammatory changes and degree of pancreatic necrosis
into a CT severity index that can predict reliably the severity of disease and
the prognosis (Table 3). When intravenous contrast is contraindicated, pre-
cluding an accurate evaluation of extent of necrosis, a noncontrast multislice
CT seems to be informative; patients who have peripancreatic fluid collec-
tions (grade D or E on the CT severity index) had a mortality of 14%
and morbidity of 54%, whereas patients who did not have fluid collections
(grades A, B, or C) had no mortality and only 4% morbidity [119].
Peripancreatic fat necrosis can occur from extravasation of activated
pancreatic enzymes without pancreatic necrosis [117]. In a retrospective,
cohort study, CT grading of the extent of extrapancreatic inflammation
(ascites, pleural effusion, and retroperitoneal inflammation) was noted to
predict local complications and persistent organ failure accurately [120].
The optimal timing of the CT scan is important. Because pancreatic necro-
sis may not be appreciated by CT scan until at least 2 to 3 days after symptom
onset [121], an earlier CT scan may underestimate the severity of disease.
Also, a high-quality CT scan, with appropriate technique, is mandatory.
MR imaging/magnetic resonance cholangiopancreatography

Recent studies suggest that MR imaging and CT have comparable
reliability in the evaluation of severity and local complications of acute
pancreatitis [122,123]. MR imaging/MRCP may offer an advantage over
Table 3
CT severity index with correlation to prognosis
Degree of CT Severity
Necrosis Index Complications Mortality
CT Grading Score (%) Score (range) (%) (%)
A: normal pancreas 0 none 0 0–3 8 3
B: edematous pancreatitis 1 none 0
C: pancreatic/peripancreatic 2 !30 2 4–6 35 6
inflammation
D: one peripancreatic fluid 3 30–50 4
collection
E: multiple peripancreatic 4 O50 6 7–10 92 17
fluid collections
Data from Refs. [117–119].
CT scanning, with better detection of pancreatic hemorrhage [122] and bile

duct stones. Secretin-MRCP may help define pancreatic ductal anatomy,
such as pancreas divisum, as well as pancreatic duct disruption undetected
by CT scan [123]. Unlike CT scan, MR imaging reliably distinguishes a pan-
creatic fluid collection from liquefied necrosis [124]. The use of MR imaging
has been limited by its lack of availability on an urgent basis, its technical
infeasibility in critically ill patients, and its variable reliability between cen-
ters. Furthermore, most bile duct stones causing GSP are small (! 5 mm),
and MRCP has limited accuracy in detection of these stones. One small,
prospective series reported the sensitivity, specificity, and accuracy of
MRCP in detection of bile duct stones in setting of GSP to be 80%, 83%
and 81%, respectively [39].
Endoscopic ultrasound
EUS is a very accurate, less invasive means to detect biliary stones. Be-
cause of its accuracy in detecting bile duct stones, EUS may serve as a useful
guide about whether to proceed with therapeutic ERCP for GSP. A normal
EUS can obviate the need for ERCP because it has a high negative predic-
tive value for the diagnosis of bile duct stones. The technical success rate of
early EUS (median, ! 3 days from admission) in 123 patients suspected of
having GSP has been reported to be as high as 97.5% [125]. EUS followed
by ERCP, if indicated, seems o be a reasonable approach, particularly in
critically ill patients who have a borderline probability of bile duct stones,
because ERCP is performed only if bile duct stones are confirmed by EUS.
Intraductal EUS with ERC has been shown to increase the diagnostic
accuracy of bile duct stones to 95% to 97%, whereas the accuracy of
ERC alone is 87% to 90% [39,52]. It does not obviate the need for
ERCP, however. Although it is available at only a few centers in the United
States, EUS may be useful in select patients (eg. postcholecystectomy) in
whom the detection of stones at the time of ERCP guides therapy.
Determining severity and predicting prognosis

Once acute pancreatitis has been diagnosed, the severity of disease can be
assessed to guide further management and to predict prognosis. Although
most patients who have acute pancreatitis have mild, self-limited disease
(acute interstitial pancreatitis), which carries a mortality rate of 1% to
3%, about 15% to 25% of patients develop pancreatic necrosis. If this
necrotic tissue becomes infected, mortality approaches 30% [107].
Several clinical scoring systems have been used to predict the severity of
pancreatitis, most commonly Ranson’s criteria (overall, and biliary pancre-
atitis) [126,127], Glasgow criteria [128], and APACHE-II [129]. Both
Ranson’s and Glasgow criteria require a 48-hour duration to complete the
assessment, which is relatively long because organ failure may be evident
by this time. The APACHE-II score can be determined at admission and
repeated at 24 or 48 hours. These scoring criteria provide moderate overall
accuracy. Because of the low prevalence of severe disease, these clinical pre-
dictors yield a low positive predictive value (43%–49%) [107]. The clinically
based Atlanta classification of acute pancreatitis is widely accepted [130].
Severe pancreatitis is defined by the presence of organ failure (systolic blood
pressure ! 90 mm Hg, PaO2 % 60 mm Hg, creatinine level O 2.0 mg/dL
after rehydration, and gastrointestinal bleeding O 500 cm3/24 hours); local
complications such as pancreatic necrosis, abscess or pseudocyst; or sys-
temic complications such as laboratory evidence of disseminated intravascu-
lar coagulation or a serum calcium level of 7.5 mg/dL or higher. A Ranson’s
score of 3 or higher or an APACHE II score of 8 or higher also predicts
severe pancreatitis. The authors’ group does not use a formal grading system
to manage these patients.
A distinction between transient organ failure (! 48 hours) and persistent
organ failure (O 48 hours) is important [107] because the former can occur
in patients who have interstitial pancreatitis with a low mortality, but the
latter has been associated with a mortality of 36% and local complication
rate of 77% [131]. Moreover, early (! 72 hours after symptom onset),
progressive multiorgan organ failure is the most important predictive factor
for mortality, with a reported mortality greater than 50% in one study
[132].
Obesity, defined by a body mass index of 30 or higher, was associated
with increased morbidity and mortality of acute pancreatitis in a recent
meta-analysis of 739 patients from five studies [133]. Elevated hematocrit
and C-reactive protein [107] are correlated modestly with severe disease.
Several markers, such as interleukins, procalcitonin, polymorphonuclear
elastase, and trypsinogen activation peptide, have been evaluated in limited
studies but are not used routinely.
Treatment
General
Adequate hydration, prevention of hypoxemia, correction of metabolic
derangements, and pain control are the mainstays of supportive care.
Aggressive fluid resuscitation to preserve pancreatic microcirculation pre-
vented or minimized pancreatic necrosis in an experimental model [134].
Oxygen supplementation generally is recommended because most patients
require narcotic analgesia, which can compromise ventilatory function.
Effective pain control is tailored to the individual patient. Nasogastric
tube decompression is needed only in patients who have significant ileus
or vomiting. Empiric proton-pump inhibitor therapy is reasonable to pre-
vent stress-related mucosal injury, although firm supportive evidence is
lacking.
Close monitoring is needed to detect early deterioration of correctable
conditions (eg. hypoxia). In patients who have severe pancreatitis, treatment
in an ICU using a multidisciplinary team approach (consisting of
gastroenterologists, endoscopists with expertise in ERCP, pancreatobiliary

surgeons, interventional radiologists, and a critical care team) is needed to
optimize outcome.
Nutrition
In patients who have mild pancreatitis, nutritional support is not neces-
sary because rapid recovery is expected within several days. Optimal timing
for initiating oral intake is determined according to clinical status: improv-
ing pain scores, return of appetite or active bowel function, and absence of
significant nausea or vomiting.
In patients who have severe pancreatitis for whom prolonged pancreatic
rest is expected, adequate nutritional support is needed to meet metabolic
requirements. Early enteral feeding within 48 hours after admission is well
tolerated, is safer (with fewer infectious complications), and is less expensive
than parenteral nutrition [135]. In the absence of ileus, jejunal feeding is
preferable, although tube placement occasionally can be difficult. Gastric
feeding also seems to be feasible and safe [136]. Parenteral nutrition may
be considered in patients who cannot tolerate enteral feeding or when jeju-
nal tube placement is not feasible technically.
Antibiotic prophylaxis
Based on a recent guideline, antibiotic prophylaxis is recommended in pa-
tients who have suspected or confirmed bile duct obstruction undergoing
ERCP [137]. Generally, empiric antibiotic prophylaxis is given to patients
who have GSP when early ERCP is indicated because these patients are
likely to have retained or impacted bile duct stones.
Patients who have pancreatic necrosis have a significant risk of infectious
complications, which constitute a major cause of death after 2 weeks of
disease. Antibiotic prophylaxis to prevent infected pancreatic necrosis there-
fore is an attractive concept. Several randomized, unblinded studies using
either selective gut decontamination with oral antibiotics or systemic antibi-
otics with various regimens in patients who have pancreatic necrosis have
shown conflicting results. One meta-analysis published in 2003 concluded
that prophylactic antibiotics significantly reduced both mortality and
pancreatic sepsis [138]. Because of the heterogenous studies (eg, different
antibiotic regimens, selection criteria) included in this meta-analysis, its
reliability has been questioned. Recently, two prospective, double-blind,
placebo-controlled studies showed no beneficial effects of antibiotics (cipro-
floxacin/metronidazole in one; meropenem in the other) on reduction of
pancreatic infection or mortality [139,140]. Moreover, superimposed fungal
infection is a risk emerging from the prolonged use of broad-spectrum anti-
biotics [107]. Currently, routine use of prophylactic antibiotics seems to be
unjustified and is not recommended [107]. Rather, empiric antibiotics should
be used only when infected necrosis is suspected and the work-up for sepsis
is pending.
Specific therapy
Most patients who have GSP have a self-limited, uncomplicated course
with mild to moderate disease, because the offending stone passes spontane-
ously into the duodenum in most patients. Routine ERCP therefore is not
recommended because of its low yield and significant risks. ERCP is used
in mild, self-limited GSP when the findings of other noninvasive tests such
as MRCP, EUS, or an intraoperative cholangiogram performed during
the interval cholecystectomy indicate the need for definitive therapy of
bile duct stones.
Urgent endoscopic retrograde cholangiopancreatography for acute

biliary pancreatitis
The extent of pancreatic injury is related to the duration of ampullary
obstruction [141], and patients who have severe GSP are more likely to
have retained/impacted stones [142]. Therefore early restoration of ampul-
lary patency at ERCP is desirable to prevent further pancreatic injury.
Clinically, persistent severe pain, progressive rise of liver function tests or
of the serum lipase/amylase level during the 24 to 48 hours after admission,
and an elevation of bilirubin to more than 1.35 mg/dL on day 2 of hospital-
ization have been used to predict retained bile duct stones in patients who
have GSP. These predictors have variable accuracy [143,144]. With the
increasing availability of MRCP and EUS, patients who are likely to have
retained bile duct stones requiring ERCP can be selected more precisely.
Clinical studies of the role of urgent endoscopic retrograde

cholangiopancreatography in gallstone pancreatitis
Four landmark randomized, controlled trials have compared urgent
ERCP with conservative therapy [142,145–147]. Neoptolemos and col-
leagues [142] first reported a randomized trial comparing urgent ERCP
within 72 hours of admission with conservative therapy plus selective
ERCP after 5 days if indicated. Urgent ERCP was performed successfully
in 88% of patients, and biliary stones were documented in 19 patients
(32%) in this group. In patients who had predicted severe GSP, early
ERCP led to a significant reduction in the overall complication rate and hos-
pital stay compared with the control group (24% versus 61%, and 9.5 days
versus 17 days, respectively). No significant difference in mortality was
noted between the two groups. This study demonstrated that an expert
could perform ERCP safely in the setting of acute pancreatitis.
Fan and colleagues [145] randomly assigned 195 patients who had pan-
creatitis, 127 of whom had GSP, to early ERCP within 24 hours after admis-
sion or to conservative therapy. Early ERCP was performed successfully in
90% of patients; bile duct stones were discovered in 38%. Notably, 18 of the
patients (45%) who had predicted severe pancreatitis who were assigned to
conservative therapy eventually had ERCP performed (for cholangitis/
septic shock) at a median of less than 72 hours after admission. Subgroup
analysis of the 127 patients who had GSP demonstrated that the rate of
complications was significantly lower in the group receiving early ERCP
than in the control group (16% versus 33%), as was biliary sepsis (0% ver-
sus 12%). The reduction in biliary sepsis was confined to those who were
predicted to have severe pancreatitis. There also was a trend toward lower
mortality in the ERCP group (2% versus 8%; P ¼ .09). This study con-
firmed the benefits of early ERCP in patients predicted to have severe
GSP, as reported in the earlier British study [142].
A large preliminary study from Poland [146] evaluated 280 patients sus-
pected of having GSP. All patients underwent duodenoscopy within 24
hours of admission. Seventy-five patients were found to have impacted
stones at the papilla and were treated immediately with BES. The remainder
of the patients, who had a normal-appearing papilla, were assigned ran-
domly to early ERCP (! 24 hours after admission) or conservative therapy.
The patients who had early ERCP (including the 75 patients who impacted
stones, who were immediately treated) had significantly lower complication
rates (17% versus 36%) and mortality (0% versus 7%) than the patients
treated with conservative therapy. The benefit of early ERCP was significant
regardless of the severity of GSP and was most pronounced in patients who
had ERCP less than 24 hours after the onset of symptoms. This study has
not been fully published, however, and some relevant data (eg, criteria for
severity, percentage of visualized bile duct stones) are not available. Hence,
the clinical applicability of this preliminary report is limited.
The fourth study, reported by Fölsch and colleagues [147], evaluated
238 patients suspected of having GSP from 22 centers in Germany.
Patients who had a bilirubin level greater than 5 mg/dL or high fever
(O 39 C) were excluded. Patients assigned to early intervention had
ERCP performed within 72 hours of symptom onset. This study did not
demonstrate a significant benefit of early ERCP in reduction of either
morbidity or mortality. Instead, the study was terminated prematurely
because the interim analysis demonstrated an increased mortality (7.9%
versus 3.6%) and a higher rate of respiratory failure (12% versus 4.5%;
P ¼ .03) in the early ERCP group. This study has been criticized, however,
because of its higher rate of overall morbidity in comparison with the
other three studies and an unclear association of early ERCP with respira-
tory distress. The expertise of the participating centers also was questioned,
because 19 of the 22 centers contributed fewer than a mean of 2 patients
per year to the trial [148].
Two subsequent meta-analyses concluded that early endoscopic therapy,
particularly in patients who have severe disease, significantly reduces mor-
bidity [149,150]. A significant reduction in mortality was evident only
when the Polish study was included in one meta-analysis [149], with the
number needed to treat for avoidance of complication being 7.6 and the
number needed to treat for avoidance of death being 25.6. It is difficult to
establish firm conclusions based on these meta-analyses because of the
lack of homogeneity (eg, in selection criteria, predictors of severity, and tim-

ing of intervention) among these randomized trials.
Two recent prospective, randomized studies addressing the use of early
ERCP to restore biliary patency in patients who have GSP have included
only patients who met the preset criteria for ampullary obstruction
[144,151]. Acosta and colleagues [144] randomly assigned patients suspected
of having ampullary obstruction (defined by persistent severe pain, bile-free
gastric aspirate, and rising bilirubin level measured every 6 hours) to early
ERCP (within 48 hours of admission if obstruction persisted more than
24 hours) versus conservative therapy with selective ERCP after more
than 48 hours. Ten percent of patients in each group had severe pancreatitis.
Ampullary obstruction was confirmed by early ERCP in 13 of 14 patients
who met the criteria of persistent obstruction (11 had impacted stones at
the ampulla; 2 had papillary edema). This study was aborted prematurely
after recruiting 61 patients because the interim analysis demonstrated that
morbidity (29% versus 7%; P ¼ .04) and immediate complications (26%
versus 3%; P ¼ .02) were significantly higher in the conservative group
than in the early ERCP group. There were no deaths in this study. Notably,
most immediate complications in this study were classified as pancreatic
phlegmons, which were not fully defined.
Subsequently, Oria and colleagues [151] recruited 103 patients suspected
of having GSP who met criteria for ampullary obstruction (bilirubin level
O 1.2 mg/dL and distal bile duct diameter measured by TUS R 8 mm) with-
out cholangitis. Patients were assigned randomly to early ERCP (within
72 hours after admission) or to conservative therapy. Early ERCP was suc-
cessful in 92% of patients. Bile duct stones were found in 66% of patients in
the early ERCP group versus 40% in the conservative group (who under-
went elective cholecystectomy with intraoperative cholangiogram). This
study showed no significant benefit from early ERCP in reduction of organ
failure, local complications (6% versus 6%), overall morbidity (21% versus
18%; P ¼ .8), and mortality (6% versus 2%; P ¼ 1). The timing of early
ERCP (within 72 hours) was relatively delayed in this study as compared
with the former study. The validity of their criteria for biliary obstruction
is unknown, because the rate of documented bile duct stones seems to be
similar to that of previous studies without the preset criteria of biliary ob-
struction [150,152]. In addition, it is unclear how many patients in this study
actually had evidence of bile duct obstruction, rather than merely having
bile duct stones. The accuracy of TUS in measuring the distal bile duct
also has been questioned, particularly in the setting of acute pancreatitis,
when overlying bowel gas commonly is present.
These six studies are summarized in Table 4. In summary, early ERCP
seems to be beneficial, particularly if performed within 24 to 48 hours of
admission or symptom onset in patients who have GSP and who have simul-
taneous acute cholangitis or persistent biliary obstruction (persistent severe
pain and elevation of liver function tests). In patients who have severe,
950
Table 4
Prospective randomized, controlled trials: urgent endoscopic retrograde cholangiopancreatography (ERCP) in gallstone pancreatitis (GSP)
Criteria Success rate Documented Complications (%) Mortality (%)
Number of predicted Timing of early stones at early
Study of patients severe GSP of ERCP ERCP (%) ERCP (%) ERCP Control ERCP Control Notes
Neoptolemos 146 O Three 72 hours 88 32 12/24a,b 12/61a,b 2 8 Decreased
et al [142] modified after morbidity in
Glasgow’s admission predicted
criteria severe GSP
Shortened
hospital stay
ATTASARANYA
(9.5 days for
ERCP versus
17 days for
controls)
Fan 195/127 On admission: 24 hours 90 38 16a/0a,c 33a/12a 5 9 Early ERCP
et al
et al [145] (with serum urea after significantly
GSP) O 45 mg/dL or admission reduces
plasma glucose morbidity in
O 198 mg/dL patients
O Three predicted to
Ranson’s have severe
criteria GSP
Nowak 280 Not mentioned 24 hours Not 42 (impacted 17a 36a 2a 13a Decreased
et al [146] after mentioned stones) complication
admission rate and
mortality in
both predicted
mild and
severe cases
Fölsch 121 R Three Glasgow 72 hours after 96 46 46 51 7.9 3.6 Significantly
et al [147] criteria onset of higher rate of
symptoms respiratory
failure in the
early ERCP
group
Acosta 61 Ranson’s and ! 48 hours 100 (of 14 93 29a 7a 0 0 Excluded
et al [144] Acosta criteria; after patients cholangitis
CHOLEDOCHOLITHIASIS AND GALLSTONE PANCREATITIS

selected patients admission with (biliary sepsis)
with suspected only if obstruction Main
ampullary obstruction O 24 hours) complication
obstructiond persists O 24 in control
hours group was
pancreatic
phlegmon
Oria 102 APACHE-II, ! 72 hours 92 66 21 18 6 2 Excluded acute
et al [151] selected patients after onset cholangitis
with suspected of symptoms
ampullary
obstructione
a
Numbers are statistically significantly different.
b
All severity/ predicted severe.
c
Total complications/ biliary sepsis.
d
Defined by severe persisting pain, bile-free gastric aspirate, and elevated serum bilirubin.
e
Defined by distal bile duct measuring R 8 mm by ultrasound with a total bilirubin R 1.2 mg/dL on admission.
951
nonobstructive GSP, the benefit of urgent ERCP is controversial. Practice

varies among experts and centers, and recommendations are inconsistent
[49,107,113,152,153]. The authors perform urgent ERCP on selected cases
in this situation when retained bile duct stones are suspected based on per-
sistent elevation of liver function tests for more than 24 to 48 hours. Patients
who have spontaneously resolving liver function tests may not require ur-
gent ERCP.
Finally, whether BES should be performed when bile duct stones are not
visualized is unclear, and each case should be judged individually. Because
of possibility of overlooking tiny bile duct stones, particularly in a dilated
duct, performing BES empirically in severe GSP seems reasonable. Further-
more, BES may prevent recurrent episodes of pancreatitis, particularly if
cholecystectomy cannot be performed in the near future or is impossible be-
cause of the high surgical risk. Indeed, one guideline advocates BES in pa-
tients who have severe GSP, regardless of the presence or absence of bile
duct stones [153].
An algorithm for endoscopic intervention in acute GSP is proposed in
Fig. 2.
Cholecystectomy for gallstone pancreatitis

The primary objective of cholecystectomy is to prevent recurrent GSP.
Early laparoscopic cholecystectomy seems to be safe and effective in pre-
venting recurrent attacks in patients who have mild GSP [154]. Early
Gallstone pancreatitis (intact gallbladder with stones)
Predicted/actual severe pancreatitis* Cholangitis no Predicted/actual mild pancreatitis

yes
Persistent/progressive severe pain

Early ERCP ± biliary yes
sphincterotomy Persistent liver function tests > 48 hours
(< 24-48 hours after
admission) no
no
Surgical candidate
yes
Surgical candidate Laparoscopic cholecystectomy with
intraoperative cholangiogram (IOC)
(in the same admission)
yes no
empirical
Presence of bile duct stones?
Elective
laparoscopic no
yes
cholecystectomy
(when pancreatitis Follow up ERCP with Follow up
subsides) biliary sphincterotomy
Fig. 2. Algorithm of endoscopic therapy in acute gallstone pancreatitis.

cholecystectomy may be unsafe in patients who have severe disease, how-

ever, because overall complication rates and sepsis were significantly higher
in those undergoing early surgery than in those undergoing delayed surgery
(44% versus 5.5% and 47% versus 7%, respectively) [155].
Because of the high recurrence rate of GSP unless gallstones are removed,
it currently is recommended that cholecystectomy should be performed in
the same hospitalization, when pancreatitis subsides, or within 2 to 4 weeks
after discharge [152,153]. Patients who have little evidence of retained ductal
stones (resolved pain, fully normalized serum liver chemistries) may proceed
directly to laparoscopic cholecystectomy and intraoperative cholangiogram.
If any bile duct stones are documented, they can be managed by intraoper-
ative or postoperative ERCP or by laparoscopic bile duct exploration, de-
pending on the local expertise.
Gallstone pancreatitis after cholecystectomy

In patients who have had cholecystectomy, other causes such as sphincter
of Oddi dysfunction, pancreas divisum, and pancreatic neoplasms need to
be excluded. Less invasive investigations, such as MRCP or EUS, should
be considered to guide further management. If these tests do not confirm
the presence of common duct stones, a presumptive diagnosis of idiopathic
pancreatitis should be made. Further discussion of this issue is beyond the
scope of this article. Because of the frequent need for complex biliary pro-
cedures, such as biliary and pancreatic manometry, and for minor/major
pancreatic sphincter therapy, and because of the high frequency of serious
procedure-related complications, management of these patients should be
undertaken by experienced hands.
Summary
Gallstone disease is encountered commonly in clinical practice. The diag-
nosis of biliary stones has become less problematic with current, less-inva-
sive imaging methods. The relatively invasive endoscopic techniques
should be reserved for therapy and not used for diagnosis. Acute cholangitis
and GSP are two major complications that require prompt recognition and
timely intervention to limit morbidity and prevent mortality or recurrence.
Appropriate noninvasive diagnostic studies, adequate monitoring/support-
ive care, and proper patient selection for invasive therapeutic procedures
are elements of good clinical practice.
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Choledocholithiasis, Ascending Cholangitis, and Gallstone Pancreatitis

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Choledocholithiasis, Ascending Cholangitis, and Gallstone Pancreatitis

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Med Clin N Am 92 (2008) 925–960

bilirubinate to form biliary sludge, which can aggregate eventually into

Risk factors for gallstones

Box 1. Risk factors of gallstones

Role of gallbladder stasis

Choledocholithiasis: special consideration

inﬂammation (such as sclerosing cholangitis, parasitic infestation) and,

Symptomatic bile duct stones

Diagnosis of bile duct stones

Imaging studies for diagnosis of bile duct stones

applications and limitations of imaging studies in the diagnosis of bile duct

Recurrent bile duct stones

Detection of bile duct stones after endoscopic therapy

Therapy of bile duct stones

Treatment of diﬃcult bile duct stones

Electrohydraulic lithotripsy. An electrohydraulic lithotripsy system consists

Extracorporeal shockwave lithotripsy. ESWL generates a shockwave origi-

Laser lithotripsy. In laser lithotripsy, laser light at a particular wavelength is

Supplemental large-diameter biliary oriﬁce balloon dilation

rate comparable to that of ERCP. Either a transcystic approach (for stones

Long-term biliary stenting

Acute ascending cholangitis

cholangitis in Western countries [73]. Malignant obstruction rarely presents

Diagnosis and clinical manifestations

gram-negative organisms including Escherichia coli, Klebsiella, and Entero-

Mild Severe /unstable

Close monitoring/reassess in 6-12 hours altered anatomy (e.g.

Elective ERCP with ± definitive therapy

Elective ERCP Percutaneous drainage

Fig. 1. Algorithm for management of patients who have acute cholangitis.

piperacillin/tazobactam, third- or fourth-generation cephalosporins, quino-

Endoscopic biliary decompression

Evaluation before endoscopic retrograde cholangiopancreatography. The

Endoscopic techniques of biliary drainage in acute cholangitis. When ERCP

of postsphincterotomy bleeding is correlated signiﬁcantly with the presence

Percutaneous transhepatic biliary drainage

Liver function tests

Box 2. Differential diagnosis of acute pancreatitis

raise the possibility of GSP. A normal alanine aminotransferase level does

Abdominal plain roentgenograms

MR imaging/magnetic resonance cholangiopancreatography

CT scanning, with better detection of pancreatic hemorrhage [122] and bile

Determining severity and predicting prognosis

gastroenterologists, endoscopists with expertise in ERCP, pancreatobiliary

Urgent endoscopic retrograde cholangiopancreatography for acute

Clinical studies of the role of urgent endoscopic retrograde

lack of homogeneity (eg, in selection criteria, predictors of severity, and tim-

CHOLEDOCHOLITHIASIS AND GALLSTONE PANCREATITIS

nonobstructive GSP, the beneﬁt of urgent ERCP is controversial. Practice

Cholecystectomy for gallstone pancreatitis

Gallstone pancreatitis (intact gallbladder with stones)

Predicted/actual severe pancreatitis* Cholangitis no Predicted/actual mild pancreatitis

Persistent/progressive severe pain

Fig. 2. Algorithm of endoscopic therapy in acute gallstone pancreatitis.

cholecystectomy may be unsafe in patients who have severe disease, how-

Gallstone pancreatitis after cholecystectomy

[2] National Institutes of Health Consensus Development Conference statement on gallstones

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