The n e w e ng l a n d j o u r na l of m e dic i n e

clinical practice

Acute Calculous Cholecystitis

Steven M. Strasberg, M.D.

This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the author’s clinical recommendations.

A previously well 42-year-old woman presents with severe pain in the right upper
quadrant, which started 15 hours earlier. She has previously noted episodic pain in
that location that lasted for up to 2 hours but has not sought medical advice. She has
had one episode of vomiting with the current attack. On physical examination, her
temperature is 38.5°C, and the heart rate is 95 beats per minute. She has tenderness
and guarding in the right upper quadrant. How should her condition be evaluated and
treated?

The Cl inic a l Probl e m

From the Section of Hepatobiliary–Pan- Acute calculous cholecystitis is a complication of cholelithiasis, a condition that
creatic Surgery, Washington University afflicts more than 20 million Americans annually1 and results in direct costs of
in St. Louis and Barnes–Jewish Hospital,
St. Louis. Address reprint requests to Dr. more than $6.3 billion.2 Most patients with gallstones are asymptomatic. Of such
Strasberg at Box 8109, 660 Euclid Ave., patients, biliary colic develops in 1 to 4% annually,3-5 and acute cholecystitis even-
St. Louis, MO 63110, or at strasbergs@ tually develops in about 20% of these symptomatic patients if they are left un-
wustl.edu.
treated.6 Such patients tend to be somewhat older than those with uncomplicated
N Engl J Med 2008;358:2804-11. symptomatic cholelithiasis. Most patients with acute cholecystitis have had attacks
Copyright © 2008 Massachusetts Medical Society. of biliary colic, but some have had no previous biliary symptoms.3-5 After an initial
attack of acute cholecystitis, additional attacks of pain or inflammation are com-
mon.7 In a small proportion of patients, acute cholecystitis may coexist with choledo-
cholithiasis, cholangitis, or gallstone pancreatitis.
About 120,000 cholecystectomies are performed for acute cholecystitis annu-
ally in the United States. However, the incidence of acute cholecystitis seems to be
falling because of the greater acceptance by patients of laparoscopic cholecystec-
tomy as a treatment for symptomatic gallstones.8 About 60% of patients with acute
cholecystitis are women. However, acute cholecystitis develops in men more fre-
quently than would be expected from the relative prevalence of gallstones (about
half that in women),1 and cholecystitis tends to be more severe in men.9 In patients
with diabetes who have symptomatic gallstones, acute cholecystitis seems to develop
more frequently than in patients without diabetes, and such patients are more
likely to have complications of acute cholecystitis when it occurs.10

Pathogenetic Features
More than 90% of cases of acute cholecystitis are associated with cholelithiasis
(acute calculous cholecystitis). The key elements in pathogenesis seem to be an
obstruction of the cystic duct in the presence of bile supersaturated with choles-
terol.11 Brief impaction may cause pain only, but if impaction is prolonged over
many hours, inflammation can result. With inflammation, the gallbladder becomes
enlarged, tense, and reddened, and wall thickening and an exudate of pericholecys-
tic fluid may develop. The inflammation is initially sterile in most cases, but sec-

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 clinical pr actice

ondary infection with microorganisms in the amylase level suggests concomitant gallstone
Enterobacteriaceae family or with enterococci or pancreatitis or gangrenous cholecystitis. In elder­
anerobes occurs in the majority of patients.12,13 ly patients, delays in diagnosis are common,
The wall of the gallbladder may undergo necrosis since the only symptoms may be a change in
and gangrene (gangrenous cholecystitis). Bacte- mental status or decreased food intake, and phy­
rial superinfection with gas-forming organisms sical examination and laboratory indexes may be
may lead to gas in the wall or lumen of the gall- normal.16,17
bladder (emphysematous cholecystitis). Without
appropriate treatment, the gallbladder may per- Imaging
forate, with the development of an abscess in the Abdominal ultrasonography and hepatobiliary
right upper quadrant or liver or generalized peri- scintigraphy are the imaging studies most com-
tonitis. monly used in diagnosis. Ultrasonography de-
tects cholelithiasis in about 98% of patients
S t r ategie s a nd E v idence (Fig. 1). Acute calculous cholecystitis is diag-
nosed radiologically by the concomitant pres-
Diagnosis ence of thickening of the gallbladder wall (5 mm
The main symptom of uncomplicated cholelithia- or greater), pericholecystic fluid, or direct tender-
sis is biliary colic, caused by the obstruction of the ness when the probe is pushed against the gall-
gallbladder neck by a stone. The pain is character- bladder (ultrasonographic Murphy’s sign). In a
istically episodic, severe, and located in the epi- study involving 497 patients with suspected
gastrium or right upper quadrant. It frequently acute cholecystitis, the positive predictive value
follows food intake or comes on at night. Patients of the presence of stones and a positive ultraso-
commonly have pain that radiates into the back, nographic Murphy’s sign was 92%, and that of
accompanied by nausea and vomiting. Acute cho- stones and thickening of the gallbladder wall
lecystitis usually begins with an attack of biliary was 95%.18 The negative predictive value of the
colic, often in a patient who has had previous at- absence of stones combined with either a normal
tacks, but the pain persists and localizes in the gallbladder wall or a negative Murphy’s sign
right upper quadrant. The bilirubin level may rise was 95%.18
to 4 mg per deciliter (68 μmol per liter) in the Hepatobiliary scintigraphy involves intrave-
absence of complications. However, frank jaun- nous injection of technetium-labeled analogues
dice is uncommon; when present, it should raise of iminodiacetic acid, which are excreted into
suspicion of concomitant choledocholithiasis, Mi- bile. The absence of gallbladder filling within 60
rizzi’s syndrome (obstruction of the bile duct as a minutes after the administration of tracer indi-
result of external compression of a stone in the cates obstruction of the cystic duct and has a
gallbladder or cystic duct), or other complication, sensitivity of 80 to 90% for acute cholecystitis
such as gallbladder perforation. (Fig. 2). The false positive rate of 10 to 20% is
Tenderness and guarding in the right upper largely explained by cystic-duct obstruction in-
quadrant are frequent signs. A palpable mass is duced by chronic inflammation, although in
present in one quarter of patients after 24 hours some cases normal gallbladders do not fill as a
of symptoms but is rarely present early in the result of insufficient resistance at the sphincter
clinical course. Murphy’s sign — the arrest of of Oddi. The specificity of the test can be im-
inspiration while palpating the gallbladder dur- proved by intravenous administration of mor-
ing a deep breath — may be useful, particularly phine, which induces spasm of this sphincter.19
when direct tenderness is absent (e.g., in a sub- When the cystic duct is patent (i.e., no cholecys-
siding case). Occasionally, acute cholecystitis titis), the gallbladder is normally visualized with-
may cause systemic sepsis and organ failure, in 30 minutes. When gallbladder filling occurs
usually in the setting of gangrenous or emphy- within 30 minutes, the false negative rate (i.e.,
sematous cholecystitis. Fever and an elevation in the presence of cholecystitis despite negative re-
the white-cell count are classically described in sults) is only 0.5%,20 but filling between 30 min-
patients with acute cholecystitis, but either or utes and 4 hours is associated with false nega-
both may be absent.14 The C-reactive protein tive rates of 15 to 20%.20 The “rim sign” is a
level is frequently elevated.15 An elevated serum blush of increased pericholecystic radioactivity,

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 The n e w e ng l a n d j o u r na l of m e dic i n e

availability, ease, a lack of interference from

A raised serum bilirubin levels (since cholestasis
interferes with biliary excretion of the agents
used in scintigraphy), the absence of ionizing ra-
diation, and an ability to provide information re-
garding the presence of stones. Increasingly,
emergency medicine physicians are being trained
in the use of ultrasonography.23 Hepatobiliary
scintigraphy is usually reserved for the 20% of
patients in whom the diagnosis is unclear after
ultrasonography has been performed.
B Diagnosis and Grading
The gold standard for diagnosis is pathological
examination of the gallbladder. There is contro-
versy regarding the optimal criteria for clinical
diagnosis. Table 1 summarizes a recently recom-
mended set of diagnostic criteria, called the “To-
kyo guidelines.”24,25 Limitations of these criteria
are that the condition of patients with few sys-
temic symptoms tends to be underdiagnosed and
that testing of the C-reactive protein level is un-
C commonly used for the diagnosis of acute chole-
cystitis in the United States. The Tokyo consen-
sus conference also classified the severity of
acute cholecystitis with the goal of guiding ther-
apy, particularly cholecystectomy (Table 2).25 Al-
though no prospective study has determined the
breakdown of cases falling into the three catego-
ries of the classification, a large majority of cases
are mild.

Treatment
Figure 1. Ultrasonographic Images of Three Timing of Cholecystectomy
Gallbladders. Cholecystectomy can be performed by laparotomy
A normal, sonolucent gallbladder (Panel A) is character- or by laparoscopy, either at the time of the initial
izedICM
by a thin wall and
AUTHOR an absence of acoustic
Strasberg shadows.
RETAKE 1st
In aREG
patient with symptomatic
F FIGURE 1a-c gallstones (Panel B),2ndthe
attack (early treatment) or 2 to 3 months after
gallbladder
CASE contains small echogenic objects
TITLE with
3rd
pos- the initial attack has subsided (delayed treat-
Revised
EMail
terior acoustic shadows thatLine are typical
4-C of gallstones ment). A factor complicating the assessment of
SIZE
Enon
(arrow), with a normal
ARTIST: mst wall H/T
thickness. In a patient
H/T
16p6
with outcomes of early treatment is that “early” has
acute calculous cholecystitisCombo
FILL
(Panel C), thickening is been variably defined as anywhere from 24 hours
visible in the gallbladder
AUTHOR,wall (arrow),
PLEASE NOTE:along with a large
Figure
gallstone has been redrawn and type has been reset.
(arrowhead).
to 7 days after either the onset of symptoms or
Please check carefully. the time of diagnosis. If delayed, or “conserva-
tive,” treatment is selected, patients are treated
JOB: 35826 ISSUE: 6-26-08
which is present in about 30% of patients with during the acute phase with antibiotics and in-
acute cholecystitis and in about 60% with acute travenous fluids and are given nothing by mouth.
gangrenous cholecystitis. Narcotics and, in some cases, nonsteroidal anti-
In comparisons of ultrasonography and hepa- inflammatory drugs are used for pain, and occa-
tobiliary scintigraphy in patients with suspected sionally patients undergo percutaneous cholecys-
acute cholecystitis, scintigraphy had significantly tostomy (placement of a tube in the gallbladder).
higher specificity21 and higher accuracy22 than Early laparoscopic cholecystectomy is consid-
ultrasonography. Nonetheless, ultrasonography is ered the treatment of choice for most patients.
usually favored as the first test because of ready In randomized and prospective trials compar-

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Copyright © 2008 Massachusetts Medical Society. All rights reserved.
 clinical pr actice

A B C

Figure 2. Hepatobiliary Scintigraphy.

In Panel A, a normal liver is visible 10 minutes after the intravenous injection of a technetium-labeled analogue of
­iminodiacetic acid. In Panel B, at 55 minutes after tracer injection, filling of the bile duct (arrow) and gallbladder
­(arrowhead) can be seen. In Panel C, ICMat 1 AUTHOR
hour afterStrasberg RETAKE with
tracer injection in a patient 1st acute cholecystitis and ob-
F FIGURE 2nd
2a-cduct (arrow) but no filling of the
struction of the cystic duct, there isREG
filling of the bile gallbladder.
CASE 3rd
TITLE Revised
EMail Line 4-C
Enon ARTIST: mst SIZE
H/T H/T
ing early laparoscopic cholecystectomy
FILL
with a 33p9
small, randomized,
Combo controlled trials comparing
delayed procedure, 26-31 as well asFigure
in meta-analy- open
AUTHOR, PLEASE cholecystectomy
NOTE: with laparoscopic chole-
has been redrawn and type has been reset.
ses of these trials,7,32-34 early treatment hasPlease
con-checkcystectomy
carefully. did not show an increased risk of
sistently been associated with shorter overall biliary injury with laparoscopic cholecystectomy,
JOB: 35826 ISSUE: 6-26-08
hospitalization. Also favoring early cholecystec- yet this trend became apparent through analysis
tomy is that approximately 15 to 20% of patients of large registries of patients that documented
who underwent delayed procedures in the ran- procedural complications. Adequately powered
domized trials had persistent or recurrent symp- studies are still needed to determine whether the
toms requiring intervention before their planned timing of laparoscopic cholecystectomy in acute
operation.7 cholecystitis affects the rate of major bile-duct
The individual trials and meta-analyses have injuries.
also shown no significant differences between There were no deaths reported in any of the
groups in morbidity or mortality or in operative cited randomized trials, but mortality was more
time or conversion rates to open cholecystec- than 15% in a recent study of patients with acute
tomy. However, the relatively small size of the cholecystitis who were at high risk (a score of 12
studies (the largest meta-analysis involved only or more on the Acute Physiology and Chronic
504 patients) means that an increased risk of un­ Health Evaluation [APACHE]).38 When laparo-
common complications — in particular, major scopic cholecystectomy is performed in patients
bile-duct injury, a complication associated with with moderately severe acute cholecystitis, it
significant morbidity and, in rare cases, mortal- should be done by a highly experienced surgeon.
ity — cannot be convincingly ruled out. For in- If operative conditions make anatomical iden­
stance, in the Cochrane review, conclusions were tification difficult, the laparoscopic procedure
drawn from a total of four bile-duct injuries should be converted to an open cholecystectomy
among 438 patients (0.9%).7 Bile-duct leaks, a or terminated by cholecystostomy.
form of biliary injury35 but considered separate- The rate of conversion to open cholecystec-
ly, were more frequent in the group undergoing tomy is higher when laparoscopic cholecystec-
early procedures (3.2%) than in those undergo- tomy is performed for acute cholecystitis than
ing delayed procedures (0%).7 Data from large, for uncomplicated cholelithiasis, and this is true
population-based studies suggest that biliary whether the operation is performed in the acute
injury is more common when the laparoscopic phase39 or after a delay.40 Conversion rates range
cholecystectomy is performed on an acutely in- from under 5% to 30%. Predictors of the need
flamed gallbladder.36,37 Also of concern is that for conversion include a white-cell count of more

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Diagnostic Criteria for Acute Cholecystitis, According to Tokyo antibiotic should be given within 1 hour before
Guidelines.* cholecystectomy. It is advisable to culture the
Clinical manifestations
gallbladder bile at the time of surgery to guide
the selection of antibiotics in the event that post-
Local symptoms and signs
operative septic complications should arise. The
Murphy’s sign
nonsteroidal antiinflammatory drug diclofenac
Pain or tenderness in the right upper quadrant
has been shown to reduce pain in patients with
Mass in the right upper quadrant biliary colic,48 but trials are lacking to assess its
Systemic signs effects in patients with acute cholecystitis.
Fever
Leukocytosis Percutaneous Cholecystostomy
Elevated C-reactive protein level Percutaneous cholecystostomy that is performed
Imaging findings under local anesthesia with radiologic guidance is
A confirmatory finding on ultrasonography or hepatobiliary scintigraphy often used when the patient presents with sepsis
Diagnosis (severe acute cholecystitis, according to the Tokyo
The presence of one local sign or symptom, one systemic sign, and a confir- guidelines) and in cases in which conservative
matory finding on an imaging test treatment alone fails, especially in patients who
are poor candidates for surgery. Percutaneous
* Data are from Takada et al.24 and Hirota et al.25 cholecystostomy has a high technical success rate
and low complication rate and usually results in
than 18,000 cells per cubic millimeter at the time resolution of acute cholecystitis.49 However, in a
of presentation,41,42 a duration of symptoms of randomized trial in high-risk patients, routine
more than a range of 72 to 96 hours,41,43 and an percutaneous cholecystostomy was not superior to
age over 60 years.41,44,45 conservative measures followed by percutaneous
cholecystostomy when needed.38 Drainage may be
Antibiotic Therapy followed by delayed cholecystectomy or percuta-
The rationales for the use of antibiotics and the neous stone extraction in patients who are poor
choice of which antibiotic to use are based on the operative candidates. Operative cholecystostomy
results of bile cultures from patients with acute is used when cholecystectomy cannot be complet-
cholecystitis.12,13 The guidelines of the Infectious ed because of difficult operative conditions.
Diseases Society of America recommend that an-
timicrobial therapy be instituted if infection is Guidel ine s
suspected on the basis of laboratory and clinical
findings (more than 12,500 white cells per cubic The Tokyo guidelines provide recommendations
millimeter or a temperature of more than 38.5°C) for management depending on the severity of
and radiographic findings (e.g., air in the gall- acute cholecystitis.50 For mild acute cholecystitis,
bladder or gallbladder wall). Such therapy should early laparoscopic cholecystectomy is recommend-
include coverage against microorganisms in the ed. For moderate acute cholecystitis, the guide-
Enterobacteriaceae family (e.g., a second-gen- lines state that either early or delayed cholecystec-
eration cephalosporin or a combination of a qui- tomy may be selected but that early laparoscopic
nolone and metronidazole); activity against en- cholecystectomy should be performed only by a
terococci is not required.46 Antibiotics are also highly experienced surgeon and promptly termi-
recommended for routine use in patients who are nated by conversion to open cholecystostomy if
elderly or have diabetes or immunodeficiency operative conditions make anatomical identifica-
and for prophylaxis in patients undergoing cho- tion difficult. In the small minority of patients
lecystectomy to reduce septic complications even with severe acute cholecystitis, initial conservative
when infection is not suspected. In a randomized management with antibiotics is recommended,
trial of the use of cefamandole in patients with preferably in a high-acuity setting, with the use of
acute cholecystitis who underwent open chole- percutaneous cholecystostomy as needed; surgery
cystectomy, a short course (three doses) was as is reserved for patients in whom this treatment
effective as a 7-day course.47 The first dose of an fails. The guidelines of the Infectious Diseases So-

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 clinical pr actice

Table 2. Severity Grading for Acute Cholecystitis, According to Tokyo Guidelines.*

Grade Criteria
Mild (grade 1) Acute cholecystitis that does not meet the criteria for a more severe grade
Mild gallbladder inflammation, no organ dysfunction
Moderate (grade 2) The presence of one or more of the following:
Elevated white-cell count (>18,000 cells per cubic millimeter)
Palpable, tender mass in the right upper quadrant
Duration >72 hr
Marked local inflammation including biliary peritonitis, pericholecystic abscess, hepatic
­abscess, gangrenous cholecystitis, emphysematous cholecystitis
Severe (grade 3) The presence of one or more of the following:
Cardiovascular dysfunction (hypotension requiring treatment with dopamine at ≥5 μg per
­kilogram of body weight per minute or any dose of dobutamine)
Neurologic dysfunction (decreased level of consciousness)
Respiratory dysfunction (ratio of partial pressure of arterial oxygen to the fraction of inspired
oxygen <300)
Renal dysfunction (oliguria; creatinine level, >2.0 mg/deciliter)
Hepatic dysfunction (prothrombin time–­international normalized ratio, >1.5)
Hematologic dysfunction (platelet count, <100,000 per cubic millimeter)

* Data are from Hirota et al.25

ciety of America for the use of antibiotics in acute

C onclusions a nd
cholecystitis are discussed above.46 R ec om mendat ions

A r e a s of Uncer ta in t y The patient in the vignette has symptoms highly

suggestive of acute cholecystitis. She should be
Most published studies of outcomes of laparo- hospitalized, given nothing by mouth, and start-
scopic cholecystectomy are from tertiary care ed on intravenous fluids. Abdominal ultrasonog-
centers and involve a relatively small number of raphy, which is likely to show gallstones and
patients. Large, population-based studies are re- signs of acute cholecystitis such as a thickened
quired to determine outcomes and rates of com- gallbladder wall and pericholecystic fluid, should
plications, particularly rates of biliary injury. Ran- be performed immediately. Since her presenta-
domized trials of early versus late cholecystectomy tion is consistent with mild (grade 1) acute cho-
with a particular focus on patients with moder- lecystitis, prompt laparoscopic cholecystectomy
ately severe acute cholecystitis are also needed. with perioperative antibiotic coverage would be
Most general surgeons are very adept at laparo- recommended, given the available data suggest-
scopic cholecystectomy but are increasingly less ing that early laparoscopic cholecystectomy is
experienced at open cholecystectomy, especially in safe and results in a reduced overall duration of
the presence of a high degree of acute or chronic hospitalization.
inflammation (“the difficult gallbladder”). It has Dr. Strasberg reports receiving consulting fees from Covi-
been recommended that surgeons and centers dien and grant support from Tissue Link and serving as an
with less experience in difficult cholecystectomies expert witness in cases related to biliary injuries. No other
potential conflict of interest relevant to this article was re-
should perform cholecystostomy when operative ported.
difficulty is encountered due to advanced inflam- I thank Dr. Joseph Solomkin, Department of Surgery, Univer-
mation, followed by referral to a high-volume cen- sity of Cincinnati College of Medicine, and Dr. Victoria ­Fraser,
Department of Medicine, Washington University in St. Louis
ter for later cholecystectomy,51 but studies are School of Medicine, for their advice regarding the se­lection of
needed to assess whether this approach reduces antibiotics; and Drs. Barry Siegel and William Middleton of the
the rate of complications. More data are needed to Mallinckrodt Institute of Radiology, Washington University in
St. Louis, for providing the hepatobiliary and ultrasonographic
guide the most appropriate use of antibiotics in scans from which the figures were produced.
this condition. An audio version of this article is available at www.nejm.org.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

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Namib Desert, Namibia Tracey Robinson, M.D.

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