J Hepatobiliary Pancreat Sci (2013) 20:1–7

DOI 10.1007/s00534-012-0566-y

GUIDELINE TG13: Updated Tokyo Guidelines for acute cholangitis

and acute cholecystitis

TG13: Updated Tokyo Guidelines for the management of acute

cholangitis and cholecystitis
Tadahiro Takada • Steven M. Strasberg • Joseph S. Solomkin • Henry A. Pitt • Harumi Gomi • Masahiro Yoshida •

Toshihiko Mayumi • Fumihiko Miura • Dirk J. Gouma • O. James Garden • Markus W. Büchler •
Seiki Kiriyama • Masamichi Yokoe • Yasutoshi Kimura • Toshio Tsuyuguchi • Takao Itoi • Toshifumi Gabata •
Ryota Higuchi • Kohji Okamoto • Jiro Hata • Atsuhiko Murata • Shinya Kusachi • John A. Windsor •
Avinash N. Supe • SungGyu Lee • Xiao-Ping Chen • Yuichi Yamashita • Koichi Hirata • Kazuo Inui •
Yoshinobu Sumiyama

Published online: 11 January 2013

 Japanese Society of Hepato-Biliary-Pancreatic Surgery and Springer 2012

Abstract In 2007, the Tokyo Guidelines for the man-
agement of acute cholangitis and cholecystitis (TG07) were
first published in the Journal of Hepato-Biliary-Pancreatic
Surgery. The fundamental policy of TG07 was to achieve
the objectives of TG07 through the development of con-
sensus among specialists in this field throughout the world.
Considering such a situation, validation and feedback from
the clinicians’ viewpoints were indispensable. What had
been pointed out from clinical practice was the low diag-
nostic sensitivity of TG07 for acute cholangitis and the
T. Takada (&)
F. Miura
Department of Surgery, Teikyo University School of Medicine,
2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan
e-mail: takada@med.teikyo-u.ac.jp
S. M. Strasberg
Section of Hepatobiliary and Pancreatic Surgery, Washington
University in Saint Louis School of Medicine, Saint Louis,
MO, USA
J. S. Solomkin
Department of Surgery, University of Cincinnati College of
Medicine, Cincinnati, OH, USA
H. A. Pitt
Department of Surgery, Indiana University School of Medicine,
Indianapolis, IN, USA
H. Gomi
Center for Clinical Infectious Diseases, Jichi Medical University,
Tochigi, Japan
M. Yoshida
Clinical Research Center Kaken Hospital, International
University of Health and Welfare, Ichikawa, Japan
T. Mayumi
Department of Emergency and Critical Care Medicine,
Ichinomiya Municipal Hospital, Ichinomiya, Japan
presence of divergence between severity assessment and
clinical judgment for acute cholangitis. In June 2010, we
set up the Tokyo Guidelines Revision Committee for the
revision of TG07 (TGRC) and started the validation of
TG07. We also set up new diagnostic criteria and severity
assessment criteria by retrospectively analyzing cases of
acute cholangitis and cholecystitis, including cases of non-
inflammatory biliary disease, collected from multiple
institutions. TGRC held meetings a total of 35 times as
well as international email exchanges with co-authors
abroad. On June 9 and September 6, 2011, and on April 11,
D. J. Gouma
Department of Surgery, Academic Medical Center, Amsterdam,
The Netherlands
O. J. Garden
Clinical Surgery, The University of Edinburgh, Edinburgh, UK
M. W. Büchler
Department of Surgery, University of Heidelberg,
Heidelberg, Germany
S. Kiriyama
Department of Gastroenterology, Ogaki Municipal Hospital,
Ogaki, Japan
M. Yokoe
General Internal Medicine, Nagoya Daini Red Cross Hospital,
Nagoya, Japan
Y. Kimura
Department of Surgical Oncology and Gastroenterological
Surgery, Sapporo Medical University School of Medicine,
Sapporo, Japan
T. Tsuyuguchi
Department of Medicine and Clinical Oncology, Graduate
School of Medicine Chiba University, Chiba, Japan

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2 J Hepatobiliary Pancreat Sci (2013) 20:1–7
2012, we held three International Meetings for the Clinical
Assessment and Revision of Tokyo Guidelines. Through
these meetings, the final draft of the updated Tokyo Guide-
lines (TG13) was prepared on the basis of the evidence from
retrospective multi-center analyses. To be specific, discus-
sion took place involving the revised new diagnostic criteria,
and the new severity assessment criteria, new flowcharts of
the management of acute cholangitis and cholecystitis, rec-
ommended medical care for which new evidence had been
added, new recommendations for gallbladder drainage and
antimicrobial therapy, and the role of surgical intervention.
Management bundles for acute cholangitis and cholecystitis
were introduced for effective dissemination with the level of
evidence and the grade of recommendations. GRADE sys-
tems were utilized to provide the level of evidence and the
grade of recommendations. TG13 improved the diagnostic
sensitivity for acute cholangitis and cholecystitis, and pre-
sented criteria with extremely low false positive rates
adapted for clinical practice. Furthermore, severity assess-
ment criteria adapted for clinical use, flowcharts, and many
new diagnostic and therapeutic modalities were presented.
The bundles for the management of acute cholangitis and
cholecystitis are presented in a separate section in TG13.
Free full-text articles and a mobile application of TG13
are available via http://www.jshbps.jp/en/guideline/tg13.html.
T. Itoi
Department of Gastroenterology and Hepatology, Tokyo
Medical University, Tokyo, Japan
T. Gabata
Department of Radiology, Kanazawa University Graduate
School of Medical Science, Kanazawa, Japan
R. Higuchi
Department of Surgery, Institute of Gastroenterology, Tokyo
Women’s Medical University, Tokyo, Japan
K. Okamoto
Department of Surgery, Kitakyushu Municipal Yahata Hospital,
Kitakyushu, Japan
J. Hata
Department of Endoscopy and Ultrasound, Kawasaki Medical
School, Okayama, Japan
A. Murata
Department of Preventive Medicine and Community Health,
School of Medicine, University of Occupational and
Environmental Health, Kitakyushu, Japan
S. Kusachi
Department of Surgery, Toho University Medical Center Ohashi
Hospital, Tokyo, Japan
J. A. Windsor
Department of Surgery, The University of Auckland, Auckland,
New Zealand
123
Keywords Acute cholangitis
Acute cholecystitis

Charcot’s triad
Biliary infection
GRADE
Background before Tokyo Guidelines 2007
Acute cholangitis and cholecystitis require appropriate
treatment in the acute phase. Severe acute cholangitis may
result in early death if no appropriate medical care is
provided in the acute phase. Before the publication of the
Tokyo Guidelines for the management of acute cholangitis
and cholecystitis (TG07) in January 2007 [1], there were no
practical guidelines throughout the world primarily tar-
geting acute cholangitis and cholecystitis.
TG07 had substantial influence on medical care for
biliary infections throughout the world in that they clearly
defined the diagnostic criteria and severity assessment
criteria for acute cholangitis and cholecystitis, the defini-
tion of which had until then been ambiguous. TG07 has
provided international standards for diagnostic and severity
assessment criteria. This has enabled the comparison and
integration of multiple studies (i.e., meta-analysis or sys-
tematic reviews).
TG07 was initially developed through the following
processes. An international consensus meeting was held in
Tokyo on April 1 and 2, 2006. A total of 29 experts from
A. N. Supe
Department of Surgical Gastroenterology, Seth G S Medical
College and K E M Hospital, Mumbai, India
S. Lee
HepatoBiliary Surgery and Liver Transplantation, Asan Medical
Center, Ulsan University, Seoul, Korea
X.-P. Chen
Department of Surgery, Hepatic Surgery Centre,
Tongji Hospital, Tongi Medical College,
Huazhong Universty of Science & Technology,
Wuhan, China
Y. Yamashita
Department of Gastroenterological Surgery, Fukuoka University
School of Medicine, Fukuoka, Japan
K. Hirata
Department of Internal Medicine, Second Teaching Hospital,
Fujita Health University School of Medicine, Nagoya, Aichi,
Japan
K. Inui
Department of Surgery I, Sapporo Medical University Hospital,
Sapporo, Hokkaido, Japan
Y. Sumiyama
Toho University School of Medicine, Tokyo, Japan
J Hepatobiliary Pancreat Sci (2013) 20:1–7 3

22 countries and Japanese experts in this field attended the Table 1 Summary of citations of TG07 (from January 2007 to
meeting. To obtain consensus, a voting system was used. December 2011)
As the final product of this international consensus meet- Number of papers in TG07 cited at least once 14
ing, TG07 [2] was published in 2007. Total number of times of citation 209
The process of preparation was by no means easy. TG07 Number of articles citing papers in TG07 122
was the world’s first clinical practice guidelines on the Number of journals publishing articles citing papers in TG07 77
management of acute cholangitis and cholecystitis. There
were many obstacles to overcome. The preparation of
TG07 started according to the principle of evidence-based
medicine. However, due to the absence of diagnostic cri-
teria and severity assessment criteria, studies available at
that time were very few in number, and even if there was
extracted evidence, the criteria lacked unity and the con-
tents were often ambiguous. Furthermore, items to be
discussed included diagnostic methods and clinical deci-
sion-making such as the selection of antimicrobial agents
and their biliary penetration, the route and timing of biliary
drainage, the timing of surgical intervention, and health-
care-associated (e.g., postoperative) cholangitis and cho-
lecystitis. It took an enormously long time to cover the Fig. 1 Annual number of citations of TG07
overall guidelines.
5.2
3.9
Citation analysis 2007–2011 of TG07 6.5 33.8
11.7
TG07 has been cited widely since its publication. The
number of papers citing TG07 [1, 3–5] has been increasing 14.3
every year [6] and has reached approximately 209 treatises.
Those treatises have been cited in textbooks of surgery,
internal medicine, and guidelines of abdominal infections
[7–9]. The significance of this is that TG07 has had sub-
stantial influence on medical education and has become
Fig. 2 Categories of the journals publishing articles citing papers in
disseminated throughout the world as a global standard. TG07 (n = 77)
The results of the survey that examined the number of
citations of TG07 until December 2011 show that the total
1.6 1.6
number of citations of TG07 was 209 in 2009 (Table 1).
The number of citations occurring each year since 2007 is 11.5
presented in Fig. 1. 32.8
23.8
The number of journals that cited TG07 was 77.
Figure 2 provides a breakdown of the fields of the journals
that cited TG07. 28.7
There were 112 treatises that had been cited from TG07.
Figure 3 provides a breakdown of the residential areas of
the authors. Table 2 shows the types of articles which cited
TG07. Of the 76 original treatises, 20 (26.3 %) were cited Fig. 3 Geographical origin of authors citing papers in TG07
(n = 122)
in method sections (Fig. 4). The citation of original trea-
tises in method sections has been on a rapid increase since
2011 (Fig. 5). Of the treatises cited in the method sections, Need for revision of TG07
studies had been conducted in 17 titles concerning diag-
nostic criteria and/or severity assessment criteria (Fig. 4). 1. The development of evidence-based guidelines, clinical
In summary, TG07 has been cited in journals in various practice and assessment
fields throughout the world, although only 5 years’ cita- The publication of TG07 enabled the presentation of the
tions were totaled. first international diagnostic criteria and severity assessment

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4 J Hepatobiliary Pancreat Sci (2013) 20:1–7
Table 2 Types of articles citing TG07
Types of articles
Original article
Review
Case report
Guideline
Others
Total
In 17 articles, patients were diagnosed according to the diagnostic
criteria and severity assessment of TG.
Fig. 4 Section where cited in original articles (n = 76)
Fig. 5 Annual number of original articles citing papers in TG07
criteria [1, 3–6] and, at the same time, the presentation of
those criteria improved the quality of medical care
throughout the world, and the usefulness of TG07 has
become a target of appraisal from clinical viewpoints [10,
11]. TG07 should have been prepared primarily on the
basis of evidence. However, due to the paucity of evidence,
it was completed through combining ‘‘best available evi-
dence’’ and the worldwide knowledge cultivated at the
international consensus meeting. Therefore, a test by cli-
nicians for its usefulness is indispensable. TG07 has now
reached the stage when it can be further improved on the
basis of evidence and consensus as well as feedback from
clinical practice.
In general, following the publication of clinical practice
guidelines, new findings are reported concerning diagnosis
123
Develop Clinical Guidelines
Evidence and consensus based
No. of articles
76 (62.3 %)
20 (16.4 %) Publication and assessment
distribution
11 (9.0 %)
7 (5.7 %)
8 (6.6 %)
122
Use Guidelines
Fig. 6 Evidence–practice cycle
and therapeutic methods. Therefore clinical practice
guidelines require regular update and revision [12]. In view
of these circumstances, an evidence-based revision process
is also required for TG07. After its publication, an
appraisal from clinicians has been taking place concerning
dissemination/use and the results are being made good use
of for future revision (Fig. 6).
2. Validity of TG07
Given the critical appraisal of TG07, there are problems
in applying it in clinical settings. First, the sensitivity of
acute cholangitis is low. Second, there are impractical
aspects in the severity assessment criteria for moderate
acute cholangitis such as deciding the timing of biliary
drainage. There were discordances between clinical
judgement by clinicians and the level of severity utilizing
TG07 severity assessment criteria.
Process of the development of Tokyo Guidelines 2013
(TG13)
1. The First International Meeting for the development of
TG13
On June 9, 2011, the first International Meeting for
Clinical Assessment and Revision of the Tokyo Guidelines
was held. In this meeting, it was made clear that: (1) TG07
should be updated due to the presence of divergence
between TG07 and real clinical settings; (2) the validity of
the diagnostic criteria for acute cholangitis was to be
investigated on the basis of retrospective analysis of
patients with acute cholangitis collected from multiple
institutions; (3) there was divergence between severity
assessment and clinical judgement for acute cholangitis.
2. The Second International Meeting for the develop-
ment of TG13
On September 6, 2011, the Second International Meet-
ing for Clinical Assessment and Revision of the Tokyo
Guidelines was held. At the meeting, the overall action
plans for the new guidelines were determined with the draft
revision of the TG07 and the newly introduced Grades of
Recommendation, Assessment, Development and Evaluation
J Hepatobiliary Pancreat Sci (2013) 20:1–7
(GRADE) systems to provide the levels of evidence and
grade of recommendations. In this meeting, antimicrobial
therapy was mainly discussed. Using the two international
meetings mentioned above as a basis, the revision work of
TG07 started in 2011.
3. The validation study for acute cholangitis was pre-
sented in Kiriyama et al.’s paper [13].
4. The clinical study for Charcot’s triad was also
described in Kiriyama et al.’s paper [13].
5. The validation study for acute cholecystitis was pre-
sented in Yokoe et al.’s paper [14].
6. Third International Meeting for the development of
TG13
On April 11, 2012, the Third International Meeting for
the Clinical Assessment and Revision of Tokyo Guide-
lines was held. In this meeting, the final draft of the
updated Tokyo Guidelines was prepared on the basis of
the evidence from the validation studies of TG07. To
begin with, a discussion took place involving the updated
new diagnostic criteria for which sensitivity and speci-
ficity had been improved, the new severity assessment
criteria adapted for practical medical care, new flowcharts
prepared for reducing divergence between evidence and
clinical care, recommended medical care to which new
evidence had been added, the new idea of gallbladder
drainage and biliary drainage methods in clinical use,
antimicrobial therapy, and the role of surgical
intervention.
The concept and methodology of management bundles
was introduced and discussed as tools for the effective
dissemination and implementation of clinical practice
guidelines by utilizing the GRADE systems for evidence
assessment, and the concept of the grade of recommenda-
tion. As the results of the Third International Meeting for
the Clinical Assessment and Revision of Tokyo Guidelines,
the final draft was prepared through an international email
conference with overseas co-authors. Thus TG13 was
formulated.
The GRADE systems
The assessment of the evidence and the grading of rec-
ommendations in TG13 are based on the GRADE systems
reported in 2004 and 2008 by the working team for the
GRADE [15–17]. The assessment of the quality of evi-
dence and the strength of recommendation are shown in
Figs. 7 and 8), respectively.
In the assessment of the quality of evidence, the level of
evidence is classified as ‘‘high’’ (level A), ‘‘moderate’’
(level B), ‘‘low’’ (level C), or ‘‘very low’’ (level D). A
randomized trial is, in general, classified as having high-
level evidence. However, due to limitations in each study,
5
the quality of the study was re-assessed based on the lim-
itations and the body of evidence was re-classified as
‘‘moderate’’ evidence. Observational studies (a non-ran-
domized study, a cohort study, or a case–control study) are
classified as having low-level evidence in general. The
body of evidence may be upgraded to ‘‘high level’’ if it has
significant influences in clinical practice. Case series or
case reports are classified as having very low evidence, in
general. It is extremely rare that the body of evidence is
re-classified to a higher level. However, reports of cases of
deaths due to complications or cases of significant side
effects may be considered as a higher level.
The strength of recommendations was classified as
‘‘high (strong)’’ (recommendation 1) and ‘‘low (weak)’’
(recommendation 2). Four factors that determine the
strength of recommendations are: (1) the quality of evi-
dence; (2) sense of value and patient’s preference (less
burden on staff members and patients); (3) net profits and
cost/source (cost saving); and (4) benefits and harm burden
(benefits and risks). The general decision was made by
taking into account these four factors. Strong and weak
recommendations were then determined by the Tokyo
Guidelines Revision Committee. A strong recommendation
suggests that desirable effects clearly exceed undesirable
effects and is applied to recommendations on which more
than 70 % of the members of the Tokyo Guidelines
Revision Committee have agreed. The use of ‘‘We rec-
ommend …’’ has been adopted for the style of the
expression. A weak recommendation shows that desirable
effects probably exceed undesirable effects and the use of
‘‘We suggest …’’ has been adopted.
The recommendation 1 level A (strong recommenda-
tion; evidence level high), 1B, 1C, 1D, 2A, 2B, 2C, and 2D
(weak recommendation; evidence level very low) are
shown at the end of recommendations. However, cases
with strong recommendation (recommendation 1) may
include those cases for which ‘‘to perform …’’ is strongly
recommended and those for which ‘‘not to perform …’’ is
strongly recommended.
Introduction of bundles for the management of acute
cholangitis and cholecystitis
We presented and discussed the concept and the method of
management bundles in TG13. Concrete objectives and
anticipated effects of the bundles are as follows: (1) to
achieve improved prognosis by using bundles of treatment
methods with evidence presented in the guidelines (TG13);
(2) to achieve higher compliance and remove barriers
among institutions by presenting a list of guidelines in the
form of bundles; (3) to carry out a survey involving com-
pliance with the items of the medical care recommended by
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6 J Hepatobiliary Pancreat Sci (2013) 20:1–7

Fig. 7 GRADE system (quality Study design Lower if Higher if

Initial quality of
of evidence) [15–17]
evidence
High RCT, systematic Study limitations: Magnitude of effect:
review, meta- 1 Serious 2 Very strong
analysis 2 Very serious 1 Strong
Moderate Inconsistency:
1 Serious Dose-response
2 Very serious gradient
Low Observational Indirectness: 1
study 1 Serious
(cohort study, case 2 Very serious All plausible
control study Impression: confounders would
Very low Any other 1 Serious have reduced the
evidence 2 Very serious effect
(case series, case Publication bias 1
study) 1 likely
2 Very likely

Definition: Overall quality of evidence across studies for the outcome

level A High level B Moderate level C Low level D Very low

1. How to judge a Grade of recommendation References

Totally judgment with evidence, harm and benefit
Level of evidence A, B, C, D
Patient’s preference Yes, No
Harm and benefit Yes, No
Cost effectiveness Yes, No
2. How to show a Grade of recommendation 2 steps
Recommendation 1 : Strong recommendation (Do it, Don’t do it):
Over 70 of clinical practitioners will agree
= We recommend
Recommendation 2 Weak recommendation (probably do it,
probably don’t do it)
Less than 70 will agree = We suggest
Fig. 8 GRADE system (grade of recommendation) [15–17]
the guidelines and to provide guidelines for conducting a
survey concerning changes in medical care before and after
publication of TG13.
Summary
This paper presents the background of TG07, its clinical
impact since publication, the clinical appraisal emerging
from clinical research, the process of revision of TG07, and
the development of TG13. The guidelines need continuous
evaluation and revision. TG13 has been developed to
improve the quality of medical care for patients with acute
cholangitis and cholecystitis. The guidelines should be
widely utilized and prospective clinical studies are needed
for further improvement in the near future.
Conflict of interest None.
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J Hepatobiliary Pancreat Sci (2013) 20:8–23
DOI 10.1007/s00534-012-0564-0
GUIDELINE
TG13 current terminology, etiology, and epidemiology of acute
cholangitis and cholecystitis
Yasutoshi Kimura • Tadahiro Takada • Steven M. Strasberg • Henry A. Pitt • Dirk J. Gouma • O. James Garden
Markus W. Büchler • John A. Windsor • Toshihiko Mayumi • Masahiro Yoshida • Fumihiko Miura •
Ryota Higuchi • Toshifumi Gabata • Jiro Hata • Harumi Gomi • Christos Dervenis • Wan-Yee Lau •
Giulio Belli • Myung-Hwan Kim • Serafin C. Hilvano • Yuichi Yamashita
Published online: 11 January 2013
Ó Japanese Society of Hepato-Biliary-Pancreatic Surgery and Springer 2012
Abstract While referring to the evidence adopted in the
Tokyo Guidelines 2007 (TG07) as well as subsequently
obtained evidence, further discussion took place on ter-
minology, etiology, and epidemiological data. In particular,
new findings have accumulated on the occurrence of
symptoms in patients with gallstones, frequency of severe
cholecystitis and cholangitis, onset of cholecystitis
and cholangitis after endoscopic retrograde cholangiopan-
creatography and medications, mortality rate, and recur-
rence rate. The primary etiology of acute cholangitis/
Electronic supplementary material The online version of this
article (doi:10.1007/s00534-012-0564-0) contains supplementary
material, which is available to authorized users.
Y. Kimura (&)
Department of Surgical Oncology and Gastroenterological
Surgery, Sapporo Medical University School of Medicine,
S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan
e-mail: kimuray@sapmed.ac.jp
T. Takada
F. Miura
Department of Surgery, Teikyo University School of Medicine,
Tokyo, Japan
S. M. Strasberg
Section of Hepatobiliary and Pancreatic Surgery, Washington
University in Saint Louis School of Medicine,
Saint Louis, MO, USA
H. A. Pitt
Department of Surgery, Indiana University School of Medicine,
Indianapolis, IN, USA
D. J. Gouma
Department of Surgery, Academic Medical Center, Amsterdam,
The Netherlands
O. J. Garden
Clinical Surgery, The University of Edinburgh, Edinburgh, UK
123
TG13: Updated Tokyo Guidelines for acute cholangitis
and acute cholecystitis
•
cholecystitis is the presence of stones. Next to stones, the
most significant etiology of acute cholangitis is benign/
malignant stenosis of the biliary tract. On the other hand,
there is another type of acute cholecystitis, acute acalcu-
lous cholecystitis, in which stones are not involved as
causative factors. Risk factors for acute acalculous chole-
cystitis include surgery, trauma, burn, and parenteral
nutrition. After 2000, the mortality rate of acute cholangitis
has been about 10 %, while that of acute cholecystitis has
generally been less than 1 %. After the publication of
TG07, diagnostic criteria and severity assessment criteria
were standardized, and the distribution of cases according
to severity and comparison of clinical data among target
populations have become more subjective. The concept of
M. W. Büchler
Department of Surgery, University of Heidelberg, Heidelberg,
Germany
J. A. Windsor
Department of Surgery, The University of Auckland, Auckland,
New Zealand
T. Mayumi
Department of Emergency and Critical Care Medicine,
Ichinomiya Municipal Hospital, Ichinomiya, Japan
M. Yoshida
Clinical Research Center Kaken Hospital, International
University of Health and Welfare, Ichikawa, Japan
R. Higuchi
Department of Surgery, Institute of Gastroenterology,
Tokyo Women’s Medical University, Tokyo, Japan
T. Gabata
Department of Radiology, Kanazawa University Graduate
School of Medical Science, Kanazawa, Japan
J Hepatobiliary Pancreat Sci (2013) 20:8–23
healthcare-associated infections is important in the current
treatment of infection. The treatment of acute cholangitis
and cholecystitis substantially differs from that of com-
munity-acquired infections. Cholangitis and cholecystitis
as healthcare-associated infections are clearly described in
the updated Tokyo Guidelines (TG13).
Free full-text articles and a mobile application of TG13
are available via http://www.jshbps.jp/en/guideline/tg13.
html.
Keywords Terminology
Etiology
Epidemiology

Acute cholangitis
Acute cholecystitis
Introduction
Acute biliary infection comprises manifold disease con-
cepts and is mostly separated into [1] acute cholangitis, a
systemic infectious disease that is occasionally life-threat-
ening and requires immediate treatment, and [2] acute
cholecystitis, frequently presenting a mild clinical course.
The definition, pathophysiology, and epidemiology of
acute cholangitis are presented in the Tokyo Guidelines for
the management of acute cholangitis and chlecystitis 2007
(TG07) [1], while the updated Tokyo Guidelines (TG13)
present more subjective data acquired throughout the
revision of TG07. As for the data of current clinical trials in
particular, the data concerning frequency of severe cases,
J. Hata
Department of Endoscopy and Ultrasound, Kawasaki Medical
School, Okayama, Japan
H. Gomi
Center for Clinical Infectious Diseases, Jichi Medical University,
Tochigi, Japan
C. Dervenis
First Department of Surgery, Agia Olga Hospital, Athens,
Greece
W.-Y. Lau
Faculty of Medicine, The Chinese University of Hong Kong,
Hong Kong, Hong Kong
G. Belli
General and HPB Surgery, Loreto Nuovo Hospital, Naples, Italy
M.-H. Kim
Department of Internal Medicine, Asan Medical Center,
University of Ulsan, Seoul, Korea
S. C. Hilvano
Department of Surgery, College of Medicine-Philippine General
Hospital, University of the Philippines, Manila, Philippines
Y. Yamashita
Department of Gastroenterological Surgery, Fukuoka University
School of Medicine, Fukuoka, Japan
9
mortality rate, and recurrence rate are introduced along
with epidemiological data.
Terminology
Acute cholangitis
Definition
Acute cholangitis is a morbid condition with acute
inflammation and infection in the bile duct [1, 2].
Pathophysiology
The onset of acute cholangitis involves two factors: (1)
increased bacteria in the bile duct, and (2) elevated intra-
ductal pressure in the bile duct allowing translocation of
bacteria or endotoxin into the vascular and lymphatic
system (cholangio-venous/lymphatic reflux). Because of its
anatomical characteristics, the biliary system is likely to be
affected by the elevated intraductal pressure. In acute
cholangitis, bile ductules tend to become more permeable
to the translocation of bacteria and toxins with the elevated
intraductal biliary pressure. This process results in serious
and fatal infections such as hepatic abscess and sepsis [1].
Historical aspect of terminology
Signs of hepatic fever Hepatic fever was a term used for
the first time by Charcot in his report published in 1887 [3].
Intermittent fever accompanied by chills, right upper
quadrant abdominal pain, and jaundice have been estab-
lished as Charcot’s triad.
Acute obstructive cholangitis Acute obstructive cholan-
gitis was defined by Reynolds and Dargan [4] in 1959 as a
syndrome consisting of lethargy or mental confusion and
shock, as well as fever, jaundice, and abdominal pain
caused by biliary obstruction. They indicated that emer-
gency surgical biliary decompression was the only effec-
tive procedure for treating the disease. These five
symptoms were thus called Reynold’s pentad.
Longmire’s classification Longmire classified patients
with three characteristics of intermittent fever accompanied
by chills and shivering, right upper quadrant abdominal
pain, and jaundice as acute suppurative cholangitis, and
those with lethargy or mental confusion and shock along
with the triad as acute obstructive suppurative cholangitis
(AOSC). He also reported that the latter corresponded to
the morbidity of acute obstructive cholangitis as defined by
Reynolds [5].
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However, terms such as acute obstructive cholangitis Pathological classification

and acute obstructive suppurative cholangitis (AOSC) are
not appropriate as current clinical terminology because (1) Edematous cholecystitis: 1st stage (2–4 days) The
their definition is conceptual and ambiguous. gallbladder has interstitial fluid with dilated capillar-
ies and lymphatics. The gallbladder wall is edema-
Acute cholangitis/cholecystitis as healthcare-associated tous. Gallbladder tissue is intact histologically with
infections edema in the subserosal layer [1].
(2) Necrotizing cholecystitis: 2nd stage (3–5 days) The
In the US IDSA/SIS guidelines on abdominal infection, gallbladder has edematous changes with areas of
acute cholangitis/cholecystitis refers to biliary tract infec- hemorrhage and necrosis. When the gallbladder wall
tion that has developed in any of the following patients: is subject to elevated internal pressure, the blood flow
patients with a history of less than 12 months hospital stay, is obstructed with histological evidence of vascular
patients undergoing dialysis, patients staying at nursing thrombosis and occlusion. There are areas of scattered
home/rehabilitation facility, and patients in an immune- necrosis but they are superficial and do not involve
compromised state [6]. the full thickness of the gallbladder wall [1] (Fig. 1).
That concept has been extrapolated, and acute cho-
langitis/cholecystitis as a healthcare-associated infection
in Japan refers to infection that has developed in patients a
(long-term recumbency, admission to nursing home,
gastrostomy, tracheostomy, repeated aspiration pneu-
monia, bed sore, uretheral catheter placement, history of
recent postoperative infection, or undergoing antimi-
crobial therapy due to other diseases) at risk of having
resistant bacteria (bacteria with a high minimum inhib-
itory concentration, MIC). Those infections should
be treated independently from community-required
infections.

Acute cholecystitis

Definition
b
Acute inflammatory disease of the gallbladder, often
attributable to gallstones, but many factors, such as ische-
mia, motility disorders, direct chemical injury, infections
by microorganism, protozoon and parasites, collagen dis-
ease, and allergic reaction are also involved [1].

Pathophysiology

In the majority of patients, gallstones are the cause of

acute cholecystitis. The process is one of physical
obstruction of the gallbladder at the neck or in the cystic
duct by a gallstone. This obstruction results in increased
pressure in the gallbladder. There are two factors which
determine the progression to acute cholecystitis—the
degree of obstruction and the duration of the obstruction.
Fig. 1 Necrotizing cholecystitis. a Contrast-enhanced CT images
If the obstruction is partial and of short duration, the show discontinuity of the gallbladder wall, suggesting possible
patient experiences biliary colic. If the obstruction is presence of necrosis in a portion of the wall. b Resected specimen
complete and of long duration, the patient develops acute showing extensive falling-off of the gallbladder membrane, erosion,
ulcer, and exposed fascia. Histologically, necrosis of the gallbladder
cholecystitis. If the patient does not receive early treat-
wall and suppurative inflammation accompanying abscess (data not
ment, the disease becomes more serious and complica- shown) were observed with fibrillation and regenerating hyperplastic
tions can occur [1]. epithelium as background

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(3) Suppurative cholecystitis: 3rd stage (7–10 days) The position, pendulum-like movement in the anteflexion
gallbladder wall has white blood cells that present position, hyperperistalsis of the organs near the gall-
areas of necrosis and suppuration. In this stage, the bladder, defecation, and blow to the abdomen.
active repairing process of inflammation is evident.
The enlarged gallbladder begins to contract and the
Advanced forms of and the type of complications of acute
wall is thickened due to fibrous proliferation. Intra-
cholecystitis [1]
mural abscesses are observed and do not involve the
entire thickness of the wall. Pericholecystic abscesses
(1) Perforation of gallbladder: Perforation of the gall-
are also present [1] (Fig. 2).
bladder is caused by acute cholecystitis, injury, or
(4) Chronic cholecystitis: Chronic cholecystitis occurs
tumors, and occurs most frequently as a result of
after the repeated occurrence of mild cholecystitis
ischemia and necrosis of the gallbladder wall.
attacks, and is characterized by mucosal atrophy and
(2) Biliary peritonitis: Biliary peritonitis occurs with the
fibrosis of the gallbladder wall. It can also be caused
entry into the peritoneal cavity of bile leakage due to
by the chronic irritation of large gallstones and may
various causes including cholecystitis-induced gall-
often induce acute cholecystitis [1]. Acute on chronic
bladder perforation, trauma, and a detached catheter
cholecystitis refers to acute infection that has
during biliary drainage and incomplete suture after
occurred in chronic cholecystitis [7, 8] (Fig. 3).
biliary operation.
Histologically, neutrophil invasion is observed in
(3) Pericholecystic abscess: A morbid condition in which
the gallbladder wall with chronic cholecystitis accom-
perforation of the gallbladder wall is covered by the
panying lymphocyte/plasma cell infiltration and
surrounding tissues along with the formation of
fibrosis.
abscesses around the gallbladder
(4) Biliary fistula: A biliary fistula can occur between the
gallbladder and the duodenum following an episode
of acute cholecystitis. This is usually caused by a
Special forms of acute cholecystitis
large gallbladder stone eroding through the wall of
the gallbladder into the duodenum. If the stone is
(1) Acalculous cholecystitis: Acute cholecystitis without
large in size, the patient can develop gallstone ileus
cholecystolithiasis
with the stone causing mechanical small bowel
(2) Xanthogranulomatous cholecystitis: Cholecystitis
obstruction at the ileocecal valve.
characterized by xanthogranulomatous thickening of
the gallbladder wall [9] and elevated intra-gallbladder
pressure due to stones with a rupture of the Rokit-
ansky–Achoff sinuses. This causes leakage and entry Frequency of symptom appearance
of bile into the gallbladder wall. It is ingested by
histocytes to form granulomas consisting of foamy Incidence
histocytes. Patients usually have symptoms of acute
cholecystitis in the initial stage. Q1. What is the incidence proportion of the appearance
(3) Emphysematous cholecystitis: In emphysematous of symptoms in patients with asymptomatic gallstones
cholecystitis, air appears in the gallbladder wall due or those with mild gallstones?
to infection by gas-forming anerobes including Clos-
tridium perfringens. It is often seen in diabetic Asymptomatic, mild symptom- patients ~40 %/5 - 10years
patients, and is likely to progress to sepsis and Acute cholangitis 0.3 ~ 1.6 %
gangrenous cholecystitis [1]. Acute cholecystitis 3.8 ~ 12%
(4) Torsion of the gallbladder: Cause of acute chole-
Annual proportion; 1~3%/year
cystitis [10]. Torsion of the gallbladder is known to
occur by inherited, acquired, and other physical causes.
The inherited factor is the floating gallbladder, which is Incidence in patients with gallstones
very mobile because the gallbladder and cystic ducts are Acute cholecystitis is the most frequent complication
connected with the liver by a fused ligament. The occurring in patients with cholelithiasis. According to the
acquired factors include splanchnoptosis, senile hump- Comprehensive Survey of Living Conditions of the People
back, scoliosis, and weight loss. Physical factors causing on Health and Welfare (conducted by the Medical Statistics
torsion of the gallbladder include sudden change of Bureau of the Ministry of Health and Welfare), the number
intraperitoneal pressure, sudden change of body of cases with acute cholecystitis has increased from 3.9

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a b

Fig. 2 Suppurative cholecystitis. a Contrast-enhanced CT visualizing b–c Many minute stones were observed within the gallbladder. d The
the gallbladder wall under extrinsic compression (up arrow) suggests resected specimen shows the gallbladder membrane accompanying
possible presence of abscess in a portion of the gallbladder wall. extensive abscess formation within the wall (arrowhead)

a b

GB GB

Fig. 3 US images of acute-on-chronic cholecystitis patients. a The with striated intraluminal lucency (up arrow). Only by comparing the
gallbladder wall is shown to have thickened prior to the onset of acute images before (a) and after (b) the onset of acute inflammation can a
inflammation. b The gallbladder itself continued to swell after the decision of the wall thickening and the swelling of gallbladder be
onset of acute inflammation and the wall has further thickened along correctly made

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Table 1 Natural history of asymptomatic, mildly symptomatic, and symptomatic cholelithiasis patients
References Characteristic No. of Average No. of acute Only those Cholangitis Cholecystitis Gallbladder
cases follow-up cholecystitis with remarkable cancer
period (years) cases (%) jaundice cases
(%)

Comfort Asymptomatic 112 15 0 0 0 0 0

et al.
Lund Asymptomatic 95 13 ? ? 1(?) 0 0
Gracie Asymptomatic 123 11 2 0 0 1 0
et al.
McSherry Asymptomatic 135 5 3 0 0 0 0
et al.
Friedman Asymptomatic 123 7 4 2 2 0 0
et al.
Thistle Asymptomatic ? 305 2 C3 0 0 0 0
et al. symptomatic
Wenckert Mildly 781 11 81 (10.4) \59a 0 \59a 3
et al. symptomatic
Ralston Mildly 116 22 ? ? ? ? 2
et al. symptomatic
Friedman Mildly 344 9 20 (5.8) 10 1 3 2
et al. symptomatic
Newman Symptomatic 332 10 38(11.4) ? ? 1 2
et al.
McSherry Symptomatic 556 7 47 (8.5) 19 0 0 1
et al.
Review by Friedman [12]
a
In this report, 59 cases were diagnosed as jaundice and/or acute pancreatitis based on the serum bilirubin and amylase values

million in 1979 to over 10 million in 1993 (Public Welfare observation (median), and 42 % of those with mild
Index in Japan, 1993). No large epidemiological study has symptoms developed abdominal pain of higher than mild
been conducted to date, but it can be estimated that severity (n = 856), respectively. The above data show
approximately 10 % of the general population have gall- that 20–40 % of patients with asymptomatic cholelithiasis
stones [11]. have a risk for developing some type of symptoms/signs
Natural history of patients with asymptomatic gallstones (1–3 % annually) [12–18].
According to a review by Friedman, 1–2 % of patients
with asymptomatic gallstones and 1–3 % of patients with
Incidence of severe cases of acute cholecystitis
mild symptoms annually presented severe symptoms or
and cholangitis
complications (acute cholecystitis, acute cholangitis,
severe jaundice, or pancreatitis (Table 1)). The risk of
Q2. What is the incidence proportion of severe cases of
such complications was high during the first few years
acute cholangitis?
after gallstones had been detected and it decreased sub-
sequently. The probability of undergoing operation due to
subsequent severe symptoms was 6–8 %/year in patients
The proportion of severe cases is 12.3%based on the severity
initially presenting moderate symptoms and the symptoms
assessment criteria of TG07
decreased year by year [12]. Observational studies
involving patients with mild cholecystolithiasis have
found that, during 5–7 years’ observation, 15 % of the Severe cases (grade III) in TG07 refer to those having
subjects presenting mild or nonspecific symptoms devel- poor prognostic factors including shock, consciousness
oped complications associated with gallstones, 12 % disturbance, organ failure, and disseminated intravascular
developed acute cholecystitis (n = 153), 21.9 % of the coagulation. The definition was ambiguous before the
subjects were without symptoms during 8.7 years’ publication of TG07, which, after review of the frequency

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of acute cholangitis, reported that the incidence of severe Etiology

cases was 7–25.5 % for shock, 7–22.2 % for conscious-
ness disturbance, and 3.5–7.7 % for Reynold’s pentad Acute cholangitis
[19].
The proportion of cases diagnosed as severe (grade III) Q5. What are the etiology and mechanism of acute
according to the TG07 severity assessment criteria was cholangitis?
12.3 % or 23 of the 187 cases of acute cholangitis due to
bile duct stones [20].
Acute cholangitis occurs as results of a biliary tract obstruction
Q3. What is the proportion of severe cases of acute (cholestasis) and bacterial growth in bile (bile infection).
cholecystitis?

The onset of acute cholangitis requires two factors, [1]

The proportion of severe cases (accompanying organ dysfunction)
is 6.0% according to TG07 severity assessment criteria.
‘‘Severe’’ in TG07 refers to acute cholecystitis accom-
panying organ dysfunction (grade III), and the proportion
of the above cases was 6.0 % (14 of 235 cases) [21].
Acute cholangitis and cholecystitis as complications
following ERCP
Q4. What is the proportion of acute cholangitis and
cholecystitis following ERCP?
biliary obstruction and [2] bacterial growth in bile (bile
infection). Causes of frequent biliary obstruction are cho-
ledocholithiasis, benign biliary stenosis, stricture of the
biliary anastomosis, and stenosis by malignant diseases
[38, 39]. Choledocholithiasis used to be the most frequent
cause, but recently the incidence of acute cholangitis
caused by malignant disease, sclerosing cholangitis, and
non-surgical instrumentation of the biliary tract has been
increasing. It is reported that malignant disease accounts
for about 10–30 % of cases with acute cholangitis [38, 39].
Tables 2 and 3 show the results of studies on the causes of
acute cholangitis.

Acute cholangitis; 0.5~2.4 %

Acute cholecystitis; 0.2~1.0 % Table 2 Etiology of acute cholangitis
Cholelithiasis
Benign biliarystricture
The incidence of complications following endo-
Congenital factors
scopic retrograde cholangiopancreatography (ERCP) is
Post-operative factors (damaged bile duct, strictured
0.8–12.1 % and the mortality rate is 0.0023–1.5 % [22– choledojejunostomy, etc.)
37]. The most frequently encountered complication is acute Inflammatory factors (oriental cholangitis, etc.)
pancreatitis, although mild to moderate cases account for Malignant occlusion
the greater part (Supplementary Table 1). Bile duct tumor
The proportion of acute cholangitis and cholecystitis Gallbladder tumor
after ERCP is 0.5–2.4 % for cholangitis and 0.2–1.0 % for
Ampullary tumor
cholecystitis [22–26, 29–33].
Pancreatic tumor
There are differences in the proportion of complications
Duodenal tumor
between diagnostic ERCP and therapeutic ERCP, and those
Pancreatitis
of cholangitis and overall complications associated with
Entry of parasites into the bile ducts
therapeutic ERCP are more likely to become elevated
External pressure
[31, 33, 42].
Fibrosis of the papilla
Due to the diffusion of procedures and improved
Duodenal diverticulum
techniques of operators, complications following ERCP
Blood clot
have increased in recent years, although no change has
Sump syndrome after biliary enteric anastomosis
been observed in the frequency of the occurrence of
Iatrogenic factors
acute cholecystitis, so its occurrence is unpredictable
[31]. Reviewed by Kimura et al. [1]

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Acute cholecystitis ‘‘4Fs’’ and ‘‘5Fs’’

Q6. What are the etiology and mechanism of acute
cholecystitis?
Etiology Cystic duct obstruction (Galltones are involved
in 90 95% of the causes.)
Mechanism Bile stasis, activation of inflammatory
mediators and mucosal injuries
Gallstones account for 90–95 % of the causes of acute
cholecystitis [46–49]. Following cystic duct obstruction
and cholestasis within the gallbladder due to the torsion of
stones, gallbladder mucosa disorder occurs, thereby
inducing the activation of infectious mediator [50]. On the
other hand, acute acalculous cholecystitis accounts for
3.7–14 % of acute cholecystitis [51–55]. Risk factors
include surgery, trauma, long-term intensive care unit
stay, infection, thermal burn, and parenteral nutrition [56,
57].
Risk factors
Q7. What are the factors for which association with
the development of acute cholangitis/cholecystitis is
suggested?
Obesity; Acute cholecystitis
Medication;
Hormone replacement therapy: Increased risk for the
development of cholecystitis
or cholecystectomy
Statin: Decreased risk for carrying out cholecystectomy
Acute cholecystitis and four (or five) ‘‘Fs’’
The ‘‘4Fs’’ (forties, female, fat, fair) and ‘‘5Fs’’ (4Fs
plus fecund or fertile) have been shown to be associated
with lithogenesis in the gallbladder [50]. However, it has
not been established whether or not all these factors are
associated with the development of acute cholangitis/
cholecystitis.
Age and female gender
There is no evidence to suggest the association of age/
sex with the onset of acute cholangitis/cholecystitis.
According to the Framingham study which examined
risk factors of cholelithiasis in subjects 30–59 years of age
followed for 10 years, the risk for the development of
cholelithiasis was largest in those subjects in the age range
55–62 years, and the incidence of onset in females was
more than twice as large as in males in any age range, and
increased with age [58].
Obesity
Patients with cholelithiasis are more likely to be obese
than those without [58], and cholelithiasis is a major
comorbidity of obesity. The proportion of cholelithiasis
and cholecystitis in the obese aged 37–60 years (female
BMI [ 34 [(weight kg)/(height m)2], and male BMI [ 38)
was significantly higher than that in the non-obese
(cholelithiasis: 5.8 vs. 1.5 %, odds ratio [OR] = 4.9;
cholecystitis: 0.8 vs. 3.4 %, OR = 5.2) [59].
Role of pregnancy, fecundity, and fertility
No evidence exists to suggest an association between
pregnancy/fecundity and the onset of acute cholangitis/
cholecystitis.
The risk for cholecystectomy due to gallbladder diseases
in middle-aged females (50–64 years of age) increased
with the frequency of delivery and decreased in proportion
to the duration of lactation [60]. Cholelithiasis accounted

Table 3 Percentage causes of acute cholangitis

References Years Setting N Causes
Gallbladder Benign Malignant Sclerosing Others/
stones (%) stenosis stenosis cholangitis unknown
(%) (%) (%) (%)

Gigot [39] 1963–1983 University Paris 412 48 28 11 1.5 –

Saharia and Cameron [40] 1952–1974 Johns Hopkins Hospital, USA 76 70 13 17 0 –
Pitt and Couse [41] 1976–1978 Johns Hopkins Hospital, USA 40 70 18 10 3 –
Pitt and Couse [41] 1983–1985 Johns Hopkins Hospital, USA 48 32 14 30 24 –
Thompson [42] 1986–1989 Johns Hopkins Hospital, USA 96 28 12 57 3 –
Basoli [43] 1960–1985 University of Rome 80 69 16 13 0 4
Daida [44] 1979 Questionnaire throughout Japan 472 56 5 36 – 3
Salek [45] 2000–2005 Long Island Jewish Medical 108 68 4 24 3 1
Center, USA

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Table 4 Etiological
Etiological mechanism
mechanism of gallbladder
diseases Direct chemical toxicity
Promoted stone formation by bile
Inhibition of ACAT activity
Increased hepatic lipoprotein receptors
Induction of acute cholecystitis in patients with
cholelithiasis
Promoted precipitation of calcium salt in bile
Altered mobility of the gallbladder
Promoted hemolysis
Immunological mechanism
Review by Michielsen et al.
[62]
for more than 90 % of the causes of cholelithiasis in
pregnancy and cholelithiasis was the most frequently
encountered surgical disease next to appendicitis [61].
Gallstones were detected by routine ultrasound imaging in
3.5 % of pregnant women, although it is not known whe-
ther or not pregnancy is associated with an increased risk of
cholangitis [61].
Drugs as etiological agents
According to a review by Michielsen et al., drugs pro-
moting the generation of gallbladder stones were indirectly
associated with a risk of acute cholecystitis [62]. A
developmental mechanism of drug-associated gallbladder
diseases in that review is presented in Table 4.
Statins, which are drugs for hyperlipidemia, may
decrease the risk for cholecystectomy due to gallbladder
stones [63–66]. There are also reports suggesting that
thiazide was involved in the increased risk for cholecys-
tectomy due to acute cholecystitis/gallbladder diseases
[67–69], although there is a report that failed to detect an
association [70]. Transcatheter hepatic arterial chemo-
therapy has been indicated to potentially induce chemical
cholecystitis due to direct toxicity [62, 71]. The relative
risk for the onset of cholecystitis or cholecystectomy due
to hormone replacement therapy was two-fold larger [72,
73].
AIDS as a risk factor
Typical gallbladder diseases in AIDS patients are AIDS
cholangiopathy and acute acalculous cholecystitis [74].
The former showed higher frequency similar to sclerosing
cholangititis while the latter showed relatively low
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Drug/treatment
Hepatic artery infusion
Progesterone, fibrate
Estrogen
Thiazides (unconfirmed)
Ceftriaxone
Octreotide
Narcoid
Anticholinergic drugs
Dapson
Antimicrobial drugs (erythromycin,
ampicillin)
Immunotherapy
frequency. Abdominal operations in AIDS patients have
found that the most frequently encountered causative dis-
ease was acute cholecystitis [75].
AIDS cholangiopathy is frequently observed in middle-
aged patients (mean age 37 years; 21–59) with a mean
15 ± 2.2 month history of AIDS, and 90 % of chief
complaints occur in the right upper quadrant abdomen.
Biochemical examination demonstrates a marked elevation
in the level of alkaline phosphatase [74]. Abdominal
ultrasound, computed tomography (CT) [74], magnetic
resonance imaging/magnetic resonance cholangiopancrea-
tography (MRI/MRCP) [76], CT [74], and MRI/MRCP
[76] shows imaging (occasionally, beading) of stenosis/
dilatation in the intra-/extrahepatic bile duct.
Acute acalculous cholecystitis in AIDS patients was
characterized by young age, availability of oral intake, pain
in the right upper quadrant abdomen, marked elevation in
the level of alkaline phosphatase and a slight increase in
the serum bilirubin level, and accompanying cytomegalo-
virus infection or cryptosporidium infection [74].
Other etiologies of acute cholangitis
There are two other etiologies of acute cholangitis: Mirizzi
syndrome and Lemmel syndrome. Mirizzi syndrome is a
morbid condition with stenosis of the common bile duct
caused by mechanical pressure and/or inflammatory chan-
ges caused by the stones present in the gallbladder neck
and cystic ducts [77]. Two types have been described: type
I, which is a morbid condition with the bile duct com-
pressed from the left by the stones present in the gall-
bladder neck and cystic ducts and pericholecystic
inflammatory changes (Fig. 4a–c, Supplementary Fig. 1a–c);
and type II, which is a morbid condition with biliobilary
J Hepatobiliary Pancreat Sci (2013) 20:8–23 17

a
c

Fig. 4 Mirizzi syndrome. a MRCP showed the obstructed common enhanced CT clearly showing that stones impacted in the gallbladder
hepatic duct but failed to visualize the gallbladder. b Cholangiography duct have expanded the common hepatic duct, thereby inducing
with an ENBD tube showed the stenosed common hepatic duct but stenosis
failed to visualize the gallbladder. c Coronal images by contrast-

Fig. 5 Lemmel syndrome.

a Upper gastrointestinal a b
endoscopy showing a
diverticulum just above the
papilla of Vater (right arrow).
b ERCP demonstrating findings
of extrinsic compression in the
lower biliary tract (right arrow)

fistulation caused by pressure necrosis of the bile duct due compresses or displaces the opening of the bile duct or
to cholecystolithiasis [77]. Lemmel syndrome (Fig. 5a, b; pancreatic duct and obstructs the passage of bile in the bile
Supplementary Fig. 2a, b) is a series of morbid conditions duct or hepatic duct, thereby causing cholestasis, jaundice,
in which the duodenal parapapillary diverticulum gallstone, cholangitis, and pancreatitis [78].

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Prognosis 1981–1990s, and 2.7–10 % after 2000 [42, 45, 79–97].

Such differences in mortality rate are assumed to have
Mortality arisen from differences in severity and diagnostic criteria
for the accumulated cases.
Q8. What is the mortality rate of acute cholangitis/
cholecystitis? Acute cholecystitis (Table 6)

The mortality rate in patients with acute cholecystitis has

Acute cholangitis 2.7-10 % been reported to be 0–10 % [17, 21, 98–115]. According to
Acute cholecystitis ~1 % reports after 2000, the mortality rate was less than 1 % [17,
105–115], and no marked difference according to eras and
communities is present.
The mortality rate according to severity in TG07 was
Acute cholangitis (Table 5) classified as mild (grade I) (1/161, 0.6 %), moderate
(grade II) (0/60, 0 %), or severe (grade III) (3/14,
It has been reported that the mortality rate of acute cho- 21.4 %). Overall, acute cholecystitis accounts for 1.7 %
langitis was higher than 50 % before 1980, 10–30 % in [21].

Table 5 Mortality rate of acute cholangitis

References Period/year Country No. of cases Mortality (%)

Andrew [79] 1957–1967 US 17c 64.71

Shimada [80] 1975–1981 Japan 42b 57.1
Csendes [81] 1980–1988 Chile 512 11.91
Himal [82] 1980–1989 Canada 61 18.03
c
Chijiiwa [83] 1980–1993 Japan 27 11.11
Liu [84] 1982–1987 Taiwan 47a 27.66
Lai [85] 1984–1988 Hong Kong 86b 19.77
Thompson [42] 1984–1988 USA 127 3.94
Arima [86] 1984–1992 Japan 163 2.45
Kunisaki [87] 1984–1994 Japan 82 10.98
Tai [88] 1986–1987 Taiwan 225 6.67
Thompson [89] 1986–1989 USA 96 5.21
Sharma [90] 2000–2004 India 75 (7Fr-NBD) 2.7
75 (7Fr stent) 2.7
c
Lee [91] 2001–2002 Taiwan 112 (bacteremia) 13.4
Rahman [92] 2005 UK 122 10
Pang [93] 2003–2004 Hong Kong 171 6.4
Agarwal [94] 2001–2005 India 175 2.9
Tsujino [95] 1994–2005 Japan 343 (38d) 5.3d
Rosing [96] 1995–2005 USA 117 8
Salek [45] 2000–2005 USA 108 24.1
Yeom [97] 2005–2007 Korea 181 0.5 (2d)
a
Only patients with shock
b
Only severe cases
c
Only patients with AOSC(Acute Obstructive Supprative Cholangitis)
d
Only patients with Acute supprative cholangitis

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J Hepatobiliary Pancreat Sci (2013) 20:8–23 19

Table 6 Mortality rate of acute cholecystitis

Author Period/year Country Subjects No. of cases Mortality (%)

Meyer [98] 1958–1964 USA 245 4.49

Ranasohoff [99] 1960–1981 USA 298 3.36
Gagic [100] 1966–1971 USA 93 9.68
Girald [101] 1970–1986 Canada 1691 0.65
Addison [102] 1971–1990 UK 236 4.66
Bedirli [103] 1991–1994 Turkey 368 2.72
Gharaibeh [104] 1994–1999 Jordan 204 0
Russo MW [105] 2004 USA 262,411 0.6
Papi [106] 2004 Meta Cholecystectomy 1009 0.9
LC 246 0
Giger [107] 2005 System. rev. 0.26–0.6
Johansson [108] 2002–2004 Sweden Cholecystectomy 35 0
LC 35 0
Al Salamah [109] 1997–2002 Saudi Arabia LC 311 0
Gurusamy [110] 2006 Meta Early operation 223 0
Delayed operation 228 0
Borzellino [111] 2008 Meta 1408 0
Lee [112] 2005–2006 USA 202 0
Csikesz [113] 2000–2005 USA Cholecystectomy 152,202 3
LC 859,747 0.4
Lee [21] 2007–2008 Taiwan 235 1.7
Gurusamy [114] 2010 Meta Early operation 223 0
Delayed operation 228 0
Sekimoto [115] 2004–2005 Japan Total (operated cases) 738 (512) 0.9 (0.2)
2006–2007 Japan Total (operated cases) 3,858 (1,897) 1.9 (0.4)
2008–2009 Japan Total (operated cases) 8,026 (5,158) 2.9 (0.5)
Meta meta-analysis, System. rev. systematic review, LC laparoscopic cholecystectomy

Recurrence According to randomized controlled trials comparing

Recurrence rate of acute cholecystitis
Q9. What is the recurrence rate for cases having
undergone conservative treatment for acute
cholecystitis?
The recurrence rate for cases needed emergent hospitalization
after having undergone conservative treatment or waiting for
cholecystectomy was 19~36% (level B) and 22~47%
for cases that do not undergo surgery after percutaneous
gallbladder drainage.
Fundamentally, no recurrence has occurred for cases
undergoing cholecystectomy for acute cholecystitis.
(1) Recurrence of acute cholecystitis for which remis-
sion was achieved with conservative treatment
outcomes of cholecystectomy and follow-up after remis-
sion of acute cholecystitis, 36 % of the cases in the follow-
up group subsequently required emergency hospitalization
due to pain and gallstone-associated complications (acute
cholecystitis, bile duct stones, acute pancreatitis) [116,
117] and 24–30 % required cholecystectomy [116–118].
On the other hand, the recurrence rate of acute chole-
cystitis cases waiting for cholecystectomy was 2.5–22 %
[104, 116, 117, 119], and 19 % required emergency hos-
pitalization [116, 117]. It has been reported that, of these
recurrence cases, the recurrence of acute cholecystitis
accounted for 2.5 % [104], 22 % [119], and gallbladder
perforation 6 %, respectively [119].
(2) Recurrence of acute cholecystitis for which no
cholecystectomy was carried out for some reason
Recurrence occurred in 22–47 % of acute cholecystitis
cases undergoing follow-up without cholecystectomy sub-
sequent to percutaneous gallbladder drainage [120–122].

123
20
Recurrence rate after treatment for gallbladder stones
Q10. What is the recurrence rate after endoscopic
treatment for cholelithiasis?
Biliary events (cholelithiasis biliary colic cholangitis) 7~47%
Acute cholecystitis with gallstone in-situ 5.6 -22%
Recurrence of complications in the biliary system
Following endoscopic sphincterectomy (EST), recur-
rence occurred in 7–47 % of cases with complications in
the biliary tract system (cholelithiasis, biliary tract colic,
cholangitis) within the 2.5–15-year follow-up period [123–
129].
Recurrence of acute cholecystitis
It has been reported that the proportion of symptom
appearance of acute cholecystitis (including cases in which
symptoms have appeared) was 5.6–22 % [123, 125, 126,
128–130] when calculous gallbladder was left untreated
after EST [123–126, 128–133] and 0–7 % for cases with
acalculous gallbladder or after cholecystectomy [123–126,
130, 133] (Supplementary Table 2).
A risk factor for recurrence after endoscopic treatment
for bile duct stones by means of endoscopic papillary
balloon dilation (EPBD) is the occurrence of calculous
gallbladder [134, 135]. Compared with treatment by means
of EST, the incidence of acute cholecystitis a long time
after treatment with EPBD is lower [136], although the
recurrence rates of bile duct stones are the same (5.5 and
8.8 %) for both treatment methods [137].
Acknowledgments We would like to express our deep gratitude to
the Japanese Society of Hepato-Biliary-Pancreatic Surgery, the Jap-
anese Society of Abdominal Emergency Medicine, the Japanese
Society of Surgical Infection, the Japan Biliary Association, and the
Japan Radiological Society for their substantial support and guidance
in the preparation of this article.
Conflict of interest None.
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J Hepatobiliary Pancreat Sci (2013) 20:24–34
DOI 10.1007/s00534-012-0561-3

GUIDELINE TG13: Updated Tokyo Guidelines for acute cholangitis

and acute cholecystitis

TG13 guidelines for diagnosis and severity grading of acute

cholangitis (with videos)
Seiki Kiriyama • Tadahiro Takada • Steven M. Strasberg • Joseph S. Solomkin • Toshihiko Mayumi •
Henry A. Pitt • Dirk J. Gouma • O. James Garden • Markus W. Büchler • Masamichi Yokoe • Yasutoshi Kimura •

Toshio Tsuyuguchi • Takao Itoi • Masahiro Yoshida • Fumihiko Miura • Yuichi Yamashita • Kohji Okamoto •
Toshifumi Gabata • Jiro Hata • Ryota Higuchi • John A. Windsor • Philippus C. Bornman • Sheung-Tat Fan •
Harijt Singh • Eduardo de Santibanes • Harumi Gomi • Shinya Kusachi • Atsuhiko Murata • Xiao-Ping Chen •
Palepu Jagannath • SungGyu Lee • Robert Padbury • Miin-Fu Chen • Christos Dervenis • Angus C. W. Chan •
Avinash N. Supe • Kui-Hin Liau • Myung-Hwan Kim • Sun-Whe Kim

Published online: 11 January 2013

1
Ó Japanese Society of Hepato-Biliary-Pancreatic Surgery and Springer 2012

Abstract Since the publication of the Tokyo Guidelines
for the management of acute cholangitis and cholecystitis
(TG07), diagnostic criteria and severity assessment criteria
for acute cholangitis have been presented and extensively
used as the primary standard all over the world. However,
it has been found that there are crucial limitations in these
criteria. The diagnostic criteria of TG07 do not have
enough sensitivity and specificity, and its severity assess-
ment criteria are unsuitable for clinical use. A working
Electronic supplementary material The online version of this
article (doi:10.1007/s00534-012-0561-3) contains supplementary
material, which is available to authorized users.
S. Kiriyama (&)
Department of Gastroenterology, Ogaki Municipal Hospital,
4-86 Minaminokawa-cho, Ogaki, Gifu 503-8502, Japan
e-mail: skiriya@ip.mirai.ne.jp
T. Takada
F. Miura
Department of Surgery, Teikyo University School of Medicine,
Tokyo, Japan
S. M. Strasberg
Section of Hepatobiliary and Pancreatic Surgery,
Washington University in Saint Louis School of Medicine,
Saint Louis, MO, USA
J. S. Solomkin
Department of Surgery, University of Cincinnati College of
Medicine, Cincinnati, OH, USA
T. Mayumi
Department of Emergency and Critical Care Medicine,
Ichinomiya Municipal Hospital, Ichinomiya, Japan
H. A. Pitt
Department of Surgery, Indiana University School of Medicine,
Indianapolis, IN, USA
team for the revision of TG07 was organized in June, 2010,
and these criteria have been updated through clinical
implementation and its assessment by means of multi-
center analysis. The diagnostic criteria of acute cholangitis
have been revised as criteria to establish the diagnosis
where cholestasis and inflammation demonstrated by clin-
ical signs or blood test in addition to biliary manifestations
demonstrated by imaging are present. The diagnostic cri-
teria of the updated Tokyo Guidelines (TG13) have high
sensitivity (87.6 %) and high specificity (77.7 %). TG13
has better diagnostic capacity than TG07. Severity
assessment is classified as follows: Grade III: associated
with organ failure; Grade II: early biliary drainage should
D. J. Gouma
Department of Surgery, Academic Medical Center, Amsterdam,
The Netherlands
O. J. Garden
Clinical Surgery, The University of Edinburgh, Edinburgh, UK
M. W. Büchler
Department of Surgery, University of Heidelberg, Heidelberg,
Germany
M. Yokoe
General Internal Medicine, Nagoya Daini Red Cross Hospital,
Nagoya, Japan
Y. Kimura
Department of Surgical Oncology and Gastroenterological
Surgery, Sapporo Medical University School of Medicine,
Sapporo, Japan
T. Tsuyuguchi
Department of Medicine and Clinical Oncology, Graduate
School of Medicine Chiba University, Chiba, Japan

123
J Hepatobiliary Pancreat Sci (2013) 20:24–34
be conducted; Grade1: others. As for the severity assess-
ment criteria of TG07, separating Grade II and Grade I at
the time of diagnosis was impossible, so they were
unsuitable for clinical practice. Therefore, the severity
assessment criteria of TG13 have been revised so as not to
lose the timing of biliary drainage or treatment for etiology.
Based on evidence, five predictive factors for poor prog-
nosis in acute cholangitis––hyperbilirubinemia, high fever,
leukocytosis, elderly patient and hypoalbuminemia––have
been extracted. Grade II can be diagnosed if two of these
five factors are present.
Free full-text articles and a mobile application of TG13 are
available via http://www.jshbps.jp/en/guideline/tg13.html.
Keywords Acute cholangitis
Diagnostic criteria

Severity assessment
Diagnostic imaging guidelines
Introduction
Patients with acute cholangitis are at risk of developing
severe and potentially lethal infections such as sepsis
unless appropriate medical care is provided promptly. As a
therapeutic procedure for severe cases or to prevent
increased severity, decompression of the biliary tract (i.e.,
biliary tract drainage) is necessary. Recent advances in and
diffusion of endoscopic biliary tract drainage along with
the administration of antimicrobial agents have contributed
to the decrease in the number of deaths due to acute cho-
T. Itoi
Department of Gastroenterology and Hepatology, Tokyo
Medical University, Tokyo, Japan
M. Yoshida
Clinical Research Center Kaken Hospital, International
University of Health and Welfare, Ichikawa, Japan
Y. Yamashita
Department of Gastroenterological Surgery, Fukuoka University
School of Medicine, Fukuoka, Japan
K. Okamoto
Department of Surgery, Kitakyushu Municipal Yahata Hospital,
Kitakyushu, Japan
T. Gabata
Department of Radiology, Kanazawa University Graduate
School of Medical Science, Kanazawa, Japan
J. Hata
Department of Endoscopy and Ultrasound, Kawasaki Medical
School, Okayama, Japan
R. Higuchi
Department of Surgery, Institute of Gastroenterology Tokyo
Women’s Medical University, Tokyo, Japan
25
langitis. However, it remains a life-threatening disease if
the timing of biliary tract drainage has been missed.
Therefore, immediate and precise judgment of severity is
of the utmost importance.
Since Charcot reported a patient with severe acute
cholangitis as a case of ‘‘hepatic fever’’ in 1877, Charcot’s
triad has been widely used as one of the most important
diagnostic criteria [1–5]. However, Charcot’s triad has
extremely low sensitivity despite its high specificity. In
2006, we conducted a systematic review of references and
sponsored the International Consensus Meeting of Tokyo
Guidelines, which resulted in the introduction of new
diagnostic criteria and severity assessment criteria in the
Tokyo Guidelines for the management of acute cholangitis
and cholecystitis (TG07) [6].
Diagnostic criteria and severity assessment criteria
should be reconsidered and updated according to their
implementation in clinical settings and their assessment. In
TG07, there are impractical aspects and discrepancies
between the diagnostic criteria and severity assessment
criteria of acute cholangitis and the actual clinical settings
[7]. Therefore, in order to make the updated Tokyo
Guidelines (TG13), the working team carried out a retro-
spective observational study in multiple tertiary care cen-
ters in Japan. This study found limitations in the diagnostic
criteria and severity assessment criteria of TG07. The
problems which were made clear by the implementation
and assessment of TG07 were then corrected, and new
updated diagnostic criteria and severity assessment criteria
were presented [8]. TG13 provides more accurate and
J. A. Windsor
Department of Surgery, The University of Auckland, Auckland,
New Zealand
P. C. Bornman
Division of General Surgery, Health Sciences, University of
Cape Town, Cape Town, South Africa
S.-T. Fan
Department of Surgery, The University of Hong Kong, Queen
Mary Hospital, Hong Kong, Hong Kong
H. Singh
Department of Hepato-Pancreato-Biliary Surgery, Hospital
Selayang, Kuala Lampur, Malaysia
E. de Santibanes
Department of Surgery, Hospital Italianio, University of Buenos
Aires, Buenos Aires, Argentina
H. Gomi
Center for Clinical Infectious Diseases, Jichi Medical University,
Tochigi, Japan
S. Kusachi
Department of Surgery, Toho University Medical Center Ohashi
Hospital, Tokyo, Japan
123
26
reliable diagnostic criteria and severity assessment criteria
for acute cholangitis to enable us to perform biliary
drainage or other procedures without delay as compared
with TG07.
Diagnostic criteria for acute cholangitis
Background
Charcot’s triad
Q1. What is the role of Charcot’s triad in the diagnostic
criteria for acute cholangitis?
Charcot’s triad shows very high specificity. The presence
of any one sign of Charcot’s triad strongly suggests the
presence of acute cholangitis. However, due to the low sensitivity,
it is not applicable in using as diagnosis criteria for acute
cholangitis (level B).
A diagnosis of acute cholangitis has traditionally been
made according to the presence of Charcot’s triad, that is, a
clinical sign. Charcot’s triad has high specificity [9] but
low sensitivity. According to several reports, cases pre-
senting all the symptoms of Charcot’s triad accounted for
26.4–72 % [2, 3, 8–14].
The previous definition of acute cholangitis was not
clear and varied in different references. Therefore, in the
analysis of cases of biliary tract diseases collected from
A. Murata
Department of Preventive Medicine and Community Health,
School of Medicine, University of Occupational and
Environmental Health, Kitakyushu, Japan
X.-P. Chen
Hepatic Surgery Centre, Department of Surgery, Tongji
Hospital, Tongi Medical College, Huazhong University of
Science and Technology, Wuhan, China
P. Jagannath
Department of Surgical Oncology, Lilavati Hospital and
Research Centre, Mumbai, India
S. Lee
HepatoBiliary Surgery and Liver Transplantation, Asan Medical
Center, Ulsan University, Seoul, Korea
R. Padbury
Division of Surgical and Specialty Services, Flinders Medical
Centre, Adelaide, Australia
M.-F. Chen
Chang Gung Memorial Hospital, Chang Gung University,
Taoyuan, Taiwan
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J Hepatobiliary Pancreat Sci (2013) 20:24–34
multiple facilities, we defined the ‘‘gold standard’’ for acute
cholangitis, that one of the three following conditions was
present: (1) Purulent bile was observed. (2) Clinical
remission followed bile duct drainage. (3) Remis-
sion was achieved by antibacterial therapy alone, in
patients in whom the only site of infection was the biliary
tree. So it showed low sensitivity (26.4 %) when Charcot’s
triad was adopted as a diagnostic criterion for acute cho-
langitis. On the other hand, the specificity was very
favorable (95.9 %), but it was positive (11.9 %) for acute
cholecystitis. The presence of Charcot’s triad supports the
diagnosis of acute cholangitis. However, judging from the
low sensitivity, Charcot’s triad as a diagnostic criterion for
acute cholangitis is doubtful [8].
TG07 diagnostic criteria for acute cholangitis
Q2. How are the diagnostic criteria for acute cholangitis
in TG07 appraised?
Although the sensitivity has been improved compared a with
Charcot’s triad, TG07 have limitations and their validity is
insufficient for using them to make a diagnosis of life-threatening
acute cholangitis without a rapid clinical suspicion and appropriate
treatment (level B).
As has already been mentioned, there were limitations in
Charcot’s triad due to its low diagnostic sensitivity; how-
ever, there was no alternative diagnostic criterion. Under
these circumstances, the International Consensus Meeting
was held in Tokyo in 2006 so that an international
C. Dervenis
First Department of Surgery, Agia Olga Hospital, Athens,
Greece
A. C. W. Chan
Surgery Centre, Department of Surgery, Hong Kong Sanatorium
and Hospital, Hong Kong, Hong Kong
A. N. Supe
Department of Surgical Gastroenterology, Seth G. S. Medical
College and K. E. M. Hospital, Mumbai, India
K.-H. Liau
Hepatobiliary and Pancreatic Surgery, Nexus Surgical
Associates, Mount Elizabeth Hospital, Singapore, Singapore
M.-H. Kim
Department of Internal Medicine, Asan Medical Center
University of Ulsan, Seoul, Korea
S.-W. Kim
Department of Surgery, Seoul National University College of
Medicine, Seoul, Korea
J Hepatobiliary Pancreat Sci (2013) 20:24–34
agreement could be reached on diagnostic criteria and
severity assessment criteria. At that meeting, diagnostic
criteria were presented combining blood tests and diag-
nostic imaging together with Charcot’s triad [15]. Diag-
nostic criteria were then established in TG07.
However, there has been a report showing that, even in
TG07, the sensitivity is low (63.9 %) for making a defi-
nite diagnosis of acute cholangitis [7]. We carried out a
multi-center analysis and found that the sensitivity was
82.6 % and the specificity was 79.8 % [8]. The diagnostic
criteria for acute cholangitis in TG07 were found to be
insufficient for making a diagnosis of life-threatening
acute cholangitis without a rapid diagnosis and appro-
priate treatment.
Revision of TG07 diagnostic criteria for acute cholangitis
Due to the inappropriate combination of such items as
clinical context and manifestations, laboratory data and
imaging findings, TG07 failed to associate them with three
types of morbid conditions of acute cholangitis. We then
performed an analysis of each of the items of the diagnostic
criteria in TG07, which can be classified as the following
three morbidities: (1) fever and/or evidence of inflamma-
tory response such as inflammation, (2) jaundice and
abnormal liver function test results such as cholestasis, and
(3) a history of biliary diseases, abnormal pain and biliary
dilatation, or evidence of etiology such as biliary mani-
festations. It was considered that those cases meeting these
3 categories can be diagnosed as acute cholangitis. How-
ever, a history of biliary diseases and abdominal pain is not
specific to biliary manifestations, thus making the differ-
entiation from acute cholecystitis or acute hepatitis
impossible. Consequently, abdominal pain and a history of
biliary diseases were excluded. To make up for the reduced
sensitivity due to the exclusion of abdominal pain, ‘‘sus-
pected diagnosis’’ in which inflammatory findings are
dispensable was added. By establishing ‘‘suspected diag-
nosis,’’ early biliary drainage or source control of infection
among patients with acute cholangitis can be provided
without waiting for the definitive diagnosis [8].
TG13 diagnostic criteria for acute cholangitis
The revised diagnostic criteria for acute cholangitis are
shown in Table 1. The morbidity of acute cholangitis is
associated with the occurrence of cholangiovenous and
cholangiolymphatic reflux along with elevated pressure in
the biliary ducts and bile infections due to bile duct
obstruction induced by stones and tumors. TG13 Diag-
nostic Criteria of Acute Cholangitis are criteria to establish
the diagnosis when cholestasis and inflammation based on
27
clinical signs or blood test in addition to biliary manifes-
tations based on imaging are present.
Q3. How are TG13 diagnostic criteria for acute cho-
langitis appraised?
TG13 diagnostic criteria for acute cholangitis is more accurate
and reliable diagnostic capacity than TG07 (recommendation
1, level B).
A multi-center analysis assessing TG13 found that the
sensitivity was 91.8 % and the specificity was 77.7 %.
TG13 showed similar specificity to TG07 but showed
markedly increased sensitivity and further improvement in
diagnostic ability (Table 2). The specificity of Charcot’s
triad was the highest. The presence of Charcot’s triad
strongly suggested the presence of acute vasculitis [8].
Systemic inflammation
Acute cholangitis is accompanied by the findings of sys-
temic inflammation due to fever or an increased inflam-
matory response such as an increased white blood cell
count and high levels of C-reactive protein (CRP). While
an increase in the white blood cell count is observed in
82 %, a decrease may be observed in severe vasculitis [5].
Cholestasis
Many reports show that jaundice is observed in 60–70 % of
cases of acute cholangitis (Table 2). A blood test shows an
increase in the levels of ALP, cGTP, LAP and transami-
nases (AST, ALT). The threshold in liver function tests is
particularly important in differentiating from acute chole-
cystitis when making a diagnosis of acute cholangitis
according to the present diagnostic criteria. The thresholds
of the tests needed to be established. However, the normal
range of liver function tests differs from facility to facility.
A fixed threshold is, therefore, not practical. From the
results of multi-center analysis, it is appropriate and prac-
tical that the threshold is set at 1.5 times the normal upper
limit for the liver function test [8].
Imaging findings
There were no direct imaging findings which showed evi-
dence of bile infection. Recently, it has been reported that
acute cholangitis can directly be depicted by computed
tomography (CT) of the abdomen with contrast (Figs. 1, 2).
However, in clinical practice, imaging modalities usu-
ally support the diagnosis of acute cholangitis by showing
indirect findings, which are biliary dilatation or evidence of
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28 J Hepatobiliary Pancreat Sci (2013) 20:24–34

Table 1 TG13 diagnostic criteria for acute cholangitis

A. Systemic inflammation
A-1. Fever and/or shaking chills
A-2. Laboratory data: evidence of inflammatory response
B. Cholestasis
B-1. Jaundice
B-2. Laboratory data: abnormal liver function tests
C. Imaging
C-1. Biliary dilatation
C-2. Evidence of the etiology on imaging (stricture, stone, stent etc.)
Suspected diagnosis: One item in A ? one item in either B or C
Definite diagnosis: One item in A, one item in B and one item in C
Note:
A-2: Abnormal white blood cell counts, increase of serum C-reactive protein levels, and other changes indicating inflammation
B-2: Increased serum ALP, cGTP (GGT), AST and ALT levels.
Other factors which are helpful in diagnosis of acute cholangitis include abdominal pain [right upper quadrant (RUQ) or upper abdominal] and
a history of biliary disease such as gallstones, previous biliary procedures, and placement of a biliary stent.
In acute hepatitis, marked systematic inflammatory response is observed infrequently. Virological and serological tests are required when
differential diagnosis is difficult.
Thresholds
A-1 Fever BT [38 °C
A-2 Evidence of inflammatory response WBC (91000/lL) \4, or [10
CRP (mg/dl) C1
B-1 Jaundice T-Bil C2 (mg/dL)
B-2 Abnormal liver function tests ALP (IU) [1.5 9 STD
cGTP (IU) [1.5 9 STD
AST (IU) [1.5 9 STD
ALT (IU) [1.5 9 STD
Cited from the Ref. [8]
STD upper limit of normal value, ALP alkaline phosphatase, cGTP (GGT) c-glutamyltransferase, AST aspartate aminotransferase, ALT alanine
aminotransferase

Table 2 Retrospective comparison of various diagnostic criteria of (Figs. 1, 2; Supplementary Figure 3) and magnetic reso-
acute cholangitis in a multi-center study in Japan nance cholangiopancreatography (MRCP) (Supplementary
Charcot’s TG07 The first draft criteria TG13 Figure 6).
triad (%) (%) (with abdominal pain (%)
and history of biliary Q4. Is it possible to diagnose acute cholangitis by
disease) (%) computed tomography (CT) of the abdomen?
Sensitivity 26.4 82.6 95.1 91.8
Specificity 95.9 79.8 66.3 77.7 We suggested that dynamic CT of the abdomen with
[Positive rate] contrast enables making the diagnosis of acute cholangitis
Acute 11.9 15.5 38.8 5.9 (recommendation 2, level D).
cholecystitis
Cited from Ref. [8]
Radiological examinations such as ultrasonography, CT
and magnetic resonance imaging (MRI) are carried out for
its etiology. A diagnosis of acute cholangitis requires that evaluation of the site and cause of biliary obstruction and
the presence of stones, tumors or stents inducing bile duct degree of biliary dilatation. However, CT of the abdomen
dilatation or cholangitis is confirmed with ultrasonography with contrast has limitations in the diagnosis and evalua-
(US) of the abdomen (Supplementary Figures 1, 2, Sup- tion of acute cholangitis [16]. Because helical CT is clin-
plementary Movie), CT of the abdomen with contrast ically available, the whole of the upper abdominal organs

123
J Hepatobiliary Pancreat Sci (2013) 20:24–34 29

Fig. 1 CT demonstrating acute cholangitis with gallstone and diffuse inhomogeneous enhancement of the liver. In the equilibrium
common bile duct stone (74-year-old female). Precontrast CT phase of dynamic CT (c), the inhomogeneous enhancement
(a) shows gallstone (arrow) and common bile duct stone (arrowhead). disappears
The arterial phase of contrast-enhanced dynamic CT (b) shows

Fig. 2 CT demonstrating acute cholangitis with gallstone and CT shows enhanced papillary tumor of the duodenum (d arrowhead).
papillary tumor of the duodenum (77-year-old female). a, b Precon- The liver parenchyma shows inhomogeneous enhancement surround-
trast CT, c, d arterial phase of dynamic CT, e, f equilibrium phase. ing the bile ducts, indicating acute cholangitis. In the equilibrium
Precontrast CT shows gallstones (b arrow). Arterial phase of dynamic phase, inhomogeneous enhancement disappears

123
30
can be assessed by contrast-enhanced dynamic CT. Pre-
and postcontrast CT can depict biliary stones, pneumo-
bilia, bile duct dilatation, bile duct wall thickening, and
bile duct stenosis or occlusion. However, such CT find-
ings do not necessarily suggest the presence of acute
cholangitis.
Hepatic parenchymal changes seen at imaging in acute
cholangitis are likely to be related to the extension of the
inflammatory process into the periportal tissues [17–20]. In
acute cholangitis, the inflammatory process of the periph-
eral bile duct spreading as far as the periportal areas
(Glisson’s sheath) causes a decreased portal blood flow and
an increased arterial blood flow. On the arterial phase of
dynamic CT, inhomogeneous hepatic parenchymal
enhancement (nodular, patchy, wedge-shaped or geo-
graphic) is frequently seen in patients with acute cholan-
gitis [16, 17] (Figs. 1, 2). This inhomogeneous hepatic
enhancement of contrast-enhanced dynamic CT appears in
the arterial phase only, and disappears in the portal and
equilibrium phases. Follow-up dynamic CT performed
after treatment for acute cholangitis showed decreased or
no inhomogeneous enhancement, according to the
improvement of biliary inflammation (Supplementary
Figure 4).
In conclusion, contrast-enhanced dynamic CT is rec-
ommended for making a prompt diagnosis of clinically
suspected acute cholangitis.
Q5. Can CT make a diagnosis of the etiology and
complications of acute cholangitis?
CT is suggested as the most effective imaging method for the
diagnosis of etiology and complication of acute cholangitis
(recommendation 2, level D).
CT scan is a useful imaging modality for exploring the
etiology of acute cholangitis such as biliary stones (cho-
lelithiasis, choledocholithiasis, hepatolithiasis) and pan-
creaticobiliary malignancies (extrahepatic bile duct
carcinoma, gallbladder carcinoma, pancreatic head carci-
noma). Because non-calcified biliary stones cannot be
detected by CT, ultrasonography and/or MRI (MRCP) is
also recommended (Supplementary Figure 5).
Hepatic abscesses sometimes occur in patients with
acute cholangitis. It is important to differentiate abscesses
from malignant hepatic tumors such as liver metastasis or
intrahepatic cholangiocarcinoma. Characteristic imaging
findings of hepatic abscesses have also been reported in
dynamic CT as well as acute cholangitis [21–24] (Sup-
plementary Figure 6). Hepatic abscess shows a double
target sign with a transient segmental enhancement in the
arterial phase of dynamic CT. The segmental enhancement
123
J Hepatobiliary Pancreat Sci (2013) 20:24–34
disappears in the equilibrium phase. This transient seg-
mental enhancement in dynamic CT reflects a decrease in
segmental portal blood flow and an increase in compen-
satory hepatic arterial blood flow due to periportal
inflammation within the Glison’s sheath adjacent to the
hepatic abscess [24, 25].
Q6. What are the indication and significance of MRI
(MRCP) for acute cholangitis?
MRI (MRCP) is suggested for the etiologic diagnosis of acute
cholangitis (recommendation 2, level D).
Magnetic resonance cholangiopancreatography (MRCP)
has a high sensitivity for detecting biliary calculi and
malignant biliary obstruction [25–27] (Supplementary
Figure 7). Inhomogeneous enhancement in dynamic MRI
as well as dynamic CT is also able to depict acute cho-
langitis [28].
Other factors which are helpful in diagnosis of acute
cholangitis
A past history of gallbladder diseases is found in many
reports of acute cholangitis [2, 3, 10–14], and it is referred
to as ‘the past history of surgery for the diseases of
the biliary system’, supposedly cholecystectomy for
gallbladder stones in particular [3, 10–13].
The importance of ‘the past history of biliary diseases’
in a diagnosis of acute cholangitis was recognized at the
International Consensus Meeting in 2006. The presence of
bile stones and the placement of stents in the biliary tract
were also considered to be contributing factors in making a
diagnosis of acute cholangitis.
Abdominal pain is reported to be observed in 80 % or
more cases (Table 3). However, it is not a symptom spe-
cific to cholangitis. It was excluded from the diagnostic
criteria for acute cholangitis for the reason that its presence
reduced the specificity and complicated the differentiation
from acute cholecystitis [8].
Severity assessment criteria for acute cholangitis
Background
Patients with acute cholangitis may present with any
severity ranging from self-limiting to severe and/or
potentially life-threatening diseases. Most cases respond to
initial medical treatment consisting of general supportive
therapy and intravenous antimicrobial therapy.
J Hepatobiliary Pancreat Sci (2013) 20:24–34 31

Table 3 Incidence of clinical manifestations of acute cholangitis

Disease N Charcot’s Fever Jaundice Abdominal Reynolds’ Shock Disturbed History of
triad (%) (%) (%) pain (%) pentad (%) (%) consciousness biliary diseases
(%)

Welch [2] ASC 5 50 80 60 0 20 100

AOSC 15 50 88 67 33 27 46.7
Boey [3] AC 99 69.7 93.9 78.8 87.9 5.1 16.2 16.2 75
SC 14 7 57 28
NonSC 72 4 8 12
Csendes ASC 512 22 38.7 65.4 92.2 7 7.2
[9]
Thompson AC 66 About 60 100 66 59 7 9 66
[10]
Gigot [11] AC 412 72 3.5 7.8 7 61
O’Connor AC 65 60 7.7 32 14 21.5
[12] SC 19 53 5 47 11
NonSC 46 63 9 26 15
Lai [13] Severe 86 56 66 93 90 64 27.9
AC
Haupert ASC 13 15.4 100 61.5 100 7.7 23.1 7.7 53.8
[14]
AC acute cholangitis, SC suppurative cholangitis, AOSC acute obstructive suppurative cholangitis

It has been reported in the United States that approxi-
mately 70 % of patients with acute cholangitis are able to
achieve improvement with medical therapy alone [29].
Some cases do not respond to medical treatment and the
clinical manifestations and laboratory data do not improve.
Such cases may progress to sepsis with or without organ
dysfunction and require appropriate management that
includes intensive care, organ-supportive care, and urgent
biliary drainage, in addition to medical treatment. There is
also a report showing approximately a 10 % mortality rate
due to acute cholangitis despite the occurrence of responses
to antimicrobial therapy and biliary drainage [30, 31].
provision of early biliary drainage is impossible. Acute
cholangitis can progress rapidly to sepsis and disseminated
intravascular coagulation (DIC) and the ‘‘observation
strategy’’ in TG07 may induce increased severity during the
initial treatment. In Japan, many cases (46.8 %, 258 of 551
cases) of Grades II or I underwent urgent biliary drainage in
the same manner as Grade III. In these cases, differentiation
between Grade II and Grade I was impossible, because the
definition of Grade II in TG07 was ambiguous [8].
Revision of TG07 severity assessment criteria for acute
cholangitis

TG07 severity assessment criteria for acute cholangitis
TG07 established the world’s first severity assessment
criteria for acute cholangitis at the International Consensus
Meeting in Tokyo in 2006 [6] and classified those condi-
tions with organ dysfunction as ‘severe’ (Grade III), those
showing no responses to the initial treatment as ‘moderate’
(Grade II), and those responding to the initial treatment as
‘mild’ (Grade I).
However, the use of TG07 severity assessment criteria in
actual situations has shown that it is impossible to distin-
guish moderate cases (Grade II) and mild cases (Grade I) as
soon as the initial diagnosis has been made. In TG07,
Grades II and I were only assessed after observation of the
treatment courses. In this treatment strategy, urgent biliary
drainage can be indicated for cases assessed as severe, but
Given these inconveniences of TG07 in clinical practice,
revision was made to improve severity assessment strate-
gies upon diagnosis to allow provision of immediate source
control of infection among patients with acute cholangitis.
To begin with, we examined the items reported as pre-
dictive factors of poor prognosis among patients with acute
cholangitis and those who required urgent biliary drainage.
Furthermore, factors endoscopic gastroenterologists value
in determining the timing of biliary drainage were inte-
grated, except for the factors that define Grade III cases
(severe cases). Factors which were inappropriate for use as
items of severity assessment were excluded. Consequently,
five factors––hypoalbuminemia, elderly patients,
high fever, leukocytosis and hyperbilirubinemia––were
extracted [8, 32]. Cases with two of these five factors
present were classified as Grade II (moderate) [8].

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32 J Hepatobiliary Pancreat Sci (2013) 20:24–34

Table 4 TG13 severity assessment criteria for acute cholangitis

Grade III (Severe) acute cholangitis
‘‘Grade III’’ acute cholangitis is defined as acute cholangitis that is associated with the onset of dysfunction in at least one of any of the
following organs/systems:
1. Cardiovascular dysfunction Hypotension requiring dopamine C5 lg/kg per min, or any dose of norepinephrine
2. Neurological dysfunction Disturbance of consciousness
3. Respiratory dysfunction PaO2/FiO2 ratio \300
4. Renal dysfunction Oliguria, serum creatinine [2.0 mg/dl
5. Hepatic dysfunction PT-INR [1.5
6. Hematological dysfunction Platelet count \100,000/mm3
Grade II (moderate) acute cholangitis
‘‘Grade II’’ acute cholangitis is associated with any two of the following conditions:
1. Abnormal WBC count ([12,000/mm3, \4,000/mm3)
2. High fever (C39 °C)
3. Age (C75 years old)
4. Hyperbilirubinemia (total bilirubin C5 mg/dL)
5. Hypoalbuminemia (\STD 9 0.7)
Grade I (mild) acute cholangitis
‘‘Grade I’’ acute cholangitis does not meet the criteria of ‘‘Grade III (severe)’’ or ‘‘Grade II (moderate)’’ acute cholangitis at initial diagnosis.
Notes
Early diagnosis, early biliary drainage and/or treatment for etiology, and antimicrobial administration are fundamental treatments for acute
cholangitis classified not only as Grade III (severe) and Grade II (moderate) but also Grade I (mild).
Therefore, it is recommended that patients with acute cholangitis who do not respond to the initial medical treatment (general supportive care
and antimicrobial therapy) undergo early biliary drainage or treatment for etiology (see flowchart).
Cited from Ref. [8]
STD lower limit of normal value

TG13 severity assessment criteria for acute cholangitis
The revised assessment criteria for acute cholangitis are
shown in Table 4.
The severity of acute cholangitis is classified as follows;
Grade III (severe): presence of organ dysfunction.
Grade II (moderate): risk of increased severity without
early biliary drainage.
Grade I (mild).
The severity assessment criteria are very important for
determining the treatment strategy for acute cholangitis,
especially for Grade II cases which may progress to Grade
III without immediate intervention. Treatment of acute
cholangitis requires ‘‘treatment for causes’’ for cases with
any severity, along with the administration of antimicrobial
agents and biliary drainage.
Q7. What morbid conditions are referred to as ‘Grade
III (severe)’ in assessing severity for acute cholangitis?
‘Severe’ is referred to as a condition that gives rise to organ
dysfunction due to acute cholangitis requiring intensive care
such as respiratory and circulatory support.
Organ dysfunction is the most common predictor of poor
outcome. On the other hand, based on the pathophysiology,
‘‘severe’’ acute cholangitis can also be defined as that which
accompanies organ dysfunction caused by sepsis. Thus, ‘‘the
presence of organ dysfunction’’ is an important factor in the
definition of Grade III (severe) acute cholangitis [6].
Q8. What morbid conditions are referred to as ‘mod-
erate’ in assessing severity for acute cholangitis?
‘Grade II (moderate)’ is referred to as a condition suggesting
cholangitis requiring emergent or early biliary drainage without
presence of organ dysfunction, but with risks of progression to
Grade III.
Q9. How are TG13 Severity Assessment Criteria for
acute cholangitis appraised?
TG13 Severity Assessment Criteria for Acute Cholangitis
is more suitable and practical for clinical use than TG07,
because of enabling us to identify Grade II which requires
early biliary drainage at the time of initial diagnosis
(recommendation 1, level B).

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J Hepatobiliary Pancreat Sci (2013) 20:24–34
According to TG13 severity assessment criteria, the
number of cases for which biliary drainage was carried out
within 48 h included 50 Grade III cases (69.4 %), 129
Grade II cases(59.7 %), and 181 Grade I cases (54.0 %).
However, many of the Grade I cases that had undergone
biliary drainage within 48 h were accounted for as the
treatment of etiology such as bile stones. Grade I cases that
had undergone biliary drainage as an urgent treatment were
very few in number [8].
Q10. Are the acute cholangitis cases that meet Char-
cot’s triad considered as severe cases?
The presence or absence of Charcot’s triad does not reflect
severity. So, cases that meet Charcot’s triad are not necessarily
assessed as severe (level B).
In the multi-center analysis, of the 110 cases of acute
cholangitis that showed Charcot’s triad, only 13 cases
(11.8 %) were classified as Grade III. Compared with the
cases that did not show Charcot’s triad, there were no
differences in terms of severity. Furthermore, many
(approximately 80 %) of the Grade III cases in TG13 failed
to satisfy Charcot’s triad [8]. The presence or absence of
conformity with Charcot’s triad was not associated with
severity. Cases that meet Charcot’s criteria are not neces-
sarily classified as severe cases.
Conflict of interest None.
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J Hepatobiliary Pancreat Sci (2013) 20:35–46
DOI 10.1007/s00534-012-0568-9
GUIDELINE
TG13 diagnostic criteria and severity grading of acute
cholecystitis (with videos)
Masamichi Yokoe • Tadahiro Takada • Steven M. Strasberg • Joseph S. Solomkin • Toshihiko Mayumi •
Harumi Gomi • Henry A. Pitt • O. James Garden • Seiki Kiriyama • Jiro Hata • Toshifumi Gabata •
Masahiro Yoshida • Fumihiko Miura • Kohji Okamoto • Toshio Tsuyuguchi • Takao Itoi • Yuichi Yamashita •
Christos Dervenis • Angus C. W. Chan • Wan-Yee Lau • Avinash N. Supe • Giulio Belli • Serafin C. Hilvano •
Kui-Hin Liau • Myung-Hwan Kim • Sun-Whe Kim • Chen-Guo Ker
Published online: 11 January 2013
Ó Japanese Society of Hepato-Biliary-Pancreatic Surgery and Springer 2012
Abstract Since its publication in 2007, the Tokyo
Guidelines for the management of acute cholangitis and
cholecystitis (TG07) have been widely adopted. The vali-
dation of TG07 conducted in terms of clinical practice has
shown that the diagnostic criteria for acute cholecystitis are
highly reliable but that the definition of definite diagnosis is
ambiguous. Discussion by the Tokyo Guidelines Revision
Committee concluded that acute cholecystitis should be
suspected when Murphy’s sign, local inflammatory find-
ings in the gallbladder such as right upper quadrant
Electronic supplementary material The online version of this
article (doi:10.1007/s00534-012-0568-9) contains supplementary
material, which is available to authorized users.
M. Yokoe (&)
General Internal Medicine, Nagoya Daini Red Cross Hospital,
2-9 Myoken-cho, Showa-ku, Nagoya, Aichi 466-8650, Japan
e-mail: yokoe@nagoya2.jrc.or.jp
T. Takada
F. Miura
Department of Surgery, Teikyo University School of Medicine,
Tokyo, Japan
S. M. Strasberg
Section of Hepatobiliary and Pancreatic Surgery,
Washington University in Saint Louis School of Medicine,
Saint Louis, MO, USA
J. S. Solomkin
Department of Surgery, University of Cincinnati College
of Medicine, Cincinnati, OH, USA
T. Mayumi
Department of Emergency and Critical Care Medicine,
Ichinomiya Municipal Hospital, Ichinomiya, Japan
H. Gomi
Center for Clinical Infectious Diseases, Jichi Medical University,
Tochigi, Japan
TG13: Updated Tokyo Guidelines for acute cholangitis
and acute cholecystitis
abdominal pain and tenderness, and fever and systemic
inflammatory reaction findings detected by blood tests are
present but that definite diagnosis of acute cholecystitis can
be made only on the basis of the imaging of ultrasonog-
raphy, computed tomography or scintigraphy (HIDA scan).
These proposed diagnostic criteria provided better speci-
ficity and accuracy rates than the TG07 diagnostic criteria.
As for the severity assessment criteria in TG07, there is
evidence that TG07 resulted in clarification of the concept
of severe acute cholecystitis. Furthermore, there is evi-
dence that severity assessment in TG07 has led to a
reduction in the mean duration of hospital stay. As for the
factors used to establish a moderate grade of acute chole-
cystitis, such as leukocytosis, ALP, old age, diabetes, being
H. A. Pitt
Department of Surgery, Indiana University School of Medicine,
Indianapolis, IN, USA
O. J. Garden
Clinical Surgery, The University of Edinburgh, Edinburgh, UK
S. Kiriyama
Department of Gastroenterology, Ogaki Municipal Hospital,
Ogaki, Japan
J. Hata
Department of Endoscopy and Ultrasound, Kawasaki Medical
School, Okayama, Japan
T. Gabata
Department of Radiology, Kanazawa University Graduate
School of Medical Science, Kanazawa, Japan
M. Yoshida
Clinical Research Center Kaken Hospital, International
University of Health and Welfare, Ichikawa, Japan
123
36
male, and delay in admission, no new strong evidence has
been detected indicating that a change in the criteria used
in TG07 is needed. Therefore, it was judged that the
severity assessment criteria of TG07 could be applied in
the updated Tokyo Guidelines (TG13) with minor changes.
TG13 presents new standards for the diagnosis, severity
grading and management of acute cholecystitis.
Free full-text articles and a mobile application of TG13 are
available via http://www.jshbps.jp/en/guideline/tg13.html.
Keywords Acute cholecystitis
Diagnostic criteria

Severity grading
Diagnostic imaging
Guidelines
Introduction
Acute cholecystitis is a disease frequently encountered in
daily practice presenting with right hypochondrial pain as
the main symptom [1–4]. However, there were no diag-
nostic criteria and severity assessment criteria for this
commonplace disease before the publication in 2007 of the
Tokyo Guidelines for the management of acute cholangitis
and cholecystitis (TG07) in the Journal of Hepato-Biliary-
Pancreatic Surgery (vol. 14.1:1–121, 2007). There is a
treatise in TG07 released with the expectation that it will
present international guidelines for improvement in the
diagnosis and treatment of acute cholecystitis [5].
The diagnostic criteria in TG07 were set at high sensi-
tivity to provide medical care suitable for a larger number
of cases and the sensitivity has been reported as 84.9 % on
K. Okamoto
Department of Surgery, Kitakyushu Municipal Yahata Hospital,
Kitakyushu, Japan
T. Tsuyuguchi
Department of Medicine and Clinical Oncology, Graduate
School of Medicine Chiba University, Chiba, Japan
T. Itoi
Department of Gastroenterology and Hepatology, Tokyo
Medical University, Tokyo, Japan
Y. Yamashita
Department of Gastroenterological Surgery, Fukuoka University
School of Medicine, Fukuoka, Japan
C. Dervenis
First Department of Surgery, Agia Olga Hospital, Athens,
Greece
A. C. W. Chan
Department of Surgery, Surgery Centre, Hong Kong Sanatorium
and Hospital, Hong Kong, Hong Kong
W.-Y. Lau
Faculty of Medicine, The Chinese University of Hong Kong,
Hong Kong, Hong Kong
123
J Hepatobiliary Pancreat Sci (2013) 20:35–46
the basis of the test results for TG07 diagnostic criteria [6].
TG07 guidelines have already been recognized as the
diagnostic criteria to be recommended in today’s medical
care for acute cholecystitis [1]; however, guidelines should
achieve further evolution. In view of the current situation
where diagnostic imaging such as ultrasonography (US),
CT and scintigraphy (HIDA scan) are frequently used for
the definite diagnosis of acute cholecystitis, integration of
such diagnostic modalities in guidelines is the main theme
in the present revision.
Acute cholecystitis sometimes requires emergency
treatment for morbidities such as gangrenous cholecystitis,
emphysematous cholecystitis and gallbladder torsion. An
indication that it may require high-level skills is given by
its other name, ‘‘difficult gallbladder’’ [7, 8]. In making a
diagnosis of acalculous cholecystitis, challenges may be
encountered. There may be cases with a poor prognosis
[9, 10]. The severity assessment criteria in TG07 defined
severe acute cholecystitis as acute cholecystitis accompa-
nying organ dysfunction directly related to vital prognosis.
Actually, the overall mortality rate of acute cholecystitis is
approximately 0.6 % [11, 12], and that of severe cases was
reported in TG07 as 6.0 % [13]. Acute cholecystitis is
essentially not a disease with a high mortality rate. How-
ever, it was thought that guidelines should make it clear
that appropriate management with appropriate use of
severity assessment criteria does lead to improved vital
prognosis.
A. N. Supe
Department of Surgical Gastroenterology, Seth G S Medical
College and K E M Hospital, Mumbai, India
G. Belli
General and HPB Surgery, Loreto Nuovo Hospital, Naples, Italy
S. C. Hilvano
Department of Surgery, College of Medicine-Philippine General
Hospital, University of the Philippines, Manila, Philippines
K.-H. Liau
Hepatobiliary and Pancreatic Surgery, Nexus Surgical
Associates, Mount Elizabeth Hospital, Singapore, Singapore
M.-H. Kim
Department of Internal Medicine, Asan Medical Center,
University of Ulsan, Seoul, Korea
S.-W. Kim
Department of Surgery, Seoul National University College of
Medicine, Seoul, Korea
C.-G. Ker
Yuan’s General Hospital, Kaohsiung, Taiwan
J Hepatobiliary Pancreat Sci (2013) 20:35–46
Six years have passed since the publication of TG07 and
the Tokyo Guidelines Revision Committee has been
charged with examining the results of the validation that has
been conducted so far, involving problems such as incon-
venience of their use in actual clinical settings [6, 13–15].
Considering the progress of diagnostic technology and
detection of new evidence, diagnostic criteria and severity
grading revised as the updated Tokyo Guidelines (TG13) are
presented in accordance with actual clinical settings [16].
Diagnostic criteria for acute cholecystitis; TG13
Background
Murphy’s sign
Q1. How large is the diagnostic capacity of Murphy’s
sign for acute cholecystitis?
Murphy’s sign shows high specificity, however the sensitivity
has been reported low. It is not applicable in making a
diagnosis of acute cholecystitis due to the low sensitivity
(level D).
Murphy’s sign refers to where the patient stops breathing
due to pain when an examiner touches the inflammatory
gallbladder of the patient. In 1903, Murphy [17] described
the condition as a sign of cholelithiasis. Murphy’s sign has
also been widely known as a diagnostic factor of acute
cholecystitis. Substantial numbers of clinicians throughout
the world providing treatment for acute cholecystitis refer to
Murphy’s sign. It has been reported in previous studies to
have a sensitivity of 50–65 % and a high specificity of 79 %
[18] or 96 % [2] for the diagnosis of acute cholecystitis
although the sensitivity was once reported to be as low as
20.5 %, while the specificity was 87.5 % [6]. It has a weak
point in that an accurate diagnosis of cholecystitis can be
made when Murphy’s sign is present, while its absence does
not necessarily mean the absence of cholecystitis.
TG07 diagnostic criteria for acute cholecystitis
Q2. How are the diagnostic criteria for acute chole-
cystitis in TG07 appraised?
Although the sensitivity had been improved compared with
Murphy ’s sign, TG07 diagnostic criteria have limitations
and their validity is insufficient for using them to make
a definite diagnosis (level D).
37
At an international consensus meeting held in Tokyo in
2007, the world’s first diagnostic criteria were presented in
the Tokyo Guidelines for the management of acute cho-
langitis and cholecystitis; these are international clinical
practice guidelines. According to a review referring to
these diagnostic criteria, a definite diagnosis of acute
cholecystitis can be made when a local sign or symptom
and a systemic sign are present, and test imaging provides
confirmation [1]. There is a report of cases for which
favorable sensitivity (84.9 %) and specificity (50.0 %)
have been achieved when using TG07 diagnostic criteria in
clinical practice [6]. Multicenter analysis by the Tokyo
Guidelines Revision Committee showed that the sensitivity
was 92.1 % and the specificity was 93.3 % in TG07 [16].
Revision of TG07 diagnostic criteria for acute cholecystitis
The most important problem in TG07 was that the criteria
for definite diagnosis were ambiguous and difficult to use.
In TG07, there were two categories determining the defi-
nite diagnosis of acute cholecystitis. ‘‘Definite diagnosis
1’’: To obtain a definite diagnosis one item in A and one
item in B had to be positive. ‘‘Definite diagnosis 2’’:
Imaging findings (criterion C) confirmed the diagnosis
when acute cholecystitis was suspected clinically.
The Tokyo Guidelines Revision Committee concluded
that the term ‘‘definite diagnosis’’ could not be supported in
current practice without positive diagnostic imaging stud-
ies. We have now changed the expressions: ‘‘suspected’’
diagnosis is achieved when one item from section A and
one item from section B are present. ‘‘Definite’’ diagnosis
is achieved when imaging findings characteristic of acute
cholecystitis (item C) are also present (one item in
A ? one item in B ? C) [16].
TG13 diagnostic criteria for acute cholecystitis
The revised diagnostic criteria for acute cholecystitis are
shown in Table 1.
A diagnosis of acute cholecystitis is made as follows
according to diagnostic criteria. When acute cholecystitis is
suspected from clinical signs and results of blood tests, a
definite diagnosis is made after it has been confirmed by
diagnostic imaging.
Q3. How are the diagnostic criteria for acute chole-
cystitis in TG13 appraised?
TG13 diagnostic criteria of acute cholecystitis have a high
sensitivity and a high specificity (recommendation 1, level B).
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38 J Hepatobiliary Pancreat Sci (2013) 20:35–46

Table 1 TG13 diagnostic criteria for acute cholecystitis
A. Local signs of inflammation etc.
(1) Murphy’s sign, (2) RUQ mass/pain/tenderness
B. Systemic signs of inflammation etc.
(1) Fever, (2) elevated CRP, (3) elevated WBC count
C. Imaging findings
Imaging findings characteristic of acute cholecystitis
Suspected diagnosis: One item in A ? one item in B
Definite diagnosis: One item in A ? one item in B ? C
Acute hepatitis, other acute abdominal diseases, and chronic chole-
cystitis should be excluded
RUQ right upper abdominal quadrant, CRP C-reactive protein, WBC
white blood cell
An assessment by multicenter analysis of TG13 diag-
nostic criteria shows that sensitivity (91.2 %) and speci-
ficity (96.9 %) are favorable and that diagnostic capacity is
almost the same as that in TG07 [16]. It is pointed out that
the diagnostic criteria for acute cholecystitis in TG07 have
limitations in that patients with few systemic symptoms
tends to be underdiagnosed [1]. There is also a report
showing that neither fever nor an elevated white cell count
were observed in 16 % of cases with gangrenous chole-
cystitis or in 28 % of cases with non-gangrenous chole-
cystitis [8]. It is important that the diagnosis is confirmed
repeatedly for cases with suspected cholecystitis.
Clinical context and manifestations
Q4. What is the most important physical manifestation
for making a diagnosis of acute cholecystitis?
The most typical clinical sign of acute cholecystitis is abdominal
pain.
The main symptom of uncomplicated cholelithiasis
is biliary colic caused by the obstruction of the gall-
bladder neck by stones [1]. The proportion of patients
with right hypochondrial pain and epigastric pain
combined is 72–93 %. This is followed in frequency
by nausea and vomiting. Note that the proportion of
patients with fever is not high; that of fever exceeding
38 (°C) is low (about 30 %). Muscular defense is
observed in about half of cases; palpable tumors are
rare in the right hypochondrial region. Rebound ten-
derness and stiffness are also rare (Tables 2, 3) [2–4,
19–23].
Laboratory data
What is the most important blood test for making
a diagnosis of acute cholecystitis?
There are no specific blood tests for making a diag-
nosis of acute cholecystitis. So, the diagnosis can be
made if the following findings are present: general
inflammatory findings (abnormal white blood cell
count, elevated CRP level), an increase in blood cell
count of more than 10000 mm3/dl, an increase in CRP
level of more than 3 mg/dl, and a mild increase of
serum enzymes in the hepato-biliary-pancreatic system
and bilirubin.
The bilirubin level may rise to 4 mg/dl (68 lmol/dl) in
the absence of complications [1]. When ultrasonography
shows findings that suggest acute cholecystitis and a CRP
level exceeding 3 mg/dl, a diagnosis of acute cholecystitis
can be made with 97 % sensitivity, 76 % specificity, and
95 % positive predictive value [24].

Table 2 Incidence of clinical symptoms of acute cholecystitis

n RUQ Epigastralgia Nausea Emesis Fever Rebound Guarding Rigidity Mass Murphy’s
pain (%) (%) (%) (%) (%) (%) (%) (%) sign (%)
(%)

Eskelinen [2] 124 56 25 31 60 62 (C37.1 °C) 48 30 66 16 62

Brewer [19] 26 77 30 (C38 °C) 35 58 3.9
Schofield [20] 64 83 31 ([37.5 °C) 14
Staniland [21] 100 38 34 About 80 About 70 About 30 About 45 About 10 About 25
Halasz [3] 191 93 23
Johnson [4] 37 70 11 73 62 24 62
Singer [22] 40 10 ([38.0 °C) 65
Adedeji [23] 62 48
RUQ right upper abdominal quadrant

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J Hepatobiliary Pancreat Sci (2013) 20:35–46 39

Imaging findings On the basis of a meta-analysis of five treatises

involving a total of 532 cases, Shea et al. show that the
Ultrasonography (US) diagnostic capability of ultrasonography for acute chole-
cystitisis: sensitivity 88 % (95 % CI 0.74–1.00) and spec-
Q5. Which type of diagnostic imaging method should be ificity 80 % (95 % CI 0.62–0.98) [28]. The diagnostic
used, first of all, for making a diagnosis of acute capacity of ultrasonography for acute cholecystitis is gen-
cholecystitis? erally thought to be good.

Ultrasonography should be performed at the initial consultation
for all cases for which acute cholecystitis is suspected
(recommendation 1, level A).
Ultrasonography is the test that should be performed
first of all for every case of suspected acute cholecystitis.
Even emergency physicians who are not specialists in
ultrasonography are able to make a satisfactory diagnosis
[25, 26].
In view of its convenience and lack of invasiveness,
ultrasonography should be considered the first option
among morphological tests for this morbidity.
Q6. How large is the diagnostic capacity of ultra-
sonography for acute cholecystitis?
Ultrasonography shows 50~88 % sensitivity and 80~88 %
specificity.
A report by Chatziioannou et al. [27] discussing 107 cases
of acute cholecystitis in terms of the diagnostic capacity of
ultrasonography has found that sensitivity is 50 %, speci-
ficity 88 %, PPV 64 %, NPV 80 %, and accuracy 77 %.
Q7. What are the ultrasonographic imaging findings
characteristic of acute cholecystitis?
They are mainly enlarged gallbladder, thickening of the
gallbladder wall, gallbladder stones, and debris echo.
A diagnosis of acute calculous cholecystitis can be made
radiologically when the following findings are present at
the same time: thickening of the gallbladder wall (5 mm or
greater), pericholecystic fluid, or direct tenderness when
the probe is pushed against the gallbladder (ultrasono-
graphic Murphy’s sign) [1]. Other ultrasonographic find-
ings may include gallbladder enlargement, gallbladder
stones, debris echo and gas imaging (Fig. 1).
However, due to differences among reports in the fre-
quency of the occurrence of individual findings, sensitivity,
and specificity, diagnosis should be made after a compre-
hensive judgment has been made of individual findings
[29, 30] (Supplement Table 1).
There are many diagnostic modalities enabling depiction
of stones. However, there is a report showing that bile
stones could be depicted by ultrasonography in only 13 %
of cases (1 of 7 cases). Therefore, the use of other

Table 3 Diagnostic capability of clinical symptoms for acute cholecystitis

No. of studies No. of patients Summary LR (95 % CI) Sensitivity (95 % CI) Specificity (95 % CI)
Positive Negative

Anorexia 2 1135 1.1–1.7 0.5–0.9 0.65 (0.57–0.73) 0.50 (0.49–0.51)

Emesis 4 1338 1.5 (1.1–2.1) 0.6 (0.3–0.9) 0.71 (0.65–0.76) 0.53 (0.52–0.55)
Fever 8 1292 1.5 (1.0–2.3) 0.9 (0.8–1.0) 0.35 (0.31–0.38) 0.80 (0.78–0.82)
Guarding 2 1170 1.1–2.8 0.5–1.0 0.45 (0.37–0.54) 0.70 (0.69–0.71)
Murphy’s sign 3 565 2.8 (0.8–8.6) 0.5 (0.2–1.0) 0.65 (0.58–0.71) 0.87 (0.85–0.89)
Nausea 2 669 1.0–1.2 0.6–1.0 0.77 (0.69–0.83) 0.36 (0.34–0.38)
Rebound 4 1381 1.0 (0.6–1.7) 1.0 (0.8–1.4) 0.30 (0.23–0.37) 0.68 (0.67–0.69)
Rectal tenderness 2 1170 0.3–0.7 1.0–1.3 0.08 (0.04–0.14) 0.82 (0.81–0.83)
Rigidity 2 1140 0.50–2.32 1.0–1.2 0.11 (0.06–0.18) 0.87 (0.86–0.87)
RUQ mass 4 408 0.8 (0.5–1.2) 1.0 (0.9–1.1) 0.21 (0.18–0.23) 0.80 (0.75–0.85)
RUQ pain 5 949 1.5 (0.9–2.5) 0.7 (0.3–1.6) 0.81 (0.78–0.85) 0.67 (0.65–0.69)
RUQ tenderness 4 1001 1.6 (1.0–2.5) 0.4 (0.2–1.1) 0.77 (0.73–0.81) 0.54 (0.52–0.56)
Cited from Ref. [18]
RUQ right upper abdominal quadrant, LR likelihood ratio, CI confidence interval

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techniques, such as MR cholangiography (MRCP), should
be considered depending on conditions [31].
According to a report by Cohan et al. [32] who exam-
ined 51 cases that had developed thickening of the gall-
bladder wall, including 13 cases of acute cholecystitis, a
so-called sonolucent layer (hypoechoic layer), referred to
as a low-echo zone, within the gallbladder wall showed
8 % sensitivity (95 % CI 0–22.1) and 71.0 % specificity
(95 % CI 56.6–85.5). Therefore, it cannot be considered a
good diagnostic measure for acute cholecystitis. The
presence of a low-echoic area with an irregular multiple
structure showing 62 % sensitivity (95 % CI 35.1–88.0)
and 100 % specificity (95 % CI 100–100) has a higher
diagnostic value [32] (Supplement Fig. 1; Supplement
Movie 1).
Q8. What findings are to be noted when ultrasonogra-
phy is conducted for cases for which acute cholecystitis
is suspected?

Ultrasonographic Murphy’s sign shows high specificity and it

is useful for making a diagnosis .
hypoechoic layer

Ultrasonographic Murphy’s sign refers to the pain that

occurs when the gallbladder is pressed while it is being
depicted with an ultrasonographic probe. It is superior to
the ordinary Murphy’s sign in that it is possible to press the
Wall thickening gallbladder accurately. On the basis of the examination of
liver
219 cases of right upper quadrant abdominal pain, Ralls
et al. have reported that ultrasonographic Murphy’s sign is
debris somewhat inferior to the ordinary Murphy’s sign in sen-
sitivity (63.0 %, 95 % CI 49.1–77.0 %), although it is
superior in specificity (93.6 %, 95 % CI 90.0–97.3 %)
[33]. According to Bree et al. who examined 200 cases (of
which 73 cases were acute cholecystitis) with complaints
Stone impaction of right upper quadrant abdominal pain, the sensitivity of
ultrasonographic Murphy’s sign is good (86.3 %; 95 % CI
78.4–94.2 %) although the specificity is inferior (35.0 %;
95 % CI 26.4–43.0 %), so the presence of bile stones
should be taken into account when a diagnosis is made
Fig. 1 US images of acute cholecystitis. Gallbladder swelling, wall
thickening with hypoechoic layer, massive debris, and stone impac- [34]. Ultrasonographic Murphy’s sign can also be used to
tion are demonstrated distinguish acute cholecystitis from cases of Murphy’s sign

Fig. 2 US images of perforated

duodenal ulcer case with
positive Murphy’s sign (non-
ultrasonographic), increased
white blood cell count and
elevated C-reactive protein.
Wall thickening of the anterior
wall of the duodenal bulb as
well as a large wall defect
accompanied with extramural
air is clearly demonstrated by
US

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positive due to other diseases and for diagnosis of the
causative disease, such as duodenal ulcer (Fig. 2).
Q9. Is color or power Doppler imaging useful for
making a diagnosis of acute cholecystitis?
The findings of power Doppler imaging are useful for making
a diagnosis of acute cholecystitis (recommendation 2, level C).
Soyer et al. examined 129 cases complaining of acute
pain in the upper right quadrant abdomen and reported that
the diagnostic capacity for acute cholecystitis on the basis
of Doppler sonographic findings were: sensitivity 95 %,
specificity 100 %, accuracy 99 %, PPV 100 %, and NPV
99 %, exceeding that of the B-mode Doppler sonography
(sensitivity 86 %, specificity 99 %, accuracy 92 %, PPV
92 %, and NPV 87 %) [35] (Supplement Table 2).
On the other hand, Tessler et al. [36] who examined a small
number of cases have found that intramural Doppler signals
are also observed in normal cases and that signal depiction
becomes more remarkable after food intake. Furthermore,
Jeffrey et al. carried out detailed discussion of 54 cases
undergoing surgery for cholecystitis and 115 normal controls
including the area of depiction and have found that the pres-
ence or absence of signal depiction alone is not a finding
specific to cholecystitis. They looked at the presence of a
blood flow signal extending over more than half of the anterior
wall (26 % occurrence rate compared with 2 % for normal
cases), and discovered that the signal depicted on the bottom is
a more specific finding (the frequency of occurrence being
0 % for normal cases and 19 % for cholecystitis cases) [37].
On the basis of the above observations, it may be possible
to make a diagnosis of cholecystitis by means of color or
power Doppler sonography. However, the detective capacity
of Doppler signals is influenced by the performance and
settings of the instruments used and, and the physique of
subjects. Careful judgment should be made when using
Doppler sonographic findings as the only reference findings
including B-mode findings (Supplement Fig. 2).
CT
Q10. What are the characteristic contrast enhanced CT
findings of acute cholecystitis?
CT findings of acute cholecystitis are gallbladder distention,
pericholecystic fat stranding, gallbladder wall thickening,
subserosal edema, mucosal enhancement, transient focal
enhancement of the liver adjacent to the gallbladder,
pericholecystic fluid collection, pericholecystic abscess,
gas collection within gallbladder.
41
CT findings of acute cholecystitis were reported as: GB
distention (41 %), gallbladder wall thickening (59 %),
pericholecystic fat density (52 %), pericholecystic fluid
collection (31 %), subserosal edema (31 %), and high-
attenuation gallbladder bile (24 %) (Fig. 3; Supplement
Fig. 3) [38].
Anatomically, a part of the cholecystic vein directly
drains into the liver parenchyma surrounding the gall-
bladder fossa. In patients with acute cholecystitis, venous
blood flow from the gallbladder wall into the liver
increases. So, the arterial phase of dynamic CT shows
transient focal enhancement of the liver adjacent to the
inflamed gallbladder (Fig. 3; Supplement Fig. 3) [39–42].
This enhancement disappears during the portal and equi-
librium phase.
In mild acute cholecystitis, gallbladder distention
without wall thickening or edema are the only signs on
CT. Because gallbladder size is variable depending on the
individual, gallbladder distention is difficult to evaluate
on diagnostic imaging (such as ultrasonography or non-
contrast CT) of acute cholecystitis. Dynamic CT, espe-
cially during the arterial phase, is very useful in mild
cholecystitis because of the high sensitivity of transient
focal enhancement of the liver adjacent to the gallbladder
[41].
Tc-HIDA scans
Hepatobiliary scintigraphy involves intravenous injection
of technetium-labeled analogues of iminodiacetic acid,
which are excreted into the bile. The failure of the gall-
bladder to fill within 60 min after administration of the
tracer indicates that the cystic duct is obstructed and has a
sensitivity of 80–90 % for acute cholecystitis. The false
positive rate of 10–20 % is largely explained by cystic duct
obstruction induced by chronic inflammation, although in
some cases normal gallbladders do not fill due to insuffi-
cient resistance at the sphincter of Oddi. When the cystic
duct is patent (i.e., no cholecystitis), the gallbladder is
normally visualized within 30 min. The ‘‘rim sign’’ is a
blush of increased pericholecystic radioactivity, which is
present in about 30 % of patients with acute cholecystitis
and in about 60 % with acute gangrenous cholecystitis [1].
In patients with suspected acute cholecystitis, hepatobiliary
scintigraphy has significantly higher specificity [27] and
higher accuracy [43] than ultrasonography. Nevertheless,
ultrasonography is usually preferred as the first test because
of its immediate availability, easy access, a lack of inter-
ference by elevated serum bilirubin levels (since chole-
stasis interferes with biliary excretion of the agents used for
scintigraphy), the absence of ionizing radiation, and the
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42
a b
f d
Fig. 3 Acute cholecystolithiasis (62-year-old male). Non-contrast
CT (a) shows gallbladder distention, wall thickening, and gallstone
(arrow). The arterial phase of contrast-enhanced dynamic CT (b, c,
ability to provide information regarding the presence of
stones [1].
Severity assessment criteria for acute cholecystitis;
TG13
Background
Patients with acute cholecystitis may present a spectrum
of disease stages ranging from a mild, self-limited illness
to a fulminant and potentially life-threatening disease. In
fact, the overall mortality rate of acute cholecystitis is
approximately 0.6 % [11, 12]. There were no severity
assessment criteria for this common disease until 2007
[16].
TG07 severity assessment criteria for acute cholecystitis
The severity assessment criteria were first presented
throughout the world in TG07 [5], where the severity
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c
e
f) shows gallbladder wall edema (asterisk) and focal hepatic
enhancement adjacent to the gallbladder (arrowheads). Hepatic
enhancement disappears on the equilibrium phase of CT (d, e)
grading of acute cholecystitis was classified into the fol-
lowing 3 categories: ‘‘mild (Grade I)’’, ‘‘moderate (Grade
II)’’ and ‘‘severe (Grade III)’’. Severe (Grade III) acute
cholecystitis was defined as acute cholecystitis associated
with organ dysfunction.
Moderate (Grade II) acute cholecystitis was defined as
acute cholecystitis in which the degree of acute inflam-
mation is likely to be associated with increased operative
difficulty in performing cholecystectomy [44–49].
Mild (Grade I) acute cholecystitis was defined as
occurring in a patient who has no findings of organ dys-
function and mild disease in the gallbladder, enabling
cholecystectomy as a safe and low risk procedure. These
patients do not have a severity index that meets the criteria
for ‘‘moderate (Grade II)’’ and ‘‘severe (Grade III)’’ acute
cholecystitis in TG07.
There are reports that discussed and appraised the TG07
severity assessment criteria. According to those papers, the
distribution varies as follows: 39.3–68.5 % of the cases
were classified as Grade I, 25.5–59.5 % as Grade II, and
1.2–6 % as Grade III [14, 15]. In addition, there is a report
J Hepatobiliary Pancreat Sci (2013) 20:35–46 43

suggesting that the assessment criteria have contributed to
a decrease in the period of hospital stay [13]. This dem-
onstrates that TG07 severity assessment criteria have
received good appraisal; there has so far been no treatise or
report that has pointed out matters to be improved and
weak points of TG07.
TG13 severity assessment criteria for acute cholecystitis
The revised severity grading for acute cholecystitis is
shown in Table 4.
TG07 severity assessment criteria have been adopted in
TG13 with minor changes [16].

Q11. What morbid conditions are referred to as severe

Revision of severity grading for acute cholecystitis; TG07 in assessing severity for acute cholecystitis?

There are reports on poor prognostic factors of acute

cholecystitis and those enabling the estimation of emer-
gency surgery. Factors reported after 2000 include leu-
kocytosis [13, 15, 50–55], ALP [50, 56, 57], old age [53,
54, 58], diabetes [51, 52], male sex [51, 53], and
admission delay [55]. There are also reports of imaging
findings such as ultrasonographic findings of gallbladder
wall thickening [53] and common bile duct distention
[57]. To date there has been a small number of new
reports of AST, ALT, LDH, BUN, and creatinine. The
severity assessment criteria were reconsidered by the
Tokyo Guidelines Revision Committee with new infor-
mation, evidence, and evaluations of TG07. Conse-
quently, the TG07 severity assessment criteria did not
have significant problems that required major revision of
the definitions or structures [16]. However, minor chan-
ges were made to the description of Grade III severity:
dopamine and norepinephrine were both considered as
evidence of cardiovascular dysfunction consistent with
the SOFA scoring system [59].
“ Severe” is referred to as a condition that has developed
organ dysfunction as circulatory failure consciousness
disturbance respiratory failure renal failure hepatic
failure or blood coagulation disorder . Intensive care with
respiratory and circulatory management should be performed.
Acute cholecystitis has a better outcome/prognosis than
acute cholangitis but requires prompt treatment when
gangrenous cholecystitis, emphysematous cholecystitis, or
torsion of the gallbladder are present. The progression of
acute cholecystitis from the mild/moderate to the severe
form means the development of multiple organ dysfunction
syndrome (MODS). Organ dysfunction scores, such as
Marshall’s multiple organ dysfunction (MOD) score and
the sequential organ failure assessment (SOFA) score [60],
are sometimes used to evaluate organ dysfunction in crit-
ically ill patients. The six factors involved in organ dys-
function have therefore been adopted in TG07 as factors
that enable severity assessment.

Table 4 TG13 severity grading for acute cholecystitis

Grade III (severe) acute cholecystitis
Associated with dysfunction of any one of the following organs/systems:
1. Cardiovascular dysfunction Hypotension requiring treatment with dopamine C5 lg/kg per min, or any dose of norepinephrine
2. Neurological dysfunction Decreased level of consciousness
3. Respiratory dysfunction PaO2/FiO2 ratio \300
4. Renal dysfunction Oliguria, creatinine [2.0 mg/dl
5. Hepatic dysfunction PT-INR [1.5
6. Hematological dysfunction Platelet count \100,000/mm3
Grade II (moderate) acute cholecystitis
Associated with any one of the following conditions:
1. Elevated white blood cell count ([18,000/mm3)
2. Palpable tender mass in the right upper abdominal quadrant
3. Duration of complaints [72 h
4. Marked local inflammation (gangrenous cholecystitis, pericholecystic abscess, hepatic abscess, biliary peritonitis, emphysematous
cholecystitis)
Grade I (mild) acute cholecystitis
Does not meet the criteria of ‘‘Grade III’’ or ‘‘Grade II’’ acute cholecystitis. Grade I can also be defined as acute cholecystitis in a healthy
patient with no organ dysfunction and mild inflammatory changes in the gallbladder, making cholecystectomy a safe and low-risk operative
procedure

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44
Fig. 4 Emphysematous cholecystitis. The presence of intramural/intraluminal gas indicates emphysematous cholecystitis. The echo from small
gas bubbles shows multiple reverberation
Q12. What morbid conditions are referred to as mod-
erate in assessing severity for acute cholecystitis?
“Moderate” is referred to as a condition of acute cholecystitis
without organ dysfunction but with its risk, accompanying
serious local complication , and for which cholecystectomy
and biliary drainage are to be carried out immediately.
Q13. In making a diagnosis of acute cholecystitis, what
are the factors that enable the assessment of moderate
cases?
The presence of leucocytosis palpable right upper quadrant
abdominal pain persistence of symptoms for more than 72
hours after onset or severe inflammation findings.
TG07 included findings such as an elevated level of
WBC and imaging findings in assessment items specifi-
cally applied in moderate (Grade II) acute cholecystitis.
Included in these items is evidence such as leukocytosis
([18,000 mm3) detected at the time of hospitalization,
prognostic factors that contribute to the change of sur-
gical techniques from laparoscopic surgery to open sur-
gery, and the time of symptom persistence (of more than
72 h) from the onset of symptoms [44, 61]. The criteria
for Grade II (moderate) acute cholecystitis can be
defined as acute cholecystitis associated with local
inflammatory conditions that make cholecystectomy
difficult.
As for the factor ‘‘old age’’, the following statement had
been adopted to call attention in TG07; however the
statement is useful for the revised edition, too. ‘‘Elderly’’
per se is not a criterion for severity itself but indicates a
propensity to progress to the severe form, and thus is not
included in the criteria for severity assessment [5].
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When acute cholecystitis is accompanied by acute
cholangitis, the criteria for the severity assessment of acute
cholangitis should also be taken into account [62, 63].
Q14. What are the findings to be noted when the
assessment of gangrenous cholecystitis and emphyse-
matous cholecystitis is carried out by means of
ultrasonography?
Irregular thickening of the gallbladder wall and imaging
of the ruptured gallbladder wall should be noted.
Through the discussion of 19 cases of gangrenous cho-
lecystitis, Jeffrey et al. [7] found that the membraneous
structure of the lumen within the gallbladder is observed in
31.6 % (6 cases), irregular thickening of the gallbladder
wall in 47.4 % (9 cases), both of these findings in 21.1 %
(4 cases), and either of these findings in 57.9 % (11 cases).
Regarding perforation, Forsberg et al. [64] also reported on
the basis of the discussion involving 24 cases of perforation
and 21 cases of acute cholecystitis without perforation that
no specific findings were observed, although a slightly
thickened wall was observed (3–20 mm, mean 7 mm, for
cases with perforation; 2–13 mm, mean 5.3 mm, for cases
without perforation). On the other hand, according to Sood
et al. [65] depiction of the ruptured wall as a direct finding
of gallbladder perforation was able to be made with
ultrasonography in 70 % (16 of 23 cases) and with CT in
78 % (14 of 18 cases). Depending on the performance of
the instrument used, it can be assumed that the diagnosis
can be made for considerable numbers of cases (Fig. 4;
Supplement Movie 2).
Acknowledgments We would like to express our deep gratitude to
the Japanese Society for Abdominal Emergency Medicine, the Japan
Biliary Association, Japan Society for Surgical Infection, and the
Japanese Society of Hepato-Biliary-Pancreatic Surgery, which
J Hepatobiliary Pancreat Sci (2013) 20:35–46
provided us with great support and guidance in the preparation of the
Guidelines.
Conflict of interest None.
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J Hepatobiliary Pancreat Sci (2013) 20:47–54
DOI 10.1007/s00534-012-0563-1
GUIDELINE
TG13 flowchart for the management of acute cholangitis
and cholecystitis
Fumihiko Miura • Tadahiro Takada • Steven M. Strasberg • Joseph S. Solomkin • Henry A. Pitt • Dirk J. Gouma
O. James Garden • Markus W. Büchler • Masahiro Yoshida • Toshihiko Mayumi • Kohji Okamoto •
Harumi Gomi • Shinya Kusachi • Seiki Kiriyama • Masamichi Yokoe • Yasutoshi Kimura • Ryota Higuchi •
Yuichi Yamashita • John A. Windsor • Toshio Tsuyuguchi • Toshifumi Gabata • Takao Itoi • Jiro Hata •
Kui-Hin Liau
Published online: 11 January 2013
Ó Japanese Society of Hepato-Biliary-Pancreatic Surgery and Springer 2012
Abstract We propose a management strategy for acute
cholangitis and cholecystitis according to the severity
assessment. For Grade I (mild) acute cholangitis, initial
medical treatment including the use of antimicrobial agents
may be sufficient for most cases. For non-responders to
initial medical treatment, biliary drainage should be con-
sidered. For Grade II (moderate) acute cholangitis, early
biliary drainage should be performed along with the
administration of antibiotics. For Grade III (severe) acute
cholangitis, appropriate organ support is required. After
hemodynamic stabilization has been achieved, urgent
F. Miura (&)
T. Takada
Department of Surgery, Teikyo University School of Medicine,
2-11-1, Kaga, Itabashi-ku, Tokyo 173-8605, Japan
e-mail: f-miura@med.teikyo-u.ac.jp
S. M. Strasberg
Section of Hepatobiliary and Pancreatic Surgery,
Washington University in Saint Louis School of Medicine,
Saint Louis, MO, USA
J. S. Solomkin
Department of Surgery, University of Cincinnati College
of Medicine, Cincinnati, OH, USA
H. A. Pitt
Department of Surgery, Indiana University School of Medicine,
Indianapolis, IN, USA
D. J. Gouma
Department of Surgery, Academic Medical Center,
Amsterdam, The Netherlands
O. J. Garden
Clinical Surgery, The University of Edinburgh, Edinburgh, UK
M. W. Büchler
Department of Surgery, University of Heidelberg,
Heidelberg, Germany
TG13: Updated Tokyo Guidelines for acute cholangitis
and acute cholecystitis
•
endoscopic or percutaneous transhepatic biliary drainage
should be performed. In patients with Grade II (moderate)
and Grade III (severe) acute cholangitis, treatment for the
underlying etiology including endoscopic, percutaneous, or
surgical treatment should be performed after the patient’s
general condition has been improved. In patients with
Grade I (mild) acute cholangitis, treatment for etiology
such as endoscopic sphincterotomy for choledocholithiasis
might be performed simultaneously, if possible, with bili-
ary drainage. Early laparoscopic cholecystectomy is the
first-line treatment in patients with Grade I (mild) acute
M. Yoshida
Clinical Research Center Kaken Hospital, International
University of Health and Welfare, Ichikawa, Japan
T. Mayumi
Department of Emergency and Critical Care Medicine,
Ichinomiya Municipal Hospital, Ichinomiya, Japan
K. Okamoto
Department of Surgery, Kitakyushu Municipal Yahata Hospital,
Kitakyushu, Japan
H. Gomi
Center for Clinical Infectious Diseases, Jichi Medical University,
Shimotsuke, Tochigi, Japan
S. Kusachi
Department of Surgery, Toho University Medical Center Ohashi
Hospital, Tokyo, Japan
S. Kiriyama
Department of Gastroenterology, Ogaki Municipal Hospital,
Ogaki, Japan
M. Yokoe
General Internal Medicine, Nagoya Daini Red Cross Hospital,
Nagoya, Japan
123
48 J Hepatobiliary Pancreat Sci (2013) 20:47–54

cholecystitis while in patients with Grade II (moderate) Acute

acute cholecystitis, delayed/elective laparoscopic chole- Cholangitis
cystectomy after initial medical treatment with antimicro- Suspicion of Diagnostic
Acute Biliary Criteria
bial agent is the first-line treatment. In non-responders to of TG13
Infection
initial medical treatment, gallbladder drainage should be
considered. In patients with Grade III (severe) acute cho- Acute
Cholecystitis
lecystitis, appropriate organ support in addition to initial
medical treatment is necessary. Urgent or early gallbladder Other
drainage is recommended. Elective cholecystectomy can Diseases
be performed after the improvement of the acute inflam-
Fig. 1 General guidance for the management of acute biliary
matory process. inflammation/infection
Free full-text articles and a mobile application of TG13 are
available via http://www.jshbps.jp/en/guideline/tg13.html.
General guidance for the management of acute
cholangitis
Keywords Acute cholangitis
Acute cholecystitis

Biliary drainage
Laparoscopic cholecystectomy

The general guidance for the management of acute biliary
Guidelines
inflammation/infection including acute cholangitis is pre-
sented in Fig. 1.
Introduction
Clinical presentations
This article describes strategies for the management of
Clinical findings associated with acute cholangitis include
acute cholangitis and cholecystitis including initial medical
abdominal pain, jaundice, fever (Charcot’s triad), and
treatment flowcharts. We established a flowchart for the
rigor. The triad was reported in 1887 by Charcot [2] as the
diagnosis and treatment of acute cholangitis and chole-
indicators of hepatic fever and has been historically used as
cystitis as reported in the Tokyo Guidelines 2007 [1].
the generally accepted clinical findings of acute cholangi-
Flowcharts for the management of acute cholangitis and
tis. All three symptoms are observed in about 50–70 % of
cholecystitis have been revised in the updated Tokyo
the patients with acute cholangitis [3–6]. Reynolds’ pen-
Guidelines (TG13).
tad––Charcot’s triad plus shock and decreased level of
We consider that the primary purpose of the flowcharts
consciousness––were presented in 1959 when Reynolds
is to allow clinicians to grasp, at a glance, the outline of the
and Dargan [7] defined acute obstructive cholangitis.
management strategy of the disease. Flowcharts have been
Reynolds’ pentad is often referred to as the findings rep-
colored for easy access and rapid understanding, and most
resenting serious conditions, but shock and a decreased
of the treatment methods are included in the flowcharts to
level of consciousness are only observed in less than 30 %
achieve their primary purpose.
of patients with acute cholangitis [3–6]. A history of biliary

Y. Kimura T. Gabata
Department of Surgical Oncology and Gastroenterological Department of Radiology, Kanazawa University Graduate
Surgery, Sapporo Medical University School of Medicine, School of Medical Science, Kanazawa, Japan
Sapporo, Japan
T. Itoi
R. Higuchi Department of Gastroenterology and Hepatology,
Department of Surgery, Institute of Gastroenterology, Tokyo Medical University,
Tokyo Women’s Medical University, Tokyo, Japan Tokyo, Japan

Y. Yamashita J. Hata
Department of Gastroenterological Surgery, Fukuoka University Department of Endoscopy and Ultrasound,
School of Medicine, Fukuoka, Japan Kawasaki Medical School, Okayama, Japan

J. A. Windsor K.-H. Liau

Department of Surgery, The University of Auckland, Hepatobiliary and Pancreatic Surgery,
Auckland, New Zealand Nexus Surgical Associates, Mount Elizabeth Hospital,
Singapore, Singapore
T. Tsuyuguchi
Department of Medicine and Clinical Oncology, Graduate
School of Medicine Chiba University, Chiba, Japan

123
J Hepatobiliary Pancreat Sci (2013) 20:47–54
diseases such as gallstones, previous biliary procedures, or
the placement of a biliary stent is very helpful when a
diagnosis of acute cholangitis is suspected [1].
Blood test
The diagnosis of acute cholangitis requires the measure-
ment of white blood cell count, C-reactive protein, and
liver function test including alkaline phosphatase, GGT,
AST, ALT, and bilirubin [8]. The assessment of the
severity of the illness requires knowledge of the platelet
count, blood urea nitrogen, creatinine, prothrombin time-
international normalized ratio (PT-INR), albumin, and
arterial blood gas analysis. Blood cultures are also helpful
for selection of antimicrobial drugs [8–10]. Hyperamyla-
semia is a useful parameter for identifying complications
such as choledocholithiasis causing biliary pancreatitis
[11].
Diagnostic imaging
Abdominal ultrasound (US) and abdominal computerized
tomography (CT) with intravenous contrast are very useful
test procedures for evaluating patients with acute biliary
tract disease. Abdominal US should be performed in all
patients with suspected acute biliary inflammation/infec-
tion [1]. Ultrasonic examination has satisfactory diagnostic
capabilities when performed not only by specialists but
also by emergency physicians [12, 13]. The role of diag-
nostic imaging in acute cholangitis is to determine the
presence of biliary obstruction, the level of obstruction, and
the cause of the obstruction such as gallstones and/or bil-
iary strictures [1]. The assessment should include US and
CT. These studies complement each other and CT may
yield better imaging of bile duct dilatation and
pneumobilia.
Differential diagnosis
Diseases which should be differentiated from acute cho-
langitis are acute cholecystitis, liver abscess, gastric and
duodenal ulcer, acute pancreatitis, acute hepatitis, and
septicemia from other origins.
Q1. What is the initial medical treatment of acute
cholangitis?
On condition that biliary drainage is conducted during hospital
stay as a rule, sufficient infusion, electrolyte correction, and
antimicrobial and analgesic administration take place while
fasting (recommendation 1, level C).
49
Early treatment, while fasting as a rule, includes suffi-
cient infusion, the administration of antimicrobial and
analgesic agents, along with the monitoring of respiratory
hemodynamic conditions in preparation for emergency
drainage [1].
When acute cholangitis has become more severe, that is,
if any one of the following signs is observed such as shock
(reduced blood pressure), consciousness disturbance, acute
lung injury, acute renal injury, hepatic injury, and dis-
seminated intravascular coagulation (DIC) (decreased
platelet count), emergency biliary drainage is carried out
together with appropriate organ support (sufficient infusion
and anti-microbial administration), and respiratory and
circulatory management (artificial respiration, intubation,
and use of vasopressors) [1].
Q2. Should the severe sepsis bundle be referred to for
the early treatment of acute cholangitis accompanying
severe sepsis?
The severe sepsis bundle should be referred to for the early
treatment of acute cholangitis accompanying severe sepsis
(recommendation 1, level B).
Acute cholangitis is frequently accompanied by sepsis.
As for the early treatment of severe sepsis, there is a
detailed description in ‘‘Surviving Sepsis Campaign
Guidelines (SSCG)’’ published in 2004 and updated in
2008. To improve treatment results, a severe sepsis bun-
dle (Table 1, http://www.ihi.org/knowledge/Pages/Changes/
ImplementEffectiveGlucoseControl.aspx) has been pre-
sented in SSCG as the core part of the treatment for septic
shock. However, there are reports of validation by several
multi-institutional collaborative studies that have found a
significant decrease in mortality rate in patients with a
higher rate of compliance [14] or after the implementation of
the severe sepsis bundle [15–17]. These studies include
severe sepsis cases induced by a disease other than acute
cholangitis [14–17]. However, the severe sepsis bundle
should be referred to for the early treatment of acute cho-
langitis accompanying severe sepsis.
Flowchart for the management of acute cholangitis
A flowchart for the management of acute cholangitis is
shown in Fig. 2. Treatment of acute cholangitis should be
performed according to the severity grade of the patient.
Biliary drainage and antimicrobial therapy are the two most
important elements of treatment. When a diagnosis of acute
cholangitis is determined based on the diagnostic criteria of
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50 J Hepatobiliary Pancreat Sci (2013) 20:47–54

Table 1 Severe sepsis bundle, quoted from http://www.survi
vingsepsis.org/Bundles/Pages/default.aspx
Sepsis resuscitation bundle
Tasks that should start immediately but must be performed
within 6 h in patients with severe sepsis or septic shock:
1. Measure serum lactate.
2. Obtain blood cultures prior to antibiotic administration.
3. Administer broad-spectrum antibiotics within 3 h after admission
to the emergency department (ED) and within 1 h after
admission to the department other than ED.
4. In the event of hypotension and/or serum lactate [4 mmol/L:
a. Deliver the initial minimum of 20 mL/kg of crystalloid
or the equivalent.
b. Apply vasopressors for hypotension showing no response
to initial fluid resuscitation in order to maintain the
mean arterial pressure (MAP) [65 mmHg.
5. In the event of persistent hypotension despite fluid resuscitation
(septic shock) and/or lactate [4 mmol/L:
a. Achieve central venous pressure (CVP) of [8 mmHg.
b. Achieve central venous oxygen saturation (ScvO2) [70 %
or mixed venous oxygen saturation (SvO2) [65 %.
Sepsis management bundle
Tasks that should be initiated immediately but must be carried
out within 24 h in patients with severe sepsis or septic shock:
1. Administer low-dose steroids for septic shock in accordance
with the standardized ICU policy. If not administered, document
why the patient did not qualify for low-dose steroids based
upon the standardized protocol.
2. Administer recombinant human activated protein C (rhAPC)
in accordance with the standardized ICU policy. If not
administered, document why the patient did not qualify for rhAPC.
3. Maintain glucose control \180 mg/dL.
4. Maintain the median inspiratory plateau pressure
(IPP) \30 cmH2O in patients on mechanical ventilation.
acute cholangitis of TG13 [9], initial medical treatment
including nil per os (NPO), intravenous fluid, antimicrobial
therapy, and analgesia together with close monitoring of
blood pressure, pulse, and urinary output should be initi-
ated. Simultaneously, severity assessment of acute cho-
langitis should be conducted based on the severity
assessment criteria for acute cholangitis of TG 13 [9] in
which acute cholangitis is classified into Grade I (mild),
Grade II (moderate), or Grade III (severe). Frequent reas-
sessment is mandatory and patients may need to be re-
classified into Grade I, II, or III based on the response to
initial medical treatment. Appropriate treatment should be
performed in accordance with the severity grade. Patients
with acute cholangitis sometimes suffer simultaneously
from acute cholecystitis. A treatment strategy for patients
with both acute cholangitis and cholecystitis should be
determined in consideration of the severity of those dis-
eases and the surgical risk in patients.
Grade I (mild) acute cholangitis
Initial medical treatment including antimicrobial therapy may
be sufficient. Biliary drainage is not required for most cases.
However, for non-responders to initial medical treatment,
biliary drainage should be considered. Endoscopic, percuta-
neous, or operative intervention for the etiology of acute
cholangitis such as choledocholithiasis and pancreato-biliary
malignancy may be performed after pre-intervention work-up.
Treatment for etiology such as endoscopic sphincterotomy for
choledocholithiasis might be performed simultaneously, if
possible, with biliary drainage. Some patients who have

Fig. 2 Flowchart for the

Diagnosis and Treatment According to Grade, According to Response,
management of acute
Severity and According to Need for Additional Therapy
cholangitis: TG13
Assessment by
TG13
Guidelines Finish course
of antibiotics
Antibiotics †
Grade I
and General
(Mild) Treatment
Supportive Care
Biliary
for etiology
Drainage
Early Biliary Drainage if still needed
Grade II
Antibiotics (Endoscopic treatment,
(Moderate)
General Supportive Care
percutaneous treatment,
or surgery)
Urgent Biliary Drainage
Grade III
Organ Support
(Severe) Antibiotics

Performance of a blood culture should be taken into consideration before initiation of administration of
antibiotics. A bile culture should be performed during biliary drainage.
† Principle of treatment for acute cholangitis consists of antimicrobial administration and biliary drainage
including treatment for etiology. For patient with choledocholithiasis, treatment for etiology might be
performed simultaneously, if possible, with biliary drainage.

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J Hepatobiliary Pancreat Sci (2013) 20:47–54
developed postoperative cholangitis may require antimicrobial
therapy only and generally do not require intervention.
Grade II (moderate) acute cholangitis
Early endoscopic or percutaneous drainage, or even emer-
gency operative drainage with a T-tube, should be per-
formed in patients with Grade II acute cholangitis. A
definitive procedure should be performed to remove a cause
of acute cholangitis after the patient’s general condition has
improved and following pre-intervention work-up.
Grade III (severe) acute cholangitis
Patients with acute cholangitis accompanied by organ
failure are classified as Grade III (severe) acute cholangitis.
These patients require appropriate organ support such as
ventilatory/circulatory management (non-invasive/invasive
positive pressure ventilation and use of vasopressor, etc.).
Urgent biliary drainage should be anticipated. When
patients are stabilized with initial medical treatment and
organ support, urgent (as soon as possible) endoscopic or
percutaneous transhepatic biliary drainage or, according to
the circumstances, an emergency operation with decom-
pression of the bile duct with a T-tube should be per-
formed. Definitive treatment for the cause of acute
cholangitis including endoscopic, percutaneous, or opera-
tive intervention should be considered once the acute ill-
ness has resolved.
General guidance for the management of acute
cholecystitis
The general guidance for the management of acute biliary
inflammation/infection including acute cholecystitis is
presented in Fig. 1.
Clinical presentations
Clinical symptoms of acute cholecystitis include abdominal
pain (right upper abdominal pain), nausea, vomiting, and
pyrexia [18–20]. The most typical symptom is right epigas-
tric pain. Tenderness in the right upper abdomen, a palpable
gallbladder, and Murphy’s sign are the characteristic findings
of acute cholecystitis. A positive Murphy’s sign shows
79–96 % specificity [18, 20] for acute cholecystitis.
Blood test
There is no specific blood test for acute cholecystitis;
however, the measurement of white blood cell count and
C-reactive protein is very useful in confirming an
51
inflammatory response [21]. The platelet count, bilirubin,
blood urea nitrogen, creatinine, prothrombin time-interna-
tional normalized ratio (PT-INR), and arterial blood gas
analysis are useful in assessing the severity status of the
patient [21].
Diagnostic imaging
Abdominal ultrasound (US) and abdominal computerized
tomography (CT) with intravenous contrast are very
helpful procedures for evaluating patients with acute bil-
iary tract disease. Abdominal US should be performed in
every patient with suspected acute biliary inflammation/
infection [1]. Ultrasonic examination has satisfactory
diagnostic capability when it is performed not only by
specialists but also by emergency physicians [12, 13].
Characteristic findings of acute cholecystitis include the
enlarged gallbladder, thickened gallbladder wall, gall-
bladder stones and/or debris in the gallbladder, sono-
graphic Murphy’s sign, pericholecystic fluid, and
pericholecystic abscess [21]. Sonographic Murphy’s sign
is a reliable finding of acute cholecystitis showing about
90 % sensitivity and specificity [22, 23], which is higher
than those of Murphy’s sign.
Differential diagnosis
Diseases which should be differentiated from acute cho-
lecystitis are gastric and duodenal ulcer, hepatitis, pan-
creatitis, gallbladder cancer, hepatic abscess, Fitz-Hugh–
Curtis syndrome, right lower lobar pneumonia, angina
pectoris, myocardial infarction, and urinary infection.
Q3. What is the initial medical treatment of acute
cholecystitis?
While considering indications for surgery and emergency
drainage, sufficient infusion and electrolyte correction
take place, and antimicrobial and analgesic agents are
administered while fasting continuing the monitoring of
respiratory and hemodyanamics (recommendation 1, level C).
Early treatment, with fasting as a rule, includes suffi-
cient infusion, the administration of antimicrobial and
analgesic agents, along with the monitoring of respiratory
hemodynamics in preparation for emergency surgery and
drainage [1].
When any one of the following morbidities is observed:
further aggravation of acute cholecystitis, shock (reduced
blood pressure), consciousness disturbance, acute respira-
tory injury, acute renal injury, hepatic injury, and DIC
(reduced platelet count), then appropriate organ support
123
52
(sufficient infusion and antimicrobial administration), and
respiratory and circulatory management (artificial respira-
tion, intubation, and use of vasopressors) are carried out
together with emergency drainage or cholecystectomy [1].
There are many reports showing that remission can be
achieved by conservative treatment only [24–26]. On the
other hand, there is a report demonstrating that mild cases
may not require antimicrobial agents; however, prophy-
lactic administration should take place due to possible
complications such as bacterial infection. Furthermore,
there is a report that was unable to detect a difference in the
positive rate of sonographic Murphy’s sign depending on
the presence or absence of the use of analgesic agents [27].
The administration of analgesic agents should therefore be
initiated in the early stage.
CQ4. Is the administration of NSAID for the attack of
impacted stones gallstone attack effective for prevent-
ing acute cholecystitis?
NSAID administration is effective for impacted gallstone
attack for preventing acute cholecystitis (recommendation
1, level A).
Administration of non-steroidal anti-inflammatory drugs
(NSAIDs) for gallstone attack is effective in preventing
acute cholecystitis, and they are also widely known as
analgesic agents. A NSAID such as diclofenac is thus used
for early treatment. According to a report of a double blind
randomized controlled trial (RCT) that compared the use of
NSAIDs (diclofenac 75 mg intramuscular injection) with
placebo [28] or hyoscine 20 mg intramuscular injection
[29] for cases of impacted gallstone attack, NSAIDs pre-
vented progression of the disease to acute cholecystitis and
also reduced pain. Although NSAIDs have been effective
for the improvement of gallbladder function in cases with
chronic cholecystitis, there is no report showing that the
administration of NSAIDs has contributed to improving the
course of cholecystitis after its acute onset [30].
Flowchart for the management of acute cholecystitis
A flowchart for the management of acute cholecystitis is
shown in Fig. 3. The first-line treatment of acute chole-
cystitis is early or urgent cholecystectomy, with laparo-
scopic cholecystectomy as a preferred method. In high-risk
patients, gallbladder drainage such as percutaneous tran-
shepatic gallbladder drainage (PTGBD), percutaneous
transhepatic gallbladder aspiration (PTGBA), and endo-
scopic nasobiliary gallbladder drainage (ENGBD) is an
alternative therapy in patients who cannot safely undergo
123
J Hepatobiliary Pancreat Sci (2013) 20:47–54
urgent/early cholecystectomy [31, 32]. When a diagnosis of
acute cholecystitis is determined based on the diagnostic
criteria of acute cholecystitis in TG13 [33], initial medical
treatment including NPO, intravenous fluids, antibiotics,
and analgesia, together with close monitoring of blood
pressure, pulse, and urinary output should be initiated.
Simultaneously, severity assessment of acute cholecystitis
should be conducted based on the severity assessment cri-
teria for the acute cholecystitis of TG13 [33], in which acute
cholecystitis is classified into Grade I (mild), Grade II
(moderate), or Grade III (severe). Assessment of the oper-
ative risk for comorbidities and the patient’s general status
should also be evaluated in addition to the severity grade.
After resolution of acute inflammation with medical
treatment and gallbladder drainage, it is desirable that
cholecystectomy is performed to prevent recurrence. In
surgically high-risk patients with cholecystolithiasis,
medical support after percutaneous cholecystolithotomy
should be considered [34–36]. In patients with acalculous
cholecystitis, cholecystectomy is not always required since
recurrence of acute acalculous cholecystitis after gall-
bladder drainage is rare [31, 37].
Grade I (mild) acute cholecystitis
Early laparoscopic cholecystectomy is the first-line treat-
ment. In patients with surgical risk, observation (follow-up
without cholecystectomy) after improvement with initial
medical treatment could be indicated.
Grade II (moderate) acute cholecystitis
Grade II (moderate) acute cholecystitis is often accompa-
nied by severe local inflammation. Therefore, surgeons
should take the difficulty of cholecystectomy into
consideration in selecting a treatment method. Elective
cholecystectomy after the improvement of the acute
inflammatory process is the first-line treatment. If a patient
does not respond to initial medical treatment, urgent or
early gallbladder drainage is required. Early laparoscopic
cholecystectomy could be indicated if advanced laparo-
scopic techniques are available. Grade II (moderate) acute
cholecystitis with serious local complications is an indi-
cation for urgent cholecystectomy and drainage.
Grade III (severe) acute cholecystitis
Grade III (severe) acute cholecystitis is accompanied by
organ dysfunction. Appropriate organ support such as
ventilatory/circulatory management (noninvasive/invasive
positive pressure ventilation and use of vasopressors, etc.)
in addition to initial medical treatment is necessary. Urgent
or early gallbladder drainage should be performed. Elective
J Hepatobiliary Pancreat Sci (2013) 20:47–54 53

Fig. 3 Flowchart for the

Diagnosis and Treatment According to Grade and According to Response
management of acute
Severity
cholecystitis: TG13
Assessment by
TG13
Observation
Guidelines

Antibiotics
Grade I
and General Early LC
(Mild)
Supportive Care Advanced laparoscopic
technique
available
Emergency
Surgery
Antibiotics
Grade II Successful therapy
and General
(Moderate)
Supportive Care Failure
therapy Delayed/
Elective
† LC
Antibiotics
Grade III Urgent/early
and General
(Severe) GB drainage
Organ Support
LC: laparoscopic cholecystectomy, GB: gallbladder
Performance of a blood culture should be taken into consideration before initiation of administration of
antibiotics.
† A bile culture should be performed during GB drainage.

cholecystectomy may be performed after the improvement
of acute illness has been achieved by gallbladder drainage.
Acknowledgments We would like to express our deep gratitude to
the Japanese Society for Abdominal Emergency Medicine, the Japan
Biliary Association, Japan Society for Surgical Infection, and the
Japanese Society of Hepato-Biliary-Pancreatic Surgery, which pro-
vided us with great support and guidance in the preparation of the
Guidelines.
Conflict of interest None.
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DOI 10.1007/s00534-012-0562-2
GUIDELINE
TG13 management bundles for acute cholangitis and cholecystitis
Kohji Okamoto • Tadahiro Takada • Steven M. Strasberg • Joseph S. Solomkin • Henry A. Pitt •
O. James Garden • Markus W. Büchler • Masahiro Yoshida • Fumihiko Miura • Yasutoshi Kimura •
Ryota Higuchi • Yuichi Yamashita • Toshihiko Mayumi • Harumi Gomi • Shinya Kusachi • Seiki Kiriyama
Masamichi Yokoe • Wan-Yee Lau • Myung-Hwan Kim
Published online: 11 January 2013
Ó Japanese Society of Hepato-Biliary-Pancreatic Surgery and Springer 2012
Abstract Bundles that define mandatory items or proce-
dures to be performed in clinical practice have been
increasingly used in guidelines in recent years. Observance
of bundles enables improvement of the prognosis of target
diseases as well as guideline preparation. There were no
bundles adopted in the Tokyo Guidelines 2007, but the
updated Tokyo Guidelines 2013 (TG13) have adopted this
useful tool. Items or procedures strongly recommended in
clinical practice have been prepared in the practical
guidelines and presented as management bundles. TG13
defined the mandatory items for the management of acute
cholangitis and acute cholecystitis. Critical parts of the
bundles in TG13 include diagnostic process, severity
K. Okamoto (&)
Department of Surgery, Kitakyushu Municipal Yahata Hospital,
4-18-1 Nishihon-machi, Yahatahigashi-ku, Kitakyushu,
Fukuoka 805-8534, Japan
e-mail: kohji.okamot@gmail.com
T. Takada
F. Miura
Department of Surgery, Teikyo University School of Medicine,
Tokyo, Japan
S. M. Strasberg
Section of Hepatobiliary and Pancreatic Surgery,
Washington University in Saint Louis School of Medicine,
Saint Louis, MO, USA
J. S. Solomkin
Department of Surgery, University of Cincinnati College
of Medicine, Cincinnati, OH, USA
H. A. Pitt
Department of Surgery, Indiana University School of Medicine,
Indianapolis, IN, USA
O. J. Garden
Clinical Surgery, The University of Edinburgh, Edinburgh, UK
TG13: Updated Tokyo Guidelines for acute cholangitis
and acute cholecystitis
•
assessment, transfer of patients if necessary, therapeutic
approach, and time course. Their observance should
improve the prognosis of acute cholangitis and cholecys-
titis. When utilizing TG13 management bundles, further
clinical research needs to be conducted to evaluate the
effectiveness and outcomes of the bundles. It is also
expected that the present report will lead to evidence
construction and contribute to further updating of the
Tokyo Guidelines.
Free full-text articles and a mobile application of TG13 are
available via http://www.jshbps.jp/en/guideline/tg13.html.
Keywords Cholangitis bundle
Cholecystitis bundle
M. W. Büchler
Department of Surgery, University of Heidelberg,
Heidelberg, Germany
M. Yoshida
Clinical Research Center Kaken Hospital, International
University of Health and Welfare, Ichikawa, Japan
Y. Kimura
Department of Surgical Oncology and Gastroenterological
Surgery, Sapporo Medical University School of Medicine,
Sapporo, Japan
R. Higuchi
Department of Surgery, Institute of Gastroenterology,
Tokyo Women’s Medical University, Tokyo, Japan
Y. Yamashita
Department of Gastroenterological Surgery, Fukuoka University
School of Medicine, Fukuoka, Japan
T. Mayumi
Department of Emergency and Critical Care Medicine,
Ichinomiya Municipal Hospital, Ichinomiya, Japan
123
56
Introduction
A bundle is a group of therapies for a disease that, when
implemented together, may result in better outcomes than
if implemented individually. In recent years, bundles that
define mandatory items or procedures to be performed in
clinical practice have been increasingly used in guidelines
[1]. Compliance with bundles results in the preparation of
guidelines as well as an improved prognosis of targeted
diseases arising from the use of the guidelines [2, 3]. Levy
et al. [4] reported that data from 15,022 subjects at 165
sites were analyzed to determine compliance with bundle
targets and association with hospital mortality, and com-
pliance with the entire resuscitation bundle increased lin-
early from 10.9 % in the first site quarter to 31.3 % by the
end of 2 years. Furthermore the odds ratio for mortality
improved the longer a site was in the Surviving Sepsis
Campaign, resulting in an adjusted absolute drop of 0.8 %
per quarter and 5.4 % over 2 years.
Murata et al. [5, 6] examined a total of 60,842 patients
with acute cholangitis using the Japanese national adminis-
trative database. This report demonstrated the improved
prognosis of in-hospital mortality with odds ratio of 0.856
among patients who were managed with high compliance
with the items of recommendation Grades A and B in Tokyo
Guidelines 2007 (TG07) as compared with the patients who
were low-compliance. This shows the importance of pre-
paring bundles by setting the recommended items to be
observed in the guidelines. Although TG07 did not prepare
bundles at that time, the updated Tokyo Guidelines 2013
(TG13) have adopted the management bundles for acute
cholangitis and cholecystitis. The care bundles are designed
H. Gomi
Center for Clinical Infectious Diseases, Jichi Medical University,
Tochigi, Japan
S. Kusachi
Department of Surgery, Toho University Medical Center Ohashi
Hospital, Tokyo, Japan
S. Kiriyama
Department of Gastroenterology, Ogaki Municipal Hospital,
Ogaki, Japan
M. Yokoe
General Internal Medicine Nagoya Daini Red Cross Hospital,
Nagoya, Japan
W.-Y. Lau
Faculty of Medicine, The Chinese University of Hong Kong,
Shatin, Hong Kong
M.-H. Kim
Department of Internal Medicine, Asan Medical Center,
University of Ulsan, Seoul, Korea
123
J Hepatobiliary Pancreat Sci (2013) 20:55–59
to be easily achievable and sustainable both to implement
and to audit.
Furthermore, we made a checklist. We hope to use the
acute cholangitis and cholecystitis bundle checklist to help
track your organization’s compliance with implementing
each element of these bundles.
Efficacy of the bundle
In the process of developing TG13, mandatory items or
procedures to be included in the management bundles have
been discussed and defined among the Tokyo Guidelines
Revision Committee members. The bundles have been
developed and finalized by obtaining consensus. Based on
the recommendations in TG13, items which are expected to
yield favorable treatment results are included in the bun-
dles. To underscore the time course or timing of the per-
formance of each item, management bundles for acute
cholangitis and cholecystitis have been developed. A
checklist has also been prepared to confirm compliance
with the bundles.
The bundles such as sepsis bundle [7–9], ventilator
bundle [10, 11] or central line bundle [12], when imple-
mented together, may result in better outcomes than if
implemented individually. Good prognosis is also reported
in cases in which a bundle has been achieved, but this
may show that those cases which have achieved a bundle
are in such good condition as to enable achievement of a
bundle.
However, the improvement in prognosis in patients
achieved through education concerning bundles demon-
strates that implementation of bundles and education con-
cerning them have been useful [9, 13].
Controversial points and harmful effects of bundles
There are many problems to be solved for the spread and
implementation of bundles. In the guidelines, even if useful
items have been implemented, the prognosis in patients is
not improved without common knowledge of management
bundles among medical care workers [13]. Furthermore, it
is not possible to put bundles into practice without suffi-
cient manpower and equipment [14], which should be
improved, if possible. If improvement is impossible, an
alternative treatment should be provided or patients should
be transferred to a medical facility where the contents of
bundles can be put into practice [15].
There is also a concern that bundles are used not for the
purpose of improving the prognosis in patients and
increasing efficiency, but for limiting the contents of
medical care to keep health care costs down. Furthermore,
J Hepatobiliary Pancreat Sci (2013) 20:55–59 57

failure to carry out the contents of bundles should not lead
to lawsuits [15].
Acute cholangitis management bundle (Table 1)
been discussed and defined among the Tokyo Guidelines
Revision Committee members. The diagnostic criteria and
the severity assessment of acute cholangitis in TG13 was
made based on the article of Kiriyama et al. [16].

Items in the cholangitis management bundle are described Acute cholecystitis management bundle (Table 2)
in Table 1. The content of every bundle is developed from
the recommendation of TG13. The mandatory items or Items in the cholecystitis management bundle are described
procedures to be included in the management bundles have in Table 2. The content of every bundle is classified into

Table 1 Management bundle of acute cholangitis

1. When acute cholangitis is suspected, diagnostic assessment is made using TG13 diagnostic criteria every 6–12 h
2. Abdominal X-ray (KUB) and abdominal US are carried out, followed by CT scan, MRI, MRCP and HIDA scan
3. Severity is repeatedly assessed using severity assessment criteria; at diagnosis, within 24 h after diagnosis, and during the time zone of
24–48 h
4. As soon as a diagnosis has been made, the initial treatment is provided. The treatment is as follows: sufficient fluids replacement,
electrolyte compensation, and intravenous administration of analgesics and full dose of antimicrobial agents are provided
5. For patients with Grade I (mild), when no response to the initial treatment is observed within 24 h, biliary tract drainage is carried out
immediately
6. For patients with Grade II (moderate), biliary tract drainage is immediately performed along with the initial treatment. If early drainage
cannot be performed due to the lack of facilities or skilled personnel, transfer of the patient is considered
7. For patients with Grade III (severe), urgent biliary tract drainage is performed along with the initial treatment and general supportive care.
If urgent drainage cannot be performed due to the lack of facilities or skilled personnel, transfer of the patient is considered
8. For patient with Grade III (severe), organ supports (noninvasive/invasive positive pressure ventilation, use of vasopressors and
antimicrobial agents, etc.) are immediately performed
9. Blood culture and/or bile culture is performed for Grade II (moderate) and III (severe) patients
10. Treatment for etiology of acute cholangitis with endoscopic, percutaneous, or operative intervention is considered once acute illness has
resolved. Cholecystectomy should be performed for cholecystolithiasis after acute cholangitis has resolved
KUB kidney–ureter–bladder, US ultrasonography, CT computed tomography, MRI magnetic resonance imaging, MRCP magnetic resonance
cholangiopancreatography, HIDA hepatobiliary iminodiacetic acid

Table 2 Management bundle of acute cholecystitis

1. When acute cholecystitis is suspected, diagnostic assessment is made using TG13 diagnostic criteria every 6–12 h
2. Abdominal US is carried out, followed by HIDA scan and CT scan if needed to make the diagnosis
3. Severity is repeatedly assessed using severity assessment criteria; at diagnosis, within 24 h after diagnosis, and during the time zone of
24–48 h
4. Take that cholecystectomy is performed into consideration, as soon as a diagnosis has been made, the initial treatment takes place involving the
replacement of sufficient fluid after fasting, electrolyte compensation, intravenous injection of analgesics and full dose antimicrobial agents
5. For patients with Grade I (mild), cholecystectomy at an early stage within 72 h of onset of symptoms is recommended
6. If conservative treatment patients with Grade I (mild) is selected and no response to the initial treatment is observed within 24 h, reconsider
early cholecystectomy if still within 72 h of onset of symptoms or biliary tract drainage
7. For patients with Grade II (moderate), perform immediate biliary drainage or drainage if no early improvement (or cholecystectomy in
experienced centers) along with the initial treatment
8. For patients with Grade II (moderate) and III (severe) at high surgical risk, biliary drainage is immediately carried out
9. Blood culture and/or bile culture is performed for Grade II (moderate) and III (severe) patients
10. Among patients with Grade II (moderate), for those with serious local complications including biliary peritonitis, pericholecystic abscess,
liver abscess or for those with gallbladder torsion, emphysematous cholecystitis, gangrenous cholecystitis, and purulent cholecystitis,
emergency surgery is conducted (open or laparoscopic depending on experience) along with the general supportive care of the patient. If
surgery cannot be performed due to the lack of facilities or skilled personnel, transfer of the patient is considered
11. For patients with Grade III (severe) with jaundice and those in poor general conditions, emergency gallbladder drainage is considered with
initial therapy with antibiotics and general support measures. For patients who are found to have gallbladder stones during biliary
drainage, cholecystectomy is performed at after 3 month interval after the patient’s general conditions are improved
US ultrasonography, CT computed tomography, HIDA hepatobiliary iminodiacetic acid

123
58
Table 3 Acute cholangitis bundle checklist
h Repeat diagnosis every 6–12 h
h Diagnostic imaging X-ray (KUB), US, CT scan, MRI, MRCP,
HIDA scan
h Severity assessment at diagnosis and within 24 h after a
diagnosis
h Repeat severity assessment every 24 h
h Immediately start antibiotics administration and general
supportive care
h Grade I (mild): carry out biliary drainage when no symptom
improvement is observed within 24 h
h Grade II (moderate): carry out biliary drainage immediately
h Grade III (severe): conduct emergency biliary drainage and
perform organ support
h Consider transfer when procedures are unavailable as above
h Grade II (moderate) and III (severe): blood culture and bile
culture
h Consider surgical procedures to remove causes after biliary
drainage and improvement of organ failure
Table 4 Acute cholecystitis bundle checklist
h Repeat a diagnosis every 6–12 h
h Diagnostic imaging US, HIDA scan and CT scan
h Severity assessment at diagnosis and within 24 h after
diagnosis
h Repeat severity assessment every 24 h
h Immediately initiate antibiotics administration and general
supportive care
h Grade I (mild): Cholecystectomy at an early stage within 72 h of
onset of symptoms
h Conservative treatment for Grade I (mild): Worsening condition
or no improvement is in condition observed within 24 h.
Reconsider early cholecystectomy if still within 72 h or biliary
drainage (cholecystostomy)
h Grade II (moderate): Immediate biliary drainage or drainage if no
early improvement (or cholecystectomy in experienced centers)
along with the initial treatment*
h After drainage treatment for Grade II (moderate): Elective
cholecystectomy after symptom improvement at after 3 month
interval
h Poor local control** for Grade II (moderate): Emergency abdominal
drainage and/or cholecystectomy in experienced centers
h Grade II (moderate) and III (severe) at high surgical risk:
Immediately biliary drainage
h Grade II (moderate) and III (severe): Blood culture and/or bile
culture
h Grade III (severe): Initiate therapy with antibiotics and general
support measures. Conduct emergency biliary drainage as soon
as stable
h After drainage treatment for Grade III (severe): Elective
cholecystectomy after symptom improvement at after 3 month
interval
h Consider transfer when procedures are unavailable as above
* see bundle No.4
**see bundle No.10
123
J Hepatobiliary Pancreat Sci (2013) 20:55–59
the recommendation of TG13. The mandatory items or
procedures to be included in the management bundles have
been discussed and defined among the Tokyo Guidelines
Revision Committee members. The diagnostic criteria and
the severity assessment of acute cholecystitis in TG13 was
made based on the article of Yokoe et al. [17].
Check list for the use of management bundles for acute
cholangitis and cholecystitis (Tables 3, 4)
A check list is shown for the effective use of bundles. The
use of this list for medical care ensures standards, and is
thought to improve effectiveness of the bundles. These
check lists, including procedures, laboratories, monitoring
and interventions required, should be placed by the
bedside.
Conclusions
Bundles consist of important items for the effective use of
TG13. Compliance with the bundles is expected to improve
the prognosis of acute cholangitis and acute cholecystitis.
Reports from various facilities have demonstrated that
improved prognosis is expected through the use of the
Tokyo Guidelines for acute cholangitis and cholecystitis.
Furthermore, good use of those reports will contribute to
evidence construction and future revision of TG13.
Acknowledgments We would like to express our deep gratitude to
the following organizations for their great support and guidance in the
preparation of TG13: Japanese Society for Abdominal Emergency
Medicine, Japan Biliary Association, Japan Society for Surgical
Infection, and the Japanese Society of Hepato-Biliary-Pancreatic
Surgery.
Conflict of interest None.
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J Hepatobiliary Pancreat Sci (2013) 20:60–70
DOI 10.1007/s00534-012-0572-0
GUIDELINE
TG13 antimicrobial therapy for acute cholangitis and cholecystitis
Harumi Gomi • Joseph S. Solomkin • Tadahiro Takada • Steven M. Strasberg • Henry A. Pitt • Masahiro Yoshida
Shinya Kusachi • Toshihiko Mayumi • Fumihiko Miura • Seiki Kiriyama • Masamichi Yokoe • Yasutoshi Kimura
Ryota Higuchi • John A. Windsor • Christos Dervenis • Kui-Hin Liau • Myung-Hwan Kim
Published online: 11 January 2013
Ó Japanese Society of Hepato-Biliary-Pancreatic Surgery and Springer 2012
Abstract Therapy with appropriate antimicrobial agents
is an important component in the management of patients
with acute cholangitis and/or acute cholecystitis. In the
updated Tokyo Guidelines (TG13), we recommend anti-
microbial agents that are suitable from a global perspective
for management of these infections. These recommenda-
tions focus primarily on empirical therapy (presumptive
H. Gomi (&)
Center for Clinical Infectious Diseases, Jichi Medical University,
3311-1, Yakushiji, Shimotsuke, Tochigi 329-0431, Japan
e-mail: hgomi-oky@umin.ac.jp
J. S. Solomkin
Department of Surgery, University of Cincinnati
College of Medicine, Cincinnati, OH, USA
T. Takada
F. Miura
Department of Surgery, Teikyo University School of Medicine,
Tokyo, Japan
S. M. Strasberg
Section of Hepatobiliary and Pancreatic Surgery,
Washington University in Saint Louis School of Medicine,
Saint Louis, MO, USA
H. A. Pitt
Department of Surgery, Indiana University School of Medicine,
Indianapolis, IN, USA
M. Yoshida
Clinical Research Center Kaken Hospital, International
University of Health and Welfare, Ichikawa, Japan
S. Kusachi
Department of Surgery, Toho University Medical Center
Ohashi Hospital, Tokyo, Japan
T. Mayumi
Department of Emergency and Critical Care Medicine,
Ichinomiya Municipal Hospital, Ichinomiya, Japan
123
TG13: Updated Tokyo Guidelines for acute cholangitis
and acute cholecystitis
•
•
therapy), provided before the infecting isolates are identi-
fied. Such therapy depends upon knowledge of both local
microbial epidemiology and patient-specific factors that
affect selection of appropriate agents. These patient-spe-
cific factors include prior contact with the health care
system, and we separate community-acquired versus
healthcare-associated infections because of the higher risk
S. Kiriyama
Department of Gastroenterology, Ogaki Municipal Hospital,
Ogaki, Japan
M. Yokoe
General Internal Medicine, Nagoya Daini Red Cross Hospital,
Nagoya, Japan
Y. Kimura
Department of Surgical Oncology and Gastroenterological
Surgery, Sapporo Medical University School of Medicine,
Sapporo, Japan
R. Higuchi
Department of Surgery, Institute of Gastroenterology,
Tokyo Women’s Medical University, Tokyo, Japan
J. A. Windsor
Department of Surgery, The University of Auckland,
Auckland, New Zealand
C. Dervenis
First Department of Surgery, Agia Olga Hospital,
Athens, Greece
K.-H. Liau
Hepatobiliary and Pancreatic Surgery, Nexus Surgical
Associates, Mount Elizabeth Hospital, Singapore, Singapore
M.-H. Kim
Department of Internal Medicine, Asan Medical Center,
University of Ulsan, Seoul, Korea
J Hepatobiliary Pancreat Sci (2013) 20:60–70
of resistance in the latter. Selection of agents for commu-
nity-acquired infections is also recommended on the basis
of severity (grades I–III).
Free full-text articles and a mobile application of TG13 are
available via http://www.jshbps.jp/en/guideline/tg13.html.
Keywords Acute cholangitis
Acute cholecystitis

Antimicrobial therapy
Treatment guidelines
Biliary tract
infection
Introduction
Acute cholangitis and cholecystitis are common conditions
that may result in progressively severe infection, particu-
larly in debilitated hosts. Epidemiology and risk factors for
acute cholangitis and cholecystitis are provided in a sepa-
rated section of ‘‘TG13: Current terminology, etiology, and
epidemiology of acute cholangitis and cholecystitis.’’ The
primary goal of antimicrobial therapy in acute cholangitis
and cholecystitis is to limit both the systemic septic
response and local inflammation, to prevent surgical site
infections in the superficial wound, fascia, or organ space,
and to prevent intrahepatic abscess formation [1].
In acute cholangitis, drainage of the obstructed biliary
tree (termed source control) was recognized as the mainstay
of therapy long before the introduction of antimicrobial
agents [1]. An additional role of antimicrobial therapy,
allowing delay in operation until patients are more physio-
logically stable, was initially defined by Boey and Way [2].
They retrospectively reviewed 99 consecutive patients with
acute cholangitis, and reported that 53 % of their patients
who responded well to antimicrobial therapy were therefore
given elective instead of emergency operation [1, 2].
The role of antimicrobial therapy in the broad range of
diseases subsumed under the term ‘‘acute cholecystitis’’
also varies with severity and pathology. In early and non-
severe cases, it is not obvious that bacteria play a signifi-
cant role in the pathology encountered. In these patients,
antimicrobial therapy is at best prophylactic, preventing
progression to infection. In other cases, with clinical find-
ings of a systemic inflammatory response, antimicrobial
therapy is therapeutic, and treatment may be required until
the gallbladder is removed.
Rationale for changes in these guidelines
Five years have passed since the Tokyo Guidelines were
published in 2007, and it is now referred to as TG07 [3, 4].
During the last five years, there have been several develop-
ments in the management of biliary tract infections. For
antimicrobial therapy, other guideline sources for biliary tract
infections have been revised. These include the Surviving
61
Sepsis Campaign 2008 [5] and treatment guidelines for
complicated intra-abdominal infections developed by the
Surgical Infection Society of North America (SIS-NA) and
the Infectious Diseases Society of America (IDSA) 2010 [6].
Additionally, new agents and dosing regimens have been
approved, including higher dose regimens for piperacillin/
tazobactam, meropenem, levofloxacin and doripenem. The
issues of pharmacokinetics and pharmacodynamics of anti-
microbial agents have been clarified [3, 4]. Since the release
of TG07 [3, 4], the emergence of antimicrobial resistance
among clinical isolates of Enterobacteriaceae from patients
with community-acquired intra-abdominal infections has
been more widely reported [7–14]; in particular, antimicro-
bial resistance in Gram-negative bacilli driven by the
appearance of extended-spectrum b-lactamases (ESBL) and
carbapenemases (i.e., metallo-b-lactamase and non-metallo-
b-lactamase) [15–19]. Finally, in the updated Tokyo
Guidelines (TG13), both the diagnostic and severity criteria
for acute cholangitis and cholecystitis have been revised and
recommendations for antimicrobial therapy are reconsidered
against this new structure.
There are new topics dealt with in these guidelines. We
now make specific recommendations for antimicrobial
therapy of healthcare-associated biliary infections. This
was prompted by recognition of the increasing number of
elderly patients with multiple medical problems exposed to
the health care system and thereby being at risk of
acquiring resistant organisms [14]. In addition, there are
several agents that are no longer recommended by the SIS-
NA/IDSA 2010 guidelines [6]. We also clarify concerns
regarding the importance (or lack thereof) of biliary pen-
etration. We also now address prophylaxis for elective
endoscopic retrograde cholangiopancreatography (ERCP).
Background
The bacteria commonly found in biliary tract infections are
well known, and are presented in Tables 1 and 2 [3, 4, 20–31].
Antimicrobial therapy largely depends on local antimicro-
bial susceptibility data. In the international guidelines for
acute cholangitis and cholecystitis (TG13), a framework for
selecting antimicrobial agents will be provided, with class-
based definitions of appropriate therapy. Listed agents in
the guideline are appropriate for use, and recommendations
for modification based upon the local microbiological
findings, referred to as antibiogram, are made.
Decision process
A systematic literature review was performed using Pub-
Med from January 1, 2005 to May 15, 2012. All references
were searched with the keywords ‘‘Acute cholangitis’’
AND ‘‘Antibiotics OR Antimicrobial therapy,’’ and ‘‘Acute
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62 J Hepatobiliary Pancreat Sci (2013) 20:60–70

Table 1 Common microorganisms isolated from bile cultures among and few new developments on clinical questions addressed
patients with acute biliary infections since 2005, a consensus process was used by the members
Isolated microorganisms Proportions of isolated of the Tokyo Guidelines Revision Committee after con-
from bile cultures organisms (%) sultations with internationally recognized experts.
The structure of recommendations for selecting antimi-
Gram-negative organisms
crobial agents has been revised. Antimicrobial agents
Escherichia coli 31–44
appropriate for initial therapy (empirical therapy or pre-
Klebsiella spp. 9–20
sumptive therapy) for various grades of severity of biliary
Pseudomonas spp. 0.5–19
tract infections have been developed. Table 3 lists anti-
Enterobacter spp. 5–9
microbial agents appropriate for use for the treatment of
Acinetobacter spp. –
patients with both community-acquired and healthcare-
Citrobacter spp. –
associated cholangitis and cholecystitis.
Gram-positive organisms
Enterococcus spp. 3–34
Streptococcus spp. 2–10 Clinical questions
Staphylococcus spp. 0a
Anaerobes 4–20 Clinically relevant questions are provided with brief
Others – answers and explanations below.
The data are from references [3, 20–27, 30] Q1. What specimen should be sent for culture to iden-
a
A recent study by Salvador et al. [27] reported none from bile tify the causative organisms in acute cholangitis and
cultures, while a study by Sung et al. [14] reported 3.6 % from blood cholecystitis?
cultures among community-acquired (2 %) and healthcare-associated
(4 %) bacteremic acute biliary infections
Bile cultures should be obtained at the beginning of any
Table 2 Common isolates from patients with bacteremic biliary tract procedure performed. Gallbladder bile should be sent for
infections culture in all cases of acute cholecystitis excepting those
with grade I severity (recommendation 1, level C).
Isolated microorganisms Proportions of isolates (%)
from blood cultures We suggest cultures of bile and tissue when perforation,
Community- Healthcare- emphysematous changes, or necrosis of gallbladder are
acquired associated
noted during cholecystectomy (recommendation 2,
infectionsa infectionsb
level D).
Gram-negative organisms Blood cultures are not routinely recommended for
Escherichia coli 35–62 23 grade I community-acquired acute cholecystitis
Klebsiella spp. 12–28 16 (recommendation 2, level D).
Pseudomonas spp. 4–14 17
Enterobacter spp. 2–7 7
Identifying the causative organism(s) is an essential step
Acinetobacter spp. 3 7
in the management of acute biliary infections. Positive
Citrobacter spp. 2–6 5
rates of bile cultures range from 59 to 93 % for acute
Gram-positive organisms cholangitis [3, 4, 20–27], and positive rates of either bile or
Enterococcus spp. 10–23 20 gallbladder cultures range from 29 to 54 % for acute
Streptococcus spp. 6–9 5 cholecystitis [3, 4, 20–27]. In a recent study which utilized
Staphylococcus spp. 2 4 the TG07 diagnostic classification, positive rates of bile
Anaerobes 1 2 cultures among patients with cholangitis were 67 % (66 of
Others 17 11 98 patients) and 33 % (32 of 98) without [27]. Table 1
a
The data are from references [14, 28–30] shows common microbial isolates from bile cultures
b
The data are from reference [14] among patients with acute biliary infections [3, 4, 20–27].
Common duct bile should be sent for culture in all cases of
cholecystitis’’ AND ‘‘Antibiotics OR Antimicrobial ther- suspected cholangitis.
apy’’ among human studies. Sixty-five and 122 articles On the other hand, previous studies indicated that posi-
were found, respectively. These references were further tive rates of blood cultures among patients with acute cho-
narrowed using keywords ‘‘Clinical trials’’ and ‘‘Ran- langitis ranged from 21 to 71 % [3]. For acute cholecystitis,
domized trials.’’ Literature cited in the TG07 was also the prevalence of positive blood cultures is less than acute
reviewed and integrated for revision. If there were few data cholangitis, and in the last two decades it has been reported

123
 Table 3 Antimicrobial recommendations for acute biliary infections
Community-acquired biliary infections Healthcare-associated biliary
infectionse
Severity Grade I Grade II Grade IIIe
Antimicrobial Cholangitis Cholecystitis Cholangitis and cholecystitis Cholangitis and cholecystitis Healthcare-associated
agents cholangitis and cholecystitis

Penicillin-based Ampicillin/sulbactamb is not Ampicillin/sulbactamb is not Piperacillin/tazobactam Piperacillin/tazobactam Piperacillin/tazobactam

therapy recommended without an recommended without an
J Hepatobiliary Pancreat Sci (2013) 20:60–70

aminoglycoside aminoglycoside
Cephalosporin- Cefazolina, or cefotiama, or Cefazolina, or cefotiama, or Ceftriaxone, or cefotaxime, or Cefepime, or ceftazidime, or Cefepime, or ceftazidime, or
based therapy cefuroximea, or ceftriaxone, or cefuroximea, or ceftriaxone, or cefepime, or cefozopran, or cefozopran ± metronidazoled cefozopran ± metronidazoled
cefotaxime ± metronidazoled cefotaxime ± metronidazoled ceftazidime ± metronidazoled
Cefmetazole,a Cefoxitin,a Cefmetazole,a Cefoxitin,a Cefoperazone/sulbactam
Flomoxef,a Cefoperazone/ Flomoxef,a Cefoperazone/
sulbactam sulbactam
Carbapenem- Ertapenem Ertapenem Ertapenem Imipenem/cilastatin, Imipenem/cilastatin,
based therapy meropenem, doripenem, meropenem, doripenem,
ertapenem ertapenem
Monobactam- – – – Aztreonam ± metronidazolec Aztreonam ± metronidazoled
based therapy
Fluoroquinolone- Ciprofloxacin, or levofloxacin, or Ciprofloxacin, or levofloxacin, or Ciprofloxacin, or levofloxacin, or – –
based therapyc pazufloxacin ± metronidazoled pazufloxacin ± metronidazoled pazufloxacin ± metronidazolec
Moxifloxacin Moxifloxacin Moxifloxacin
a
Local antimicrobial susceptibility patterns (antibiogram) should be considered for use
b
Ampicillin/sulbactam has little activity left against Escherichia coli. It is removed from the North American guidelines [6]
c
Fluoroquinolone use is recommended if the susceptibility of cultured isolates is known or for patients with b-lactam allergies. Many extended-spectrum b-lactamase (ESBL)-producing Gram-
negative isolates are fluoroquinolone-resistant
d
Anti-anaerobic therapy, including use of metronidazole, tinidazole, or clindamycin, is warranted if a biliary-enteric anastomosis is present. The carbapenems, piperacillin/tazobactam,
ampicillin/sulbactam, cefmetazole, cefoxitin, flomoxef, and cefoperazone/sulbactam have sufficient anti-anerobic activity for this situation
e
Vancomycin is recommended to cover Enterococcus spp. for grade III community-acquired acute cholangitis and cholecystitis, and healthcare-associated acute biliary infections. Linezolid or
daptomycin is recommended if vancomycin-resistant Enterococcus (VRE) is known to be colonizing the patient, if previous treatment included vancomycin, and/or if the organism is common in
the community
63

123
64
to range from 7.7 to 15.8 % [28, 31]. Table 2 shows the most
recently reported microbial isolates from patients with
bacteremic biliary tract infections [14, 28–30].
There is a lack of clinical trials examining the benefit of
blood cultures in patients with acute biliary tract infections.
Most of the bacteremic isolates reported (Table 2) are
organisms that do not form vegetations on normal cardiac
valves nor miliary abscesses. Their intravascular presence
does not lead to an extension of therapy or selection of
multidrug regimens. We therefore recommend such cul-
tures be taken only in high-severity infections when such
results might mandate changes in therapy [5]. Blood cul-
tures are not routinely recommended for grade I commu-
nity-acquired acute cholecystitis (level D).
The SIS-NA/IDSA 2010 guidelines recommended
against routine blood cultures for community-acquired
intra-abdominal infections, since the results do not change
the management and outcomes [6]. This is in part driven by
a study of the clinical impact of blood cultures taken in the
emergency department [32]. In this retrospective study,
1,062 blood cultures were obtained during the study period,
of which 92 (9 %) were positive. Of the positive blood
cultures, 52 (5 %) were true positive, and only 18 (1.6 %)
resulted in altered management.
Q2. What considerations should be taken when select-
ing antimicrobial agents for the treatment of acute
cholangitis and cholecystitis?
When selecting antimicrobial agents, targeted organisms,
pharmacokinetics and pharmacodynamics, local antibiogram,
a history of antimicrobial usage, renal and hepatic function,
and a history of allergies and other adverse events
should be considered (recommendation 1, level D).
We suggest anaerobic therapy if a biliary-enteric
anastomosis is present (recommendation 2, level C).
There are multiple factors to consider in selecting
empiric antimicrobial agents. These include targeted
organisms, local epidemiology and susceptibility data
(antibiogram), alignment of in-vitro activity (or spectrum)
of the agents with these local data, characteristics of the
agents such as pharmacokinetics and pharmacodynamics,
and toxicities, renal and hepatic function, and any history of
allergies and other adverse events with antimicrobial agents
[3, 4, 20–27]. A history of antimicrobial usage is important
because recent (\6 months) antimicrobial therapy greatly
increases the risk of resistance among isolated organisms.
Before dosing antimicrobial agents, renal function should
be estimated with the commonly used equation: Serum cre-
atinine = (140 – age) [optimum body weight (kg)]/
72 9 serum creatinine (mg/dl) [3, 4, 33]. Individual dosage
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J Hepatobiliary Pancreat Sci (2013) 20:60–70
adjustments for altered renal and hepatic function are avail-
able in several recent publications [34, 35]. Consultation with
a clinical pharmacist is recommended if there are concerns.
Regarding the timing of therapy, it should be initiated as
soon as the diagnosis of biliary infection is suspected. For
patients in septic shock, antimicrobials should be admin-
istered within 1 h of recognition [5]. For other patients, as
long as 4 h may be spent obtaining definitive diagnostic
studies prior to beginning antimicrobial therapy. Antimi-
crobial therapy should definitely be started before any
procedure, either percutaneous, endoscopic, or operative, is
performed. In addition, anaerobic therapy is appropriate if
a biliary-enteric anastomosis is present (level C) [6].
Selected newer agents
Moxifloxacin has been investigated for intra-abdominal
infections in several randomized studies [36–39]. It was
demonstrated that moxifloxacin is safe, well-tolerated, and
non-inferior to the comparators, such as ceftriaxone plus
metronidazole [37], or piperacillin/tazobactam followed by
amoxicillin/clavulanic acid [39]. This study was conducted
prior to the appearance of ESBL-mediated resistance [40].
There are few data specifically regarding the treatment of
acute cholangitis or cholecystitis, and resistance rates of
E. coli and other common Enterobacteriacae to fluoro-
quinolones have risen [7–14].
Tigecycline was under clinical trials for approval during
preparation of the manuscript, and is now approved for clin-
ical use in Japan. Tigecycline has in-vitro activity against a
wide range of clinically significant Gram-positive and Gram-
negative bacteria [41]. These include multidrug-resistant
Gram-positive cocci such as methicillin-resistant Staphylo-
coccus aureus and vancomycin-resistant Enterococcus spp.
For Gram-negative bacilli, ESBL-producing Enterobacteria-
ceae are susceptible, as are most anaerobes. Tigecycline has
no activity against Pseudomonas aeruginosa. Tigecycline has
been investigated for skin and soft tissue infections and
complicated intra-abdominal infections [41]. Tigecycline
causes nausea and vomiting in approximately 10–20 % of
patients, and is dose-related. This limits the dose that can be
routinely administered and suggests only a secondary role for
this agent, in the event of unusual pathogens or allergy to
other classes of antimicrobial agents. Recent meta-analyses
have demonstrated an increased mortality rate and treatment
failure rate in randomized trials with this agent [42].
Antimicrobial agents appropriate for use
in the management of community-acquired acute
cholangitis and cholecystitis
Table 3 summarizes antimicrobial recommendations. It
should be kept in mind that in the treatment of cholangitis,
J Hepatobiliary Pancreat Sci (2013) 20:60–70
source control (i.e., drainage) is an essential part of man-
agement. The indications and timing for drainage are
provided in the severity and flowchart of the management
sections regarding acute cholangitis. Since 2005, there
have been no randomized clinical trials of antimicrobial
therapy for community-acquired acute cholangitis and/or
acute cholecystitis. There have been multiple reports on
clinical isolates with multiple drug resistance from intra-
abdominal infections worldwide, and biliary infections in
particular [7–14, 40].
Recommendations for antimicrobial therapy are based
primarily upon extrapolations of microbiological efficacy
and behavior of these agents against the more susceptible
isolates treated in the clinical trials cited [36–39, 43–49].
Some concerns about this approach to defining efficacy
against resistant isolates has been raised [50].
The use of severity of illness as a guide to antimicrobial
agent selection has been questioned in the face of the
increasing numbers of ESBL-producing E. coli and Kleb-
siella in the community. These organisms are not reliably
susceptible to cephalosporins, penicillin derivatives, or
fluoroquinolones. Previous guidelines have recommended
that if more than 10–20 % of community isolates of E. coli
are so resistant, then empiric coverage should be provided
for these organisms until susceptibility data demonstrates
sensitivity to narrower spectrum agents. Carbapenems,
piperacillin/tazobactam, tigecycline, or amikacin may also
be used to treat these isolates [6].
For grade III community-acquired acute cholangitis and
cholecystitis, agents with anti-pseudomonal activities are
recommended as initial therapy (empirical therapy) until
causative organisms are identified. Pseudomonas aerugin-
osa is present in approximately 20 % of recent series [14,
27], and is a known virulent pathogen. Failure to empiri-
cally cover this organism in critically ill patients may result
in excess mortality.
Enterococcus spp. is another important pathogen for
consideration in patients with grade III community-
acquired acute cholangitis and cholecystitis. Vancomycin
is recommended to cover Enterococcus spp. for patients
with grade III community-acquired acute cholangitis and/
or cholecystitis, until the results of cultures are available.
Ampicillin can be used if isolated strains of Enterococcus
spp. are susceptible to ampicillin. Ampicillin covers most
of the strains of Enterococcus faecalis from community-
acquired infections in general. For Enterococcus faecium,
vancomycin is the drug of choice for empirical therapy.
However, in many hospitals, vancomycin-resistant
Enterococcus spp., both E. faecium and E. faecalis, have
emerged as important causes of infection. Treatment for
these organisms requires either linezolid or daptomycin.
Surgeons and other physicians making treatment decisions
for patients with healthcare-associated infections should be
65
aware of the frequency of these isolates in their hospital
and unit. Then, regarding infrequently isolated anaerobes
such as the Bacteroides fragilis group, we suggest to cover
these organisms empirically when a biliary-enteric anas-
tomosis is present (level C) [6].
For grade I and II community-acquired cholangitis and
cholecystitis, Table 3 shows the agents appropriate for use.
Of note, the intravenous formulation of metronidazole has
not been approved in Japan. As a result, clindamycin is one
of the alternatives where intravenous metronidazole is not
available. Clindamycin resistance among Bacteroides spp.
is significant and the use of clindamycin is no longer rec-
ommended in other intra-abdominal infections [6]. Cefox-
itin, cefmetazole, flomoxef, and cefoperazone/sulbactam
are the agents in cephalosporins that have activities against
Bacteroides spp. Cefoxitin is no longer recommended by
the SIS-NA/IDSA 2010 guidelines due to the high preva-
lence of resistance among Bacteroides spp. [6]. Local
availability of agents as well as local susceptibility results
are emphasized when choosing empirical therapy.
Table 4 summarizes antimicrobial agents with high
prevalence of resistance among Enterobacteriaceae [7–14].
Ampicillin/sulbactam is one of the most frequently used
agents for intra-abdominal infections. Nonetheless, the
activity of ampicillin/sulbactam against E. coli, with or
without ESBLs, has fallen to levels that prevent a recom-
mendation for its use.
In the TG13, ampicillin/sulbactam alone is not recom-
mended as empirical therapy if the local susceptibility is
\80 %. It is reasonable to use ampicillin/sulbactam as
definitive therapy when the susceptibility of this agent is
proven. Ampicillin/sulbactam may be used if an amino-
glycoside is combined until susceptibility testing results are
available.
Table 4 Antimicrobial agents with high prevalence of resistance
among Enterobacteriaceae
Antimicrobial class Antimicrobial agents
Penicillin Ampicillin/sulbactam
Cephalosporins Cefazolin
Cefuroxime
Cefotiam
Cefoxitin
Cefmetazole
Flomoxef
Ceftriaxonea or cefotaximea
Fluoroquinolones Ciprofloxacin
Levofloxacin
Moxifloxacin
References [4–11]
a
This resistance indicates the global spread of extended-spectrum b-
lactamase (ESBL)-producing Enterobacteriaceae
123
66
Fluoroquinolone use is only recommended if the sus-
ceptibility of cultured isolates is known since antimicrobial
resistance has been increasing significantly [7–14]. This
agent can also be used as an alternative agent for patients
with b-lactam allergies.
Antimicrobial agents appropriate for use
in the management of healthcare-associated acute
cholangitis and cholecystitis
There is no evidence to support any agent as optimal
treatment of healthcare-associated acute cholangitis and
cholecystitis. The principles of empirical therapy of health-
care-associated infections include using agents with anti-
pseudomonal activity until definitive causative organisms are
found. This paradigm is now expanded to include empirical
coverage for ESBL-producing Gram-negative organisms
based on local microbiological findings (local antibiogram).
Table 3 shows empirical agents (presumptive therapy) for
healthcare-associated acute cholangitis and cholecystitis.
Vancomycin is recommended when patients are colonized
with resistant Gram-positive bacteria such as methicillin-
resistant Staphylococcus aureus and/or Enterococcus spp. or
when these multidrug-resistant Gram-positives are of con-
cern. Staphylococcus aureus is not as common an isolate for
acute biliary infections as Enterococcus spp. Vancomycin-
resistant Enterococcus (VRE) should be covered empirically
with linezolid or daptomycin if this organism is known to be
colonizing the patient, if previous treatment included vanco-
mycin, and/or if the organism is common in the community.
Regarding anaerobes such as the Bacteroides fragilis
group, we suggest to cover these organisms empirically in
the presence of a biliary-enteric anastomosis (level C) [6].
Is it necessary for agents used in acute biliary infections
to be concentrated in bile?
Historically, biliary penetration of agents has been consid-
ered in the selection of antimicrobial agents. However, there
is considerable laboratory and clinical evidence that as
obstruction occurs, secretion of antimicrobial agents into bile
stops [1]. Well-designed randomized clinical trials compar-
ing agents with or without good biliary penetration are nee-
ded to determine the clinical relevance and significance of
biliary penetration in treating acute biliary infections.
How should highly resistant causative organisms be
managed in treating acute cholangitis and cholecystitis?
The major microbiological phenomenon of the last decade has
been the emergence of novel b-lactamase-mediated resistance
mechanisms in Enterobacteriaceae. These have been seen in
intra-abdominal infections worldwide [7–19, 27]. These
123
J Hepatobiliary Pancreat Sci (2013) 20:60–70
organisms have moved into many communities, and are now
seen increasingly in community-acquired infections such as
cholangitis and cholecystitis. The frequency of ESBL-
producing E. coli and Klebsiella spp. has reached the point in
some countries where decisions regarding empirical therapy
must be guided by their prevalence. ESBL-producing E. coli
is highly susceptible to carbapenems and to tigecycline. In
some communities, highly resistant Klebsiella spp. and
E. coli with carbapenemases are now seen [51–54]. The
widely accepted rule for empirical therapy is that resistant
organisms occurring in more than 10–20 % of patients
should be treated. Colistin is the salvage agent for the above
multidrug-resistant Gram-negative bacilli epidemic strains
[40, 54]. This agent is toxic, dosing is uncertain, and its
use should involve consultation with infectious disease
specialists [40].
In the SIS-NA/IDSA 2010 guidelines [6], antimicrobial
agents as empirical therapy for healthcare-associated
intra-abdominal infections were given. In the guidelines,
carbapenems, piperacillin/tazobactam, and ceftazidime or
cefepime, each combined with metronidazole, have been
recommended when the prevalence of resistant Pseudomonas
aeruginosa, ESBL-producing Enterobacteriaceae, Acineto-
bacter or other multidrug-resistant Gram-negative bacilli is
less than 20 %. For ESBL-producing Enterobacteriaceae,
carbapenems, piperacillin/tazobactam, and aminoglycosides
are recommended. For Pseudomonas aeruginosa, if the
prevalence of resistance to ceftazidime is more than 20 %,
carbapenems, piperacillin/tazobactam, and aminoglycosides
are recommended. Even with this guide, selecting appropriate
agents for antimicrobial stewardship is often difficult.
Q3. What are the special concerns for community-
acquired acute cholecystitis in management with
antimicrobial agents?
When cholecystectomy is performed, antimicrobial therapy
can be stopped within 24 hours since the source of infection
is controlled (recommendation 2, level C).
Grade II or Grade III acute cholecystitis should be treated
with antimicrobial therapy even after cholecystectomy is
performed (recommendation 1, level D).
In patients with pericholecystic abscesses or perforation of
the gallbladder, treatment with an antimicrobial regimen as
listed in Table 3 is recommended. Therapy should be continued
until the patient is afebrile, with a normalized white count,
and without abdominal findings (recommendation 1, level D).
In most cases, cholecystectomy removes the infection,
and little if any infected tissue remains. Under these cir-
cumstances, there is no benefit to extending antimicrobial
therapy beyond 24 h.
J Hepatobiliary Pancreat Sci (2013) 20:60–70 67

Recent randomized clinical trials for antimicrobial
therapy of acute cholecystitis are limited [43, 46–48]. In
these randomized studies, comparisons were made such as
ampicillin plus tobramycin versus piperacillin or cefope-
razone, pefloxacin versus ampicillin and gentamicin, and
cefepime versus mezlocillin plus gentamicin [4, 43, 46,
48]. There were no significant differences between the
agents compared. In the TG13, the agents considered as
appropriate therapy, and detailed in Table 3, have all been
utilized in randomized controlled trials of intra-abdominal
infections. These studies included patients with patholog-
ically advanced cholecystitis (abscess or perforation).
Table 3 is provided for both community-acquired and
healthcare-associated acute cholecystitis.
significantly affected the overall management strategies for
at least the last two decades.
In the SIS-NA/IDSA 2010 guidelines, the recommended
duration of antimicrobial therapy for complicated intra-
abdominal infections is 4–7 days once the source of infec-
tion is controlled [6]. Since there are very few data available
for the duration of either community-acquired or health-
care-associated acute cholangitis and cholecystitis, Table 5
was developed to guide the duration of antimicrobial ther-
apy as expert opinion. When bacteremia with Gram-posi-
tive bacteria such as Enterococcus spp. and Streptococcus
spp. is present, it is prudent to offer antimicrobial therapy
for two weeks since these organisms are well known to
cause infective endocarditis.

Antimicrobial therapy after susceptibility testing results
are available
Once susceptibility testing results of causative microor-
ganisms are available, specific therapy (or definitive ther-
apy) should be offered. This process is called de-escalation
[5]. Agents in Table 4 can be used safely once the sus-
ceptibility is proven.
Duration of treatment of patients with clinical
and laboratory success
The optimal duration of antimicrobial therapy for commu-
nity-acquired and healthcare-associated acute cholangitis
and cholecystitis has not been determined in well-designed
randomized controlled studies. Whether the source of
infection (i.e., biliary obstruction) is well controlled or not is
critical in determining the duration of therapy. In addition,
recent technological advances for biliary drainage have
Conversion to oral antimicrobial agents
Patients with acute cholangitis and cholecystitis who can
tolerate oral feeding may be treated with oral therapy [55].
Depending on the susceptibility patterns of the organisms
identified, oral antimicrobial agents such as fluoroquino-
lones (ciprofloxacin, levofloxacin, or moxifloxacin),
amoxicillin/clavulanic acid, or cephalosporins may also be
used. Table 6 lists commonly used oral antimicrobial agents
with good bioavailabilities.
What is the optimal prophylaxic agent before elective
endoscopic retrograde cholangiopancreatography
(ERCP)?
A Cochrane meta-analysis examining the benefits of anti-
biotic prophylaxis for elective ERCP has been performed,
and found benefit to the practice [56]. The international
guidelines on prophylaxis with endoscopy indicated that

Table 5 Recommended duration of antimicrobial therapy

Community-acquired biliary infections Healthcare-associated biliary infections
Severity Grade I Grade II Grade III
Diagnosis Cholecystitis Cholangitis Cholangitis Cholangitis Healthcare-associated cholangitis and
and and cholecystitis
cholecystitis cholecystitis

Duration of Antimicrobial therapy can be Once source of infection is controlled, If bacteremia with Gram-positive cocci
therapy discontinued within 24 h after duration of 4–7 days is recommended such as Enterococcus spp.,
cholecystectomy is performed If bacteremia with Gram-positive cocci Streptococcus spp. is present, minimum
such as Enterococcus spp., duration of 2 weeks is recommended
Streptococcus spp. is present, minimum
duration of 2 weeks is recommended
Specific If perforation, emphysematous changes, If residual stones or obstruction of the bile tract are present, treatment should be
conditions and necrosis of gallbladder are noted continued until these anatomical problems are resolved
for during cholecystectomy, duration of
extended 4–7 days is recommended
therapy

123
68
Table 6 Representative oral antimicrobial agents for community-
acquired and healthcare-associated acute cholangitis and cholecystitis
with susceptible isolates
Antimicrobial class Antimicrobial agents
Penicillins Amoxicillin/clavulanic acid
Cephalosporins Cephalexin ± metronidazolea
Fluoroquinolones Ciprofloxacin or
levofloxacin ± metronidazolea
Moxifloxacin
a
Anti-anaerobic therapy, including use of metronidazole, tinidazole,
or clindamycin, is warranted if a biliary-enteric anastomosis is present
prophylaxis with ERCP is recommended [57]. As consen-
sus statements, the guidelines [57] recommended the
standard prophylaxis regimen to prevent infective endo-
carditis. The regimen includes amoxicillin or clindamycin
orally, or ampicillin or cefazolin as intravenous agents, and
vancomycin for patients with b-lactam allergies to prevent
infective endocarditis. However, the regimens for pre-
venting cholangitis and bacteremia due to obstructive bil-
iary tract were not included.
Recent meta-analyses [56, 58] had conflicting conclu-
sions regarding the effectiveness of prophylactic therapy
before elective ERCP. Bai et al. concluded that prophylaxic
agents cannot prevent cholangitis [58], while a Cochrane
review indicated that prophylaxic antimicrobial therapy
before elective ERCP reduces the incidence of bacteremia
[relative risk (RR) 0.50], cholangitis (RR 0.54), and pan-
creatitis (RR 0.54) [56]. However, overall mortality was
not reduced with prophylaxis before elective ERCP [RR
1.33, confidence interval (CI) 0.32–5.44]. In this review,
the numbers needed to treat (NNT) to prevent bacteremia
(NNT = 11) and cholangitis (NNT = 38) were also dem-
onstrated. The Cochrane review concluded that further
studies are needed, including randomized placebo-
controlled studies, to investigate the effectiveness of
prophylaxis for elective ERCP with low risk of bias,
randomized comparison of the timing of administration of
prophylaxis (before vs. during or after ERCP), and ran-
domized head-to-head comparison of antimicrobial agents
as prophylactic therapy with elective ERCP [56].
Antimicrobial agents investigated with elective ERCP
include minocycline orally [59], piperacillin [60, 61],
clindamycin plus gentamicin [62], cefuroxime [63], cefo-
taxime [64, 65], and ceftazidime [66].
In the TG13, antimicrobial prophylactic agents appro-
priate for use in preventing cholangitis or bacteremia due to
biliary tract obstruction are provided on a consensus basis.
Table 7 lists those agents. Cefazolin or other narrower-
spectrum cephalosporins can be used as prophylactic
agents. Cefazolin is one of the agents for preventing
infective endocarditis with endoscopy and a convenient
agent to be used to prevent both endocarditis and
123
J Hepatobiliary Pancreat Sci (2013) 20:60–70
Table 7 Antimicrobial prophylaxic agents for elective endoscopic
retrograde pancreatocholangiography (ERCP)
Antimicrobial class Antimicrobial agents
Cephalosporins Cefazolin
Cefoxitin
Cefmetazole
Flomoxef
Penicillins Piperacillina
Piperacillin/tazobactama
a
Anti-pseudomonal agents
cholangitis. Piperacillin is one of the anti-pseudomonal
agents that have been studied as a prophylactic agent for
elective ERCP [60, 61]. Given the emergence of resistance
among Gram-negative organisms worldwide, including
ESBL-producing strains [7–14, 27], we recommend anti-
pseudomonal agents such as piperacillin or piperacillin/
sulbactam listed in Table 7.
Use of antibiotic irrigation
There has been continuing interest in irrigation of surgical
fields with antimicrobial agents, and the subject has
recently been reviewed [67]. The authors concluded that
topical antimicrobial agents are clearly effective in reduc-
ing wound infections and may be as effective as the use of
systemic antimicrobial agents. The combined use of sys-
temic and topical antimicrobial agents may have additive
effects, but this is lessened if the same agent is used for
both topical and systemic administration.
Conclusions
Antimicrobial agents should be used prudently while pro-
moting antimicrobial stewardship in each institution, local
area, and country. The recent global spread of antimicrobial
resistance gives us warning in current practice. TG13 pro-
vides a practical guide for physicians and surgeons who are
involved in the management of community-acquired and
healthcare-associated acute biliary infections. There are still
many areas of uncertainty in this subject. Continuous mon-
itoring of local antimicrobial resistance and further studies
on acute cholangitis and cholecystitis should be warranted.
Conflict of interest None.
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J Hepatobiliary Pancreat Sci (2013) 20:71–80
DOI 10.1007/s00534-012-0569-8
GUIDELINE
TG13 indications and techniques for biliary drainage
in acute cholangitis (with videos)
Takao Itoi • Toshio Tsuyuguchi • Tadahiro Takada • Steven M. Strasberg • Henry A. Pitt •
Myung-Hwan Kim • Giulio Belli • Toshihiko Mayumi • Masahiro Yoshida • Fumihiko Miura •
Markus W. Büchler • Dirk J. Gouma • O. James Garden • Palepu Jagannath • Harumi Gomi •
Yasuyuki Kimura • Ryota Higuchi
Published online: 11 January 2013
Ó Japanese Society of Hepato-Biliary-Pancreatic Surgery and Springer 2013
Abstract The Tokyo Guidelines of 2007 (TG07) descri-
bed the techniques and recommendations of biliary
decompression in patients with acute cholangitis. TG07
recommended that endoscopic transpapillary biliary
drainage should be selected as a first-choice therapy for
acute cholangitis because it is associated with a low mor-
tality rate and shorter duration of hospitalization. However,
TG07 did not include the whole technique of standard
endoscopic transpapillary biliary drainage, for example,
biliary cannulation techniques including contrast medium-
Electronic supplementary material The online version of this
article (doi:10.1007/s00534-012-0569-8) contains supplementary
material, which is available to authorized users.
T. Itoi (&)
Department of Gastroenterology and Hepatology,
Tokyo Medical University, 6-7-1 Nishishinjuku,
Shinjuku-ku, Tokyo 160-0023, Japan
e-mail: itoi@tokyo-med.ac.jp
T. Tsuyuguchi
F. Miura
Department of Medicine and Clinical Oncology, Graduate
School of Medicine, Chiba University, Chiba, Japan
T. Takada
Department of Surgery, Teikyo University School of Medicine,
Tokyo, Japan
S. M. Strasberg
Section of Hepatobiliary and Pancreatic Surgery, Washington
University School of Medicine, St. Louis, USA
H. A. Pitt
Department of Surgery, Indiana University School of Medicine,
Indianapolis, IN, USA
M.-H. Kim
Department of Internal Medicine, Asan Medical Center,
University of Ulsan, Seoul, Korea
TG13: Updated Tokyo Guidelines for acute cholangitis
and acute cholecystitis
assisted cannulation, wire-guided cannulation, and treat-
ment of duodenal major papilla using endoscopic papillary
balloon dilation (EPBD). Furthermore, recently single-
or double-balloon enteroscopy-assisted biliary drainage
(BE-BD) and endoscopic ultrasonography-guided biliary
drainage (EUS-BD) have been reported as special tech-
niques for biliary drainage. Nevertheless, the updated
Tokyo Guidelines (TG13) recommends that endoscopic
drainage should be first-choice treatment for biliary
decompression in patients with non-surgically altered
anatomy and suggests that the choice of cannulation tech-
nique or drainage method (endoscopic naso-biliary drain-
age and stenting) depends on the endoscopist’s preference
but EST should be selected rather than EPBD from the
G. Belli
General and HPB Surgery, Loreto Nuovo Hospital, Naples, Italy
T. Mayumi
Department of Emergency and Critical Care Medicine,
Ichinomiya Municipal Hospital, Ichinomiya, Japan
M. Yoshida
Clinical Research Center Kaken Hospital, International
University of Health and Welfare, Ichikawa, Japan
M. W. Büchler
Department of Surgery, University of Heidelberg, Heidelberg,
Germany
D. J. Gouma
Department of Surgery, Academic Medical Center, Amsterdam,
The Netherlands
O. J. Garden
Clinical Surgery, The University of Edinburgh, Edinburgh, UK
P. Jagannath
Department of Surgical Oncology, Lilavati Hospital and
Research Centre, Mumbai, India
123
72
aspect of procedure-related complications. In terms of BE-
BD and EUS-BD, although there are many reports on the
their usefulness, they should be performed by skilled en-
doscopists in high-volume institutes, who are good at ent-
eroscopy or echoendosonography, respectively, because
procedures and devices are not yet established.
Free full-text articles and a mobile application of TG13
are available via http://www.jshbps.jp/en/guideline/tg13.
html.
Keywords Cholangitis
Percutaneous biliary drainage

Endoscopic biliary drainage
Endoscopic cholangio-
pancreatography
Guidelines
Introduction
Acute cholangitis varies in severity, ranging from a mild form
which can be treated by conservative therapy to a severe form
which leads to a life-threatening state, e.g. shock state and
altered sensorium. In particular, the severe form often results in
mortality in the elderly [1–3]. Biliary drainage, which is the
most essential therapy for acute cholangitis, is divided into
three types, surgical, percutaneous transhepatic, and endo-
scopic drainage. Of these therapies, it is well known that sur-
gical intervention leads to the highest mortality rate [1].
Recently, mortality due to acute cholangitis has decreased due
to development of percutaneous transhepatic cholangial
drainage (PTCD) [4] and endoscopic biliary drainage [5, 6].
Nevertheless, acute cholangitis can still be fatal unless it is
treated in a timely way. The Tokyo Guidelines of 2007 (TG07)
described the fundamental biliary drainage techniques for acute
cholangitis [7]. Subsequently, new biliary drainage techniques
for the therapy of acute cholangitis have been reported. Herein,
we describe the indications and techniques of biliary drainage
for acute cholangitis in the updated Tokyo Guidelines (TG13).
Indications and techniques of biliary drainage
In TG13, biliary drainage is recommended for acute cho-
langitis regardless of degree of severity other than some
H. Gomi
Center for Clinical Infectious Diseases, Jichi Medical University,
Tochigi, Japan
Y. Kimura
Department of Surgical Oncology and Gastroenterological
Surgery, Sapporo Medical University School of Medicine,
Sapporo, Japan
R. Higuchi
Department of Surgery, Institute of Gastroenterology, Tokyo
Women’s Medical University, Tokyo, Japan
123
J Hepatobiliary Pancreat Sci (2013) 20:71–80
cases of mild acute cholangitis in which antibiotics and
general supportive care are effective.
Q1. What is the most preferable biliary drainage?
endoscopic vs percutaneous vs surgical drainage for
acute cholangitis?
We recommend endoscopic biliary drainage for acute
cholangitis (recommendation 1, level B).
We suggest that percutaneous transhepatic biliary
drainage may be considered as alternative
methods when endoscopic biliary drainage is difficult
(recommendation 2, level C).
Endoscopic drainage should be considered the first-choice
drainage procedure because several studies have described it
as less invasive than other drainage techniques [7–11].
Percutaneous transhepatic cholangial drainage
(supplement video 1)
Indications
Nowadays, percutaneous transhepatic cholangial drainage
(PTCD), also known as percutaneous transhepatic biliary
drainage (PTBD), has become the second choice of therapy
for acute cholangitis following endoscopic drainage
because of possible complications, including intraperito-
neal hemorrhage and biliary peritonitis, and the need for a
long hospital stay. However, PTCD can still be conducted
in any of the following circumstances: (1) in patients with
an inaccessible papilla due to upper GI tract obstruction, as
in duodenal obstruction or surgically altered anatomy like
Whipple resection or Roux-en-Y anastomosis, in which the
passage of endoscope or endoscopic drainage is thought to
be difficult or impossible; (2) when skilled pancreaticob-
iliary endoscopists are not available in the institution.
Furthermore, even in patients with non-surgically altered
anatomy, PTCD can be salvage therapy when conventional
endoscopic drainage has failed. In general, coagulopathy is
a relative contraindication. However, if there is no other
life-saving method, PTCD would be indicated.
Techniques
Before the prevalence of transabdominal ultrasonography,
needle puncture of the bile duct was conducted under
fluoroscopy [4]. Currently, needle puncture is safely per-
formed under ultrasonography to avoid the intervening
blood vessel [12]. Therefore, in the current PTCD proce-
dure, operators should continuously observe the bile duct
using ultrasonography regardless of the presence of
J Hepatobiliary Pancreat Sci (2013) 20:71–80
dilation. The PTCD procedure is performed as follows, and
as previously described [4]. Briefly, at first, ultrasonogra-
phy-guided transhepatic puncture of the intrahepatic bile
duct is conducted using an 18- to 22-G needle. After
confirming backflow of bile, a guidewire is advanced into
the bile duct. Finally, a 7- to 10-Fr catheter is placed in the
bile duct under fluoroscopic control over the guidewire.
Puncture using a small-gauge (22-G) needle is safer in
patients without biliary dilation than with biliary dilation.
According to the Quality Improvement Guidelines pro-
duced by American radiologists, the success rates of
drainage are 86 % in patients with biliary dilation and
63 % in those without biliary dilation [12].
Surgical drainage
Indications
In benign diseases like bile duct stones, surgical drainage is
extremely rare because of the prevalence of endoscopic
drainage or PTCD for the therapy of acute cholangitis.
However, in patients with acute cholangitis due to unre-
sectable neoplasms like cancer of the pancreatic head,
hepaticojejunostomy can be performed as bypass surgery
only in limited patients without severe acute cholangitis. In
particular, when periampullary neoplastic lesions like
cancer of the pancreatic head or ampullary cancer, show
both acute cholangitis and duodenal obstruction, double
bypass surgery, hepaticojejunostomy and gastrojejunos-
tomy, may be a rare choice.
Techniques
Open drainage for decompression of the bile duct is per-
formed as a surgical intervention. When surgical drainage
in critically ill patients with bile duct stones is performed,
prolonged operations should be avoided and simple pro-
cedures, such as T-tube placement without choledocholi-
thotomy, are recommended [13].
Endoscopic biliary drainage
Indications
Endoscopic transpapillary biliary drainage has become the
gold standard technique for acute cholangitis, regardless of
whether the pathology is benign or malignant, because it is a
minimally invasive drainage method [4]. On the other hand,
endoscopic drainage using a standard duodenoscope in pati-
ents with duodenal obstruction and surgically altered anatomy,
like Roux-en-Y anastomosis, seems to be contraindicated.
73
The timing of endoscopic biliary drainage is very
important for the clinical outcome. Khashab et al. [14]
described that delayed (more than 72 h after administration)
and unsuccessful ERCP are associated with worse outcomes
in patients with acute cholangitis. Actually, in TG07, two
thirds of outstanding pancreatobiliary surgeons and endos-
copists supported the use of emergent or early drainage in
patients with moderate or severe cholangitis [15].
Techniques
Biliary cannulation
Biliary cannulation should be conducted in advance of
biliary drainage. Basically, there are two biliary cannula-
tion techniques, namely contrast medium-guided cannula-
tion (standard cannulation) and wire-guided cannulation.
Q2. What technique should be used for biliary
cannulation? Standard cannulation or wire-guided
cannulation?
We suggest that either standard cannulation or wire-guided
cannulation can be considered for bile duct access
(recommendation 2, level B).
Two meta-analyses of a randomized controlled trial (RCT)
on the comparison between standard cannulation and wire-
guided cannulation showed that wire-guided cannulation
was able to increase the successful biliary cannulation rate
and prevent post-ERCP pancreatitis [16, 17]. Recently,
however, two RCTs have shown that there is no statisti-
cally significant difference between standard cannulation
and wire-guided cannulation on the success rate of biliary
cannulation or the prevention rate of post-ERCP pancrea-
titis [18, 19]. Therefore, the choice of techniques for biliary
cannulation is still controversial.
When biliary cannulation using standard cannulation or
wire-guided cannulation techniques fails, precutting, which
means an incision of the papilla enabling the bile duct
orifice to be opened for biliary cannulation, may be per-
formed if an alternative method, like PTCD or surgical
intervention, is not performed. In the main, two types of
precutting methods are used. Needle knife precutting using
needle-type sphincterotome is well known as a basic pre-
cutting method (Fig. 1a). Alternatively, several endosco-
pists prefer pancreatic sphincter precutting using a pull-
type sphincterotome for biliary access (Fig. 1b). The use of
precutting methods depends on the institution and endos-
copist. It is known that precutting is likely to cause serious
complications, such as acute pancreatitis and perforation,
and therefore it should be performed only by skilled
endoscopists [20, 21].
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Fig. 1 Precutting technique. a Needle knife precutting using needle-
type sphincterotome. Bile duct orifice is opened by precutting.
b Schema of pancreatic sphincter precutting. Cutting wire is bowed
toward the bile duct direction
Endoscopic naso-biliary drainage and endoscopic
biliary stenting
Indications
Endoscopic transpapillary biliary drainage is divided into
two types: endoscopic naso-biliary drainage (ENBD) as an
external drainage and endoscopic biliary stenting (EBS) as
an internal drainage. Although, basically, both endoscopic
biliary drainage types can be conducted in all acute
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J Hepatobiliary Pancreat Sci (2013) 20:71–80
cholangitis, they may be contraindicated in patients in
whom the endoscope cannot reach the papilla due to GI
tract obstruction or surgically altered anatomy, or in whom
endoscopic procedures are inadequate because of critical
illness. In particular, ENBD should be avoided in patients
with poor compliance, who may remove the tube, and those
with abnormalities of the nasal cavity causing difficulty in
naso-biliary tube insertion.
In the case of biliary drainage for therapy of acute
cholangitis, skillful endoscopic technique is mandatory
because long and unsuccessful procedures may lead to
serious complications in critical ill patients. Therefore,
endoscopists who perform endoscopic biliary drainage in
these patients, should already have a high success rate of
biliary cannulation including the precutting technique.
Q3. What procedure should be used for endoscopic
biliary drainage? ENBD or EBS?
We suggest that either ENBD or EBS may be considered
for biliary drainage (recommendation 2, level B).
Three comparative studies have shown that there is no
statistically significant difference in technical success,
clinical success, complications and mortality between
ENBD and EBS, although a visual analogue scale was
higher in the ENBD group than in the EBS group
(Table 1) [22–24]. In consequence of these results, TG13
suggests that either drainage procedure can be selected
according to the preference of the endoscopist. However,
if ENBD is selected for the treatment of acute cholan-
gitis, we should bear in mind that if the patient has
discomfort from the transnasal tube placement, they are
likely to remove the tube themselves, especially elderly
patients.
One RCT has revealed that biliary drainage is not
mandatory after endoscopic clearance of the common bile
duct in patients with choledocholithiasis-induced cholan-
gitis (level B) [25].
Techniques
ENBD (supplement video 2)
ENBD procedures are described in detail in TG07 [4].
Briefly, after selective biliary cannulation, a 5-Fr to 7-Fr
tube is placed in the bile duct as an external drainage over
the guidewire (Fig. 2a).
EBS (supplement video 3)
EBS procedures is also described in the previous guideline
[4]. In brief, after selective biliary cannulation, a 7- to
J Hepatobiliary Pancreat Sci (2013) 20:71–80 75

Table 1 Comparison of results between ENBD and stent placement in acute cholangitis cases
References Method n RCT Technical success (%) Clinical success (%) VAS Adverse events (%) Mortality rate (%)

Lee [22] ENBD 40 100 85–100 3.9 (2.7) 5 2.5

Yes p = 0.02
EBS 34 98 82–92a 1.8 (2.6) 0 12
Sharma [23] ENBD 74 99 100 0 2.7
Yes N/A
EBS 73 98 100 0 2.7
Park [24] ENBD 41 100 86–100b 32 0
No N/A
EBS 39 100 80–100b 39 0
ENBD endoscopic naso-biliary drainage, EBS endoscopic biliary stenting, RCT randomized controlled trial, VAS visual analog scale [mean
(SD)], N/A not applicable
a
Including pain, fever, and jaundice
b
Including pain, fever, altered sensorium, hypotension, and renal failure

10-Fr plastic stent is placed in the bile duct as an internal
drainage over the guidewire. There are two different stent
shapes, a straight type with a single flap with a sidehole
(Amsterdam type) (Fig. 2b) or radial flaps without a side-
hole (Tannenbaum type) on both sides, and a double pig-
tail type to prevent inward and outward stent migration.
There is no comparative study between straight type and
pig-tail type stents. Therefore, either stent can be selected
according to the preference of the endoscopist.
Treatment of the major papilla
Endoscopic sphincterotomy (EST)
Indications
EST technique is usually used for stone removal and, at
times, prevention of the occlusion of the pancreatic duct
orifice by placement of a large-bore biliary stent (more than
10-Fr or a self-expandable metal stent).
Q4. Is EST necessary in endoscopic biliary drainage?
We suggest that addition of EST should be determined
according to the patient’s condition and the operator’s
skill (recommendation 2, level C).
We suggest that EST followed by stone removal without
biliary drainage can be recommended as an alternative
procedure in patients with choledocholithiasis - induced
acute cholangitis (recommendation 2, level C).
As TG07 described, an additional EST is not necessary in
acute cholangitis as follows: (1) additional EST causes
complications such as hemorrhage [26, 27]; (2) post-EST
hemorrhage is one of the risk factors of acute cholangitis
[20]. In particular, the use of EST in patients with severe
(grade III) disease complicated by coagulopathy should be
avoided. Nevertheless, EST has some advantages as fol-
lows: (1) it provides not only drainage but also clearance of
bile duct stones at a single session in patients with cho-
ledocholithiasis (not complicated by severe cholangitis).
(2) Precutting can allow bile duct access, providing biliary
drainage in patients in whom selective biliary cannulation
is impossible using the standard cannulation technique. In
particular, stone removal in one session can shorten the
hospital stay. Therefore, TG13 suggests that addition of
EST should be determined according to the patient’s con-
dition and the operator’s skill.
Techniques
The detail of EST procedures is described in TG07 [4].
Briefly, after selective biliary cannulation with or without a
guidewire, a pull-type sphincterotomy incision is per-
formed below the transverse fold (Fig. 3). When the
transverse fold is not present, the superior margin of the
papilla bulge is used as a landmark to determine the length
of the sphincterotomy (supplement video 4). An electro-
surgical generator with a controlled cutting system
(Endocut mode, ICC200, VIO300, ERBE Elektromedizin
GmbH, Tubingen, Germany) is used for EST; the push-
type is used for EST in patients with Billroth II gastrec-
tomy or Roux-en-Y anastomosis. Only a limited incision is
necessary in EST for drainage purposes using a large-bore
stent, unlike that for stone removal [10]. Endoscopists
should remember that EST may cause acute pancreatitis or
cholangitis, which may become life-threatening when
severe [20].

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Fig. 2 Endoscopic biliary drainage. a Endoscopic naso-biliary
drainage. b Endoscopic biliary stenting. A 7-Fr plastic stent is placed
after performing EST and pus comes from the bile duct
Endoscopic papillary balloon dilation (EPBD)
Indications
The EPBD procedure is usually used instead of EST for
removal of bile duct stones [28]. Until now, there has been
no comparative study on the use of EPBD during biliary
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J Hepatobiliary Pancreat Sci (2013) 20:71–80
Fig. 3 Endoscopic sphincterotomy. A pull-type sphincterotomy
incision was performed below the transverse fold
drainage to treat acute cholangitis due to bile duct stones.
EPBD, like EST, has the advantage of reducing the number
of therapeutic sessions and shortening the hospital stay in
patients with acute cholangitis caused by bile duct stones.
One systematic review revealed that EPBD is statistically
less successful for stone removal, requires higher rates of
mechanical lithotripsy, and carries a higher risk of pan-
creatitis, although it also has statistically significant lower
rates of bleeding [29]. Thus, TG13 suggests that EPBD
appears to be useful for treatment in patients who have
coagulopathy and acute cholangitis caused by a small
stone.
On the other hand, theoretically, since the aim of EPBD
is to preserve the function of the sphincter of Oddi, EPBD
alone without biliary drainage is contraindicated for the
therapy of acute cholangitis. In addition, EPBD should be
avoided in patients with biliary pancreatitis.
Techniques
After selective biliary cannulation, a small balloon up to
8-mm in diameter, depending on the diameters of the bile
duct and the stone, is advanced into the bile duct across the
papilla. Then, the sphincter of Oddi is gradually dilated by
inflation of the balloon until the waist of the balloon dis-
appears. Then, clearance of the bile duct stone is conducted
using a basket catheter and balloon catheter.
Special techniques of endoscopic biliary drainage
Recently, several new techniques of endoscopic biliary
drainage have been developed.
J Hepatobiliary Pancreat Sci (2013) 20:71–80 77

Balloon enteroscope-assisted bile duct drainage
Indications
ERCP in patients with surgically altered anatomy can be
challenging. In general, Roux-en-Y anastomosis has been
thought to preclude endoscopic access for ERCP because of
the extensive lengths of the efferent and afferent limbs that
must be traversed to reach the major papilla or hepaticojej-
unostomy site. Recently, single balloon enteroscopy (SBE)
and double balloon enteroscopy (DBE) have enabled suc-
cessful ERCP to be performed in patients with such surgi-
cally altered anatomy. Several investigators have reported
various success rates (40 to 95 %) with adverse events rates
below 5 % (Tables 2, 3) [30–42]. However, since this
technique may be unsuccessful and time-consuming, its
indication should be cautiously decided. Although ideal
operators are those who are skilled in both balloon enteros-
copy and ERCP, in some institutions, GI endoscopists
advance an endoscope to the papilla or anastomotic site and
then pancreaticobiliary endoscopists perform ERCP.
Therefore, if the operators are not good at this technique,
therapy using balloon enteroscopy should be avoided.
Tokyo, Japan and long-type DBE: EN-450T5, short-type
DBE: EC-450B15/EI-530B, Fujifilm Co., Ltd., Saitama,
Japan), a sliding tube with a balloon and a balloon con-
troller. The DBE has a balloon at the tip of the endoscope
in addition to the balloon of the overtube. Endoscopes are
advanced to the papilla or anastomotic site using the
pushing and pulling techniques (Fig. 4a, b). An injection
catheter and a tapered catheter are used for initial cannu-
lation. First, 0.025–0.035-inch guidewires are inserted into
the bile duct. Finally, 5–8.5-Fr naso-biliary drainage
catheters and self-expandable metallic stents are placed
into the bile duct for biliary decompression. In cases
requiring an endoscopic sphincterotomy, a sphincterotome
and needle knife are advanced into the bile duct over or
alongside the guidewire. In cases of EPBD, a conventional
dilation catheter is used for the papilla or

Techniques (supplement video 5)

The SBE and DBE balloon system consists of a video

enteroscope (XSIF-Q260Y; Olympus Medical Systems,

Table 2 Outcome of single-balloon enteroscopy-assisted ERCP

References n Technical success Adverse
(1st attempt) (%) events (%)

Itoi [30] 11 72 None

Saleem [31] 56 91 None
Wang [32] 12 90 17
Total 79 89 2.50

Table 3 Outcome of double-balloon enteroscopy-assisted ERCP

(n [ 5)
References n Technical success Adverse
(1st attempt) (%) events (%)

Mehdizadeh [34] 5 40 None

Emmett [35] 14 80 None
Aabakken [36] 13 85 None
Masser [37] 9 67 None
Kuga [38] 6 83 None
Pohl [39] 15 87 None
Shimatani [40] 68 96 5
Tsujino [41] 12 94 17
Itoi [42] 9 67 None Fig. 4 Balloon enteroscope-assisted ERCP. a ERCP in esophagojej-
unostomy with Roux-en-Y patient. b ERCP in hepaticojejunostomy
Total 151 86 3.3
with Roux-en-Y patient

123
78
hepaticojejunostomy site. When selective cannulation is
not possible, a needle knife is used for pre-cutting. A
basket catheter, retrieval balloon catheter, and/or mechan-
ical lithotriptor are used for removal of stones.
Endoscopic ultrasonography-guided bile duct drainage
Indications
Recently, endoscopic ultrasonography (EUS)-guided bili-
ary drainage has been reported as a salvage therapy when
standard endoscopic drainage has failed [43–54]. Since the
technique and devices of this procedure are not yet estab-
lished and there is no dedicated device for this procedure, it
should be conducted only in selected patients in whom
standard biliary drainage by means of ERCP or PTCD has
failed or is contraindicated for various reasons like con-
siderable ascites. There are two methods of approach in
EUS-guided biliary drainage: (1) EUS-guided intrahepatic
Fig. 5 EUS-guided biliary approaches. a EUS-guided intrahepatic
bile duct approach. b EUS-guided extrahepatic bile duct approach
123
J Hepatobiliary Pancreat Sci (2013) 20:71–80
Table 4 Outcome of endosonography-guided bile duct drainage
Drainage No. of Technical Clinical Complications
cases success (%) success (%) (%)
EUS-guided HES 4 100 100 25
IHBD HGS 50 96 98 16
drainage
HJS 4 75 100 0
EUS-guided CDS 61 95 100 16
EHBD CGS 6 100 100 17
drainage
IHBD intrahepatic bile duct, EHBD extrahepatic bile duct, HES he-
paticoesophagostomy, HGS hepaticogastrostomy, HJS hepaticojejun-
ostomy, CDS choledochoduodenostomy, CGS choledochogastrostomy
bile duct drainage (Fig. 5a) by a transesophageal, trans-
gastric or transjejunal approach; (2) EUS-guided extrahe-
patic bile duct drainage (Fig. 5b) by a transduodenal or
transgastric approach. The choice of drainage route
depends on the presence of a gastric outlet obstruction and
the stricture site of the bile duct. Several published data on
EUS-guided intrahepatic bile duct drainage and extrahe-
patic bile duct drainage show that the success rate is high
(95 %), with 93–100 % (intention-to-treat) response rates
(Table 4) [43–54]. Most of the reported cases of adverse
events were pneumoperitonitis but there was no serious
adverse event. However, since the procedure is not yet
established, it should be conducted by endoscopists skilled
in both echoendosonography and ERCP.
Techniques [55] (supplement video 6 and video 7)
Theoretically, the intrahepatic bile duct and liver, including
the extrahepatic bile duct does not adhere to the GI tract.
Therefore, there is a possibility of bile leakage during the
procedure; particularly, if the procedure fails, serious bile
peritonitis can occur. A needle knife (Zimmon papillotomy
knife, or Cystotome, Wilson-Cook, Winston-Salem, NC)
catheter using electrocautery (EndoCut ICC200, VIO300D,
ERBE Elektromedizin GmbH, Tübingen, Germany), or a
19-gauge needle (EchoTip, Wilson-Cook), is advanced into
the bile duct under EUS visualization after confirming the
absence of intervening blood vessels to avoid bleeding.
After the stylet is removed, bile is aspirated and then
contrast medium is injected into the gallbladder for cho-
lecystography, then a 450 cm long, 0.025- or 0.035-inch
guidewire is advanced into the outer sheath. If necessary, a
biliary catheter for dilation (Soehendra Biliary Dilator,
Wilson-Cook), papillary balloon dilation catheter (Max-
pass, Olympus Medical Systems), and electrical cautery
needle, are used for dilation of the hepaticoenterostomy
site and choledochoenterostomy site. Finally, a 7-Fr plastic
stent or a self-expandable metal stent are advanced into the
bile duct.
J Hepatobiliary Pancreat Sci (2013) 20:71–80
Acknowledgments We are indebted to Professor J. Patrick Barron,
Chairman of the Department of International Medical Communica-
tions at Tokyo Medical University, for his editorial review of the
English manuscript.
Conflict of interest None.
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J Hepatobiliary Pancreat Sci (2013) 20:81–88
DOI 10.1007/s00534-012-0570-2
GUIDELINE
TG13 indications and techniques for gallbladder drainage
in acute cholecystitis (with videos)
Toshio Tsuyuguchi • Takao Itoi • Tadahiro Takada • Steven M. Strasberg • Henry A. Pitt • Myung-Hwan Kim
Avinash N. Supe • Toshihiko Mayumi • Masahiro Yoshida • Fumihiko Miura • Harumi Gomi •
Yasutoshi Kimura • Ryota Higuchi • Kohji Okamoto • Yuichi Yamashita • Toshifumi Gabata •
Jiro Hata • Shinya Kusachi
Published online: 11 January 2013
Ó Japanese Society of Hepato-Biliary-Pancreatic Surgery and Springer 2012
Abstract Percutaneous transhepatic gallbladder drainage
(PTGBD) is considered a safe alternative to early chole-
cystectomy, especially in surgically high-risk patients with
acute cholecystitis. Although randomized prospective
controlled trials are lacking, data from most retrospective
studies demonstrate that PTGBD is the most common
gallbladder drainage method. There are several alternatives
to PTGBD. Percutaneous transhepatic gallbladder aspira-
tion is a simple alternative drainage method with fewer
Electronic supplementary material The online version of this
article (doi:10.1007/s00534-012-0570-2) contains supplementary
material, which is available to authorized users.
T. Tsuyuguchi (&)
Department of Medicine and Clinical Oncology,
Graduate School of Medicine Chiba University,
1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan
e-mail: tsuyuguchi@faculty.chiba-u.jp
T. Itoi
Department of Gastroenterology and Hepatology,
Tokyo Medical University, Tokyo, Japan
T. Takada
F. Miura
Department of Surgery, Teikyo University School of Medicine,
Tokyo, Japan
S. M. Strasberg
Section of Hepatobiliary and Pancreatic Surgery, Washington
University in Saint Louis School of Medicine, Saint Louis, MO,
USA
H. A. Pitt
Department of Surgery, Indiana University School of Medicine,
Indianapolis, IN, USA
M.-H. Kim
Department of Internal Medicine, Asan Medical Center,
University of Ulsan, Seoul, Korea
TG13: Updated Tokyo Guidelines for acute cholangitis
and acute cholecystitis
•
complications; however, its clinical usefulness has been
shown only by case-series studies. Endoscopic naso-gall-
bladder drainage and gallbladder stenting via a transpap-
illary endoscopic approach are also alternative methods in
acute cholecystitis, but both of them have technical diffi-
culties resulting in lower success rates than that of PTGBD.
Recently, endoscopic ultrasonography-guided transmural
gallbladder drainage has been reported as a special tech-
nique for gallbladder drainage. However, it is not yet an
established technique. Therefore, it should be performed in
high-volume institutes by skilled endoscopists. Further
prospective evaluations of the feasibility, safety, and effi-
cacy of these various approaches are needed. This article
A. N. Supe
Department of Surgical Gastroenterology, Seth G S Medical
College and K E M Hospital, Mumbai, India
T. Mayumi
Department of Emergency and Critical Care Medicine,
Ichinomiya Municipal Hospital, Ichinomiya, Japan
M. Yoshida
Clinical Research Center Kaken Hospital, International
University of Health and Welfare, Ichikawa, Japan
H. Gomi
Center for Clinical Infectious Diseases, Jichi Medical University,
Shimotsuke, Tochigi, Japan
Y. Kimura
Department of Surgical Oncology and Gastroenterological
Surgery, Sapporo Medical University School of Medicine,
Sapporo, Japan
R. Higuchi
Department of Surgery, Institute of Gastroenterology, Tokyo
Women’s Medical University, Tokyo, Japan
123
82
describes indications and techniques of drainage for acute
cholecystitis.
Free full-text articles and a mobile application of TG13
are available via http://www.jshbps.jp/en/guideline/tg13.html.
Keywords Acute cholecystitis
Gallbladder drainage

Endoscopic ultrasound
Percutaneous transhepatic
gallbladder drainage (PTGBD)
Endoscopic
naso-gallbladder drainage (ENGBD)
Introduction
The Tokyo Guidelines (TG07) defined diagnostic criteria
and severity assessment of acute cholecystitis in January
2007[1]. In the TG07, percutaneous transhepatic gallblad-
der drainage (PTGBD) should be used in patients with
grade II (moderate) cholecystitis only when they do not
respond to conservative treatment and for patients with
grade III (severe) disease [2]. One controlled study (level
C) [3] compared PTGBD with medical treatment alone and
did not find lower mortality using PTGBD, but this study
has several serious limitations as follows; (1) selection bias
[the PTGBD group had many intensive care unit (ICU)
patients] , (2) drainage methods were changed after a fatal
complication, (3) randomization was achieved using a
playing card and was not blinded. Thus, PTGBD, which
has been endorsed by many studies of case-series but not
by proper controlled trials (level C) [4–14], is the most
common gallbladder drainage method for elderly and
critically ill patients. There are several alternatives to
PTGBD. Percutaneous transhepatic gallbladder aspiration
(PTGBA) is an alternative in which the gallbladder con-
tents are puncture-aspirated without placing a drainage
catheter (level C) [6, 15]. Endoscopic naso-biliary gall-
K. Okamoto
Department of Surgery, Kitakyushu Municipal Yahata Hospital,
Kitakyushu, Japan
Y. Yamashita
Department of Gastroenterological Surgery, Fukuoka University
School of Medicine, Fukuoka, Japan
T. Gabata
Department of Radiology, Kanazawa University Graduate
School of Medical Science, Kanazawa, Japan
J. Hata
Department of Endoscopy and Ultrasound, Kawasaki Medical
School, Okayama, Japan
S. Kusachi
Department of Surgery, Toho University Medical Center Ohashi
Hospital, Tokyo, Japan
123
J Hepatobiliary Pancreat Sci (2013) 20:81–88
bladder drainage (ENGBD) and endoscopic gallbladder
stenting (EGBS) are also alternatives via the transpapillary
route [16]. With the recent improvement in endoscopic
ultrasound (EUS), EUS-guided gallbladder drainage is
performed via the antrum of the stomach and the bulbus of
the duodenum [16]. However, these alternatives are not
fully examined; PTGBD is still recognized as a standard
drainage method.
In this article, we describe the indication and details of
gallbladder drainage for acute cholecystitis, and show the
grades of recommendation for the procedures established
by the Guidelines.
Q1. What are the standard gallbladder drainage
methods for surgically unfit patients with acute
cholecystitis?
PTGBD is an essential technique for non-surgical gallbladder
drainage. Thus, we recommend PTGBD for surgically unfit
patients with acute cholecystitis (recommendation 1, level B).
We recommend PTGBD as a standard drainage method
according to the GRADE system [17]. Factors that affect
the strength of a recommendation are summarized in
Table 1.
Indications and significance of PTGBD
Although early cholecystectomy, a one-shot definitive
treatment for acute cholecystitis, remains the reference
standard, perioperative mortality rates in elderly or criti-
cally ill patients are reported to be high (up to 19 %) [18].
Therefore, PTGBD is considered a safe alternative, espe-
cially in surgically high-risk populations. There is no doubt
that PTGBD with administration of antibiotics can convert
a septic cholecystitis into a non-specific condition. From a
technical point of view, it is a rather uncomplicated pro-
cedure with a low complication rate reported to range from
0 to 13 % [4–12]. A systematic review [18] reports that
30-day or in-hospital mortality after PTGBD is high
(15.4 %), but that procedure-related mortality is low
(0.36 %). Of note, mortality is predominantly related to the
severity of the underlying disease rather than the ongoing
gallbladder sepsis. By contrast, mortality rates after cho-
lecystectomy in elderly patients with acute cholecystitis
have been lower than those of previous years (prior to 1995
vs. after 1995, 12.0 vs. 4.0 %) [18]. Recent advances in
anesthesiology and perioperative care may have improved
the outcomes of cholecystectomy for critically ill patients.
There are no controlled studies evaluating the outcomes of
J Hepatobiliary Pancreat Sci (2013) 20:81–88
Table 1 A critical comparison of drainage methods for acute cholecystitis according to GRADE system [17]
Drainage methoda Factors that affect the strength of a recommendation
Quality The balance between
of evidence desirable and undesirable effects
PTGBD B (moderate) Very good
PTGBA C (low) Good (insufficient drainage effect)
ENGBD/EGBS C (low) Good (low success rate)
Surgical cholecystostomy C (low) Good (surgical risk)
a
See details in each section
PTGBD versus early cholecystectomy. A few papers report
comparative studies in a well-defined patient group.
Melloul et al. [19] analyzed a matched case-controlled
study of critically ill patients with acute cholecystitis. A
series of 42 consecutive patients at a single ICU center
during a 7-year period were retrospectively analyzed.
Surgery was associated with an increased complication
rate of 47 % compared with PTGBD (8.7 %), but mor-
tality rates were not different. One Spanish retrospective
study [20] compared mortality rates in 62 consecutive
patients critically ill with acute cholecystitis divided
between a PTGBD group and a cholecystectomy group,
and they found a significantly higher mortality rate in the
PTGBD group (17.2 vs. 0 %). This study, however, has
several limitations: the study design is not prospective,
inclusion criteria in the PTGBD group may have selection
bias because the highest-risk patients could have been
treated mainly by PTGBD. These biases and shortcomings
in the study design make any comparison between the
outcomes of PTGBD and early cholecystectomy hazard-
ous. Therefore, it is not possible to make definitive rec-
ommendations regarding treatment using PTGBD or
cholecystectomy in elderly or critically ill patients with
acute cholecystitis. Large multicenter randomized trials of
PTGBD versus early cholecystectomy are undoubtedly
needed to resolve these controversies.
Optimal timing of gallbladder drainage
For patients with moderate (grade II) disease, gallbladder
drainage should be used only when a patient does not
respond to conservative treatment. For patients with severe
(grade III) disease, gallbladder drainage is recommended
with intensive care. One prospective study [21] shows that
predictors for failure of conservative treatment are: age
above 70 years old, diabetes, tachycardia and a distended
gallbladder at admission. Likewise, WBC [15000 cell/ll,
an elevated temperature and age above 70 years old were
found to be predictors for the failure of conservative
treatment at 24-h and 48-h follow-up.
83
Technical Patient values Cost
difficulty and preferences
No Yes Low cost
No No Very low cost
Yes (difficult) Yes/no Low cost
No Yes High cost
Procedures for gallbladder drainage
Percutaneous transhepatic gallbladder drainage
(Video 1)
PTGBD is a standard technique for nonoperative gall-
bladder drainage. After ultrasound-guided transhepatic
gallbladder puncture has been performed with an 18-G
needle, a 6- to 10-Fr pigtail catheter is placed in the gall-
bladder, using a guidewire under fluoroscopy (Seldinger
technique; Fig. 1). There was no technical difficulty and
the technique could be available around the world
(Table 1). However, it has several disadvantages as fol-
lows: (1) the drainage tube cannot be extracted until a
fistula forms around the tube, (2) there is a risk of
dislocation of the tube, (3) patient discomfort may cause
self-decannulation of the PTGBD tube.
Percutaneous transhepatic gallbladder aspiration
PTGBA is a method to aspirate bile via the gallbladder
with a small-gauge needle under ultrasonographic guidance
(Fig. 2). This method is an easy low-cost bedside-appli-
cable procedure, without the patient discomfort seen in
PTGBD (Table 1). Theoretically, the drainage effect of
single PTGBA is lower than that of PTGBD as described in
a randomized controlled trial (RCT) [12]. However,
repetitive PTGBA [6, 15] can improve its effectiveness
(from 71.1 to 95.6 %) and this methodology has not been
compared with PTGBD. Although PTGBA with a small-
gauge (21-G) needle has a lower risk of leakage after
removal, aspiration of highly viscous bile is difficult with
such needles and should be conducted while washing with
saline containing antibiotics.
Endoscopic transpapillary gallbladder drainage
Endoscopic naso-biliary gallbladder drainage (Video 2)
ENGBD can be used for patients with severe comorbid
conditions, especially those with end-stage liver disease, in
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84 J Hepatobiliary Pancreat Sci (2013) 20:81–88

Fig. 1 Percutaneous
transhepatic gallbladder
drainage (PTGBD) procedure.
A guidewire is inserted into the
gallbladder after a needle is
inserted into the gallbladder
(left). Then a drainage tube is
passed over the guide-wire into
the gallbladder (right)

Fig. 2 Percutaneous
transhepatic gallbladder
aspiration (PTGBA) procedure.
Under ultrasound guidance, the
gallbladder is punctured
transhepatically by a needle
(left). Then bile is aspirated by
using a syringe (right)

Fig. 3 Endoscopic nasobiliary

gallbladder drainage (ENGBD)
procedure. Left Schema of
ENGBD. Right X-ray shows
nasobiliary catheter placed in
the gallbladder

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J Hepatobiliary Pancreat Sci (2013) 20:81–88
Fig. 4 Endoscopic gallbladder
stenting (EGBS) procedure. Left
Schema of EGBS. Right X-ray
shows double-pig tail stent
placed in the gallbladder
whom the percutaneous approach is difficult to perform.
However, because it requires a difficult endoscopic tech-
nique (technical success rate varies from 64 to 100 %), and
relevant case-series studies have been conducted only at a
limited number of institutions [22–28], ENGBD has not yet
been established as a standard method. Therefore, it should
be performed in high-volume institutes by skilled
endoscopists.
ENGBD involves placement of a naso-gallbladder
drainage tube and generally does not require biliary
sphincterotomy. After successful bile duct cannulation, a
0.035-in. guidewire is advanced into the cystic duct and
subsequently into the gallbladder. At times, a hydrophilic
guidewire is useful for seeking the cystic duct. Finally, a
5–8.5 Fr pigtail naso-gallbladder drainage tube catheter is
placed into the gallbladder (Fig. 3).
Endoscopic transpapillary gallbladder stenting
Since endoscopic transpapillary gallbladder stenting
(EGBS) requires a difficult endoscopic technique, and
relevant case-series studies have been conducted only at a
limited number of institutions [29–36], EGBS also has
not been established as a standard method. Therefore, it
should be performed in high-volume institutes by skilled
endoscopists. The procedure is identical to ENGBD, but a
6–10-Fr diameter double pigtail stent is placed (Fig. 4).
When 10-Fr stents or a gallbladder stent and a biliary stent
85
are placed (for example in Mirizzi’s syndrome), an endo-
scopic biliary sphincterotomy is performed to prevent post-
ERCP pancreatitis.
Q2. What are the special techniques as gallbladder
drainage?
There is endoscopic ultrasonography - guided gallbladder
drainage (EUS-guided gallbladder drainage).
EUS-guided gallbladder drainage is performed via the
antrum of the stomach and bulbus of the duodenum (Fig. 5)
[16, 42]. It includes EUS-guided naso-gallbladder drainage
[37, 38] and EUS-guided gallbladder stenting [39, 44]
(Table 2). Recently one controlled study [42] showed that
EUS-GBD is comparable to PTGBD in terms of the tech-
nical feasibility and efficacy. However, EUS-guided gall-
bladder drainage has not been established as a standard
method. Therefore, they should be performed in high-
volume institutes by skilled endoscopists [37–46].
Technique of EUS-guided gallbladder drainage [16, 44]
(Video 3)
Theoretically, the gallbladder does not have adhesions to
the GI tract. Therefore, there is a possibility of bile leakage
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86 J Hepatobiliary Pancreat Sci (2013) 20:81–88

Fig. 5 EUS-guided gallbladder

approach via bulbus of the
duodenum. Left Schema of
EUS-guided gallbladder
drainage. Right X-ray shows
double-pig tail stent placed in
the gallbladder

Table 2 Outcome of endosonography-guided gallbladder drainage

References No. of NGD/ Approach Technical Clinical Complication (no. of cases)
cases Stenting route success success
(%) (%)

Baron [39] 1 PS TD 100 100 None

Kwan [37] 3 NGD TD 100 100 Bile leakage (1)a
Lee [38] 9 NGD TD 100 100 Pneumoperitoneum (1)
Takasawa [40] 1 PS TG 100 100 None
Kamata [46] 1 SEMS TD 100 100 None
Song [41] 8 PS 1TG/7TD 100 100 Bile leakage (1)a, pneumoperitoneum (1),
stent migration (1)
Itoi [42] 2 PS 1TG/1TD 100 100 Bile leakage (1)a
Jang [43] 15 SEMS 10TG/5TD 100 100 None
Itoi [44] 5 SEMS 1TG/4TD 100 100 None
Jang [45] 30 NGD NA 97 100 Pneumoperitoneum (2)
SEMS self-expandable metal stent, PS plastic stent, NGD naso-gallbladder drain, TD transduodenal approach, TG transgastric approach, NA not
available
a
Minor bile leakage without serious bile peritonitis

during the procedures; in particular, if the procedure fails,
serious bile peritonitis can occur. The choice of endoscope
position is important to accomplish the procedure safely.
The gallbladder is visualized from the duodenal bulb or the
antrum of the stomach using a curved linear array
echoendoscope in a long scope position (pushing scope
position) (Fig. 5). At this time, the direction of the EUS
probe is toward the right side of the body. A needle knife
(Zimmon papillotomy knife, or Cystotome, Wilson-Cook,
Winston-Salem, NC, USA) catheter using electrocautery,
or a 19-gauge needle (EchoTip, Wilson-Cook), is advanced
into the gallbladder under EUS visualization after con-
firming the absence of intervening blood vessels to avoid
bleeding. After the stylet has been removed, first bile is
aspirated and then contrast medium is injected into the
gallbladder for cholecystography, then a 0.025- or 0.035-in.
guidewire is advanced into the outer sheath. If necessary, a
biliary catheter for dilation (Soehendra Biliary Dilator,
Wilson-Cook), or papillary balloon dilation catheter
(Maxpass, Olympus Medical Systems) are used for dilation
of the gastrocholecystic and duodenocholecystic fistula.
Finally, a 5-10 Fr naso-gallbladder tube is advanced via the
cholecystogastrostomy and cholecystoduodenostomy site
into the gallbladder. The basic procedure of EUS-guided
gallbladder stenting is the same as EUS-guided naso-
gallbladder drainage. A 7-10Fr double pigtail plastic or
self-expanding metallic stent is placed in the final step.
There have been 9 retrospective and 1 prospective
analyses on 3 EUS-guided naso-gallbladder drainages and
7 EUS-guided gallbladder stentings (4 plastic stent, 3 self-
expanding metal stent) (Table 2). The success rates and
response rates of both procedures were approximately

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J Hepatobiliary Pancreat Sci (2013) 20:81–88
100 %, but the incidence of accidents was fairly high
(11–33 %), indicating the necessity for further investiga-
tions emphasizing safety evaluation. There are several
possible procedure-related early adverse events, e.g., bile
leakage, stent migration into the gallbladder or intra-
abdominal space, deviation of stent from the gallbladder,
puncture-induced hemorrhage, and perforation of perito-
neum. Late adverse events include relapse of acute chole-
cystitis due to stent occlusion, and inadvertent tube
removal.
Conflict of interest None.
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J Hepatobiliary Pancreat Sci (2013) 20:89–96
DOI 10.1007/s00534-012-0567-x
GUIDELINE
TG13 surgical management of acute cholecystitis
Yuichi Yamashita • Tadahiro Takada • Steven M. Strasberg • Henry A. Pitt • Dirk J. Gouma •
O. James Garden • Markus W. Büchler • Harumi Gomi • Christos Dervenis • John A. Windsor •
Sun-Whe Kim • Eduardo de Santibanes • Robert Padbury • Xiao-Ping Chen • Angus C. W. Chan •
Sheung-Tat Fan • Palepu Jagannath • Toshihiko Mayumi • Masahiro Yoshida • Fumihiko Miura •
Toshio Tsuyuguchi • Takao Itoi • Avinash N. Supe
Published online: 11 January 2013
Ó Japanese Society of Hepato-Biliary-Pancreatic Surgery and Springer 2012
Abstract
Background Laparoscopic cholecystectomy is now
accepted as a surgical procedure for acute cholecystitis
when it is performed by an expert surgeon. There are
several lines of strong evidence, such as randomized con-
trolled trials (RCTs) and meta-analyses, supporting the
introduction of laparoscopic cholecystectomy for patients
with acute cholecystitis. The updated Tokyo Guidelines
2013 (TG13) describe the surgical treatment for acute
cholecystitis according to the grade of severity, the timing,
Y. Yamashita (&)
Department of Gastroenterological Surgery, Fukuoka University
Hospital, Fukuoka University School of Medicine,
7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
e-mail: yuichiya@fukuoka-u.ac.jp
T. Takada
F. Miura
Department of Surgery, Teikyo University School of Medicine,
Tokyo, Japan
S. M. Strasberg
Section of Hepatobiliary and Pancreatic Surgery,
Washington University in Saint Louis School of Medicine,
Saint Louis, MO, USA
H. A. Pitt
Department of Surgery, Indiana University School of Medicine,
Indianapolis, IN, USA
D. J. Gouma
Department of Surgery, Academic Medical Center,
Amsterdam, The Netherlands
O. J. Garden
Clinical Surgery, The University of Edinburgh, Edinburgh, UK
M. W. Büchler
Department of Surgery, University of Heidelberg,
Heidelberg, Germany
TG13: Updated Tokyo Guidelines for acute cholangitis
and acute cholecystitis
and the procedure used for cholecystitis in a question-and-
answer format using the evidence concerning surgical
management of acute cholecystitis.
Methods and materials Forty-eight publications were
selected for a careful examination of their full texts, and the
types of surgical management of acute cholecystitis were
investigated using this evidence. The items concerning the
surgical management of acute cholecystitis were the opti-
mal surgical treatment for acute cholecystitis according to
H. Gomi
Center for Clinical Infectious Diseases, Jichi Medical University,
Tochigi, Japan
C. Dervenis
First Department of Surgery, Agia Olga Hospital,
Athens, Greece
J. A. Windsor
Department of Surgery, The University of Auckland,
Auckland, New Zealand
S.-W. Kim
Department of Surgery, Seoul National University College
of Medicine, Seoul, Korea
E. de Santibanes
Department of Surgery, Hospital Italianio,
University of Buenos Aires, Buenos Aires, Argentina
R. Padbury
Division of Surgical and Specialty Services,
Flinders Medical Centre, Adelaide, Australia
X.-P. Chen
Department of Surgery, Hepatic Surgery Centre,
Tongji Hospital, Tongi Medical College, Huazhong Universty
of Science and Technology, Wuhan, China
123
90
the grade of severity, optimal timing for the cholecystec-
tomy, surgical procedure used for cholecystectomy, opti-
mal timing of the conversion of cholecystectomy from
laparoscopic to open surgery, and the complications of
laparoscopic cholecystectomy.
Results There were eight RCTs and four meta-analyses
concerning the optimal timing of the cholecystectomy.
Consequently, it was found that cholecystectomy is pref-
erable early after admission. There were three RCTs and
two meta-analyses concerning the surgical procedure,
which concluded that laparoscopic cholecystectomy is
preferable to open procedures. Literature concerning the
surgical treatment according to the grade of severity could
not be quoted, because there have been no publications on
this topic. Therefore, the treatment was determined based
on the general opinions of professionals.
Conclusion Surgical management of acute cholecystitis
in the updated TG13 is fundamentally the same as in the
Tokyo Guidelines 2007 (TG07), and the concept of a critical
view of safety and the existence of extreme vasculobiliary
injury are added in the text to call the surgeon’s attention
to the need to reduce the incidence of bile duct injury.
Free full-text articles and a mobile application of TG13
are available via http://www.jshbps.jp/en/guideline/tg13.
html.
Keywords Acute cholecystitis
Laparoscopic
cholecystectomy
Cholecystostomy
Bile duct injury

Gallbladder drainage
Introduction
Cholecystectomy has been widely used as a surgical
procedure for acute cholecystitis. There have been several
A. C. W. Chan
Department of Surgery, Surgery Centre, Hong Kong Sanatorium
and Hospital, Hong Kong, Hong Kong
S.-T. Fan
Department of Surgery, The University of Hong Kong,
Queen Mary Hospital, Hong Kong, Hong Kong
P. Jagannath
Department of Surgical Oncology, Lilavati Hospital and
Research Centre, Mumbai, India
T. Mayumi
Department of Emergency and Critical Care Medicine,
Ichinomiya Municipal Hospital, Ichinomiya, Japan
M. Yoshida
Clinical Research Center Kaken Hospital, International
University of Health and Welfare, Ichikawa, Japan
123
J Hepatobiliary Pancreat Sci (2013) 20:89–96
studies on the timing of cholecystectomy beginning in the
era of open surgery and also in the current era of lapa-
roscopic surgery. These studies have shown that early
surgery conducted within 72–96 h after the onset of
symptoms is associated with advantages such as reduced
hospital stay, sick leave, and health care expenditures, and
no disadvantages with regard to mortality and morbidity.
Since the initial introduction of laparoscopic cholecys-
tectomy, it has been considered to be contraindicated for
acute cholecystitis. However, due to the establishment of
the critical view of safety introduced by Strasberg et al.
[1] for the dissection of Calot’s triangle, the development
of new techniques, and the improvements made to the
instruments used for endoscopic surgery, laparoscopic
cholecystectomy is now accepted as a safe surgical
technique when it is performed by expert surgeons.
Recent randomized clinical trials and meta-analyses have
indicated that laparoscopic cholecystectomy is preferable
to open cholecystectomy.
In 2007, the Tokyo Guidelines for the management of
acute cholangitis and cholecystitis [2] were published in
the Journal of Hepato-Biliary-Pancreatic Surgery, in
which a severity classification was presented for the first
time. Previously, there was no severity classification for
acute cholecystitis. There were therefore no reports of the
effects of surgical treatment or gallbladder drainage
according to the severity of acute cholecystitis. Conse-
quently, the treatment methods were determined based on
the general opinions of professionals. Four years have
passed since the publication of the Tokyo Guidelines 2007
[2], but there are still no reliable reports of the optimal
treatment for each severity grade of acute cholecystitis.
The therapeutic strategy for acute cholecystitis is presented
here in the question-and-answer format prepared in the
revision of TG07 [2] while referring to recent reports.
T. Tsuyuguchi
Department of Medicine and Clinical Oncology, Graduate
School of Medicine, Chiba University, Chiba, Japan
T. Itoi
Department of Gastroenterology and Hepatology,
Tokyo Medical University, Tokyo, Japan
A. N. Supe
Department of Surgical Gastroenterology, Seth G S Medical
College and K E M Hospital, Mumbai, India
J Hepatobiliary Pancreat Sci (2013) 20:89–96
Q1. What is the optimal surgical treatment for acute
cholecystitis according to the grade of severity?
We recommend the optimal treatment according to the grade
of severity as follows;
Grade I (Mild) acute cholecystitis: Early
laparoscopic cholecystectomy is the preferred procedure.
Grade II (Moderate) acute cholecystitis: Early cholecystectomy
is recommended in experienced centers. However, if
patients have severe local inflammation, early gallbladder
drainage (percutaneous or surgical) is indicated. Because early
cholecystectomy may be difficult, medical treatment and
delayed cholecystectomy are necessary.
Grade III (Severe) acute cholecystitis: Urgent
management of organ dysfunction and management of severe
local inflammation by gallbladder drainage should be carried
out. Delayed elective cholecystectomy should be performed
when cholecystectomy is indicated.
The optimal treatment for acute cholecystitis is essen-
tially early cholecystectomy, and the use of an established
optimal surgical treatment for each grade of severity of
acute cholecystitis is necessary. Early laparoscopic chole-
cystectomy is indicated for patients with Grade I (Mild)
acute cholecystitis, because laparoscopic cholecystectomy
can be performed in most of these patients. Early laparo-
scopic or open cholecystectomy (within 72 h after the
onset of acute cholecystitis) is required in patients with
Grade II (Moderate) acute cholecystitis in experienced
centers, but for some patients with Grade II (Moderate)
acute cholecystitis, it is difficult to remove the gallbladder
surgically because of severe inflammation limited to the
gallbladder. This severe local inflammation of the gall-
bladder is defined by factors such as [72 h from the onset,
a white blood cell count [18,000, and a palpable tender
mass in the right upper abdominal quadrant. Continued
medical treatment or drainage of the contents of the
swollen gallbladder by percutaneous transhepatic gall-
bladder drainage or surgical cholecystostomy is preferable,
and a delayed cholecystectomy after the improvement of
inflammation of the gallbladder is indicated. Among
patients with Grade II (Moderate), for those with serious
local complications including biliary peritonitis, perichol-
ecystic abscess, liver abscess or for those with gallbladder
torsion, emphysematous cholecystitis, gangrenous chole-
cystitis, and purulent cholecystitis, emergency surgery is
conducted (open or laparoscopic depending on experience)
along with the general supportive care of the patient. The
urgent management of Grade III (Severe) acute cholecys-
titis is always necessary because the patients have organ
dysfunction, and the simultaneous drainage of the gall-
bladder contents is required to treat the severe
91
inflammation of the gallbladder. Delayed cholecystectomy
is required 2 to 3 months later, after the improvement of the
patients’ general condition when cholecystectomy is
indicated.
Q2. Which surgical procedure is preferred, laparo-
scopic cholecystectomy or open cholecystectomy?
We recommend that laparoscopic cholecystectomy is preferable
to open cholecystectomy (recommendation 1, level A).
Gallstones are one of the major causes of acute chole-
cystitis, and cholecystectomy is now being carried out in
many of the patients with cholecystolithiasis. Until the first
half of the 1990s, there were opinions that laparoscopic
surgery was not indicated in patients with acute cholecys-
titis [3]. Open cholecystectomy was the standard technique.
However, more recently, laparoscopic surgery has also
been introduced for acute cholecystitis, and is now gener-
ally considered to be the first option for surgery, similar to
open cholecystectomy. Several reports, including random-
ized controlled trials (RCTs) comparing laparoscopic
cholecystectomy and open cholecystectomy, have indi-
cated that laparoscopic cholecystectomy is associated with
a significantly shorter postoperative hospital stay and a
lower incidence of complications [4–7]. A meta-analysis
has also shown that laparoscopic cholecystectomy not only
resulted in treatment effects similar to those produced by
open cholecystectomy, but that it is also a useful surgical
procedure in terms of its low mortality and morbidity[8, 9].
However, the above reports have failed to examine its use
for acute cholecystitis according to the grade of severity.
Laparoscopic cholecystectomy is not recommended for all
cases of acute cholecystitis due to the possibility of patients
in whom cholecystectomy is difficult because of severe
inflammation [10].
On the other hand, there has been a change in the per-
ioperative management of open cholecystectomy patients
in the last few years, and the current management aims to
reduce postoperative pain and encourage early ambulation
and early discharge. These changes show that, in terms of
the postoperative course, open cholecystectomy with mini-
incision is able to produce as good results as those obtained
by laparoscopic cholecystectomy, although the superiority
of laparoscopic cholecystectomy as a surgical technique for
acute cholecystolithiasis can be recognized [8, 9]. In fact, a
RCT was carried out to reappraise the use of laparoscopic
cholecystectomy and open cholecystectomy by a subcostal
muscle transection incision [11]. This study indicated that
no significant differences were observed between the two
types of cholecystectomies with regard to the rate of
postoperative complications, the degree of pain at dis-
charge, the duration of sick leave, and the direct medical
123
92
cost. At the moment, laparoscopic cholecystectomy is
comprehensively preferred as the surgical treatment for
acute cholecystitis. However, the first priority is the safety
of the patients. With this in mind, open surgery can be
considered to be as effective as laparoscopic surgery.
A cohort study was carried out in a total of approxi-
mately 30,000 patients with acute cholecystitis aged
66 years or older concerning the surgical procedures for
acute cholecystitis; 75 % of those patients underwent
cholecystectomy at the time of the initial hospitalization,
with 71 % undergoing laparoscopic cholecystectomy and
29 % undergoing open surgery. The results of the analysis
showed that laparoscopic cholecystectomy is being used as
the first option for surgical procedures that can be per-
formed urgently for acute cholecystitis [12].
Q3. What is the optimal timing of cholecystectomy for
acute cholecystitis?
We recommend that it is preferable to perform cholecystectomy
soon after admission, particularly when less than 72 hours have
passed since the onset of symptoms (recommendation1, level A).
With regard to the timing of the surgery for acute cho-
lecystitis, there are several reports of RCTs conducted in
the 1970s and 1980s that compared early surgery and
elective surgery (from the initial onset until 4 months later)
by open cholecystectomy. The trials failed to find a dif-
ference between the surgical procedures in terms of the
amount of bleeding, duration of surgery, and incidence of
complications; however, they were able to show that early
surgery is preferable because it reduces the hospital stay
and leads to an early cessation of pain in the patients [12–
17]. In recent years, laparoscopic cholecystectomy has
been actively used for acute cholecystitis and the rate of its
use has been increasing every year since its introduction
[18]. The usefulness of early surgery (rather than delayed
surgery) has been indicated in RCTs [19–21] and in meta-
analyses in patients with acute cholecystitis [22–25].
However, the definition of early surgery differed in each
report, because there were different starting times for the
operations, such as onset of symptoms, time of diagnosis,
and use of randomization. Early surgery was mainly con-
ducted within 72–96 h from onset of symptoms. On the
other hand, elective surgery was performed 6 weeks or
more after the onset. Thus, the results of several reports
indicated with a high level of evidence that laparoscopic
cholecystectomy performed during the first admission was
associated with a shorter hospital stay, quicker recovery,
and reduction in overall medical costs compared to open
cholecystectomy. Early laparoscopic cholecystectomy is
now accepted to be sufficiently safe for routine use.
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J Hepatobiliary Pancreat Sci (2013) 20:89–96
After evaluating a patient’s overall condition and con-
firmation of the diagnosis by ultrasonography, computed
tomography (CT), and/or magnetic resonance cholangio-
pancreatography, the timing of the surgical management of
acute cholecystitis patients should be decided by experi-
enced surgeons. Unfortunately, early surgery is performed
less frequently than is recommended at present because of
the scarcity of surgeons [18, 26, 27]. However, the fact that
the above trials excluded patients with pan-peritonitis
caused by perforation of the gallbladder, patients with
common bile duct stones, and those with concomitant
severe cardiopulmonary disease should be kept in mind
when evaluating the results of these trials.
Additionally, each meta-analysis indicated that there
was no statistically significant difference in the incidence
of bile duct injury (BDI). However, these meta-analyses
did not include a large enough number of patients to detect
a difference, because the incidence of BDI in the laparo-
scopic era is generally less than 1.0 % [28–30]. Therefore,
it is impossible to assert that there are no significant dif-
ferences in the incidence of BDI on the basis of its fre-
quency in these meta-analyses.
Q4. When is the optimal time for conversion from
laparoscopic to open cholecystectomy?
We recommend that surgeons should never hesitate to convert
to open surgery to prevent injuries when they experience
difficulties in performing laparoscopic cholecystectomy
(recommendation 1, level C).
There is a relatively high rate of conversion from lap-
aroscopic cholecystectomy to open cholecystectomy for
acute cholecystitis because of technical difficulties, and
laparoscopic cholecystectomy is associated with a high
complication rate [10, 31]. Although preoperative factors
such as male gender, previous abdominal surgery, the
presence or history of jaundice, advanced cholecystitis, and
infectious complications are associated with a need for
conversion from laparoscopic to open cholecystectomy,
they have limited predictive ability [32–34]. Surgeons
assess patients using various factors when deciding whe-
ther or not conversion to open cholecystectomy, particu-
larly during laparoscopic cholecystectomy, is necessary.
Therefore, experience not only of the individual surgeons,
but also of the institution where the laparoscopic chole-
cystectomy is conducted, is required to successfully per-
form cholecystectomy for all patients with acute
cholecystitis.
The critical view of safety described by Strasberg et al.
[1] in 1995 is of the utmost importance (Fig. 1). Above all,
this critical view is now the ultimate principle for
J Hepatobiliary Pancreat Sci (2013) 20:89–96
Fig. 1 Creation of a critical view of safety. Calot’s triangle is
dissected free of fat and fibrous tissue and the lower end of the
gallbladder is dissected off the liver bed. It is not necessary to expose
the common bile duct. The critical view of safety is now the ultimate
standard to prevent BDI during laparoscopic cholecystectomy. Failure
to create this view is an indication for conversion to open
cholecystectomy
preventing BDI during laparoscopic cholecystectomy, and
involves conclusive identification of the indicated struc-
tures by dissection in Calot’s triangle. Surgeons who failed
to create this surgical view should consider which proce-
dure is more appropriate for conversion to define the bile
duct anatomy, i.e. conversion to open cholecystectomy or
intraoperative cholangiography.
Since conversion to open cholecystectomy to prevent
intraoperative accidents and postoperative complications is
not disadvantageous for patients, surgeons should never
hesitate to perform such a conversion when they experi-
ence difficulty while performing laparoscopic cholecys-
tectomy. A low threshold for the conversion to open
cholecystectomy is important to minimize the risk of major
complications.
Q5. When is the optimal time for cholecystectomy fol-
lowing PTGBD?
The optimal time, however, remains controversial due to a lack
of any strong evidence.
There have been no randomized controlled trials that
have examined the surgical management of patients with
acute cholecystitis undergoing percutaneous transhepatic
gallbladder drainage (PTGBD). However, PTGBD is
93
known to be an effective option in critically ill patients,
especially in elderly patients and patients with complica-
tions. Cholecystectomy is often performed following
PTGBD after an interval of several days [35, 36]. However,
performing a cholecystectomy 2 weeks later is also com-
mon [37]. Overall, early cholecystectomy following
PTGBD is preferable when the patient’s condition
improves, and if the patient has no complications. Com-
plications of PTGBD sometimes occur, such as intrahepatic
hematoma, pericholecystic abscess, biliary pleural effu-
sion, and biliary peritonitis, which may be caused by
puncture of the liver and the migration of the catheter.
However, such migration should be prevented. On the other
hand, PTGBA (percutaneous transhepatic gallbladder
aspiration) is often used by many facilities, and produces
good treatment outcomes. However, a RCT indicated that
PTGBD was superior to PTGBA in terms of its clinical
effectiveness [38].
Q6. What are the complications to be avoided that are
associated with laparoscopic cholecystectomy?
Bile duct injury, bleeding, and the injury of other organs
(level C).
Complications of laparoscopic cholecystectomy were
reported soon after its introduction, and include BDI,
intraperitoneal hemorrhage needing laparotomy, bowel
injury, and hepatic injury, as well as the commonly
observed complications associated with conventional open
cholecystectomy, such as wound infection, ileus, atelecta-
sis, deep vein thrombosis, and urinary tract infection. Bile
duct injury is considered to be a serious complication.
Bowel and hepatic injuries should also be carefully avoided
as serious complications [28]. These injuries have been
attributable to the limitations of laparoscopic procedures,
such as the narrow view and non-tactile manipulation.
Laparoscopic cholecystectomy is not always associated
with a higher incidence rate compared with open chole-
cystectomy [30–32], but any serious complication that
requires re-operation and/or prolonged hospitalization may
become a serious problem for patients, even those who
firmly believe that laparoscopic cholecystectomy is less
invasive. In spite of many improvements in the technique
and equipment, as well as the surgeon’s learning curve, the
BDI rate remains high compared to open cholecystectomy.
Table 1 shows the laparoscopic BDI rates in Japan from
biannual questionnaire surveys performed by the Japan
Society of Endoscopic Surgery (JSES) [28]. The incidence
of BDI in the laparoscopic era is higher than that in the
open cholecystectomy era, and is consistently around
0.6 %. Because of this rate, if a RCT is planned, two arms
123
94
Table 1 The complications of laparoscopic cholecystectomy in Japan [28, 48]
1990–2001 2002 2003
BDI rate (%) 0.66 0.79 0.77
Organ injury (%) 0.25 0.43 0.17
Bleeding (%) 0.65 0.72 0.72
No. of LCs 176,294 19,557 19,084
Japanese annual rates of bile duct injury, organ injury and bleeding to need laparotomy caused by laparoscopic cholecystectomy are shown
LC laparoscopic cholecystectomy
consisting of thousands of patients are required to detect
bile duct injury. There has been no RCT consisting of such
a large number of patients in individual arms. Even the
arms of the meta-analyses of RCTs were not large enough
to detect a difference. Therefore, it is possible that large
population studies would suggest that there are some
severe complications caused by laparoscopic cholecystec-
tomy, whereas smaller studies do not indicate those
problems.
We therefore performed an extensive search of the lit-
erature for all types of bile duct injury. The most extreme
bile duct injury seems to be a vasculobiliary injury
involving the major hepatic artery and portal vein. The
incidence of extreme vasculobiliary injury is approxi-
mately 2 % of the patients who sustain major biliary
injuries requiring surgical reconstruction during laparo-
scopic cholecystectomy [39]. Such an extreme vasculob-
iliary injury is more likely to occur when fundus-down
cholecystectomy is attempted in the presence of severe
inflammation of the gallbladder, usually after the conver-
sion from laparoscopic to open cholecystectomy. This
injury is caused by dissection behind the cystic plate into
the right portal pedicle. To prevent such an injury, the
surgeon involved should recognize the features of severe
inflammation, particularly severe contractive inflammation,
and refrain from using the fundus-down technique when
these symptoms are present.
Q7. When is the optimal time for cholecystectomy fol-
lowing endoscopic stone extraction of the bile duct in
patients with cholecysto-choledocholithiasis?
No definitive conclusions could be made due to the insufficient
evidence.
Combining endoscopic stone extraction (ESE) with
laparoscopic cholecystectomy during endoscopic retro-
grade cholangiography has been found to be a useful means
of treating patients with cholecysto-choledocholithiasis.
However, the optimal timing of laparoscopic cholecystec-
tomy following ESE is still a matter of controversy in
patients with acute cholecystitis. There have been several
123
J Hepatobiliary Pancreat Sci (2013) 20:89–96
2004 2005 2006 2007 2008 2009
0.66 0.77 0.65 0.58 0.54 0.62
0.17 0.22 0.14 0.14 0.20 0.20
0.72 0.69 0.56 0.58 0.52 0.55
19,067 20,203 21,550 22,599 25,174 26,140
reports including meta-analysis on combinations of ESE
and laparoscopic cholecystectomy for patients only without
acute cholecystitis. A meta-analysis report showed that
intraoperative endoscopic sphincterotomy is as effective
and safe as postoperative endoscopic sphincterotomy and
resulted in a significantly shorter hospital stay [40], and
there were some reports which mentioned that the interval
between the two procedures was a few days [41–44]. The
interval between ESE and laparoscopic cholecystectomy is
therefore left to the individual surgeon. At the moment,
early laparoscopic cholecystectomy following ESE during
the same hospital stay is preferable in some patients
without complications related to ESE.
A report of an analysis of approximately 30,000 patients
who were urgently admitted or admitted through the emer-
gency department for acute cholecystitis demonstrated that a
lack of definitive therapy was associated with a 38 % gall-
stone-related cumulative readmission rate over the subsequent
2 years [12]. This report also demonstrated that patients with
acute cholecystitis were more likely to have gallstone-related
readmission than patients who had common bile duct stones.
However, common bile duct stones are undoubtedly one of the
factors predicting readmission, including gallstone-related
pancreatitis [45–47]. Therefore, obtaining informed consent
concerning readmission is indispensable for the possible risk
for those patients who did not undergo cholecystectomy
during the initial hospitalization.
Acknowledgments We would like to express our deep gratitude to
the Japanese Society for Abdominal Emergency Medicine, the Japan
Biliary Association, the Japan Society for Surgical Infection, and the
Japanese Society of Hepato-Biliary-Pancreatic Surgery, who provided
us with great support and guidance in the preparation of these
Guidelines.
Conflict of interest None.
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J Hepatobiliary Pancreat Sci (2013) 20:97–105
DOI 10.1007/s00534-012-0565-z
GUIDELINE
TG13 miscellaneous etiology of cholangitis and cholecystitis
Ryota Higuchi • Tadahiro Takada • Steven M. Strasberg • Henry A. Pitt • Dirk J. Gouma • O. James Garden
Markus W. Büchler • John A. Windsor • Toshihiko Mayumi • Masahiro Yoshida • Fumihiko Miura •
Yasutoshi Kimura • Kohji Okamoto • Toshifumi Gabata • Jiro Hata • Harumi Gomi • Avinash N. Supe •
Palepu Jagannath • Harijt Singh • Myung-Hwan Kim • Serafin C. Hilvano • Chen-Guo Ker • Sun-Whe Kim
Published online: 11 January 2013
Ó Japanese Society of Hepato-Biliary-Pancreatic Surgery and Springer 2012
Abstract This paper describes typical diseases and
morbidities classified in the category of miscellaneous
etiology of cholangitis and cholecystitis. The paper also
comments on the evidence presented in the Tokyo Guide-
lines for the management of acute cholangitis and chole-
cystitis (TG 07) published in 2007 and the evidence
Electronic supplementary material The online version of this
article (doi:10.1007/s00534-012-0565-z) contains supplementary
material, which is available to authorized users.
R. Higuchi (&)
Department of Surgery, Institute of Gastroenterology,
Tokyo Women’s Medical University, 8-1 Kawada-cho,
Shinjuku-ku, Tokyo 162-8666, Japan
e-mail: higuchi@ige.twmu.ac.jp
T. Takada
F. Miura
Department of Surgery, Teikyo University
School of Medicine, Tokyo, Japan
S. M. Strasberg
Section of Hepatobiliary and Pancreatic Surgery,
Washington University in Saint Louis School of Medicine,
Saint Louis, MO, USA
H. A. Pitt
Department of Surgery, Indiana University School
of Medicine, Indianapolis, IN, USA
D. J. Gouma
Department of Surgery, Academic Medical Center,
Amsterdam, The Netherlands
O. J. Garden
Clinical Surgery, The University of Edinburgh,
Edinburgh, UK
M. W. Büchler
Department of Surgery, University of Heidelberg,
Heidelberg, Germany
TG13: Updated Tokyo Guidelines for acute cholangitis
and acute cholecystitis
•
reported subsequently, as well as miscellaneous etiology
that has not so far been touched on. (1) Oriental cholangitis
is the type of cholangitis that occurs following intrahepatic
stones and is frequently referred to as an endemic disease
in Southeast Asian regions. The characteristics and diag-
nosis of oriental cholangitis are also commented on. (2) TG
07 recommended percutaneous transhepatic biliary drain-
age in patients with cholestasis (many of the patients have
obstructive jaundice or acute cholangitis and present clin-
ical signs due to hilar biliary stenosis or obstruction).
J. A. Windsor
Department of Surgery, The University of Auckland,
Auckland, New Zealand
T. Mayumi
Department of Emergency and Critical Care Medicine,
Ichinomiya Municipal Hospital, Ichinomiya, Japan
M. Yoshida
Clinical Research Center Kaken Hospital, International
University of Health and Welfare, Ichikawa, Japan
Y. Kimura
Department of Surgical Oncology and Gastroenterological
Surgery, Sapporo Medical University School of Medicine,
Sapporo, Japan
K. Okamoto
Department of Surgery, Kitakyushu Municipal
Yahata Hospital, Kitakyushu, Japan
T. Gabata
Department of Radiology, Kanazawa University Graduate
School of Medical Science, Kanazawa, Japan
J. Hata
Department of Endoscopy and Ultrasound, Kawasaki Medical
School, Okayama, Japan
123
98
However, the usefulness of endoscopic naso-biliary drain-
age has increased along with the spread of endoscopic
biliary drainage procedures. (3) As for biliary tract infec-
tions in patients who underwent biliary tract surgery, the
incidence rate of cholangitis after reconstruction of the
biliary tract and liver transplantation is presented. (4) As
for primary sclerosing cholangitis, the frequency, age of
predilection and the rate of combination of inflammatory
enteropathy and biliary tract cancer are presented. (5) In
the case of acalculous cholecystitis, the frequency of
occurrence, causative factors and complications as well as
the frequency of gangrenous cholecystitis, gallbladder
perforation and diagnostic accuracy are included in the
updated Tokyo Guidelines 2013 (TG13).
Free full-text articles and a mobile application of TG13 are
available via http://www.jshbps.jp/en/guideline/tg13.html.
Keywords Oriental cholangitis
Calculous cholecystitis

Primary sclerosing cholangitis
Guidelines
Biliary
infection
Introduction
Along with the addition of the evidence that has been
reported since 2007, we report on the miscellaneous
H. Gomi
Center for Clinical Infectious Diseases, Jichi Medical University,
Tochigi, Japan
A. N. Supe
Department of Surgical Gastroenterology, Seth G S Medical
College and K E M Hospital, Mumbai, India
P. Jagannath
Department of Surgical Oncology, Lilavati Hospital and
Research Centre, Mumbai, India
H. Singh
Department of Hepato-Pancreato-Biliary Surgery, Hospital
Selayang, Kuala Lampur, Malaysia
M.-H. Kim
Department of Internal Medicine, Asan Medical Center,
University of Ulsan, Seoul, Korea
S. C. Hilvano
Department of Surgery, College of Medicine-Philippine General
Hospital, University of the Philippines, Manila, Philippines
C.-G. Ker
Yuan’s General Hospital, Kaohsiung, Taiwan
S.-W. Kim
Department of Surgery, Seoul National University
College of Medicine, Seoul, Korea
123
J Hepatobiliary Pancreat Sci (2013) 20:97–105
etiology of cholangitis and cholecystitis included in the
Tokyo Guidelines for the management of acute cholangitis
and cholecystitis (TG 07) [1] published in 2007. In view of
the presence of miscellaneous evidence that has not so far
been touched on, we thought it necessary that the updated
Tokyo Guidelines 2013 (TG13) prepare new items, put the
evidence so far collected in its due place, and provide
explanations. Diseases and morbidities classified in this
category include (1) oriental cholangitis, (2) acute cho-
langitis and cholecystitis associated with pancreaticobiliary
malignancies, (3) biliary tract infections in patients who
underwent previous biliary tract surgery, (4) primary
sclerosing cholangitis, and (5) acalculous cholecystitis.
In this paper, we present comments not only on the
characteristics of miscellaneous etiology of cholangitis and
cholecystitis but also on diagnostic and therapeutic meth-
ods, along with the addition of the newly reported
evidence.
Oriental cholangitis (cholangiohepatitis)
Characteristics
Oriental cholangitis (Fig. 1, Supplement Fig. 1) is defined
as that type of cholangitis characterized by recurrent right
upper quadrant pain, fever, chill and jaundice induced by
intrahepatic biliary stricture and intrahepatic stones. It is a
pandemic disease observed in Southeast Asian regions,
and people in the low-income group are frequently
affected by the disease. Involvement of b-glucuronidase
due to parasitic and bacterial biliary tract infections is
suggested as a causative factor [2–7]. In recent years,
however, it is rare that the presence of parasites is con-
firmed by a resected specimen of the liver [8]. Terms such
as ‘‘oriental cholangitis,’’ ‘‘recurrent pyogenic cholangi-
tis’’ and ‘‘primary hepatolithiasis’’ are frequently used in
Korea, Hong Kong and Japan. They have been referred to
as the terms that describe different aspects of the same
morbidities [9]: emphasis is placed on ethnic predilection
and the mysterious nature of ‘‘oriental cholangitis’’,
clinical presentation and suppurative inflammation in
‘‘recurrent pyogenic cholangitis’’, and pathological
changes in ‘‘primary hepatolithiasis’’, respectively [9].
Pathologically, ‘‘oriental cholangitis’’ is characterized by
dilatation and stricture of the extrahepatic/intrahepatic
bile duct accompanying intrahepatic pigment calculi,
and hypertrophy is observed in the bile duct wall
accompanied by intrahepatic pigment calculus and
thickening accompanied by fibrosis and inflammatory cell
invasion [2–5, 7].
As for parasites related to oriental cholangitis, round-
worms and Chinese liver flukes have been reported. Adult
J Hepatobiliary Pancreat Sci (2013) 20:97–105
Fig. 1 Oriental cholangitis: dynamic contrast-enhanced CT shows
inhomogeneous enhancement (especially of the peripheral portion of
the liver: arrowheads) and intrahepatic bile duct dilatation (arrows)
roundworms sometimes enter the bile duct through the
duodenal papilla and give rise to cholangitis in 16–56.6 %
of patients [10]. Chinese liver flukes colonize the intrahe-
patic bile duct and then live there for 20–30 years, causing
chronic inflammatory parasitic changes [11].
Q1. What are the imaging findings of oriental
cholangitis?
The imaging findings of oriental cholangitis are follows;
extrahepatic bile duct dilatation, intrahepatic calculi,
localized dilatation / stricture in the biliary tree of the
medial segment of the liver, atrophy of the liver
segment/decreased blood flow, increased echogenicity
(US) of the hepatic portal vein, and liver abscess.
Diagnosis
Ultrasound/computed tomography (US/CT) enables
observation of bile duct dilatation and pneumobilia (Fig. 1,
Supplement Fig. 1), increased US echogenicity in the
portal vein segment of the liver, and atrophy of the liver
segment/decreased blood flow [4–6, 8]. However, US does
not necessarily depict intrahepatic stones accompanied by
acoustic shadow [8]. Calcium bilirubinate calculi are also
observed as a high-absorption region on CT; however, due
to the low absorption level of cholesterol stones, depiction
of cholesterol stones sometimes becomes difficult [8].
Magnetic resonance imaging/magnetic resonance cholan-
giopancreatography (MRI/MRCP) is able to provide better
imaging without the risk of aggravated sepsis cholangitis
99
and is good at depicting lesions on the proximal side of the
obstruction and stricture and those outside of the biliary
duct [6]. However, when cholestasis is present, a diagnosis
of stones can become impossible or it may be impossible to
visualize the bile duct because of bile concentration and
low signal. Pneumobilia is likely to be mistaken for stones
because it presents a low signal [8]. The rate of correct
diagnosis of the obstructed location by MRI/MRCP is
96–100 %, a diagnosis of a cause of obstruction is made in
90 % and one of intrahepatic stones is the same as that by
endoscopic retrograde cholangiopancreatography (ERCP).
Direct cholangiography such as percutaneous transhepatic
cholangiography is an invasive test [6] and it has merits in
that 1it simultaneously enables (1) the removal of intra-
hepatic stones, (2) biopsy of bile duct lesions, and (3) stent
placement in the bile duct [8]. The reported imaging
findings from direct cholangiography are those of the
dilated bile duct and stones, straightening of the bile duct,
rigidity, decreased arborization, increased branching angle,
acute peripheral tapering and multiple focal strictures
[5, 6]. The diagnostic sensitivity of direct cholangiography
for making a diagnosis of bile duct obstruction is 100 %,
that for stones is somewhat inferior to that of MRCP
(90–96 %), and specificity is 98 %. The incidence of liver
abscess in oriental cholangitis is 20 % lower; there is often
a number of partitions. Abscess should therefore be sus-
pected when the limbus is depicted with CT [6].
Acute cholangitis and cholecystitis associated
with pancreaticobiliary malignancy
Characteristics
Biliary drainage is carried out for pancreaticobiliary
malignancies because they are frequently accompanied by
obstructive jaundice. However, patients with morbidities
accompanied by acute cholangitis requiring urgent biliary
drainage are few in number (Supplement Fig. 2). Acute
cholangitis requiring urgent biliary drainage is frequently
observed in the following patients: (1) those who failed to
undergo biliary drainage even if the bile duct at the upper
stream of the liver above the obstructed site of the bile duct
was depicted, and (2) those in whom drainage was
unsuccessful due to catheter obstruction even though a
drainage tube had been placed in the bile duct at the upper
stream of the liver above the obstructed site of the bile duct
due to malignant tumor [1].
The destruction of papillary function due to stent
placement and re-obstruction of the bile duct arising from
tumor enlargement have been reported as a risk factor for
acute cholangitis after metal stent placement for internal
123
100
biliary drainage. Furthermore, cancer progression to the
cystic duct and cystic duct obstruction due to stent
replacement in the bile duct have been reported as risk
factors for the development of acute cholecystitis after
stent placement [12–15].
Diagnosis
As for the diagnostic accuracy of diagnostic imaging for
malignant tumors, there is a report showing that the sen-
sitivity/specificity/rate of correct diagnosis of US for
extrahepatic bile duct cancers are 85.6/76.9/84.4 % for
cancers of the hilar bile duct; 59.1/50/57.1 % for cancers of
the middle bile duct; and 33.3/42.8/36.8 % for cancers of
the lower bile duct, respectively [16]. There are reports
showing that about 100 % of the tumors of the biliary
system, except early cancers, are recognized with multi-
detector CT and a judgment of the usefulness of resection
can be made in 74.5–91.7 % of the cases [17, 18]. A meta-
analysis of MRCP has found that its sensitivity and spec-
ificity are 97/88 and 98/95 %, respectively, when the
detection of obstruction/malignancy has been set as the end
point [19].
Q2. How drainage should be carried out for postoper-
ative acute cholangitis following pancreaticobiliary
malignancies?
We suggest a safe and reliable method should be selected
at the facility concerned. When it is difficult, emergency
transportation to an appropriate facility should take
place (recommendation 1, level C).
Treatment
The presence of preoperative cholangitis and cholecystitis
without control of pancreaticobiliary malignancies is an
independent risk factor for postoperative death during
hospital stay and the development of complications, so it is
considered that the control of those morbidities is impor-
tant [20–23]. In recent years, we have occasionally come
across opinions that recommend the use of endoscopic
naso-biliary drainage for hilar cholangiocarcinoma also, in
view of the occurrence of vascular injuries (8 %), perito-
neal dissemination (4 %) and recurrence of fistula (5.2 %)
[24, 25]. However, there are so far no reports of random-
ized controlled trails comparing the modalities of preop-
erative biliary drainage. Therefore, it is thought that what
matters at this time will be whether or not there are phy-
sicians expert in endoscopic or percutaneous drainage at
the facility involved, and the selection of a method
123
J Hepatobiliary Pancreat Sci (2013) 20:97–105
enabling safe and reliable emergency biliary drainage
[26]. When the above conditions are not applicable,
patients should be transferred to an appropriate facility to
undergo biliary drainage.
Due to possible risks associated with preoperative per-
cutaneous biliary drainage for fistula recurrence and car-
cinomatous peritonitis [1], one-stage radical surgery should
be conducted as far as the circumstances allow.
Biliary tract infections in patients who have undergone
previous biliary tract surgery
Q3. What is the frequency of cholangitis after biliary
tract reconstruction?
Cholangitis occurs in about 10% of the patients after biliary
tract reconstruction.
Characteristics
After ERCP and biliary tract surgery, there can be latent
cholangitis and cholecystitis. According to reports that
have examined patients undergoing biliary tract recon-
struction, cholangitis occurred during 29–129 months’
follow-up in 11.3 % of the patients after papilloplasty,
10.3–10.9 % after choledochoduodenostomy, and 6.4–11.3 %
after choledochojejunostomy (Supplement Fig. 3), and in
about 4 % of patients in whom cholangitis was recurrent
and severe [27, 28]. Although there are no differences
between perioperative mortality rate and the incidence rate
of complications [28], bile duct carcinomas occurred after
biliary tract reconstruction in 1.9–7.6 % of the patients,
suggesting the presence of a relationship between inflam-
matory changes in the bile duct following biliary tract
reconstruction and biliary tract cancer that occurs in the
late stage [27]. According to a report on patients who were
followed up for more than 10 years after surgery for con-
genital biliary tract dilatation conducted in childhood
(mean age 4.2 years), impairment of the liver occurred in
10.7 % of the patients, bile duct dilatation in 10.7 %, and
repeated cholangitis in 1.8 % [29].
A systematic review of liver transplantation in adult
patients shows that bile duct stricture occurred in 12 % of
patients undergoing brain-dead donor liver transplantation
and in 19 % of patients undergoing live-donor liver
transplantation [30]. According to a discussion of the result
according to the surgical techniques of biliary tract
reconstruction in 51 patients who had undergone liver
transplantation due to primary sclerosing cholangitis
(PSC), there were no differences in the survival rate in
J Hepatobiliary Pancreat Sci (2013) 20:97–105
patients who had undergone choledochoduodenostomy,
choledochojejunostomy or choledochocholedochostomy.
However, the incidence of postoperative biliary tract
complications that had occurred more than once was 48, 60
and 17 %, respectively [31].
It is reported that the incidence of cholecystitis differs
(0.06–12.6 %) according to underlying diseases other than
biliary tract surgery or surgical techniques and that the
frequency of acalculous cholecystitis is high [32–37].
Primary sclerosing cholangitis
Characteristics
Primary sclerosing cholangitis (PSC) (Fig. 2) causes
stricture and obstruction due to progressive and non-spe-
cific inflammation of the intra- and extrahepatic bile duct
wall and progresses from cholestasis to liver cirrhosis and
hepatic failure. Its etiology remains unknown [38, 39]. It is
therefore important that secondary sclerosing cholangitis
is excluded [40]. PSC is frequently observed in males,
Caucasians and Northern Europeans [38]; the incidence rate is
0.41–1.25 patients/100,000 person-years [41, 42], and the
mean age at onset is 42 years [38]. There are reports that
the age distribution is bipolar in shape with one peak at
the 20s and another peak between the 50s and 60s [43, 44].
It is classified into the following 4 stages: (1) small
duct cholangitis, (2) progressive cholestasis, (3) cirrhosis,
and (4) decompensation [38, 45]. Clinical symptoms differ
Fig. 2 Primary sclerosing cholangitis (PSC): ERCP shows stenosis
and beaded appearance
101
according to the stage of the disease. It is detected by blood
test and is often asymptomatic [44]. When the disease has
progressed, cutaneous pruritus following cholestasis,
jaundice, fever due to cholangitis, and abdominal pain
occur. A combination of inflammatory intestinal disease
and biliary tract cancer occurs in 4.3–16.6 % of PSC cases
[41, 42, 44, 46–51].
Diagnosis
ERCP is a standard imaging test. MRCP has shown
promise in recent years as a minimally invasive imaging
test procedure [38]. Imaging findings in the bile duct
include band-like stricture, beaded appearance (Fig. 2),
pruned tree-like appearance, and diverticulum-like out-
pouching [52]. The Mayo Clinic diagnostic criteria,
which are widely used [40] (Supplementary Table 1),
make much of the imaging findings of intra/extrahepatic
bile duct stricture and the biliary tract. Elevated levels of
serum ALP and T-Bil and an increased leukocyte count
are findings common to acute cholangitis. An increased
eosinophilic count, a serum c-globulin level, an ele-
vated IgG/IgM level, positive anti-nuclear antibody and
positive perinuclear antineutrophil cytoplasmic antibody
(p-ANCA) are useful for differentiation from acute
cholangitis [38, 43, 44]. The positive rates are ALP
88 %, ALT 73 %, T-Bil 39 %, P-ANKA 7–77 %, and
anti-nuclear antibody 33–87 % [38, 44]. According to
meta-analyses, MRCP shows 86 % diagnostic sensitivity
and 94 % specificity, demonstrating that it is somewhat
inferior in terms of the depiction of the intra/extrahepatic
bile duct and a diagnosis of liver cirrhosis and cancer at
the early stage [53, 54]. However, it is considered that
MRCP has sufficient capacity to enable a diagnostic test
for various types of diseases [55]. A diagnosis of chol-
angiocarcinoma occurring in PSC patients without tumor
formation remains a challenging task, so the diagnosis of
cholangiocarcinoma is made comprehensively by means
of diagnostic modalities such as CA19-9, diagnostic
imaging and scraping cytology [56–59]. It is reported
that the diagnostic sensitivity/specificity of US, CT and
MRI for cholangiocarcinoma are about 57/94, 75/80,
63/79 %, respectively [58]. There is a report showing
that positron emission tomography (PET)-CT is useful
for making a diagnosis of cholangiocarcinoma [49].
On the other hand, there are also reports showing that
PET-CT is not useful [60]. Concomitant use of intra-
ductal ultrasound is reported to be associated with the
elevated sensitivity and specificity of endoscopic retro-
grade cholangiography [61, 62]. The sensitivity and
specificity of scraping cytology for the bile duct are
reported to be about 18–73 and 95–100 %, respectively
[56, 59, 63, 64].
123
102
Acalculous cholecystitis
Characteristics
Patients with acute acalculous cholecystitis (Fig. 3) account
for 3.7–14 % of the patients with acute cholecystitis,
12–49 % of which occurs after trauma and major surgery
[65, 66]. Acute acalculous cholecystitis occurs in about 1 %
of patients admitted to intensive care units (ICUs) [67],
about 1.2 % of patients with severe burns [68], 59–63 % of
patients with gangrenous cholecystitis, and 15–20 % of
patients with gallbladder perforation [65, 69–71] together
with frequent multiple organ dysfunction. The mortality
rate is 0 % when the patient’s general status is maintained
[65, 72]; however, it is high (30–53 %) in critically ill
patients [67–69]. Early and appropriate diagnosis and
treatment are necessary to reduce the mortality rate [69, 71].
Risk factors for the development of acalculous cholecystitis
include surgery, trauma, long-term ICU stays, infections,
burns and parenteral nutrition [67, 68]. It is reported
that ischemia, reperfusion injury and proinflammatory
a b
d e
* *
Fig. 3 Acalculous acute cholecystitis: dynamic CT (a–c) shows
gallbladder distention, mucosal enhancement (b, c arrows), and
transient pericholecystic liver enhancement (b arrowheads). MRCP
123
J Hepatobiliary Pancreat Sci (2013) 20:97–105
mediators such as eicosanoids are involved in the mecha-
nisms for developing such conditions [69, 73].
Diagnosis
Patients are under respiratory control and frequently
develop consciousness disturbance arising from the use of
analgesics. Findings such as an elevated leukocyte count,
liver function disorder and clinical symptoms such as
sonographic Murphy’s sign, right hypochondriac pain and
fever that are highly specific for acute calculous chole-
cystitis presents are not specific for acute acalculous cho-
lecystitis [66, 71]. US/CT findings include thickening of
the wall ([3.5 mm), pericholecystic fluid, emphysematous
gallbladder, sloughed mucosal membrane, and lack of
gallbladder wall enhancement (only for CT). The sensi-
tivity/specificity of US are 30–92/89–100 %, and those
of CT are 33–100/99–100 % [70, 74, 75]. When HIDA
(hepatobiliary iminodiacetic acid) scan fails to visualize the
gallbladder, the case is judged positive. The sensitivity and
specificity of HIDA scan are 68–100 and 38–100 %,
c
f
(d) shows gallbladder distension. Gallbladder shows marked hyper-
intensity (asterisk) on fat-suppressed T1-weighted MR image (e) and
T2-weighted image (f) indicating inspissated bile juice
J Hepatobiliary Pancreat Sci (2013) 20:97–105
respectively. HIDA scan is likely to detect positive cases
depending on complications (intravenous hyperalimenta-
tion, fasting, hepatic failure) [71]. The rate of correct
diagnosis of diagnostic laparoscopy in critically ill patients
is reported to be 90–100 % [76].
Q4. What treatment is being carried out for acute
acalculous cholecystitis?
Cholecystectomy and/or cholecystostomy (drainage of the GB)
are being conducted.
Treatment
Cholecystectomy and/or cholecystostomy (drainage of the
gallbladder) are carried out. However, appropriate timing
and necessity of cholecystectomy and cholecystostomy are
controversial [71]. There are many opinions that chole-
cystostomy should be conducted in patients with poor
general status and that cholecystectomy should be carried
out after recovery has been achieved [69, 71, 77, 78].
However, there is a group arguing that cholecystectomy
only should be performed [79] and a group asserting that
cholecystostomy is the definitive treatment in patients with
extremely high risk [80].
Conflict of interest None.
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J Hepatobiliary Pancreat Sci (2013) 20:106–109
DOI 10.1007/s00534-012-0588-5

ANNOUNCEMENT

Newsletter, January 1, 2013

A-P HPBA activities

Third Congress of Asian-Pacific HPBA

The Third Biennial Congress, 2011 A-P HPBA, was held in

Tadahiro Takada, MD, FACS, FRCS
Founding President of A-P HPBA
Dear Colleagues,
As the founding president of the Asian-Pacific HPBA, I
would like to underline once again that this journal is the
official journal of the following three societies:
The Asian-Pacific Hepato-Pancreato-Biliary Association
(A-P HPBA)
The Japanese Society of Hepato-Biliary-Pancreatic Surgery
(JSHBPS)
The Japan Biliary Association (JBA)
It is my pleasure to inform you of the current activities
of the Asian-Pacific Hepato-Pancreato-Biliary Association
(A-P HPBA).
Melbourne, Australia, 27–30 September 2011 and was
chaired by Professor Christopher Christophi.
The 2011 Congress focused on ‘‘making a difference
with new technologies’’ and provided an exciting and
innovative scientific program in a unique destination—
Melbourne, Australia.
There were postgraduate courses held on 27 September,
followed by three packed days from 28 to 30 September
with a variety of different presentation types including
symposia, debates, video sessions, and case presentations.
To supplement the scientific program, the Congress social
events provided an ideal opportunity for networking with
colleagues and industry associates in an atmosphere of
typical Melbourne hospitality.
Fourth Congress of Asian-Pacific HPBA
The Fourth Biennial Congress, 2013 A-P HPBA, will take
place in Shanghai, China, 27–30 March 2013 with Pro-
fessor Meng Chao Wu at the helm.
The theme for the A-PHPBA2013 Shanghai Congress will
be ‘‘Seeking Common Ground While Reserving Differ-
ences’’. This Congress will be unique as our Scientific Com-
mittee has prepared an outstanding program combining the
best science and education. It will comprise pre-congress
postgraduate courses and a variety of symposia, debates, video
sessions, and case presentations. As China’s largest city,
Shanghai is an outstanding conference destination, located at
the hub of this ancient country. There will be no shortage of
activities for delegates and accompanying persons.

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J Hepatobiliary Pancreat Sci (2013) 20:106–109 107

Please visit the Congress website http://www.aphpba Xiao-Ping Chen,

2013shanghai.org, where you will find further information. President-Elect
We look forward to welcoming you to Shanghai in Tongji Hospital
2013, and we are confident that the event will be a mem- Tongji Medical College
orable occasion for exchanging knowledge and strength- Department of General
ening friendship. Surgery
Huazhong University of
Science and Technology
A-P HPBA officers and councilors (2011–2013) Wuhan
China
President: Palepu Jagannath (India)
President-Elect: Xiao-Ping Chen (China)
Immediate Past-President: Joseph WY Lau (Hong Kong)
Joseph WY Lau, Immediate
Secretary: Sung-Gyu Lee (Korea)
Past-President
Treasurer: Sheung-Tat Fan (Hong Kong)
The Chinese University of
Chairman of Scientific Committee: Masao Tanaka (Japan)
Hong Kong
Secretary-Elect: Norihiro Kokudo (Japan)
Department of Surgery
Congress Chairman: Meng-Chao Wu (China)
Prince of Wales Hospital
Members-at-large (2011–2013)
Shatin
Christopher Christophi (Australia/New Zealand)
New Territories
Feng Shen (China)
Hong Kong
Avinash Supe (India)
Masakazu Yamamoto (Japan)
Sun-Whe Kim (Korea)
Harjit Singh (Malaysia)
Winston Wei-Liang Woon (Singapore) Sung-Gyu Lee
Chao-Long Chen (Taiwan) Secretary
Korea

A-P HPBA officers and councilors (2011–2013)

Palepu Jagannath, President
Lilavati Hospital and
Research Centre
Department of Surgical
Oncology
Bandra (West)
Mumbai
India Sheung-Tat Fan
Treasurer
Hong Kong

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108 J Hepatobiliary Pancreat Sci (2013) 20:106–109

Masao Tanaka Feng Shen

Chairman of Scientific Member-at-Large
Committee China
Japan

Norihiro Kokudo Avinash Supe

Secretary-Elect Member-at-Large
Japan India

Masakazu Yamamoto
Meng-Chao Wu
Member-at-Large
Congress Chairman, Fourth
Japan
Congress
Shanghai Eastern
Hepatobiliary Surgery
Hospital
Shanghai
China

Sung-Whe Kim
Member-at-Large
Christopher Christophi
Korea
Member-at-Large
Australia

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J Hepatobiliary Pancreat Sci (2013) 20:106–109
Harjit Singh
Member-at-Large
Malaysia
Winston WL Woon
Member-at-Large
Singapore
Chao-Long Chen
Member-at-Large
Taiwan
A-PHPBA Committees
Executive Committee (2011–2013)
Chairman: Palepu Jagannath (India), President
Members: Xiao-Ping Chen (China), President-Elect
Joseph WY Lau (Hong Kong), Immediate Past-President
Sung-Gyu Lee (Korea), Secretary
Sheung-Tat Fan (Hong Kong), Treasurer
Masao Tanaka (Japan), Chairman of Scientific Committee
Education and Training Committee (2011–2013)
Chairman: Palepu Jagannath (President)
Members: Xiao-Ping Chen (President-Elect)
Christopher Christophi (Member-at-Large, Australia/New
Zealand)
Feng Shen (Member-at-Large, China)
109
Avinash Supe (Member-at-Large, India)
Masakazu Yamamoto (Member-at-Large, Japan)
Sun-Whe Kim (Member-at-Large, Korea)
Winston WL Woon (Member-at-Large, Singapore)
Harjit Singh (Member-at-Large, Malaysia)
Chao-Long Chen (Member-at-Large, Taiwan)
Development Committee (2011–2013)
Chairman: Joseph Lau (Hong Kong), Immediate Past-President
Members: Palepu Jagannath (India), President
Sheung-Tat Fan (Hong Kong), Treasurer
Christopher Christophi (Member-at-Large, Australia/New
Zealand)
Membership Committee (2011–2013)
Chairman: Palepu Jagannath (President)
Members: Sung-Gyu Lee (Secretary)
Xiao-Ping Chen (China)
Rajeev Joshi (India)
Masakazu Yamamoto (Japan)
Hong Jin Kim (Korea)
Saxon Connor (New Zealand)
Kui Hin Liau (Singapore)
Chao-Long Chen (Taiwan)
Vajarapong Bhudisawasdi (Thailand)
Nominating Committee (2011–2013)
Chairman: Joseph Lau (Hong Kong), Immediate Past-President
Members: Palepu Jagannath (India), President
Xiao-Ping Chen (China), President-Elect
Publication Committee (2011–2013)
Chairman: Sheung-Tat Fan (Treasurer)
Members: Palepu Jagannath (President)
Masao Tanaka (Chair of Scientific Committee)
Xiao-Ping Chen (President-Elect)
Sung Gyu Lee (Secretary)
Scientific Committee (2011–2013)
Chairman: Masao Tanaka (Japan)
Vice-Chairman: Saxon Connor (New Zealand)
Members: Palepu Jagannath (President)
Sung-Gyu Lee (Secretary)
Meng-Chao Wu (Congress Chairman)
Krishnakumar Madhavan (Singapore, next Congress Chairman)
Feng Shen (China)
Zhi-Yong Huang (China)
See-Ching Chan (Hong Kong)
Eric CH Lai (Hong Kong)
Regulagedda A Sastry (India)
Shailesh V. Shrikhande (India)
Itaru Endo (Japan)
Hong-Jin Kim (Korea)
Sun Whe Kim (Korea)
Krishna Raman (Malaysia)
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