Hepatobiliary & Pancreatic Diseases International

400 Hepatobiliary Pancreat Dis IntVol 12No 4 August 152013 www.hbpdint.com

Original Article / Biliary
Author Afliations: Department of Gastroenterology and Hepatology
(Sun G, Yang YS, Linghu EQ, Li W, Cai FC, Kong JY, Wang XD, Meng JY,
Du H, Wang HB, Huang QY and Zhang XL), and Department of General
Oncology (Han L), Chinese PLA General Hospital, Beijing 100853, China;
Department of Gastroenterology, Pakistan Institute of Medical Sciences,
G-8-3, Islamabad, Pakistan (Hyder Q)
Corresponding Author: Yun-Sheng Yang, MD, PhD, Department of
Gastroenterology and Hepatology, Chinese PLA General Hospital, 28
Fuxing Road, Beijing 100853, China (Tel/Fax: 86-10-68212267; Email:
sunny888@medmail.com.cn)
2013, Hepatobiliary Pancreat Dis Int. All rights reserved.
doi: 10.1016/S1499-3872(13)60062-4
BACKGROUND: The lack of widely-accepted guidelines for
acute cholangitis largely lags behind the progress in medical and
surgical technology and science for the management of acute
cholangitis. This study aimed to verify the Tokyo guidelines for
the management of acute cholangitis and cholecystitis of 2007
edition (TG07) in patients with obstructive cholangitis due to
benign and malignant diseases.
METHODS: The patients were retrieved from our existing
ERCP database. Final diagnosis of acute cholangitis was made by
detecting purulent bile during biliary drainage. We examined
and compared the guidelines concerning benign and malignant
obstruction.
RESULTS: In 120 patients in our study, 82 and 38 had benign
and malignant biliary obstruction, respectively. Guidelines
based diagnosis was made in 68 (82.9%), 36 (94.7%), and 104
(86.7%) patients with benign, malignant, and overall biliary
obstruction, respectively, which were signicantly higher than
44 (53.7%), 17 (44.7%), and 61 (50.8%) diagnosed by Charcot's
triad (P<0.001). Treatment consistent with the guidelines was
offered to 58 (70.7%) patients with benign obstruction and
15 (39.5%) patients with malignant obstruction (P=0.001).
No signicant association was observed between clinical
compliance, guidelines-based severity grades and clinical
outcomes. In the multivariate model, intrahepatic obstruction
(OR=11.2, 95% CI: 1.55-226.9) and hypoalbuminemia (25.0
g/L; OR=17.3, 95% CI: 3.5-313.6) were independent risk factors
for a 30-day mortality.
CONCLUSIONS: The TG07 are more reliable than Charcot's
triad for the diagnosis of acute cholangitis albeit with
limited prognostic values. Intrahepatic obstruction and
hypoalbuminemia are new predictors of poor prognosis and
need further assessment.
(Hepatobiliary Pancreat Dis Int 2013;12:400-407)
KEY WORDS: acute cholangitis;
the Tokyo guidelines;
endoscopic biliary drainage;
diagnosis
Introduction
A
cute cholangitis (AC) is a bacterial infection of
the biliary tract. The spectrum of its severity
ranges from mild to life-threatening with
mortality rates between 8% and 10%.
[1, 2]
Choledo-
cholithiasis has been the leading cause of AC.
[3, 4]
However,
underlying malignancies of the bile duct, the pancreas
and liver are seen with increasing frequency in the past
two decades.
[5-7]
Although right upper quadrant abdominal pain,
fever and jaundice (i.e. Charcot's triad, 1877
[8]
) with
or without mental confusion and hypotension (i.e.
Reynolds' pentad, 1959
[9]
) are still used as the clinical
Verifcation of the Tokyo guidelines for acute
cholangitis secondary to benign and malignant
biliary obstruction: experience from a Chinese
tertiary hospital
Gang Sun, Lu Han, Yun-Sheng Yang, En-Qiang Linghu, Wen Li, Feng-Chun Cai,
Jin-Yan Kong, Xiang-Dong Wang, Jiang-Yun Meng, Hong Du, Hong-Bin Wang,
Qi-Yang Huang, Quratulain Hyder and Xiu-Li Zhang
Beijing, China
Acute cholangitis secondary to biliary obstruction
Hepatobiliary Pancreat Dis IntVol 12No 4 August 152013 www.hbpdint.com 401
parameters to diagnose AC, the full complement of
the signs and symptoms remains elusive in planning
further management.
[10]
Several scoring systems have
been devised for the diagnosis and severity grading of
AC,
[11-13]
but the standard guidelines for clinical practice
virtually do not exist, lagging behind the progress in
medical and surgical technology.
[14]
The Tokyo guidelines for the management of acute
cholangitis and cholecystitis, formulated in 2007 (TG07)
for the diagnosis, severity assessment, and treatment of
AC,
[15]
aimed to be accommodated in clinical practice
based on worldwide expert consensus. However,
minimal recognition of the TG07 has been achieved
outside Japan.
[16-20]
Several retrospective studies
[16, 17, 20]

have validated its diagnostic value in comparison with
Charcot's triad albeit with little agreement on the
criteria for severity assessment and treatment strategy.
For example, the TG07 require 24-hour observation of
patients to differentiate between mild and moderate AC.
This is practically inapplicable if an urgent intervention
is performed aiming to prevent progression of sepsis.
[20]

There are no potential benets on applying the TG07 in
the treatment of AC. Moreover, the application of the
guidelines has been mostly examined in AC patients
due to choledocholithiasis with minimal reference to
malignant etiology, thereby reinforcing the need for
a continuous update.
[18, 21]
The present study includes
patients with benign as well as malignant biliary
obstruction to verify the TG07 with the intent to provide
evidences for further optimization.
Methods
This study was approved by the institutional review
board of the Chinese PLA General Hospital. Clinical
information between January 2000 and December
2009 was collected from our prospectively established
endoscopic retrograde cholangiopancreatography (ERCP)
database. The inclusion criterion was identication of
purulent bile during endoscopic biliary drainage. The
patients <18 years of age and those with prior biliary
drainage after onset were excluded from the study. For
patients with multiple hospitalizations during the study
period, only the initial episode was reviewed.
Patient management
The initial diagnosis in the majority of our
hospitalized patients was made on Charcot's triad. Upon
admission, the patients were fasted and hematologic and
radiologic evaluations were carried out for evidence of
biliary obstruction and acute infection. Their vital signs
and urinary output were monitored 6 hourly. Blood
counts, blood cultures, hepatic and renal function tests,
along with urinary biochemistry including glucose
and amylase levels were estimated on admission and
regularly thereafter. Abdominal ultrasonography was
routinely performed within 12 hours, while plain or
enhanced computed tomography (CT) and magnetic
resonance cholangiopancreatography (MRCP) were
chosen appropriately according to the clinical necessity
and the patient's tolerance. Intravenous uid with
broad-spectrum antibiotics was given immediately
and a central venous line was established in case of
hypotension or in shock.
In our institution, emergent endoscopic drainage
within 24 hours of admission is recommended to any
AC patients once the causes and site of obstruction
are identied, regardless of etiology and severity of
diseases. A waiting period of 24 to 48 hours is permitted
for pretreatment assessment in complicated cases and
an immediate endoscopic drainage will be performed
in those who present signs of worsening illness.
Therapeutic ERCP was performed under conscious
sedation with propofol. Commonly, procedures were
done in a prompt fashion to avoid unanticipated
worsening of sepsis due to prolonged manipulation. In
our institution, the high risk patients, as dened by
advanced age 75 years, hypotension with a systolic
blood pressure of <90 mmHg, peritonism, altered
sensorium, and associated renal failure are deemed
to urgent biliary decompression either by stents
placement or by nasobiliary drainage. The denitive
management would be undertaken until cholangitis
subsided. The selection of drainage modality is merely
based on the site of obstruction and sufciency of
cholangiography. For denite extrahepatic obstruction,
a 10-Fr plastic straight ap stent is preferred, while
a short-term use of 7-Fr nasobiliary catheter will be
considered in complicated cases either with intrahepatic
obstruction or inadequate cholangiography due to
hemodynamically unstable status. Multiple ERCP
sessions were also needed for those who had residual
bile duct stones and undrained segments. Intensive
postoperative observation was continued for ERCP-
related complications. ERCP was deemed successful
if it resulted in complete and effective relief of biliary
obstruction, regardless of the nal clinical outcomes.
Ultrasound-guided percutaneous transhepatic biliary
drainage or surgery was used as the alternate modalities
if ERCP was non-rewarding. Hospital stay was dened
as the time period from admission of a patient to his/her
exit from the hospital. Given the different etiologies in
our patient cohort, death of the patient within 30 days
of admission was regarded as the clinical endpoint.
Hepatobiliary & Pancreatic Diseases International
402 Hepatobiliary Pancreat Dis IntVol 12No 4 August 152013 www.hbpdint.com
Re-validation of the TG07
The data on demography, presenting features,
diagnostic evaluation of patients, and clinical outcomes
were retrieved and summarized to compare between
AC patients due to benign and malignant biliary
obstruction. The TG07 for AC were re-examined in
depth with a special reference to:
1) The diagnostic yield of the TG07 in comparison
with Charcot's triad. Table 1 shows the TG07 for AC,
[15]

including three components (A, B, and C) and seven
subcategorized items; by which a denite diagnosis is
made either by Charcot's triad or by addition of positive
ndings in both laboratory (component B) and imaging
(component C) data in suspected patients.
2) Clinical compliance with the TG07. In terms
of severity assessment of AC, there are three severity
grades with respective treatment as follows: grade
I (i.e. favorable response to antibiotics; elective
biliary drainage); grade II (i.e. failure of conservative
treatment; biliary drainage within 24 hours); grade III
(i.e. progression to organ dysfunction; biliary drainage
within 12 hours).
[15]
In the present study, patients were
classied into consistent and inconsistent groups based
on whether complied with the timing of biliary drainage
recommended by the TG07.
3) The impact of severity grades and clinical
compliance on the clinical outcomes.
4) The identication of potential risk factors
predicting the mortality.
Statistical analysis
The Chi-square test and Student's t test/Wilcoxon's
rank-sum test were applied to determine the categorical
data and continuous variables, respectively. JMP package
9.0 (SAS Institute Inc., Cary, NC, USA) was used for all
statistical analyses. The risk factors were analyzed by
univariate and multivariate (stepwise) logistic regression
tests. A P value of <0.05 was considered statistically
signicant.
Results
Of the 120 AC patients, 83 (69.2%) were male (age 66.0
15.1 years). The patients were divided into two groups
on the basis of etiology of AC: 82 (68.3%) in the benign
group and 38 (31.7%) in the malignant group. In terms
of the characteristics such as age, gender, comorbidity
and changes in vital signs, no signicant difference was
observed in both groups (Table 2). Typical Charcot's
triad and Reynolds' pentad occurred in 61 (50.8%) and
12 (10.0%) of our patients, respectively, with a similar
incidence between the two groups (P=0.36). The
patients with acute biliary pancreatitis were observed
Table 1. Performance of the diagnostic criteria of the TG07 in benign and malignant biliary obstruction
Parameters in the 2007 Tokyo diagnostic criteria Total (%, n=120) Benign group (%, n=82) Malignant group (%, n=38) P value
A. Clinical context and clinical manifestations
1. History of biliary disease 93 (77.5) 64 (78.0) 29 (76.3) 0.83
2. Fever and/or chills 96 (80.0) 61 (74.4) 35 (92.1) 0.02
*
3. Jaundice 105 (87.5) 68 (82.9) 37 (97.4) 0.01
*
4. Abdominal pain (RUQ or upper abdomen) 86 (71.7) 69 (84.1) 17 (44.7) <0.001
*
B. Laboratory data
5. Evidence of inammatory response (abnormal
WBC count, increased serum CRP level, and other
changes indicating inammation)
101 (84.2) 70 (85.4) 31 (81.6) 0.60
6. Abnormal liver function tests (increased serum
ALP, GGT, ALT and AST levels)
116 (96.7) 78 (95.1) 38 (100) 0.07
C. Imaging ndings
7. Biliary dilatation or evidence of an etiology
(stricture, stone, stent, etc.)
109 (90.8) 72 (87.8) 37 (97.4) 0.06
Suspected diagnosis
Two or more items in A 54 (45.0) 32 (39.0) 22 (57.9) 0.06
Denite diagnosis
#
104 (86.7) 68 (82.9) 36 (94.7) 0.05
Charcot's triad (2+3+4)
#
61 (50.8) 44 (53.7) 17 (44.7) 0.36
Two or more items in A+both items in B and item C 43 (35.8) 24 (29.3) 19 (50.0) 0.36
*: P<0.05, benign group vs malignant group; #: P<0.001, vs Charcot's triad (seen in benign, malignant, and overall patients). RUQ: right upper quadrant;
WBC: white blood cell; CRP: C-reactive protein; ALP: alkaline phosphatase; GGT: -glutamyl transpeptidase; ALT: alanine aminotransferase; AST:
aspartate aminotransferase.
Acute cholangitis secondary to biliary obstruction
Hepatobiliary Pancreat Dis IntVol 12No 4 August 152013 www.hbpdint.com 403
only in the benign group (P<0.05). The total white
blood cell count, polymorphonuclear neutrophil count
and C-reactive protein (CRP) level were identical in
both groups (P>0.05). The platelet count was higher
in the malignant group. The levels of total bilirubin,
direct bilirubin and alkaline phosphatase (ALP) were
also signicantly higher in the malignant group than
in the benign group (P<0.05). However, alanine
aminotransferase (ALT) was lower in the malignant
group than in the benign group (94.621.6 vs 164.6
15.0 U/L, P=0.01).
Table 2. Baseline characteristics of patients with acute cholangitis
Characteristics
Total
(n=120)
Malignant
group
(n=38)
Benign
group
(n=82)
P value
Age (yr) 66.015.1 66.112.5 66.011.1 0.90
Male 83 (69.2%) 27 (69.2%) 56 (68.3%) 0.76
Comorbidities
Diabetes 18 (15.0%) 4 (10.5%) 14 (17.1%) 0.34
Cardiovascular disease 48 (40.0%) 20 (52.6%) 28 (34.1%) 0.06
Cerebrovascular
disease
6 (5.0%) 3 (7.9%) 3 (3.7%) 0.34
Chronic pulmonary
disease
5 (4.2%) 2 (5.3%) 3 (3.7%) 0.69
Chronic smoking 26 (21.7%) 10 (26.3%) 16 (19.5%) 0.41
Vital signs
Body temperature 38.21.2 38.11.2 38.40.9 0.12
Pulse 87.412.0 87.612.3 86.911.5 0.76
Shock (SBP90
mmHg)
14 (11.7%) 3 (7.9%) 11 (13.4%) 0.37
Charcot's triad 61 (50.8%) 17 (44.7%) 44 (53.7%) 0.36
Reynolds' pentad 12 (10.0%) 4 (10.5%) 8 (9.8%) 0.90
Coexisting disease
Acute pancreatitis 18 (15.0%) 0 18 (22.0%) <0.0001
Liver abscess 3 (2.5%) 1 (2.6%) 2 (2.4%) 0.95
GI bleeding 3 (2.5%) 2 (5.3%) 1 (1.2%) 0.21
Renal failure 2 (1.7%) 0 2 (2.4%) 0.33
Laboratory tests
Mean WBC (10
9
/L) 12.05.8 12.14.5 12.66.3 0.66
Neutrophil 0.850.09 0.840.1 0.860.09 0.57
Mean platelet (10
9
/L) 207.7110.9 249.5126.0 187.997.8 0.006
T-Bil (mol/L) 147.4111.5 211.9125.6 117.290.3 <0.0001
D-Bil (mol/L) 103.379.9 145.989.7 82.866.1 <0.0001
ALT (U/L) 142.5132.9 94.621.6 164.615.0 0.01
AST (U/L) 140.4138.7 104.3107.7 158.0149.0 0.05
GGT (U/L) 573.7429.8 609.1322.3 555.8477.4 0.61
ALP (U/L) 363.3255.4 510.0266.1 297.7223.2 0.0004
CRP (mg/dL) 7.54.0 6.83.4 7.84.3 0.67
SBP: systolic blood pressure; GI: gastrointestinal; WBC: white blood
cell; T-Bil: total bilirubin; D-Bil: direct bilirubin; ALT: alanine amino-
transferase; AST: aspartate aminotransferase; GGT: gamma-glutamyl
transpeptidase; ALP: alkaline phosphatase; CRP: C-reactive protein.
Table 3. Etiology and site of biliary obstruction
Variables Data (n, %)
Etiology of acute cholangitis
Benign group (n=82)
Biliary duct stones 74 (90.2)
Biliary stricture 2 (2.4)
Primary biliary cirrhosis 2 (2.4)
Liver transplantation 2 (2.4)
Mirrize's syndrome 2 (2.4)
Malignant group (n=38)
Cholangiocarcinoma 22 (57.9)
Periampullary carcinoma 5 (13.2)
Pancreatic cancer 8 (21.1)
Liver metastases 3 (7.9)
Site of biliary obstruction
Benign group (n=82)
*
Intrahepatic obstruction 11 (13.4)
Extrahepatic obstruction 71 (86.6)
Malignant group (n=38)
Intrahepatic obstruction 21 (55.3)
Extrahepatic obstruction 17 (44.7)
*: P<0.001, vs malignant group.
Malignant AC resulted from cholangiocarcinoma,
periampullary carcinoma, pancreatic cancer, and
metastatic liver disease in 22 (57.9%), 5 (13.2%), 8 (21.1%),
and 3 (7.9%) patients, respectively (Table 3). Bile duct
stones accounted for 90.2% (74/82) of the patients with
benign AC. Intrahepatic biliary obstruction was caused
more frequently by malignancies (55.3%, 21/38) than by
benign conditions (13.4%, 11/82) (P<0.001).
Endoscopic biliary drainage as the rst line
treatment was successful in 105 (87.5%) of the patients
with no serious procedure-related complications such
as perforation and severe pancreatitis. However, mild
to moderate post-ERCP complications were recorded
in 12 (10.0%) patients: acute pancreatitis in 8 (6.7%),
and bleeding from sphincterotomy in 4 (3.3%). No
signicant difference in the complication rate was
observed between the two groups (P=0.89). Alternative
modalities were successful in 10 (8.3%) patients:
percutaneous transhepatic biliary drainage in 2 (1.7%),
and surgical drainage in 8 (6.7%). Six (5.0%) of our
patients died early of refractory biliary infection (5,
4.2%) and cerebral hemorrhage (1, 0.8%), including
the malignant group 5 (13.2%) and the benign group 1
(1.2%) (P=0.007).
Based on the diagnostic criteria contained in TG07
for AC (Table 1), the denite diagnosis of AC was
achieved in 68 (82.9%), 36 (94.7%), and 104 (86.7%)
benign, malignant, and overall patients, respectively,
which were signicantly higher than 44 (53.7%),
Hepatobiliary & Pancreatic Diseases International
404 Hepatobiliary Pancreat Dis IntVol 12No 4 August 152013 www.hbpdint.com
17 (44.7%), and 61(50.8%), diagnosed by Charcot's
triad (P<0.001 for each pair comparison). Although the
diagnostic rate for malignant patients was higher than
that for benign patients numerically, the difference did
not reach a statistical signicance (P=0.05). Sixteen
(13.3%) patients were misinterpreted by the TG07:
14 (11.7%) in the benign group and 2 (1.7%) in the
malignant group (P=0.05). In the benign patients, 3
patients only met 1 item in component A; none of the
remaining 11 patients with suspected diagnosis could
satisfy both component B and C necessary to establish
a denite diagnosis. Two malignant patients were
suspected but were precluded for a denite diagnosis
due to the absence of evidence of inammatory response
(item 5) in component B.
The numerical distribution of severity grades in
our patients revealed: grade I 27 patients (22.5%),
grade II 68 (56.7%), and grade III 25 (20.8%). There
were totally 73 (60.8%) consistent patients, in which
the benign patients (58/82, 70.7%) were treated more
frequently in accordance with the Tokyo guidelines than
the malignant patients (15/38; 39.5%) (P<0.001). Such
a difference was predominately seen in grade I and II
patients, but with an inverse trend (Fig.). No signicant
difference in the clinical outcome was observed among
patients of different severity grades (P>0.05; Table 4)
and between consistent and inconsistent categories
(P>0.05; Table 5).
A total of 14 prognostic variables for a 30-day mortality
were analyzed: 6 variables for organ dysfunction in
severity grade III;
[15]
8 variables predicting mortality
or urgent biliary drainage in previously published
studies.
[5, 18, 22, 23]
Univariate analysis revealed that serum
creatinine >2.0 mg/dL, PT-INR>1.5, intrahepatic biliary
Fig. Clinical compliance with the TG07 for the treatment of acute
cholangitis. Benign patients were more likely to comply with the
TG07 than malignant patients, with an inverse trend in grade I
and II classication.
Table 5. Impact of clinical compliance with the TG07 on the clinical
outcomes
Grading n
Hospital
stay (d)
Multiple
ERCP
session
Success
rate of
ERCP
Incidence
of ERCP
compli-
cations
30-day
mortality
Benign
Grade I
Consistent 14 14.811.9 1 (7.1%) 13 (92.9%) 1 (7.1%) 0
Inconsistent 8 9.85.6 2 (25.0%) 7 (87.5%) 1 (12.5%) 0
P value 0.27 0.25 0.68 0.68 NA
Grade II
Consistent 32 12.09.4 8 (25.0%) 31 (96.9%) 2 (6.3%) 0
Inconsistent 9 13.78.2 1 (11.1%) 9 (100%) 2 (22.2%) 0
P value 0.64 0.35 0.48 0.19 NA
Grade III
Consistent 12 14.68.9 4 (33.3%) 11 (91.7%) 1 (8.3%) 1 (8.3%)
Inconsistent 7 17.818.7 3 (42.9%) 5 (71.4%) 1 (14.3%) 0
P value 0.61 0.68 0.25 0.69 0.33
Malignant
Grade I
Consistent 5 13.29.5 0 4 (80.0%) 1 (20.0%) 1 (20.0%)
Inconsistent 0 NA 0 0 0 0
P value NA NA NA NA NA
Grade II
Consistent 6 17.75.0 3 (50.0%) 4 (66.7%) 0 2 (33.3%)
Inconsistent 21 19.213.3 4 (19.0%) 17 (81.0%) 2 (9.5%) 1 (4.8%)
P value 0.79 0.14 0.47 0.30 0.07
Grade III
Consistent 4 21.316.0 1 (25.0%) 3 (75.0%) 1 (25.0%) 1 (25.0%)
Inconsistent 2 17.07.4 1 (50.0%) 1 (50.0%) 0 0
P value 0.74 0.54 0.54 0.34 0.34
ERCP: endoscopic retrograde cholangiopancreatography; NA: not
available.
Table 4. Impact of the severity assessment criteria of the TG07 on
the clinical outcomes
Grading n
Hospital
stay (d)
Success
rate of
ERCP
ERCP
compli-
cations
Multiple
ERCP
session
30-day
mortality
Benign
Grade I 22 13.010.2 20 (90.9%) 2 (9.1%) 3 (13.6%) 0
Grade II 41 12.49.0 40 (97.6%) 4 (9.8%) 9 (22.0%) 0
Grade III 19 15.813.1 16 (84.2%) 2 (10.5%) 7 (36.8%) 1 (5.3%)
P value 0.49 0.17 0.99 0.21 0.23
Malignant
Grade I 5 13.25.4 4 (80.0%) 1 (20.0%) 0 1 (20.0%)
Grade II 27 18.92.3 21 (77.8%) 2 (7.4%) 7 (25.9%) 3 (11.1%)
Grade III 6 19.84.9 4 (66.7%) 1 (16.7%) 2 (33.3%) 1 (16.7%)
P value 0.59 0.83 0.63 0.22 0.84
ERCP: endoscopic retrograde cholangiopancreatography.
Acute cholangitis secondary to biliary obstruction
Hepatobiliary Pancreat Dis IntVol 12No 4 August 152013 www.hbpdint.com 405
obstruction, malignant etiology and serum albumin level
25.0 g/L were signicantly associated with a 30-day
mortality (Table 6). In a multivariate regression model,
intrahepatic biliary obstruction (OR=11.2, 95% CI:
1.55-226.9; P=0.007) and serum albumin level 25.0 g/L
(OR=17.3, 95% CI: 3.5-313.6; P<0.001) were independent
risk factors for a 30-day mortality in the present series.
Discussion
The present study tries to reinforce the concept that
the diagnosis of AC due to benign or malignant biliary
obstruction can be achieved more accurately by
application of the TG07 as compared with Charcot's
triad. However, irrespective of the underlying etiology,
the TG07 severity grading appears to have no signicant
impact on the clinical outcome in AC. We have also
observed that intrahepatic biliary obstruction and
hypoalbuminemia (25.0 g/L) are independent risk
factors for AC related mortality.
The diagnostic value of the TG07 has been previously
demonstrated in studies from Japan with sensitivity
rates between 63.9%-94% in comparison with <40%
by Charcot's triad.
[16, 18, 20]
Our results are in conformity
with these reports. Of note, approximately 95% of our
Table 6. Univariate analysis of risk factors predicting a 30-day
mortality
Factors Odds ratio 95% CI P value
Parameters based on the Tokyo guidelines
Hypotension requiring dopamine 5
L/kg per min or any dose of
dobutamine
1.6 0.9-10.7 0.7
Disturbance of consciousness 2.1 0.1-14.7 0.6
PaO
2
/FiO
2
ratio <300 NA
Serum creatinine >2.0 mg/dL 22.6 8.1-632.4 0.03
*
PT-INR >1.5 8.91 1.1-56.8 0.04
*
Platelet count <10010
9
/L 3.5 0.4-19.7 0.2
Parameters beyond the Tokyo guidelines
Age 75 yr 3.3 0.5-63.5 0.2
Intrahepatic obstruction 16.1 2.5-315.6 0.002
*
WBC count 1510
9
/L 1.1 0.2-5.9 0.9
CRP 5 mg/dL 2.5 1.5-16.9 0.9
T-Bil >5 mg/dL 10.1 1.3-267.7 0.2
Body temperature 40 9.8 3.5-101.0 0.4
Malignant etiology 12.3 1.9-239.8 0.007
*
Serum albumin level 25.0 g/L 21.3 3.9-352.8 0.001
*
*: P<0.05, independent risk factors of a 30-day mortality in univariate
analysis. CI: condence interval; NA: not available for all subjects because
this test was not routinely performed for all hospitalized AC patients in
our institution; WBC: white blood cell; CRP: C-reactive protein; T-Bil:
total bilirubin.
patients in the malignant group were positive for the
TG07 diagnostic criteria. This observation apparently
has important implications such as early diagnosis
and timely treatment of these high risk patients. The
current guidelines are superior to the conventional
guidelines primarily based on clinical symptoms
due to incorporation of Charcot's triad as one of the
diagnostic criteria for AC, and patients without full
complement of Charcot's triad can still be identied if
the abnormalities are demonstrated in both laboratory
data and image ndings. However, some confounding
factors may affect the diagnostic potential of these
guidelines in AC. For examples, decompensate liver
cirrhosis and hypersplenism are responsible for normal
peripheral blood counts in AC in these cases. Urgent
ultrasonography for detection biliary obstruction is
somewhat experience-dependent and can be falsely
negative in some other subjects. Therefore, an early
identication of these confounding factors may
facilitate modication of the current diagnostic criteria.
Redening leukocytosis in subjects with hypersplenism/
hematopoietic abnormality and the use of enhanced CT
or MRCP in suspected cases with negative sonography
may improve the reliability of the TG07.
The TG07 dene the severity of AC on the basis
of clinical response to antibiotics within 24 hours
and the onset of organ dysfunction.
[15]
However,
controversies exist over these consensus-based criteria.
The differentiation between mild and moderate AC
may be difcult while conducting biliary drainage
within 24 hours.
[20]
The physicians remain cautious
about the 24-hour time period for observation lest the
delay in endoscopic intervention results in progression
of sepsis.
[20, 21]
Moreover, no predictive and prognostic
values of the TG07 severity criteria were observed in our
study, which might partially reect the insufciency
of the TG07 in evaluation of the actual status of
AC. On the other hand, the widespread use of early
biliary drainage in our patients presumably played an
important protective role, attenuating the prognostic
values of the TG07. Nevertheless, two independent
risk factors for 30-day mortality were identied, i.e.
intrahepatic obstruction and hypoalbuminemia (25.0
g/L). Similar observations were also reported by other
researchers. Using the TG07, Tsuyuguchi et al
[19]
have
revealed signicant association of hypoalbuminemia
(25.0 g/L) with refractoriness of AC. Nishino et al
[21]

have identied four independent predictors of urgent
ERCP in univariate analysis and by addition of organ
dysfunction index, they have also devised a severity
scoring system for AC, yielding a sensitivity of 87.5%
and a specicity of 95.8%, respectively in predicting the
Hepatobiliary & Pancreatic Diseases International
406 Hepatobiliary Pancreat Dis IntVol 12No 4 August 152013 www.hbpdint.com
need for urgent ERCP. These controversies of the TG07
have obliged the scientists to revise and optimize the
TG07. In the new revised guidelines 2013 (TG13), the
item about clinical response to conservative treatment in
the rst 24-hour has been omitted and new clinical and
laboratory parameters are added.
[18]
The revised version
seems more practical although there is an obvious
need to validate the efcacy and reliability of the added
features.
In the TG07, timing of the biliary drainage is
determined by severity grades of AC, i.e. with more
severe illness, an earlier drainage is recommended
and vice versa. Tsuyuguchi et al
[19]
investigated this
strategy with the conclusion that the overall AC-related
mortality was 4.2%: being 20%, 2.3% and 0% in severe,
moderate and mild AC, respectively. However, the
clinical outcome remains unclear with this strategy
because no control group was used in this report. This
limitation had actually obliged us to place our patients
in consistent and inconsistent subgroups. The protocol
at our facility is to perform early biliary drainage
irrespective of the etiology and severity grade of AC.
This strategy is supported by the present study with
adherence to the TG07 showing no impacts on clinical
outcome of our cohort. A low 30-day mortality of 5%
and a morbidity of 10% at 10-year time span further
augment our therapeutic approach, which is apparently
inconsistent with the Tokyo guidelines. Further
investigations with better study design especially
randomized controlled trials are required to address this
issue.
With regard to certain limitations, there is selection
bias due to retrospective nature of the present study,
which was carried out exclusively on hospitalized cases
in a single center. Moreover, AC might be diagnosed
when (i) presence of purulent bile, (ii) symptoms relief
by biliary decompression; or (iii) remission achieved by
antibiotics alone as dened by Kiriyama et al.
[18]
Our
inclusion criteria of considering only the patients with
purulent bile on ERCP might have been inadvertently
missed some atypical cases and may lead to a higher
sensitivity and a lower specicity. The inclusion of
outpatients and control group, and recruitment of
AC patients using new standards would have further
strengthened our observations through a broader
evaluation.
In summary, this is the rst study to verify the
application of the TG07 for diagnosis and treatment
of AC in Chinese patients. We, therefore, support and
recommend the TG07 based on their feasibility and
reliability in comparison with Charcot's triad in the
diagnosis of AC. However, the TG07 are insufcient
and less practical in predicting grade of severity and
clinical outcome in these patients. The latest 2013
edition of the Tokyo guidelines for AC has been recently
proposed with updated items in many aspects compared
to the former edition, but limited data available at the
present time. We are in the process of conducting new
studies with better study design to validate its potential
advantages.
Contributors: YYS proposed the study. SG, LEQ, LW, CFC,
HQY and ZXL performed ERCP procedures. SG and HL
collected, analyzed the data and wrote the rst draft. SG and
HL contributed equally to this study. HQ analyzed the data and
revised the manuscript. All authors contributed to the design
and interpretation of the study and to further drafts. YYS is the
guarantor.
Funding: None.
Ethical approval: This study was approved by the institutional
review board of the Chinese PLA General Hospital.
Competing interest: No benets in any form have been received
or will be received from a commercial party related directly or
indirectly to the subject of this article.
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Received February 4, 2013
Accepted after revision June 10, 2013