These authors contributed equally to this study.
Comparison of two editions of Tokyo guidelines for the management of acute cholangitis
Article first published online: 30 JUN 2013
© 2013 Japanese Society of Hepato-Biliary-Pancreatic Surgery
Journal of Hepato-Biliary-Pancreatic Sciences
Volume 21, Issue 2, pages 113–119, February 2014
How to Cite
Sun, G., Han, L., Yang, Y., Linghu, E., Li, W., Cai, F., Kong, J., Wang, X., Meng, J., Du, H., Wang, H., Huang, Q., Hyder, Q. and Zhang, X. (2014), Comparison of two editions of Tokyo guidelines for the management of acute cholangitis. Journal of Hepato-Biliary-Panc, 21: 113–119. doi: 10.1002/jhbp.9
- Issue published online: 22 JAN 2014
- Article first published online: 30 JUN 2013
- Acute cholangitis;
- Biliary drainage;
- Interrater agreement;
- Tokyo guidelines
The Tokyo guidelines from 2007 (TG07) and 2013 (TG13) were compared for the management of acute cholangitis (AC).
We reviewed patients with clinically-proven AC by detecting purulent biles during biliary drainage. TG07 and TG13 were compared regarding diagnosis, severity grading and prognostic values. New risk factors for 30-day mortality were investigated.
Definite diagnosis for 120 eligible patients was made in 104 (86.7%) and 101 (84.2%) cases by TG07 and TG13, respectively (P = 0.36), higher than 61 (50.8%) by Charcot's triad (P < 0.001). Diagnostic overlap and concordance (κ) are 90.8% (109/120) and 0.63 (P < 0.0001). Patients classified into mild and moderate grades by TG07 and TG13 differed significantly (P = 0.043). Both guidelines could not predict clinical outcomes except the needs for multi ERCP session by TG13. 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 30-day mortality in multivariate model.
Two guidelines are reproducible and reliable in AC diagnosis but different in severity grading. TG13 are more practical for immediate severity grading, enabling planning treatment upon admission. Intrahepatic obstruction is a new candidate predictor of 30-day mortality for further assessment.
Acute cholangitis (AC) is a common clinical syndrome that develops as a result of cholestasis and infection in the biliary tract. AC can be life threatening despite the advances in minimally invasive treatment modalities, with reported mortality rates ranging from 8% to 10% [1, 2]. The early identification of AC, appropriate severity assessment, and timely intervention are crucial to resolve biliary obstruction and systemic infectious response.
Conventional diagnostic criteria based on either a triad of right upper quadrant abdominal pain, fever and jaundice (Charcot's triad, 1877 ) or combination of mental confusion and hypotension (Reynolds’ pentad, 1959 ) are still used in clinical settings. But their diagnostic value and clinical implication are problematic due to the relatively low rate of the full complement of these signs [5, 6]. In this context, several AC diagnostic criteria and scoring systems have been devised [7-9], but none was universally accepted as the standard guidelines for clinical practice.
The more recent AC guidelines were proposed after an international expert consensus meeting in Tokyo in 2007, known as the Tokyo Guidelines for the Management of Acute Cholangitis and Cholecystitis (TG07) , which encompass a set of criteria for diagnosis, severity assessment, and treatment of AC separately. Continuous review and criticisms on TG07 have been raised by endoscopists and researchers in the past 5 years. Although the favorable diagnostic performance of TG07 has been demonstrated by several retrospective studies within Japan, its severity assessment criteria and treatment recommendations remain controversial. For example, the TG07 require a 24-h observation time to differentiate mild and moderate AC [11-14]. This is particularly inapplicable when early/urgent intervention is routinely performed and moreover, such a strategy may potentially result in delay in biliary drainage and sequential sepsis progression. To modify and update the guidelines, the Tokyo Guidelines Revision Committee was organized and proposed the latest 2013 edition, known as the updated Tokyo Guidelines for Acute Cholangitis and Cholecystitis (TG13) . The development of TG13 was mainly made in an evidence-based fashion and a portion of items was based on expert opinions and still need further assessment. We therefore conducted this study to compare the two editions of guidelines in terms of diagnostic yield and their concordance, severity grading, prognostic values, and possible risk factors for mortality. We found both guidelines are reliable for AC diagnosis with good interrater agreement. But TG13 are preferred over TG07 as the revised guidelines provide more practical standard for early diagnosis, severity classification upon admission, and timely treatment strategy albeit limited prognostic roles. A panel of 14 parameters within or beyond the Tokyo Guidelines was analyzed and a new candidate risk factor for 30-day mortality was identified.
Patients and methods
We identified patients discharged from the Chinese PLA General Hospital with a principal diagnosis of AC from January 2000 to December 2009. The clinically definite AC was made by detecting purulent bile during biliary drainage, regardless of etiology. Clinical information was retrieved from our prospectively established endoscopic retrograde cholangiopancreatography (ERCP) database, with the approval of the institutional review board of our hospital. For patients with multiple hospitalizations during the study period, only the initial episode was reviewed. Patients were excluded for age < 18 years and those who underwent prior biliary drainage after onset per protocol.
The initial diagnosis of AC in over half of our patients was based on Charcot's triad. For patients without the full complement of typical symptoms, the AC was also considered when laboratory tests and imaging evaluations revealed the presence of biliary obstruction and acute infection. The laboratory tests including blood counts, serum chemistries, liver and renal function tests, coagulation assay, urinalysis with glucose and amylase level, were performed immediately on admission and repeated whenever necessary. Blood cultures were obtained in patients with body temperature > 38.5°C and an episode of chilling. Abdominal ultrasonography was routinely performed within 12 h of admission. Plain or enhanced computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) were indicated in selected cases with ambiguous ultrasonic findings or complicated cases with unknown etiology or multi intrahepatic obstruction . All patients were fasted and their vital signs including urinary output were monitored 6 hourly. Intravenous fluid with broad-spectrum antibiotics was given immediately and a central venous line was established in case of hypotension or shock.
In our institution, emergent endoscopic drainage within 24 h of admission is recommended to any AC patients once the causes and site of obstruction are identified, regardless of etiology and severity of diseases. An observation period of 24 up to 48 h is permitted for pretreatment assessment in complicated cases, during which an immediate endoscopic drainage will be performed to 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. Stent placement or nasobiliary drainage with or without sphincterotomy were adopted for high risk patients and the definitive management would be undertaken until cholangitis subsided. 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 final clinical outcomes. Ultrasound-guided percutaneous transhepatic biliary drainage (PTBD) or surgery was used as the alternate modalities if ERCP was non-rewarding. Hospital stay was defined as the time duration from admission to exit from the hospital. Given the malignant etiology that existed in our patients, death of the patient within 30 days of admission was regarded as the clinical endpoint.
Comparison of guidelines
TG13 provide novel standards and items for diagnosis, severity assessment, and treatment of AC on the basis of TG07. We re-examined and compared all of these aspects in eligible patients as follows:
- (1) Diagnostic yields and concordance. Definite diagnosis of AC can be made by TG07 either by presence of Charcot's triad or by addition of positive findings in both laboratory and imaging data in suspected cases . TG13 omitted the prior items of abdominal pain and history of biliary diseases from the diagnostic criteria and reconstructed remaining items into three components: (A) systemic infection, (B) cholestasis, and (C) imaging findings. Only patients satisfying at least one item of all three components were deemed definite AC . Their diagnostic yields were compared with criterion of Charcot's triad and κ-statistic was performed to test concordance.
- (2) Severity grading. Three severity categories were defined by the Tokyo guidelines: mild (Grade I), moderate (Grade II), and severe (Grade III). The standard for sever AC remains unchanged (i.e. presenting any sign of organ dysfunction). However, the TG07 need a 24-h observation period for separating mild to moderate cases based on clinical response to conservative treatment, which might be inapplicable for those who received immediate ERCP on admission. With the intent of comparing the performance of two guidelines, 36.7% (44/120) of cases who could not completely fulfill the TG07 for severity grading were appropriately excluded (Fig. 1). TG13 provides five new items in the moderate category , in which the presence of two of five items were regarded as moderate cases. We compared the case number of each severity category by two guidelines and calculated their interrater agreement as well.
- (3) Impacts on the clinical outcomes. Associations between severity grades and clinically-related outcomes including hospital stay, ERCP success rate, needs for multiple ERCP session, morbidity and 30-day mortality were investigated.
- (4) Identification of risk factors for 30-day mortality.
Demographic data and baseline characteristics were summarized with descriptive statistics using mean ± standard deviation (SD) for continuous variables and percentage (%) for categorical variables, respectively. Paired χ2 test and signed-rank test were applied to determine the differences in diagnostic yields and severity grades between TG07 and TG13. Interrater agreement with strength estimation was performed using κ-statistics with Bowker's test. Prognostic values of two guidelines and risk factors for 30-day mortality were analyzed using univariate and/or multivariate logistic regression models. JMP package 9.0 (SAS Institute, Cary, NC, USA) was used for overall statistical analysis. A P-value of <0.05 was considered statistically significant.
We identified 120 eligible patients: 83 (69.1%) were male and the mean age was 66.0 ± 15.1 years. Benign obstruction was found in 82 (68.3%) cases and 76 (90.2%) presented with choledocholithiasis; in 38 (31.7%) malignant patients, 35 (92.1%) were demonstrated as primary hepatopancreaticobiliary carcinoma. The demographic and baseline characteristics were summarized in Table 1. Typical Charcot's triad and Reynolds’ pentad occurred in 61 (50.8%) and 12 (10.0%) cases, respectively. Coexisting acute biliary pancreatitis was exclusively seen in 18 (15.0%) benign patients, and all presented with mild pancreatitis as shown by normal morphology in pancreas by CT in four, and only mild gland enlargement with peripancreatic inflammatory changes in the remaining 14. Baseline blood routine and biochemistry tests revealed leukocytosis, hyperbilirubinemia, elevated serum transaminase, high level of CRP value, and prolonged international normalized ratio (INR) in our patient cohort.
|Age (mean ± SD)||66.0 ± 15.1|
|Gender (male, %)||83 (69.1%)|
|Etiology (n, %)|
|Benign obstruction||82 (68.3%)|
|Malignant obstruction||38 (31.7%)|
|Body temperature||38.2 ± 1.2|
|Pulse||87.4 ± 12.0|
|Shock (SBP ≤ 90 mmHg)||14 (11.7%)|
|Charcot's triad (n, %)||61 (50.8%)|
|Reynolds’ pentad (n, %)||12 (10.0%)|
|Co-existing diseases (n, %)|
|Acute pancreatitis||18 (15.0%)|
|Liver abscess||3 (2.5%)|
|Gastrointestinal bleeding||3 (2.5%)|
|Renal failure||2 (1.7%)|
|Laboratory tests (mean ± SD)|
|WBC (×109/l)||12.0 ± 5.8|
|T-Bil (umol/l)||147.4 ± 111.5|
|ALT (U/l)||142.5 ± 132.9|
|AST (U/l)||140.4 ± 138.7|
|γ-GT (U/l)||573.7 ± 429.8|
|ALP (U/l)||363.3 ± 255.4|
|ALB (g/l)||34.5 ± 6.3|
|CRP (mg/dl)||8.9 ± 4.0|
|PT-INR||1.2 ± 0.8|
Endoscopic biliary drainage as the first treatment option was successful in 105 (87.5%) of 120 patients with no serious procedure-related complications such as severe gastrointestinal bleeding, perforation, severe pancreatitis, and death. However, mild to moderate post-ERCP complications were recorded in 12 patients (10.0%): acute pancreatitis in eight (6.7%); and bleeding from sphincterotomy in four (3.3%). Alternative treatments for ERCP-failed cases were performed and symptoms relieved in 10 (8.3%) patients: PTBD in two (1.7%); and surgical drainage in eight (6.7%). The causes of early death in six (5.0%) cases were refractory biliary infection (5, 4.2%) and cerebral hemorrhage (1, 0.8%) despite successful biliary drainage.
The definite diagnosis of AC was made in 104 (86.7%) and 101 (84.2%) cases by TG07 and TG13, respectively (P = 0.36); both were significantly higher than 50.8% (61) by Charcot's triad (Table 2, P < 0.001). Diagnostic overlap was found in 109 (90.8%) cases of whom 97 cases were correctly identified and 12 were misinterpreted by TG07 and TG13 simultaneously. Hence, the statistical concordance shown by the κ-value were 0.63 (P < 0.0001), which was deemed good agreement in strength. When subjects were placed into two groups by etiology, the diagnostic sensitivity of TG07 and TG13 reached 94.7% and 92.1% in malignant patients, respectively as opposed to the decreased sensitivity of 44.7% by Charcot's triad (Table 2, P < 0.001).
|Malignant etiologyc (n = 38)||Benign etiology (n = 82)||Total (n = 120)|
|TG13a, b||35 (92.1%)||66 (80.5%)||101 (84.2%)|
|TG07a||36 (94.7%)||68 (82.9%)||104 (86.7%)|
|Charcot's triad||17 (44.7%)||44 (53.7%)||61 (50.8%)|
With respect to severity classification of AC, the numerical distribution of severity grades (TG07 vs. TG13) in our patients was: Grade I (11, 14.5%: 39, 32.5%); Grade II (40, 52.6%: 56, 46.7%); and Grade III (25, 32.9%: 25, 20.8%), (Fig. 1, P = 0.036 for the whole group). TG13 were more likely to downgrade AC patients versus TG07.
We further assessed the prognostic values of two sets of guidelines. Numerically, patients with high severity grades appeared to have trends towards extended hospital stay, decreased ERCP success rate, and elevated mortality rate in the Tokyo Guidelines (Table 3, P = 0.09–0.64). However, only the need for multiple ERCP sessions was significantly associated with severity grading in TG13 (P = 0.04) rather than TG07 (P = 0.09). Such findings obliged us to investigate the possible risk factors of bad prognosis. We gathered 14 prognostic variables of 30-day mortality for analysis. Six variables were parameters of organ dysfunction proposed in both TG07 and TG13, another five candidates were parameters for Grade II category in TG13, and an additional two variables were malignant etiology and intrahepatic biliary obstruction. These were the important characteristics in our cohort. Univariate analysis revealed that serum creatinine > 2.0 mg/dl, prothrombin time-international normalized ratio (PT-INR) > 1.5, intrahepatic biliary obstruction, malignant etiology and serum albumin level (0.7 × STD, ≤25 g/dl) were significantly associated with 30-day mortality (Table 4). 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 g/dl (OR = 17.3, 95% CI: 3.5–313.6; P < 0.001) were independent risk factors for 30-day mortality.
|Grade I||Grade II||Grade III||P||Grade I||Grade II||Grade III||P|
|Hospital stay (days)||13.4 ± 10.2||16.8 ± 8.9||17.9 ± 13.2||0.67||12.8 ± 9.7||15.6 ± 11.2||16.7 ± 13.3||0.64|
|ERCP success rate||11 (100%)||39 (97.5%)||20 (80.0%)||0.08||36 (92.3%)||49 (87.5%)||20 (80.0%)||0.35|
|ERCP complication rate||1 (9.1%)||4 (10.0%)||3 (12.0%)||0.71||7 (17.9%)||2 (3.6%)||3 (12.0%)||0.88|
|Multiple ERCP session||2 (18.2%)||9 (22.5%)||9 (36.0%)||0.11||4 (10.3%)||15 (26.8%)||9 (36.0%)||0.04**|
|Early death||0||2 (5.0%)||2 (8.0%)||0.20||0||4 (7.1%)||2 (8.0%)||0.09|
|Risk factors||Odds ratio||95% CI||P-value|
|Parameters of organ dysfunction|
|Hypotension requiring dopamine ≥5 μl/kg per min or any dose of dobutamine||1.55||0.9–10.7||0.7|
|Disturbance of consciousness||2.08||0.1–14.7||0.6|
|PaO2/FiO2 ratio < 300||NA|
|Serum creatinine > 2.0 mg/dl||22.6||8.1–632.4||0.03a|
|PT-INR > 1.5||8.9||1.1–56.8||0.04a|
|Platelet count < 100 000/μl||3.5||0.4–19.7||0.2|
|Parameters of Grade II in TG13|
|WBC (>12 000/mm3, <4000/mm3)||0.8||0.3–6.7||0.6|
|High fever (≥39 °C)||3.6||2.0–88.6||0.5|
|Age (≥75 years)||3.3||0.5–63.5||0.3|
|CRP ≥ 5 mg/dl||2.5||1.5–16.9||0.9|
|Hyperbilirubinemia (total bilirubin ≥ 5 mg/dl)||10.1||1.3–267.7||0.2|
|Hypoalbuminemia (<25.0 g/l)||21.3||3.9–352.8||0.001a|
|Additional candidate variables|
Since 2007 when the Tokyo Guidelines for AC were originally proposed, the guidelines continued to be validated and commented on [11-14, 17] until the new 2013 edition was published . However, few data were available outside Japan. Herein, we re-examined and compared the two sets of guidelines by retrospective review of 120 clinically-proven AC patients from a Chinese tertiary hospital. We found the TG07 and TG13 were comparable and more reliable for AC diagnosis than conventional criterion of Charcot's triad. However, limited prognostic values were observed equally for both guidelines. Two independent risk factors for AC-related mortality were identified, including a new variable of intrahepatic biliary obstruction, which has never been incorporated into either edition of the guidelines.
Major revisions of TG07 were achieved thoroughly in all aspects. For AC diagnosis, TG13 provides new standards for suspected and definite diagnosis by reconstructing diagnostic items and appropriately omitting items of abdominal pain and history of biliary diseases. Kiriyama et al. demonstrated that the new diagnostic criteria had an improved diagnostic sensitivity (91.8%) as compared with 82.6% and 26.4% by TG07 and Charcot's triad, respectively . Our results validated the superior diagnostic sensitivity of TG13 (84.2%) and TG07 (86.7%) for AC over Charcot's triad (50.8%); however, no significant difference was observed between two criteria (P = 0.36). The diagnostic overlap was observed in 109 (90.8%) cases with a good interrater agreement (κ = 0.64), indicating that the two guidelines are considerably reproducible and reliable for AC diagnosis. Of note, patients with malignant obstruction seemed more likely to be identified by either edition of the Tokyo Guidelines (Table 2). This observation apparently has important implications that these high risk patients might have more opportunities in TG13 than the previous edition for early diagnosis and timely treatment. Further studies are still required to investigate the difference between the two sets of guidelines for AC diagnosis and whether removal of abdominal pain and history of biliary diseases by TG13 brings additional diagnostic benefits.
For severity assessment, a 24-h time period was needed by TG07 to observe clinical response to conservative treatment necessary to separate the mild and moderate cases . Such criterion has been argued due to the inability to assess the severity upon admission and conduct biliary drainage immediately, potentially inducing treatment delay and subsequent sepsis progression . In contrast, the TG13 appear more straightforward and practical for physicians. The prior standard for the severe category is preserved by TG13 and five new parameters for moderate disease are proposed, which can be available upon admission. These modifications are deemed a great improvement over TG07 as shown by 44 (36.7%) patients inapplicable for severity grading by TG07 due to early ERCP performed without 24 h waiting and all 120 patients eligible in TG13. Compared to TG07, more patients were classified as mild disease, which was more likely to reflect the actual severity spectrum in clinical settings [18, 19]. However, none of the severity assessment criteria were capable of predicting clinical outcomes except the need for multiple ERCP session by TG13. We speculated that the widespread use of early biliary drainage in our patients might play an important protective role and partially attenuate the prognostic values of the guidelines. Nevertheless, two independent risk factors for 30-day mortality were identified, of which the hypoalbuminemia (0.7 × STD, ≤25.0 g/l) has been incorporated into TG13 as one of parameters for moderate disease , another is intrahepatic obstruction, which is a new predictor and needs further assessment.
The treatment strategy, in particular the timing of biliary drainage, is primarily dependent on the severity grades in TG07, that is, elective, early (within 24 h of admission), and urgent (within 12 h of admission) interventions were designated to mild, moderate, and severe grades, respectively . Such a harsh strategy can be less practical as the treatment scheme can solely be made until the termination of the 24-h observation period . Theoretically, without timely biliary decompression the dynamic sepsis progression can be dramatic and can result in life-threatening status within 24 h [1, 8]. Therefore, we advocate early biliary drainage be performed as soon as possible to all AC patients . Our policy apparently complies with what has been proposed by TG13. In addition, this treatment strategy is amendable for suspected AC patients, broadening the application scope of early biliary drainage. Of note, we stressed the importance of pretreatment assessment of underlying etiology and biliary obstruction sites by imaging modalities . A better understanding of the nature of AC can facilitate making a better treatment strategy and reduce potential procedure-related risks [20, 21]. For complicated cases, like malignant intrahepatic obstruction, 24–48 h will be needed when enhanced CT or MRCP was necessary. These patients will be monitored intensively and an immediate biliary drainage is available when illness worsens. This might justify the favorable outcomes of our patients as shown by a 30-day mortality rate of 5% and a complication rate of 10%, comparable to previously reported results. Additional investigations on this issue are clearly warranted and should include prospective strategies and larger sample size.
Limitations of our study included relative small size and its retrospective nature, which inherently makes it susceptible to certain biases to a single center. All subjects were hospitalized cases, thus the measurement of diagnostic specificity, accuracy, and positive/negative values was inapplicable. The inclusion of outpatients and control group would have further strengthened our observation via a broader evaluation. Moreover, AC might be defined as: (1) presence of purulent biliary leakage; (2) clinical remission due to bile duct drainage; or (3) remission achieved by antimicrobial therapy alone in patients in whom the only site of infection was the biliary tree as Kiriyama's definitions . Our incomplete inclusion criteria of considering only the patients with purulent bile on ERCP might have caused us to inadvertently miss some atypical cases and may lead to higher sensitivity and lower specificity. In addition, the clinical information was collected from 2000 to 2009 in which the data representing respiratory function (PaO2/FiO2 ratio) were not available in all patients for analysis.
In summary, this is the first study to compare the two editions of the Tokyo Guidelines for AC in Chinese patients. Both guidelines are reproducible and more reliable for AC diagnosis in comparison with Charcot's triad; however, the TG13 are proven to be more practical for physicians and compatible with other guidelines and policy, enabling immediate severity assessment and treatment decision-making at the time of admission. The TG13 represent a great improvement in management of AC and should be prioritized in future clinical practice. However, the two guidelines have limited prognostic values and further studies with better design are still warranted.
Conflict of interest
- 3JM. C. Lecons sur les maladies du fore des voices biliares et des veins faites à la Faculté de Médicine de Paris [French]. (Recueillies et publliées par Bournesville et Sevestre, Paris, 1877) English translation (New York, 1878).
- 5Diagnosis and management of acute cholangitis. Curr Gastroenterol Rep. 2011;13:166–172..