Diagnostic criteria and severity assessment of acute cholangitis: Tokyo Guidelines



# Introduction
The pathogenesis of acute cholangitis is biliary infection associated with partial or complete obstruction of the biliary system caused by any of various etiologies including choledocholithiasis, benign and malignant strictures, biliary-enteric anastomotic malfunction, and indwelling biliary stent malfunction. Biliary infection alone does not cause clinical cholangitis unless biliary obstruction raises the intraductal pressure in the bile duct to levels high enough to cause cholangiovenous or cholangiolymphatic refl ux. [bib_ref] Acute cholangitis, Lipsett [/bib_ref] Thus, acute cholangitis progresses from local biliary infection to the systemic infl ammatory response syndrome (SIRS), and advanced disease leads to sepsis with or without organ dysfunction.
Prior to the 1970s the mortality rate of patients with acute cholangitis was reported to be over 50%, [bib_ref] Acute suppurative cholangitis, a medical and surgical emergency, Andrew [/bib_ref] [bib_ref] Pathogenesis and clinical features of acute cholangitis accompanied by shock, Shimada [/bib_ref] but advances in intensive care, new antibiotics, and biliary drainage dramatically reduced the mortality rate to less than 7% by the 1980s. [bib_ref] Broad spectrum penicillin as an adequate therapy for acute cholangitis, Thompson [/bib_ref] [bib_ref] Abnormal pre-drainage serum creatinine as a prognostic indicator in acute cholangitis, Tai [/bib_ref] However, even in the 1990s the reported mortality rates in severe cases still ranged from 11% to 27%, [bib_ref] Emergency surgery for severe acute cholangitis. The high-risk patients, Lai [/bib_ref] [bib_ref] Acute biliary septic shock, Liu [/bib_ref] [bib_ref] Treatment of choice for choledocholithiasis in patients with acute obstructive suppurative cholangitis..., Chijiiwa [/bib_ref] and even now the severe form of acute cholangitis remains a fatal disease unless appropriate management is instituted.
The clinical diagnosis of acute cholangitis is made on the basis of the clinical fi ndings, such as Charcot's triad,in combination with the laboratory data and imaging fi ndings, and severity assessment is important because urgent biliary drainage is essential in "severe" cases. However, no standard criteria for the diagnostis and severity assessment of acute cholangitis have ever been established. In this portion of the Tokyo Guidelines, we propose diagnostic criteria and severity assessment criteria for acute cholangitis based on a review of the literature and the consensus of experts reached at the International Consensus Meeting for the Management of Acute Cholecystitis and Cholangitis, held on April 1-2, 2006, in Tokyo.

## Diagnostic criteria for acute cholangitis
A variety of different names and defi nitions of acute cholangitis are found in the literature, depending on the authors. [bib_ref] Emergency surgery for severe acute cholangitis. The high-risk patients, Lai [/bib_ref] [bib_ref] Treatment of choice for choledocholithiasis in patients with acute obstructive suppurative cholangitis..., Chijiiwa [/bib_ref] [bib_ref] Risk factors and classifi cation of acute suppurative cholangitis, Csendes [/bib_ref] [bib_ref] Factors in management of acute cholangitis, Thompson [/bib_ref] [bib_ref] Acute cholangitis. Multivariate analysis of risk factors, Gigot [/bib_ref] [bib_ref] Acute cholangitis, Boey [/bib_ref] [bib_ref] Acute bacterial cholangitis: an analysis of clinical manifestation, O&apos;connor [/bib_ref] [bib_ref] Acute suppurative cholangitis. Experience with 15 consecutive cases, Haupert [/bib_ref] [bib_ref] The urgency of diagnosis and surgical treatment of acute suppurative cholangitis, Welch [/bib_ref] [bib_ref] Clinical management of acute cholangitis, Saharia [/bib_ref] Some authors defi ned acute cholangitis based on clinical sign's such as Charcot's triad (fever and/or chills, abdominal pain, and jaundice), 6,16-17 while others emphasized the presence of biliary obstruction or the properties of the bile (suppurative cholangitis), 10,13-14 as a result, there are no standard diagnostic criteria for acute cholangitis. The clinical information used to establish the diagnosis of acute cholangitis includes a history of biliary disease, symptoms and signs, laboratory data, and imaging fi ndings.

## Clinical context and manifestations
A history of biliary disease suggests a clinical diagnosis of cholangitis in patients who present with clinical manifestations such as fever, abdominal pain, and jaundice. Patients with a history of gallstone disease, previous biliary surgery, or the insertion of a biliary stent are more likely to develop biliary infection.
Clinical manifestations are an important factor in making the diagnosis of acute cholangitis. In 1877,Charcot was the fi rst to describe the clinical triad of fever, jaundice and abdominal pain as a clinical manifestation of acute cholangitis, and in 1959, Reynolds and Dragan 18 were the fi rst to describe a severe form of cholangitis that included Charcot's triad plus septic shock and mental status change (Reynold's Pentad). [fig_ref] Table 1: Incidence of clinical manifestation of acute cholangitis [/fig_ref] summarizes the incidence of each clinical manifestation reported in the literature. [bib_ref] Emergency surgery for severe acute cholangitis. The high-risk patients, Lai [/bib_ref] [bib_ref] Treatment of choice for choledocholithiasis in patients with acute obstructive suppurative cholangitis..., Chijiiwa [/bib_ref] [bib_ref] Risk factors and classifi cation of acute suppurative cholangitis, Csendes [/bib_ref] [bib_ref] Factors in management of acute cholangitis, Thompson [/bib_ref] [bib_ref] Acute cholangitis. Multivariate analysis of risk factors, Gigot [/bib_ref] [bib_ref] Acute cholangitis, Boey [/bib_ref] [bib_ref] Acute bacterial cholangitis: an analysis of clinical manifestation, O&apos;connor [/bib_ref] [bib_ref] Acute suppurative cholangitis. Experience with 15 consecutive cases, Haupert [/bib_ref] [bib_ref] The urgency of diagnosis and surgical treatment of acute suppurative cholangitis, Welch [/bib_ref] [bib_ref] Clinical management of acute cholangitis, Saharia [/bib_ref] Fever and abdominal pain are the most frequently observed clinical manifestations in acute cholangitis, with an incidence of each of up to 80% or more, whereas jaundice is observed in 60%-70% of cases. The incidence of Charcot's triad is reported in not more than 72% (range, 15.4% to 72%) of patients with acute cholangitis, and Reynolds' pentad is extremely rare, reported in only 3.5%-7.7% of the patients.

## Laboratory data
Laboratory data indicative of infl ammation (e.g., leukocytosis and an elevated C-reactive protein [CRP] level), and evidence of biliary stasis (e.g., hyperbilirubinemia, elevation of biliary enzymes and liver enzymes) are frequently seen in patients with acute cholangitis, and such laboratory fi ndings support the diagnosis. [fig_ref] Table 2: Positive rates for blood tests in acute cholangitis WBC, white blood cells [/fig_ref] summarizes the positive rate for various blood tests in patients with acute cholangitis reported in the literature. [bib_ref] Abnormal pre-drainage serum creatinine as a prognostic indicator in acute cholangitis, Tai [/bib_ref] [bib_ref] Acute cholangitis. Multivariate analysis of risk factors, Gigot [/bib_ref] [bib_ref] Acute cholangitis, Boey [/bib_ref] [bib_ref] Clinical management of acute cholangitis, Saharia [/bib_ref] Imaging fi ndings It is usually impossible to identify evidence of bile infection itself by imaging modalities. Imaging evidence of biliary dilatation (evidence of biliary obstruction) and/ or the etiology of the underlying disease (tumor, gallstones, stent-related, etc.) can support the clinical diagnosis of cholangitis. [fig_ref] Table 3: Diagnostic criteria for acute cholangitis [/fig_ref] shows the diagnostic criteria for acute cholangitis that were fi nally adopted by the Organizing Committee. The basic concepts of the criteria are as follows:

## Diagnostic criteria for acute cholangitis
(1) Charcot's triad is a defi nite diagnostic criterion for acute cholangitis, (2) if a patient does not have all the components of Charcot' s triad (acute cholangitis is suspected), then defi nite diagnosis can be achieved if both an "infl ammatory response" and "biliary obstruction" are demonstrated by the laboratory data (blood tests) and imaging fi ndings.

## Outcome of the tokyo consensus meeting
More than 90% of the participants at the Tokyo Consensus Meeting agreed that the four criteria of: (1) a
[formula] ---------------------------------------------------------------------------------------------------------------------------------------------------------------------- B. Laboratory data 5. Evidence of infl ammatory response a 6. Abnormal liver function tests b ---------------------------------------------------------------------------------------------------------------------------------------------------------------------- C. [/formula]

## Severity assessment of acute cholangitis
Patients with acute cholangitis may present with anything from a mild, self-limited illness to a severe, potentially life-threatening illness. Most cases respond to initial medical treatment consisting of general supportive therapy and intravenous antibiotics, but 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, requiring appropriate management that includes intensive care, organ-supportive care, and urgent biliary drainage, in addition to medical treatment. [fig_ref] Table 4: Prognostic factors in acute cholangitis [/fig_ref] summarizes the risk factors reported in the literature for poor outcome in patients with acute cholangitis. [bib_ref] Acute suppurative cholangitis, a medical and surgical emergency, Andrew [/bib_ref] [bib_ref] Pathogenesis and clinical features of acute cholangitis accompanied by shock, Shimada [/bib_ref] [bib_ref] Emergency surgery for severe acute cholangitis. The high-risk patients, Lai [/bib_ref] [bib_ref] Risk factors and classifi cation of acute suppurative cholangitis, Csendes [/bib_ref] [bib_ref] Acute cholangitis. Multivariate analysis of risk factors, Gigot [/bib_ref] [bib_ref] Acute cholangitis, Boey [/bib_ref] [bib_ref] Acute suppurative cholangitis. Experience with 15 consecutive cases, Haupert [/bib_ref] Organ dysfunction is the most common predictor of a poor outcome. On the other hand, based on the pathophysiology, "severe" acute cholangitis can also be defi ned as that which accompanies organ dysfunction caused by sepsis. Thus, "the onset of organ dysfunction" is an important factor in the defi nition of severe (grade III) acute cholangitis.

## Severity assessment criteria
Another factor for the severity assessment of acute cholangitis is "response to initial medical treatment"; treatment consisting of general supportive care and antibiotics should be instituted as soon as possible for all patients who are diagnosed with acute cholangitis. Patients diagnosed with acute cholangitis that is not complicated by organ dysfunction, who did not respond to medical treatment and who continue to have SIRS and/or sepsis require additional treatment that includes either a change of antibiotic or biliary drainage. The severity of such cases is classifi ed as moderate (grade II). Patients who respond to medical treatment and whose clinical manifestations and laboratory data improve are classifi ed as having mild (grade I) disease. and [fig_ref] Table 6: Defi nitions of severity assessment criteria for acute cholangitis [/fig_ref] show the concepts and criteria for the severity assessment of acute cholangitis.

## Outcome of the tokyo consensus meeting
More than 70% of the participants at the Tokyo Consensus Meeting agreed that the severity of acute cholangitis should be divided into three gradesmild (grade I), moderate (grade II), and severe (grade III). To stratify acute cholangitis into the three grades, two different criteria were necessary, and it was decided to use "onset of organ dysfunction" and "response to the initial medical treatment" as criteria for the severity assessment of acute cholangitis .

## Discussion at the tokyo consensus meeting
Diagnostic criteria for acute cholangitis "Acute cholangitis" is a clinical diagnosis. A defi nite diagnosis cannot be made on the basis of the results of any single test. The diagnosis of acute cholangitis is made on the basis of: (1) a history of biliary disease, (2) the clinical manifestations, (3) laboratory data that indicate the presence of infl ammation and biliary obstruction, and (4) imaging fi ndings that indicate biliary obstruction. More than 90% of participants at the International Consensus Meeting agreed that these four criteria were suitable for making the diagnosis of acute cholangitis (consensus was reached).
In terms of the clinical context and manifestations, a history of biliary disease and the clinical presentation are important factors in reaching the diagnosis. A history of biliary disease, such as gallstones, a history of previous biliary surgery, and having an indwelling biliary stent play an important role in making the diagnosis, as agreed upon by many participants at the Consensus Meeting. The more important clinical manifestations are clinical signs, such as Charcot's triad (fever and/or chills, abdominal pain, and jaundice). According to the literature, 50%-70% of acute cholangitis patients present with Charcot's triad, meaning that more than onethird of acute cholangitis patients do not present with all the components of Charcot's triad. The laboratory data and imaging fi ndings can provide evidence to support the diagnosis in patients who have clinical manifestations of acute cholangitis but who do not show all the components of Charcot's triad (refer to [fig_ref] Table 3: Diagnostic criteria for acute cholangitis [/fig_ref].

## Severity assessment criteria for acute cholangitis
A systematic review of the literature revealed that there were no standard criteria for either the diagnosis or se-verity assessment of acute cholangitis. Some authors have defi ned acute cholangitis associated with Reynold's pentad (Charcot's triad plus "shock" and "disturbance of consciousness") or organ dysfunction as "severe", while others have referred to it as "toxic cholangitis" or "acute obstructive suppurative cholangitis (AOSC)". A proposal that the onset of dysfunction of at least one organ be used as the criterion for severe (grade III) disease was supported by more than 90% of the panelists at the International Consensus Meeting (consensus was reached).
There was some argument about whether the score on an acute physiology scoring system, such as Acute physiology and chronic health evaluation (APACHE II) score or a multiple organ dysfunction scoring system, such as Marshall's system, or sepsis-related organ failure assessment (SOFA) system should be used as a criterion for severe (grade III) acute cholangitis. The principal advantage of these scoring systems is that they provide gradations of severity. The APACHE II system has been validated, especially for critical care patients, including patients with sepsis, and acute cholangitis can be interpreted as a subset of sepsis. The disadvantage of these scoring systems is that the scores are sometimes troublesome to calculate, and critically speaking, they have not been satisfactorily validated in patients with acute cholangitis. The vote on this argument showed that 37.8% of the panelists supported the use of APACHE II and 62.2% did not. As a result of this vote, the chairmen of this session, Drs. Yoshifumi Kawarada (Japan) and Henry Pitt (USA), proposed to remit the fi nal decision on whether or not APACHE II should be included as a criterion for severe (grade III) acute cholangitis to the Organizing Committee, and this proposal was approved by the audience.
After the meeting, the Organizing Committee decided not to include the use of the APACHE II score as a criterion for the defi nition of severe (grade III) acute cholangitis, and we established the criteria by evaluating the presence or absence of the dysfunctions of six major organs/systems (refer to [fig_ref] Table 6: Defi nitions of severity assessment criteria for acute cholangitis [/fig_ref].
Deciding on the criteria for the assessment of acute cholangitis as moderate was the hardest part of this session. More than 70% of the participants agreed that a middle category of severity -moderate (grade II)was necessary for acute cholangitis (consensus was reached).
The original defi nition of moderate (grade II) acute cholangitis was "acute cholangitis that requires biliary drainage but is not complicated by organ dysfunction." However, more than 80% of the participants voted against the need for biliary drainage as a criterion because it is a therapeutic intervention that should be selected only after the severity assessment has been completed. Thus, another criterion was needed in order to stratify acute cholangitis into three grades. Other criteria for assessing acute cholangitis as moderate (grade II) were suggested by the audience. The most accepted criterion during the discussion was "resistance to initial treatment", with some others being "recurrence of symptoms" and "SIRS". The chairmen of this session also proposed to remit the fi nal decision to the Organizing Committee, and this proposal was approved by the audience.
After the Meeting, the Organizing Committee concluded that the criterion for assorting into moderate (grade II) and mild (grade I) acute cholangitis should be "response to initial medical treatment consisting of general supportive care (intravenous fl uid) and antibiotics," i.e., acute cholangitis that responds to medical treatment is defi ned as mild (grade I) acute cholangitis, whereas acute cholangitis that does not respond to the initial medical treatment but does not have organ dysfunction is defi ned as moderate (grade II) acute cholangitis [fig_ref] Table 6: Defi nitions of severity assessment criteria for acute cholangitis [/fig_ref]. No specifi c data or fi ndings were adopted as criteria, because it is impossible to predict the need for biliary drainage based on the laboratory data or other fi ndings. It was therefore concluded that we considered that it is important to stratify acute cholangitis as "severe" or "non-severe" at the time of diagnosis. Patients with the former require urgent biliary drainage in addition to general and organsupportive treatment, while patients with the latter should be monitored to determine whether they respond to the initial medical treatment.
[table] Table 1: Incidence of clinical manifestation of acute cholangitis [/table]
[table] Table 2: Positive rates for blood tests in acute cholangitis WBC, white blood cells; ALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CA 19-9, carbohydrate antigen 19-9 [/table]
[table] Table 3: Diagnostic criteria for acute cholangitis [/table]
[table] Table 4: Prognostic factors in acute cholangitis [/table]
[table] Table 6: Defi nitions of severity assessment criteria for acute cholangitis [/table]