Definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis: Tokyo Guidelines

This article discusses the defi nitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis. Acute cholangitis and cholecystitis mostly originate from stones in the bile ducts and gallbladder. Acute cholecystitis also has other causes, such as ischemia; chemicals that enter biliary secretions; motility disorders associated with drugs; infections with microorganisms, protozoa, and parasites; collagen disease; and allergic reactions. Acute acalculous cholecystitis is associated with a recent operation, trauma, burns, multisystem organ failure, and parenteral nutrition. Factors associated with the onset of cholelithiasis include obesity, age, and drugs such as oral contraceptives. The reported mortality of less than 10% for acute cholecystitis gives an impression that it is not a fatal disease, except for the elderly and/or patients with acalculous disease. However, there are reports of high mortality for cholangitis, although the mortality differs greatly depending on the year of the report and the severity of the disease. Even reports published in and after the 1980s indicate high mortality, ranging from 10% to 30% in the patients, with multiorgan failure as a major cause of death. Because many of the reports on acute cholecystitis and cholangitis use different standards, comparisons are diffi cult. Variations in treatment and risk factors infl uencing the mortality rates indicate the necessity for standardized diagnostic, treatment, and severity assessment criteria.Offprint requests to: Y. Kimura

# Introduction
Acute biliary infection is a systemic infectious disease which requires prompt treatment and has a signifi cant mortality rate. [bib_ref] Emergency surgery for severe acute cholangitis. The high-risk patients, Lai [/bib_ref] The fi rst report on acute biliary infection was Charcot's "The symptoms of hepatic fever" in 1877. [bib_ref] De la fi evre hepatique symptomatique. Comparison avec la fi evre uroseptique, Charcot [/bib_ref] This section of the Tokyo Guidelines defi nes acute cholangitis and acute cholecystitis, and describes the incidence, etiology, pathophysiology, classifi cation, and prognosis of these diseases.

## Acute cholangitis

## Defi nition
Acute cholangitis is a morbid condition with acute infl ammation and infection in the bile duct.
Historical aspects of terminology Hepatic fever. "Hepatic fever" was a term used for the fi rst time by [bib_ref] De la fi evre hepatique symptomatique. Comparison avec la fi evre uroseptique, Charcot [/bib_ref] in his report published in 1877. Intermittent fever accompanied by chills, right upper quadrant pain, and jaundice became known as Charcot's triad.
Acute obstructive cholangitis. Acute obstructive cholangitis was defi ned by Reynolds and Dargan 3 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 emergent surgical biliary decompression was the only effective procedure for treating the disease. These fi ve symptoms were then called Reynolds's pentad.
Longmire's classifi cation.Longmire classifi ed patients with the three characteristics of intermittent fever accompanied by chills and shivering, right upper quadrant pain, and jaundice as having acute suppurative cholangitis. Patients with lethargy or mental confusion and shock, along with the triad, were classifi ed as having acute obstructive suppurative cholangitis (AOSC). He also reported that the latter corresponded to the morbidity of acute obstructive cholangitis as defi ned by Reynolds and Dargan, [bib_ref] Acute obstructive cholangitis. A distinct syndrome, Reynolds [/bib_ref] and he classifi ed acute microbial cholangitis as follows:
1. Acute cholangitis developing from acute cholecystitis 2. Acute non-suppurative cholangitis 3. Acute suppurative cholangitis 4. Acute obstructive suppurative cholangitis 5. Acute suppurative cholangitis accompanied by hepatic abscess.

## Incidence etiology
Acute cholangitis requires the presence of two factors:
(1) biliary obstruction and (2) bacterial growth in bile (bile infection). Frequent causes of biliary obstruction are choledocholithiasis, benign biliary stenosis, stricture of a biliary anastomosis, and stenosis caused by malignant disease (level 4). [bib_ref] Acute cholangitis, Lipsett [/bib_ref] [bib_ref] Acute cholangitis: multivariate analysis of risk factors, Gigot [/bib_ref] Choledocholithiasis used to be the most frequent cause of the obstruction, 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 of acute cholangitis. [fig_ref] Table 1: Etiology of acute cholangitis [/fig_ref] show some results of studies on the causes of acute cholangitis.
Risk factors. The bile of healthy subjects is generally aseptic. However, bile culture is positive for microorganisms in 16% of patients undergoing a non-biliary operation, in 72% of acute cholangitis patients, in 44% of chronic cholangitis patients, and in 50% of those with biliary obstruction (level 4). [bib_ref] Bacteriological investigation of the biliary system and liver in biliary tract disease..., Edlund [/bib_ref] Bacteria in bile are identifi ed in 90% of patients with choledocholithiasis accompanied by jaundice (level 4). [bib_ref] Hazards of surgical treatment due to microorganisms in the bile, Keighley [/bib_ref] Patients with incomplete [bib_ref] Collective study results on the bacteriological examination during biliary surgery, Daida [/bib_ref] 1979 Questionnaire throughout 472 56% 5% 36% -3% Japan obstruction of the bile duct present a higher positive bile culture rate than those with complete obstruction of the bile duct. Risk factors for bactobilia include various factors, as described above. 14 Post-endoscopic retrograde cholangiopancreatography (ERCP) infectious complications. The incidence of complications after ERCP ranges from 0.8% to 12.1%, though it differs depending on the year of the report and the defi nition of complications (level 4). [bib_ref] Risk factors for complications after performance of ERCP, Vandervoort [/bib_ref] [bib_ref] Complications of endoscopic biliary sphincterotomy, Freeman [/bib_ref] [bib_ref] Catheteisme retrograde et sphincterotomie endoscopique. Evaluation prospective en milieu chirurgical, Lenriot [/bib_ref] [bib_ref] Infectious complications of endoscopic retrograde cholangio-pancreatography managed in a surgical unit, Benchimol [/bib_ref] [bib_ref] Endoscopic sphincterotomy complications and their management: an attempt at consensus, Cotton [/bib_ref] [bib_ref] Complications of fi beroptic gastrointestinal endoscopy; 5 years' experience in a central..., Reiertsen [/bib_ref] [bib_ref] Post-ERCP pancreatitis: association with urographic visualization during ERCP, Roszler [/bib_ref] [bib_ref] Early and late complications after endoscopic sphincterotomy for biliary lithiasis with and..., Escourrou [/bib_ref] [bib_ref] Complications of endoscopic retrograde cholangiopancreatography (ERCP). A study of 10 000 cases, Bilbao [/bib_ref] Overall post-ERCP mortality is reported to be between 0.5% and 1.5% (level 4). [bib_ref] Infectious complications of endoscopic retrograde cholangio-pancreatography managed in a surgical unit, Benchimol [/bib_ref] The most frequent complication is acute pancreatitis, but it is usually mild or moderate. [fig_ref] Table 3: Reports of complications caused by ERCP [/fig_ref] shows the reported incidence of various post-ERCP complications.
The incidences of post-ERCP acute cholangitis and cholecystitis are, as shown in [fig_ref] Table 3: Reports of complications caused by ERCP [/fig_ref] , 0.5%-1.7% and 0.2%-0.5%, respectively. [bib_ref] Risk factors for complications after performance of ERCP, Vandervoort [/bib_ref] [bib_ref] Complications of endoscopic biliary sphincterotomy, Freeman [/bib_ref] [bib_ref] Catheteisme retrograde et sphincterotomie endoscopique. Evaluation prospective en milieu chirurgical, Lenriot [/bib_ref] [bib_ref] Infectious complications of endoscopic retrograde cholangio-pancreatography managed in a surgical unit, Benchimol [/bib_ref] [bib_ref] Endoscopic sphincterotomy complications and their management: an attempt at consensus, Cotton [/bib_ref] The complications caused by ERCP performed for diagnostic and for therapeutic purposes are different. Therapeutic ERCP tends to cause all complications, including cholangitis, more frequently than diagnostic ERCP. [bib_ref] Catheteisme retrograde et sphincterotomie endoscopique. Evaluation prospective en milieu chirurgical, Lenriot [/bib_ref] [bib_ref] Complications of fi beroptic gastrointestinal endoscopy; 5 years' experience in a central..., Reiertsen [/bib_ref] The increasing use of ERCP and the improved operators' skills and techniques in recent years have reduced the incidence of post-ERCP complications, although the incidence of acute cholecystitis has not dropped and seems unpredictable. [bib_ref] Catheteisme retrograde et sphincterotomie endoscopique. Evaluation prospective en milieu chirurgical, Lenriot [/bib_ref] 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 infl ammatory changes caused by the presence of stones in the gallbladder neck and cystic ducts. [bib_ref] The Mirizzi syndrome: suggested classifi cation and surgical therapy, Mcsherry [/bib_ref] Two types have been described: type I, which is a morbid condition with the bile duct compressed from the left by the presence of stones in the gallbladder neck and cystic ducts and pericholecystic infl ammatory changes; and type II, which is a morbid condition with biliobilary fi stulation caused by pressure necrosis of the bile duct due to cholecystolithiasis.
Lemmel syndrome is a series of morbid conditions in which the duodenal parapapillary diverticulum compresses or displaces the opening of the bile duct or pancreatic duct and obstructs the passage of bile in the bile duct or hepatic duct, thereby causing cholestasis, jaundice, gallstone, cholangitis, and pancreatitis. [bib_ref] Die kliniscle Bedeutung der Duodenal Divertikel, Lemmel [/bib_ref] 

## Pathophysiology
The onset of acute cholangitis involves two factors: (i) increased bacteria in the bile duct, and (ii) elevated intraductal pressure in the bile duct that allows translocation of bacteria or endotoxins into the vascular system (cholangio-venous refl ux). Because of its anatomical characteristics, the biliary system is likely to be affected by elevated intraductal pressure. In acute cholangitis, with the elevated intraductal biliary pressure, the bile ductules tend to become more permeable to the translocation of bacteria and toxins. This process results in serious infections that can be fatal, such as hepatic abscess and sepsis.

## Prognosis
Patients who show early signs of multiple organ failure (renal failure, disseminated intravascular coagulation , alterations in the level of consciousness, and shock) as well as evidence of acute cholangitis (fever accompanied by chills and shivering, jaundice, and abdominal pain), and who do not respond to conservative treatment, should receive systemic antibiotics and undergo emergent biliary drainage. [bib_ref] Emergency surgery for severe acute cholangitis. The high-risk patients, Lai [/bib_ref] We have to keep in mind that unless early and appropriate biliary drainage is performed and systemic antibiotics are administered, death will occur.
The reported mortality of acute cholangitis varies from 2.5% to 65% [bib_ref] Acute suppurative cholangitis, a medical and surgical emergency. A review of 10..., Andrew [/bib_ref] [bib_ref] Pathogenesis and clinical features of acute cholangitis accompanied by shock, Shimada [/bib_ref] [bib_ref] Risk factors and classifi cation of acute suppurative cholangitis, Csendes [/bib_ref] [bib_ref] Ascending cholangitis: surgery versus endoscopic or percutaneous drainage, Himal [/bib_ref] [bib_ref] Treatment of choice for choledocholithiasis in patients with acute obstructive suppurative cholangitis..., Chijiiwa [/bib_ref] [bib_ref] Acute biliary septic shock, Liu [/bib_ref] [bib_ref] Emergency surgery for severe acute cholangitis. The high risk patients, Lai [/bib_ref] [bib_ref] Broad spectrum penicillin as an adequate therapy for acute cholangitis, Thompson [/bib_ref] [bib_ref] Clinical characteristics of impacted bile duct stone in eldely, Arima [/bib_ref] [bib_ref] Clinical evaluation of acute cholangitis -with speciaal reference to detection of prognostic..., Kunisaki [/bib_ref] [bib_ref] Abnormal pre-drainage serum creatinine as a prognostic indicator in acute cholangitis, Tai [/bib_ref] [bib_ref] An analysis of infectious failures in acute cholangitis, Thompson [/bib_ref] [fig_ref] Table 4: Mortality of acute cholangitis [/fig_ref]. The mortality rate before 1980 was 50%, [bib_ref] Acute suppurative cholangitis, a medical and surgical emergency. A review of 10..., Andrew [/bib_ref] [bib_ref] Pathogenesis and clinical features of acute cholangitis accompanied by shock, Shimada [/bib_ref] and after 1980 it was 10%-30%. [bib_ref] Risk factors and classifi cation of acute suppurative cholangitis, Csendes [/bib_ref] [bib_ref] Ascending cholangitis: surgery versus endoscopic or percutaneous drainage, Himal [/bib_ref] [bib_ref] Treatment of choice for choledocholithiasis in patients with acute obstructive suppurative cholangitis..., Chijiiwa [/bib_ref] [bib_ref] Acute biliary septic shock, Liu [/bib_ref] [bib_ref] Emergency surgery for severe acute cholangitis. The high risk patients, Lai [/bib_ref] [bib_ref] Broad spectrum penicillin as an adequate therapy for acute cholangitis, Thompson [/bib_ref] [bib_ref] Clinical characteristics of impacted bile duct stone in eldely, Arima [/bib_ref] [bib_ref] Clinical evaluation of acute cholangitis -with speciaal reference to detection of prognostic..., Kunisaki [/bib_ref] [bib_ref] Abnormal pre-drainage serum creatinine as a prognostic indicator in acute cholangitis, Tai [/bib_ref] [bib_ref] An analysis of infectious failures in acute cholangitis, Thompson [/bib_ref] Such differences in mortality are probably attributable to differences in early diagnosis and improved supportive treatment.
The major cause of death in acute cholangitis is multiple organ failure with irreversible shock, and mortality rates have not signifi cantly improved over the years. [bib_ref] Acute suppurative cholangitis, a medical and surgical emergency. A review of 10..., Andrew [/bib_ref] [bib_ref] Pathogenesis and clinical features of acute cholangitis accompanied by shock, Shimada [/bib_ref] [bib_ref] Risk factors and classifi cation of acute suppurative cholangitis, Csendes [/bib_ref] [bib_ref] Ascending cholangitis: surgery versus endoscopic or percutaneous drainage, Himal [/bib_ref] [bib_ref] Treatment of choice for choledocholithiasis in patients with acute obstructive suppurative cholangitis..., Chijiiwa [/bib_ref] [bib_ref] Acute biliary septic shock, Liu [/bib_ref] [bib_ref] Emergency surgery for severe acute cholangitis. The high risk patients, Lai [/bib_ref] [bib_ref] Broad spectrum penicillin as an adequate therapy for acute cholangitis, Thompson [/bib_ref] Causes of death in patients who survive the acute stage of cholangitis include multiple organ failure, heart failure, and pneumonia. 34

## Acute cholecystitis

## Defi nition
Acute cholecystitis is an acute infl ammatory disease of the gallbladder. It is often attributable to gallstones, but many factors, such as ischemia; motility disorders; direct chemical injury; infections with microorganisms, protozoa, and parasites; collagen disease; and allergic reaction are involved.

## Incidence
Acute cholecystitis cases account for 3%-10% of all patients with abdominal pain. [bib_ref] Diagnostic approaches in acute cholecystitis; a prospective study of 1333 patients with..., Eskelinen [/bib_ref] [bib_ref] Abdominal pain. An analysis of 1000 consecutive cases in a University Hospital..., Brewer [/bib_ref] [bib_ref] Acute abdominal pain in patients over 50 years of age, Telfer [/bib_ref] The percentage of acute cholecystitis cases in patients under 50 years old with abdominal pain (n = 6317) was low, at 6.3%, whereas that in patients aged 50 and over (n = 2406) was high, at 20.9% (average, 10%) [bib_ref] Acute abdominal pain in patients over 50 years of age, Telfer [/bib_ref] [fig_ref] Table 5: Acute cholecystitis in patients with abdominal pain Risk factors [/fig_ref].

## Etiology
Cholecystolithiasis accounts for 90%-95% of all causes of acute cholecystitis, while acalculous cholecystitis accounts for the remaining 5%-10% (level 4). [bib_ref] Acute calculous cholecystitis. What is new in diagnosis and therapy?, Gouma [/bib_ref] [bib_ref] Role of surgery in the management of gallstones, Mack [/bib_ref] [bib_ref] Surgery for acute and chronic cholecystitis, Hermann [/bib_ref] [bib_ref] Acute cholecystitis, Sharp [/bib_ref] [bib_ref] Acalculous disease of the gall bladder, Williamson [/bib_ref] [bib_ref] Acute acalculous cholecystitis, Barie [/bib_ref] [bib_ref] State of the art in the diagnosis and management of acute cholecystitis, Reiss [/bib_ref] jaundice, and pancreatitis) were observed in 1%-2% of asymptomatic patients and in 1%-3% of patients with mild symptoms per year [fig_ref] Table 6: Natural history of asymptomatic, mildly symptomatic, and symptomatic cholelithiasis patients [/fig_ref] , and the risk of complications increased in the fi rst several years after the discovery of gallbladder stones, but then decreased (level 2c). Every year, 6%-8% of patients whose symptoms progress from minor to serious undergo cholecystectomy, but this percentage decreases year by year. [bib_ref] Natural history of asymptomatic and symptomatic gallstones, Friedman [/bib_ref] In a follow-up of cholelithiasis patients with mild or nonspecifi c symptoms (n = 153), acute gallstone complication was observed in 15% (n = 23) and acute cholecystitis was seen in 12% (n = 18) (level 4). [bib_ref] Expectant management of patients with gallbladder stones diagnosed at planned investigation. A..., Persson [/bib_ref] According to another report, on the follow-up of the patients with asymptomatic cholelithiasis (n = 600), 16% (96) of them presented with some symptoms (average period of observation until the manifestation of symptom, 29.8 months) during the follow-up period, while 3.8% (23 patients) presented with acute cholecystitis. The rate of change from asymptomatic to symptomatic cholelithiasis is highest during the fi rst 3 years after diagnosis (15%-26%), but then declines (level 4). However, there is a report suggesting that there is no difference in the incidence of common symptoms such as heartburn and upper abdominal pain, in cholelithiasis patients between those patients with asymptomatic cholelithiasis and controls without gallstones (level 2b). [bib_ref] Correlation between gallstones and abdominal symptoms in a random population, Glambek [/bib_ref] AIDS as a risk factor. Enlarged liver and/or abnormal liver functions are observed in two/thirds of AIDS patients, some of whom have biliary tract disease. Biliary disease may occur by two mechanisms in AIDS patients: via AIDS cholangiopathy (which is more fre-quent) and via acute acalculous cholecystitis; AIDS patients with sclerosing cholangitis are also seen.
AIDS cholangiopathy is often observed in middleaged male patients who have had AIDS for more than 1 year (average disease period, 15  2.2 months; average age, 37 years [range, 21 to 59 years]). Ninety percent of the patients complain of upper abdominal pain and have enlarged intra-and extrahepatic bile ducts on abdominal ultrasonography. Abnormal fi ndings on abdominal ultrasonography and computed tomography are seen in 81% and 78% of patients, respectively. Biochemical tests show a marked increase in the level of alkaline phosphatase (level 4). [bib_ref] AIDS-Related biliary tract disease, Cello [/bib_ref] Acalculous cholecystitis in AIDS patients is characterized by: (1) younger age than in non-AIDS patients, (2) problems with oral ingestion (3), right upper abdominal pain, (4) a marked increase in alkaline phosphatase and a mild increase in serum bilirubin level, and (5) association with cytomegalovirus and cryptosporidium infections (level 4). [bib_ref] AIDS-Related biliary tract disease, Cello [/bib_ref] According to a review of abdominal surgery for AIDS patients, acute cholecystitis is the most frequent reason for performing open surgery in AIDS patients. [bib_ref] The incidence of intra-abdominal surgery in acquired immunodefi ciency syndrome: a statistical..., Laraja [/bib_ref] Drugs as etiologic agents. According to the review by Michielsen et al., [bib_ref] Drug-induced gallbladder disease. Incidence, aetiology and management, Michielsen [/bib_ref] regarding the association between drugs and acute cholecystitis, 90%-95% of acute cholecystitis cases are caused by cholelithiasis, and drugs promoting the formation of stones are indirectly associated with a risk of acute cholecystitis (level 4). The etiological mechanism of drug-associated gallbladder diseases, as discussed in the review, 53 is shown in [fig_ref] Table 7: Etiological mechanisms of gallbladder diseases [/fig_ref]. It is reported that women taking oral conceptives have a higher risk of having gallbladder disease, but there also is a report which denies the association between the disease and these drugs (level 2a).Among various drugs used for the treatment of hyperlipidemia, only fi brate is shown to be associated with gallstone diseases (level 2b). [bib_ref] Clofi brate and gallstones, Cooper [/bib_ref] One report suggests that thiazides induce acute cholecystitis (level 3b), [bib_ref] Thiazides and acute cholecystitis, Rosenberg [/bib_ref] and another report denies this association (level 3b). [bib_ref] Acute cholecystitis and thiazides, Porter [/bib_ref] The administration of a large dose of ceftriaxone, a third-generation cephalosporin antimicrobial, in infants, precipitates calcium salt in bile and forms a sludge in 25%-45% of them, but these effects disappear when the medication is discontinued (level 4). [bib_ref] Drug-induced gallbladder disease. Incidence, aetiology and management, Michielsen [/bib_ref] It is reported that the longterm administration of octreotide causes cholestasis, and that administration for a year causes cholelithiasis in 50% of patients (level 4). [bib_ref] Drug-induced gallbladder disease. Incidence, aetiology and management, Michielsen [/bib_ref] Hepatic artery infusion will cause chemical cholecystitis (level 4). [bib_ref] Drug-induced gallbladder disease. Incidence, aetiology and management, Michielsen [/bib_ref] Erythromycin and ampicillin are reported to be a cause of hypersensitive cholecystitis (level 4). [bib_ref] Drug-induced gallbladder disease. Incidence, aetiology and management, Michielsen [/bib_ref] According to a meta-analysis of the risk of disease induced by hormone replacement therapy, the relative risks (RRs) of cholecystitis were 1.8 (95% confi dence interval [CI], 1.6-2.0) and 2.5 (95% CI, 2.0-2.9) at less than 5 years of treatment and at 5 and more years, respectively (level 1a). [bib_ref] Postmenopausal hormone replacement therapy: scientifi c review, Nelson [/bib_ref] Ascaris as an etiologic factor. The complications of ascariasis include hepatic, biliary, and pancreatic diseases. Complications in the biliary tract include: (1) cholelithiasis with the ascarid as a nidus for stone formation, (2) acalculous cholecystitis (3), acute cholangitis (4), acute pancreatitis, and (5) hepatic abscess.Biliary tract disease is caused by the obstruction of the hepatic and biliary tracts by the entry of ascarids from the duodenum through the papilla. Ascarids entering the biliary tract usually return to the duodenum in a week, but if they stay over 10 days there, they will die and form a nidus for stone formation.
Ascarid-associated biliary diseases occur more frequently in women (male/female ratio, 1 : 3) and less frequently in infants. The risk of biliary complications is higher in pregnant than in non-pregnant women (level 4).In epidemic regions such as China and Southeast Asia, ascariasis is a frequent cause of cholelithiasis.Role of pregnancy. The risk of cholelithiasis in women begins to increase when adolescence begins and it declines when the menopause begins. It is also said that the use of oral conceptives is correlated with a risk of gallbladder disease. It is considered, therefore, that levels of estrogen and progesterone are involved in the formation of gallstones. [bib_ref] The acute abdomen during pregnancy, Sharp [/bib_ref] Cholecystitis is the second most common cause of acute abdomen, following appendicitis, in pregnant women, and occurs in one of 1600 to 10 000 pregnant women (level 4). [bib_ref] The acute abdomen during pregnancy, Sharp [/bib_ref] Cholelithiasis is the most frequent cause of cholecystitis in pregnancy and accounts for 90% or more of all causes of cholecystitis (level 4). [bib_ref] The acute abdomen during pregnancy, Sharp [/bib_ref] Routine ultrasonography found cholelithiasis in 3.5% of pregnant women (level 4), [bib_ref] The acute abdomen during pregnancy, Sharp [/bib_ref] but it is unknown whether pregnancy increases the risk of cholecystitis. The frequency of cholecystectomy in pregnant women is lower than that in non-pregnant women. This is not because of the lower incidence of cholecystectomy in pregnant women, but because physicians tend to refrain from performing any operation during pregnancy. Though there are few reports of patients undergoing cholecystectomy during pregnancy, there is no evidence that laparoscopic surgery increases the maternal or fetal risks (level 2c). [bib_ref] Outcome study of cholecystectomy during pregnancy, Barone [/bib_ref] Acute cholecystitis and four (or fi ve) "Fs". It has been said that the patients with cholelithiasis have factors such as "4F" and "5F" (fair, fat, female, fertile, and Antimicrobial drugs (erythromycin, ampicillin) Immunotherapy forty). Common to all individuals with these "4/5Fs" are high levels of estrogen and progesterone.
According to the Framingham Study, which examined the risk factors for cholelithiasis in a 10-year follow-up study of 30-to 59-year-old subjects, the risk of cholelithiasis within 10 years was highest among the 55-to 62-year-old age group, and most of the patients were diagnosed with cholelithiasis in their fi fties and sixties. Although the incidence of cholelithiasis in female patients of all age groups is more than double that of male patients, the difference between the incidence in men and women tends to shrink with increasing age (level 1b). [bib_ref] The epidemiology of gallbladder disease: observations in the Framingham Study, Friedman [/bib_ref] Cholelithiasis is one of the main diseases associated with obesity. The Framingham study also confi rms that cholelithiasis patients tend to be more obese than noncholelithiasis patients (level 2a). [bib_ref] The epidemiology of gallbladder disease: observations in the Framingham Study, Friedman [/bib_ref] However, there is a report that this tendency is much more prominent in female than in male patients. [bib_ref] Age profi les of benign gallbladder disease in 2000 patients, Gutman [/bib_ref] Not only obesity but also dieting is associated with the risk of cholelithiasis. Drastic dieting increases the risk of cholelithiasis in obese people (level 2b). [bib_ref] Gallstones in obesity and weight loss, Erlinger [/bib_ref] [bib_ref] Gallstone formation during weight-reduction dieting, Liddle [/bib_ref] [bib_ref] Contributions of obesity and weight loss to gallstone disease, Everhart [/bib_ref] [bib_ref] Current status of medical and surgical therapy for obesity, Mun [/bib_ref] The incidences of both cholelithiasis and cholecystitis in obese people (age, 37-60 years; women with a body mass index [BMI] of 34 or higher and men with a BMI of 38 or more) are signifi cantly higher that those in non-obese people (cholelithiasis, 5.8% vs 1.5%; Odds ratio [OR], 4.9; women 6.4% vs 22.6%; OR, 4.7; cholecystitis, 0.8% vs 3.4%; OR, 5.2; women 4.0% vs 11.2%; OR, 3.4) (level 2b). [bib_ref] Gallstones, gallbladder disease, and pancreatitis: cross-sectional and 2-year data from the Swedish..., Torgerson [/bib_ref] The Framingham Study indicates that the number of pregnancies in those patients who had cholelithiasis at entry into a cohort or those in whom the symptoms of cholelithiasis appeared within 10 years, was signifi cantly higher than the number of pregnancies in subjects not fulfi lling these criteria (level 2b). [bib_ref] The epidemiology of gallbladder disease: observations in the Framingham Study, Friedman [/bib_ref] Though the association of "4F" and "5F" with cholelithiasis has been relatively closely examined, no study has examined the association of factors other than obesity and age with the risk of onset of acute cholecystitis.

## Pathophysiology
In the majority of patients, gallstones are the cause of acute cholecystitis. The process is one of physical obstruction of the gallbladder by a gallstone, at the neck or in the cystic duct. 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. If the obstruction is partial and of short duration the patient experiences biliary colic. If the obstruction is complete and of long duration the patient develops acute cholecystitis. If the patient does not receive early treatment, the disease becomes more serious and complications occur.
Pathological classifi cation Edematous cholecystitis: fi rst stage . The gallbladder has interstitial fl uid with dilated capillaries and lymphatics. The gallbladder wall is edematous. The gallbladder tissue is intact histologically, with edema in the subserosal layer.
Necrotizing cholecystitis: second stage . The gallbladder has edematous changes with areas of hemorrhage and necrosis. When the gallbladder wall is subjected to elevated internal pressure, the blood fl ow is obstructed, with histological evidence of vascular thrombosis and occlusion. There are areas of scattered necrosis, but it is superfi cial and does not involve the full thickness of the gallbladder wall.
Suppurative cholecystitis: third stage (7-10 days). The gallbladder wall has white blood cells present, with areas of necrosis and suppuration. In this stage, the active repair process of infl ammation is evident. The enlarged gallbladder begins to contract and the wall is thickened due to fi brous proliferation. Intrawall abscesses are present and involve the entire thickness of the wall. Pericholecystic abscesses are present.
Chronic cholecystitis. Chronic cholecystitis occurs after the repeated occurrence of mild attacks of cholecystitis, and is characterized by mucosal atrophy and fi brosis of the gallbladder wall. It can also be caused by chronic irritation by large gallstones and may often induce acute cholecystitis.
Specifi c forms of acute cholecystitis. There are four specifi c forms of acute cholecystitis: (1) acalculous cholecystitis, which is acute cholecystitis without cholecystolithiasis; (2) xanthogranulomatous cholecystitis, which is characterized by the xanthogranulomatous thickening of the gallbladder wall and elevated intra-gallbladder pressure due to stones, with rupture of the the Rokitansky-Achoff sinuses. This rupture causes leakage and bile entry into the gallbladder wall. The bile is ingested by histocytes, forming granulomas consisting of foamy histocytes. Patients usually have symptoms of acute cholecystitis in the initial stage. (3) emphysematous cholecystitis, in which air appears in the gallbladder wall due to infection with gas-forming anaerobes, including Clostridium perfringens. This form is likely to progress to sepsis and gangrenous cholecystitis; it is often seen in diabetic patients. (4) Torsion of the gallbladder. [bib_ref] Congenital anomalies of the gallbladder, Gross [/bib_ref] Torsion of the gallbladder is known to occur by inherent, acquired, and other physical causes. An inherent factor is a fl oating gallbladder, which is very mobile because the gallbladder and cystic ducts are connected with the liver by a fused ligament. Acquired factors in-clude splanchnoptosis, senile humpback, scoliosis, and weight loss. Physical factors causing torsion of the gallbladder include sudden changes of intraperitoneal pressure, sudden changes of body position, a pendulum-like movement in the antefl exion position, hyperperistalsis of organs near the gallbladder, defecation, and trauma to the abdomen.

## Incidence of complications with advanced forms of acute cholecystitis
The incidence of complications with advanced forms of acute cholecystitis ranges widely, from 7.2% to 26%, in reports published since 1990. [bib_ref] Gangrenous cholecystitis in the laparoscopic era, Hunt [/bib_ref] [bib_ref] Gangrenous cholecystitis: analysis of risk factors and experience with laparoscopic cholecystectomy, Merriam [/bib_ref] [bib_ref] Gangrenous cholecystitis in an urban VA hospital, Wilson [/bib_ref] [bib_ref] Factors effecting the complications in the natural history of acute cholecystitis, Bedirli [/bib_ref] [bib_ref] Surgical risks of acute cholecystitis in elderly, Tokunaga [/bib_ref] In patients with acute cholecystitis (n = 368), the incidence of morbidity was 17%, with the incidences of gangrenous, suppurative, perforating, and emphysematous cholecystitis being 7.1%, 6.3%, 3.3%, and 0.5%, respectively. 74

## Types of complications.
There are four types of complications. (1) Perforation of the gallbladder, which is caused by acute cholecystitis, injury, or tumors, and occurs most often as a result of ischemia and necrosis of the gallbladder wall. (2) Biliary peritonitis, which occurs with the entry into the peritoneal cavity of bile leaked due to various causes, including cholecystitis-induced gallbladder perforation, trauma, a catheter detached during biliary drainage, and incomplete suture after biliary operation. (3) Pericholecystic abscess, a morbid condition in which a perforation of the gallbladder wall is covered by the surrounding tissue, with the formation of an abscess around the gallbladder. (4) Biliary fi stula, which can occur between the gallbladder and the duodenum following an episode of acute cholecystitis. The fi stula is usually caused by a large gallbladder stone eroding through the wall of the gallbladder into the duodenum. If the stone is large, the patient can develop gallstone ileus, with the stone causing mechanical smallbowel obstruction at the ileocecal valve.

## Prognosis
The mortality in patients with acute cholecystitis is 0-10% [bib_ref] Outcome of acute cholecystitis in patients with diabetes mellitus, Ransohoff [/bib_ref] [bib_ref] Personal experiences with 1261 cases of acute and chronic cholecystitis and cholelithiasis, Meyer [/bib_ref] [bib_ref] Acute cholecystitis, Gagic [/bib_ref] [bib_ref] Open cholecystectomy: its morbidity and mortality as a reference standard, Girard [/bib_ref] [bib_ref] Urgent and early cholecystectomy for acute gallbladder disease, Addison [/bib_ref] [bib_ref] Factors effecting the complications in the natural history of acute cholecystitis, Bedirli [/bib_ref] [bib_ref] Effects of timing of surgery, type of infl ammation, and sex on..., Gharaibeh [/bib_ref] [fig_ref] Table 8: Mortality of acute cholecystitis cholecystitis when cholecystectomy is not performed for some... [/fig_ref] , whereas the mortality in patients with postoperative cholecystitis and acalculous cholecystitis is as high as 23%-40%. [bib_ref] Acute acalculous cholecystitis: incidence, risk factors, diagnosis, and outcome, Kalliafas [/bib_ref] [bib_ref] Postoperative acute cholecystitis: a collective review of 494 cases in Japan, Inoue [/bib_ref] [bib_ref] The increasing prevalence of acalculous cholecystitis in outpatients. Results of a 7-year..., Savoca [/bib_ref] The mortality of elderly patients (75 years and older) tends to be higher than that of younger patients, [bib_ref] The management of acute cholecystitis in elderly patients, Hafi F [/bib_ref] [bib_ref] Surgical management of acute cholecystitis in patients 65 years of age and..., Glenn [/bib_ref] and a comorbidity such as diabetes may increase the risk of death. [bib_ref] Outcome of acute cholecystitis in patients with diabetes mellitus, Ransohoff [/bib_ref] Many reports of the mortality and morbidity of acute cholecystitis are diffi cult to compare, because there are signifi cant variations in the diagnostic criteria, timing and type of operation, presence of comor bidities, and hospital support systems for critically ill patients, as well as variations in available surgical expertise.
According to reports published in 1980 and before, most of the causes of death after cholecystectomy were related to postoperative infections, such as ascending cholangitis, hepatic abscess, and sepsis. [bib_ref] Personal experiences with 1261 cases of acute and chronic cholecystitis and cholelithiasis, Meyer [/bib_ref] [bib_ref] Acute cholecystitis, Gagic [/bib_ref] Since 1980, postoperative mortality from infection has decreased and the major causes of death include myocardial infarction, cardiac failure, and pulmonary infarction. [bib_ref] Open cholecystectomy: its morbidity and mortality as a reference standard, Girard [/bib_ref] [bib_ref] Urgent and early cholecystectomy for acute gallbladder disease, Addison [/bib_ref] Cholecystostomy was a common form of treatment in 1970 and before, and the most common cause of death during that period was pneumonia and sepsis. [bib_ref] Cholecystectomy in acute cholecystitis. Factors infl uencing morbidity and mortality, Gingrich [/bib_ref] Currently, the major causes of death following cholecystostomy include malignant tumor, respiratory failure, and cardiac failure. [bib_ref] Complication and late outcome following percutaneous drainage of the gallbladder in acute..., Andren-Sandberg [/bib_ref] [bib_ref] Ultrasoundguided percutaneous cholecystectomy in high-risk surgical patients, Granlund [/bib_ref] Recurrence rate of acute cholecystitis after conservative treatment Most patients with acute cholecystitis are treated with a cholecystectomy, and it is diffi cult to anticipate whether the outcome will show recurrence. Recurrences of clinical concern include the recurrence of (1) acute cholecystitis after spontaneous recovery without the undergoing of any treatment; (2) acute cholecystitis while waiting for cholecystectomy after conservative treatment with diet modifi cation and antibiotics; (3) acute There are no data on the recurrence of acute cholecystitis after resolution of the initial symptoms. The recurrence of acute cholecystitis while patients are waiting for cholecystectomy following conservative treatment ranges from 2.5% to 22%. [bib_ref] Outcome of acute cholecystitis in patients with diabetes mellitus, Ransohoff [/bib_ref] [bib_ref] Acute cholecystitis treated by early and delayed surgery. A controlled clinical trial, Lahtinen [/bib_ref] In 311 patients with acute calculous cholecystitis , 25 of 39 patients who did not have a cholecystectomy during the acute stage were scheduled to undergo delayed operation after being discharged from hospital. Only 1 of the 25 patients (2.5%) developed recurrent acute cholecystitis while waiting for an operation. [bib_ref] Outcome of acute cholecystitis in patients with diabetes mellitus, Ransohoff [/bib_ref] In non-severe cases, acute cholecystitis recurred in 2% of patients within an 8-to 10-week waiting period, 6% of whom showed gallbladder perforation. [bib_ref] Acute cholecystitis treated by early and delayed surgery. A controlled clinical trial, Lahtinen [/bib_ref] Long-term recurrence is reported to be 10%-50% in 6 months to several years of observation, though there are few reports. According to a randomized controlled trial comparing non-operative treatment and cholecystectomy for patients with acute cholecystitis, excluding those with severe cases (n = 56), 11% had a history of acute cholecystitis, and 8 (24%) of 33 patients assigned to non-operative treatment underwent cholecystectomy during an observation period of 1.5-4 years. [bib_ref] Randomization to surgery or observation in patients with symptomatic gallbladder stone disease...., Sondenaa [/bib_ref] In patients with acute cholecystitis who were observed after treatment with percutaneous drainage, acute cholecystitis recurred once or more in 28 of 60 patients (47%) during an average observation period of 18 months, [bib_ref] Complication and late outcome following percutaneous drainage of the gallbladder in acute..., Andren-Sandberg [/bib_ref] and it recurred once or more in 11 of 36 (31%) patients who were observed for 37 months on average. [bib_ref] Ultrasoundguided percutaneous cholecystectomy in high-risk surgical patients, Granlund [/bib_ref] In a report of 114 patients who underwent only cholecystostomy, among 585 patients who were hospitalized because of acute cholecystitis, acute cholecystitis recurred in 5 of 23 patients observed for 6 months to 14 years and 14 of the 23 patients remained asymptomatic. [bib_ref] Radiologically guided percutaneous cholecystectomy for acute cholecystitis: long-term outcome in 50 patients, Mcloughlin [/bib_ref] 
[table] Table 1: Etiology of acute cholangitis [/table]
[table] Table 3: Reports of complications caused by ERCP [/table]
[table] Table 4: Mortality of acute cholangitis [/table]
[table] Table 5: Acute cholecystitis in patients with abdominal pain Risk factors. Acute cholecystitis is the most frequent complication occurring in patients with cholelithiasis. According to the Comprehensive Survey of Living Conditions of the People on Health and Welfare conducted by the Medical Statistics Bureau of the Japanese Ministry of Health and Welfare, the number of those with acute cholecystitis has increased, from 3.9 million in 1979 to over 10 million in 1993 (Public Welfare Index in Japan; 1933; level 4). According to the review by Friedman, 48 of the natural history of cholelithiasis, serious symptoms or complications (acute cholecystitis, acute cholangitis, clinical [/table]
[table] Table 6: Natural history of asymptomatic, mildly symptomatic, and symptomatic cholelithiasis patients [/table]
[table] Table 7: Etiological mechanisms of gallbladder diseases [/table]
[table] Table 8: Mortality of acute cholecystitis cholecystitis when cholecystectomy is not performed for some reason, such as surgical risk or the patient's decision (with or without biliary drainage); and (4) cholangitis after cholecystectomy. [/table]
 [bib_ref] Drug-induced gallbladder disease. Incidence, aetiology and management, Michielsen [/bib_ref]