Biochemical Prediction of Acute Cholangitis and Symptomatic Bile Duct Stones by Gallstone Hepatitis

We have adopted the clinical concept of gallstone hepatitis indicated by marked serum transaminase elevation due to an acute inflammatory liver cell necrosis in the early stages of gallstone impaction in the bile duct as clinical and biochemical criteria for identifying high-risk patients for acute cholangitis or bile duct stones causing symptoms (symptomatic bile duct stones, SBDS). One hundred and fifty-eight (80.2%) of 197 patients with acute gallstone disease and concomitant elevation of serum transaminase (gallstone hepatitis) underwent emergency treatment, either surgery (138 patients) or percutaneous transhepatic biliary drainage (PTBD)/endoscopic sphincterotomy (ES) (20 patients). One hundred and forty-two (89.9%) and 67 (42.4%) were confirmed to have SBDS and acute cholangitis, respectively, in the early stage of the disease. The majority of the patients who had no bile duct stones identified at surgery had either biliary pancreatitis or multiple small stones in the gallbladder. They were assumed to have migrating stones or false negative operative cholangiograms. In conclusion, gallstone hepatitis indicates that SBDS and acute cholangitis are probable, and facilitates rapid selection of patients for urgent biliary tract exploration in patients with acute gallstone disease.


INTRODUCTION
Acute cholangitis is a potentially life-threatening disease that results from biliary tract obstruction and subsequent infection. Recognition of the clinical manifestations is important in diagnosing and managing these patients 1. However, reliance on Charcot's triad (abdominal pain, fever, and jaundice) is insufficient and the clinical presentation can be nonspecific2. Accordingly, a diagnosis of acute cholangitis should be considered whenever there are signs of biliary tract obstruction and infection 1. Ideally, bile duct stones SBDS) should be identified early before acute cholangitis develops. With the rapid and widespread acceptance of laparoscopic cholecystectomy as the preferred primary operation for cholelithiasis, the identification of SBDS also becomes clinically important. What, then, is the diagnostic feature that identifies SBDS or biliary tract obstruction?
We have been involved in a clinicopathological study to clarify the cause of markedly elevated serum transaminases in patients with acute gallstone disease, which might have led to the diagnosis of so-called hepatitis. We concluded that serum transaminases might be raised markedly in the very early stage of biliary obstruction, that this highly elevated serum transaminases might be a reflection of an acute in-268 M. ISOGAI et al. flammatory liver cell necrosis caused by impacted bile duct stones (gallstone hepatitis3 '4), and that therefore gallstone hepatitis might be a sign of early biliary tract obstruction caused by impacted bile duct stones before serum bilirubin and alkaline phosphatase became elev-ated4. A case presented below provided further insight into the pathogenesis of gallstone hepatitis which could develop into severe acute cholangitis unless biliary decompression occurred3.
Based upon this background and knowledge, we have adopted the clinical concept of gallstone hepatitis as a criterion for identifying patients with acute cholangitis or SBDS. At our hospital, almost all patients with acute gallstone disease who do not respond to initial conservative treatment are operated on immediately, after necessary biliary tract examination, provided the patients present a reasonable surgical risk. Here, we present a review of 197 patients who had gallstone hepatitis and therefore were suspected of having acute cholangitis or SBDS and were treated at the Department of Surgery, Ogaki Municipal Hospital, during the past 5 years. The main purpose of this study is to report the actual biliary pathology ultimately confirmed at surgery, especially in the acute stage of the disease, of patients with gallstone hepatitis.

CASE STUDY
A 69-year-old female was referred to the Department of Gastroenterology, Ogaki Municipal Hospital, with epigastric pain and a liver function disorder which had developed two days before. Serum liver chemistry test results one day after the onset of symptoms were: glutamic oxalacetic transaminase (GOT) 2,380 (Karmen unit, normal <40); glutamic pyruvic transaminase (GPT) 747 (Karmen unit, normal < 35); and bilirubin 2.0 (mg/dl, normal < 1.2). She was diagnosed as having so-called hepatitis and underwent medical treatment. However, the abdominal pain did not abate and serum transaminases, especially GPT, remained high while serum bilirubin fluctuated (Table 1). On the sixth day after the onset of symptoms she developed a high fever and shock. An abdominal ultrasonography (US) scan on that day revealed gallstones in the dilated bile duct. The diagnosis of gallstone hepatitis followed by severe acute cholangitis was made, and she underwent percutaneous transhepatic biliary drainage (PTBD) (Fig. 1). Following this procedure, a rapid fall in serum transaminase and bilirubin activity and an immediate remission of symptoms were observed. After the resolution of cholangitis, she underwent delayed biliary surgery safely. In this patient, the initial very high levels of serum transaminases (gallstone hepatitis) led to misdiagnosis of so-called hepatitis, and this led to a delay in biliary decompression and to the resultant development of severe acute cholangitis.

PATIENTS AND METHODS
We have previously classified gallstone hepatitis as a new clinical entity3''. The clinical diagnostic criteria for gallstone hepatitis are: (1) severe abdominal pain; (2) markedly elevated serum transaminase levels which might lead to the diagnosis of so-called hepatitis; and (3) gallstones, usually revealed in the dilated biliary tract, including the gallbladder, by using US. The histological features of gallstone hepatitis included: (1) degeneration and necrosis of liver cells (an accumulation of neutrophils in an area where liver cells had vanished from liver cell plates); and (2) acute cholangitis (neutrophil infiltration around and into the lumen of the bile duct in the portal triad). With regard to serum transaminase levels, the initial levels might depend on the extent of the liver cell necrosis caused by the impacted bile duct stones. The highly elevated serum transaminase levels during the onset of symptoms fall rapidly after resolution of the bile duct ob-struction3'. Serum transaminases, however, remain slightly elevated to various levels above normal when bile duct stones remain floating, causing bile statis. Thus, serum transaminase levels might depend on the extent of ductal obstruction or on the interval between the onset of the symptoms and the time of carrying out the biochemical tests. We believe, therefore, that serum transaminase elevation, no matter how slight, in patients with acute gallstone disease should lead doctors to suspect that patients have had gallstone hepatitis in the course of the disease.
Based upon the features of the course of serum transaminases in gallstone hepatitis, all patients with gallstones and with serum transaminases at abovenormal levels were diagnosed as having gallstone hepatitis. As a result, 197 patients were diagnosed as having gallstone hepatitis from January 1987 to December 1991. They were treated under suspicion of having acute cholangitis or SBDS, and entered into this study.
Patients with viral hepatitis or other potential causes of transaminase elevation such as heart failure or drug or alcohol abuse were excluded. The patients were analyzed with respect to clinical presentation, preoperative examinations, management, biliary tract pathology, operative procedures, and outcome.

Clinical Presentation
There were 99 males and 98 females; age range was 24 to 98 years, with a mean of 63.2 years. Jaundice was present in 49 patients (24.9%), fever exceeding 38C was present in 25 (12.7%), and Charcot's triad was present in 38 (19.3%). Seven patients (3.6%) showed progression of biliary sepsis (severe acute cholangitisS): mental confusion and shock in one patient; shock and disseminated intravascular coagulopathy (DIC) in one; shock in 4; and DIC in one.
The serum levels (mean_+ SD) of  Group III patients and all Group II patients except one (total of 58 patients) subsequently underwent operation during the same period of hospitalization, after an average of 14 days. In one Group II patient who had previously undergone cholecystectomy, bile duct stones were removed by ES and delayed surgery was not required.
In the seven patients with severe acute cholangitis, emergency surgery was performed in one (Group I), PTBD in five (Group II), and initial medical management in one (Group III). The majority of Group I patients showed no objective improvement in response to conventional supportive therapy such as antibiotic, analgesic, or fluid therapy. ES was unsuccessful in two cases. Deterioration of their general condition and peritonitis were the important factors determining emergency surgery. In some cases, the attending physician performed emergency surgery for the proven SBDS without initial conservative management.
Group II patients underwent PTC or ERC prior to PTBD/ES, which revealed bile duct stones. In nine patients, pus was identified within the bile duct at PTBD/ES. Group III patients responded promptly to initial medical management.   (2/197). These two patients were a 66-yearold male and a 79-year-old male who both had SBDS and underwent ductal exploration. The former died of ruptured hepatic artery aneurysm, and the latter of aspiration pneumonia, 13 days and 12 days, respectively, after the initial biliary surgery. The postoperative courses in the remaining 195 patients were generally uneventful. There were no deaths associated with severe acute cholangitis.

DISCUSSION
Several attempts have been made to define the clinical and laboratory criteria that would identify high-risk groups of patients with choledocholithiasis6-, SBDS xx, or acute cholangitis2'2. Liver function tests have been reported to be useful for identifying patients with choledocholithiasis7'9, SBDS , and acute cholangitis2. Few studies, however, have specifically explained the reasons why liver function tests were useful. In the study by Saharia et al., 2 elevated serum transaminase levels were considered to be a reflection of the pathological condition of the bile duct2.
We have adopted the clinical concepts of gallstone hepatitis as clinical and laboratory criteria for identifying high-risk patients with acute cholangitis or SBDS. The reasons were: (1) gallstone hepatitis might be a sign of early biliary obstruction caused by impacted bile duct stones; and (2) SBDS might result from biliary tract obstruction, and acute cholangitis from biliary tract obstruction and subsequent infection. As a result, 197 patients with acute gallstone disease and concomitant elevation of serum transaminases (gallstone hepatitis) were suspected of having acute cholangitis or SBDS. Among them, 158 (80.2%) underwent emergency treatment either surgery (138 patients) or PTBD/ES (20 patients). In the acute stage of the disease, the majority (142; 89.9%) of the 158 patients were confirmed to have SBDS, and less than half (67; 42.4%) were confirmed to have ASC.
The majority of patients who had no bile duct stones identified at surgery had either biliary pancreatitis or multiple small stones in the gallbladder. Biliary pancreatitis is thought to be caused by the migration of a stone into or through the ampulla of Vater. Accordingly, a considerable proportion of those patients may have either passed stones or small stones not detected by operative cholangiograms8'4.
The majority of patients had also acute inflammation of the gallbladder. The intensity of the gallbladder inflammation, however, was slight. Accordingly, acute inflammation of the gallbladder in patients with gallstone hepatitis was considered to be secondary to SBDS4.
Seven patients had severe acute cholangitis. Our previous study demonstrated necrosis of liver cells and cholangitis in liver biopsy specimens taken from patients with gallstone hepatitisa'4. It must be stressed that elevation of serum transaminases in patients with gallstone hepatitis is a reflection of liver cell necrosis caused by impacted bile duct stones. Once the bile duct is obstructed by impacted bile duct stones, it becomes a closed system filled with bile, and pathological changes in the bile duct such as bile statis, increased pressure in the biliar tract or infection may affect the liver cells which bound the bile canaliculus and might cause hepatocellular necrosis3'. Thus, it is possible that bacterial cholangiovenous reflux might occur through damaged tight junctional complexes and also directly through hepatocytes 15 if bile stasis and infection remain in the bile duct, leading to the development of severe acute cholangitis as shown in the case presented. The operative mortality rate in the 196 patients of whom 63 (32.4%) and seven (3.6%) had ASC and severe acute cholangitis, respectively, was 1.0% (2/196). This low mortality rate could be attributable to: (1) early biochemical prediction of SBDS and acute cholangitis by gallstone hepatitis; and (2) initial nonoperative management for the majority of patients with severe acute cholangitis using PTBD/ES.
In conclusion, the results of our study show that gallstone hepatitis correctly predicted SBDS and acute cholangitis in 89.8% and 42.4% of attacks, respectively. In patients with acute gallstone disease, gallstone hepatitis indicates that SBDS and acute cholangitis are probable, and facilitates rapid selection ofpatients for urgent biliary tract exploration. Patients with gallstone hepatitis could develop into severe acute cholangitis and should be managed promptly and properly.