Biliary tract cancer and stones in relation to chronic liver conditions: A population-based study in Shanghai, China
Biliary tract cancers are relatively rare but fatal tumors. Apart from a close link with gallstones and cholangitis, risk factors for biliary tract cancer are obscure. Chronic liver conditions, including liver cirrhosis, have been linked to a higher risk of biliary tract cancer. In a population-based case-control study conducted in Shanghai, China, we investigated the relationships of a history of chronic hepatitis and liver cirrhosis as well as a family history of liver cancer with biliary tract cancer risk. The study included 627 patients with biliary tract cancers (368 gallbladder, 191 bile duct and 68 ampulla of Vater), 1,037 patients with biliary stones (774 gallbladder stones and 263 bile duct stones) and 959 healthy subjects randomly selected from the population. Bile duct cancer was associated with self-reports of chronic liver conditions, including a history of chronic hepatitis (OR = 2.0, 95% CI 0.9–4.4), liver cirrhosis (OR = 4.7, 95% CI 1.9–11.7) and a family history of primary liver cancer (OR = 2.0, 95% CI 1.0–3.9). The excess risk persisted after adjustment for gallstones and were more pronounced among subjects without gallstones (OR = 5.0, 95% CI 1.3–20.0 and OR = 4.9, 95% 2.0–12.2, respectively). History of liver conditions was also associated with an excess of biliary stones (OR = 1.9, 95% CI 1.2–3.0). No association was found for cancers of the gallbladder and ampulla of Vater. A history of chronic hepatitis and cirrhosis may be risk factors for extraheptic bile duct cancer. Given that chronic infection with hepatitis B virus (HBV) is the most common cause of liver disease in China, serologic markers of HBV need to be measured in future studies to examine the link between HBV and bile duct cancer. © 2007 Wiley-Liss, Inc.
Cancers of the biliary tract encompass tumors arising from the gallbladder, extrahepatic bile ducts and ampulla of Vater. Biliary tract cancer is relatively uncommon in most parts of the world, although high-risk populations and upward incidence trends have been reported in certain areas.1, 2 From 1972 to 1994, biliary tract cancer incidence rose the most rapidly of any malignancy in Shanghai, China, with an increase of 119% in men and 124% in women,3 although the absolute rates were modest, less than 5 per 100,000 person-years. Higher rates of biliary tract cancer are reported from populations such as Japan, Korea, India, Eastern Europeans, Hispanics and native Americans in the U.S.,1 with rates ranging from 5 to 10 per 100,000 person-years. Gallbladder cancer is one of the few cancers with a female excess, while bile duct cancer is more likely to occur in men.1
Other than gallstones, the risk factors for biliary tract cancer are poorly understood.1, 4, 5, 6, 7, 8 Although gallstones are common risk factors for all three subsites of biliary tract cancer, data from descriptive epidemiology and molecular studies suggest that these three subsites have distinct etiologic pathways, with cancer of the extrahepatic bile duct more closely linked to infection.1 Chronic liver conditions, including viral hepatitis and liver cirrhosis, have been associated with a higher risk of biliary tract cancer,9, 10, 11, 12, 13 although the mechanism is unclear. Bacterial infection, such as the typhoid carrier state and Helicobacter sp. and pylori, may also play a role.1, 14, 15, 16
To provide further clues to the etiology of biliary tract cancer, we examined the associations of a personal history of hepatitis or liver cirrhosis and a family history of hepatitis or liver cancer with biliary tract cancer in a large population-based case-control study conducted in Shanghai, China.
Materials and methods
Details of the study have been reported elsewhere.17, 18, 19, 20, 21, 22 Briefly, patients with primary biliary tract cancer (ICD9 156) newly diagnosed between 1997 and 2000 were identified through a rapid-reporting system established between the Shanghai Cancer Institute (SCI) and 42 collaborating hospitals in 10 urban districts of Shanghai (henceforth referred to as urban Shanghai). This reporting system captured over 95% of biliary tract cancer patients in Shanghai. Cases for the study were permanent residents of urban Shanghai who had no history of any other cancer. In addition, patients with gallstones undergoing cholecystectomy or nonsurgical interventions and patients with bile duct stones undergoing a surgical intervention were selected for comparison. These patients were selected from the same hospitals as the cancer cases and were frequency-matched by age and sex. Healthy subjects, without a history of cancer, were randomly selected from the population of 6.5 million permanent residents of Shanghai, based on the personal registry cards of all adults aged above 18 residing in urban Shanghai and were frequency-matched to the expected age distribution (by 5-year category) of biliary tract cancer cases.
The diagnoses of the cancer cases and gallstone patients were confirmed by a review of pathology slides conducted independently by two pathologists. Clinical data and imaging studies, such as ultrasonography, CT scan and endoscopic retrograde cholangiopancreatography, were used to confirm the diagnoses of cancer cases without histologic materials and gallstone controls without a surgery. Abdominal ultrasound was performed on all population controls to assess the status of gallstones (including silent gallstones). The primary site of cancer was obtained from the surgical/pathological report of the local hospital and was confirmed by imaging studies and/or histopathology.
Information on potential risk factors, including smoking, use of alcohol, body size, diet, reproductive history, family history of cancer, medical history, occupation and physical activity, was elicited from all study subjects through an in-person interview conducted by trained interviewers using a structured questionnaire. Response rates for interview were over 95% for eligible cases and 83% for controls. Each interview was tape-recorded and verified by a study supervisor. In addition, 5% of the subjects were randomly selected for a second interview several months after the original interview to assess the reproducibility of the information. Concordance between the two interviews was more than 90%. Hepatitis-related information obtained by interview included self-reports of a personal history of acute and chronic hepatitis, a personal history of liver cirrhosis as well as a family history of chronic hepatitis and primary liver cancer among first-degree relatives. Information about the age at diagnosis was also collected. For cancer and biliary stone cases, medical records were abstracted to collect information on gallstones, diabetes, hypertension and heart disease.
The response rates for in-person interviews were over 90% for cases and controls. For all study subjects, informed consent was obtained and clearance for human subjects was approved by the Institution Review Boards at both the National Cancer Institute (NCI) and SCI.
Fisher's exact test was used to detect differences between cases and controls for selected characteristics. To make the appropriate case control comparisons, gallbladder cancer cases were compared to controls without a history of cholecystectomy; bile duct cancer cases and ampulla of Vater cancer cases were compared to all controls; and biliary stone cases were compared to population controls without biliary stones. Factors, including education, body mass index, gallstones and diabetes, with statistically significant differences (p < 0.05) were considered potential confounders for biliary tract cancers or stones. Unconditional logistic regression analyses were used to compute the odds ratios (ORs) and 95% confidence intervals (CIs) for biliary tract cancer in relation to personal and family history of hepatitis, liver cirrhosis or primary liver cancer.23 ORs were estimated for biliary tract cancer and subsequently for each anatomic subsite separately. We further analyzed the family history in parents, siblings and offspring separately. In all the analyses, ORs were adjusted for age and subsequently adjusted for education, body mass index (BMI) [(weight (kg)/height (m2)], diabetes and other potential confounding factors.
The study included a total of 627 patients with biliary tract cancers (368 gallbladder, 191 bile duct and 68 ampulla of Vater), 1,037 patients with biliary stones (774 gallbladder stones and 263 bile duct stones) and 959 healthy controls randomly selected from the population (Table I). Age at diagnosis ranged from 35 to 75 (median 67) for cancer cases. Compared with controls, gallbladder cancer cases had less education and were less likely to be smokers or alcohol drinkers, while bile duct and ampulla of Vater cases were more likely to be smokers. Diabetes was more common among gallbladder cancer patients. Gallbladder cancer patients and biliary stone patients were more likely to have hypertension and a higher BMI, relative to population controls. The prevalence of gallstones in cancer patients was significantly higher than that in population controls.
Table I. Selected Characteristics of Cases and Controls
| Jr. middle||233||24.3||79||21.5||43||22.6||16||23.5||220||28.4||67||25.5|
| Sr. middle||190||19.8||50||13.6||31||16.3||15||22.1||194||25.1||56||21.3|
| Some college||140||14.6||41||11.1||30||15.8||8||11.8||139||18.0||44||16.7|
| Never married||12||1.3||3||0.8||2||1.1||0||0.0||6||0.8||3||1.1|
|Alcohol use (%)||198||20.7||52||14.1*||50||26.2||15||22.1||116||15.0*||51||19.5|
|Body mass index|
The prevalence of liver conditions was relatively low, with 3% in controls, 6% in biliary stone patients, and 7% in bile duct cancer cases (Table II). A history of chronic livier conditions, including a history of chronic hepatitis or liver cirrhosis, was associated with a 2.3-fold risk (95% CI 1.2–4.6) of bile duct cancer, a 2.7-fold risk (95% CI 1.0–7.3) of ampulla of Vater cancer, and a 1.9-fold risk (95% CI 1.2–3.0) for biliary stones (2.9-fold for bile duct stones). Bile duct cancer was associated with a history of hepatitis (OR = 2.0, 95% CI 0.9–4.4) and a history of liver cirrhosis (OR = 4.7, 95% CI 1.9–11.7). In addition, a family history of primary liver cancer was associated with a 2-fold risk of bile duct cancer (95% CI 1.0–3.9), but not with cancers of the gallbladder or ampulla of Vater or biliary stones. Further adjustments for education, gallstones, BMI, smoking, and drinking, and diabetes did not materially change the risk estimates.
Table II. Odds Ratios (ORs) and 95% Confidence Intervals for Biliary Tract Cancer and Biliry Stones in Relation to History of Chronic Hepatitis, and Liver Cirrhosis, and to Family History OF Hepatitis and Liver Cancer, Shanghai, China
|History of liver conditions2|
| No||930||359||1.0|| ||178||1.00|| ||63||1.0|| ||977||1.0|| |
|History of hepatitis|
| No||936||363||1.0|| ||182||1.0|| ||65||1.0|| ||985||1.0|| |
|History of liver cirrhosis|
| No||949||364||1.0|| ||182||1.0|| ||66||1.0|| ||1025||1.0|| |
|Family history of liver conditions3|
| No||735||276||1.0|| ||139||1.0|| ||52||1.0|| ||801||1.0|| |
|Family history of hepatitis3|
| No||759||287||1.0|| ||148||1.0|| ||54||1.0|| ||831||1.0|| |
|Family history of primary liver cancer3|
| No||924||355||1.0|| ||177||1.0|| ||65||1.0|| ||982||1.0|| |
Table III shows the risk of bile duct cancer associated with chronic liver conditions by gallstone status among study subjects. As shown, the risk imposed by certain liver conditions was more pronounced in the absence of gallstones, with those reporting a history of liver cirrhosis having a 5-fold risk (95% CI 1.3–20.0) and those reporting a family history of primary liver cancer having a 4.9-fold risk (95% CI 2.0–12.2).
Table III. Odds Ratios (ORs) and 95% Confidence Intervals (CIs) for Bile Duct Cancer in Relation to History of Chronic Hepatitis, Liver Cirrhosis, Family History of Hepatitis, and Family History of Liver Cancer, by Gallstone Status, Shanghai, China
|History of liver conditions2|
| No||217||118||1.0|| ||713||60||1.0|| || |
|History of hepatitis|
| No||219||120||1.0|| ||717||62||1.0|| || |
|History of liver cirrhosis2|
| No||221||121||1.0|| ||728||61||1.0|| || |
|Family history of liver conditions3|
| No||167||94||1.0|| ||568||45||1.0|| || |
|Family history of hepatitis3|
| No||180||98||1.0|| ||579||50||1.0|| || |
|Family history of primary liver cancer3|
| No||208||120||1.0|| ||716||57||1.0|| || |
Results from our large population-based case-control study show that a history of chronic liver conditions, including chronic hepatitis or liver cirrhosis and a family history of primary liver cancer is associated with a 2-fold risk of gallstones and a significantly increased risk of extrahepatic bile duct cancer but not of cancers of the gallbladder or ampulla of Vater.
The observed 2-fold risk of gallstones associated with a history of liver conditions is consistent with previous reports of a higher prevalence and incidence of gallstones among patients with liver cirrhosis,24, 25, 26, 27, 28, 29, 30, 31, 32, 33 with higher risk associated with a longer duration and the severity of liver cirrhosis. The high incidence of gallstones in cirrhotic patients has been attributed mainly to metabolic changes, including increased unconjugated bilirubin in bile and decreased secretion of cholesterol, bile acid and apolipoprotein secretion,32, 33 all of these are lithogenic factors that increase the risk of gallstone formation. Cirrhotic patients also have impaired gallbladder motility because of higher serum estrogen levels.31
Although a history of gallstones is associated with both bile duct cancer and liver cirrhosis, the observed associations between a history of liver cirrhosis and bile duct cancer cannot be explained entirely by the confounding effect of gallstones. This excess risk persisted after adjustment for gallstone status among study subjects. Furthermore, among subjects without gallstones, those with a history of liver cirrhosis had a 5-fold risk of bile duct cancer, further supporting the hypothesis that the effect of liver cirrhosis on bile duct cancer is not mediated entirely by gallstones.
Despite small numbers, the finding of a 5-fold risk of bile duct cancer associated with a history of liver cirrhosis among subjects without gallstones suggests that a certain fraction of the bile duct cancer cases may develop through a non-gallstone mechanism. In fact, although gallstones alone were associated with an 8-fold risk of bile duct cancer in our study, nearly 45% of the bile duct cancer cases did not have gallstones. Chronic infection with the Hepatitis B virus (HBV) is the most likely explanation for the observed association between bile duct cancer and a history of chronic liver conditions, since chronic HBV infection accounts for most of the hepatitis, liver cirrhosis and primary liver cancer in China.34, 35, 36, 37 This hypothesis is further supported by recent clinical surveys in China that detected HBV DNA in tissue specimens from both intrahepatic bile duct cancer (this is considered primary liver cancer) and hilar cholangiocarcinoma (extrahepatic bile duct cancer).17, 18, 19 Factors other than HBV, such as primary sclerosing cholangitis or parasitic infection, may also be involved in the pathogenesis of bile duct cancer,1, 38, 39, 40 but their prevalence is extremely low and they are not the major cause of hepatitis, liver cirrhosis and liver cancer in China.
Misreporting of jaundice, a complication of bile duct obstruction as a result of tumor growth or stones, for hepatitis, by subjects due to similar symptoms, especially among cancer cases, is possible but is unlikely to explain entirely the 2-fold risk associated with bile duct cancer. In fact, this positive association persisted after excluding from the analysis subjects reporting having hepatitis within 2 years of cancer diagnosis. In addition, the observation that a history of liver cirrhosis and a family history of primary liver cancer are associated with bile duct cancer further supports the notion that misclassification by jaundice reported by the subjects is minimal, since reporting of a family history of cancer is unlikely to be affected by jaundice in study subjects.
Our study has several strengths. First, selection bias is minimal, because of the relatively complete case ascertainment and high response rates in study subjects. Second, misclassification of cancer should be minimal, since rigorous procedures, including imaging studies, were implemented for pathological and clinical review. Third, the location of tumors was reviewed carefully to minimize misclassification of anatomic subsites of tumors. Fourth, the assessment of gallstone status was nearly complete, as a result of careful review of medical records for cases and ultrasound examination of population control subjects.
Limitations of the study should be noted. We did not validate the reporting of family history of primary liver cancer against medical records. However, it is likely that misreporting, if any, is small, since liver cancer is 10 times more common than biliary tract cancer in China41 and the Chinese names for liver and bile duct cancer are distinctively different. Chronic HBV infection is the most likely explanation for the observed association between bile duct cancer and a history of chronic liver conditions, but we were unable to differentiate different types of viral hepatitis in our study because the histories (either personal or family) of hepatitis and related conditions were based on self-report. Hepatitis C virus (HCV) infection is a major risk factor for primary liver cancer and extrahepatic bile duct cancer in Japan, but it is a less important risk factor for liver and extrahepatic bile duct cancer in Shanghai, since the prevalence of HCV infection is low (about 2%) in the general population. Misreporting of acute hepatitis for chronic hepatitis is possible but should be minimal, since hepatitis is quite common in China and most subjects should have been able to distinguish chronic from acute hepatitis. We could not assess the association between a family history of biliary tract cancer and the risk of biliary tract cancer in this report since only 2 cancer cases and none of the controls reported a family history of biliary tract cancer.
In summary, results from this population-based study suggest that a history of liver conditions, in particular liver cirrhosis, is a risk factor for gallstones and extrahepatic bile duct cancer in China, although the specific type of viral hepatitis could not be determined. Although biliary tract cancer has a low incidence in most populations (other than in American Indians, Hispanics and some eastern Europeans), its fatality rate is among the highest for any cancer. It is estimated that there are 350 million chronic carriers of HBV worldwide and that 50 million new cases of HBV infection occur annually. Of the 50 million individuals with incident infections every year, 5–10% of adults and 90% of infants will become chronic carriers.42, 43, 44, 45, 46, 47 Given the global prevalence of HBV infection and the increasing number of HCV-infected subjects in western populations, future studies should measure serologic markers of HBV and HCV in cases and controls to clarify further the role of HBV/HCV in extrahepatic bile duct cancer.
We thank Ms. Jiarong Cheng, Ms. Lu Sun, Mr. Kai Wu, and the staff at the Shanghai Cancer Institute for data collection, specimen collection and processing; collaborating hospitals and surgeons for data collection; local pathologists for pathology review; Ms. Lisa McFarland, Ms. Kathy Hurt-Mullen, Ms. Sara Glashofer, Ms. Nancy Odaka, Mr. John Heinrich and Ms. Linda Lannom of Westat for data preparation and management; and Ms. Janis Koci of the Scientific Applications International Corporation for management of the biological samples.