Risk Factors For Intrahepatic Cholangiocarcinoma Research Articles

Risk factors for intrahepatic cholangiocarcinoma: a possible role of hepatitis B virus.

There are several established risk factors for intrahepatic cholangiocarcinoma (ICC), namely primary sclerosing cholangitis, fibropolycystic liver disease, parasitic infection, intrahepatic biliary stones and chemical carcinogen exposure. However, the majority of patients with ICC do not have any of these risk factors. Therefore, identification of other risk factors is warranted for the prevention and early detection of ICC. We evaluated the risk factors for ICC in a large-scale cohort study in the province of Osaka, Japan. This retrospective cohort study included 154,814 apparently healthy individual blood donors, aged 40–64 years at the time of blood donation in the period 1991–1993. The average observation period was 7.6 years, resulting in 1.25 million person-years of observation. Incident ICC cases were identified by linking the blood-donor database to the records in the population-based cancer registry for the province. There were 11 incident ICC cases during follow-up, with an incidence rate of 0.88 per 100 000 person-years. Compared with subjects aged 40–49 years, the subjects aged 50–54 years and 55–59 years had a significantly higher risk for ICC (hazard ratio [HR] = 5.90; 95%CI:1.08–32.31 and 11.07; 95%CI:1.98–61.79, respectively). Compared with those with ALT level of 19 Karmen Units (KU) or less, subjects with ALT level of 40 KU or higher had a significantly higher risk for ICC (HR: 8.30; 95%CI:1.47–46.83). Compared with those who tested negative for both HBsAg and anti-HCV, those who tested HBsAg-positive had a significantly higher risk for ICC (HR: 8.56; 95%CI: 1.33–55.20). Our results suggest that HBV infection and liver inflammation are independently associated with ICC development. These findings need to be verified by further large cohort studies.

Hepatitis B virus-associated intrahepatic cholangiocarcinoma and hepatocellular carcinoma may hold common disease process for carcinogenesis

Aims To evaluate potential risk factors for intrahepatic cholangiocarcinoma (ICC) and analyse clinicopathologic characteristics of ICC patients with seropositive hepatitis B surface antigen (HBsAg). Methods A retrospective case–control study was conducted. Cases were 317 ICC patients referred to the Eastern Hepatobiliary Surgery Hospital in China between 2003 and 2006. Controls were 634 healthy individuals. Adjusted odds ratios (ORs) were calculated in logistic regression analysis. Among 317 consecutively enrolled ICC patients, 154 patients were seropositive HBsAg (48.6%). We compared clinicopathologic characteristics of these patients (group I) with ICC patients seronegative for HBsAg (group II; n = 163) and compared the age and sex distributions of patients in group I with randomly selected hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) (group III; n = 1140). Results Compared with the controls, ICC patients had a high prevalence of seropositive HBsAg, cirrhosis, hepatolithiasis and hepatic schistosomiasis. Compared with seronegative-HBsAg ICC patients, seropositive-HBsAg ICC patients were younger, more frequently male and had a higher proportion of abnormal aminotransferase and serum alpha-fetoprotein (AFP) level, histological inflammation and cirrhosis, right-lobe focus, poor tumour differentiation, tumour encapsulation and microvascular invasion; had a lower proportion of abnormal serum carbohydrate antigen 19-9 (CA19-9) level and lymphatic metastasis. The age and sex distribution profiles were nearly identical between seropositive-HBsAg ICC patients and HBV-associated HCC patients. Conclusions The HBV infection, cirrhosis, hepatolithiasis and hepatic schistosomiasis may be potential risk factors for ICC. HBV-associated ICC shares many clinicopathological similarities with HBV-associated HCC. The result indicated HBV-associated ICC and HBV-associated HCC may hold common disease process for carcinogenesis.

Risk factors of intrahepatic cholangiocarcinoma: a case-control study

To explore the potential risk factors of intrahepatic cholangiocarcinoma (ICC) in China. A case-control study including 317 patients with pathologically confirmed ICC and 634 healthy individuals was conducted. The cases and controls were matched in age, sex and inhabitancy. Data were statistically analyzed by Chi-square test and conditional logistic regression. Univariate analysis showed significant difference in HBsAg seropositivity, liver cirrhosis, hepatolithiasis, choledocholithiasis and schistosomiasis between ICC patients and healthy controls (P < 0.05). Multivariate analysis confirmed that HBsAg seropositivity, liver cirrhosis, hepatolithiasis and hepatic schistosomiasis were associated with ICC, and their adjusted odds ratio (95% confidence interval) were 10.265 (6.676-15.783), 13.101 (5.265-32.604), 18.242 (3.580-92.958), 18.435 (1.930-176.082), 15.102 (4.607-49.499) and 11.820 (3.522-39.668), respectively. The incidence of hepatic cyst, cholecystolithiasis, hepatic hemangioma, fatty liver, diabetes mellitus, smoking and drinking were not significantly different between ICC patients and controls. The HBV infection, liver cirrhosis, hepatolithiasis and hepatic schistosomiasis may be the risk factors for ICC in China.

Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a case–control study in China

The risk factors for cholangiocarcinoma are incompletely defined in China, especially for intrahepatic cholangiocarcinoma (ICC). We evaluated the risk factors for both ICC and extrahepatic cholangiocarcinoma (ECC). A case-control study in which cases were cholangiocarcinoma patients referred to Peking Union Medical College Hospital (PUMCH) between 1998 and 2008 and controls were healthy individuals. Controls were randomly selected from an existing database of healthy individuals at the Health Screening Center of PUMCH. Data on liver disease, family history, diabetes, smoking and drinking were collected by a retrospective review of the patients' records and health examination reports or by interview. A total of 190 patients (61 ICC; 129 ECC) and 380 age- and sex-matched controls were enrolled. HBsAg (P<0.001) and anti-HBc without HBsAg (P=0.001) were significantly related to ICC. The adjusted odds ratios (OR) and 95% confidence intervals (CI) were 18.1 (95% CI: 7.5-44.0) and 3.6 (95% CI: 1.7-7.6) respectively. Diabetes mellitus (P=0.007), cholecystolithiasis (P=0.004) and previous cholecystectomy (P<0.001) were significantly associated with ECC. The prevalence of cirrhosis was higher in ICC than that in ECC (P<0.001). Furthermore, on excluding the ICC patients with cirrhosis, ICC patients showed significant independent associations with HBsAg (OR: 7.3; 95% CI: 3.1-17.2) and anti-HBc without HBsAg (OR: 2.4; 95% CI: 1.1-5.2). Cirrhosis and chronic hepatitis B virus infection are risk factors for ICC, while cholecystolithiasis, diabetes and previous cholecystectomy are risk factors for ECC.

Case-control study of risk factors in cholangiocarcinoma

To investigate the risk factors of intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). The clinicopathological data of 190 patients with cholangiocarcinomas (61 ICC and 129 ECC) diagnosed and treated in the Peking Union Medical College Hospital between 1998 and 2008 were collected. The clinicopathological data of 380 matched healthy controls were also collected. The information about liver diseases, family history, diabetes, smoking and drinking were recorded and analyzed. The positive rate of HBsAg(+) and anti-HBc(+), HBsAg(-) and anti-HBc(+) and the incidence of choledocholithiasis or hepatolithiasis in ICC patients were 27.9%, 50.8% and 14.8%, respectively. The incidence of diabetes mellitus, cholecystolithiasis, choledocholithiasis or hepatolithiasis and previous cholecystectomy in ECC patients were 18.6%, 15.5%, 18.6% and 13.2%, respectively. The incidences of all above mentioned factors in the ICC or ECC patients were significantly higher than that in the controls (P < 0.05). Compared with the patients with ECC, the ICC patients had a significantly higher cirrhosis rate (P < 0.05). Our study results show that choledocholithiasis or hepatolithiasis, liver cirrhosis and chronic HBV infection are possible risk factors for intrahepatic cholangiocarcinoma, while choledocholithiasis or hepatolithiasis, diabetes mellitus, cholecystolithiasis, history of cholecystectomy are risk factors for extrahepatic cholangiocarcinoma.

Viral hepatitis-associated intrahepatic cholangiocarcinoma shares common disease processes with hepatocellular carcinoma

Bile duct cells and hepatocytes differentiate from the same hepatic progenitor cells. To investigate the possible association of viral hepatitis B and C with intrahepatic cholangiocarcinoma (ICC), we conducted a retrospective case–control study using univariate and multivariate logistic analyses to identify risk factors for ICC. Besides hepatic lithiasis (25.6%; P<0.001), seropositivity for hepatitis B surface antigen (37.5% of all ICC patients; odds ratio (OR) =4.985, P<0.001) and seropositivity for hepatitis C antibodies (13.1%; OR=2.709; P=0.021) are the primary independent risk factors for ICC. Cirrhosis exerted synergic effects on the development of ICC. We compared the age distributions of viral-hepatitis associated ICC to that of viral hepatitis-associated hepatocellular carcinoma (HCC). The mean age of ICC patients with viral hepatitis B (56.4±11.1 years) were 9 years younger than that of ICC patients with viral hepatitis C (65.6±9.17 years), similar to that observed in HCC. The incidence ratio of HCC : ICC : CHC (combined hepatocellular cholangiocarcinoma) in our population was 233 : 17 : 1 consistent with the theoretic ratio of hepatocyte number to cholangiocyte number in the liver. Our findings indicated that both viral hepatitis-associated ICC and HCC shared common disease process for carcinogenesis and, possibly, both arose from the hepatic progenitor cells.

Hepatitis B Virus Infection and Intrahepatic Cholangiocarcinoma in Korea: A Case-Control Study

There is a wide variation in risk factors for intrahepatic cholangiocarcinoma (ICC) among various populations. Several studies have suggested that hepatitis C virus (HCV) infection may play a role in the development of ICC, whereas the role of hepatitis B virus (HBV) infection is less clear. To determine whether HBV or HCV infection is a risk factor of ICC, we compared baseline demographic and clinical factors in 622 patients diagnosed between 2000 and 2004 with histologically confirmed ICC and 2,488 healthy controls, matched 4:1 with ICC patients for sex and year of birth. HBV infection (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.6-3.3), but not HCV infection, was significantly related to ICC. Other significant risk factors for ICC included liver cirrhosis (OR 13.6), heavy alcohol consumption (OR 6.6), diabetes (OR 3.2), Clonorchis sinensis infection (OR 13.6), hepatolithiasis (OR 50.0), and choledochal cysts (OR 10.7). Our results indicate that development of ICC seems to be more closely related to HBV infection than to HCV infection in Korea, where both HBV and ICC are endemic.

Risk factors for intrahepatic cholangiocarcinoma: A case-control study in China

To carry out a hospital-based case-control study to investigate risk factors for intrahepatic cholangiocarcinoma (ICC) in China. A total of 312 ICC cases and 438 matched controls were included in the study. The presence of diabetes mellitus, hypertension, hepatolithiasis, primary sclerosing cholangitis, liver fluke infection (Clonorchis sinensis), was investigated through clinical records. Blood from all participants was tested for hepatitis B surface antigen (HBsAg) and anti-HCV antibodies. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression. Compared with controls, ICC patients had a higher prevalence of HBsAg seropositivity (48.4% vs 9.6%, P<0.000), and hepatolithiasis (5.4% vs 1.1%, P=0.001). By multivariate analysis, the significant risk factors for development of ICC were HBsAg seropositivity (adjusted OR, 8.876, 95% CI, 5.973-13.192), and hepatolithiasis (adjusted OR, 5.765, 95% CI, 1.972-16.851). The prevalence of anti-HCV seropositivity, diabetes mellitus, hypertension, cigarette smoking, and alcohol consumption were not significantly different between cases and controls. These findings suggest that HBV infection and hepatolithiasis are strong risk factors for development of ICC in China.

Bile Duct Dysplasia in the Setting of Chronic Hepatitis C and Alcohol Cirrhosis

Intrahepatic cholangiocarcinomas are rare and risk factors remain incompletely understood, but one recently identified potential risk factor is chronic hepatitis C (HCV) infection. To further study this potential association, we searched for dysplasia in the intrahepatic bile ducts in native explanted livers in cases of chronic HCV and control groups. Cases of chronic biliary tract disease were excluded. A total of 1058 explants were reviewed: HCV (511), alcohol alone (112), HCV and alcohol (85), HBV (67), cirrhosis from other causes (149), and noncirrhotic livers, for example, cases transplanted for acute liver failure (134). Dysplasia of the intrahepatic bile ducts was seen in 19/1058 (1.8%) of cases and was associated with chronic HCV infection and alcohol use, P=0.01. Ten out of 19 cases of dysplasia were in the setting of chronic HCV, 5/19 were in the setting of alcohol alone, and the remaining 4/19 were in the setting of combined HCV and alcohol. Seventeen out of 19 cases were classified as low-grade dysplasia and 2/19 as high-grade dysplasia. In all cases of dysplasia, the lesions were multifocal and involved septal-sized bile ducts. In 16/19 cases, the dysplasia was papillary whereas in 3/19 cases the dysplasia was flat. In conclusion, dysplasia can be found within the intrahepatic bile ducts in chronic HCV cirrhosis, supporting recent epidemiologic studies identifying chronic HCV as a major risk factor for intrahepatic cholangiocarcinoma. Alcohol also seems to be a risk factor. The dysplastic changes are multifocal, involve septal sized bile ducts, and are typically papillary.

Risk Factors for Intrahepatic and Extrahepatic Cholangiocarcinoma: A Hospital-Based Case?Control Study

The risk factors for cholangiocarcinoma are poorly defined in the United States. We evaluated hepatitis C virus (HCV), hepatitis B virus (HBV), and liver cirrhosis as risk factors for intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). A case-control study in which cases were cholangiocarcinoma patients referred to the M.D. Anderson Cancer Center between 1992 and 2002 and controls were healthy individuals. Information about liver diseases, family history, diabetes, smoking, and alcohol consumption were collected on both groups. Blood from all participants was tested for HBV and HCV markers. We identified 246 cases (83 ICC and 163 ECC) and matched them to 236 controls. Compared with controls, ICC patients had a higher prevalence of anti-HCV antibodies (6.0%vs 0.8%, P=0.01), anti-HBc (9.6%vs 0%, P<0.0001), and heavy alcohol consumption (21.7%vs 3.8%, P<0.0001). The adjusted odds ratio and 95% confidence interval (CI) were 7.9 (95% CI 1.3-84.5), 28.6 (95% CI 3.9-1,268.1), and 5.9 (95% CI 2.1-17.4), respectively. Only heavy alcohol consumption was higher in patients with ECC than in controls (17.8%vs 3.8%, P=0.003). The prevalence of diabetes and smoking were not significantly different between cases (ICC or ECC) and controls. The prevalence of cirrhosis was higher in patients with ICC than those with ECC (24.1%vs 4.9%, P<0.0001). Liver cirrhosis and chronic HCV infection are possible risk factors for ICC but not ECC. Heavy alcohol consumption is a risk factor for both ICC and ECC.

Risk factors for intrahepatic cholangiocarcinoma in a low‐risk population: A nationwide case‐control study

Recently, the incidence of intrahepatic cholangiocarcinoma (ICC) has been increasing in a number of developed (Western) countries. However, risk factors in these low-risk populations are poorly understood. In this nationwide population based case-control study in Denmark, we examined the relationship between selected medical conditions and subsequent ICC risk to provide additional clues to etiopathogenesis. All histologically confirmed ICC cases diagnosed in Denmark between 1978 and 1991 were identified from the Danish cancer registry. Population controls were selected from the central population registry and were matched 4:1 to cases on sex and year of birth. Cases and controls were linked to the Danish hospital discharge registry to obtain information on prior hospital diagnoses. Odds ratios (OR) and 95% confidence intervals (95% CI) were derived using conditional logistic regression. A total of 764 ICC cases and 3,056 population controls were included in the study. Chronic liver diseases were significantly related to ICC: alcoholic liver disease (OR = 19.22, 95% CI = 5.55-66.54), unspecified cirrhosis (OR = 75.9, 95% CI 10.2-565.7). Bile duct diseases were also associated with risk: cholangitis (OR = 6.3, 95% CI = 2.3-17.5), choledocholithiasis (OR = 23.97, 95% CI = 2.9-198.9), cholecystolithiasis (OR = 4.0, 95% CI = 2.0-7.99), though gallbladder removal did not change risk (OR = 1.6, 95% CI = 0.65-3.7). Among other conditions, chronic inflammatory bowel disease (OR = 4.7, 95% CI = 1.65-13.9) was significantly associated with ICC. Diabetes was associated with risk in the year prior to diagnosis of ICC (OR = 3.02, 95% CI = 1.05-8.69). Obesity was unrelated to risk. These results confirm that prior bile duct diseases increase risk of ICC and suggest that alcoholic liver disease and diabetes may also increase risk.

Risk Factors of Intrahepatic Cholangiocarcinoma in the United States: A Case-Control Study

Risk Factors of Intrahepatic Cholangiocarcinoma in the United States: A Case-Control Study

Risk factors of intrahepatic cholangiocarcinoma in the United States: A case-control study

The incidence of intrahepatic cholangiocarcinoma has been recently increasing in the United States. In this case-control study, we used the Surveillance, Epidemiology, and End Results-Medicare database to evaluate the prevalence of known risk factors for intrahepatic cholangiocarcinoma and explore other potential risk factors. We identified all patients with intrahepatic cholangiocarcinoma aged 65 years and older diagnosed between 1993 and 1999 in the population-based Surveillance, Epidemiology, and End Results registries (14% of the US population). Controls were randomly chosen from individuals without any cancer diagnosis in the underlying population of the Surveillance, Epidemiology, and End Results regions. We obtained information on risk factors from Medicare claims (parts A and B) for all cases and controls with at least 2 years of continuous Medicare enrollment. Unadjusted and adjusted odds ratios were calculated in logistic regression analysis. A total of 625 cases and 90,834 controls satisfied the inclusion and exclusion criteria. Cases were older than controls (78.7 vs. 76.5 years; P=.02) and were more likely to be male (48.3% vs. 36.8%; P <.0001). The racial composition was similar between cases and controls. Several risk factors were significantly more prevalent among cases. These included nonspecific cirrhosis (adjusted odds ratio, 27.2; P <.0001), alcoholic liver disease (adjusted odds ratio, 7.4; P <.0001), hepatitis C virus infection (adjusted odds ratio, 6.1; P <.0001), human immunodeficiency virus infection (adjusted odds ratio, 5.9; P=.003), diabetes (adjusted odds ratio, 2.0; P <.0001), and inflammatory bowel diseases (adjusted odds ratio, 2.3; P=.002). This population-based study shows that in addition to previously well described risk factors, several others could be associated with intrahepatic cholangiocarcinoma. These include hepatitis C virus, human immunodeficiency virus, liver cirrhosis, and diabetes.

Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma.

Although hepatitis C virus (HCV)-related cirrhosis has been suggested as a risk factor for intrahepatic cholangiocarcinoma (ICC), few sizeable studies have tested this hypothesis. We investigated ICC risk factors, with special reference to HCV infection. We conducted a hospital-based case-control study including 50 ICC patients and 205 other surgical patients without primary liver cancer. HCV seropositivity was detected in 36% of ICC patients and 3% of controls. By univariate analysis, the odds ratio (OR) for association of anti-HCV antibodies with development was 16.87 (95% confidence interval (CI), 5.69 to 50.00). History of blood transfusion or diabetes mellitus, elevated serum total bilirubin, elevated aspartate aminotransferase and alanine aminotransferase, decreased serum albumin and decreased platelet count were identified as other possible ICC risk factors. By multivariate analysis, anti-HCV antibodies (adjusted OR, 6.02; 95% CI, 1.51 to 24.1), elevated alanine aminotransferase, decreased serum albumin, and decreased platelet count were found to be independent risk factors for ICC development. As liver status worsened, the adjusted OR for ICC tended to increase. HCV infection is a likely etiology of ICC in Japan.