Risk Factors for Cholangiocarcinoma, Role of Diabetes Mellitus and Hepatitis B Virus Infection in the Intrahepatic and Extrahepatic Cholangiocarcinoma: A case-control study in China

Risk Factors for Cholangiocarcinoma, Role of Diabetes Mellitus and Hepatitis B Virus Infection in the Intrahepatic and Extrahepatic Cholangiocarcinoma: A case-control study in China | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Risk Factors for Cholangiocarcinoma, Role of Diabetes Mellitus and Hepatitis B Virus Infection in the Intrahepatic and Extrahepatic Cholangiocarcinoma: A case-control study in China Hasan Md Rasadul, Yun-fu Cui, Peng-cheng Kang, Jing-lin Li, Shi-hui Ma, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6483124/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Jul, 2025 Read the published version in Infectious Agents and Cancer → Version 1 posted 10 You are reading this latest preprint version Abstract Background: Diabetes mellitus (DM) and hepatitis B virus infection enhance the incidence of intrahepatic and extrahepatic cholangiocarcinoma, but their significance is unclear. Here, we conducted a population-based case-control study in China to evaluate the effects of DM, HBV infection, and other possible risk factors for cholangiocarcinoma. Methods: A hospital-based, case-control study of 245 CCA patients (168 eCCA and 77 iCCA) diagnosed at The Second Affiliated Hospital of Harbin Medical University in China between January 2019 and June 2024 and 490 healthy controls matched 2:1. Cholangiocarcinoma risk variables and correlations were analyzed using conditional logistic regression and the synergism index. Results: Cholangiocarcinoma (CCA) was significantly and positively correlated with diabetes mellitus, HBV infection, cholecystolithiasis, choledocholithiasis, hepatolithiasis, cholecystectomy history, and thyroid diseases, with adjusted odds ratios AOR= 1.41, 0.35, 1.70, 5.40, 0.30, 0.49, 5.42, respectively. Without complications, diabetes mellitus had an AOR=0.21 and with complications, AOR=0.46, which are substantial risk factors for CCA. eCCA Cholelithiasis (AOR=1.51), CBD stones (AOR=4.51), hepatolithiasis (AOR=0.29), and thyroid disorders (AOR=8.56) were significant in subgroup analyses. Diabetes mellitus without and with complications (AOR=0.43 and AOR=0.70) also increased eCCA risk. Cholelithiasis, cholecystectomy, hepatolithiasis, and HBV infection were risk factors for iCCA (AOR=4.91, 0.39, 0.34, and 0.20), respectively. However, diabetic mellitus (AOR=1.30) is also a significant risk factor for iCCA. Conclusion: In this study, cholelithiasis, hepatolithiasis, CBD stones, HBV infection, and diabetes mellitus (DM) were independent risk factors for cholangiocarcinoma, especially extrahepatic and intrahepatic cholangiocarcinoma. By understanding this synergy, high-risk cholangiocarcinoma prevention methods can be devised. Cholangiocarcinoma Extrahepatic cholangiocarcinoma (eCCA) Intrahepatic cholangiocarcinoma (iCCA) Risk factor Hepatitis Diabetes mellitus (DM) Introduction Cholangiocarcinoma (CCA), also known as bile duct cancer, is a rare group of epithelial cell malignancies that arise from the bile duct (intrahepatic & extrahepatic). It has been considered a rare disease, accounting for less than 1% of all human cancers. [ 1 ] Despite being the second most common cancer of the liver (primary hepatobiliary cancer), cholangiocarcinoma remains a rare disease. [ 2 ] However, the overall incidence has increased worldwide in recent decades, especially in China. [ 3 ] It has been demonstrated that cholangiocarcinoma is characterized by a low survival rate, with a median survival rate of less than 24 months. [ 4 ] Anatomically, it can be subtyped into intrahepatic and extrahepatic cholangiocarcinoma. Extrahepatic cholangiocarcinoma (eCCA) can be subdivided into perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA). [ 5 ] Intrahepatic cholangiocarcinoma (iCCA) is similar to HCC's presentation as mass lesions within the liver. Both originated from the primary epithelial cells of the liver. Cholangiocarcinoma can be pretty challenging to diagnose and treat because of its rarity. Defending the risk factors for cholangiocarcinoma can be beneficial, and search for better ways to pre vent the occurrence of these diseases. Recently, a study in China demonstrated that HBV infection could be used as a predictive marker for a favorable prognosis. [ 5 , 6 ] All the risk factors indistinctly lead to chronic inflammation of the biliary epithelium and biliary stasis, which represent common features that play a fundamental role in the pathogenesis of cholangiocarcinoma. The increasing rate of cholangiocarcinoma has led researchers to analyze new and emerging risk factors. Therefore, in addition to the well-known risk factors listed hepatolithiasis, PSC, liver flukes, biliary tract cysts, specific toxins, IBD, genetic polymorphism, alcoholic cirrhosis, tobacco, chronic liver diseases, cholecystectomy, choledocholithiasis, cholecystolithiasis, obesity, diabetes mellitus, chronic pancreatitis, alcoholic liver disease, thyroid diseases, pancreatic cancer, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. [ 7 , 8 ] These risk variables still cannot account for the increasing prevalence or number of CCA cases. Because of their rarity, only approximately 10% of CCA (including iCCA and eCCA) cases are associated with a recognized risk factor. [ 9 ] While it is true that traditional risk factors may not account for all cases, it's essential to consider other potential factors that could be contributing to the rise. This scenario raises concern about the impact of underexplored factors beyond these etiologies. [ 7 ] The occurrence of diabetes mellitus (DM) has significantly increased in both developed and developing nations over the last twenty years. [ 10 ] Several studies have explored the connection between DM and various types of cancer, such as breast, endometrial, non-Hodgkin's lymphoma, pancreatic, and liver cancer. [ 11 – 13 ] It is commonly known that diabetes is a risk factor for several cancers. Several molecular pathways have been predicted to explain the possible relationship between diabetes and cancer risk. Insulin resistance and hyperinsulinemia can stimulate the production of the insulin-like growth factor-1 (IGF-1), which may contribute to cancer initiation and progression. [ 14 ] The immunologic, hormonal, and metabolic features of diabetes mellitus may also facilitate cancer development. Most research shows a positive correlation between DM and cholangiocarcinoma (CCA) risk, including iCCA and eCCA, but some publications find no correlation. [ 15 ] The reason for these inconsistent results is unknown; however, it is uncertain if methodological inconsistencies or inequalities among study groups contribute to these findings. Oxidative stress, lipotoxicity, hyperinsulinemia, insulin resistance, and cholangiocyte transformation have been connected to the development of liver disease and fat deposition, with insulin in bile and leptin in adipose tissue possibly increasing cholangiocarcinogenesis. [ 16 , 17 ] However, few studies have focused on analyzing interactions between risk factors for CCA. Because of the multifactorial nature of biliary tract carcinogenesis, possible interactions between risk factors may exist. We conducted a hospital-based case-control study to assess potential risk factors for CCA in China. We aimed to identify possible synergisms between the risk factors of cholangiocarcinoma and the role of the risk factors of diabetes mellitus and HBV infection for intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA). Methods Source of data / Study population and design A hospital-based case-control study was performed by enrolling 735 cases (245 cases with pathologically diagnosed CCA and 490 healthy controls) from The Second Affiliated Hospital of Harbin Medical University of the General Surgery departments. The Second Affiliated Hospital of Harbin Medical University is considered one of the most common hospitals visited by CCA patients in Heilongjiang. All patients diagnosed with CCA through pathological findings at The Second Affiliated Hospital of Harbin Medical University between January 2019 and June 2024 were reviewed for study enrollment. We conducted Control subjects, matched 2:1 (490:245), with control cases who were male 247 and female 243 for a mean age of 58 years, and CCA cases were 152 males and 93 females for a mean age of 61 years. Control subjects were randomly chosen with cases for age, sex, and date of diagnosis (± 3 months) among individuals who had visited The Second Affiliated Hospital of Harbin Medical University for a routine checkup during the same time the CCA cases were selected. We randomized the control group by using a random number generator. We include cases between ages 30 and 90 years old with symptoms and risk factors of CCA, pathologically diagnosed CCA, and cases with clinical, biochemical, and radiological information, which are all found in the data system. We excluded cases below ages 30 and above 90 years old, without radiologic information, and ampulla of Vater carcinoma. In the control group, those who were diagnosed with other cancers were also excluded. Gallbladder carcinoma and hilar cholangiocarcinoma were included as extrahepatic cholangiocarcinoma. Finally, 245 cases and 490 controls were included in the analysis. The Second Affiliated Hospital of Harbin Medical University approved the study protocol. Data collection Patient records were manually and retrospectively reviewed to extract demographical and clinical data and risk factors. In this study, we reported demographical data and detailed information on drinking and smoking. Relevant data were obtained by retrospectively reviewing patient data records from the general surgery department of The Second Affiliated Hospital of Harbin Medical University data systems, which a physician simultaneously documented in a structured data collection sheet. The abovementioned data collection was routinely conducted in our liver surgery clinic, and the relevant sheet was conserved as a part of the medical records. Data of age, sex, smoking, alcohol consumption, patient obesity, diabetes mellitus, hypertension, cholecystolithiasis, choledocholithiasis, cholecystectomy, ulcerative colitis, alcoholic liver disease, thyroid diseases, chronic pancreatitis, pancreatic cancer, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, liver cirrhosis, liver fluke infestation were abstracted. Control patients were selected from The Second Affiliated Hospital of Harbin Medical University of the General Surgery departments, which was not representative of the entire community; consequently, it could not represent the overall population properly. The selection of matched controls from the Health Screening Centre of General Surgery departments, rather than the general community, minimized selection bias due to the origin of the case group from General Surgery department patients. A total of 490 individuals were chosen as controls. From January 2019 to July 2024, cases and controls at the Health Screening Centre of General Surgery departments were matched based on age and sex in a one-to-two ratio. Definitions of events There were two types of CCA: extrahepatic cholangiocarcinoma (eCCA) and intrahepatic cholangiocarcinoma (iCCA). This study did not include Ampulla of Vater carcinoma, although perihilar cholangiocarcinoma (pCCA) was included in (eCCA). Alcohol consumption was defined as someone who consumes at least 80 g (male) or 40 g (female) of alcohol each day. Obesity was classified as having a body mass index (BMI) of 25.0 kg/m2 or more, as per the Asian-Pacific standards. Serum HBV surface antigen (HBsAg) and HCV antibody (anti-HCV) were measured by retrospectively reviewing clinical data; participants were classified as anti-HCV-positive if they tested positive for HCV RNA, and HBV infection was defined as positive if they tested positive for hepatitis B surface antigen. The diagnostic criteria for liver cirrhosis were as follows: clinical manifestations of chronic hepatitis with portal hypertension (e.g., collateral varices, varices, thrombocytopenia, or splenomegaly) and/or hepatic decompensation (e.g., jaundice, prolonged prothrombin time, and ascites), laboratory tests, and radiologic studies. In patients undergoing surgical treatment, cirrhosis was also confirmed pathologically. The presence of cirrhosis is defined as nonspecific cirrhosis without the presence of HCV, HBV, or alcoholic liver disease. The diagnosis of liver fluke infestation, alcoholic liver diseases, and ulcerative colitis was made based on the patient's data, reviewing laboratory tests as well as from the radiologic finding of diffuse, uniform dilatation of the small intrahepatic bile ducts with no or minimal dilatation of larger bile ducts and with no focal obstructing lesion. Chronic pancreatitis and pancreatic cancer were diagnosed by the radiological findings and confirmed by the pathological findings. Choledocholithiasis was defined as the presence of at least one stone in the extrahepatic bile duct. In contrast, hepatolithiasis was defined as the presence of a stone in the intrahepatic bile duct. The presence of cystic duct stones was classified as cholecystolithiasis. The cholecystectomy was diagnosed from the patient's operation history review. Diabetes was diagnosed according to the World Health Organization Criteria and categorized into two groups: (1) complicated diabetes (presence of any stage of retinopathy, nephropathy, or macrovascular complications) and (2) uncomplicated diabetes. Thyroid disease includes hyperthyroidism and hypothyroidism. Statistical analysis The statistical analyses were conducted using SPSS 20.0 software. The Mann-Whitney U test was used to compare continuous data, whereas the Pearson χ2 test with the Fisher exact test was utilized to analyze discrete variables. Univariate and multivariate correlation studies were conducted using conditional logistic regression with maximum likelihood estimations of parameter values to evaluate the risk for CCA. All variables were investigated with P-values of < 0.05 in the univariate analyses and were subsequently adjusted to be examined in multiple logistic regression analyses. Logistic regression analysis was used to identify risk factors associated with CCA development and calculate ORs, adjusted ORs (AORs), and 95% confidence intervals (CIs). Two-sided tests with P < 0.05 were deemed statistically significant for all analyses. Furthermore, the population-attributable risk fraction for risk factors found to be statistically significant was determined using the adjusted odds ratio (AOR) of the underlying factor and its prevalence in the control group. Results Patient characteristics The baseline attributes of CCA patients and controls are summarized in Table 1. For this study, there were 245 CCA patients, 152(62.0%) male, 93 female (38.0%), and 490 controls, 247 male (50.4%), female 243(49.6%), a total of 735 that qualified for this clinical study (Table 2). Of these, 168(68.6%) were eCCA and 77(31.4%) were iCCA. We groped the age in 29-49 years 27(11.0%) CCA patients, and controls 127(25.9%) patients; age in 50-69 years 165(67.3%) CCA patients and controls 276(56.3%) patients; age in 70-89 years 53(21.6%) CCA patients, and controls 87(17.8%) patients were conducted (Table 1). The CCA case and control groups had mean ages of 61.60 and 57.77 years, respectively (Table 1). CCA population The outcomes are summarized in Table 2. As expected, the relative odds of CCA in the multivariate conditional logistic analysis showed that the relative odds of CCA were significantly elevated in subjects with a history of cholelithiasis (AOR = 1.70; 95% CI = 1.12-2.57; P = <0.011), CBD stones (choledocholithiasis) (AOR = 5.40; 95% CI = 2.05-14.21; P = <0.001), hepatolithiasis (AOR = 0.30; 95%Cl = 0.10-0.89; P = <0.031), cholecystectomy history (AOR = 0.49; 95% CI = 0.29-0.83; P = <0.008), thyroid diseases (AOR = 5.42; 95%Cl = 2.02-14.50; P = <0.001), HBV infection (AOR = 0.35; 95%Cl = 0.19-0.64; P = <0.001), and diabetes mellitus (AOR = 1.41; 95% CI = 1.17-1.70; P = <0.001). Diabetes mellitus Divided into two categories without complication (AOR = 0.21; 95% Cl = 0.11-0.40); P = <0.001), with complication (AOR = 0.46; 95% Cl = 0.22-0.99; P = <0.049) were the significant risk factors for CCA (Table 2). Age (AOR = 1.02; 95%CI = 1.00-1.03; P = 20 years (AOR = 0.27; 95%CI = 0.13-0.58; P = <0.001) were also related to increased CCA risk factors. We observed that alcohol consumption (AOR = 1.57; 95%Cl = 0.98-2.52; P = 0.058), liver cirrhosis (AOR = 1.06; 95% CI = 0.29-3.87; P = 0.919) and HCV infection (AOR = 1.21; 95% CI = 0.19-7.46; P = 0.831) were not significantly associated for CCA. Table 1 Age characteristics of CCA patients and controls Age group Participant CCA patient (n=245) Control (n=490) Mean ±SD CCA Control 29-49 years 27(11.0%) 127(25.9%) 61.60 57.77 50-69 years 165(67.3%) 276(56.3%) 70-89 years 53(21.6%) 87(17.8%) Table 2 Comparison of risk factors in patients with cholangiocarcinoma (CCA) and matched controls n (%) Independent variable CCA patient (n = 245) Control (n=490) Univariable analysis Multivariable analysis OR (95% CI) P value AOR (95% CI) P value Age in years ----- ------ 1.03 (1.02-1.05) <.001 1.02(1.00-1.03) <0.016 Sex Male 152(62.0%) 247(50.4%) Reference Female 93(38.0%) 243(49.6%) 1.601(1.18-2.20) <0.003 1.49(1.01-2.18) 0.040 Smoking Yes 9(3.7%) 27(5.5%) 0.62(0.39-.96) 0.034 0.53(0.30-0.92) 0.024 One pack per day for 20 years 43(17.6%) 53(10.8%) 0.34(0.17-0.68) <0.002 0.27(0.13-0.58) <0.001 Alcohol consumption 58(23.7%) 130(26.5%) 1.16(0.81-1.66) 0.403 1.57(0.98-2.52) 0.058 Obesity 65(26.5% 157(32.0%) 1.30(0.92-1.83) 0.126 1.38(0.93-2.04) 0.104 Diabetes mellitus 65(26.6%) 68(13.9%) 1.40(1.20-1.66) <0.001 1.41(1.17-1.70) <0.001 Without complication 43(17.6%) 50(10.2%) 0.22(0.12-0.40) <0.001 0.21(0.11-0.40) <0.001 With complication 22(9.0%) 18(3.7%) 0.48(0.24-0.95) 0.036 0.46(0.22-0.99) 0.049 Hypertension 64(26.1%) 118(24.1%) 0.89(0.63-1.27) 0.546 1.13(0.75-1.70) 0.534 Cholelithiasis 53(21.6%) 170(34.7%) 1.92(1.34-2.74) <0.001 1.70(1.12-2.57) <0.011 CBD stones 6(2.4%) 50(10.2%) 4.52(1.91-10.71) <0.001 5.40(2.05-14.21) <0.001 Hepatolithiasis 11(4.5%) 8(1.6%) 0.35(0.14-0.89) 0.027 0.30(0.10-0.89) 0.031 Cholecystectomy 41(16.7%) 39(8.0%) 0.43(0.26-0.68) <0.001 0.49(0.29-0.83) 0.008 Ulcerative colitis 2(0.8%) 16(3.3%) 4.10(0.93-17.98) 0.061 4.18(0.88-19.85) 0.071 ALD 2(0.8%) 4(0.8%) 1.00(0.18-5.49) 1.000 1.49(0.24-9.04) 0.661 Thyroid diseases 5(2.0%) 49(10.0%) 5.33(2.09-13.56) <0.001 5.42(2.02-14.50) <0.001 Chronic pancreatitis 0(0.0%) 7(1.4%) 819444698.56(-) 0.999 448308451.13(-) 0.999 Pancreatic cancer 8(3.3%) 6(1.2%) 0.36(0.12-1.07) 0.066 0.39(0.12-1.22) 0.108 HBV infection 33(13.5%) 29(5.9%) 0.40(0.23-0.68) <0.001 0.35(0.19-0.64) <0.001 HCV infection 2(0.8%) 6(1.2%) 1.50(0.30-7.51) 0.618 1.21(0.19-7.46) 0.831 Liver cirrhosis 5(2.0%) 7(1.4%) 0.69(0.21-2.21) 0.539 1.06(0.29-3.87) 0.919 Liver fluke infestation 2(0.8%) 0(0.0%) 0.00(0.00-) 0.999 0.00(--) 0.999 Abbreviations: CCA, cholangiocarcinoma; ECC, extrahepatic cholangiocarcinoma; ICC, intrahepatic cholangiocarcinoma; CBD, Common Bile Duct stones; ALD, Alcoholic liver diseases; HBV, hepatitis B virus; HCV, hepatitis C virus; 1. One pack-year = 1 pack per day for a year; 2. Daily amount of ≥ 80 g (male) or ≥ 40 g (female); 3. Obesity was defined as a body mass index > 25 kg/m2 according to the Asian-Pacific criteria for obesity; 4. Any stage of retinopathy, nephropathy, or macrovascular complications. CCA: Cholangiocarcinoma; HBV: Hepatitis B virus; HCV: Hepatitis C virus; AOR: Adjusted odds ratio. Subgroup analysis, eCCA and iCCA population Subgroup analysis was used to identify risk variables for eCCA and iCCA. In the conditional logistic regression model, we included 168(68.6%) eCCA patients 109(64.9%) male, 59(35.1%) female and control 336 controls169(50.3%) male, 167(49.7%) female (Table 4). We groped the age in 29-49 years 10(6.0%) eCCA patients, and controls 83(24.7%) patients; age in 50-69 years 118(70.2%) eCCA patients, and controls 188(56.0%) patients; age in 70-89 years 40(23.8%) eCCA patients, and controls 65(19.3%) patients were conducted (Table 3). The eCCA case and control groups had mean ages of 63.01 and 58.30 years, respectively (Table 3). In the conditional logistic regression model result of cholelithiasis (AOR = 1.51; 95%CI = 0.94-2.41; P = 0.083), CBD stones (choledocholithiasis) (AOR = 4.51; 95% CI = 1.70-11.98; P = 0.002); hepatolithiasis (AOR = 0.29; 95%Cl = 0.09-0.94; P = <0.040), thyroid diseases (AOR = 8.56; 95%Cl = 1.97-37.12; P = <0.004) were significant for eCCA. Diabetes mellitus (AOR = 1.30; 95%Cl = 1.05-1.61; P = <0.014), diabetes mellitus without complication (AOR = 0.43; 95%C l= 0.19-0.96; P = 0.041), was also a significant risk factor for eCCA but with complication diabetes mellitus (AOR = 0.70; 95%Cl = 0.28-1.78; P = 0.465) was not significant. Cigarette smoking one pack per day for more than 20 years (AOR = 0.36; 95%CI = 0.15-0.85; P = <0.021) was also a significant risk factor for eCCA (Table 4). In the subgroup iCCA case 77 patients 44(57.1%) male, 33(42.9%) female and in control 154 cases, 79(51.3%) male ,75(48.7%) female (Table 6). In the age group, age in 29-49 years16(20.8%) iCCA patients, and controls 43(27.9%) patients; age in 50-69 years 48(62.3%) iCCA patients, and controls 89(57.8%) patients; age in 70-89 years 40(23.8%) iCCA patients, and controls 22(14.3%) patients were conducted (Table 5). The iCCA case and control groups had mean ages of 58.45 and 56.79 years, respectively (Table 5). In the conditional logistic regression model, it was also found that cholelithiasis (AOR = 4.91; 95%CI = 1.73-13.97; P = <0.003), cholecystectomy (AOR = 0.39; 95% CI = 0.15-0.99; P = 0.050), and hepatolithiasis (AOR = 0.34; 95% CI = (0.02-5.48); P = <0.020) were related to the iCCA. HBV infection (AOR = 0.20; 95%CI = 0.06-0.62; P = <0.006) was also a significant risk factor for iCCA. Cigarette smoking one pack per day for more than 20 years (AOR = 0.06; 95%CI = 0.01-0.56; P = 0.014) was also a significant risk factor for iCCA. However, diabetic mellitus (AOR = 3.01; 95%CI = 1.63-5.53; P = <0.001) is significant, but when for complication and without complication, diabetes mellitus is insignificant to correlate to iCCA where HCV also was not reach statistically significant to an enhanced risk of subtype iCCA (Table 6). Table 3 Age characteristics of ECC patients and controls Age group Participant ECC patient(n=168) Control (n=336) Mean ±SD ECC Control 29-49 years 10(6.0%) 83(24.7%) 63.01 58.30 50-69 years 118(70.2%) 188(56.0%) 70-89 years 40(23.8%) 65(19.3%) Table 4 Comparison subgroup analysis of risk factors in patients with Extrahepatic cholangiocarcinoma (ECC) and matched controls n (%) Independent variable ECC patient (n = 168) Control (n=336) Unadjusted Adjusted OR (95% CI) P value AOR (95% CI) P value Age in years ----- ------ 1.03 (1.02-1.05) <.001 1.02(1.01-1.03) <0.001 Sex Male 109(64.9%) 169(50.3%) Reference Female 59(35.1%) 167(49.7%) 1.82(1.24-2.67) <0.002 1.69(1.06-2.68) 0.026 Smoking Yes 4(2.4%) 20(6.0%) 0.69(0.41-1.17) 0.178 0.81(0.42-1.53) 0.519 One pack per day for 20 years 30(17.9%) 40(11.9%) 0.38(0.17-0.83) <0.016 0.36(0.15-0.85) 0.021 Alcohol consumption 43(25.6%) 92(27.4%) 1.09(0.71-1.67) 0.670 1.31(.75-2.26) 0.332 Obesity 47(28.0%) 109(32.4%) 1.23(0.82-1.85) 0.307 1.24(0.78-1.98) 0.356 Diabetes mellitus 47(28.0%) 58(17.3%) 1.33(1.10-1.60) <0.002 1.30(1.05-1.61) <0.014 Without complication 28(16.7%) 43(12.8%) 0.34(0.16-0.69) <0.003 0.43(0.19-0.96) 0.041 With complication 19(11.3%) 15(4.5%) 0.51(0.22-1.17) 0.115 0.70(0.28-1.78) 0.465 Hypertension 37(22.0%) 80(23.8%) 1.10(0.71-1.72) 0.655 1.36(0.81-2.28) 0.241 Cholelithiasis 45(26.8%) 124(36.9%) 1.59(1.06-2.40) 0.024 1.51(0.94-2.41) 0.083 CBD stones 6(3.6%) 36(10.7%) 3.24(1.33-7.85) <0.009 4.51(1.70-11.98) <0.002 Hepatolithiasis 9(5.4%) 6(1.8%) 0.32(0.11-0.91) 0.034 0.29(0.09-0.94) 0.040 Cholecystectomy 25(14.9%) 31(9.2%) 0.58(0.33-1.02) 0.059 0.75(0.39-1.43) 0.390 Ulcerative colitis 2(1.2%) 10(3.0%) 2.54(0.55-11.75) 0.231 3.12(0.61-15.84) 0.170 ALD 2(1.2%) 2(0.6%) 0.49(0.06-3.56) 0.486 0.52(0.06-4.30) 0.552 Thyroid diseases 2(1.2%) 37(11.0%) 10.27(2.44-43.15) <0.001 8.56(1.97-37.12) <0.004 Chronic pancreatitis 0(0.0%) 4(1.2%) 817468342.60(-) 0.999 228077265.27(-) 0.999 Pancreatic cancer 7(4.2%) 6(1.8%) 0.41(0.13-1.26) 0.123 0.48(0.14-1.67) 0.252 HBV infection 14(8.3%) 23(6.8%) 0.80(0.40-1.61) 0.547 0.75(0.34-1.67) 0.492 HCV infection 0(0.0%) 4(1.2%) 817467318.704(-) 0.999 1396133325.54() 0.999 Liver cirrhosis 0(0.0%) 6(1.8%) 822422772.45(-) 0.999 883186620.67(-) 0.999 Liver fluke infestation 1(0.6%) 0(0.0%) 0.00(0.00-) 1.000 000 (-) 1.000 Abbreviations: CCA, cholangiocarcinoma; ECC, extrahepatic cholangiocarcinoma; ICC, intrahepatic cholangiocarcinoma; CBD, Common Bile Duct stones; ALD, Alcoholic liver diseases HBV, hepatitis B virus; HCV, hepatitis C virus; Table 5 Age characteristics of ICC patients and controls Age group Participant ICC patient(n=77) Control (n=154) Mean ±SD ICC Control 29-49 years 16(20.8%) 43(27.9%) 58.45 56.79 50-69 years 48(62.3%) 89(57.8%) 70-89 years 13(16.9%) 22(14.3%) Table 6 Comparison subgroup analysis of risk factors in patients with Intrahepatic cholangiocarcinoma (ICC) and matched controls n (%) Independent variable ICC patient (n = 77) Control (n=154) Unadjusted Adjusted OR (95% CI) P value AOR (95% CI) P value Age in years ----- ------ 1.01(0.98-1.03) 0.311 0.99(0.96-1.02) 0.897 Sex Male 44(57.1%) 79(51.3%) Reference Female 33(42.9%) 75(48.7%) 1.26(0.73-2.19) 0.402 1.37(0.63-2.99) 0.416 Smoking Yes 4(5.2%) 6(3.9%) 0.69(0.31-1.51) 0.357 0.71(0.21-2.40) 0.590 One pack per day for 20 years 13(16.9%) 18(11.7%) 0.30(0.08-1.12) 0.075 0.06(0.01-0.56) <0.014 Alcohol consumption 15(19.5%) 43(27.9%) 1.60(0.82-3.11) 0.165 2.22(0.70-7.02) 0.172 Obesity 18(23.4%) 45(29.2%) 1.35(0.71-2.54) 0.348 1.20(0.49-2.96) 0.678 Diabetes mellitus 18(23.4%) 10(6.3%) 1.85(1.28-2.69) <0.001 3.01(1.63-5.53) <0.001 Without complication 15(19.5%) 7(4.5%) 0.41(0.08-2.08) 0.809 0.30(0.03-2.63) 0.282 With complication 3(3.9%) 3(1.9%) 2.14(0.34-13.42) 0.416 10.2(0.61-170.3) 0.106 Hypertension 26(33.8%) 42(27.3%) 0.73(0.40-1.32) 0.308 0.71(0.32-1.58) 0.408 Cholelithiasis 8(10.4%) 55(35.7%) 4.79(2.14-10.69) <0.001 4.91(1.73-13.97) <0.003 CBD stones 0(0.0%) 12(7.8%) 875997086.98(- ) 0.999 293033710.84(-) 0.999 Hepatolithiasis 2(2.6%) 4(2.6%) 1.00(0.17-5.58) 1.000 0.34(0.02-5.48) 0.448 Cholecystectomy 16(20.8%) 13(8.4%) 0.35(0.15-0.77) <0.010 0.39(0.15-0.99) 0.050 Ulcerative colitis 0(0.0%) 5(3.2%) 834841676.36(-) 0.999 9334525639.6() 0.999 ALD 0(0.0%) 2(1.3%) 818363030.34(-) 0.999 12187135586.2() 0.999 Thyroid diseases 3(3.9%) 14(9.1%) 2.46(0.68-8.85) 0.166 3.13(0.67-14.47) 0.143 Chronic pancreatitis 0(0.0%) 2(1.3%) 818363518.12(-) 0.999 4660280295.32() 0.999 Pancreatic cancer 1(1.3%) 2(1.3%) 1.00(0.08-11.20) 1.000 3.98(0.13-120.1) 0.426 HBV infection 19(24.7%) 15(9.7%) 0.32(0.15-0.69) <0.003 0.20(0.06-0.62) <0.006 HCV infection 2(2.6%) 3(1.9%) 0.74(0.12-4.55) 0.750 1.42(0.06-29.34) 0.820 Liver cirrhosis 5(6.5%) 0(0.0%) 0.000 (000) 0.999 0.000(000) 0.999 Liver fluke infestation 1(1.3%) 0(0.0%) 0.00(000) 1.000 0.000(000) 1.000 Abbreviations: CCA, cholangiocarcinoma; ECC, extrahepatic cholangiocarcinoma; ICC, intrahepatic cholangiocarcinoma; CBD Common Bile Duct stones; ALD, Alcoholic liver diseases; HBV, hepatitis B virus; HCV, hepatitis C virus Discussion The underlying cause and carcinogenesis of CCA remain uncertain despite numerous identified risk factors. A hospital-based case-control study in China established that diabetes mellitus (DM) is an independent risk factor for cholangiocarcinoma (CCA), especially for the extrahepatic cholangiocarcinoma (eCCA), and also for intrahepatic cholangiocarcinoma (iCCA), while diabetics mellitus with complications. Choledocholithiasis, hepatolithiasis, and diabetes mellitus are significantly connected with CCA in both subtypes, extrahepatic cholangiocarcinoma (eCCA) and intrahepatic cholangiocarcinoma (iCCA). While hepatitis B virus (HBV) infection is a risk factor for CCA, especially for iCCA, meanwhile, CBD stones are also risk factors for CCA, especially for eCCA. However, HCV did not reach a statistically significant level to enhance the risk of CCA. Global epidemiological studies indicate that diabetes elevates the risk of developing cholangiocarcinoma (CCA). [10] Elevated glucose, insulin, and obesity are risk factors for CCA. [18] Northeastern Thailand exhibits the highest prevalence of cholangiocarcinoma associated with O. viverrini. [7] Understanding whether diabetes is an overlooked factor may facilitate effective prevention in endemic regions. However, no research has substantiated this correlation. Understanding if DM is the unexplained variable in a small proportion of infected patients may facilitate effective prophylaxis in regions endemic to liver flukes. The hepatitis B virus (HBV) is identified as a risk factor for hepatocellular carcinoma (HCC). [19] The associations between HBV and CCA, as well as the impact of HBV on CCA development, are inadequately comprehended. Consistent with prior data, our findings indicate that HBV is substantially associated with cholangiocarcinoma (CCA), significantly increasing the risk of cholangiocarcinoma (CCA). Incorporating HBV DNA into human chromosomes and the persistent production of viral proteins, including HBx proteins and large proteins (LHBs), can activate oncogenes, generate oxidative stress, and result in genetic instability. [20] Furthermore, viruses can induce persistent hepatocyte death and regeneration within the inflammatory milieu established by the host's immune response to infection. This fosters an environment conducive to genetic alterations that result in hepatocyte transformation. [21] A prior study indicated that HBV may induce carcinogenesis in cholangiocytes through the exact mechanism as in hepatocytes, owing to their shared progenitor cells. [8] Unlike HBV infection, HCV infection was not a significant risk factor for cholangiocarcinoma (CCA) in this study. This finding aligns with a prior China study. There was no significant association between iCCA development and HCV infection in East Asian groups, although a subsequent meta-analysis revealed a significant association (OR = 6.91) in Western populations. [22] Our study found that HCV (P = 0.831) was not a substantial risk factor for cholangiocarcinoma (CCA). However, due to the small number of studies and participants analyzed, a more thorough investigation in Eastern regions is required to confirm the geographic disparity. Our findings also demonstrated a substantial correlation between diabetes mellitus and the development of cholangiocarcinoma, consistent with prior research. Insulin resistance and hyperinsulinemia have been demonstrated to promote the proliferation of many cancer cell types. [23] Furthermore, elevated insulin-like growth factor 1 levels may promote liver cell proliferation, contributing to cholangiocarcinoma's carcinogenesis (CCA). [23, 24] Once all diabetic patients were divided into groups based on how long they had been diabetic and whether they had any complications, tests were done again for a more accurate evaluation. There was no significant link between the length of diabetes mellitus (DM) and the risk of cholangiocarcinoma (CCA). However, DM had a more substantial effect on CCA risk when there were other health problems related to DM. Because of the long period between the onset of diabetes mellitus and its clinical diagnosis, the disease's duration from diagnosis does not fully reflect the actual duration of the condition. [25] Furthermore, diabetes mellitus management and disease severity may be more important predictors than just the duration of the condition. The frequency of diabetes mellitus complications relies upon glycemic management and the length of the condition. [18] A further well-structured analysis with more detailed information is necessary to explain the role of DM duration on the risk of CCA development. This study revealed several significant findings regarding the relationship between cholelithiasis and cholangiocarcinoma (CCA): CBD stones were identified as a risk factor for extrahepatic cholangiocarcinoma (eCCA) but not for intrahepatic cholangiocarcinoma (iCCA); Cholelithiasis was a risk factor for both eCCA and iCCA and hepatolithiasis was a risk factor for iCCA and eCCA. These findings may be attributed to the effects of cholestasis, altered bile composition, and chronic proliferative inflammation in proximity to the stone-bearing ducts. Previous studies conducted in China have also demonstrated the association between hepatolithiasis and eCCA, [26] Further supporting our findings. The principal finding of this study is the role of diabetes mellitus and hepatitis B virus infection on the risk of cholangiocarcinoma. While the precise mechanism remains ambiguous, a plausible explanation for the relationship exists. Hyperglycemia may induce glucose oxidation, lipid peroxidation, and protein glycosylation, generating free radicals contributing to oxidative stress. [27] Oxidative stress may subsequently enhance HBV gene expression, trigger viral replication reactivation, and contribute to the chronicity of liver disease, resulting in DNA damage and the formation of CCA. [27, 28] Given that oxidative stress is a recognized principal mediator in the advancement of diabetes mellitus (DM) and its complications, [28] Our discovery of enhanced synergism between complex DM and HBV infection corroborates this assertion. CCA and HCC are believed to have shared etiological components, and a prior study on HCC risk factors similarly demonstrated the synergistic relationship between diabetes mellitus and HBV infection in cancer development, [29] This corroborates our findings. The current study possesses several potential limitations: diagnostic bias cannot be dismissed as cancer patients undergo supplementary testing, resulting in a higher number of diagnoses compared to non-cancer individuals; this was a hospital-based study conducted at a single institution rather than a population-based design, which introduces the possibility of selection bias due to varying referral patterns; nevertheless, a hospital-based design may be more suitable for CCA given the low incidence and brief survival of CCA patients. The study did not examine the hepatitis B core antibody (anti-HBc) or occult HBV infection; nevertheless, subsequent research has shown minimal levels of HBV DNA in individuals with just anti-HBc (absent surface antigen/antibody) and a very low occurrence of occult HBV infection. [30] Moreover, the prevalence of HBV identified in this study was consistent with prior HBV prevalence estimates in China. Additionally, DM was not categorized by type. Given the lack of young-onset (≤ 30 years) DM in our cohort and the significantly lower incidence of type 1 DM in Asia, [25] it is inferred that most DM cases in this study were type 2 DM. Despite these limitations, this study has several remarkable advantages: It is the initial study to investigate risk factors for CCA (including eCCA and iCCA) in China, and it has been conducted within a multivariable framework that accounts for any possible confounding factors. In a previous study conducted in China, the prevalence of significant metabolic risk factors in the control group was comparable to that of the general population of China or other Asian nations. We stratified biliary lithiasis and diabetes mellitus based on the presence of complications and location, respectively. To the best of our knowledge, this study is the initial one to investigate the impact of complicated and uncomplicated diabetes mellitus on the risk of cholangiocarcinoma following the stratification of diabetes mellitus. This recent study has the potential to assist in the stratification of patients at risk for CCA and the CCA surveillance algorithms that are based on classification. Moreover, a synergistic connection existed between the two parameters for the probability of CCA development. Conducting an in-depth investigation to verify this synergistic relationship and clarify potential underlying mechanisms is essential. This synergy's fundamental mechanisms could be investigated to develop preventative methods for high-risk individuals who are at risk of developing CCA. Declarations Conflict of Interest Statement All the authors report having no conflicts of interest for this article. Ethical statement The protocol for this research project has been approved by the Ethics Committee of The Second Affiliated Hospital of Harbin Medical University, which approved the investigation. Ethics Committee approved number KY2025-096. All the patients in this study signed written informed consent. Funding The authors received no financial support for this research, authorship, and/or publication of this article. The articles are financially supported by the Heilongjiang Province's important research Project for the publication of this article grant number: 2024ZX12C21 Author Contribution Yunfu Cui contributed to Conceptualization and Supervision, Md Rasadul Hasan contributed to the literature search, writing, data analysis, interpretation of data, statistical analysis, and drafting of the manuscript, Jinglin Li contributed to review and editing, Pengcheng Kang contributed to the study design, Shihui Ma, Xu-dong Zhao, and Chenghong Duan contributed to Data collection. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6483124","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":445566405,"identity":"e24a895e-92ca-44c4-8202-124221c70390","order_by":0,"name":"Hasan Md Rasadul","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIiWNgGAWjYFCCBBBhYccmf7DhQEKFDZDD2HiACC0SyfwSzI0HPpxJA2lpIEoL48wZ7M0HZ7YcBovh1aLbnvvw448KCWaD240Nh3kbztutbT8MtKXGJhqXFrMzz42lec5I8BncOQjUsuN28rYziUAtx9JyG3BpuZHGIM3YBrTlQCJQy5nbyWZAxgHGhsP4tDD//PlPgnEDWEvbuWSz8w8JamGT4G0AeT+x4eDMtgN2ZjcI2XLmGZs1zzFgIPMA4+XDmeQEsxtAWxLw+eV4GvPNHzU2dmzs7Y8/JFTY2ZudT3/44EONDU4tGCARrDKBWOUgYE+K4lEwCkbBKBgZAACDHG6F3lduWwAAAABJRU5ErkJggg==","orcid":"","institution":"The Second Affiliated hospital of Harbin Medical University, Heilongjiang","correspondingAuthor":true,"prefix":"","firstName":"Hasan","middleName":"Md","lastName":"Rasa","suffix":"Md"},{"id":445566406,"identity":"c8153ff6-efd8-4483-87c5-8c8d91684996","order_by":1,"name":"Yun-fu Cui","email":"","orcid":"","institution":"The Second Affiliated hospital of Harbin Medical University, Heilongjiang","correspondingAuthor":false,"prefix":"","firstName":"Yun-fu","middleName":"","lastName":"Cui","suffix":""},{"id":445566407,"identity":"4d54a11a-e321-4aec-8eb2-db6f3e0f0dff","order_by":2,"name":"Peng-cheng Kang","email":"","orcid":"","institution":"The Second Affiliated hospital of Harbin Medical University, Heilongjiang","correspondingAuthor":false,"prefix":"","firstName":"Peng-cheng","middleName":"","lastName":"Kang","suffix":""},{"id":445566408,"identity":"10d10726-6a5f-4ff5-80eb-1b34117ad6ab","order_by":3,"name":"Jing-lin Li","email":"","orcid":"","institution":"The Second Affiliated hospital of Harbin Medical University, Heilongjiang","correspondingAuthor":false,"prefix":"","firstName":"Jing-lin","middleName":"","lastName":"Li","suffix":""},{"id":445566409,"identity":"3f25513d-80d3-4d6a-9aa3-2370af6fd5c8","order_by":4,"name":"Shi-hui Ma","email":"","orcid":"","institution":"The Second Affiliated hospital of Harbin Medical University, Heilongjiang","correspondingAuthor":false,"prefix":"","firstName":"Shi-hui","middleName":"","lastName":"Ma","suffix":""},{"id":445566410,"identity":"db13fa0b-8dba-40e1-9315-16c5ee36ec75","order_by":5,"name":"Cheng-hong Duan","email":"","orcid":"","institution":"The Second Affiliated hospital of Harbin Medical University, Heilongjiang","correspondingAuthor":false,"prefix":"","firstName":"Cheng-hong","middleName":"","lastName":"Duan","suffix":""},{"id":445566411,"identity":"7ea9436c-17cf-4c5a-a818-3d99c52a075c","order_by":6,"name":"Xu-dong Zhao","email":"","orcid":"","institution":"The Second Affiliated hospital of Harbin Medical University, Heilongjiang","correspondingAuthor":false,"prefix":"","firstName":"Xu-dong","middleName":"","lastName":"Zhao","suffix":""}],"badges":[],"createdAt":"2025-04-19 07:23:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6483124/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6483124/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13027-025-00681-z","type":"published","date":"2025-07-15T15:56:51+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87219432,"identity":"b70358a1-b4f2-4391-a540-3c06fa806088","added_by":"auto","created_at":"2025-07-21 16:04:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1514335,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6483124/v1/3aba1fde-96df-49ae-93e4-4ddda6f3041c.pdf"},{"id":81111241,"identity":"cae31630-2025-491f-b075-c1087b6dff97","added_by":"auto","created_at":"2025-04-22 10:35:19","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":37449,"visible":true,"origin":"","legend":"","description":"","filename":"STROBEStatementchecklistsandflowchart.docx","url":"https://assets-eu.researchsquare.com/files/rs-6483124/v1/fd97c927286fd786ff1693ae.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Risk Factors for Cholangiocarcinoma, Role of Diabetes Mellitus and Hepatitis B Virus Infection in the Intrahepatic and Extrahepatic Cholangiocarcinoma: A case-control study in China","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCholangiocarcinoma (CCA), also known as bile duct cancer, is a rare group of epithelial cell malignancies that arise from the bile duct (intrahepatic \u0026amp; extrahepatic). It has been considered a rare disease, accounting for less than 1% of all human cancers.\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e Despite being the second most common cancer of the liver (primary hepatobiliary cancer), cholangiocarcinoma remains a rare disease.\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e However, the overall incidence has increased worldwide in recent decades, especially in China.\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e It has been demonstrated that cholangiocarcinoma is characterized by a low survival rate, with a median survival rate of less than 24 months.\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAnatomically, it can be subtyped into intrahepatic and extrahepatic cholangiocarcinoma. Extrahepatic cholangiocarcinoma (eCCA) can be subdivided into perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA).\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e Intrahepatic cholangiocarcinoma (iCCA) is similar to HCC's presentation as mass lesions within the liver. Both originated from the primary epithelial cells of the liver. Cholangiocarcinoma can be pretty challenging to diagnose and treat because of its rarity. Defending the risk factors for cholangiocarcinoma can be beneficial, and search for better ways to pre\u003c/p\u003e \u003cp\u003event the occurrence of these diseases. Recently, a study in China demonstrated that HBV infection could be used as a predictive marker for a favorable prognosis.\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAll the risk factors indistinctly lead to chronic inflammation of the biliary epithelium and biliary stasis, which represent common features that play a fundamental role in the pathogenesis of cholangiocarcinoma. The increasing rate of cholangiocarcinoma has led researchers to analyze new and emerging risk factors. Therefore, in addition to the well-known risk factors listed hepatolithiasis, PSC, liver flukes, biliary tract cysts, specific toxins, IBD, genetic polymorphism, alcoholic cirrhosis, tobacco, chronic liver diseases, cholecystectomy, choledocholithiasis, cholecystolithiasis, obesity, diabetes mellitus, chronic pancreatitis, alcoholic liver disease, thyroid diseases, pancreatic cancer, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection.\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e These risk variables still cannot account for the increasing prevalence or number of CCA cases. Because of their rarity, only approximately 10% of CCA (including iCCA and eCCA) cases are associated with a recognized risk factor.\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e While it is true that traditional risk factors may not account for all cases, it's essential to consider other potential factors that could be contributing to the rise. This scenario raises concern about the impact of underexplored factors beyond these etiologies.\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe occurrence of diabetes mellitus (DM) has significantly increased in both developed and developing nations over the last twenty years.\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e Several studies have explored the connection between DM and various types of cancer, such as breast, endometrial, non-Hodgkin's lymphoma, pancreatic, and liver cancer.\u003csup\u003e[\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e It is commonly known that diabetes is a risk factor for several cancers. Several molecular pathways have been predicted to explain the possible relationship between diabetes and cancer risk. Insulin resistance and hyperinsulinemia can stimulate the production of the insulin-like growth factor-1 (IGF-1), which may contribute to cancer initiation and progression.\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e The immunologic, hormonal, and metabolic features of diabetes mellitus may also facilitate cancer development. Most research shows a positive correlation between DM and cholangiocarcinoma (CCA) risk, including iCCA and eCCA, but some publications find no correlation.\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e The reason for these inconsistent results is unknown; however, it is uncertain if methodological inconsistencies or inequalities among study groups contribute to these findings. Oxidative stress, lipotoxicity, hyperinsulinemia, insulin resistance, and cholangiocyte transformation have been connected to the development of liver disease and fat deposition, with insulin in bile and leptin in adipose tissue possibly increasing cholangiocarcinogenesis.\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHowever, few studies have focused on analyzing interactions between risk factors for CCA. Because of the multifactorial nature of biliary tract carcinogenesis, possible interactions between risk factors may exist. We conducted a hospital-based case-control study to assess potential risk factors for CCA in China. We aimed to identify possible synergisms between the risk factors of cholangiocarcinoma and the role of the risk factors of diabetes mellitus and HBV infection for intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA).\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSource of data / Study population and design\u003c/h2\u003e \u003cp\u003eA hospital-based case-control study was performed by enrolling 735 cases (245 cases with pathologically diagnosed CCA and 490 healthy controls) from The Second Affiliated Hospital of Harbin Medical University of the General Surgery departments. The Second Affiliated Hospital of Harbin Medical University is considered one of the most common hospitals visited by CCA patients in Heilongjiang. All patients diagnosed with CCA through pathological findings at The Second Affiliated Hospital of Harbin Medical University between January 2019 and June 2024 were reviewed for study enrollment.\u003c/p\u003e \u003cp\u003eWe conducted Control subjects, matched 2:1 (490:245), with control cases who were male 247 and female 243 for a mean age of 58 years, and CCA cases were 152 males and 93 females for a mean age of 61 years. Control subjects were randomly chosen with cases for age, sex, and date of diagnosis (\u0026plusmn;\u0026thinsp;3 months) among individuals who had visited The Second Affiliated Hospital of Harbin Medical University for a routine checkup during the same time the CCA cases were selected. We randomized the control group by using a random number generator. We include cases between ages 30 and 90 years old with symptoms and risk factors of CCA, pathologically diagnosed CCA, and cases with clinical, biochemical, and radiological information, which are all found in the data system. We excluded cases below ages 30 and above 90 years old, without radiologic information, and ampulla of Vater carcinoma. In the control group, those who were diagnosed with other cancers were also excluded. Gallbladder carcinoma and hilar cholangiocarcinoma were included as extrahepatic cholangiocarcinoma. Finally, 245 cases and 490 controls were included in the analysis. The Second Affiliated Hospital of Harbin Medical University approved the study protocol.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003ePatient records were manually and retrospectively reviewed to extract demographical and clinical data and risk factors. In this study, we reported demographical data and detailed information on drinking and smoking. Relevant data were obtained by retrospectively reviewing patient data records from the general surgery department of The Second Affiliated Hospital of Harbin Medical University data systems, which a physician simultaneously documented in a structured data collection sheet. The abovementioned data collection was routinely conducted in our liver surgery clinic, and the relevant sheet was conserved as a part of the medical records. Data of age, sex, smoking, alcohol consumption, patient obesity, diabetes mellitus, hypertension, cholecystolithiasis, choledocholithiasis, cholecystectomy, ulcerative colitis, alcoholic liver disease, thyroid diseases, chronic pancreatitis, pancreatic cancer, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, liver cirrhosis, liver fluke infestation were abstracted.\u003c/p\u003e \u003cp\u003eControl patients were selected from The Second Affiliated Hospital of Harbin Medical University of the General Surgery departments, which was not representative of the entire community; consequently, it could not represent the overall population properly. The selection of matched controls from the Health Screening Centre of General Surgery departments, rather than the general community, minimized selection bias due to the origin of the case group from General Surgery department patients. A total of 490 individuals were chosen as controls. From January 2019 to July 2024, cases and controls at the Health Screening Centre of General Surgery departments were matched based on age and sex in a one-to-two ratio.\u003c/p\u003e\n\u003ch3\u003eDefinitions of events\u003c/h3\u003e\n\u003cp\u003eThere were two types of CCA: extrahepatic cholangiocarcinoma (eCCA) and intrahepatic cholangiocarcinoma (iCCA). This study did not include Ampulla of Vater carcinoma, although perihilar cholangiocarcinoma (pCCA) was included in (eCCA). Alcohol consumption was defined as someone who consumes at least 80 g (male) or 40 g (female) of alcohol each day. Obesity was classified as having a body mass index (BMI) of 25.0 kg/m2 or more, as per the Asian-Pacific standards. Serum HBV surface antigen (HBsAg) and HCV antibody (anti-HCV) were measured by retrospectively reviewing clinical data; participants were classified as anti-HCV-positive if they tested positive for HCV RNA, and HBV infection was defined as positive if they tested positive for hepatitis B surface antigen.\u003c/p\u003e \u003cp\u003eThe diagnostic criteria for liver cirrhosis were as follows: clinical manifestations of chronic hepatitis with portal hypertension (e.g., collateral varices, varices, thrombocytopenia, or splenomegaly) and/or hepatic decompensation (e.g., jaundice, prolonged prothrombin time, and ascites), laboratory tests, and radiologic studies. In patients undergoing surgical treatment, cirrhosis was also confirmed pathologically. The presence of cirrhosis is defined as nonspecific cirrhosis without the presence of HCV, HBV, or alcoholic liver disease. The diagnosis of liver fluke infestation, alcoholic liver diseases, and ulcerative colitis was made based on the patient's data, reviewing laboratory tests as well as from the radiologic finding of diffuse, uniform dilatation of the small intrahepatic bile ducts with no or minimal dilatation of larger bile ducts and with no focal obstructing lesion. Chronic pancreatitis and pancreatic cancer were diagnosed by the radiological findings and confirmed by the pathological findings. Choledocholithiasis was defined as the presence of at least one stone in the extrahepatic bile duct. In contrast, hepatolithiasis was defined as the presence of a stone in the intrahepatic bile duct. The presence of cystic duct stones was classified as cholecystolithiasis. The cholecystectomy was diagnosed from the patient's operation history review. Diabetes was diagnosed according to the World Health Organization Criteria and categorized into two groups: (1) complicated diabetes (presence of any stage of retinopathy, nephropathy, or macrovascular complications) and (2) uncomplicated diabetes. Thyroid disease includes hyperthyroidism and hypothyroidism.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe statistical analyses were conducted using SPSS 20.0 software. The Mann-Whitney U test was used to compare continuous data, whereas the Pearson χ2 test with the Fisher exact test was utilized to analyze discrete variables. Univariate and multivariate correlation studies were conducted using conditional logistic regression with maximum likelihood estimations of parameter values to evaluate the risk for CCA. All variables were investigated with P-values of \u0026lt;\u0026thinsp;0.05 in the univariate analyses and were subsequently adjusted to be examined in multiple logistic regression analyses. Logistic regression analysis was used to identify risk factors associated with CCA development and calculate ORs, adjusted ORs (AORs), and 95% confidence intervals (CIs). Two-sided tests with P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were deemed statistically significant for all analyses. Furthermore, the population-attributable risk fraction for risk factors found to be statistically significant was determined using the adjusted odds ratio (AOR) of the underlying factor and its prevalence in the control group.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe baseline attributes of CCA patients and controls are summarized in Table 1. For this study, there were 245 CCA patients, 152(62.0%) male, 93 female (38.0%), and 490 controls, 247 male (50.4%), female 243(49.6%), a total of 735 that qualified for this clinical study (Table 2). Of these, 168(68.6%) were eCCA and 77(31.4%) were iCCA. We groped the age in 29-49 years 27(11.0%) CCA patients, and controls 127(25.9%) patients; age in 50-69 years 165(67.3%) CCA patients and controls 276(56.3%) patients; age in 70-89 years 53(21.6%) CCA patients, and controls 87(17.8%) patients were conducted (Table 1). The CCA case and control groups had mean ages of 61.60 and 57.77 years, respectively (Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCCA population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe outcomes are summarized in Table 2. As expected, the relative odds of CCA in the multivariate conditional logistic analysis showed that the relative odds of CCA were significantly elevated in subjects with a history of cholelithiasis (AOR = 1.70; 95% CI = 1.12-2.57; P = \u0026lt;0.011), CBD stones (choledocholithiasis) (AOR = 5.40; 95% CI = 2.05-14.21; P = \u0026lt;0.001), hepatolithiasis (AOR = 0.30; 95%Cl = 0.10-0.89; P = \u0026lt;0.031), cholecystectomy history (AOR = 0.49; 95% CI = 0.29-0.83; P = \u0026lt;0.008), thyroid diseases (AOR = 5.42; 95%Cl = 2.02-14.50; P = \u0026lt;0.001), HBV infection (AOR = 0.35; 95%Cl = 0.19-0.64; P = \u0026lt;0.001), and diabetes mellitus (AOR = 1.41; 95% CI = 1.17-1.70; P = \u0026lt;0.001). Diabetes mellitus Divided into two categories without complication (AOR = 0.21; 95% Cl = 0.11-0.40); P = \u0026lt;0.001), with complication (AOR = 0.46; 95% Cl = 0.22-0.99; P = \u0026lt;0.049) were the significant risk factors for CCA (Table 2). Age (AOR = 1.02; 95%CI = 1.00-1.03; P = \u0026lt;0.016) and smoking one pack per day for \u0026gt;20 years (AOR = 0.27; 95%CI = 0.13-0.58; P = \u0026lt;0.001) were also related to increased CCA risk factors. We observed that alcohol consumption (AOR = 1.57; 95%Cl = 0.98-2.52; P = 0.058), liver cirrhosis (AOR = 1.06; 95% CI = 0.29-3.87; P = 0.919) and HCV infection (AOR = 1.21; 95% CI = 0.19-7.46; P = 0.831) were not significantly associated for CCA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1 Age characteristics of CCA patients and controls\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"594\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eAge group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 324px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Participant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eCCA patient (n=245)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eControl (n=490)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eMean \u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eCCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e29-49 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e27(11.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e127(25.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e61.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e57.77\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e50-69 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e165(67.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e276(56.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e70-89 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e53(21.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e87(17.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 Comparison of risk factors in patients with cholangiocarcinoma (CCA) and matched controls n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"702\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eIndependent variable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003eCCA patient\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(n = 245)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003eControl (n=490)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 192px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Univariable analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eMultivariable analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eAOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge in years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e-----\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e------\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.03 (1.02-1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.02(1.00-1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.016\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e152(62.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e247(50.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e93(38.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e243(49.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.601(1.18-2.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.49(1.01-2.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.040\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoking\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e9(3.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e27(5.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.62(0.39-.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.034\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.53(0.30-0.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eOne pack per day for \u0026lt;20 years \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e17(6.9%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e60(12.2%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.41(0.17-0.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.36(0.14-0.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.035 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eOne pack per day for \u0026gt;20 years \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e43(17.6%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e53(10.8%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.34(0.17-0.68) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.002 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.27(0.13-0.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.001 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlcohol consumption\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e58(23.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e130(26.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.16(0.81-1.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.403\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.57(0.98-2.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.058\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eObesity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e65(26.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e157(32.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.30(0.92-1.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.38(0.93-2.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.104\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiabetes mellitus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e65(26.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e68(13.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.40(1.20-1.66) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.41(1.17-1.70) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eWithout complication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e43(17.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e50(10.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.22(0.12-0.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.21(0.11-0.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eWith complication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e22(9.0%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e18(3.7%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.48(0.24-0.95) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.036 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.46(0.22-0.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.049\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHypertension \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e64(26.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e118(24.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.89(0.63-1.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.546\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.13(0.75-1.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.534\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCholelithiasis \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e53(21.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e170(34.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.92(1.34-2.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.70(1.12-2.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCBD stones\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e6(2.4%) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e50(10.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e4.52(1.91-10.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e5.40(2.05-14.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHepatolithiasis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e11(4.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e8(1.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.35(0.14-0.89) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.027\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.30(0.10-0.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.031\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCholecystectomy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e41(16.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e39(8.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.43(0.26-0.68) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.49(0.29-0.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUlcerative colitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e2(0.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e16(3.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e4.10(0.93-17.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.061\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e4.18(0.88-19.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.071\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eALD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e2(0.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e4(0.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.00(0.18-5.49) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.49(0.24-9.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.661\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eThyroid diseases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e5(2.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e49(10.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e5.33(2.09-13.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e5.42(2.02-14.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChronic pancreatitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e7(1.4%) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e819444698.56(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e448308451.13(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePancreatic cancer\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e8(3.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e6(1.2%) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.36(0.12-1.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.066\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.39(0.12-1.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.108\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHBV infection\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e33(13.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e29(5.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.40(0.23-0.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.35(0.19-0.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHCV infection\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e2(0.8%) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e6(1.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.50(0.30-7.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.618 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.21(0.19-7.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.831\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLiver cirrhosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e5(2.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e7(1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.69(0.21-2.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.539 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.06(0.29-3.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.919\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLiver fluke infestation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e2(0.8%) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.00(0.00-) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.00(--)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: CCA, cholangiocarcinoma; ECC, extrahepatic cholangiocarcinoma; ICC, intrahepatic cholangiocarcinoma; CBD, Common Bile Duct stones; ALD, Alcoholic liver diseases; HBV, hepatitis B virus; HCV, hepatitis C virus; 1. One pack-year = 1 pack per day for a year; 2. Daily amount of \u0026ge; 80 g (male) or \u0026ge; 40 g (female); 3. Obesity was defined as a body mass index \u0026gt; 25 kg/m2 according to the Asian-Pacific criteria for obesity; 4. Any stage of retinopathy, nephropathy, or macrovascular complications. CCA: Cholangiocarcinoma; HBV: Hepatitis B virus; HCV: Hepatitis C virus; AOR: Adjusted odds ratio.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubgroup analysis, eCCA and iCCA population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSubgroup analysis was used to identify risk variables for eCCA and iCCA. In the conditional logistic regression model, we included 168(68.6%) eCCA patients 109(64.9%) male, 59(35.1%) female and control 336 controls169(50.3%) male, 167(49.7%) female (Table 4). We groped the age in 29-49 years 10(6.0%) eCCA patients, and controls 83(24.7%) patients; age in 50-69 years 118(70.2%) eCCA patients, and controls 188(56.0%) patients; age in 70-89 years 40(23.8%) eCCA patients, and controls 65(19.3%) patients were conducted (Table 3). The eCCA case and control groups had mean ages of 63.01 and 58.30 years, respectively (Table 3). In the conditional logistic regression model result of cholelithiasis (AOR = 1.51; 95%CI = 0.94-2.41; P = 0.083), CBD stones (choledocholithiasis) (AOR = 4.51; 95% CI = 1.70-11.98; P = 0.002); hepatolithiasis (AOR = 0.29; 95%Cl = 0.09-0.94; P = \u0026lt;0.040), thyroid diseases (AOR = 8.56; 95%Cl = 1.97-37.12; P = \u0026lt;0.004) were significant for eCCA. Diabetes mellitus (AOR = 1.30; 95%Cl = 1.05-1.61; P = \u0026lt;0.014), diabetes mellitus without complication (AOR = 0.43; 95%C l= 0.19-0.96; P = 0.041), was also a significant risk factor for eCCA but with complication diabetes mellitus (AOR = 0.70; 95%Cl = 0.28-1.78; P = 0.465) was not significant. Cigarette smoking one pack per day for more than 20 years (AOR = 0.36; 95%CI = 0.15-0.85; P = \u0026lt;0.021) was also a significant risk factor for eCCA (Table 4).\u003c/p\u003e\n\u003cp\u003eIn the subgroup iCCA case 77 patients 44(57.1%) male, 33(42.9%) female and in control 154 cases, 79(51.3%) male ,75(48.7%) female (Table 6). In the age group, age in 29-49 years16(20.8%) iCCA patients, and controls 43(27.9%) patients; age in 50-69 years 48(62.3%) iCCA patients, and controls 89(57.8%) patients; age in 70-89 years 40(23.8%) iCCA patients, and controls 22(14.3%) patients were conducted (Table 5). The iCCA case and control groups had mean ages of 58.45 and 56.79 years, respectively (Table 5). In the conditional logistic regression model, it was also found that cholelithiasis (AOR = 4.91; 95%CI = 1.73-13.97; P = \u0026lt;0.003), cholecystectomy (AOR = 0.39; 95% CI = 0.15-0.99; P = 0.050), and hepatolithiasis (AOR = 0.34; 95% CI = (0.02-5.48); P = \u0026lt;0.020) were related to the iCCA. HBV infection (AOR = 0.20; 95%CI = 0.06-0.62; P = \u0026lt;0.006) was also a significant risk factor for iCCA. Cigarette smoking one pack per day for more than 20 years (AOR = 0.06; 95%CI = 0.01-0.56; P = 0.014) was also a significant risk factor for iCCA. However, diabetic mellitus (AOR = 3.01; 95%CI = 1.63-5.53; P = \u0026lt;0.001) is significant, but when for complication and without complication, diabetes mellitus is insignificant to correlate to iCCA where HCV also was not reach statistically significant to an enhanced risk of subtype iCCA (Table 6). \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3 Age characteristics of ECC patients and controls\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"594\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eAge group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 324px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Participant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eECC patient(n=168)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003eControl (n=336)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eMean \u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eECC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e29-49 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e10(6.0%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e83(24.7%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e63.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e58.30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e50-69 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e118(70.2%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e188(56.0%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e70-89 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e40(23.8%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e65(19.3%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4 Comparison subgroup analysis of risk factors in patients with Extrahepatic\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003echolangiocarcinoma (ECC) and matched controls n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"702\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eIndependent variable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003eECC patient\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(n = 168)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003eControl (n=336)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 192px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Unadjusted\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Adjusted\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eAOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge in years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e-----\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e------\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.03 (1.02-1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.02(1.01-1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e109(64.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e169(50.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e59(35.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e167(49.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.82(1.24-2.67) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.69(1.06-2.68) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.026 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoking \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e4(2.4%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e20(6.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.69(0.41-1.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.178 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.81(0.42-1.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.519 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eOne pack per day for \u0026lt;20 years \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e13(7.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e45(13.4%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.26(0.08-0.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.027 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.28(0.08-1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.051 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eOne pack per day for \u0026gt;20 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e30(17.9%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e40(11.9%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.38(0.17-0.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.016 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.36(0.15-0.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.021 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlcohol consumption\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e43(25.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e92(27.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.09(0.71-1.67) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.670 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.31(.75-2.26) \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.332 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eObesity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e47(28.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e109(32.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.23(0.82-1.85) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.307 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.24(0.78-1.98) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.356 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiabetes mellitus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e47(28.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e58(17.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.33(1.10-1.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.002 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.30(1.05-1.61) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.014 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eWithout complication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e28(16.7%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e43(12.8%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.34(0.16-0.69) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.003 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.43(0.19-0.96) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.041 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eWith complication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e19(11.3%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e15(4.5%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.51(0.22-1.17) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.115 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.70(0.28-1.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.465 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHypertension \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e37(22.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e80(23.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.10(0.71-1.72) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.655 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.36(0.81-2.28) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.241 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCholelithiasis \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e45(26.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e124(36.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.59(1.06-2.40) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.024 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.51(0.94-2.41) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.083 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCBD stones\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e6(3.6%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e36(10.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e3.24(1.33-7.85) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.009 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e4.51(1.70-11.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.002 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHepatolithiasis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e9(5.4%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e6(1.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.32(0.11-0.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.034 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.29(0.09-0.94) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.040 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCholecystectomy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e25(14.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e31(9.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.58(0.33-1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.059 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.75(0.39-1.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.390 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUlcerative colitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e2(1.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e10(3.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e2.54(0.55-11.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.231 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e3.12(0.61-15.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.170 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eALD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e2(1.2%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e2(0.6%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.49(0.06-3.56) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.486 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.52(0.06-4.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.552 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eThyroid diseases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e2(1.2%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e37(11.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e10.27(2.44-43.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e8.56(1.97-37.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.004 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChronic pancreatitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e4(1.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e817468342.60(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e228077265.27(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.999 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePancreatic cancer\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e7(4.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e6(1.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.41(0.13-1.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.123 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.48(0.14-1.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.252 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHBV infection\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e14(8.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e23(6.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.80(0.40-1.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.547 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.75(0.34-1.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.492 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHCV infection\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e0(0.0%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e4(1.2%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e817467318.704(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.999 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1396133325.54()\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.999 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLiver cirrhosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e6(1.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e822422772.45(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.999 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e883186620.67(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.999 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLiver fluke infestation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e1(0.6%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.00(0.00-) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1.000 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e000 (-) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e1.000 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: CCA, cholangiocarcinoma; ECC, extrahepatic cholangiocarcinoma; ICC, intrahepatic cholangiocarcinoma; CBD, Common Bile Duct stones; ALD, Alcoholic liver diseases HBV, hepatitis B virus; HCV, hepatitis C virus;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5 Age characteristics of ICC patients and controls\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"594\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eAge group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 324px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Participant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eICC patient(n=77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003eControl (n=154)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eMean \u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eICC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e29-49 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e16(20.8%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e43(27.9%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e58.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e56.79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e50-69 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e48(62.3%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e89(57.8%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e70-89 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e13(16.9%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e22(14.3%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 6 Comparison subgroup analysis of risk factors in patients with Intrahepatic cholangiocarcinoma (ICC) and matched controls n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"702\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eIndependent variable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003eICC patient\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n = 77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003eControl (n=154)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 192px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Unadjusted\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Adjusted\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eAOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge in years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e-----\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e------\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.01(0.98-1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.311 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.99(0.96-1.02) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.897 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 24px;\"\u003e\u0026nbsp;\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e44(57.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e79(51.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\u0026nbsp;\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\u0026nbsp;\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\u0026nbsp;\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e33(42.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e75(48.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.26(0.73-2.19) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.402 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.37(0.63-2.99) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.416 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoking \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e4(5.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e6(3.9%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.69(0.31-1.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.357 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.71(0.21-2.40) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.590 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eOne pack per day for \u0026lt;20 years \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e4(5.2%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e18(11.7%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.92(0.21-3.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.914 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.81(0.10-6.43) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.842 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eOne pack per day for \u0026gt;20 years \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e13(16.9%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e18(11.7%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.30(0.08-1.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.075 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.06(0.01-0.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.014 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlcohol consumption\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e15(19.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e43(27.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.60(0.82-3.11) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.165 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e2.22(0.70-7.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.172 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eObesity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e18(23.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e45(29.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.35(0.71-2.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.348 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.20(0.49-2.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.678 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiabetes mellitus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e18(23.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e10(6.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.85(1.28-2.69) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.001 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e3.01(1.63-5.53) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eWithout complication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e15(19.5%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e7(4.5%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.41(0.08-2.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.809\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.30(0.03-2.63) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.282 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eWith complication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e3(3.9%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e3(1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e2.14(0.34-13.42) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.416 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e10.2(0.61-170.3) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.106 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHypertension \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e26(33.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e42(27.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.73(0.40-1.32) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.308 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.71(0.32-1.58) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.408 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCholelithiasis \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e8(10.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e55(35.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e4.79(2.14-10.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.001 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e4.91(1.73-13.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.003 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCBD stones\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e12(7.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e875997086.98(- \u0026nbsp; )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.999 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e293033710.84(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.999 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHepatolithiasis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e2(2.6%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e4(2.6%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.00(0.17-5.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.34(0.02-5.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.448 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCholecystectomy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e16(20.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e13(8.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.35(0.15-0.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.010 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.39(0.15-0.99) \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.050 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUlcerative colitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e0(0.0%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e5(3.2%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e834841676.36(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.999 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e9334525639.6()\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.999 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eALD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e2(1.3%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e818363030.34(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.999 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e12187135586.2()\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.999 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eThyroid diseases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e3(3.9%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e14(9.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e2.46(0.68-8.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.166 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e3.13(0.67-14.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.143 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChronic pancreatitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e2(1.3%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e818363518.12(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e4660280295.32()\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.999 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePancreatic cancer\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e1(1.3%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e2(1.3%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1.00(0.08-11.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1.000 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e3.98(0.13-120.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.426 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHBV infection\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e19(24.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e15(9.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.32(0.15-0.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.003 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.20(0.06-0.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u0026lt;0.006 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHCV infection\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e2(2.6%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e3(1.9%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.74(0.12-4.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.750 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e1.42(0.06-29.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.820 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLiver cirrhosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e5(6.5%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e0(0.0%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.000 (000) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.999 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.000(000) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e0.999 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLiver fluke infestation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e1(1.3%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.00(000) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1.000 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e0.000(000) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 63px;\"\u003e\n \u003cp\u003e1.000 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: CCA, cholangiocarcinoma; ECC, extrahepatic cholangiocarcinoma; ICC, intrahepatic cholangiocarcinoma; CBD Common Bile Duct stones; ALD, Alcoholic liver diseases; HBV, hepatitis B virus; HCV, hepatitis C virus\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe underlying cause and carcinogenesis of CCA remain uncertain despite numerous identified risk factors. A hospital-based case-control study in China established that diabetes mellitus (DM) is an independent risk factor for cholangiocarcinoma (CCA), especially for the extrahepatic cholangiocarcinoma (eCCA), and also for intrahepatic cholangiocarcinoma (iCCA), while diabetics mellitus with complications. Choledocholithiasis, hepatolithiasis, and diabetes mellitus are significantly connected with CCA in both subtypes, extrahepatic cholangiocarcinoma (eCCA) and intrahepatic cholangiocarcinoma (iCCA). While hepatitis B virus (HBV) infection is a risk factor for CCA, especially for iCCA, meanwhile, CBD stones are also risk factors for CCA, especially for eCCA. However, HCV did not reach a statistically significant level to enhance the risk of CCA.\u003c/p\u003e\n\u003cp\u003eGlobal epidemiological studies indicate that diabetes elevates the risk of developing cholangiocarcinoma (CCA).\u003csup\u003e[10]\u003c/sup\u003e Elevated glucose, insulin, and obesity are risk factors for CCA.\u003csup\u003e[18]\u003c/sup\u003e Northeastern Thailand exhibits the highest prevalence of cholangiocarcinoma associated with O. viverrini.\u003csup\u003e[7]\u003c/sup\u003e Understanding whether diabetes is an overlooked factor may facilitate effective prevention in endemic regions. However, no research has substantiated this correlation. Understanding if DM is the unexplained variable in a small proportion of infected patients may facilitate effective prophylaxis in regions endemic to liver flukes.\u003c/p\u003e\n\u003cp\u003eThe hepatitis B virus (HBV) is identified as a risk factor for hepatocellular carcinoma (HCC).\u003csup\u003e[19]\u003c/sup\u003e The associations between HBV and CCA, as well as the impact of HBV on CCA development, are inadequately comprehended. Consistent with prior data, our findings indicate that HBV is substantially associated with cholangiocarcinoma (CCA), significantly increasing the risk of cholangiocarcinoma (CCA). Incorporating HBV DNA into human chromosomes and the persistent production of viral proteins, including HBx proteins and large proteins (LHBs), can activate oncogenes, generate oxidative stress, and result in genetic instability.\u003csup\u003e[20]\u003c/sup\u003e Furthermore, viruses can induce persistent hepatocyte death and regeneration within the inflammatory milieu established by the host's immune response to infection. This fosters an environment conducive to genetic alterations that result in hepatocyte transformation.\u003csup\u003e[21]\u003c/sup\u003e A prior study indicated that HBV may induce carcinogenesis in cholangiocytes through the exact mechanism as in hepatocytes, owing to their shared progenitor cells.\u003csup\u003e[8]\u003c/sup\u003e Unlike HBV infection, HCV infection was not a significant risk factor for cholangiocarcinoma (CCA) in this study. This finding aligns with a prior China study. There was no significant association between iCCA development and HCV infection in East Asian groups, although a subsequent meta-analysis revealed a significant association (OR = 6.91) in Western populations.\u003csup\u003e[22]\u003c/sup\u003e Our study found that HCV (P = 0.831) was not a substantial risk factor for cholangiocarcinoma (CCA). However, due to the small number of studies and participants analyzed, a more thorough investigation in Eastern regions is required to confirm the geographic disparity.\u003c/p\u003e\n\u003cp\u003eOur findings also demonstrated a substantial correlation between diabetes mellitus and the development of cholangiocarcinoma, consistent with prior research. Insulin resistance and hyperinsulinemia have been demonstrated to promote the proliferation of many cancer cell types.\u003csup\u003e[23]\u003c/sup\u003e Furthermore, elevated insulin-like growth factor 1 levels may promote liver cell proliferation, contributing to cholangiocarcinoma's carcinogenesis (CCA).\u003csup\u003e[23, 24]\u003c/sup\u003e Once all diabetic patients were divided into groups based on how long they had been diabetic and whether they had any complications, tests were done again for a more accurate evaluation. There was no significant link between the length of diabetes mellitus (DM) and the risk of cholangiocarcinoma (CCA). However, DM had a more substantial effect on CCA risk when there were other health problems related to DM. Because of the long period between the onset of diabetes mellitus and its clinical diagnosis, the disease's duration from diagnosis does not fully reflect the actual duration of the condition.\u003csup\u003e[25]\u003c/sup\u003e Furthermore, diabetes mellitus management and disease severity may be more important predictors than just the duration of the condition. The frequency of diabetes mellitus complications relies upon glycemic management and the length of the condition.\u003csup\u003e[18]\u003c/sup\u003e A further well-structured analysis with more detailed information is necessary to explain the role of DM duration on the risk of CCA development.\u003c/p\u003e\n\u003cp\u003eThis study revealed several significant findings regarding the relationship between cholelithiasis and cholangiocarcinoma (CCA): CBD stones were identified as a risk factor for extrahepatic cholangiocarcinoma (eCCA) but not for intrahepatic cholangiocarcinoma (iCCA); Cholelithiasis was a risk factor for both eCCA and iCCA and hepatolithiasis was a risk factor for iCCA and eCCA. These findings may be attributed to the effects of cholestasis, altered bile composition, and chronic proliferative inflammation in proximity to the stone-bearing ducts. Previous studies conducted in China have also demonstrated the association between hepatolithiasis and eCCA,\u003csup\u003e[26]\u003c/sup\u003e Further supporting our findings.\u003c/p\u003e\n\u003cp\u003eThe principal finding of this study is the role of diabetes mellitus and hepatitis B virus infection on the risk of cholangiocarcinoma. While the precise mechanism remains ambiguous, a plausible explanation for the relationship exists. Hyperglycemia may induce glucose oxidation, lipid peroxidation, and protein glycosylation, generating free radicals contributing to oxidative stress.\u003csup\u003e[27]\u003c/sup\u003e Oxidative stress may subsequently enhance HBV gene expression, trigger viral replication reactivation, and contribute to the chronicity of liver disease, resulting in DNA damage and the formation of CCA.\u003csup\u003e[27, 28]\u003c/sup\u003e Given that oxidative stress is a recognized principal mediator in the advancement of diabetes mellitus (DM) and its complications,\u003csup\u003e[28]\u003c/sup\u003e Our discovery of enhanced synergism between complex DM and HBV infection corroborates this assertion. CCA and HCC are believed to have shared etiological components, and a prior study on HCC risk factors similarly demonstrated the synergistic relationship between diabetes mellitus and HBV infection in cancer development,\u003csup\u003e[29]\u003c/sup\u003e This corroborates our findings.\u003c/p\u003e\n\u003cp\u003eThe current study possesses several potential limitations: diagnostic bias cannot be dismissed as cancer patients undergo supplementary testing, resulting in a higher number of diagnoses compared to non-cancer individuals; this was a hospital-based study conducted at a single institution rather than a population-based design, which introduces the possibility of selection bias due to varying referral patterns; nevertheless, a hospital-based design may be more suitable for CCA given the low incidence and brief survival of CCA patients. The study did not examine the hepatitis B core antibody (anti-HBc) or occult HBV infection; nevertheless, subsequent research has shown minimal levels of HBV DNA in individuals with just anti-HBc (absent surface antigen/antibody) and a very low occurrence of occult HBV infection.\u003csup\u003e[30]\u003c/sup\u003e Moreover, the prevalence of HBV identified in this study was consistent with prior HBV prevalence estimates in China. Additionally, DM was not categorized by type. Given the lack of young-onset (≤ 30 years) DM in our cohort and the significantly lower incidence of type 1 DM in Asia,\u003csup\u003e[25]\u003c/sup\u003e it is inferred that most DM cases in this study were type 2 DM.\u003c/p\u003e\n\u003cp\u003eDespite these limitations, this study has several remarkable advantages: It is the initial study to investigate risk factors for CCA (including eCCA and iCCA) in China, and it has been conducted within a multivariable framework that accounts for any possible confounding factors. In a previous study conducted in China, the prevalence of significant metabolic risk factors in the control group was comparable to that of the general population of China or other Asian nations. We stratified biliary lithiasis and diabetes mellitus based on the presence of complications and location, respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo the best of our knowledge, this study is the initial one to investigate the impact of complicated and uncomplicated diabetes mellitus on the risk of cholangiocarcinoma following the stratification of diabetes mellitus. This recent study has the potential to assist in the stratification of patients at risk for CCA and the CCA surveillance algorithms that are based on classification. Moreover, a synergistic connection existed between the two parameters for the probability of CCA development. Conducting an in-depth investigation to verify this synergistic relationship and clarify potential underlying mechanisms is essential. This synergy's fundamental mechanisms could be investigated to develop preventative methods for high-risk individuals who are at risk of developing CCA.\u003c/p\u003e"},{"header":"Declarations","content":" \u003ch2\u003eConflict of Interest Statement\u003c/h2\u003e \u003cp\u003eAll the authors report having no conflicts of interest for this article.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eEthical statement\u003c/h2\u003e \u003cp\u003e The protocol for this research project has been approved by the Ethics Committee of The Second Affiliated Hospital of Harbin Medical University, which approved the investigation. Ethics Committee approved number KY2025-096. All the patients in this study signed written informed consent.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThe authors received no financial support for this research, authorship, and/or publication of this article.\u003c/p\u003e \u003cp\u003eThe articles are financially supported by the Heilongjiang Province's important research\u003c/p\u003e \u003cp\u003eProject for the publication of this article grant number: 2024ZX12C21\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eYunfu Cui contributed to Conceptualization and Supervision, Md Rasadul Hasan contributed to the literature search, writing, data analysis, interpretation of data, statistical analysis, and drafting of the manuscript, Jinglin Li contributed to review and editing, Pengcheng Kang contributed to the study design, Shihui Ma, Xu-dong Zhao, and Chenghong Duan contributed to Data collection. All the authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eI would like to thank all the staff of the General Surgery Department for their cooperation and kind support throughout my study period.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eElvevi A, Laffusa A, Scaravaglio M, Rossi RE, Longarini R, Stagno AM, et al. Clinical treatment of cholangiocarcinoma: an updated comprehensive review. Ann Hepatol. 2022;27(5):100737.PMID: 35809836 DOI: 10.1016/j.aohep.2022.100737\u003c/li\u003e\n\u003cli\u003eKhan SA, Davidson BR, Goldin RD, Heaton N, Karani J, Pereira SP, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut. 2012;61(12):1657-69.PMID: 22895392 DOI: 10.1136/gutjnl-2011-301748\u003c/li\u003e\n\u003cli\u003eRazumilava N, Gores GJ. Cholangiocarcinoma. 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J Med Virol. 2010;82(9):1508-14.PMCID: PMC9719384 PMID: 36504614,doi: 10.18683/germs.2022.1318\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"infectious-agents-and-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"iaac","sideBox":"Learn more about [Infectious Agents and Cancer](http://infectagentscancer.biomedcentral.com/)","snPcode":"13027","submissionUrl":"https://submission.nature.com/new-submission/13027/3","title":"Infectious Agents and Cancer","twitterHandle":"@IAC_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cholangiocarcinoma, Extrahepatic cholangiocarcinoma (eCCA), Intrahepatic cholangiocarcinoma (iCCA), Risk factor, Hepatitis, Diabetes mellitus (DM)","lastPublishedDoi":"10.21203/rs.3.rs-6483124/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6483124/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Diabetes mellitus (DM) and hepatitis B virus infection enhance the incidence of intrahepatic and extrahepatic cholangiocarcinoma, but their significance is unclear. Here, we conducted a population-based case-control study in China to evaluate the effects of DM, HBV infection, and other possible risk factors for cholangiocarcinoma. \u003cbr\u003e\n\u003cstrong\u003eMethods:\u003c/strong\u003e A hospital-based, case-control study of 245 CCA patients (168 eCCA and 77 iCCA) diagnosed at The Second Affiliated Hospital of Harbin Medical University in China between January 2019 and June 2024 and 490 healthy controls matched 2:1. Cholangiocarcinoma risk variables and correlations were analyzed using conditional logistic regression and the synergism index. \u003cbr\u003e\n\u003cstrong\u003eResults:\u003c/strong\u003e Cholangiocarcinoma (CCA) was significantly and positively correlated with diabetes mellitus, HBV infection, cholecystolithiasis, choledocholithiasis, hepatolithiasis, cholecystectomy history, and thyroid diseases, with adjusted odds ratios AOR= 1.41, 0.35, 1.70, 5.40, 0.30, 0.49, 5.42, respectively. Without complications, diabetes mellitus had an AOR=0.21 and with complications, AOR=0.46, which are substantial risk factors for CCA. eCCA Cholelithiasis (AOR=1.51), CBD stones (AOR=4.51), hepatolithiasis (AOR=0.29), and thyroid disorders (AOR=8.56) were significant in subgroup analyses. Diabetes mellitus without and with complications (AOR=0.43 and AOR=0.70) also increased eCCA risk. Cholelithiasis, cholecystectomy, hepatolithiasis, and HBV infection were risk factors for iCCA (AOR=4.91, 0.39, 0.34, and 0.20), respectively. However, diabetic mellitus (AOR=1.30) is also a significant risk factor for iCCA. \u003cbr\u003e\n\u003cstrong\u003eConclusion:\u003c/strong\u003e In this study, cholelithiasis, hepatolithiasis, CBD stones, HBV infection, and diabetes mellitus (DM) were independent risk factors for cholangiocarcinoma, especially extrahepatic and intrahepatic cholangiocarcinoma. By understanding this synergy, high-risk cholangiocarcinoma prevention methods can be devised.\u003c/p\u003e","manuscriptTitle":"Risk Factors for Cholangiocarcinoma, Role of Diabetes Mellitus and Hepatitis B Virus Infection in the Intrahepatic and Extrahepatic Cholangiocarcinoma: A case-control study in China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-22 10:27:14","doi":"10.21203/rs.3.rs-6483124/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-29T12:10:16+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-29T01:05:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-26T16:42:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"65272755109830033256110989383681083482","date":"2025-05-08T08:29:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"151642127082692669583454812760923662623","date":"2025-05-08T00:14:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"58122525000595028694055137166341782377","date":"2025-05-06T15:07:31+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-25T09:28:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-21T06:04:03+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-21T06:02:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"Infectious Agents and Cancer","date":"2025-04-19T07:09:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"infectious-agents-and-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"iaac","sideBox":"Learn more about [Infectious Agents and Cancer](http://infectagentscancer.biomedcentral.com/)","snPcode":"13027","submissionUrl":"https://submission.nature.com/new-submission/13027/3","title":"Infectious Agents and Cancer","twitterHandle":"@IAC_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6570dc84-50ba-46fe-a9ce-967d96fe266d","owner":[],"postedDate":"April 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-21T16:02:09+00:00","versionOfRecord":{"articleIdentity":"rs-6483124","link":"https://doi.org/10.1186/s13027-025-00681-z","journal":{"identity":"infectious-agents-and-cancer","isVorOnly":false,"title":"Infectious Agents and Cancer"},"publishedOn":"2025-07-15 15:56:51","publishedOnDateReadable":"July 15th, 2025"},"versionCreatedAt":"2025-04-22 10:27:14","video":"","vorDoi":"10.1186/s13027-025-00681-z","vorDoiUrl":"https://doi.org/10.1186/s13027-025-00681-z","workflowStages":[]},"version":"v1","identity":"rs-6483124","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6483124","identity":"rs-6483124","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}