Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: A population-based study in SEER-Medicare
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OBJECTIVES: Intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinomas are rare tumors that arise from the epithelial cells of the bile ducts, and the etiology of both cancer types is poorly understood. Thus, we utilized the Surveillance, Epidemiology, and End Results (SEER)-Medicare resource to examine risk factors and novel preexisting medical conditions that may be associated with these cancer types. METHODS: Between 2000 and 2011, 2,092 ICC and 2,981 ECC cases and 323,615 controls were identified using the SEER-Medicare database. Logistic regression was used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Non-alcoholic fatty liver disease was associated with approximately 3-fold increased risks of ICC (OR = 3.52, 95% CI: 2.87-4.32) and ECC (OR = 2.93, 95% CI: 2.42-3.55). Other metabolic conditions, including obesity and type 2 diabetes, were also associated with increased risks of both cancer types. Smoking was associated with a 46% and 77% increased ICC and ECC risk, respectively. Several autoimmune/inflammatory conditions, including type 1 diabetes and gout, were associated with increased risks of ICC/ECC. As anticipated, viral hepatitis, alcohol-related disorders, and bile duct conditions were associated with both cancer types. However, thyrotoxicosis and hemochromatosis were associated with an increased risk of ICC but not ECC, but did not remain significantly associated after Bonferroni correction. CONCLUSIONS: In this study, risk factors for ICC and ECC were similar, with the exceptions of thyrotoxicosis and hemochromatosis. Notably, metabolic conditions were associated with both cancer types. As metabolic conditions are increasing in prevalence, these could be increasingly important risk factors for both types of cholangiocarcinoma.
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Major risk factors for cholangiocarcinoma vary by region and include liver flukes (e.g., in the northeast region of Thailand, where Opisthorchis viverrini is endemic) and metabolic conditions (including obesity, diabetes, and nonalcoholic fatty liver disease), alongside heavy alcohol consumption and HBV and HCV infections.
“Major risk factors for cholangiocarcinoma also vary by region and include liver flukes (e.g., in the northeast region of Thailand, where Opisthorchis viverrini, is endemic) 121 and metabolic conditions (including obesity, diabetes, and nonalcoholic fatty liver disease), alongside heavy alcohol consumption and HBV and HCV infections.122-124”
From Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. (2024) · cites this paper as [122]
The Discussion reports associations of obesity, diabetes, NAFLD, HBV, and HCV with cholangiocarcinoma, and the Results report increased risk with alcohol-related disorders. The paper does not measure heavy alcohol consumption specifically. The Thailand liver-fluke example has a separate citation in the citing sentence and is not attributed to this source. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPatients with PSC, fluke infections, and MASLD have an increased risk of cholangiocarcinoma, whereas patients with PBC have a relatively lower risk.
“Patients with PSC, fluke infections, and MASLD have an increased risk of cholangiocarcinoma, whereas patients with PBC have a relatively lower risk [208, 209].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [209]
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“Choledochal cysts, rare congenital anomalies resulting in cystic dilatation of the biliary tree, represent another well-established risk factor for CCA [21,22].”
Background
- Authors
- Petrick, J. L., Yang, B., Altekruse, S. F., Van Dyke, A. L., Koshiol, J., Graubard, B. I., & McGlynn, K. A.
- Affiliations
- National Cancer Institute (US)
- National Heart, Lung, and Blood Institute (US)
- Corresponding author
- Petrick, Jessica L.
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2017-10-19
- Volume
- 12
- Issue
- 10
- Pages
- e0186643
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC5648218
- OpenAlex
- W2766085363
- Cited by
- 210
- References
- 55
- Citations by year
- 2026: 11 · 2025: 26 · 2024: 28 · 2023: 22 · 2022: 34 · 2021: 33 · 2020: 20 · 2019: 27 · 2018: 7
- FWCI
- 15.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- creativecommons.org/publicdomain/zero/1.0/ (vor)
- Locations
- PLoS ONE (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Cancer Institute (Intramural Funds)
- Topics
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gallbladder and Bile Duct Disorders
- Keywords
- intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, cholangiocarcinoma, cancer risk factors, non-alcoholic fatty liver disease, obesity, type 2 diabetes, smoking, type 1 diabetes, gout, viral hepatitis, alcohol-related disorders, thyrotoxicosis, hemochromatosis, metabolic disorders
- MeSH terms
- Bile Duct Neoplasms, Medicare, Humans, Risk Factors, United States, Cholangiocarcinoma, SEER Program
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