BACKGROUND: Autoimmune diseases are associated with many cancers but there is a lack of population-based studies with different autoimmune diseases that have a long follow-up. This is also true of hepatobiliary cancers, which include hepatocellular cancer (HCC) and rarer entities of gallbladder cancer (GBC), intra- and extrahepatic cholangiocarcinoma (iCCA and eCCA), and ampullary cancer. METHODS: Diagnostic data on 43 autoimmune diseases were collected from the Swedish Inpatient Register from 1987 to 2018, and cancer data were derived from the national cancer registry from 1997 onward. Relative risks were expressed as standardized incidence ratios (SIRs). RESULTS: In a population of 13.6 million, 1.1 million autoimmune diseases were diagnosed and subsequent hepatobiliary cancer was diagnosed in 3191 patients (17.2% of cancers). SIRs for HCC were 2.73 (men) and 2.86 (women), 3.74/1.96 for iCCA, 2.65/1.37 for GBC, 2.38/1.64 for eCCA, and 1.80/1.85 for ampullary cancer. Significant associations between autoimmune disease and HCC were observed for 13 autoimmune diseases, with the highest risks being for autoimmune hepatitis (48.92/73.53, men/women) and primary biliary cirrhosis (38.03/54.48). GBC was increased after six autoimmune diseases, with high SIRs for ulcerative colitis (12.22/3.24) and men with Crohn disease (9.16). These autoimmune diseases were also associated with a high risk of iCCA, which had seven other associations, and eCCA, which had five other associations. Ampullary cancer occurrence was increased after four autoimmune diseases. CONCLUSION: An autoimmune disease is a common precursor condition for hepatobiliary cancers. This calls for careful control of autoimmune disease symptoms in each patient and encouragement to practice a healthy lifestyle.

Biomedical Center Faculty of Medicine and Biomedical Center in Pilsen Charles University Prague Pilsen Czech Republic

Cancer Gene Therapy Group Translational Immunology Research Program University of Helsinki Helsinki Finland

Center for Primary Health Care Research Lund University Malmo Sweden

Comprehensive Cancer Center Helsinki University Hospital Helsinki Finland

Department of Family Medicine and Community Health Department of Population Health Science and Policy Icahn School of Medicine at Mount Sinai New York New York USA

Department of Functional Pathology School of Medicine Center for Community based Healthcare Research and Education Shimane University Matsue Japan

Department of Surgery University Hospital Charles University School of Medicine in Pilsen Pilsen Czech Republic

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany

Hopp Children's Cancer Center Heidelberg Germany

See more in PubMed

Valle JW, Kelley RK, Nervi B, Oh DY, Zhu AX. Biliary tract cancer. Lancet. 2021;397(10272):428-444. doi:10.1016/s0140-6736(21)00153-7

Villanueva A, Longo DL. Hepatocellular carcinoma. New Engl J Med. 2019;380(15):1450-1462. doi:10.1056/nejmra1713263

Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Prim. 2021;7(1):6. doi:10.1038/s41572-020-00240-3

Hemminki K, Sundquist K, Sundquist J, et al. Personal comorbidities and their subsequent risks for liver, gallbladder and bile duct cancers. Int J Cancer. 2023;152(6):1107-1114.

Hemminki K, Sundquist K, Sundquist J, et al. Familial risks for liver, gallbladder and bile duct cancers and for their risk factors in Sweden, a low-incidence country. Cancers. 2022;14(8):1938. doi:10.3390/cancers14081938

Henriksson M, Björnsson B, Sternby Eilard M, et al. Treatment patterns and survival in patients with hepatocellular carcinoma in the Swedish national registry SweLiv. BJS Open. 2020;4(1):109-117. doi:10.1002/bjs5.50226

Pinheiro PS, Medina HN, Callahan KE, et al. The association between etiology of hepatocellular carcinoma and race-ethnicity in Florida. Liver Int. 2020;40(5):1201-1210. doi:10.1111/liv.14409

Clements O, Eliahoo J, Kim JU, Taylor-Robinson SD, Khan SA. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Hepatol. 2020;72(1):95-103. doi:10.1016/j.jhep.2019.09.007

Rawla P, Sunkara T, Thandra KC, Barsouk A. Epidemiology of gallbladder cancer. Clin Exp Hepatol. 2019;5(2):93-102. doi:10.5114/ceh.2019.85166

Biological agents. Volume 100 B. A review of human carcinogens. IARC Monogr Eval Carcinog Risks Hum. 2012;100(Pt B):1-441.

McGee EE, Jackson SS, Petrick JL, et al. Smoking, alcohol, and biliary tract cancer risk: a pooling project of 26 prospective studies. J Natl Cancer Inst. 2019;111(12):1263-1278. doi:10.1093/jnci/djz103

Barner-Rasmussen N, Pukkala E, Hadkhale K, Färkkilä M. Risk factors, epidemiology and prognosis of cholangiocarcinoma in Finland. United European Gastroenterol J. 2021;9(10):1128-1135. doi:10.1002/ueg2.12154

Nakagawa H, Maeda S. Inflammation- and stress-related signaling pathways in hepatocarcinogenesis. World J Gastroenterol. 2012;18(31):4071-4081. doi:10.3748/wjg.v18.i31.4071

Fridman WH, Zitvogel L, Sautes-Fridman C, Kroemer G. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol. 2017;14(12):717-734. doi:10.1038/nrclinonc.2017.101

Shalapour S, Karin M. Immunity, inflammation, and cancer: an eternal fight between good and evil. J Clin Invest. 2015;125(9):3347-3355. doi:10.1172/jci80007

Shalapour S, Karin M. Pas de deux: control of anti-tumor immunity by cancer-associated inflammation. Immunity. 2019;51(1):15-26. doi:10.1016/j.immuni.2019.06.021

Li X, Ramadori P, Pfister D, Seehawer M, Zender L, Heikenwalder M. The immunological and metabolic landscape in primary and metastatic liver cancer. Nat Rev Cancer. 2021;21(9):541-557. doi:10.1038/s41568-021-00383-9

Leone V, Ali A, Weber A, Tschaharganeh DF, Heikenwalder M. Liver inflammation and hepatobiliary cancers. Trends Cancer. 2021;7(7):606-623. doi:10.1016/j.trecan.2021.01.012

Wang L, Wang FS, Gershwin ME. Human autoimmune diseases: a comprehensive update. J Intern Med. 2015;278(4):369-395. doi:10.1111/joim.12395

Giat E, Ehrenfeld M, Shoenfeld Y. Cancer and autoimmune diseases. Autoimmun Rev. 2017;16(10):1049-1057. doi:10.1016/j.autrev.2017.07.022

Castro FA, Liu X, Försti A, et al. Increased risk of hepatobiliary cancers after hospitalization for autoimmune disease. Clin Gastroenterol Hepatol. 2014;12(6):1038-1045.e7. doi:10.1016/j.cgh.2013.11.007

McGee EE, Castro FA, Engels EA, et al. Associations between autoimmune conditions and hepatobiliary cancer risk among elderly US adults. Int J Cancer. 2019;144(4):707-717. doi:10.1002/ijc.31835

Hortlund M, Arroyo Muhr LS, Storm H, Engholm G, Dillner J, Bzhalava D. Cancer risks after solid organ transplantation and after long-term dialysis. Int J Cancer. 2017;140(5):1091-1101. doi:10.1002/ijc.30531

Klöß S, Dehmel S, Braun A, Parnham MJ, Köhl U, Schiffmann S. From cancer to immune-mediated diseases and tolerance induction: lessons learned from immune oncology and classical anti-cancer treatment. Front Immunol. 2020;11:1423.

Thomsen H, Li X, Sundquist K, Sundquist J, Försti A, Hemminki K. Familial risks between Graves disease and Hashimoto thyroiditis and other autoimmune diseases in the population of Sweden. J Transl Autoimmun. 2020;3:100058. doi:10.1016/j.jtauto.2020.100058

Lindberg A, Bjerg A, Rönmark E, Larsson LG, Lundbäck B. Prevalence and underdiagnosis of COPD by disease severity and the attributable fraction of smoking Report from the Obstructive Lung Disease in Northern Sweden Studies. Respir Med. 2006;100(2):264-272. doi:10.1016/j.rmed.2005.04.029

Hemminki K, Hemminki O, Försti A, Sundquist K, Sundquist J, Li X. Surveillance bias in cancer risk after unrelated medical conditions: example urolithiasis. Sci Rep. 2017;7(1):8073. doi:10.1038/s41598-017-08839-5

Rigopoulou EI, Dalekos GN. Current trends and characteristics of hepatocellular carcinoma in patients with autoimmune liver diseases. Cancers. 2021;13(5):1023. doi:10.3390/cancers13051023

Cooper N, Ghanima W. Immune thrombocytopenia. N Engl J Med. 2019;381(10):945-955. doi:10.1056/nejmcp1810479

Rizzo A, Dadduzio V, Lombardi L, Ricci AD, Gadaleta-Caldarola G. Ampullary carcinoma: an overview of a rare entity and discussion of current and future therapeutic challenges. Curr Oncol. 2021;28(5):3393-3402. doi:10.3390/curroncol28050293

Strauss R, Törner A, Duberg AS, Hultcrantz R, Ekdahl K. Hepatocellular carcinoma and other primary liver cancers in hepatitis C patients in Sweden - a low endemic country. J Viral Hepat. 2008;15(7):531-537. doi:10.1111/j.1365-2893.2008.00979.x

De Angelis R, Sant M, Coleman MP, et al. Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE-5-a population-based study. Lancet Oncol2014;15(1):23-34. doi:10.1016/s1470-2045(13)70546-1

Wang D, DuBois RN. Immunosuppression associated with chronic inflammation in the tumor microenvironment. Carcinogenesis. 2015;36(10):1085-1093. doi:10.1093/carcin/bgv123

Smyk DS, Rigopoulou EI, Muratori L, Burroughs AK, Bogdanos DP. Smoking as a risk factor for autoimmune liver disease: what we can learn from primary biliary cirrhosis. Ann Hepatol. 2012;11(1):7-14. doi:10.1016/s1665-2681(19)31481-4