Exposure to Agent Orange and Hepatocellular Carcinoma Among US Military Personnel

IMPORTANCE: Hepatocellular carcinoma (HCC) and its mortality are on the rise. Viral hepatitis and alcohol are leading risk factors; however, other risk factors among veterans are less defined, including Agent Orange (AO), an herbicide linked to several cancers. OBJECTIVE: To assess the association of AO exposure and HCC in a national cohort of Vietnam veterans. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included Vietnam veterans who served between 1966 and 1975, were male, were older than 18 years at the time of deployment, and had established follow-up in the Veterans Affairs (VA) between 2000 and 2019. Veterans with AO exposure were identified in the disability data via validated clinical surveys. Relevant clinical risk factors for cirrhosis and HCC were collected. Patients were stratified based on cirrhosis status, as defined by consecutive diagnosis found by documented International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision scores or calculated Fibrosis-4 scores. Data were collected from January 1, 2019, to December 31, 2020, and analyzed from December 2020 to October 2023. MAIN OUTCOME AND MEASURES: Incident HCC was the primary outcome. AO and HCC association was estimated using a multivariable Cox regression analysis, with death and liver transplant as competing events. RESULTS: Of the 296 505 eligible veterans (222 545 [75.1%] White individuals and 44 342 [15.0%] Black individuals), 170 090 (57%) had AO exposure (mean [SD] age, 21.62 [3.49] years; 131 552 White individuals [83.2%] and 22 767 Black individuals [14.4%]) and 35 877 (12.1%) had cirrhosis. Veterans who were not exposed to AO were more likely to smoke (109 689 of 126 413 [86.8%] vs 146 061 of 170 090 [85.9%]); use alcohol (54 147 of 126 413 [42.8%] vs 71 951 of 170 090 [42.3%]) and have viral hepatitis (47 722 of 126 413 [37.8%] vs 58 942 of 170 090 [34.7%]). In a multivariable competing risk model, AO exposure was not associated with HCC. Among veterans with cirrhosis, self-identification as Hispanic individuals (aHR, 1.51; 95% CI, 1.30-1.75; P <.001) or Black individuals (aHR, 1.18; 95% CI, 1.05-1.32; P = .004), and having a diagnosis of viral hepatitis (aHR, 3.71; 95% CI, 3.26-4.24; P <.001), alcohol-associated liver disease (aHR, 1.32; 95% CI, 1.19-1.46; P <.001), and nonalcoholic fatty liver disease (NAFLD) (aHR, 1.92; 95% CI, 1.72-2.15; P <.001) were associated with HCC. Among veterans without cirrhosis, hypertension (aHR, 1.63; 95% CI, 1.23-2.15; P <.001) and diabetes (aHR, 1.52; 95% CI, 1.13-2.05; P = .005) were also associated with HCC. Early smoking and alcohol use were significant risk factors for HCC. CONCLUSIONS AND RELEVANCE: In this large nationwide cohort study of Vietnam veterans, AO exposure was not associated with HCC. Smoking, alcohol, viral hepatitis, and NAFLD were the most important clinical risk factors for HCC.