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Hepatocellular Cancer in the Absence of Viral Hepatitis: Implications for Prevention
29 Pages Posted: 1 Nov 2021More...
Importance: Worldwide, the epidemiology of hepatocellular carcinoma (HCC) is evolving due to decreasing hepatitis B and C (HBV/HCV), increasing obesity and diabetes, and ongoing use of alcohol and tobacco.
Objective: To characterize current major risk factors for incident HCC in adults free of chronic viral hepatitis or hepatic decompensation at baseline.
Design, Setting, and Participants: Cohort study of adults from October 2007 to September 2020 in a national health care system in North America.
Exposures: Body mass index (BMI), diabetes diagnosis, unhealthy alcohol use (Alcohol Use Disorders Identification Test-Consumption [AUDIT-C] and Alcohol Use Disorder [AUD] diagnosis), and smoking status. Analyses were stratified by FIB-4 (calculated from age, liver transaminases, and platelet count) to evaluate how risk factors might vary by degree of liver fibrosis.
Main Outcomes and Measures: The primary outcome was incident HCC ascertained by the International Classification of Diseases, 9th and 10th Revisions, Clinical Modification (ICD-9/10-CM) diagnosis codes 155·0 and C22·0. We estimated incidence rates and adjusted hazard ratios (HR) of HCC, by FIB-4 (<1·45; 1·45-3·25; >3·25).
Results: Among 1,063,060 eligible adults, 988,314 (93%) were male and the mean age was 60 years. Obesity 489,030 (46·0%), diabetes 242,370 (22·8%), unhealthy alcohol use 178,577 (19·8%), and current smoking 336,379 (31·6%) were common. At baseline, only 42,476 (4·0%) had evidence of advanced fibrosis (FIB-4 >3·25) and of 1,567 patients who developed HCC, 1,158 (73·9%) had FIB-4 ≤3·25. Most (714 of 1,158 [62·0%]) HCC events in this group developed among those with intermediate FIB-4 (1·45-3·25). Risk of HCC associated with specific factors varied by FIB-4. HRs for HCC associated with obesity, diabetes, unhealthy alcohol use, and current smoking were highest among those with intermediate FIB-4 (1·45-3·25). For example, HR associated with AUD was 2·99 (95% CI 2·24 to 3·99) with FIB-4 1·45-3·25, 1·91 (95% CI 1·35 to 2·71) with a lower FIB-4 (<1·45) and 1·92 (95% CI 1·39 to 2·66) with a higher FIB-4 (>3·25).
Conclusions and Relevance: In a predominantly male, middle aged and older cohort, most incident cases of HCC arose in patients with baseline FIB-4 ≤3·25. Close attention to behavioral interventions for obesity, diabetes, unhealthy alcohol use, and smoking in those with intermediate fibrosis may prove an effective means of primary prevention.
Funding Information: Research reported in this publication was supported by the NIH NCI R01-CA206465; NIAAA U24-AA020794, U01-AA020790, U10-AA013566–completed.
Declaration of Interests: Dr. Lim reports research contracts to Yale University from Allergan, Conatus, Genfit, Gilead, and Intercept outside the submitted work. No other disclosures were reported.
Ethics Approval Statement: This study was approved by the Institutional Review Boards of the VA Connecticut Healthcare System and Yale School of Medicine. It has been granted a waiver of informed consent and is Health Insurance Portability and Accountability Act compliant.
Keywords: Hepatocellular carcinoma, FIB-4, Hepatitis C Uninfected, Obesity, Alcohol, Smoking
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