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Hepatocellular Cancer in the Absence of Viral Hepatitis: Implications for Prevention

29 Pages Posted: 1 Nov 2021

See all articles by Ysabel C. Ilagan-Ying

Ysabel C. Ilagan-Ying

Yale University - Department of Medicine

Kirsha S. Gordon

Yale University - Department of Medicine

Janet Tate

Yale University - Department of Medicine

Joseph K. Lim

Yale University - School of Medicine

Vincent Lo Re III

University of Pennsylvania

Amy C. Justice

Yale University - School of Medicine

Tamar H. Taddei

Yale University - Department of Medicine

More...

Abstract

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

Suggested Citation

Ilagan-Ying, Ysabel C. and Gordon, Kirsha S. and Tate, Janet and Lim, Joseph K. and Lo Re III, Vincent and Justice, Amy C. and Taddei, Tamar H., Hepatocellular Cancer in the Absence of Viral Hepatitis: Implications for Prevention. Available at SSRN: https://ssrn.com/abstract=3954084 or http://dx.doi.org/10.2139/ssrn.3954084

Ysabel C. Ilagan-Ying

Yale University - Department of Medicine ( email )

New Haven, CT
United States

Kirsha S. Gordon

Yale University - Department of Medicine ( email )

New Haven, CT
United States

Janet Tate

Yale University - Department of Medicine ( email )

New Haven, CT
United States

Joseph K. Lim

Yale University - School of Medicine ( email )

333 Cedar Street
New Haven, CT 06520-8034
United States

Vincent Lo Re III

University of Pennsylvania ( email )

Philadelphia, PA 19104
United States

Amy C. Justice (Contact Author)

Yale University - School of Medicine ( email )

333 Cedar Street
New Haven, CT 06520-8034
United States

Tamar H. Taddei

Yale University - Department of Medicine ( email )

New Haven, CT
United States

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