Association of High Body Mass Index and Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Virus Infection: A Korean Population-Based Cohort Study

It is well established that obesity is associated with higher risk of hepatocellular carcinoma (HCC) in the general population.¹ However, it is unclear whether body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]) is associated with the risk of HCC in patients with chronic hepatitis B virus (HBV) infection because previous studies have reported inconsistent results.^2,3 In this study, using data from a large nationwide, population-based cohort database, we provide clinical evidence on the association between BMI and development of HCC among men and women with chronic HBV infection.

We used the National Health Insurance Service (NHIS) data, which provides compulsory health insurance coverage and national health screening for all citizens in the Republic of Korea. The institutional review board (IRB) at the Seoul National University Hospital approved our study. We identified adult men and women (age ≥18 years) with chronic HBV infection who underwent health examinations between January 1, 2002, and December 31, 2006, in the NHIS database. We excluded patients with a history of cancer and those who died before the follow-up period. The patients were grouped into the BMI categories based on the World Health Organization classification for Asian populations. Patients were followed up from January 1, 2007, to December 31, 2015, and censored at the event of HCC, death, or end of follow-up, whichever occurred first. We used Cox proportional hazards models to estimate the hazard ratios (HR) and 95% CIs across the BMI categories using 18.5 to 22.9 as the reference group, and we graphically assessed the strength of the relationship between BMI and HCC with restricted cubic spline models in men and women for BMI categories and covariates (Table). Partial likelihood ratio tests in the Cox regression model were used to compare the magnitude of the association of BMI with HCC between men and women. Sensitivity analyses were conducted by excluding events of HCC up to 4 years, as well as patients with liver comorbidities.

Our study cohort of patients with chronic HBV infection comprised of 214 167 men and 156 155 women. During the 8 years of follow-up, there were 11 241 HCCs in men and 3368 HCCs in women. The risk of HCC was positively associated with BMI in a dose-response manner both in men (P_trend<.01) and women (P_trend<.001). In severely obese men and women (BMI≥30), the HR for HCC were 1.22 (95% CI, 1.09-1.36) and 1.46 (95% CI, 1.24-1.71) compared with those whose BMI was between 18.5 and 22.9 (Table). The magnitude of the association between BMI and HCC was stronger in women who were overweight compared with men (P < .001). The correlation between BMI and HCC was also higher in women compared with men (Figure). Similar results were found in the sensitivity analyses.

Our study showed that BMI is significantly associated with higher risk of HCC among patients with chronic HBV infection, and that the risk may differ by sex. The relationship between BMI and risk of HCC was significant and independent of underlying liver diseases in patients with chronic HBV infection. The difference between male and female patients with chronic HBV infection found in our study may be partially explained by the sex difference in the relationship of BMI to total body fat.⁴ A major limitation of our study should be noted: the NHIS database lacked information on serum HBV DNA levels, which is a clinically important predictor for the development of liver cirrhosis and HCC among patients with chronic HBV infection.⁵ Our findings have both clinical and public health implications that support the need for intervention strategies and medical attention for obese patients with chronic HBV infection, especially in women.

Corresponding Author: Sang Min Park, MD, MPH, PhD, Department of Family Medicine and Biomedical Sciences, College of Medicine, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul, Republic of Korea (smpark.snuh@gmail.com).

Accepted for Publication: January 3, 2018.

Published Online: March 22, 2018. doi:10.1001/jamaoncol.2018.0035

Author Contributions: Dr Park had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kim, Park.

Acquisition, analysis, or interpretation of data: Kim, Choi.

Drafting of the manuscript: Kim.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Kim, Choi.

Obtained funding: Park.

Administrative, technical, or material support: Kim, Park.

Study supervision: Park.

Conflict of Interest Disclosures: Mr Kim received a scholarship from the BK21-plus education program provided by the National Research Foundation of Korea. No other conflicts are reported.

Funding/Support: This work was supported by the Basic Science Research Program through the National Research Foundation (NRF) funded by the Ministry of Education in the Republic of Korea (grant No. 2017R1D1A1B03033721).

Role of the Funder/Sponsor: The funder/sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We would like to thank the National Health Insurance Service for providing the database for research purposes (NHIS-2015-1-074). We would also like to thank Brenda Beck, DO (University Hospitals Cleveland Medical Center), for English proofreading, as well as Jaeuk Sim for statistical assistance; they were not compensated for their contributions.