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Diabetes Mellitus Heightens the Risk of Hepatocellular Carcinoma Except in Patients With Hepatitis C Cirrhosis

Yang, Ju Dong MD1; Mohamed, Hager Amed MD1; Cvinar, Jessica L MD1; Gores, Gregory J MD1; Roberts, Lewis R MB, ChB, PhD1; Kim, Ray W MD2

American Journal of Gastroenterology: November 2016 - Volume 111 - Issue 11 - p 1573–1580
doi: 10.1038/ajg.2016.330

OBJECTIVES: As most hepatocellular carcinoma (HCC) patients have cirrhosis, the association between diabetes and HCC may be confounded by the fact that diabetes is common in patients with cirrhosis. The aim of this study is to investigate whether diabetes increases the risk of HCC in patients with cirrhosis and whether the etiology of liver disease modifies the association between diabetes and HCC.

METHODS: All liver cirrhosis patients who had repeated radiographic evaluation of the liver (that is, ultrasound, computed tomography, or magnetic resonance image) at Mayo Clinic Rochester between January 2006 and December 2011 were included. The Cox proportional hazard regression analysis was used to investigate the effect of diabetes on the risk of HCC.

RESULTS: A total of 739 patients met the eligibility criteria, of whom 253 (34%) had diabetes. After a median follow-up of 38 months, 69 (9%) patients developed HCC. In patients without hepatitis C virus (HCV) infection, diabetes was significantly associated with the risk of developing HCC (hazard ratio (HR)=2.1, 95% confidence interval (CI)=1.1–4.1), whereas in patients with HCV, there was no association (HR=0.8, 95% CI=0.4–1.8). When adjusted for covariates, the interaction between HCV and diabetes remained significant (HR for non-HCV=1.9, 95% CI=0.9–3.7; HR for HCV=0.6, 95% CI=0.2–1.3). Lack of association between diabetes and HCC was externally validated in 410 patients with HCV cirrhosis enrolled in the HALT-C trial.

CONCLUSIONS: Diabetes increases the risk of HCC in patients with non-HCV cirrhosis. In HCV cirrhosis patients who already have very high risk, diabetes may not increase the risk any further.

1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

2Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, USA

Correspondence: W. Ray Kim, MD, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California 94305, USA. E-mail:

SUPPLEMENTARY MATERIAL accompanies this paper at,,,

Received 01 March 2016; accepted 01 July 2016

Guarantor of the article: W. Ray Kim, MD.

Specific author contributions: Planning, conducting the study, collecting, interpreting data, and drafting the manuscript: Ju Dong Yang; collecting and interpreting data, and critical revision of the manuscript: Hager Amed Mohamed and Jessica L. Cvinar; planning and/or conducting the study, interpreting data and critical revision of the manuscript: Gregory J. Gores and Lewis R. Roberts; planning and conducting the study, interpreting data and critical revision, and final approval of the manuscript: W. Ray Kim; All authors (Ju Dong Yang; Hager Amed Mohamed; Jessica L. Cvinar; Gregory J. Gores; Lewis R. Roberts; W. Ray Kim) approved the final draft of the manuscript.

Financial support: This study was supported by the National Institutes of Diabetes and Digestive and Kidney Diseases (DK-34238, DK-92336; to W.R.K.) and T32 DK07198 (to J.D.Y.).

Potential competing interests: None.

© The American College of Gastroenterology 2016. All Rights Reserved.
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