Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital.
Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital.
Harvard Medical School, Boston, MA.
Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital.
Division of Gastroenterology and Hepatology, Duke University, Durham, NC.
National Cancer Centre Singapore, Singapore.
Department of Biostatistics and Epidemiology, School of Public Health, China Medical University, Shenyang, Liaoning, PR China.
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.
Yale University Cancer Center, New Haven, CT.
Dana-Farber Cancer Center, Boston, MA.
Type 2 diabetes (T2D) is a risk factor for hepatocellular carcinoma (HCC). However, it is unknown whether T2D duration or additional metabolic comorbidities further contribute to HCC risk.
From the Nurses' Health Study (NHS), 120,826 women were enrolled in 1980, and from the Health Professionals Follow-up Study (HPFS), 50,284 men were enrolled in 1986, and followed through 2012. Physician-diagnosed T2D was ascertained at baseline and updated biennially. Cox proportional hazards regression models were used to calculate age- and multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for incident HCC.
Over 32 years of follow-up (4,488,410 person-years), we documented 112 cases of HCC (69 women, 43 men). T2D was associated with an increased HCC risk (multivariable HR 4.59, 95% CI 2.98-7.07), as was an increasing T2D duration (Ptrend <0.001). Compared to non-diabetics, the multivariable HRs for HCC were 2.96 (95% CI 1.57-5.60) for 0 to <2 years; 6.08 (95% CI 2.96-12.50) for 2 to <10 years; and 7.52 (95% CI 3.88-14.58) for ≥10 years. Increasing number of metabolic comorbidities (T2D, obesity, hypertension, dyslipidemia) was associated with increased HCC risk (Ptrend <0.001); compared to individuals without metabolic comorbidity, those with four metabolic comorbidities had an 8.1-fold increased HCC risk (95% CI 2.48-26.7). In T2D, neither insulin use nor oral hypoglycemic use was significantly associated with HCC risk (HR 2.04 [95% CI 0.69-6.09], and HR 1.45 [95% CI 0.69-3.07] respectively).
T2D is independently associated with increased risk for HCC, in two prospective cohorts of U.S. men and women. This risk is enhanced with prolonged diabetes duration and with comorbid metabolic conditions, suggesting the importance of insulin resistance in the pathogenesis of HCC.