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 (CIs) 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 nondiabetics, the multivariable HRs for HCC were 2.96 (95% CI, 1.57‐5.60) for 0‐<2 years; 6.08 (95% CI, 2.96‐12.50) for 2‐<10 years; and 7.52 (95% CI, 3.88‐14.58) for ≥10 years. Increasing number of metabolic comorbidities (T2D, obesity, hypertension, and 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). Conclusion: 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. (Hepatology 2018;67:1797‐1806)

中文翻译：

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糖尿病、代谢合并症和肝细胞癌风险：两项前瞻性队列研究的结果

2 型糖尿病 (T2D) 是肝细胞癌 (HCC) 的危险因素。然而，尚不清楚 T2D 持续时间或其他代谢合并症是否会进一步增加 HCC 风险。护士健康研究 (NHS) 于 1980 年招募了 120,826 名女性，而卫生专业人员随访研究 (HPFS) 中，1986 年招募了 50,284 名男性，并持续到 2012 年。医生诊断的 T2D 在基线和每两年更新一次。Cox 比例风险回归模型用于计算 HCC 的年龄和多变量调整风险比 (HR) 和 95% 置信区间 (CI)。在 32 年的随访中（4,488,410 人年），我们记录了 112 例 HCC（69 名女性，43 名男性）。T2D 与 HCC 风险增加相关（多变量 HR，4.59；95% CI，2.98-7.07），以及增加的 T2D 持续时间（Ptrend < 0.001）。与非糖尿病患者相比，0-<2 年 HCC 的多变量 HR 为 2.96（95% CI，1.57-5.60）；6.08 (95% CI, 2.96-12.50) 2-<10 年；7.52 (95% CI, 3.88-14.58) ≥10 年。代谢合并症（T2D、肥胖、高血压和血脂异常）数量增加与 HCC 风险增加有关（Ptrend < 0.001）；与没有代谢合并症的个体相比，有四种代谢合并症的患者 HCC 风险增加了 8.1 倍（95% CI，2.48-26.7）。在 T2D 中，使用胰岛素和口服降糖药均与 HCC 风险显着相关（分别为 HR，2.04 [95% CI，0.69-6.09] 和 HR，1.45 [95% CI，0.69-3.07]）。结论：在美国男性和女性的两个前瞻性队列中，T2D 与 HCC 风险增加独立相关。这种风险随着糖尿病病程延长和代谢疾病的共存而增加，表明胰岛素抵抗在 HCC 发病机制中的重要性。（肝病学 2018；67：1797-1806）