Chen Chi-Ling, Yang Wei-Shiung, Yang Hwai-I, Chen Chuen-Fei, Wang Li-Yu, Lu Sheng-Nan, Kao Jia-Horng, Chen Pei-Jer, Chen Chien-Jen
Graduate Institute of Clinical Medicine, College of Medicine, Taipei, Taiwan.
Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
Liver Cancer. 2024 Jun 21;14(1):19-35. doi: 10.1159/000539909. eCollection 2025 Mar.
Our previous nested-case-control study demonstrated elevated adiponectin increased liver cirrhosis and HCC risk in HBV carriers. We extended the analysis to the whole REVEAL-HBV cohort to prospectively evaluate whether adiponectin directly affected end-stage liver diseases, or through affecting HBV progression.
Baseline plasma adiponectin was determined to investigate the association between adiponectin and subsequent HBeAg, HBsAg, and HBV DNA seroclearance, and the development of cirrhosis, HCC and liver-related death. Whether HBV characteristics modify the adiponectin-milestones associations was also examined.
Among 3,931 HBsAg(+)/anti-HCV(-) REVEAL-HBV participants, 3,684 had sufficient biosamples left for adiponectin assay. Elevated adiponectin was associated with a higher chance of HBeAg-seropositive, high HBV viral load (≥2 × 10 IU/mL) and high HBsAg titers (≥1,000 IU/mL) in a dose-response manner (OR = 2.25, 95% CI: 1.55-3.28; OR = 2.11, 95% CI: 1.47-3.04; and OR = 1.92, 95% CI: 1.47-2.52 for Q5 vs. Q1, respectively). Those with the highest quintile had a lower chance of achieving HBeAg (HR = 0.48, 95% CI: 0.27-0.85), HBsAg (HR = 0.69, 95% CI: 0.49-0.97), and HBV DNA seroclearance (HR = 0.63, 95% CI: 0.43-0.90) and a higher chance of developing liver cirrhosis (HR = 2.88, 95% CI: 1.98-4.20, HCC (HR = 2.38, 95% CI: 1.52-3.73), and died from liver-related causes (HR = 2.32, 95% CI: 1.51-3.54). HBV genotype significantly modified the adiponectin-HCC (P = 0.005) and adiponectin-liver death associations (P = 0.0157), with higher risk among genotype C.
Elevated adiponectin is consistently associated with all important chronic HBV infection milestones toward progression to liver cancer. The exact mechanism of how adiponectin mediates HBV infection toward carcinogenesis remains unclear and warrants further investigation. Disentangling this may help us in finding new HBV treatment target, biomarker in HBV surveillance to identify high-risk patients, or even cancer prevention.
我们之前的巢式病例对照研究表明，脂联素水平升高会增加乙肝病毒携带者患肝硬化和肝癌的风险。我们将分析扩展至整个REVEAL-HBV队列，以前瞻性评估脂联素是直接影响终末期肝病，还是通过影响乙肝病毒进展来发挥作用。
测定基线血浆脂联素水平，以研究脂联素与随后的HBeAg、HBsAg及HBV DNA血清学清除之间的关联，以及肝硬化、肝癌和肝脏相关死亡的发生情况。我们还研究了乙肝病毒特征是否会改变脂联素与这些关键指标之间的关联。
在3931名HBsAg(+) /抗-HCV(-)的REVEAL-HBV参与者中，3684人留有足够的生物样本用于脂联素检测。脂联素水平升高与HBeAg血清阳性、高HBV病毒载量（≥2×10 IU/mL）和高HBsAg滴度（≥1000 IU/mL）的可能性增加呈剂量反应关系（分别为Q5与Q1相比，OR = 2.25，95%CI：1.55 - 3.28；OR = 2.11，95%CI：1.47 - 3.04；OR = 1.92，95%CI：1.47 - 2.52）。最高五分位数组的患者实现HBeAg血清学转换（HR = 0.48，95%CI：0.27 - 0.85）、HBsAg血清学转换（HR = 0.69，95%CI：0.49 - 0.97）和HBV DNA血清学清除（HR = 0.63，95%CI：0.43 - 0.90）的可能性较低，而发生肝硬化（HR = 2.88，95%CI：1.98 - 4.20）、肝癌（HR = 2.38，95%CI：1.52 - 3.73）以及死于肝脏相关原因（HR = 2.32，95%CI：1.51 - 3.54）的可能性较高。乙肝病毒基因型显著改变了脂联素与肝癌（P = 0.005）以及脂联素与肝脏相关死亡之间的关联（P = 0.0157），C基因型患者的风险更高。
脂联素水平升高始终与慢性乙肝病毒感染向肝癌进展的所有重要关键指标相关。脂联素介导乙肝病毒感染致癌的确切机制尚不清楚，值得进一步研究。弄清楚这一点可能有助于我们找到新的乙肝治疗靶点、乙肝监测中的生物标志物以识别高危患者，甚至预防癌症。
