Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy.
Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Hepatology. 2020 Dec;72(6):1912-1923. doi: 10.1002/hep.31500. Epub 2020 Nov 20.
Genetic factors and steatosis predispose to hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus; however, their impact in patients with cirrhosis cured by direct-acting antivirals (DAAs) is still undefined. We assessed the association between a genetic risk score (GRS) of hepatic fat accumulation, combining variants in PNPLA3 (patatin-like phospholipase domain containing 3), MBOAT7 (membrane bound O-acyltransferase domain containing 7), TM6SF2 (transmembrane 6 superfamily member 2), GCKR (glucokinase regulator), and HCC in patients treated with DAAs.
We considered 509 consecutive patients with HCV cirrhosis (defined histologically or when liver stiffness ≥12 kPa) treated with DAAs. HCC was diagnosed according to international recommendations. GRS was calculated from the weighted impact of single variants on hepatic fat content quantified by H spectrometry in the general population (Dallas Heart Study). During a median follow-up of 43 (3-57) months after DAA start, 36 of 452 (8%) patients developed de novo HCC, 4-year cumulative probability being 9% (95% confidence interval 7%-12%). Male sex (hazard ratio [HR] 2.54, P = 0.02), diabetes (HR 2.39, P = 0.01), albumin (HR 0.35, P = 0.001), and GRS score >0.597 (HR 2.30, P = 0.04) were independent predictors of de novo HCC. In contrast, single genetic risk variants were not useful in stratifying HCC risk. The proportion of patients who developed HCC according to the combination of the independent risk factors ranged from 11% to 67%. HCC recurred in 28 of 57 (49%) patients with previous history; diabetes and ethnicity were the only independent predictors of HCC recurrence.
In a large cohort of DAA-treated patients with cirrhotic HCV, GRS was associated with de novo HCC independently of classical risk factors, including liver disease severity. These data suggest that hepatic fat (i.e., lipotoxicity) promotes HCC in this setting and may represent a target for chemoprevention. Combination of clinical and genetic predictors may improve HCC risk stratification.
遗传因素和脂肪变性使慢性丙型肝炎病毒患者易患肝细胞癌（HCC）；然而，在接受直接作用抗病毒药物（DAA）治愈的肝硬化患者中，其影响仍未确定。我们评估了肝脂肪堆积的遗传风险评分（GRS）与 DAA 治疗患者中 HCC 的关联，该评分结合了 PNPLA3（含有 patatin 样磷脂酶结构域 3）、MBOAT7（膜结合 O-酰基转移酶结构域 7）、TM6SF2（跨膜 6 超家族成员 2）、GCKR（葡萄糖激酶调节蛋白）的变异体。
我们考虑了 509 例连续的丙型肝炎肝硬化患者（根据组织学或当肝脏硬度≥12kPa 定义），这些患者接受了 DAA 治疗。根据国际建议诊断 HCC。GRS 是根据一般人群中 H 谱定量的肝脂肪含量的单一变异体的加权影响计算的（达拉斯心脏研究）。在 DAA 开始后中位数为 43（3-57）个月的随访期间，452 例患者中有 36 例（8%）新发 HCC，4 年累积概率为 9%（95%置信区间 7%-12%）。男性（风险比[HR]2.54，P=0.02）、糖尿病（HR 2.39，P=0.01）、白蛋白（HR 0.35，P=0.001）和 GRS 评分>0.597（HR 2.30，P=0.04）是新发 HCC 的独立预测因素。相比之下，单一遗传风险变异体不能用于分层 HCC 风险。根据独立危险因素的组合，发生 HCC 的患者比例从 11%到 67%不等。57 例有 HCC 病史的患者中有 28 例（49%）复发；糖尿病和种族是 HCC 复发的唯一独立预测因素。
在接受 DAA 治疗的大量肝硬化丙型肝炎病毒患者中，GRS 与独立于包括肝病严重程度在内的经典危险因素的新发 HCC 相关。这些数据表明，在这种情况下，肝脂肪（即脂毒性）促进 HCC 的发生，并且可能成为化学预防的目标。临床和遗传预测因素的组合可能会改善 HCC 的风险分层。
