Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Navy Medical University, Shanghai, China.
National Key Laboratory of Medical Immunology & Institute of Immunology, Navy Medical University, Shanghai, China.
Hepatol Int. 2020 May;14(3):347-361. doi: 10.1007/s12072-020-10022-4. Epub 2020 Mar 5.
With a novel finding of significantly lower incidence of acute rejection (AR) in patients with hepatocellular carcinoma (HCC) after liver transplantation, compared with those with benign end-stage liver disease (BESLD), in a large national cohort, we analyzed the correlations among the perioperative immuno-inflammation status, postoperative AR, and prognosis in HCC and BESLD patients with same etiology of hepatitis B virus (HBV), who underwent liver transplantation.
Patients who underwent liver transplantation due to HBV-related HCC or BESLD and experienced AR between September 2008 and April 2017 were analyzed retrospectively and followed up until April 2018. HCC patients with AR were matched with those without AR according to tumor stage and immunosuppressant concentration, at a 1:3 ratio. Preoperative immuno-inflammation status and prognosis of patients in both groups were compared.
The overall incidences of AR in patients with HCC and BESLD were 8.60% and 10.61%, respectively. The postoperative 28-day incidence of AR was significantly lower in HCC compared with BESLD patients (3.23% vs 7.08%, p = 0.031). Compared with BESLD patients, the rejection activity index and perioperative CD/CD ratio were significantly lower (p = 0.047 and p < 0.001, respectively), while platelet/lymphocyte ratio was significantly higher in HCC patients (p = 0.041). Later tumor stage in HCC patients was associated with higher systemic immuno-inflammation index, neutrophil/lymphocyte ratio, monocyte/lymphocyte ratio, platelet/lymphocyte ratio, aspartate aminotransferase/lymphocyte ratio, C-reactive protein/albumin ratio and fibrinogen level, and lower CD/CD ratio before transplantation. In HCC patients with AR, the percentage of regulatory T cells (CD/CD) and the level of IL-10 significantly decreased (p = 0.0023, < 0.0001, respectively), while Th1/Th2 ratio, levels of IFN-γ and IL-2 markedly increased before transplantation (p = 0.0018, 0.0059, 0.0416, respectively). Preoperative monocyte/lymphocyte ratio was an independent risk factor for overall and recurrence-free survival after liver transplantation in HCC patients (p = 0.025, < 0.001, respectively). The 1-, 3-, and 5-year survival rates were 76%, 71% and 53% in the AR group, and 67%, 37% and 25% in the non-AR group (p = 0.042).
Preoperative tumor-related immunosuppression may persist after liver transplantation in HCC patients, and reduce the incidence of AR. AR after liver transplantation may indicate a better prognosis in HCC patients.
在一项大型全国队列研究中，与良性终末期肝病（BESLD）患者相比，肝癌（HCC）患者在肝移植后急性排斥反应（AR）的发生率明显较低，这是一个新的发现。因此，我们分析了乙型肝炎病毒（HBV）相关 HCC 和 BESLD 患者在同种病因下，围手术期免疫炎症状态、术后 AR 和预后之间的相关性，这些患者均接受了肝移植。
回顾性分析了 2008 年 9 月至 2017 年 4 月期间因 HBV 相关 HCC 或 BESLD 接受肝移植且发生 AR 的患者，并随访至 2018 年 4 月。根据肿瘤分期和免疫抑制剂浓度，将 HCC 患者 AR 组与无 AR 组进行 1:3 匹配。比较两组患者的术前免疫炎症状态和预后。
HCC 和 BESLD 患者的 AR 总发生率分别为 8.60%和 10.61%。与 BESLD 患者相比，HCC 患者术后 28 天 AR 的发生率明显较低（3.23% vs 7.08%，p=0.031）。与 BESLD 患者相比，HCC 患者的排斥反应活动指数和围手术期 CD/CD 比值明显较低（p=0.047 和 p<0.001，分别），而血小板/淋巴细胞比值明显较高（p=0.041）。HCC 患者的肿瘤分期较晚与更高的全身免疫炎症指数、中性粒细胞/淋巴细胞比值、单核细胞/淋巴细胞比值、血小板/淋巴细胞比值、天门冬氨酸氨基转移酶/淋巴细胞比值、C 反应蛋白/白蛋白比值和纤维蛋白原水平相关，且 CD/CD 比值较低。在 HCC 患者 AR 中，调节性 T 细胞（CD/CD）的百分比和 IL-10 水平显著降低（p=0.0023，<0.0001，分别），而 Th1/Th2 比值、IFN-γ 和 IL-2 水平在移植前明显升高（p=0.0018，0.0059，0.0416，分别）。术前单核细胞/淋巴细胞比值是 HCC 患者肝移植后总生存率和无复发生存率的独立危险因素（p=0.025，<0.001，分别）。AR 组的 1、3 和 5 年生存率分别为 76%、71%和 53%，非 AR 组分别为 67%、37%和 25%（p=0.042）。
HCC 患者肝移植后可能持续存在与肿瘤相关的免疫抑制，从而降低 AR 的发生率。肝移植后 AR 可能预示 HCC 患者的预后较好。
