Clarification of pathogenesis and development of therapeutic strategy for small-for size syndrome after major hepatectomy in biliary tract cancer

(1)临床研究术后肝功能不全是胆道恶性肿瘤患者扩大肝切除术后的严重并发症，其中大部分患者伴有梗阻性黄疸。这项研究的目的是评估与这类肝功能障碍相关的临床参数。方法：对111例患者进行回顾。结果：Logistic回归分析显示，只有RLV/ELV比值是影响术后高胆红素血症的独立因素，RLV/ELV比值和15分钟吲哚青绿滞留率(ICG-R15)是影响生存率的独立因素。RLV/ELV和40%的患者术后高胆红素血症的风险是7.6%，而没有RLV/El…的患者更多的V&gt；40%和ICG-R15&lt；25%的患者死于肝功能衰竭。结论：RLV/ELV比值是胆道恶性肿瘤患者扩大肝切除术后对肝功能损害影响最大的因素。(2)实验研究梗阻性黄疸对肝部分切除后肝再生的影响尚不完全清楚。方法：应用LightCycler定量逆转录聚合酶链式反应(RT-β)检测胆道梗阻(BO)后肝组织和肝细胞中肝细胞生长因子及其受体、c-Met、血管内皮生长因子和转化生长因子-F31(TGFR-F31)的表达。同时对结蛋白和α-平滑肌肌动蛋白(α-SMA)进行免疫组织化学染色。结果：BO后14d，肝组织转化生长因子β1m RNA表达水平显著升高，并随时间延长而增加。肝细胞生长因子、血管内皮生长因子有升高趋势，但无统计学意义。在细胞分离株中，转化生长因子-β1m RNA主要分布在肝星状细胞部分。免疫组织化学研究显示，BO后汇管区HSCs(结蛋白阳性细胞)和活化的HSCs(α-SmA阳性细胞)数量增加。在肝切除模型中，与假手术大鼠相比，BO大鼠的肝脏再生延迟。结论：BO可诱导肝星状细胞的增殖和活化，导致肝组织中转化生长因子-β1m RNA表达上调，抑制肝细胞生长因子βm RNA的表达。这些表达模式的改变可能与阻塞性黄疸肝切除术后延迟的肝再生密切相关。较少

(1)Clinical StudyPostoperative hepatic insufficiency is a critical complication after extended hepatic resection in patients with biliary tract malignancies, the majority of whom suffer from obstructive jaundice. The aim of this study was to assess clinical parameters linked to this type of liver dysfunction.Methods : A total of 111 patients were retrospectively reviewed. Patient background, pre- and intra-operative parameters, and a ratio of remnant liver volume/entire liver volume (RLV/ELV) as a volumetric parameter, were compared between patients with and without postoperative hyperbilirubinemia and subsequent fatal outcome.Results : Logistic regression indicated that only RLV/ELV ratio was an independent factor influencing postoperative hyperbilirubinemia, and RLV/ELV ratio and indocyanine green retention rate at 15 minutes (ICG-R15) were factors affecting survival. Patients with RLV/ELV<40% had 7.6 times the risk of postoperative hyperbilirubinemia, while no patients having RLV/EL … More V>40% and ICG-R15<25% died of liver failure.Conclusions : The RLV/ELV ratio was the factor with the greatest impact on liver dysfunction after extended hepatic resection in patients with biliary tract malignancies. To prevent these morbidities, volumetric analysis should be performed in a prospective fashion, and, when necessary, preoperative portal vein embolization, or, if possible, limited hepatic resection should be applied.(2)Experimental StudyThe effects of obstructive jaundice on liver regeneration after partial hepatectomy are not yet fully understood.Methods : Hepatocyte growth factor (HGF), its receptor, c-Met, vascular endothelial growth factor (VEGF) and transforming growth factor-f31 (TGF-β1) mRNA expression in both liver tissue and isolated liver cells were investigated after biliary obstruction (BO) by quantitative reverse-transcription polymerase chain reaction (RT-PCR) using a LightCycler. Immunohistochemical staining for desmin and α-smooth muscle actin (α-SMA) was also studied. Regenerating liver weight and proliferating cell nuclear antigen (PCNA) labeling index, and growth factor expression were then evaluated after 70% hepatectomy with concomitant internal biliary drainage in BO rats or sham-operated rats.Results : Hepatic TGF-β1 mRNA levels increased significantly 14 days after BO, and further increased with length of cholestasis. Meanwhile, HGF and VEGF tended to increase, but was not significant. In cell isolates, TGF-β1 mRNA was found mainly in the hepatic stellate cell (HSC) fraction. Immunohistochemical studies revealed increased number of HSCs (desmin-positive cells) and activated HSCs (α-SMA-positive cells) in portal areas after BO. In a hepatectomy model, liver regeneration was delayed in BO rats, as compared to sham-operated rats. TGF-β1 mRNA was significantly up-regulated up to 48h after hepatectomy, and the earlier HGF mRNA peak was lost in BO rats.Conclusion : BO induces HSCs proliferation and activation, leading to up-regulation of TGF-β1 mRNA and suppression of HGF mRNA in livers. These altered expression patterns may be strongly involved in delayed liver regeneration after hepatectomy with obstructive jaundice. Less