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

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(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