Additional partial hepatectomy at the time of portal vein ligation accelerates the regeneration of the future liver remnant

Chuanfeng Hua,André Homeyer,Uta Dahmen,Tianjiao Zhang,Weiwei Wei,Fengming Xu,Utz Settmacher,Olaf Dirsch

doi:10.1038/s41598-021-90819-x

Abstract

Portal vein ligation (PVL) has been adopted to induce hypertrophy of the future liver remnant (FLR) in patients with primarily irresectable liver tumor. However, regeneration of the FLR is not always sufficient to allow curative resection of the portally-deprived tumor-bearing liver lobe. We hypothesize that simultaneous hepatectomy (PHx) and PVL augments regeneration of the FLR and that the effect is related to the extent of the additional resection. Seventy-two Lewis rats were enrolled into 3 groups: 20%PVL + 70%PHx; 70%PVL + 20%PHx; 90%PVL. Animals were observed for 1, 2, 3 and 7 days postoperatively (n = 6/time point). Liver enzymes, caudate liver/body-weight-ratio, BrdU-proliferation-index (PI), proliferating-cell-nuclear-antigen (PCNA)-mRNA-expression level and autophagy-related-proteins were evaluated. Compared with 90% PVL, additional PHx induced significantly more hypertrophy during the observation time, which was confirmed by significantly higher PI and higher level of PCNA-mRNA expression. Similarly, the additional PHx induced more autophagy in the FLR compared with PVL alone. However, both effects were not clearly related to the extent of additional resection. Additional resection augmented liver regeneration and autophagy substantially compared with PVL alone. Therefore, we concluded that autophagy might play a critical role in regulating hepatocyte proliferation and the size of the FLR after simultaneous PVL + PHx.

Highlights

Portal vein ligation (PVL) has been adopted to induce hypertrophy of the future liver remnant (FLR) in patients with primarily irresectable liver tumor
In the case of initially irresectable liver tumor, different staged procedures were introduced in the clinic: portal vein occlusion followed by PHx, two sequential hepatectomies and the combination of portal vein occlusion and two sequential hepatectomies
We hypothesized that combining PVL and PHx augments the regenerative response in an “extent of resectiondependent” manner compared to PVL alone, possibly facilitated by the induction of autophagy in the FLR. To investigate this hypothesis we designed a study with three experimental groups: (I) major PVL alone representing the conventional first step in two-stage hepatectomy without atypical resection; (II) major PVL with additional minor liver mass resection, similar to minor “cherry picking” resection; (III) minor PVL with additional major liver mass resection, mimicking a substantial liver resection at the time of portal vein occlusion

Summary

Introduction

Portal vein ligation (PVL) has been adopted to induce hypertrophy of the future liver remnant (FLR) in patients with primarily irresectable liver tumor. We concluded that autophagy might play a critical role in regulating hepatocyte proliferation and the size of the FLR after simultaneous PVL + PHx. Abbreviations PHx Partial hepatectomy PVL Portal vein ligation PVE Portal vein embolization AST Aspartate aminotransferase ALT Alanine aminotransferase BrdU 5-Bromo-2-deoxyuridine PI Proliferation index POD Postoperative day PCNA Proliferating cell nuclear antigen. The first successful clinical application of this concept was reported by Makuuchi et al.[8], who performed PVE of the tumor-bearing lobe prior to major hepatectomy. They demonstrated that the technique was feasible and decreased the post-hepatectomy liver failure

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Conclusion