Associated Liver Partition and Portal Vein Ligation (ALPPS) vs Selective Portal Vein Ligation (PVL) for Staged Hepatectomy in a Rat Model. Similar Regenerative Response?

Abstract

Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage hepatectomy technique which can be associated with a hypertrophic stimulus on the future liver remnant (FLR) stronger than other techniques–such as portal vein ligation (PVL). However, the reason of such hypertrophy is still unclear, but it is suggested that liver transection combined with portal vein ligation (ALPPS) during the first stage of this technique may play a key role. The aim of this study is to compare the hypertrophic stimulus on the FLR and the clinical changes associated with both ALPPS and PVL in a rat surgical model. For this purpose, three groups of SD rats were used, namely ALPPS (n = 30), PVL (n = 30) and sham-treated (n = 30). The second stage of ALPPS (hepatectomy of the atrophic lobes), was performed at day 8. Blood and FLR samples were collected at 1, 24, 48 hours, 8 days and 12 weeks after the surgeries. ALPPS provoked a greater degree of hypertrophy of the FLR than the PVL at 48 hours and 8 days (p<0.05). The molecular pattern was also different, with the highest expression of IL-1β at 24h, IL-6 at 8 days, and HGF and TNF-α at 48 hours and 8 days (p<0.05). ALPPS also brought about a mild proliferative stimulus at 12 weeks, with a higher expression of HGF and TGF-β (p<0.05) than PVL. Clinically, ALPPS caused a significant liver damage during the first 48 hours, with a recovery of liver function at day 8. In conclusion, ALPPS seems to induce higher functional hypertrophy on the FLR than PVL at day 8. Such regenerative response seems to be leaded by a complex interaction between pro-mitogenic (IL-6, HGF, TNF-α) and antiproliferative (IL1-β and TGF-β) cytokines.

RNA-Seq transcriptome profiling in three liver regeneration models in rats: comparative analysis of partial hepatectomy, ALLPS, and PVL

“…Our data revealed that time-dependent factors appear to be the major source of variation in post-injury alterations of gene expression in liver regeneration. Early transcriptomic changes and the upstream regulators after all the procedures included cell cycle associated genes (E2F1, CCND1, FOXM1, TP53, and RB1), transcription factors (Myc, E2F1, TBX2, FOXM1) [23][24][25][26][27][28] , DNA replication regulators (CDKN1A, EZH2, RRM2) 29 , G1/S-transition regulators (CCNB1, CCND1, RABL6) 30 , cytokines and growth factors (CSF2, IL-6, TNF, HGF, VEGF, and EGF) 9,16,31,32 . At the cellular level, this corresponds to the transition from the quiescent G0 phase to active mitosis.…”

“…At the cellular level, this corresponds to the transition from the quiescent G0 phase to active mitosis. Liver regeneration is governed by numerous growth factors, including HGF and EGF that are responsible priming the parenchymal and nonparenchymal liver cells and boosting their access into the cell cycle to proliferate to restore the original liver size after the surgical procedures 9,16,31,32 . Growth factors and signaling pathways activates cyclin-dependent kinases (CDKs), and upregulates the expression of CCND1 that encodes cyclin D1.…”

Insight on ALPPS – Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy – mechanisms: activation of mTOR pathway

“…IL-6, TNF-a, EGF and HGF are critical promoters of liver regeneration 37 and have also been described in animal models of ALPPS. 38 These cytokines and growth factors were increased in serum from patients before ALPPS Stage II.…”

Mechanistic insights of rapid liver regeneration after associating liver partition and portal vein ligation for stage hepatectomy

“…At 48h, ALPPS was associated with higher expression of HGF and TGF-α ( P < 0.05) with similar relative expression of TGF-β in both groups[59]. Later, the HGF and TGF-β levels were still higher on ALPPS group ( P < 0.005 and P < 0.05 respectively)[59].…”