The role of physical and pharmacological prehabilitation in accelerated liver regeneration
Daradics Noémi
Clinical Medicine
Dr. Reusz György
SE Sebészeti, Transzplantációs és Gasztroenterológiai Klinika
2023-05-25 09:00:00
Gastroenterology
Dr. Molnár Béla
Dr. Szijártó Attila
Dr. Sydó Nóra
Dr. Németh Norbert
Dr. Rényi-Vámos Ferenc
Dr. Csapó Zsolt
Dr. Szabó Györgyi
Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) is an emerging surgical intervention promoting accelerated liver regeneration for patients with inoperable hepatic tumors by standard techniques. However, apart from the remarkable advantages, initially high morbidity and mortality rates undermined its benefits. As evidence raised that prehabilitation could improve postoperative complications, we investigated the effect of physical prehabilitation (PP) on the postoperative outcome of ALPPS. Furthermore, we also aimed to identify potential molecular targets, which could create the ground of “pharmacological prehabilitation” being in favor of frail patients, who could not tolerate extra physical burden.
Male Wistar rats underwent ALPPS (I. and III. experiment) and (PVL) (III. experiment). Male wild type (WT) BL6/jk and Cyclophilin D knockout (CypD KO) mice underwent ALPPS procedure (II. experiment). The following measurements were performed in the experiments. I.: liver weight, Ki67 index magnetic resonance imaging (MRI) liver- volumetry, liver laboratory parameters, 99mTc-mebrofenin hepatobiliary scintigraphy (HBS), mortality and septic parameters (in endotoxemia model). II.: mitochondrial function, and -proteomic analysis of factors involved in mitochondrial biogenesis, regeneration rate and mitotic activity. III.: regeneration rate, Ki67 index, liver hemodynamic changes, bile acid (BA) levels, transcription of hepatic and intestinal farnesoid X receptor (FXR) signaling pathway, BA transport, and BA production.
PP improved volumetric and functional liver regeneration, along with postoperative vulnerability after ALLPS. CypD deletion improved mitochondrial function and biogenesis and enhanced liver growth after ALPPS. Hepatic FXR signaling were comparable between ALPPS and PVL, while a more profound activation of the intestinal FXR pathway was observed 24 h after ALPPS compared to PVL.
Our study demonstrated for the first time the beneficial role of PP on the postoperative outcomes of ALPPS. We found two further molecular targets, which could be utilized in pharmacological prehabilitation to mitigate the vulnerability after ALPPS. Based on our results the inhibition of CypD could be a pertinent mitochondrial therapy, while the induction of intestinal FXR signaling cascades could further enhance postoperative outcomes following ALPPS.
