Published online Dec 27, 2020. doi: 10.4254/wjh.v12.i12.1198
Peer-review started: June 15, 2020
First decision: July 30, 2020
Revised: August 26, 2020
Accepted: October 28, 2020
Article in press: October 28, 2020
Published online: December 27, 2020
Liver reduction is routinely performed as curative treatment of primary liver cancer and liver metastases, but its use remains limited as liver regeneration requires a minimum of 30% functional parenchyma.
As such, less than 30% of patients with hepatocellular carcinoma are eligible for surgery, and this is connected to the underlying chronic inflammation and the preoperative chemotherapies. Post-surgery accumulation of liver injuries, excessive portal blood inflow, and oxidative stress are the main causal factors suspected to give rise to liver failure, but the molecular mechanisms that block liver regeneration remain unclear.
Our objective was to monitor, step by step, the molecular events in relation to liver regeneration after extended liver resection and so to clearly delineate the blocking points that prevent liver regeneration.
Post-operative liver failure was modelled in the rat by 90% liver resection. Animals undergoing simple laparotomy and 70% hepatectomy were used as control. All animals received glucose infusion to avoid post-operative hypoglycemia. Animals were sacrificed every 3 h for the first 24 h and every 24 h for the following 7 d. Blood and liver samples were collected at the time of sacrifice and used to investigate liver function, morphology, and regeneration by biochemical methods.
Twenty-nine percent of all deaths occurred in the first 24 h in link with massive liver injuries and impaired liver function. For all other deaths, the temporal sequence of events that prime liver regeneration after 90% liver resection occurred properly, but S phase progression and mitosis were delayed by 24 h in conjunction with the rise in p27 (Kip1) and p21 (Waf1/Cip1) cell cycle inhibitor levels.
The cyclin/cyclin-dependent kinase inhibitors of the Cip/Kip family are critical regulators of the liver regeneration following extended hepatectomy.
The use of extracorporeal support devices along with inhibitors of p21 and p27 should be evaluated to manage liver failure after extended hepatectomy.