Temporary hepatic support by extra-corporeal liver cross-circulation

Thesis

There is no temporary hepatic support system that can effectively bridge patients with acute or acute-on-chronic liver failure to either recovery of native liver function or allotransplantation. This has not been achieved by artificial and bio-artificial systems because they do not replicate the many, diverse, and deeply integrated roles of an intact liver. Extra-corporeal liver cross-circulation (ELC), in which a patient’s blood is perfused through a donor liver maintained outside the body on a machine, may provide more comprehensive replacement of hepatic function, whilst avoiding the limitations of auxiliary transplantation. A novel ELC system (‘metra-ELC’) has been developed and evaluated. The donor liver is initially perfused in isolation before connecting to the recipient. During this phase, the perfusate composition must be made safe for connection. Three techniques of ex situ renal replacement therapy during liver perfusion were assessed for this purpose: haemofiltration using a haemoconcentrator was selected for the metra-ELC protocol.

The metra-ELC system was tested with healthy pigs for 3 hours, confirming feasibility in vivo. It was then evaluated for 24 hours using allografts to treat pigs with acute liver failure. ELC effectively replaced lost native hepatic detoxification, excretory, synthetic, metabolic regulatory, and immunologic functions.

Xenografts are a potential source of livers for ELC. Transgenic pig livers (triple glycan knock-out; seven human transgene insertion; porcine endogenous retrovirus inactivation) were perfused ex situ for 48 hours with pooled human whole blood, demonstrating preserved graft viability. The mechanism of liver xenograft-associated thrombocytopenia was investigated during short-duration ex situ isolated xenoperfusion.

ELC using transgenic pig livers was examined in the decedent model. Decedents 1 – 3 underwent ELC with their native livers intact for 72 – 84 hours. The xenografts consistently produced bile and augmented hepatocellular function. Decedent 4 underwent native hepatectomy, followed by 48 hours of ELC with maintenance of normal lactate, pH, international normalised ratio, ammonia, and minimal vasopressor requirement. Thrombocytopenia developed within one hour of starting ELC in all decedents.

Phase-1 clinical trials will determine the safety and feasibility of the metra-ELC system using (i) deceased donor human livers declined for transplantation and (ii) transgenic pig livers to support patients with acute-on-chronic liver failure.

Authors: Sagar, A

• DOI: 10.5287/ora-wvp4040zp
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: acute liver failure; extra-corporeal liver cross-circulation; liver xenotransplantation; normothermic liver perfusion; temporary hepatic support; acute-on-chronic liver failure
• Subjects: Preservation of organs, tissues, etc.; Liver--Transplantation; Transplantation of organs, tissues, etc.; Xenografts; Liver--Failure