Ex Vivo Human Liver Hyperperfusion Model: Study Protocol to Understand the Pathophysiology and Identify Strategies for Reduction of Small-for-Size Syndrome

Introduction

Liver has the unique ability to regenerate following surgical resection or partial liver transplantation. This underpins the surgical practice of cancer surgery and Living donor liver transplantation. A rate limiting factor for increased application of these techniques is the minimum volume of liver required for survival. Regeneration is triggered by increased portal blood flow and regenerating factors like hepatocyte growth factor through the remnant liver. However, an excessive blood flow, through a relatively smaller remnant liver has been postulated to cause injury to hepatocytes and failure to regenerate. This results in liver failure, a set of signs and symptoms together labelled as “small-for-size syndrome”. The underlying pathophysiology of injury and failure to regenerate is poorly understood. Most of the research is based on small animal studies, findings of which may not translate to human liver. The premise of this article is that a laboratory-based small-for-size graft model using human liver will enable a better understanding of the pathophysiology of increased blood flow, injury and regeneration. It is an opportunity to generate more directly translatable information.

Methods and analysis

Ex vivo human liver hyperperfusion model uses machine perfusion circuits to reproduce anatomical and physiological changes in livers that happen after a major resection or partial transplant. In this pilot study, whole liver normothermic machine perfusion is carried out for 4 hours followed by 6 hours of left lateral liver normothermic machine perfusion. This allows us to study effects and explore the role of altered mechanical forces (increased blood flow/pressure) on regeneration. Modulation of the proposed key mechanical force sensor (PIEZO1) is performed using agonist and antagonist drugs during this split liver perfusion.

Ethics

The protocol was approved by Health Research Authority and Health and Care Research Wales (23/NW/0361). It is endorsed by NHS Blood and Transplant, Research Operational Feasibility Group.