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Liver transplantation is the preferred treatment option for end stage liver disease. The demand for donor livers greatly exceeds the supply and organs from more marginal donors are being considered for transplantation. An important group of such donor livers are those obtained by donation after circulatory death (DCD). These livers are more susceptible to cold preservation injury and their use has been associated with a slight increased incidence of primary non‐function in Australia. More importantly, biliary complications such as ischaemic type biliary strictures (ITBS) are more prevalent in recipients receiving a DCD liver resulting in a higher rate of re‐ intervention, re‐transplantation and inferior long‐term graft survival. This thesis describes a series of studies examining potential factors responsible for the development of biliary injury. Furthermore, a normothermic hepatic machine perfusion protocol was established at our centre and used as a platform to study the development of biliary injury in human livers. A review of all adult Australian organ donors between 2005 and 2014 revealed that there was a 17% increase in the number of livers deemed unsuitable for transplantation, mainly attributable to the rise in DCD donors. Over the study period, only 62 (13%) livers from DCD donors were used for transplantation. In addition, advanced donor age, obesity as well as diabetes were associated with liver non‐use. The pathophysiology of biliary stricture formation following transplantation remains largely unknown and better insights into the sequence of events leading to their development are urgently needed. The work in this thesis has shown that endotoxins, in the form of lipopolysaccharides (LPS), are potent inducers of small but not large bile duct injury. Following six hours of administration of 1mg/kg LPS, small bile ducts were severely affected with biliary epithelial cells showing significant degenerative changes, infiltration of inflammatory cells and ductular proliferation. This was further associated with an increased permeability of the blood‐biliary‐barrier and the development of clinical features of cholestasis. Macrophages are activated by LPS and to determine their role in LPS‐induced biliary injury, an additional group of animals was pre‐treated with clodronate liposomes prior to LPS exposure. These macrophage depleted animals showed a similar degree of biliary injury in response to LPS, which suggests that macrophages don’t play a crucial role in the pathophysiology of LPS‐induced injury.

Optimising outcomes after liver transplantation