Humphrey J.F. Hodgson

Abstract: Background: Histidinaemia is an autosomal recessive disorder affecting the hepatic enzyme histidine ammonia lyase (histidase) resulting in elevated plasma and urinary histidine and is prototypic of a series of hepatic cytosolic enzyme defects.Aims: To characterise the physiology of murine histidinaemia with respect to histidine excretion and catabolism, and explore the potential for manipulating cellular and whole body histidase metabolism by gene transfer.Materials and Methods: We studied his/his mice which have a G to A substitution in the gene encoding histidase, using both in vitro transduction of isolated hepatocytes by lipofection with wild‐type histidase cDNA, and in vivo transduction of whole liver using a retroviral construct.Results and Conclusion: Histidase cDNA expression restored histidase activity in vivo and in vitro towards normal levels, demonstrated both at the cellular level and by whole body metabolic studies, establishing the potential of this model for the development of new gene therapeutic approaches.

Abstract:  Previous studies have demonstrated that alginate encapsulation of proliferating hepatocyte‐derived cell lines (e.g., HepG2 cells) enhances the expression of differentiated hepatocyte function compared with conventional monolayer culture. Furthermore, such capsules have the advantage of cryopreservability, and can be readily manip‐ulated, e.g., for the charging of extracorporeal devices. We utilize a rabbit model of acute liver failure caused by acetaminophen administration to rabbits pretreated to enhance cytochrome P450 enzyme activity, and demonstrate that encapsulated HepG2 cells, in an extracorporeal chamber, perfused by rabbit plasma separated on‐line at a rate of 2–5 mL/min, and perfused over cells at 40–60 mL/min, improve systemic parameters of liver failure (diastolic blood pressure and transjugular venous oxygen saturation). Such encapsulated cells have the potential to be developed for extracorporeal liver support systems for acute liver failure.

Primary hepatocellular cancer is a disease with a poor prognosis for which there is little consensus on treatment and a paucity of comparative trials. The coexistence of cancer with cirrhosis complic...