This division explores causes of liver injury, such as viruses and toxins and metabolic factors.
The long term goal of the division is to improve outcomes for patients with chronic liver diseases by reducing liver injury and fibrosis and to prevent liver cancer.
In 2009 we continued our investigation of hepatitis C virus (HCV)-induced insulin resistance. Following our results last year, we recently confirmed increased inhibitory phosphorylation of the PI3 kinase/Akt pathway inhibitor PTEN in HCV infected cells.
This suggests a novel mechanism contributing to HCV-induced insulin resistance and a manuscript is currently being drafted. We have known for several years that hepatitis C, a common cause of liver cirrhosis and cancer, also makes people three to four times more likely to develop type 2 diabetes. In studying the insulin resistance of 29 people with hepatitis C, we have now confirmed not only that they have high insulin resistance, a precursor to diabetes, but also that they have little or no insulin resistance in the liver. This is a very surprising finding given that hepatitis C is a liver disease. This observation promises to alter the way we consider hepatitis C pathogenesis and its consequences.
To study whether insulin sensitising drugs increase the effect of interferon on HCV we have established cell culture models of replicating virus that incorporate a luciferase reporter. We have shown that drugs that improve cell insulin sensitivity, especially PPAR- agonists, enhance the ability of interferon to suppress virus replication. We are currently determining optimal combination treatment conditions and are planning experiments to investigate the underlying mechanisms.
Cannabinoid receptors play an important role in the promotion of steatosis and fibrosis in chronic liver disease, but there are no data on their role in hepatitis C. We have showed that in HCV infection, CB1 cannabinoid receptors are upregulated, both in patients with chronic hepatitis C and in Huh7 cells infected with HCV (JFH-1). This suggested that the virus may directly up-regulate the endocannabinoid system. Since HCV replication is closely linked to lipid metabolism increased CB1 signalling should increase lipid storage and favour viral replication, which has been confirmed in in vitro studies.
Fatty Liver Disease
More information coming soon!
Liver fibrosis is the formation of scar tissue in the liver. This can occur from alcohol abuse, hepatitis infection and being overweight.
We have collected patient serum and tissues and are now analyzing for histological, genetic and inflammatory changes associated with the disease process. To reinforce these findings, we are employing mouse models of fibrosis to mechanistically test the role of the identified molecular changes in fibrosis pathology.
These experiments will hopefully pave the way for identifying new therapeutic approaches for treating liver fibrosis.
Genetics of treatment response in hepatitis C
Perhaps the highlight of 2009 has been our seminal paper published in Nature Genetics on the role of host genetics and treatment response in chronic hepatitis C.
This paper which followed a genome wide analysis or host factors that influence response to treatment in chronic hepatitis C infection was part of a multinational genetic consortium headed by the Storr Liver Unit and undertaken at the Westmead Millennium Institute.
In essence, we showed that polymorphisms in a gene (IL28B) are the most crucial determinant of treatment outcome (success or failure) in chronic hepatitis C.
Regarded as one of the most important advances in hepatitis C in the last decade, this discovery is the subject of a University patent and promises to significantly alter patient management.
The paper has received widespread coverage in research journals, lay publications, web sites and in News reports.
A second paper on the use of a novel form of therapy (Yttrium-90 resin microspheres) for the treatment of cancer in the liver was published in the Journal of Clinical Oncology with an editorial comment and has received much attention.
A third report (Journal of Hepatology) on the cost effectiveness of cancer screening and treatment of hepatitis B has had major public health impact and is the basis of a New South Wales Cancer Council and Storr Liver Unit initiative to increase hepatitis B case-finding and treatment in the State.
This study has received widespread interest from other States and Territories.
Disposition of Cancer Drugs
Working with the Department of Medical Oncology and Westmead Hospital we are involved in two projects that seek to develop better dosing regimes for the treatment of serious cancers.
The first project involves screening patients receiving a new generation of anti-cancer drugs called ‘kinase inhibitors’ for a large range of genetic mutations in genes involved in drug metabolism and drug transport using custom gene array technology. These mutations are then statistically compared to adverse treatment outcomes to determine if the poor outcome could have been predicted in advance by a genetic test. Screening for 378 mutations yielded one that was predictive and we are extending this work to determine if this finding can be translated to the clinic for routine patient management.
The second project revolves around the observation that the commonly used breast cancer drug Tamoxifen exerts its beneficial effects through a metabolite formed in the liver called Endoxifen.
Unfortunately, the formation of Endoxifen is highly variable between patients so not all receive the maximum effect of Tamoxifen. We have set up a mass spectrometry-based assay for Endoxifen for use in a targeted dosing study. Patients will have their Tamoxifen dose varied so that the serum Endoxifen level is within a desired range. Patients will be followed long term to see if this improves breast cancer outcomes.