Alcoholic Liver Disease

Liver damage from alcohol and alcoholic liver disease affects thousands of Australians. Find out about recent scientific breakthroughs & how you can help!

Research conducted by: Dr Devanshi Seth and Professor Paul Haber

Project Leader: Professor Geoffrey McCaughan

Recent government and community attention on alcohol related problems highlight their significance as a cause of disease and mortality.

Alcoholic liver disease is the leading cause of alcohol-related death and contributes to 50% of the total burden of liver disease and to 15% of liver transplants. Once the disease is established, abstinence from alcohol use is the only intervention that is associated with improved outcomes. At present, there is no other widely accepted treatment.

Liver damage alcohol is a complex disorder. Many years of regular and excessive drinking lead to a pathological spectrum from alcoholic steatosis (fatty liver) to alcoholic hepatitis, liver fibrosis and cirrhosis. Ethanol initiates liver injury and leads to cellular injury and inflammation.

Chronic alcoholic liver injury also increases the risk of liver cancer.

The progression of Liver Damage from Alcohol is influenced by various factors such as gender, nutrition, viral infection and iron overload. Nonetheless, the genetic and molecular factors that underlie progression to alcoholic hepatitis and cirrhosis are not well understood. Nor is it known why only a minority of heavy drinkers progress to alcoholic cirrhosis.

Dr Devanshi Seth, supported by a $2.5 million grant from the US Institutes of Health, is embarking on a project to test the genes of hundreds of Australians to work out why some heavy drinkers develop cirrhosis and some don't.

Dr Seth's research recently featured in the Sydney Morning Herald, have an in-depth read at the work we are currently undertaking.

Please invest in this vital research and support Centenary's scientists to improve liver health.

Donate to Liver Research and Help 'Liver' Longer Life

Related Links:

- Read about Dr Devanshi Seth ready to test the genes of thousands of drinkers
- Read about how the US Government backs Centenary liver study of heavy drinkers

Research focus

Genetic risk factors for alcoholic liver disease
Having established an international collaborative working group with lead alcohol researchers to create a genome wide association consortium to study the genetic risk factors in heavy drinkers for alcoholic liver disease. Dr Devanshi Seth is leading the Australian involvement by coordinating this group and seeking approval from NIH/National Institute for Alcohol Abuse and Alcoholism (NIAAA) to fund this study. This is to be the first study of its kind in Alcoholic Liver Disease and has attracted well known alcohol researchers from the USA, UK, Germany, France, Switzerland and Australia.

We have in vitro hepatic cell culture models of alcohol that are utilised in functional assays to study mechanisms of action of select molecules. We also have models for chronic and acute alcohol (single and multiple binge) for studying mechanisms of alcohol induced pathogenesis. The models represent the three major modes of alcohol drinking patterns and will be significant in comparing and identifying alcohol induced injuries within this spectrum.

This is a unique research project as there are few groups in Australia working on identifying biomarkers and genetic risk factors for Alcoholic Liver Disease. Projects on genetic risk factors associated with Alcoholic Liver Disease are also in early stages of development.

The diagnostic and therapeutic significance of Osteopontin (Opn) isoforms in liver disease and cancer
We have recently reported that Opn (a molecule involved in inflammation and celluar activity), and several Opn receptors were up-regulated in human Alcoholic Liver Disease.(2) We have cloned three Opn isoforms and have shown that they are involved in liver cell growth, migration and tumor development. Our current studies are investigating the precise mechanisms of Opn action by using molecular and cellular techniques (Opn knockouts, Opn si RNA, signalling transduction) in collaboration with leading scientific colleagues at the University of Sydney (F Braet), University of Adelaide (M Beard) and National Centre for Cell Science, India (G Kundu). These studies aim to define molecules that may be used as markers of disease severity or as targets for development of new treatments.

The role of plasmin and the fibrinolysis pathway in the progression of alcohol-mediated liver injury
We have identified alterations affecting several molecules that influence the breakdown of fibrin in the liver (fibrinolysis) of humans with Alcoholic Liver Disease.(1) We have shown that two of these molecules (annexin A2 and plasminogen activator inhibitor-1) play a role in regulating fibrinolysis in alcoholic liver injury. We are currently using specific inhibitors of these molecules to study the possible therapeutic advantage of these targets. These studies involve collaborations with a number of leading scientists including Professor Phil Hogg (University of NSW) and Professor Mathew Vadas.

Key Publications

1. Seth D, Hogg P, Gorrell MD, McCaughan GW, Haber PS. Direct effects of alcohol on hepatic fibrinolytic balance: implications for alcoholic liver disease. J Hepatol. 2008; 48(4):614-627. doi:10.1016/j.jhep.2007.12.015. [IF: 6.64]

2. Seth D, Cordoba S, Gorrell MD, McCaughan GW, Haber PS. Intrahepatic Gene Expression in Human Alcoholic Hepatitis. J Hepatology. 2006; 45:306-320. [IF: 6.64]

3. Seth D, Maria A. Leo, Peter H. McGuinness, Charles S. Lieber, Brennan Y, Williams R, Wang XM, McCaughan GW, Gorrell MD, Haber PS. Gene Expression Profiling of Alcoholic Liver Disease in the Baboon (Papio hamadryas) and Human Liver. Am J Path. 2003; 163 (6): 2303-2317. [IF: 6.441]

4. Shackel N, Seth D, Williams RW, Gorrell MD, Haber PS, McCaughan GW. The hepatic transcriptome in human liver disease. Comparative Hepatology. 2006; 5:6-54. MS ID: 1156958295883026. Review.

5. Neuman MG, Sha K, Esguerra1 R, Winkler RE, Cooper CL, Hilzenrat N, Wise J, Zakhari S, Seth D, Gorrell MD, Haber PS, McCaughan GW, Leo MA, Lieber CS, Voiculescu M, Buzatu E, Ionescu C, Dudas J, Saile B. Ramadori G. Inflammation and Repair in Viral Hepatitis C. Dig Dis Sci. 2008; 53(6):1468-87. PMID: 17994278. [IF:1.32]

For more publication information, please contact Dr Seth or Professor Haber, or search the available listings on PubMed.