Why do some heavy drinkers get liver cirrhosis and some don’t?

Centenary, Media releases

The US government is investing $2.5 million in a Sydney-based study to determine the role of genetics in alcoholic liver disease.

The study, announced today, should lead to better diagnosis and treatment of the condition – a silent epidemic that costs $3.8 billion a year in Australia alone.

“We still do not understand why only a proportion of moderate to heavy drinkers get liver cirrhosis,” says Dr Devanshi Seth, from the Royal Prince Alfred (RPA) Hospital’s Drug Health Services and the Centenary Institute who conceived and now leads the project.

“Nothing so far has been able to explain the unpredictability of why some people get cirrhosis and others who drink equal amounts don’t,” she says.

Dr Devanshi Seth Credit: Sydney Local Health District

She and her colleagues will soon start testing the genes of hundreds of Sydney-siders and thousands of others in six countries with the support of the grant from the US National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health (NIH).

“Apart from alcohol consumption, several contributory factors, including diet, lifestyle, mental health, viral infection and gender, influence the risk of developing cirrhosis,” Dr Seth says. There is evidence that genes influence the development and progression of this disease.

“We hope that by analysing the genes in a large international group comprising thousands of drinkers we can detect the genetic risks that predispose some drinkers to get alcoholic liver cirrhosis.”

Like other multi-factorial diseases, alcoholic liver cirrhosis is controlled by a number of genes, each of which makes a small overall contribution. Previous genetic searches have been inconclusive because the studies performed to date have generally been too small to yield definitive results.

“The lack of specific markers for diagnosis and effective treatment compound the burden of the disease. That is why this research is so important,” says Dr Seth. “The results will help us identify and treat the people most at risk from drinking.”

While the disease has been predominantly seen among men over 50 years of age, it is becoming more frequent worldwide among younger adults and young women.

“This study is an important addition to Centenary’s liver research effort,” says Professor Mathew Vadas
Executive Director of the Centenary Institute.

Dr Devanshi Seth Credit: Sydney Local Health District

“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,” he says.

Dr Seth leads several other projects on alcoholic liver disease in collaboration with Professors Haber and Geoff McCaughan at the RPA and Centenary Institute.

Their group is one of few groups comprehensively addressing issues related to alcohol, ranging from genetics, to clinical, biomedical, molecular, mental health co-morbidities through to treatment approaches.

“We frequently look at the social costs to the community, such as violence and vehicle accidents, but we are not looking enough at the direct damage to the drinkers themselves.  Health problems related to alcohol, especially chronic effects, are often overlooked because alcohol is so culturally embedded in our society,” says Dr Seth

Dr Seth formed the GenomALC Consortium to conduct this large study with Australian colleagues as well as clinicians and researchers from the USA, UK, Germany, Switzerland and France.

“In Sydney, we will recruit hundreds of participants over the next three years through the clinics at four hospitals – Royal Prince Alfred, Liverpool, Concord and Fairfield. Half our group will have cirrhosis and the other half, the control group, will have been heavy drinkers for 10 years but be free of liver disease.”

A pilot feasibility study for recruitment at these hospitals has already been undertaken through funding from Lion Nathan’s Alcohol Health and Research Grant Scheme

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Background information

Liver disease

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

Alcoholic liver disease (ALD) 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.

ALD is a complex disorder. Many years of regular and excessive drinking lead to a pathological spectrum from alcoholic steatosis to alcoholic hepatitis, liver fibrosis and cirrhosis. Ethanol initiates liver injury by generation of oxidative and non-oxidative ethanol metabolites and via endotoxin leading to cellular injury and inflammation. Alcoholic steatosis (fatty liver) occurs in more than 90% of drinkers and was considered a benign lesion with a favourable prognosis on alcohol abstinence but recent studies show that inflammatory changes signify an increased risk for more serious liver disease. With continuing alcohol use, the disease progresses via impairment of hepatic regeneration, and increasing fibrogenesis leading to cirrhosis and its complications. Chronic alcoholic liver injury also increases the risk of liver cancer and hepatitis C.

The progression of ALD 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. Several groups have sought evidence for an underlying genetic basis for this susceptibility but this remains unproven.

More at: http://www.centenary.org.au/p/ourresearch/liver/liverimmunobiology/alcoholicliver/

About Devanshi Seth

Dr Seth, BSc (Hons), MSc (Agriculture), MPH, PhD (Genetics), is senior scientist and clinical senior lecturer at the Drug Health Services (DHS) at the RPA, the Centenary Institute, and at the University of Sydney. Dr Devanshi Seth has more than 25 years of training and experience as a molecular biologist in the biotechnology industry and more recently in public health, with 10 years of contribution towards alcohol research. Dr Seth has several publications in peer reviewed high impact journals in this area. Her work is being increasingly recognised internationally through invitations to chair and present at international meetings and has generated several national and international collaborations. She also has long term collaboration with Prof Geoff McCaughan, Director AW Morrow Gastroenterology & Liver Clinic, RPAH and Prof Paul Haber, Medical Director, DHS, Sydney South West Area Health Service (SSWAHS). Several current research interests in Dr Seth’s group encompass from basic understanding of molecular pathogenesis to genetic and other risk factors for ALD as well as treatment options for patients with ALD.

More at: http://sydney.edu.au/medicine/people/academics/profiles/devanshi.php

About the Centenary Institute:

The Centenary Institute is an independent leader in medical research seeking improved treatments and cures for cancer, cardiovascular and infectious diseases.

We are working to discover new prevention, early diagnosis and treatment options to enable each generation to live longer, healthier lives than the one before.

Centenary’s affiliation with the RPA Hospital and the University of Sydney means that our discoveries can be quickly applied to the fight against disease in the clinic.

More at: http://www.centenary.org.au/