Alcoholic Liver Disease
Key team members (PIs): Dr Stephen D Ryder, Dr Indra Neil Guha, Dr Martin W James, Dr Emilie Wilkes, Prof Guruprasad Aithal, Dr Jane Grove, Dr Philip Kaye, Prof Mohammad Ilyas and Mr Andy Wragg
Alcoholic liver disease including its severe manifestation, alcoholic hepatitis accounts for a majority of decompensated cirrhosis that are hospitalised. We have been developing innovative methods of stratifying people at risk of progressive disease in collaboration with East Midlands Academic Health Science Network (AHSN) and evaluating new liver tissue and serum based tests to identifying those at risk of death from alcoholic hepatitis in collaboration with Nottingham Molecular Pathology Node (NMPN). Our patient advisory group collaborated with The James Lynd Alliance to identify and prioritise the questions that need to be answered by research. We were one of leading centres in enrollment for the recently completed large landmark Randomised Controlled Trial, STOPAH.
The association of alcohol and liver disease has long been known but the pathogenic mechanisms of alcoholic liver disease (ALD) involving genetic, environmental, metabolic, and immunologic factors is poorly understood. Chronic alcohol intake results in damage to the liver where it is primarily detoxified in hepatocytes. This progresses from simple steatosis (fatty liver), through stages of steatohepatitis, followed by fibrosis and then cirrhosis to hepatic failure. In addition, alcohol abuse can contribute to the development of hepatocellular carcinoma and causes injury to the brain, cardiovascular system, and other organs. The fate of alcohol, its metabolites and by-products, and the cellular responses to these molecules, is central to elucidating the component pathways involved in disease development and progression as well as for the identification of therapeutic targets.
- Toxic alcohol is usually removed by oxidation in the liver which leads to altered cellular metabolic pathways.
- Steatosis, the initiating step in alcoholic liver disease (ALD), arises as a consequence of the sequestration of resulting excessive fatty acids, as lipids.
- Alcohol causes increased gut permeability to endotoxin which leads to inflammation and production of reactive oxygen species (ROS).
- Oxidative stress arises from ROS generation during ethanol oxidation and from subsequent responses.
- Infiltration of inflammatory immune cells into the liver gives rise to alcoholic steatohepatitis.
- The effect of alcohol on inflammation and fibrosis is coordinated by Kupffer cells, activated by endotoxin, which release cytokines and chemokines, notably TNF-α.
- The transformation of hepatic stellate cells to myofibroblasts that overproduce collagen is a central feature of alcohol-induced progression of ALD to fibrosis through to cirrhosis.
- The cellular changes induced by alcohol are also, in part, dependent on genetic factors (influencing metabolic and immunologic processes) and, in part, are modulated by the presence of comorbid conditions.
We are developing research projects to identify novel biomarkers associated with progression of alcoholic liver disease and are collaborating with researchers involved in the STOPAH study http://www.wikijournalclub.org/wiki/STOPAH
|Professor Guruprasad Aithal||Biography Professor Guruprasad P. Aithal graduated with MBBS from Kasturba Medical College, Manipal, MD (Internal Medicine) from Bangalore Medical College, Bengaluru, India and completed his specialist training in Gastroenterology in the Northern…|