Metabonomic and genetic profiling in severe alcoholic hepatitis

Liver disease is the only major cause of mortality and morbidity on the rise in the United Kingdom. Alcoholic liver disease (ALD) accounts for over half of liver related deaths. It is affecting younger and younger patients. Related hospital admissions for those under 30 have more than doubled over 10 years. Alcohol causes liver disease by triggering inflammation, over time this leads to severe scarring of the liver called cirrhosis. Patients with cirrhosis may develop jaundice and liver failure; this is called decompensation. Some patients who drink alcohol excessively, with or without cirrhosis, develop severe inflammation, which leads to liver failure very rapidly. This condition is called alcoholic hepatitis. It can be very difficult to tell decompensated cirrhosis from alcoholic hepatitis, as the two conditions look very similar, doing so may require a liver biopsy. It is important to be able to tell them apart, as the treatment is different.
Patients with alcoholic hepatitis have a high risk of death. Despite the best medical treatments approximately one-third of these patients will die within a month. Currently available treatments for the condition have significant side effects and only appear to work in some patients. At the present time it is difficult to accurately identify those patients who will and those patients who will not respond to current treatments.
Although many people drink alcohol to excess not all of them develop cirrhosis or alcoholic hepatitis. Studies following twins have shown that people's genes can partly explain this. It has proven difficult however to identify the specific genetic changes which may make an individual susceptible to alcohol-induced liver damage.
Researchers at Imperial College London, led by Professor Mark Thursz, are studying the metabolism of patients who develop alcoholic hepatitis using advanced techniques to analyse blood samples. They will compare the results from different groups of patients to identify specific changes that identify patients with alcoholic hepatitis. They will also see if it is possible to predict which patients with alcoholic hepatitis will do well with treatment.
At the same time, with the help of researchers based at Newcastle University, University College London and the Sanger Institute in Cambridge, the same group will look at DNA sequences from patients who drink alcohol to excess. Around half of these patients have alcoholic hepatitis and the remainder have no liver disease. This large study will help to identify the changes in genes that are important in predisposing individuals to liver damage if they drink too much.
The results of this research will provide insights into the disease and pave the way for better diagnosis and the opportunity to develop novel treatments for the condition, which are badly needed.

This study aims to elucidate the metabolic and genetic factors that contribute to the pathogenesis of alcoholic hepatitis. It will utilise the clinical data, DNA and serum samples collected as part of the STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH) study. Serum samples drawn from patients with severe alcoholic hepatitis (modified discriminant function >32) will undergo metabonomic analysis using 1H-NMR and mass spectrometry profiling techniques. A control population of patients with chronic liver disease (compensated and decompensated) will be used. Spectral profiles will be analysed using multivariate statistical analysis to identify changes in metabolites able to discriminate between the study populations. Sub-group analysis will be undertaken to identify metabolic markers predictive of outcome or response to treatment.
DNA samples from the same group of patients with alcoholic hepatitis have undergone exome-wide single nucleotide polymorphism (SNP) genotyping at the Sanger Institute, Cambridge. Samples from a group of alcohol dependent individuals without evidence of liver disease have also been genotyped. The genetic data will be used to perform a genetic association study to identify SNPs associated with the development of progressive liver disease.
For the alcoholic hepatitis cohort datasets will be combined to generate insights into the relationship between genotype, clinical and metabolic phenotype. The STOPAH clinical data set will be used to test the ability of currently employed scoring systems to predict mortality and treatment response and compare their performance to a novel scoring system that incorporates metabonomic data.

The thrust of this application is the identification of metabolic and related genetic changes are associated with severe alcoholic liver disease. Through this we would envisage realising benefit for several groups of individuals over short, medium and longer-term horizons.
1. Academia
Impact upon and benefit to those working the field of alcoholic liver disease are outlined above. They include those working on biomarker discovery, animal models and the conduct of clinical trials in alcoholic hepatitis.
2. Commercial - diagnostics
We anticipate identifying a small panel of metabolites with diagnostic and potentially prognostic promise. We will aim to develop simplified assays to allow quantification on a larger scale. Working with Imperial Innovations we would then look to protect the intellectual property and commercialise the tests using our extensive network of commercial diagnostics companies. In addition to realising benefit for commercial partners achieving this aim would represent a significant success for the host institution and the MRC.
3. Commercial - pharmaceutical
Information regarding the metabolic and genetic signatures which diagnose or predispose to severe AH is likely to be of interest to those seeking to understand the pathophysiology of the condition in order to generate novel treatments. Such individuals may be engaged in research in either academic or commercial settings.
4. Clinical - doctors and patients
Deployment of newly discovered biomarkers in clinical practice will mean that patients, and their treating clinicians, will benefit from more accurate diagnosis and targeted treatment. The ability to accurately determine prognosis will help identify groups of patients where the use of treatments with significant potential side effects or high resource usage implications is justified.
5. Public health and health policymakers
Identification of genetic variants predisposing to progressive ALD will potentially facilitate risk stratification for this in excess alcohol consumers. This, in turn, may afford the opportunity to target treatments or interventions to those at highest risk in order to maximise health gains and cost effectiveness.