Liver Disease is the one chronic disorder that's increasing in frequency with a steady rise in deaths each year.

Professor Roger Williams CBE

Alcoholic-related Liver Disease (ArLD) & Susceptibility to Infection

The leading cause of death in patients with end stage liver disease is the development of sepsis. Recurrence of acute infections in this patient group is increasingly common and is ultimately responsible for the development of multiple organ failure. This susceptibility to sepsis is thought to be as a consequence of neutrophil dysfunction and this has been clinically documented in patients with acute liver failure.

It is well-described that alcohol-related cirrhosis (ARC) induces a state of profound immunodeficiency, known as cirrhosis-associated immunodeficiency syndrome (CAIDS). When patients with alcohol-related disease (ALD) present with severe alcoholic hepatitis (SAH), the susceptibility to bacterial infection is further heightened and infection is observed in nearly 50% of cases in the short-term. We have illustrated widespread impairment of antibacterial innate and adaptive T-cells in ALD and have described checkpoint receptors and mucosal-associated T-cells (MAIT-cell) as novel therapeutic targets. Interestingly, we did not observe adaptive T-cell dysfunctions in ARC, suggesting that alternate mechanisms drive immunoparesis in these patients. Infection in ARC precipitates severe complications including septic shock, acute-on-chronic liver failure and multi-organ failure. It is imperative that we delineate common and divergent immune pathways in ARC and SAH to develop specific and targeted immunotherapeutic strategies to reconstitute the host immunity, rather than the continued use of antibiotics in an era of multi-drug resistance and this is the emphasis of the work we are undertaking. In parallel, precision cut-liver slice models3 recapitulating immune injury observed in ALD. The aim of this latter study is to understand the role of mitochondria in orchestrating sterile inflammation, which is believed to be the initial trigger for the inflammatory cascade and also to delineate the role of megamitochondria in ALD which seem to be associated with a more positive clinical outcome.



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