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Title: Monocyte dysfunction in alcoholic hepatitis
Author: Vergis, Nikhil
ISNI:       0000 0004 7656 7759
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Severe alcoholic hepatitis (SAH) is the most florid form of alcohol-related liver disease (ALD). It is caused by hepatic inflammation after a prolonged period of heavy alcohol drinking. Causes of death include liver failure and infection. Inflammatory hepatic injury and systemic immunoparesis are therefore key features in disease pathogenesis. This thesis seeks to evaluate this immune dysfunction in detail, focussing on a key component of the innate immune system, the circulating monocyte. A variety of techniques such as flow cytometry, Western blotting and polymerase-chain reaction (PCR) were used to characterise the phenotype and function of monocytes from peripheral blood. Dysfunction was then related to patient outcome and treatments administered by the randomised placebo controlled Steroids and Pentoxyfilline for Alcoholic Hepatitis (STOPAH) clinical trial. Novel findings from this work include the identification of preserved uptake of bacteria by phagocytosis but defective monocyte oxidative burst and bacterial killing of Escherichia coli. Further, I show that the presence of this defect predicts the subsequent development of infection. In addition, this defect is associated with reduced expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme and may be treatable with N-acetylcysteine (NAC). Secondly, I identify an expanded population of an inflammatory intermediate monocyte subset in SAH that bears high expression of chemokine CC chemokine receptor type 5 (CCR-5), and may be amenable to targeted antibody therapy to reduce hepatic inflammation in SAH patients.
Supervisor: Thursz, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral