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Title: Association of monocyte activation and microbial translocation with clinical outcomes in patients with cirrhosis
Author: Gurney, Stefan
ISNI:       0000 0004 7657 5177
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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The liver is interposed between the portal and systemic circulations and enriched by a pool of specialised immune cells and its pivotal role in immune defence is increasingly recognised. Cirrhosis disrupts the architecture of the hepatic sinusoidal network, hindering liver immune surveillance function. Coupled with alterations in the gut microbiome and decreased intestinal barrier function, impaired local immunity favours translocation of pattern associated molecular patterns (PAMPs) from the gut. PAMPs activate Toll-like receptors (TLRs), widely expressed in the liver. TLR4 ligation induces chronic inflammation and activates hepatic fibroblasts accelerating cirrhosis. The net effect is a paradoxical syndrome of systemic inflammation and susceptibility to infection, termed: cirrhosis-associated immune deficiency (CAID). Bacterial infections are associated with a four-fold increase in mortality in cirrhosis and may precipitate acute-on-chronic liver failure (ACLF). Prompt diagnosis, risk stratification and aggressive treatment of bacterial infections may improve survival in these patients. I designed an observational pilot study using a biomarker panel, composed of soluble and cell surface markers of immune activation and surrogate markers of bacterial translocation to test the following hypotheses: 1) The biomarker panel would be associated with disease progression in cirrhosis. 2) The biomarker panel would identify bacterial infection in patients with cirrhosis. I demonstrated evidence of monocyte activation and bacterial translocation in cirrhotic patients as compared to healthy controls. Two soluble plasma biomarkers (sTREM-1 and sCD163) were associated with increasing disease severity and identified proven infection with higher accuracy than C-reactive protein in the study population. Increased plasma sTREM-1 identified cirrhotic patients at risk of adverse outcomes: ACLF and death. Univariate Cox regression demonstrated a significant association between sTREM-1 and mortality at 2 years (Hazard Ratio: 1.002) A multivariate Cox regression model did not confirm an independent association between sTREM-1 and 2-year mortality.
Supervisor: Singh, Suveer ; Kelleher, Peter Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral