Immune-mediated liver diseases: programmed cell death ligands and circulating apoptotic markers.
Primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis are the three major immune-mediated liver diseases. The etiologies of primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis are largely unknown, but seem to be influenced by genetic and environmental factors. Autoantibodies can be found in nearly all patients with primary sclerosing cholangitis and autoimmune hepatitis, and in the vast majority of patients with primary sclerosing cholangitis. In addition, autoimmune hepatitis is associated with high concentrations of serum globulins. Enhanced liver cell death by apoptosis has been described in all of these liver diseases, although the precise mechanisms remain unclear. In general, apoptosis can be initiated via an extrinsic pathway that is triggered by engagement of death receptors on the cell surface, or via an intrinsic pathway that is induced by mitochondrial injury and is influenced by members of the Bcl-2 family. In both pathways, effector caspases are finally activated that cleave and degrade cell structures, resulting in the release of apoptotic products into the circulation. New diagnostic tests can detect these apoptotic markers and programmed cell death ligands such as Fas and Fas-ligands, nucleosomes, caspases, cytokeratin fragments, macrophage migration inhibitory factor, soluble intracellular adhesion molecule, natural killer cells group 2D and programmed death ligands. Several of these markers have been found to be altered in tissue and/or blood of immune-mediated liver diseases, some also in nonimmune-mediated liver diseases. Beyond their potential usefulness as additional diagnostic markers, they may be valuable for the estimation of disease severity and therapy monitoring. This review summarizes current knowledge on apoptotic mechanisms, death receptor ligands and circulating apoptotic markers in immune-mediated liver diseases.
Kremer
Andreas E
AE
AMC Liver Center, S1-164, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands. a.e.kremer@amc.uva.nl
Rust
Christian
C
Eichhorn
Peter
P
Beuers
Ulrich
U
Holdenrieder
Stefan
S
D017209:Apoptosis; D001327:Autoimmune Diseases / Q000097:blood* / Q000175:diagnosis / Q000276:immunology / Q000628:therapy; D015415:Biomarkers / Q000097:blood*; D006801:Humans; D008107:Liver Diseases / Q000097:blood* / Q000175:diagnosis / Q000276:immunology / Q000628:therapy; D008991:Monitoring, Physiologic / Q000379:methods*
D015415:Biomarkers