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.