Novel and Emerging Therapies for Cholestatic Liver Diseases

Jordan Goldstein; Cynthia Levy


Liver International. 2018;38(9):1520-1535. 

In This Article


Cholangiocytes recognize the presence of pathogens through pattern recognition receptors (PRR), such as the toll-like receptors, which are activated in the presence of pathogen-associated molecular patterns (PAMPs). Activation of these PRRs triggers a signalling cascade which results in the expression of various cytokines and chemokines, immunoglobulins and adhesion molecules.[17] Histological samples from PBC and PSC patients show a strong lymphocytic predominance, with the majority being CD4+ T cells, along with the presence of CD8+ T cells, B cells, macrophages and natural killer cells. These immune cells are able to release a number of mediators with diverse activity including pro- and anti-inflammatory, angiogenic, fibrogenic and proliferative, which are directly affected by bile acids.[18] For instance, accumulation of hydrophobic bile acids can blunt the inflammatory cytokine response, inhibit lymphocyte proliferation and impair clearance of apoptotic cholangiocytes. The ineffective removal of apoptotic bodies is important in the pathogenesis of immune-mediated liver diseases, since the exposure of intracellular components generates activation of the immune system by unrecognized self-antigens. This understanding remains the basis for consideration of immunomodulatory therapies for cholestatic liver diseases, including drugs that regulate T-cell activation, such as abatacept, or deplete the pool of B cells, such as rituximab.