Primary sclerosing cholangitis--the arteriosclerosis of the bile duct?

Abstract

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of unknown aetiology affecting the large bile ducts and characterized by periductal fibrosis and stricture formation, which ultimately result in biliary cirrhosis and liver failure. Arteriosclerosis involves the accumulation of altered lipids and lipoproteins in large arteries; this drives inflammation and fibrosis and ultimately leads to narrowing of the arteries and hypoperfusion of dependent organs and tissues. Knowledge of the causative factors is crucial to the understanding of disease mechanisms and the development of specific treatment. Based on pathogenetic similarities between PSC and arteriosclerosis, we hypothesize that PSC represents "arteriosclerosis of the bile duct" initiated by toxic biliary lipids. This hypothesis is based on common molecular, cellular, and morphological features providing the conceptual framework for a deeper understanding of their pathogenesis. This hypothesis should stimulate translational research to facilitate the search for novel treatment strategies for both diseases.

Figure 1

Model of the Development of Arteriosclerosis. (1) Low-density lipoprotein (LDL) moves into the subendothelial space and becomes oxidized. (2) Inflammatory cells are recruited into the vessel wall via induced endothelial adhesion molecules (VCAM, ICAM) and (3) take up oxidized LDL and become foam cells. (4) Activation of macrophages leads to the release of inflammatory cytokines, chemokines, inflammatory molecules and reactive oxygen species leading to (5) the perpetuation of inflammation and tissue damage. (6) Antigens presented by macrophages and dendritic cells trigger the activation of cytotoxic T-cells, which produce Th-1 cytokines and heat-shock proteins as well as TGF-β, which activates smooth-muscle cells (7).

Figure 2

Model of the Development of Primary Sclerosing Cholangitis. (1) Toxic bile (e.g. toxic bile acids, oxidized/modified cholesterol and phospholipids) causes (2) the induction of a reactive phenotype of cholangiocytes characterized by de novo expression or overexpression of adhesion molecules, inflammatory and profibrogenetic cytokines, and receptors (e.g. TNF-α, TGF-β, toll-like receptors, VCAM, CD44). (3) Proinflammatory cytokines induce leakiness of the bile duct epithelium leading to regurgitation of bile into the portal space, leading to (4) transmigration of (5) neutrophils and (6) lymphocytes and their activation. Bile duct epithelial cell-derived growth factors and cytokines (e.g. TGF-β, PDGF) and reactive molecules released from neutrophils (7) (e.g. ROS, 4-HNE) stimulate extracellular matrix production, accumulation, and proliferation of (8) periductal myofibroblasts, leading to periductal fibrosis and in consequence to vascular deprivation of the bile duct system itself, causing (9) death of bile duct epithelial cells. Bile duct epithelial cell-derived growth factors (e.g. EGF, HGF, PDGF, BDNF) may also activate and recruit bone marrow derived progenitor cells into the portal field probably engaged in ductal reaction and proliferation of periductal MFBs.