Figure 4 Sequential model for primary biliary cirrhosis pathogenesis. In this model one (or more) processes causes biliary epithelial cell damage, which in turn leads to ductopenia (“upstream” phase). The cholestasis that results from this effect induces a subsequent series of secondary effects, the nature of which is independent of the cause of the upstream process (“downstream” phase). The sequelae include biliary fibrosis and the characteristic clinical features of cholestasis. There is growing interest in a more generic effect of cholestasis on clinical outcomes (including cardiovascular morbidity and mortality) that may result from pro‐inflammatory effects. EMT, Epithelial to mesenchymal transition.