The course of apoptotic markers in patients with PBC peaks in the middle stages of the disease (stages II-III) rather than in earlier stages. This could solely support a role of apoptosis as a trigger for loss of self-tolerance, with probably only a little number of cells being affected rather than being the main initiating event in PBC. In a putative positive feedback loop, apoptosis, autoreactive T cell response, cholestatic bile salt retention, and failed replicative homeostasis may result in the destruction of BECs and bile duct structures.