Jones [84] suggested a model of PBC development distinguishing "upstream" from "downstream" events. "Upstream" in this model refers to the causes of BEC loss, ductopenia and cholestasis, which are unique to PBC (and probably unique to each individual patient) and include genetic and toxic factors, infectious agents, and immune-mediated events. "Downstream" of these initiating mechanisms, nonspecific pathologic events occur resulting in bile duct damage, hepatocyte injury, inflammation, and fibrosis independently of the primary -individual variablecause. "Downstream" events such as hydrophobic bile salt retention aggravate the underlying injury, further promoting hepatic and cholangiocellular damage [205] .