Sequence of events leading to primary biliary cholangitis

Abstract

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that is observed more frequently in middle-aged women. This disorder is considered an autoimmune disease, since liver injury is sustained by the presence of self-directed antimitochondrial antibodies targeting the bile duct cells. The prognosis may vary depending on an early diagnosis and response to therapy. However, nearly a third of patients can progress to liver cirrhosis, thus requiring a liver transplant. Traditional immunosuppressive therapies, commonly employed for other autoimmune diseases, have limited effects on PBC. In fact, dramatic functional changes that occur in the biliary epithelium in the course of inflammation play a major role in perpetuating the injury. In this minireview, after a background on the disease and possible predisposing factors, the sequential cooperation of cellular/molecular events leading to end-stage PBC is discussed in detail. The rise and maintenance of the autoimmune process, as well as the response of the biliary epithelia during inflammatory injury, are key factors in the progression of the disease. The so-called "ductular reaction (DR)", intended as a reactive expansion of cells with biliary phenotype, is a process frequently observed in PBC and partially understood. However, recent findings suggest a strict relationship between this pathological picture and the progression to liver fibrosis, cell senescence, and loss of biliary ducts. All these issues (onset of chronic inflammation, changes in secretive and proliferative biliary functions, DR, and its relationship with other pathological events) are discussed in this manuscript in an attempt to provide a snapshot, for clinicians and researchers, of the most relevant and sequential contributors to the progression of this human cholestatic disease. We believe that interpreting this disorder as a multistep process may help identify possible therapeutic targets to prevent evolution to severe disease.

Keywords: Antimitochondrial antibody; Biliary proliferation; Biliary secretion; Cellular senescence; Cholangiocyte; Ductular reaction; Liver fibrosis; Primary biliary cholangitis.

Figure 1

From immune mediated damage to bile acids injury. In primary biliary cholangitis the inflammatory process induces a decrease in chloride-bicarbonate exchangerexpression. This in turn determines a reduction of bicarbonate film (bicarbonate umbrella) on the canalicular portion of bile duct cells, exposing them to hydrophobic bile acids injury. AE2: Chloride-bicarbonate exchanger.

Figure 2

Central role of ductular reaction in the progression of primary biliary cholangitis. Ductular reaction contributes to the activation of hepatic stellate cells and simultaneously favours a cell senescent phenotype. These events support the ductopenic/cirrhotic evolution of liver tissue during this cholestatic disease. PBC: Primary biliary cholangitis; SASP: Senescence-associated secretory phenotype.