Current Perspectives on the Molecular and Clinical Relationships between Primary Biliary Cholangitis and Hepatocellular Carcinoma

Abstract

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterised by the immune-mediated destruction of small and medium intrahepatic bile ducts, with variable outcomes and progression. This review summarises the state of the art regarding the risk of neoplastic progression in PBC patients, with a particular focus on the molecular alterations present in PBC and in hepatocellular carcinoma (HCC), which is the most frequent liver cancer in these patients. Major risk factors are male gender, viral infections, e.g., HBV and HCV, non-response to UDCA, and high alcohol intake, as well as some metabolic-associated factors. Overall, HCC development is significantly more frequent in patients with advanced histological stages, being related to liver cirrhosis. It seems to be of fundamental importance to unravel eventual dysfunctional molecular pathways in PBC patients that may be used as biomarkers for HCC development. In the near future, this will possibly take advantage of artificial intelligence-designed algorithms.

Keywords: HBV; HCC; HCV; PBC; UDCA; liver cancer; risk factors; sex difference.

Figure 1

Main mechanisms involved in HCC development in PBC patients. AMA autoreactive antibodies (anti-PDC-E2) trigger cholangiocytes, inducing apoptosis and dysregulation of both innate and adaptive immunity by recruiting immune cells. This leads to an increased release of cytokines, e.g., IL6, and increased ROS production. In hepatocytes, the inflammatory microenvironment activates protumoural molecular pathways, e.g., STAT3, NF-kB, NOTCH signalling. The increased level of intrahepatic BA activates FXR and further promotes HCC development. Other parenchymal cells, such as CAFs and protumoural macrophages, are also stimulated by cytokine release, helping with HCC development. PBC, primary biliary cholangitis; AMA, anti-mitochondrial autoantibody; ROS, reactive oxygen species; IL6, interleukin 6; FXR, Farnesoid X receptor; STAT3, signal transducer and activator of transcription 3; CAF, cancer-associated fibroblast; PDC-E2, pyruvate dehydrogenase complex. Created with BioRender.com.

Figure 2

Increased conversion of primary into secondary bile acids is affected by gut microbiota dysregulation in PBC patients. This alteration leads to leaky gut and alters hepatic immune cells, thereby reducing immunosurveillance and promoting tumourigenesis. BAs, bile acids; TLR4, toll-like receptor 4; CXCL16, Chemokine (C-X-C motif) ligand 16; NKT, natural killer T cells; TAM, tumour-associated macrophages. Created with BioRender.com.