Primary biliary cirrhosis: From bench to bedside

Abstract

Primary biliary cirrhosis (PBC) is a chronic nonsuppurative destructive intrahepatic cholangitis leading to cirrhosis after a protractive non cirrhotic stage. The etiology and pathogenesis are largely unknown and autoimmne mechanisms have been implicated to explain the pathological lesions. Many epitopes and autoantigens have been reported as crucial in the pathophysiology of the disease and T and B cells abnormalities have been described, the exact pathways leading to the destruction of small intrahepatic ductules are mostly speculative. In this review we examined the various epidemiologal and geoepidemiological data as well as the complex pathogenetic aspects of this disease, focusing on recent in vivo and in vitro studies in this field. Initiation and progression of PBC is believed to be a multifactorial process with strong infuences from the patient's genetic background and by various environmental factors. The role of innate and adaptive immunity, including cytokines, chemokines, macrophages and the involvement of apoptosis and reactive oxygen species are outlined in detailed. The current pathogenetic aspects are presented and a novel pathogenetic theory unifying the accumulated clinical information with in vitro and in vivo data is formulated.A review of clinical manifestations and immunological and pathological diagnosis was presented. Treatment modalities, including the multiple mechanisms of action of ursodeoxycholate were finally discussed. Core tip: Primary biliary cirrhosis (PBC) is a chronic nonsuppurative destructive intrahepatic cholangitis leading to cirrhosis of largely unknown pathophysiology. We examined the epidemiological and geoepidemiological data as well as the pathogenetic aspects of PBC. A novel pathogenetic theory unifying the accumulated clinical information with in vitro and in vivo data is formulated.

The Autoimmune Susceptibility Gene C5orf30 Regulates Macrophage-Mediated Resolution of Inflammation

“…Macrophage-mediated inflammation and tissue damage are features of many chronic inflammatory diseases (63,64). To date, C5orf30 has been associated with two autoimmune diseases, RA and primary biliary cirrhosis, which have a shared pathogenesis, including the skew of macrophages to the inflammatory phenotype and disease progression associated with increased local recruitment and activation of macrophage and fibroblast cells (17,18,65,66).…”

The clinical value of the monocyte to high-density lipoprotein cholesterol ratio and alkaline phosphatase-to-platelet ratio in primary biliary cholangitis

“…[ 29 ] In the livers of PBC patients, monocytes comprised approximately 30% of the cells that infiltrated the portal vein area, and mostly concentrated around damaged bile ducts. [ 30 ] Additionally, the number of CD14 low CD16 + monocytes were positively associated with disease progression, particularly in PBC patients with liver cirrhosis. Of course, various subsets of immune cells, including lymphocytes, dendritic cells and natural killer cells, etc., have been demonstrated to infiltrate the venous regions of patients with PBC.…”

Mesenchymal Stem Cells as New Therapeutic Agents for the Treatment of Primary Biliary Cholangitis

“…Despite the fact that a huge number of preclinical and clinical studies extensively investigated the natural history of PBC [ 3 – 10 ], etiology of PBC is still unknown. In recent years, it has become univocally accepted that an inappropriately activated immune response plays a crucial role in development and progression of PBC [ 1 , 2 , 6 ]. Current disease models envisage a T cell-driven biliary injury, resulting in secondary cholestasis, which arises on the background of combined genetic and environmental risks including infection [ 6 ].…”

“…In recent years, it has become univocally accepted that an inappropriately activated immune response plays a crucial role in development and progression of PBC [ 1 , 2 , 6 ]. Current disease models envisage a T cell-driven biliary injury, resulting in secondary cholestasis, which arises on the background of combined genetic and environmental risks including infection [ 6 ]. It is believed that, in patients who had genetic predisposition to PBC, viruses [ 7 , 8 ], bacteria [ 1 ], and xenobiotics [ 9 , 10 ] either directly induce apoptosis of biliary epithelial cells (BECs) or trigger immune response against BECs as a result of molecular mimicry.…”