Clinical Updates in Primary Biliary Cholangitis: Trends, Epidemiology, Diagnostics, and New Therapeutic Approaches

Abstract

Primary biliary cholangitis, formerly known as primary biliary cirrhosis, is a chronic, autoimmune, and cholestatic disease ameliorating the biliary epithelial system causing fibrosis and end-stage liver disease, over time. Patients range from an asymptomatic phase early in the disease course, to symptoms of decompensated cirrhosis later in its course. This review focuses on the current consensus on the epidemiology, diagnosis, and management of patients with primary biliary cholangitis. We also discuss established medical management as well as novel and investigational therapeutics in the pipeline for management of PBC.

Keywords: Epidemiology; Obeticholic acid; Primary biliary cholangitis (PBC); Treatment; UDCA.

Fig. 1.. Treatment modalities for primary biliary cholangitis: What we know in 2019.

Fig. 2.. Steroidal and nonsteroidal FXR agonists and FGF-19 mechanism of action.

FXR is a nuclear hormone receptor that is highly expressed in the gastrointestinal tract, adrenal glands, kidneys, and the liver. FXR is the primary regulator of BA homeostasis. By activating FXR, OCA is a steroidal FXR agonist and it is expected to do three things: 1) decrease fibrosis by decreasing fibrogenesis, stellate cell activation, and increase matrix degradation, 2) decrease inflammation, and 3) regulate BA homeostasis by decreasing its synthesis, uptake and absorption, and increasing its secretion. GS-9674 is a nonsteroidal FXR agonist in the intestine, which triggers release of FGF-19 from the intestinal mucosa. FGF-19, which is an endocrine hormone, then binds to hepatic receptor complex tyrosine kinase FGFR4 and its co-receptor β-klotho, which inhibits the gene transcription of the CYP7A1 BA synthesis gene (encoding cholesterol 7-alpha-hydroxylase), the SREBP1c lipogenic gene (encoding sterol regulatory element-binding protein 1C), and the G6PC gluconeogenic gene (encoding the glucose-6-phosphatase catalytic subunit), leading to decreases in BA synthesis, lipogenesis, and gluconeogenesis. Concurrently, FXR in the liver induces SHP, a negative nuclear receptor, which in turn also inhibits gene transcription of CYP7A1, SREBP1c, and G6PC. Cilofexor (GS-9674) has been shown to significantly reduce fibrosis and portal hypertension in a murine model of nonalcoholic steatohepatitis, to have anti-inflammatory property in vivo, and to increase eNOS. Abbreviations: BA, bile acid; eNOS, endothelial nitric oxide synthase; FGF, fibroblast growth factor; FXR, farnesoid X receptor; OCA, obeticholic acid; SHP, small heterodimer partner.