Primary Biliary Cholangitis: Unsolved Issues and New Treatment

Primary biliary cholangitis (PBC) is an infrequent autoimmune liver disease. It is classically autoimmune in origin but clinically manifests as a progressive cholestatic syndrome. Much is known about PBC as regards diagnosis, prognosis and treatment, but equally there remains questions related to disease pathophysiology and optimal treatment of disease and associated symptom complexes. PBC is chronic, seropositive and female-predominant. It has inflammatory and cholestatic liver disease phenotypes, with a variable rate of progression towards biliary cirrhosis. The disease biology spans genetic risk, epigenetic changes, dysregulated mucosal immunity and altered biliary epithelial cell function, all of which interact and arise in the context of ill-defined environmental triggers. A current focus of research on nuclear receptor pathway modulation that specifically and potently improves biliary excretion, reduces inflammation and attenuates fibrosis is redefining therapy. Patients are benefiting from pharmacological agonists of farnesoid X receptor and peroxisome proliferator-activated receptors. Immunotherapy remains a challenge, with a lack of target definition, pleiotropic immune pathways and an interplay between hepatic immune responses and cholestasis, wherein bile acid-induced inflammation and fibrosis are dominant clinically. In this short lecture I will: a) Aim: To provide an overview of the disease characteristics of PBC and review a patient-centred management approach for the clinical team caring for those with PBC; b) Summarise practice: A confident diagnosis of PBC is usually made based on serum liver tests and immune serology. Management of PBC should focus on 3 main ‘process’ pillars: (1) treat and risk stratify through use of biochemical and prognostic criteria; (2) manage concurrent symptoms and other associated diseases; and (3) stage disease, monitor progression, and prevent complications. With ongoing complexities in management, including newly licenced therapy (obeticholic acid), alternative non-licenced treatments (e.g. bezafibrate), and emerging clinical trial agents (e.g. elafibrinor, seladelpar). I will provide an up-to-date disease summary in the context of latest clinical scientific understanding; c) Highlight future opportunities: I will demonstrate how PBC is a dynamic disease wherein current treatment goals have become appropriately ambitious. Goals of care should prioritise prevention of end-stage liver disease and amelioration of patient symptom burden for all, and such aspirations are accessible through current practice as well as a number of evolving trial opportunities for patients.