Primary Biliary Cholangitis: Controversies and Perspectives

Abstract and Introduction

Abstract

Primary biliary cholangitis (PBC) is a rare progressive immune-mediated liver disease that, if not adequately treated, may culminate in end-stage disease and need for transplantation. According to current guidelines, PBC is diagnosed in the presence of antimitochondrial antibodies (AMA) or specific antinuclear antibodies, and of a cholestatic biochemical profile, while biopsy is recommended only in selected cases. All patients receive ursodeoxycholic acid (UDCA) in first line; the only registered second-line therapy is obeticholic acid (OCA) for UDCA-inadequate responders. Despite the recent advances in understanding PBC pathogenesis and developing new treatments, many grey areas remain. Six Italian experts selected the following topics as the most urgent to address in PBC management: diagnosis and natural history of PBC: as a portion of the subjects with isolated AMA, normal alkaline phosphatase (ALP) levels and no symptoms of liver disease could have PBC by histology, defining how to manage and follow this population is crucial; role of liver biopsy: recent evidence suggests that biopsy may provide relevant information for risk stratification and prediction of UDCA response, possibly facilitating personalized approaches; risk stratification: the tools for risk stratification are well established, but some issues (eg bile acid dosage in routine practice) remain controversial; and therapy: those in more advanced stages of development are nuclear receptor modulators and fibrates, but more data are needed to plan personalized strategies. In this manuscript, for each topic, current evidence, controversies and future perspectives are summarized with the possible implications for clinical practice.

Introduction

Primary biliary cholangitis (PBC) is a progressive immune-mediated liver disease, characterized by chronic inflammation of interlobular bile ducts that causes bile acid (BA) retention into the liver (cholestasis) and secondary hepatocyte damage. If not adequately treated, it may culminate in end-stage liver disease and need for liver transplantation.^[1] PBC epidemiology varies widely.^[2] In Italy, the incidence of PBC has been estimated to range between 2.21 and 5.31 per 100 000 inhabitants, and the prevalence between 3.86 and 27.90 per 100 000.^[3,4]

Current treatment aims to halt progression, in order to prevent end-stage complications of liver disease and manage associated symptoms.^[1] It relies on a stepwise approach, starting with administration of ursodeoxycholic acid (UDCA) monotherapy in all patients.^[1] This is a natural BA that demonstrated long-term efficacy and good safety and tolerability, with a low cost. Indeed, UDCA effectively reduces serum biochemical parameters, slows disease progression, decreases the risk of ascites and the incidence of varices and jaundice, prolongs transplant-free survival (TFS)^[5–10] and decreases mortality.^[11] Unfortunately, 25%-40% of UDCA-treated patients do not experience adequate biochemical response and are therefore considered for second-line therapies: currently, the only registered drug is the farnesoid X receptor (FXR) agonist obeticholic acid (OCA), but novel therapeutic options are under investigation.^[12,13]

The high heterogeneity of PBC presentation, symptomatology, clinical course and response to therapy requires a personalized, life-long approach to ensure patients' optimal care, and, despite the recent advances, much work remains to be done.^[1,13–15] With this in mind, a board of six experts in the field of PBC gathered in September 2019 to thoroughly review and discuss different aspects of disease management and treatment and share their daily practice experience. Although they acknowledged that many grey areas still exist, the experts selected the following as the most urgent to address: diagnosis and natural history of PBC, role of liver biopsy, risk stratification and therapy. For each topic, current evidence and controversies are summarized, and future perspectives, including novel studies that may help filling some important knowledge gaps, are proposed, together with the possible implications for clinical practice.