Primary biliary cholangitis: primary autoimmune disease or primary secretory defect

ABSTRACT

Introduction

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by the immune-mediated destruction of small and medium intrahepatic bile ducts, involving predominantly females. PBC has long been described as an autoimmune liver disease, also because it is very often associated with many autoimmune conditions. More recently, another pathogenic mechanism exploring the damage of cholangiocytes has been hypothesized, i.e. a defect in the biliary umbrella which is physiologically responsible for the exchange of the ions Cl⁻ and HCO₃⁻ and maintains the integrity of glycocalyx. To provide a state-of-the-art analysis of this topic, a systematic review of literature in PubMed, Scopus, and Science Direct was conducted (inclusive dates: 1986–2023).

Area covered

Although the etiology remains unknown, pathogenesis consists of a complex immune-mediated process resulting from a genetic susceptibility. PBC can be triggered by an immune-mediated response to an autoantigen, which leads to a progressive destruction of bile ducts and eventually to a progressive fibrosis with cirrhosis. The defect in the ‘bicarbonate umbrella’ acts as a protection against the toxic hydrophobic bile acids, leading to a toxic composition of bile.

Expert opinion

This review offers a summary of the current knowledge about the pathogenesis of PBC, indicating that this is probably based on the mutual relationship between the immune insult and the unbalanced secretory mechanisms.

KEYWORDS:

• Antimitochondrial antibodies
• bicarbonate umbrella
• cellular immunity
• extrahepatic conditions
• female preponderance
• humoral immunity

Article highlights

• PBC is a chronic liver disease characterized by the immune-mediated destruction of small and medium intrahepatic bile ducts.

• Similarly, to what occurs in autoimmune diseases, PBC has specific autoantibodies targeting autoantigens located on the inner membrane of mitochondria, a female preponderance, a genetic predisposition, and results from the immune attack of bile ducts.

• The immunological damage causes the destruction of the protective bicarbonate umbrella, with consequent penetration of protonated bile salts into biliary epithelium, increased intracellular pH in cholangiocytes, and bile salt-induced apoptosis

• It is proposed that the mutual relationship between the autoimmune damage and the unbalanced secretory mechanisms can offer an explanation of the disease pathogenesis.

• Several key points are still unmet, including why the disease initiates and what is the possible trigger for it.

Declaration of interests

A Floreani has received lecture fees from Advanz. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.