The challenges of primary biliary cholangitis: What is new and what needs to be done
Introduction
Primary Biliary Cholangitis (PBC) is an uncommon, chronic, cholestatic liver disease of autoimmune origin and unknown etiology characterized by anti-mitochondrial autoantibodies (AMA) and female preponderance. In absence of treatment, it progresses to cirrhosis and liver failure [1]. The diagnosis is made in the presence of AMA or PBC-specific anti-nuclear antibodies (ANA) coupled with a cholestatic biochemical profile, a histologic confirmation being mandatory only in seronegative cases [2,3]. Treatment is based on ursodeoxycholic acid (UDCA), which is effective in preventing disease progression in about two thirds of the patients [2,3]. The only approved second-line treatment is obeticholic acid, fibrates representing an effective but off-label alternative [4]. This article summarizes the main conclusions of a research meeting held in Lugano, Switzerland, on September 23rd to 25th gathering basic and clinical scientists from around the world with various backgrounds to share knowledge and discuss the latest advances and new challenges in PBC research. The meeting was dedicated to Professor Ian Mackay, a pioneer in the field of autoimmune liver diseases.
Section snippets
Historical aspects
PBC was first described in 1851 in a case report of a 42-year-old woman with jaundice and xanthomata [5] (Fig. 1). The name “primary biliary cirrhosis” was proposed by Dauphinée and Sinclair in 1949 [6], and in the same year the classical description of the clinical phenotype was published by Ahrens et al. [7]. Ian Mackay first reported in 1958 the association of PBC with autoantibodies to human liver and kidney tissue detected by complement fixation test [8]. This report was followed in 1965
Histology
PBC histologic hallmarks are chronic non-suppurative destructive cholangitis, characterized by lymphocytic infiltration of the biliary epithelium and biliary epithelial cells (BECs) senescence, and, most importantly, bile duct loss, with areas of macrophage-rich fibrosis replacing bile ducts in portal tracts (Fig. 2). Interface hepatitis, the characteristic histologic picture of chronic hepatitis, particularly of autoimmune hepatitis (AIH), develops universally in untreated PBC, and is
Autoantibodies generation
Autoantibodies are generated through complementary pathways:
- a)
during germline DNA rearrangement of VDJ genes, thus before antigen stimulation, by escaping clonal deletion or DNA editing mechanisms
- b)
during affinity maturation, thus after antigen stimulation, by fortuitous somatic mutations [37]. In this case, the original antigenic target does not need to be structurally similar to the antigen targeted after somatic hypermutations, in contrast to autoantibodies generated by the mechanism referred to
Disease definition
As mentioned above, PBC is defined as a chronic, cholestatic liver disease of autoimmune origin and unknown etiology with positive AMA and/or PBC-specific ANA, and female preponderance. If left untreated, it often progresses to cirrhosis and liver failure [1]. The diagnosis is based on AMA-positivity or PBC-specific ANA positivity associated with a cholestatic biochemical profile. Histologically, the disease is characterized by chronic non-suppurative destructive cholangitis, epithelioid
Conclusions
The Lugano meeting has provided a unique opportunity for scientists with different backgrounds to share the latest advances in our understanding of PBC. A number of issues to be addressed have been acknowledged, including: obtaining an orphan-disease status for PBC; identifying reliable end points for clinical trials to be universally used and novel biomarkers discriminating high-risk patients at the time of diagnosis; establishing criteria for UDCA partial response; comparing the immunological
Declarations of interest
None.
Acknowledgment
we kindly acknowledge Fondazione Epatocentro Ticino, Maurizia Bissig and Paola Messina in particular, for organizing the Ian Mackay Meeting. We also acknowledge Università della Svizzera Italiana for hosting the Meeting; we really much appreciated the hospitality of Professor Mario Bianchetti, Dean of the Faculty of Biomedical Sciences, and the kindness of his collaborators, Mr Albino Zgraggen and Mr Filippo Bertone.
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- 1
All authors were equal contributors to the Ian Mackay Symposium on Primary Biliary Cholangitis, held at Università della Svizzera Italiana, Lugano, Switzerland, on September 23rd-25th 2018.
- 2
Deceased.