Elsevier

Journal of Autoimmunity

Volume 105, December 2019, 102328
Journal of Autoimmunity

The challenges of primary biliary cholangitis: What is new and what needs to be done

https://doi.org/10.1016/j.jaut.2019.102328Get rights and content

Highlights

  • The role of histology in PBC should be reconsidered.

  • Is disrupted bile acid homeostasis cause or consequence of the autoimmune attack?

  • The role of the microbiome is linked to its close physiological interaction with bile acids.

  • High-risk patients probably would benefit from early combined treatment.

Abstract

Primary Biliary Cholangitis (PBC) is an uncommon, chronic, cholangiopathy of autoimmune origin and unknown etiology characterized by positive anti-mitochondrial autoantibodies (AMA), female preponderance and progression to cirrhosis if left untreated. The diagnosis is based on AMA- or PBC-specific anti-nuclear antibody (ANA)-positivity in the presence of a cholestatic biochemical profile, histologic confirmation being mandatory only in seronegative cases. First-line treatment is ursodeoxycholic acid (UDCA), which is effective in preventing disease progression in about two thirds of the patients. The only approved second-line treatment is obeticholic acid.

This article summarizes the most relevant conclusions of a meeting held in Lugano, Switzerland, from September 23rd-25th 2018, gathering basic and clinical scientists with various background from around the world to discuss the latest advances in PBC research. The meeting was dedicated to Ian Mackay, pioneer in the field of autoimmune liver diseases. The role of liver histology needs to be reconsidered: liver pathology consistent with PBC in AMA-positive individuals without biochemical cholestasis is increasingly reported, raising the question as to whether biochemical cholestasis is a reliable disease marker for both clinical practice and trials. The urgent need for new biomarkers, including more accurate markers of cholestasis, was also widely discussed during the meeting. Moreover, new insights in interactions of bile acids with biliary epithelia in PBC provide solid evidence of a role for impaired epithelial protection against potentially toxic hydrophobic bile acids, raising the fundamental question as to whether this bile acid-induced epithelial damage is the cause or the consequence of the autoimmune attack to the biliary epithelium. Strategies are needed to identify difficult-to-treat patients at an early disease stage, when new therapeutic approaches targeting immunologic pathways, in addition to bile acid-based therapies, may be effective. In conclusion, using interdisciplinary approaches, groundbreaking advances can be expected before long in respect to our understanding of the etiopathogenesis of PBC, with the ultimate aim of improving its treatment.

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.

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