Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Sep 19;13(18):1580.
doi: 10.3390/cells13181580.

Current Landscape and Evolving Therapies for Primary Biliary Cholangitis

Stefano Fiorucci  1 , Ginevra Urbani  1 , Cristina Di Giorgio  1 , Michele Biagioli  1 , Eleonora Distrutti  2
Affiliations
Review

Current Landscape and Evolving Therapies for Primary Biliary Cholangitis

Stefano Fiorucci et al. Cells. .

Abstract

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disorder characterized by progressive cholestatic that, if untreated, can progress to liver fibrosis, cirrhosis and liver decompensation requiring liver transplant. Although the pathogenesis of the disease is multifactorial, there is a consensus that individuals with a genetic predisposition develop the disease in the presence of specific environmental triggers. A dysbiosis of intestinal microbiota is increasingly considered among the potential pathogenic factors. Cholangiocytes, the epithelial cells lining the bile ducts, are the main target of a dysregulated immune response, and cholangiocytes senescence has been recognized as a driving mechanism, leading to impaired bile duct function, in disease progression. Bile acids are also recognized as playing an important role, both in disease development and therapy. Thus, while bile acid-based therapies, specifically ursodeoxycholic acid and obeticholic acid, have been the cornerstone of therapy in PBC, novel therapeutic approaches have been developed in recent years. In this review, we will examine published and ongoing clinical trials in PBC, including the recently approved peroxisome-proliferator-activated receptor (PPAR) agonist, elafibranor and seladelpar. These novel second-line therapies are expected to improve therapy in PBC and the development of personalized approaches.

Keywords: T cells; cholangiocytes; cholestasis; farnesoid-x-receptor (FXR); macrophages; peroxisome-proliferator-associated receptors (PPAR).

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Gut-driven pathogenesis of PBC and PSC. Gut microbiota dysbiosis, characterized by a reduction in microbial abundance and diversity, as well as pathobiont increase, represents the first step in both PBC and PSC onset. Specifically, in PBC, such a condition promotes the loss of immune tolerance with subsequent activation of B cells and AMA production directed against intrahepatic cholangiocytes; further immune cell recruitment and cytokine secretion, then, contribute to periductal fibrosis. In PSC, microbiota dysbiosis entails a decreased production of secondary bile acids and short-chain fatty acids (SCFAs) as well as reduced epithelial barrier function resulting in increased entry of bacteria into the circulation; this induces intestinal T-cell activation, the initiation of chronic liver inflammation and the formation of the characteristics of an “onion-ring”, concentric layers of fibrotic tissue around bile ducts.
Figure 2
Figure 2
Breakdown of tolerance has a pivotal role in PBC pathogenesis. Aberrant expression of PDC-E2 subunit by cholangiocytes causes the recruitment of B cells, T cells and DCs promoting anti-PDC-E2 autoantibody secretion. Pro-inflammatory cytokine secretion and further immune cell recruitment (e.g., CD8+ T and NK cells) induce cholangiocytes senescence and apoptosis, responsible for biliary cholestasis. Cholangiocytes’ senescence-associated secretory phenotype (SASP) onset, finally, promotes portal fibroblast activation and subsequent biliary fibrosis. MAIT, mucosal-associated invariant T (MAIT) cells.
Figure 3
Figure 3
Comparison between current and new paradigms of PBC treatment. Current approaches include initiation of UDCA with assessment after 1 year of therapy and eventual shift to a second-line therapy in case of insufficient response to UDCA chosen on the basis of existing symptoms, comorbidities and drug availability. In contrast, the new paradigm is based on a more personalized approach that takes into account individual risk assessment since the beginning of the therapy.
Figure 4
Figure 4
Overview of additional therapies available for the treatment of PBC patients. The therapeutic targets are multiple, corresponding to the multiple symptoms of PBC. Specifically, therapies targeting hepatocytes include the use of PPAR or FXR agonists, HMG-CoA reductase or IMPDH inhibitors and antifibrotic agents that prevent ROS generation and HSC activation. Another therapeutic target is cholangiocytes, where the use of UDCA and norUDCA increases HCO3− production and stimulates hepatobiliary secretion of bile acids. Potential intestinal therapies involve manipulating the microbiota or using apical sodium-dependent bile acid transporter (ASBT) inhibitors to reduce bile acid reabsorption. Finally, JAK1/2 inhibitors and calcineurin inhibitors can be used to modulate the immune response.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Lv T., Chen S., Li M., Zhang D., Kong Y., Jia J. Regional Variation and Temporal Trend of Primary Biliary Cholangitis Epidemiology: A Systematic Review and Meta-Analysis. J. Gastroenterol. Hepatol. 2021;36:1423–1434. doi: 10.1111/jgh.15329. - DOI - PubMed
    1. Kowdley K.V., Bowlus C.L., Levy C., Akarca U.S., Alvares-da-Silva M.R., Andreone P., Arrese M., Corpechot C., Francque S.M., Heneghan M.A., et al. Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis. N. Engl. J. Med. 2024;390:795–805. doi: 10.1056/NEJMoa2306185. - DOI - PubMed
    1. Achufusi T.G.O., Safadi A.O., Mahabadi N. Ursodeoxycholic Acid. StatPearls Publishing; Treasure Island, FL, USA: 2024. - PubMed
    1. Ishizaki K., Imada T., Tsurufuji M. Hepatoprotective Bile Acid “ursodeoxycholic Acid (UDCA)” Property and Difference as Bile Acids. Hepatol. Res. 2005;33:174–177. doi: 10.1016/j.hepres.2005.09.029. - DOI - PubMed
    1. Zukowski T.H., Jorgensen R.A., Dickson E.R., Lindor K.D. Autoimmune Conditions Associated with Primary Biliary Cirrhosis: Response to Ursodeoxycholic Acid Therapy. Am. J. Gastroenterol. 1998;93:958–961. doi: 10.1111/j.1572-0241.1998.00287.x. - DOI - PubMed

Publication types

MeSH terms

LinkOut - more resources