Incomplete response to ursodeoxycholic acid in primary biliary cholangitis: criteria, epidemiology, and possible mechanisms

ABSTRACT

Introduction

As a common autoimmune disease with the characteristic of early complication, primary biliary cholangitis (PBC) leads to an increasing number of mortalities among people with end-stage liver disease (ESLD) waiting for liver transplantation. Ursodeoxycholic acid (UDCA) is the only approved first-line medicine for PBC, and a good response to treatment could acquire an ideal prognosis. Patients with poor UDCA response usually have more adverse outcomes and worse survival, therefore, the management of this group become a major consideration.

Areas covered

Due to the complexity of race and environment for PBC, different criteria for UDCA response exhibit various predictive performances. Factors affecting UDCA response conditions include gender, age, ethnicity, serum indicators, auto-antibodies, and autoimmune comorbidities, while no agreement has been reached. In this review, we mainly focus on cellular senescence, immune-mediated damage, and vitamin D deficiency as possible mechanisms for UDCA non-responders.

Expert opinion

The pathogenesis of PBC has yet to be clarified. Immunology-related mechanisms and therapy targets ought to be the main effort made for further study. Irrespective of the response condition, UDCA is recommended for routine administration in all PBC patients without contraindication. Ongoing clinical trials of second-line and additional therapy exhibit promising prospects.

KEYWORDS:

• Mechanisms
• predicting factors
• primary biliary cholangitis
• response
• ursodeoxycholic acid

Article highlights

• Ursodeoxycholic acid (UDCA) incomplete response is common among primary biliary cholangitis (PBC) patients worldwide.

• Discrimination criteria for UDCA response have different focuses on population and predicting outcomes, with specified pros and cons.

• UDCA non-responders usually have a poor prognosis, nevertheless, routine administration of UDCA showed benefits to PBC patients irrespective of response status.

• Factors affecting UDCA response conditions include gender, age, ethnicity, serum indicators, auto-antibodies, and autoimmune comorbidities, while no agreement has been reached, regarding their effects on disease progression.

• Cellular senescence, immune-mediated damage, and vitamin D deficiency are the possible mechanisms we focused on for UDCA non-responders.

• Ongoing clinical trials of additional therapy exhibit promising results in improving biochemical markers for UDCA non-responders.

Declaration of interests

The authors have no 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.

Abbreviations

PBC, primary biliary cholangitis; HBV, hepatitis B virus; HCV, hepatitis C virus; LT, liver transplantation; ESLD, end-stage liver disease; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; TBIL, total bilirubin; FDA, Food and Drug Administration; AASLD, American Association for the Study of Liver Diseases; CX3CL1, CX3C motif chemokine ligand 1; AIH, autoimmune hepatitis; AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver; APASL, Asian Pacific Association for the Study of the Liver; UNL, upper normal limit; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALB, albumin; PLT, platelet; BZF, bezafibrate; INR, international normalized ratio; LAMP-2, lysosome-associated membrane protein 2; FGF19, fibroblast growth factor 19; AMA, antimitochondrial antibody; ANA, antinuclear antibodies; VDR, vitamin D receptor; SLE, systemic lupus erythematosus.

Additional information

Funding

This paper was not funded.