Primary Biliary Cholangitis: Immunopathogenesis and the Role of Bile Acid Metabolism in Disease Progression

Abstract

Primary biliary cholangitis (PBC) is a chronic, immune-mediated liver disease characterized by progressive destruction of the small intrahepatic bile ducts, leading to cholestasis, inflammation, and ultimately fibrosis and cirrhosis. This review emphasizes the central role of bile acids in PBC pathogenesis, exploring how disruptions in their synthesis, transport, and detoxification contribute to cholangiocyte damage and disease progression. In addition to discussing the autoimmune features of PBC, including the presence of specific autoantibodies and cellular immune responses, we examine how bile acid dysregulation exacerbates cholestasis and promotes lipid metabolic disturbances. Particular attention is given to the "bicarbonate umbrella" hypothesis, which describes a protective mechanism by which cholangiocytes resist bile acid-induced injury-an essential factor disrupted in PBC. The aim of this review is to summarize current knowledge gaps in the pathophysiology of PBC, with a focus on the role of bile acids not only as key drivers of disease mechanisms, but also as potential biomarkers of disease progression and treatment response.

Keywords: autoimmune disease; bile acids; cholestasis; primary biliary cholangitis.

Figure 2

Structure of bile acids (BAs). Ursodeoxycholic acid (UDCA) is a tertiary BA in humans, best known due to its pharmacological actions. Cholic acid (CA) and chenodeoxycholic acid (CDCA) are primary BAs in humans, whereas deoxycholic acid (DCA) and lithocholic acid (LCA) are secondary BAs. Primary and secondary BAs can undergo conjugation with taurine and glycine, leading to the corresponding conjugated forms (TCA, GCA, TCDCA, GCDCA, TDCA, GDCA, TLCA, GLCA). Hydroxyl groups (OH) in α-orientation are located below the steroid core and are axial with respect to the plane of the steroid core. Hydroxyl groups in β orientation are located above the steroid core and are equatorial to it. The BAs have been ordered from lowest to highest hydrophobicity according to octanol/water partition coefficient predictions from ChemDraw 19 software and literature [29,30,35].

Figure 1

Alterations in bile acid and lipid metabolism in patients with Primary Biliary Cholangitis (PBC). Under physiological conditions, primary bile acids (BA) are synthesized in the liver from cholesterol. The cholesterol 7α-hydroxylase (CYP7A1) is the rate limiting enzyme. In the gut, primary BAs undergo deconjugation and 7α-dehydroxylation by anaerobic bacteria, resulting in the formation of secondary BA. In patients with PBC, bile flow from the liver to the intestinal lumen is reduced. There is also a reduction in deconjugation possibly associated with intestinal dysbiosis, increasing the primary to secondary BA ratio. As secondary BAs are the most potent agonists, its reduction could lead to dysregulation of Farnesoid X receptor (FXR) and G protein-coupled BA receptor (TGR5), increasing intestinal permeability and inflammatory responses. When FXR is dysregulated, homeostatic compensation of cholestasis cannot occur and therefore PBC progresses. Main pharmacological targets—FXR, Peroxisome Proliferator-Activated Receptors (PPARs), Apical Sodium-dependent Bile Acid Transporter (ASBT) and bile composition and flow—have been depicted. BSEP: Bile Salt Export Pump; HDL: High-Density Lipoprotein; NTCP: Na-Taurocholate Cotransporting Polypeptide. VLDL: Very-Low-Density Lipoprotein. Created with BioRender.com.

Figure 3

(A) Physiologically functional cholangiocyte: The cholangiocyte is a polarized cell with basolateral and apical membranes. On the apical membrane, bicarbonate (HCO₃) secretion occurs via the Cl⁻/HCO₃ exchanger AE2. This secretion is facilitated by the chloride gradient created by the CFTR channel. Secretin levels influence this secretion. Secretin increases intracellular cAMP levels, stimulating the transport of vesicles containing AE2, CFTR, and AQP1 to the apical membrane. This HCO₃ secretion protects cholangiocytes by maintaining an alkaline pH barrier or “umbrella” over the outer surface of the apical membrane, keeping bile salts unprotonated. (B) Cholangiocyte dysfunction in PBC: There is a reduction in HCO₃ secretion due to defective hepatic AE2 expression (1). This leads to the acidification of bile at the apical membrane, which promotes the persistence of an apolar state of glycine-conjugated bile acids (2). These bile acids can penetrate into cholangiocytes, causing oxidative and ER stress, apoptosis, and cytotoxicity (3). On the other hand, stressed cholangiocytes express immunogenic forms of PDC-E2 through apoptotic blebs (4a), which consequently activate and expand autoreactive B cells, resulting in the production of autoantibodies (5a). Furthermore, senescent cholangiocytes actively participate in the recruitment of immune cells, (4b) promoting the associated immune dysregulation (5b). AE2: Anion exchanger 2. AMA: Antimitochondrial antibodies. AQP1: Water channel aquaporin 1. B cell: B lymphocyte. cAMP: Cyclic adenosine monophosphate. CFTR: Cystic fibrosis transmembrane regulator. Cl⁻: Chloride. ER: Endoplasmic reticulum. HCO₃: Bicarbonate. NK: Natural killer. PBC: Primary biliary cholangitis. PDC-E2: E2 component of pyruvate dehydrogenase complex. ROS: Reactive oxygen species. T cell: T lymphocyte. Created with BioRender.com and smart.servier.com.