Primary Biliary Cholangitis (K74.3)

Causes

Primary biliary cholangitis (PBC) is believed to arise from a combination of genetic susceptibility and environmental triggers that lead to loss of immune tolerance against the small intrahepatic bile ducts. Individuals with certain HLA and immune-regulatory gene variants appear predisposed to developing an autoimmune response directed against cholangiocytes, particularly mitochondrial antigens such as the pyruvate dehydrogenase complex E2 subunit (PDC-E2). Environmental exposures—including smoking, recurrent urinary tract infections, xenobiotic chemicals, and possibly alterations in the gut microbiome—are thought to trigger or amplify this immune dysregulation in susceptible individuals. The resulting chronic T-cell–mediated inflammatory attack progressively damages the small bile ducts, leading to cholestasis, bile acid accumulation, fibrosis, and eventually cirrhosis. PBC occurs predominantly in middle-aged women and is frequently associated with other autoimmune diseases, supporting its classification as a systemic autoimmune disorder.

Pathophysiology

The pathophysiology of primary biliary cholangitis (PBC) centers on chronic autoimmune-mediated destruction of the small intrahepatic bile ducts. Activated T lymphocytes and antimitochondrial antibodies target cholangiocytes, particularly against the pyruvate dehydrogenase complex E2 (PDC-E2) antigen found within mitochondria. Progressive bile duct injury impairs normal bile flow, leading to cholestasis and accumulation of potentially toxic bile acids within the liver. These retained bile acids promote oxidative stress, mitochondrial dysfunction, inflammatory cytokine signaling, and hepatocellular injury. Over time, chronic inflammation activates hepatic stellate cells and fibrogenic pathways, resulting in portal fibrosis, architectural distortion, and eventually cirrhosis. Beyond simple bile obstruction, PBC is increasingly recognized as a complex immunometabolic disorder involving dysregulated bile acid signaling, immune activation, and chronic inflammatory remodeling of the liver.

Clinical features

The symptoms of primary biliary cholangitis (PBC) often develop gradually and may be subtle in the early stages of disease. Many patients initially present with persistent fatigue and pruritus (itching), which can become severe and significantly affect quality of life. As cholestasis progresses, patients may develop dry eyes and dry mouth due to associated autoimmune conditions such as Sjögren syndrome. Some individuals experience right upper quadrant discomfort, hyperpigmentation of the skin, or xanthelasmas caused by altered cholesterol metabolism. In more advanced disease, impaired bile flow and progressive fibrosis can lead to jaundice, dark urine, pale stools, osteoporosis, fat-soluble vitamin deficiencies, ascites, portal hypertension, and other complications of cirrhosis and liver failure.

Diagnosis

The diagnosis of primary biliary cholangitis (PBC) is typically based on a combination of characteristic laboratory findings, autoantibody testing, and clinical evaluation. Most patients demonstrate a cholestatic pattern of liver injury with elevated alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) levels. The hallmark serologic finding is the presence of antimitochondrial antibodies (AMA), detected in approximately 90–95% of cases, particularly antibodies directed against the pyruvate dehydrogenase complex E2 (PDC-E2) antigen. Imaging studies such as ultrasound or MRCP are often performed to exclude mechanical biliary obstruction or other cholangiopathies. Liver biopsy is not always required but may be useful when the diagnosis is uncertain, AMA is negative, or overlap syndromes are suspected. Histologically, PBC is characterized by lymphocytic inflammation and destruction of the small intrahepatic bile ducts, often described as a “florid duct lesion.”

Mechanism of action videos

• Linerixibat Approved for Treatment of Itching Associated With Primary Biliary Cholangitis

Biological pathways

• Nuclear Receptor transcription pathway
• Interleukin-35 Signalling
• SUMOylation of intracellular receptors
• Transcriptional regulation of brown and beige adipocyte differentiation by EBF2
• Adipogenesis
• Interleukin-12 family signaling
• Sensory perception of salty taste
• Signaling by Interleukins
• Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)
• Interferon alpha/beta signaling
• Regulation of IFNA/IFNB signaling
• Ethanol oxidation
• TNFs bind their physiological receptors
• MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis
• Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes
• Evasion by RSV of host interferon responses
• RUNX1 regulates estrogen receptor mediated transcription
• MECP2 regulates transcription factors
• Cation-coupled Chloride cotransporters
• Epigenetic regulation by WDR5-containing histone modifying complexes
• Generic Transcription Pathway
• Gene expression (Transcription)
• Transcriptional regulation of white adipocyte differentiation
• SUMO E3 ligases SUMOylate target proteins
• SUMOylation
• RNA Polymerase II Transcription
• Interleukin-4 and Interleukin-13 signaling
• Activation of gene expression by SREBF (SREBP)

Clinical trials

• ASSURE: An Open Label Long-Term Study to Evaluate the Safety and Tolerability of Seladelpar in Subjects With Primary Biliary Cholangitis (PBC)
• The Effect of Hepatic Impairment on The Pharmacokinetics of Seladelpar: An Open-Label Study Following Oral Dosing of Seladelpar to Subjects With Primary Biliary Cholangitis (PBC) and Hepatic Impairment
• Fenofibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cholangitis
• Fenofibrate Combined With Ursodeoxycholic Acid in Compensated Cirrhosis Patients With Primary Biliary Cholangitis Who Had an Inadequate Response to Ursodeoxycholic Acid
• A Randomised, Double-blind, Placebo-controlled, Two-part Study to Evaluate the Pharmacokinetics, Safety and Tolerability, and Preliminary Efficacy of Two Dose Levels of Golexanolone in Subjects With Primary Biliary Cholangitis (PBC), Fatigue, and Cognitive Dysfunction
• A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Volixibat in the Treatment of Cholestatic Pruritus in Patients With Primary Biliary Cholangitis
• A Multicenter, Open-Label, Extension Clinical Trial to Evaluate Safety and Efficacy of Saroglitazar Magnesium in Participants With Primary Biliary Cholangitis (PBC)
• A Double-blind, Placebo-controlled, Randomized, Phase 3 Study to Evaluate the Efficacy and Safety of Saroglitazar Magnesium on Normalization of Alkaline Phosphatase Levels in Patients With Primary Biliary Cholangitis and an Incomplete Response or Intolerance to Ursodeoxycholic Acid
• A Phase III, Multicentre, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Elafibranor in Adult Participants With Primary Sclerosing Cholangitis
• A Double-blind, Randomized, Placebo-Controlled Study and Open-label Long Term Extension to Evaluate the Efficacy and Safety of Elafibranor 80 mg in Patients With Primary Biliary Cholangitis With Inadequate Response or Intolerance to Ursodeoxycholic Acid
• A Phase III, Open-label, Single Arm Study to Investigate the Efficacy and Safety of Elafibranor 80 mg in Adult Japanese Participants With Primary Biliary Cholangitis (PBC)
• A Phase IIIb Randomised, Parallel-Group, Double-Blind, Placebo-Controlled, Two-Arm Study to Evaluate the Effect of Elafibranor 80 mg on Normalisation of Alkaline Phosphatase in Adult Participants With Primary Biliary Cholangitis (PBC) and Inadequate Response or Intolerance to Ursodeoxycholic Acid.
• AFFIRM: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effect of Seladelpar on Clinical Outcomes in Patients With Primary Biliary Cholangitis (PBC) and Compensated Cirrhosis
• A Phase II, Multicenter, Double-Blind, Randomised, Placebo-Controlled Study and Open Label Long Term Extension to Evaluate the Safety and Efficacy of Elafibranor in Adult Participants With Primary Sclerosing Cholangitis (PSC).
• A Phase III Randomised, Parallel-Group, Double-Blind, Placebo-Controlled, Two-Arm Study to Evaluate the Efficacy and Safety of Elafibranor 80 mg on Long-Term Clinical Outcomes in Adult Participants With Primary Biliary Cholangitis (PBC)
• A Multicenter, Randomized, Double-blind, Placebo Controlled, Phase 2b/3 Study to Evaluate the Efficacy and Safety of Saroglitazar Magnesium in Subjects With Primary Biliary Cholangitis
• FARGO: A Randomised, Phase IIa, Multi-centre, Placebo-controlled Trial of FAecal Microbiota Transplantation in primaRy sclerosinG chOlangitis
• Fecal Microbiota Transplantation for Primary Sclerosing Cholangitis - Randomized Study Versus Sham Transplantation
• A Phase II Study to Evaluate Safety, Tolerability and Efficacy, of CS0159 in Patients Subjects With Primary Sclerosing Cholangitis, Multicenter, Randomized, 12-week Double-blind, Placebo-controlled, and 40-week Open Study
• A Phase II Study to Evaluate Safety, Tolerability and Efficacy, of CS0159 in Patients Subjects With PBC (Primary Biliary Cholangitis), Multicenter, Randomized 12-week, Double-blind, Placebo-controlled, and 40-weeks Open Study
• A Randomized, Placebo-controlled Pilot Study of Sulfasalazine for the Treatment of Primary Sclerosing Cholangitis (PSC)
• A Phase 2a Double Blind, Placebo Controlled Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Efficacy of CNP-104 in Subjects Ages 18-75 With Primary Biliary Cholangitis Who Are Unresponsive to UDCA and/or OCA
• An Open Label Long-Term Study to Evaluate the Safety and Tolerability of Fenofibrate in Combination With Ursodeoxycholic Acid in Subjects With Primary Biliary Cholangitis (PBC)
• A Phase 1, Randomized, Placebo-Controlled, Double-Blind, Sponsor-Open Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-781 in Healthy Participants and a Single-Arm, Open-Label Evaluation in Participants With Non-Cirrhotic Primary Sclerosing Cholangitis
• The Effect of Statin Therapy on Bile Acid Physiology and the Microbiome in Primary Sclerosing Cholangitis (PSC): a Multi-omics Study
• Long-term Safety and Tolerability Study of Linerixibat for the Treatment of Cholestatic Pruritus in Participants With Primary Biliary Cholangitis
• A Phase 3b/4, Multicenter, Parallel-Group, Double-Blind, Placebo Controlled, Two-Arm, Long-Term Study to Evaluate the Safety and Efficacy of Saroglitazar Magnesium on Clinical Outcomes in Participants With Primary Biliary Cholangitis (PBC)
• A Randomized Double-Blind Placebo-Controlled Study to Evaluate the Efficacy and Safety of Volixibat in the Treatment of Cholestatic Pruritus in Patients With Primary Sclerosing Cholangitis
• A Randomized, Double-blind, Dose-ranging, Placebo-controlled, Phase 2a Evaluation of the Safety, Tolerability, and Pharmacokinetics of PLN-74809 in Participants With Primary Sclerosing Cholangitis (PSC) and Suspected Liver Fibrosis (INTEGRIS-PSC)
• Investigation of Vancomycin Efficacy in Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis
• A Prospective, Multi-center, Randomized, Double-blind, Placebo-controlled Study: Fenofibrate Combined With Ursodeoxycholic Acid in Subjects With Primary Biliary Cholangitis and an Inadequate Response to Ursodeoxycholic Acid
• An Open Label Long-Term Study to Evaluate the Safety and Tolerability of Fenofibrate in Combination With Ursodeoxycholic Acid in Subjects With Primary Biliary Cholangitis (PBC)
• A Randomized, Double-Blind, Placebo-controlled, Phase III Study to Evaluate the Efficacy and Safety of CS0159 in Patients With Primary Biliary Cholangitis (PBC) With Inadequate Response or Intolerance to Ursodeoxycholic Acid (UDCA)
• A Multicenter, Randomized, Double-Blind, Double-Dummy, Active-Controlled Clinical Trial of Fenofibrate in Treatment-Naïve Patients With Primary Biliary Cholangitis
• A Multicenter, Randomized, Controlled Trial of Prednisone Combined With Ursodeoxycholic Acid in the Treatment of Primary Biliary Cholangitis With Moderate to Severe Interface Hepatitis Characteristics
• A Single Center, Randomized Controlled, Pilot Study of Fenofibrate and Ursodeoxycholic Acid in the Treatment of Newly Diagnosed Primary Biliary Cholangitis
• Evaluation of TH104 for Moderate to Severe Pruritus in Primary Biliary Cholangitis: a Double-blind, Randomized, Placebo-controlled, Phase 2a Study
• A 12-Month, Open-Label Study Evaluating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Siplizumab as Induction Therapy in Patients With Autoimmune Liver Diseases Undergoing Liver Transplantation (SET-SAIL)
• A Phase 1, First-In-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PVT201 Following Randomized, Double-blind, Placebo-controlled Single Ascending Doses in Healthy Subjects and Patients (PBC/PSC)
• Detoxification of the Liver in Primary Sclerosing Cholangitis