What is primary biliary cholangitis (PBC)?

Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease characterized by progressive immune-mediated destruction of small intrahepatic bile ducts, leading to cholestasis, hepatic fibrosis, and potential progression to cirrhosis and liver failure. 1, 2, 3

Pathophysiology and Autoimmune Mechanisms

• PBC results from a well-orchestrated immune reaction, both innate and adaptive, specifically targeting intrahepatic biliary epithelial cells through autoantibodies against mitochondrial antigens. 2

• The disease is puzzling because the immune attack is predominantly organ-specific to the liver, despite mitochondrial autoantigens being present in all nucleated cells. 2

• The etiology involves interactions between genetic predisposition and environmental triggers, including microbial and xenobiotic exposures, though the exact pathogenesis remains incompletely understood. 2, 3

Epidemiology and Demographics

• PBC primarily affects middle-aged women, typically presenting in the fifth or sixth decade of life, with a strong female predominance. 2, 3, 4

• The disease represents the most common chronic cholestatic liver disease in humans. 4

Clinical Presentation

Asymptomatic Disease

• Many patients are asymptomatic at presentation, discovered incidentally through abnormal liver biochemistry during routine screening. 3

Symptomatic Manifestations

• The most common symptoms when present include fatigue, pruritus (itching), sicca syndrome (dry eyes and mouth), and right upper quadrant abdominal discomfort. 3

• Jaundice may develop as cholestasis progresses, indicating more advanced disease. 3

• Symptoms of advanced disease include manifestations of cirrhosis and portal hypertension such as ascites, variceal bleeding, and hepatic encephalopathy. 5

Diagnostic Approach

Biochemical Features

• The characteristic laboratory pattern shows cholestatic liver biochemistry with parallel elevation of alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT). 1, 4

• Elevated serum bilirubin indicates more advanced disease and portends poor prognosis. 1

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are often mildly elevated but do not necessarily indicate autoimmune hepatitis overlap. 1

Serologic Markers

• Antimitochondrial antibodies (AMA) are present in 90-95% of PBC patients and are highly specific for the disease, often detectable years before clinical signs appear. 2, 3

• Disease-specific antinuclear antibodies (ANA) are also diagnostic when present. 3, 4

• The diagnosis is established by the combination of biochemical cholestasis plus AMA or disease-specific ANA, without requiring liver biopsy for confirmation in typical cases. 3, 4

Histologic Features

• When performed, liver biopsy shows nonsuppurative granulomatous cholangitis, which is supportive but not required to confirm the diagnosis. 3

• Histology demonstrates inflammation and progressive destruction of small bile ducts. 4

Disease Heterogeneity and Prognosis

• PBC is heterogeneous in its presentation, symptomatology, disease progression, and response to therapy. 2

• Without treatment, PBC progresses toward liver fibrosis and ultimately cirrhosis. 4

• A significant number of patients develop end-stage liver disease and eventually require liver transplantation. 2

• Risk stratification using clinical and laboratory parameters helps identify patients at greatest risk of poor outcomes and guides treatment intensification. 3

Treatment Landscape

First-Line Therapy

• Ursodeoxycholic acid (UDCA) at 13-15 mg/kg/day is the mainstay and standard of care for all patients with PBC, dramatically improving prognosis by delaying disease progression and improving survival. 1, 6, 3, 4

• UDCA has no impact on PBC-related symptoms such as fatigue and pruritus, only on disease progression. 6

Inadequate Response to UDCA

• 30-40% of patients demonstrate inadequate biochemical response to UDCA and remain at high risk for complications, necessitating second-line therapies. 6, 4, 7

• Maximizing reduction in serum alkaline phosphatase levels with UDCA is critical, and second-line agents should be added when adequate response is not achieved. 6

Second-Line Therapies

Obeticholic Acid

• Obeticholic acid (OCA), a farnesoid X receptor agonist, is the first FDA-approved second-line therapy for PBC patients with inadequate response to UDCA or who are intolerant to UDCA. 5, 6, 3, 4, 7

• OCA significantly improves liver biochemistries and has been associated with improved long-term clinical outcomes. 6

• OCA is limited by its propensity to induce or worsen pruritus, which can be severe and disabling. 5, 6

• OCA is contraindicated in PBC patients with decompensated cirrhosis, prior decompensation events, or compensated cirrhosis with evidence of portal hypertension due to risk of hepatic decompensation and failure. 5

Peroxisome Proliferator-Activated Receptor Agonists

• Elafibranor and seladelpar are recently approved peroxisome proliferator-activated receptor (PPAR) agonists showing biochemical improvements in patients with inadequate UDCA response. 6

• These agents may improve pruritus symptoms, unlike OCA. 6

• Bezafibrate and fenofibrate are available as off-label second-line options where approved fibrates are accessible. 6, 3

Critical Management Considerations

• Patients who develop laboratory or clinical evidence of hepatic decompensation while on OCA must have the drug permanently discontinued. 5

• Care encompasses therapies to slow disease progression, manage cholestasis-related symptoms (particularly pruritus), and treat complications of advanced liver disease. 3

• The therapeutic landscape continues to evolve with novel agents including bile acid transport inhibitors, anti-fibrotic agents, immunomodulatory drugs, and gut microbiome-targeted therapies under investigation. 7