Primary biliary cholangitis

Primary biliary cholangitis (PBC; also known as primary biliary cirrhosis) is a chronic progressive liver disease of autoimmune origin that is characterized by destruction of the intralobular bile ducts. The pathogenesis of PBC is unclear; however, it primarily affects middle-aged women and is frequently associated with other autoimmune conditions. In the early stages, PBC is typically asymptomatic. Fatigue is the most common initial complaint. In advanced disease, increased fibrotic changes lead to typical signs of cholestasis (e.g., jaundice), portal hypertension (e.g., ascites, gastrointestinal bleeding), and severe hypercholesterolemia (e.g., xanthomas, xanthelasmas). Elevated cholestasis parameters (ALP, γ-GT, bilirubin) in addition to antimitochondrial antibodies (AMAs) help establish the diagnosis. Management consists of slowing disease progression with ursodeoxycholic acid and relieving symptoms. Liver transplantation is the only definitive treatment.

• Sex: : ♀ > ♂ (∼ 9:1) ^[1]
• Age range: : 30–65 years ^[2]
• Miscellaneous: most common cause of vanishing bile duct syndrome (a condition in which intrahepatic ducts are progressively destroyed) ^[3]

Epidemiological data refers to the US, unless otherwise specified.

• The exact cause of PBC is still unclear; however, it is considered as an autoimmune disease.
• Associated with other autoimmune conditions (see “Clinical features” below)
• Positive family history is a predisposing factor.

References:^[4]

• Inflammation and progressive destruction (likely due to an autoimmune reaction) of the small and medium-sized intrahepatic bile ducts (progressive ductopenia) → defective bile duct regeneration → chronic cholestasis → secondary hepatocyte damage due to increased concentration of toxins that typically get excreted via bile → gradual portal and periportal fibrotic changes → liver failure → liver cirrhosis and portal hypertension (in advanced stage) ^[5]

Patients are initially often asymptomatic. Signs and symptoms are mainly due to the resulting cholestasis, liver cirrhosis, and portal hypertension.

• Fatigue (usually the first symptom)
• Marked generalized pruritus
• Hyperpigmentation ^[6]
• Hepatomegaly, dull lower margin, RUQ discomfort
• Splenomegaly
• Jaundice
• Pale stool, dark urine
• Maldigestion (may involve manifestations of deficiency of fat-soluble vitamins; e.g., osteoporosis) ^[2]
• Xanthomas and xanthelasma ^[2]
• Frequently associated with other autoimmune conditions ^[6]
  • Rheumatoid arthritis
  • Autoimmune thyroid disease, especially Hashimoto thyroiditis
  • Celiac disease
  • CREST syndrome
  • Sicca syndrome

• Laboratory tests
  • ↑ Cholestasis parameters (ALP, γ-GT, conjugated bilirubin)
  • Transaminases (AST/ALT) are within normal limits or slightly elevated
  • Hypercholesterolemia
  • ↑ Antimitochondrial antibodies (AMA) (> 95%)
  • ↑ ANA (up to 70%)
  • ↑ IgM
• Imaging:
  • Abdominal ultrasound: to screen for mechanical bile obstruction
  • Magnetic resonance cholangiopancreatography: to confirm intrahepatic bile duct occlusion
• Liver biopsy
  • Performed in case of suspicion for an overlap syndrome or uncertain diagnosis (e.g., if AMA are negative but clinical suspicion is strong)
  • Necessary for staging

References:^[2][7]

Histopathological stages

• Stage I: lymphocytic infiltration of portal areas and periductal granulomas
• Stage II: bile duct ductopenia, progressive fibrosis
• Stage III: bridging fibrosis
• Stage IV: liver cirrhosis

• Autoimmune hepatitis
• Primary sclerosing cholangitis (See “Differential diagnoses of cholestatic biliary disease” for details.)
• Biliary obstruction (malignant or benign)
• Drug-induced liver damage
• Sarcoidosis

The differential diagnoses listed here are not exhaustive.

There is no cure for PBC. Treatment consists of slowing disease progression and alleviating symptoms. Liver transplantation is the only definitive treatment.

• First-line medical therapy: ursodeoxycholic acid (also known as ursodiol, or UDCA)
  • Slows progression of the disease and improves clinical symptoms
  • Delays the need for transplantation
  • Active ingredient is a hydrophilic bile acid
    • Hepatoprotective; antiapoptotic ^[5]
    • Immunomodulatory: UDCA suppresses immune reactions that promote disease progression
    • Also used in primary sclerosing cholangitis, cholestasis of pregnancy, and small cholesterol stones
• Second-line medical therapy: obeticholic acid (agonist of the farnesoid X receptor, a nuclear receptor that inhibits synthesis of cholesterol by promoting the transport of bile acids out of the hepatocytes)
• Treatment of cholestatic pruritus
• Liver transplantation necessary if liver cirrhosis is advanced

• Malabsorption
• Liver cirrhosis and portal hypertension
• Osteoporosis

We list the most important complications. The selection is not exhaustive.