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. PBC is frequently associated with other autoimmune conditions and primarily affects middle-aged women. In the early stages, PBC is typically asymptomatic. Fatigue is the most common initial symptom. 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 alkaline phosphatase (ALP) levels, antimitochondrial antibodies (AMA), and liver biopsy findings can establish the diagnosis. Management involves supportive care, e.g., management of cholestasis-associated pruritus, and slowing disease progression with ursodeoxycholic acid. Liver transplantation is the only definitive treatment.

• Sex: : ♀ > ♂ (∼ 9:1) ^[1]
• Age range: : 30–65 years ^[2]

Epidemiological data refers to the US, unless otherwise specified.

• PBC is considered an autoimmune disease and is thought to be triggered by environmental factors in individuals with a genetic predisposition. ^[3][4]
• Positive family history is a predisposing factor.
• Often associated with other autoimmune conditions, e.g.: ^[3][5]
  • CREST syndrome
  • Systemic sclerosis
  • Sjogren syndrome
  • Sicca syndrome
  • Autoimmune thyroid disease, especially Hashimoto thyroiditis
  • Celiac disease ^[3][6][7]
  • Rheumatoid arthritis ^[8][9]

• 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) ^[10]

Patients with PBC are usually initially asymptomatic. ^[3][4]

• Fatigue: most common and often the first symptom
• Marked pruritus: generalized or localized, typically worse at night ^[3]
• Symptoms of cholestasis
  • Jaundice
  • Pale stool, dark urine
  • Maldigestion (more common in advanced disease) ^[5]
• Signs of cirrhosis and portal hypertension
  • Hepatomegaly with dull lower margin, RUQ discomfort
  • Splenomegaly
• Hyperpigmentation ^[3]
• Xanthomas and xanthelasma ^[11]
• May be accompanied by clinical features of any associated autoimmune diseases (e.g., sclerodactyly in scleroderma, xerophthalmia in sicca syndrome)

Approach ^[3]

• Suspect PBC in patients with chronic cholestasis.
• Obtain laboratory studies for all patients.
• Consider liver biopsy if the diagnosis remains unclear.
• Diagnosis is confirmed if ≥ 2 of the following are present: ^[3]
  • Elevated ALP
  • Characteristic autoantibodies, e.g., AMA
  • Typical findings on liver biopsy
• Imaging can help exclude alternative diagnoses.

Laboratory studies ^[3]

• Liver chemistries: cholestatic pattern of injury
  • ↑ ALP, ↑ GGT, ↑ direct bilirubin
  • Mild transaminitis (or normal AST and ALT) ^[3]
• Liver synthetic function tests: ↓ albumin, ↑ INR in patients with advanced disease
• CBC: thrombocytopenia, e.g., in patients with hypersplenism due to portal hypertension or concomitant ITP ^[12][13]
• Lipid panel: hypercholesterolemia
• PBC-specific autoantibodies
  • Antimitochondrial antibodies (AMA) (present in > 95% of patients) ^[3]
  • If AMA negative: PBC-specific ANA, e.g., anti-sp100 or anti-gp210 ^[4]
• Immunoglobulins (nonspecific)
  • ↑ IgM
  • ↑ IgG (less common) ^[3]

The combination of hyperbilirubinemia with hypoalbuminemia, thrombocytopenia, and increased INR suggests decompensated cirrhosis, which indicates a poor prognosis. ^[4]

Liver biopsy ^[3]

• Most patients do not require a liver biopsy to confirm PBC.
• Obtain in certain patients to either:
  • Confirm PBC diagnosis in patients without characteristic autoantibodies
  • Evaluate for alternative diagnoses or concomitant liver disease ^[3]
• Supportive findings
  • Nonsuppurative cholangitis and destruction of small and medium bile ducts ^[4]
  • See “Pathology” below for findings according to the histopathological stage of disease.

Imaging

Imaging is not routinely indicated but may be used to exclude alternative diagnoses and/or evaluate for complications. See also “Diagnostics” in “Jaundice and cholestasis.”

• Abdominal ultrasound: to exclude mechanical bile obstruction
• MRCP: to evaluate for PSC
• Transient elastography: to evaluate for fibrosis

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 disease
• Sarcoidosis
• See also “Common cholestatic causes of conjugated hyperbilirubinemia.”

The differential diagnoses listed here are not exhaustive.

General principles

• Start pharmacotherapy with ursodeoxycholic acid for all patients.
• Offer supportive care, including management of cholestasis-associated pruritus.
• Screen for complications and comorbidities.
• Patients with PBC-AIH overlap should receive simultaneous treatment of AIH (i.e., immunosuppression). ^[4]
• Liver transplantation is necessary if liver cirrhosis is advanced.

Liver transplantation is the only definitive treatment, although most cases of PBC can be managed effectively with pharmacotherapy.

Pharmacotherapy ^[3][4]

• First-line: ursodeoxycholic acid (UDCA, ursodiol) : a hydrophilic, nontoxic bile acid with immunomodulatory, anti-inflammatory, choleretic, and cytoprotective effects ; ^[14][15]
  • Slows disease progression and development of complications (e.g., esophageal varices)
  • Prolongs transplant-free and overall survival
  • Also used in primary sclerosing cholangitis, cholestasis of pregnancy, and small cholesterol stones (off-label)
• Second-line options
  • Obeticholic acid (OCA): an agonist of the farnesoid X receptor, which is a nuclear receptor that inhibits bile acid synthesis and intake
    • Consider in addition to UDCA if there is an inadequate response after 1 year of treatment. ^[3]
    • Consider as monotherapy in patients with sensitivity or intolerance to UDCA.
    • Contraindicated in patients with advanced cirrhosis, i.e., a history of decompensation or signs of decompensated cirrhosis or portal hypertension. ^[16]
  • Fibrates, e.g., fenofibrate (off-label): may be considered for patients without decompensated cirrhosis and inadequate response to UDCA ^[16]

Because bile acid sequestrants can interfere with UDCA absorption, these medications should not be taken at the same time. ^[3]

Supportive care ^[3][4]

• Symptom relief
  • Management of cholestasis-associated pruritus
  • Treatment of sicca syndrome in patients with secondary Sjogren syndrome
• Prevention of complications
  • Provide treatment for hypertension.
  • Encourage lifestyle modifications for ASCVD prevention.
  • Consider lipid-lowering therapy based on ASCVD risk assessment. ^[3]
  • Optimize bone health, e.g., consider supplementing calcium and vitamin D if needed.

Monitoring and screening ^[3][4]

• Monitoring for disease progression
  • Obtain liver and cholestatic enzymes every 3–6 months to assess for:
    • Disease progression
    • Therapy adherence
    • Development of PBC-AIH overlap
• Screening for complications of cholestasis
  • Osteoporosis
    • Bone mineral density assessment at diagnosis, then every 2 years
    • Annual vitamin D levels in patients with advanced liver disease
  • Screen for fat-soluble vitamin deficiency in patients with jaundice and/or bilirubin > 2.0 mg/dL.
• Screening for complications of cirrhosis
  • HCC screening: ultrasound every 6 months
  • Screening for esophageal varices: esophagogastroduodenoscopy at the time of diagnosis, then every 1–3 years
• Comorbidities
  • Measure TSH annually.
  • Regularly assess for signs and symptoms of commonly associated autoimmune diseases (see “Etiology”). ^[4]

• Malabsorption
• Liver cirrhosis and portal hypertension
• Osteoporosis

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