Primary Biliary Cholangitis (PBC)

Summary

Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is a chronic autoimmune liver disease characterized by progressive destruction of small intrahepatic bile ducts. The disease predominantly affects middle-aged women (40-60 years) with a female to male ratio of 9:1. The hallmark of PBC is the presence of anti-mitochondrial antibodies (AMA), which are positive in approximately 95% of cases. Patients typically present with an insidious onset of fatigue and pruritus, though many are diagnosed incidentally through abnormal liver function tests showing a cholestatic pattern. The diagnosis requires 2 of 3 criteria: elevated alkaline phosphatase, positive AMA, and characteristic histological findings. First-line treatment is ursodeoxycholic acid (UDCA), which slows disease progression when started early. Without treatment, the disease progresses through stages from portal inflammation to cirrhosis over 15-20 years.

Overview

• Definition: Chronic autoimmune destruction of small intrahepatic bile ducts leading to cholestasis
• Demographics:
  • 90% of patients are women
  • Typical age at diagnosis: 40-60 years
  • More common in Northern Europeans
  • Prevalence: 40-400 cases per million
• Natural history: Slow progression over 15-20 years from asymptomatic disease to cirrhosis if untreated
• Prognosis: Excellent with early treatment; patients responding to UDCA have near-normal life expectancy

Epidemiology

• Age: Peak incidence 40-60 years (mean age ~55 years)
• Sex: Female >> Male (9:1 ratio)
• Geography: More common in Northern Europe and North America
• Prevalence: 19-402 cases per million population
• Risk factors:
  • Family history of PBC (increased risk in first-degree relatives)
  • Presence of other autoimmune diseases
  • Environmental factors (smoking, nail polish use, hair dye - controversial)

Pathophysiology

• Autoimmune mechanism:
  • T-cell mediated destruction of cholangiocytes (bile duct epithelial cells)
  • Target antigen: M2 subtype of mitochondrial pyruvate dehydrogenase complex (PDC-E2)
  • Environmental trigger in genetically susceptible individuals
• Histological progression:
  • Stage 1: Portal inflammation with florid duct lesions (granulomas around bile ducts)
  • Stage 2: Periportal inflammation and fibrosis
  • Stage 3: Bridging fibrosis
  • Stage 4: Cirrhosis
• Consequences of bile duct destruction:
  • Cholestasis → accumulation of bile acids
  • Reduced bile flow → malabsorption of fat-soluble vitamins (A, D, E, K)
  • Progressive fibrosis → cirrhosis and portal hypertension

Clinical Features

• Early symptoms (may be absent in 50-60% at diagnosis):
  • Fatigue (65%): Most common symptom, often profound and disproportionate to disease severity
  • Pruritus (55%):
    • Worse at night
    • Often affects palms and soles first
    • Due to bile acid accumulation
    • May precede diagnosis by years
• Physical examination findings:
  • Hepatomegaly: Smooth, non-tender liver enlargement
  • Xanthelasma and xanthomas: Due to severe hypercholesterolemia
  • Skin hyperpigmentation: Related to melanin deposition
  • Excoriations: From scratching due to pruritus
• Late features (advanced disease):
  • Jaundice (indicates poor prognosis)
  • Portal hypertension: splenomegaly, varices, ascites
  • Bone pain from osteoporosis

Associated Conditions

PBC frequently occurs with other autoimmune disorders (up to 84% of patients):

• Sjögren's syndrome (50-60%): Dry eyes and dry mouth
• Autoimmune thyroid disease (20%): Usually hypothyroidism
• Raynaud's phenomenon (15%)
• Scleroderma/CREST syndrome (10%)
• Rheumatoid arthritis (10%)
• Celiac disease (6%)

Laboratory Findings

• Liver biochemistry (cholestatic pattern):
  • ↑↑ Alkaline phosphatase (ALP): 2-10× normal
  • ↑ Gamma-GT (GGT): Confirms hepatic origin of ALP
  • Normal or mildly ↑ aminotransferases (ALT, AST)
  • Bilirubin: Normal early, elevated in advanced disease
• Immunological markers:
  • Anti-mitochondrial antibodies (AMA):
    • Positive in 95% of cases
    • Highly specific (98%)
    • M2 subtype most specific
  • Elevated IgM levels
  • ANA positive in 30% (may indicate overlap syndrome)
• Lipid profile:
  • Marked hypercholesterolemia (total cholesterol may exceed 500 mg/dL)
  • Predominantly HDL elevation (not atherogenic)

Diagnosis

Diagnostic Criteria - Need 2 of 3:

1. Elevated ALP (≥1.5x upper limit of normal) for >6 months
2. Positive AMA
3. Liver biopsy showing characteristic histology (rarely needed)

Diagnostic Approach:

• Step 1: Confirm cholestatic pattern on liver tests
• Step 2: Rule out extrahepatic obstruction
  • Ultrasound abdomen - normal bile ducts in PBC
  • MRCP if PSC suspected
• Step 3: Check AMA
  • If positive → diagnosis confirmed
  • If negative → check PBC-specific ANA
• Step 4: Liver biopsy (only if AMA negative and high suspicion)

Differential Diagnosis

Management

First-line therapy:

• Ursodeoxycholic acid (UDCA) 13-15 mg/kg/day:
  • Mechanism: Replaces toxic hydrophobic bile acids with hydrophilic UDCA
  • Benefits: Improves liver biochemistry, delays progression, may improve survival
  • Response assessment at 12 months (Paris criteria)
  • Continue indefinitely, even in asymptomatic patients

Second-line therapy (for UDCA non-responders ~40%):

• Obeticholic acid (5-10 mg/day): FXR agonist, add to or replace UDCA
• Fibrates (bezafibrate, fenofibrate): Off-label use

Symptomatic treatment:

• For pruritus:
  • First-line: Cholestyramine 4-16 g/day
  • Second-line: Rifampicin 150-300 mg/day
  • Third-line: Naltrexone, sertraline
• For fatigue: Modafinil (limited evidence)
• For osteoporosis: Calcium + Vitamin D, bisphosphonates

Liver transplantation:

• Indications: Decompensated cirrhosis, intractable pruritus, recurrent variceal bleeding
• Excellent outcomes: 5-year survival >80%
• Disease recurs in 20-30% post-transplant

Monitoring

• Liver function tests: Every 3-6 months
• Assessment of UDCA response: At 12 months (Paris criteria)
• Screening for complications:
  • Bone density (DEXA): Baseline and every 2-3 years
  • Fat-soluble vitamins: Annual measurement
  • Thyroid function: Annual TSH
  • Hepatocellular carcinoma: Ultrasound every 6 months if cirrhotic
  • Varices: Endoscopy if cirrhotic

Complications

• Metabolic complications:
  • Osteoporosis/osteomalacia (30%): Due to vitamin D deficiency and cholestasis
  • Fat-soluble vitamin deficiencies (A, D, E, K)
  • Steatorrhea and malabsorption
• Portal hypertension complications:
  • Esophageal varices
  • Ascites
  • Hepatic encephalopathy
• Hepatocellular carcinoma: Increased risk (3-5%) in cirrhotic patients
• Hyperlipidemia: Usually not atherogenic due to HDL predominance

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