Key Facts

PBC is a chronic autoimmune liver disease characterised by progressive destruction of small intrahepatic bile ducts, leading to cholestasis and eventually cirrhosis if untreated. Early treatment with UDCA significantly improves outcomes.

Epidemiology

Prevalence ~35 per 100,000 in UK (one of the highest globally). Incidence ~3-4 per 100,000 per year. Female predominance 9:1. Peak age at diagnosis 40-60 years. Strong geographic clustering (North East England has highest prevalence in the world). Familial clustering — first-degree relatives have 100x increased risk.

Aetiology

Autoimmune destruction of biliary epithelial cells. Genetic susceptibility (HLA-DR8) + environmental triggers. AMA targets the E2 component of the pyruvate dehydrogenase complex (PDC-E2) on the inner mitochondrial membrane. Why biliary epithelial cells are selectively targeted remains unclear — possibly because PDC-E2 retains its immunogenic form during apoptosis of biliary cells.

Pathophysiology

Autoimmune destruction of small/medium intrahepatic bile ducts ("vanishing bile duct syndrome") → cholestasis → bile acid accumulation in hepatocytes → toxic injury → periportal inflammation → fibrosis → biliary cirrhosis. The characteristic histological lesion is the florid duct lesion (granulomatous destruction of bile ducts). Disease progresses through 4 stages: portal inflammation → periportal hepatitis → septal fibrosis → cirrhosis.

Early Disease

• Often asymptomatic (detected on routine LFTs)
• Fatigue (most common symptom — 80%; poorly correlates with disease severity; often debilitating)
• Pruritus (70%; may precede jaundice by years; often worse at night; can be severe)

Progressive Disease

• Jaundice (indicates advanced disease)
• Xanthomata and xanthelasma (hypercholesterolaemia)
• Hepatomegaly, splenomegaly
• Osteoporosis (reduced bile acid → malabsorption of calcium/vitamin D)
• Fat-soluble vitamin deficiency (A, D, E, K)

Associated Conditions

• Sjögren syndrome (70%), autoimmune thyroiditis (20%), RA, coeliac disease, scleroderma (CREST variant)

Red Flags

• Rising bilirubin (indicates disease progression)
• Variceal bleeding, ascites (decompensation)
• New hepatic mass (HCC — rare in PBC but can occur in cirrhotic stage)

Bloods

• AMA (anti-mitochondrial antibodies): positive in >95%; M2 subtype most specific
• ALP/GGT: raised (often markedly); hallmark of cholestatic disease
• Bilirubin: normal early; rising = advanced disease (prognostic)
• IgM: raised (characteristic — helps distinguish from AIH)
• ANA: positive in ~30% (ANA-positive PBC)
• Cholesterol: often raised (but NOT associated with increased CVD risk in PBC)
• LFTs: ALT may be mildly raised

Imaging

• USS abdomen: exclude biliary obstruction; assess liver/spleen
• FibroScan: fibrosis staging
• MRCP: if PSC needs exclusion (normal in PBC; beaded ducts in PSC)

Special Tests

• Liver biopsy: NOT required for diagnosis if AMA positive + cholestatic LFTs; indicated if AMA negative or overlap syndrome suspected
  • Histology: florid duct lesion, granulomatous bile duct destruction, ductopenia
  • Staging: I-IV (portal → periportal → septal → cirrhotic)
• DEXA scan: osteoporosis screening at diagnosis
• UK-PBC Risk Score: predicts transplant-free survival

Non-pharmacological

• DEXA scan: at diagnosis; calcium 1000 mg + vitamin D 800 IU daily
• Fat-soluble vitamin supplementation: if cholestasis advanced
• Vaccination: hepatitis A/B if not immune

Pharmacological

• First-line: UDCA 13-15 mg/kg/day (lifelong); improves LFTs, slows histological progression, improves transplant-free survival
  • Assess response at 12 months: adequate response = ALP <1.5× ULN + normal bilirubin + >10% ALP reduction (Paris criteria)
• Second-line (inadequate UDCA response): obeticholic acid (OCA) 5-10 mg OD (FXR agonist — POISE trial; NICE TA774) — caution: dose-related pruritus; contraindicated in decompensated cirrhosis
• Pruritus management:
  • First-line: cholestyramine 4 g QDS (take 1 hour before/4 hours after other drugs including UDCA)
  • Second-line: rifampicin 150-300 mg BD (monitor LFTs fortnightly for 2 months — hepatotoxicity risk)
  • Third-line: naltrexone 25-50 mg OD (opioid antagonist); sertraline 75-100 mg OD
• Fatigue: no specific treatment; exclude other causes (anaemia, hypothyroidism, sleep apnoea); modafinil in selected cases

Surgical/Interventional

• Liver transplantation: for decompensated disease, intractable pruritus, or HCC meeting criteria; excellent post-transplant outcomes (5-year survival >85%); PBC recurs in graft in ~20-30% but rarely clinically significant

Referral Criteria

• All PBC to hepatology for specialist management
• Transplant assessment if decompensated or refractory pruritus
• DEXA/bone health assessment

With UDCA treatment, many patients have near-normal life expectancy (especially those with adequate biochemical response). Without treatment, median time to liver failure is 10-15 years. Rising bilirubin is the strongest predictor of poor outcome. UK-PBC Risk Score predicts transplant-free survival. Post-transplant 5-year survival >85%. PBC recurrence in graft ~20-30% but usually mild.

PBC Response Criteria at 12 Months of UDCA

PBC vs PSC Comparison