Autoimmune destruction of small intrahepatic bile ducts → cholestasis, pruritus, fatigue; AMA-positive in 95%.
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Risk factors
- Female sex, age 40-60
- Family history of PBC or other autoimmune disease
- Smoking
- Recurrent urinary tract infections
- Environmental exposures (xenobiotics, hair dye)
Pathophysiology
Autoimmune injury (T-cell mediated with autoantibody markers — antimitochondrial antibodies (AMA) against the E2 subunit of pyruvate dehydrogenase) targets small bile duct epithelium, producing progressive ductopenia, cholestasis, and bile acid retention with secondary hepatocyte injury, fibrosis, and ultimately cirrhosis.
Clinical presentation
Symptoms
- Often asymptomatic at diagnosis (incidental cholestatic LFT pattern in ~60%)
- Fatigue (the most common symptom, often disabling)
- Pruritus (often nocturnal, worsens before jaundice)
- Right upper quadrant discomfort
- Sicca symptoms (dry eyes, dry mouth)
- Late: jaundice, hepatosplenomegaly, ascites, variceal bleeding (with cirrhosis)
Signs / physical exam
- Hyperpigmentation, xanthelasmas, xanthomas (from prolonged cholestasis and hyperlipidemia)
- Hepatomegaly, splenomegaly
- Excoriations from scratching
- Findings of associated autoimmune disease (Sjögren, thyroid, RA)
- Late: jaundice, ascites, asterixis
Classic findings
Middle-aged woman with fatigue, pruritus, and isolated alkaline phosphatase elevation — check AMA.
Differential diagnosis
- Primary sclerosing cholangitis — Cholestatic pattern with intrahepatic AND extrahepatic bile duct strictures on MRCP; strong IBD association; ANCA may be positive; AMA usually negative
- Autoimmune hepatitis — Hepatocellular (AST/ALT) > cholestatic pattern, ANA/ASMA positive, IgG elevation, interface hepatitis on biopsy
- Drug-induced cholestasis — Temporal relation to medication (amoxicillin-clavulanate, anabolic steroids, OCPs); resolves with withdrawal
- Extrahepatic biliary obstruction (stones, malignancy, stricture) — Dilated extrahepatic ducts on imaging; ERCP/MRCP confirms
- Sarcoidosis with hepatic involvement — Granulomas, pulmonary findings, hypercalcemia, ACE elevation
- IgG4-related sclerosing cholangitis — Elevated IgG4, characteristic imaging, response to corticosteroids
Diagnostic workup
Diagnostic criteria
2 of 3: (1) cholestatic biochemistry (elevated alkaline phosphatase ≥1.5× ULN >6 months), (2) AMA positive (≥1:40) or PBC-specific ANA, (3) liver biopsy showing nonsuppurative destructive cholangitis with bile duct injury. Biopsy not required if first two are met.
Labs
- LFTs — cholestatic pattern: elevated alkaline phosphatase and GGT, normal-to-modestly elevated AST/ALT, normal bilirubin early
- Antimitochondrial antibody (AMA) — positive in ~95%; highly specific
- If AMA negative: AMA-negative PBC variants — anti-sp100, anti-gp210 (PBC-specific ANA patterns)
- IgM (elevated), total IgG (less elevated than AIH)
- Lipid panel (often markedly elevated cholesterol; not strongly atherogenic in PBC)
- TSH (for coexistent autoimmune thyroiditis), celiac serology if symptoms
- Fat-soluble vitamins (A, D, E, K) — deficiency in advanced cholestasis
- Bone density (DEXA) — high osteoporosis risk
Imaging
- Abdominal ultrasound — exclude biliary obstruction; nonspecific for PBC
- MRCP — typically normal in PBC (distinguishes from PSC, which shows beading)
Treatment
First-line
- Ursodeoxycholic acid (UDCA) 13-15 mg/kg/day in divided doses — first-line for all PBC patients; improves transplant-free survival
- Assess biochemical response at 12 months: Paris II / Toronto criteria — alkaline phosphatase reduction to <1.67× ULN and normal bilirubin
Second-line / adjunct
- Obeticholic acid (FXR agonist) 5-10 mg/day — for incomplete UDCA response or intolerance; avoid in advanced cirrhosis (Child B/C, portal hypertension) due to hepatic decompensation risk
- Fibrates (bezafibrate, fenofibrate) — off-label; improve biochemistry in incomplete UDCA responders
- Symptomatic pruritus: cholestyramine (separate from UDCA by ≥4 h), rifampin, naltrexone, sertraline; light therapy and antihistamines adjunctive
- Liver transplantation for end-stage disease or refractory pruritus — excellent outcomes; PBC can recur in graft
Complications
- Cirrhosis with portal hypertension, varices, ascites, encephalopathy
- Hepatocellular carcinoma (lower risk than hepatitis B/C; higher in men with PBC)
- Osteoporosis with fractures
- Hyperlipidemia (paradoxically not strongly associated with atherosclerotic disease)
- Fat-soluble vitamin deficiencies (night blindness, osteomalacia, neuropathy, coagulopathy)
- Severe refractory pruritus
PANCE pearls
- Middle-aged woman + fatigue + pruritus + isolated alk phos elevation → check AMA.
- Cholestatic pattern: alk phos disproportionately elevated relative to AST/ALT. GGT confirms hepatic origin.
- UDCA is the only therapy proven to improve transplant-free survival in PBC — start in all patients.
- Obeticholic acid is now contraindicated in patients with PBC and decompensated cirrhosis (FDA boxed warning).
- PBC has the highest osteoporosis risk of any chronic liver disease — DEXA every 2 years, calcium and vitamin D for all.
References
- AASLD 2018 — AASLD Practice Guidance: Primary Biliary Cholangitis (Lindor et al., Hepatology 2019)
- EASL 2017 — EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis (J Hepatol 2017)
- ACG 2018 — ACG Clinical Guideline: Primary Sclerosing Cholangitis and Primary Biliary Cholangitis (Bowlus et al., 2023 update)
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