PBC

**Terminology:** Renamed from "primary biliary cirrhosis" to "primary biliary cholangitis" because most patients do not have cirrhosis at diagnosis. (Note: PBC can also abbreviate other terms, e.g., peripheral blood cells or pencil beam collimator, but on USMLE it means primary biliary cholangitis.)

**Pathophysiology:** - Autoimmune, T-cell–mediated (CD4+ and CD8+) attack on interlobular and septal intrahepatic bile ducts, with a loss of tolerance to the pyruvate dehydrogenase complex E2 subunit (PDC-E2) on the mitochondria of cholangiocytes. - Progressive duct destruction (ductopenia) leads to cholestasis, then portal inflammation, fibrosis, cirrhosis, and portal hypertension.

**Epidemiology/Risk factors:** - Women, age 40–60 (about 90% female). - Associated with other autoimmune diseases: Sjögren syndrome (most common), autoimmune thyroiditis, CREST/limited systemic sclerosis, celiac disease, rheumatoid arthritis. - Genetic and environmental triggers (family history, smoking, recurrent UTIs).

**Clinical features:** - Often asymptomatic, found incidentally on elevated ALP. - Fatigue (most common symptom) and pruritus (often early, worse at night). - Jaundice, xanthomas and xanthelasmas (hypercholesterolemia), and hepatosplenomegaly appear later. - Steatorrhea and fat-soluble vitamin (A, D, E, K) deficiency, with osteoporosis/osteomalacia. - Late: cirrhosis, portal hypertension (varices, ascites), and hepatic encephalopathy. Risk of hepatocellular carcinoma once cirrhotic.

**Diagnosis:** - Cholestatic pattern: ↑ ALP, ↑ GGT, with direct hyperbilirubinemia later in the disease. Aminotransferases are mildly elevated. - **Anti-mitochondrial antibodies (AMA)**: highly specific (about 95% sensitivity), the key association for boards. - ↑ IgM, ↑ cholesterol; ANA (anti-gp210, anti-sp100) may be present, and these are associated with a worse prognosis. - Diagnosis: cholestatic labs + positive AMA is enough, and biopsy is usually unnecessary. - Imaging (MRCP/ultrasound) is normal, which rules out large-duct obstruction and distinguishes PBC from PSC. - Biopsy (if done): granulomatous destruction of bile ducts ("florid duct lesion"), lymphocytic portal infiltrate, and ductopenia.

**Management:** - First-line: **ursodeoxycholic acid (UDCA)**, which slows progression. - Second-line: obeticholic acid (FXR agonist), added for inadequate UDCA response (fibrates and PPAR agonists such as seladelpar or elafibranor are also used). Obeticholic acid can worsen pruritus and is contraindicated in decompensated cirrhosis. - Symptomatic: cholestyramine for pruritus. Supplement fat-soluble vitamins, and screen and treat osteoporosis. - Liver transplant for end-stage disease. PBC can recur in the graft.

**PBC vs. PSC (high-yield comparison):** - PBC: middle-aged women, AMA+, intrahepatic small ducts, ↑ IgM, "onion-skin" fibrosis is NOT seen (that is PSC). Associated with Sjögren syndrome and other autoimmune disease. - PSC: men aged 30–50, p-ANCA+, associated with ulcerative colitis, "beaded" bile ducts on MRCP/ERCP, "onion-skin" periductal fibrosis, and risk of cholangiocarcinoma.

**Complications:** cirrhosis, portal hypertension, hepatocellular carcinoma, osteoporosis, fat-soluble vitamin deficiency, hyperlipidemia.