Episode three closes the chapter with the four inherited liver diseases beyond the metal pair: alpha-one antitrypsin deficiency, cystic-fibrosis-associated liver disease, polycystic liver disease, and the familial cholestatic syndromes. The unifying move is that mechanism predicts therapy in each one, and each carries a distinct board trap. Alpha-one antitrypsin is the two-organ split where augmentation rescues the lung and does nothing for the liver; CF liver disease is one causal chain treated at three points; polycystic liver disease is synthetic-function-preserved mass effect; and the cholestatic syndromes split by the GGT pattern and cancer risk. Ileal bile acid transporter inhibitors, CFTR modulators, and the MELD exception anchor the modern management. Topics covered Alpha-one antitrypsin two-organ split PiZZ, the null genotype, and PAS-diastase-resistant globules Augmentation and NSAID treatment traps CF-associated liver disease and CFTR modulators Polycystic liver disease and the MELD exception Familial cholestatic syndromes and the GGT split Cancer risk by mechanism IBAT inhibitors and pruritus therapy Alagille syndrome Key decisions In PiZZ alpha-one antitrypsin deficiency, IV augmentation restores circulating anti-elastase and slows lung decline but does nothing for the liver, because hepatic injury is from intracellular polymer, not circulating deficiency. Avoid NSAIDs in PiZZ patients because they increase hepatic alpha-one antitrypsin synthesis and worsen the polymer load; diagnose by phenotyping or genotyping, not the level alone, since it is an acute-phase reactant. The null genotype causes severe early emphysema with normal liver enzymes because no protein is made to accumulate, while PiZZ biopsy shows PAS-positive, diastase-resistant periportal globules. In cystic-fibrosis-associated liver disease, treat at three points: ursodeoxycholic acid downstream, fat-soluble vitamins in the middle, and CFTR modulators upstream, with triple therapy standard for any patient carrying at least one F508del allele. Polycystic liver disease is treated by symptom severity, not cyst count: first-line somatostatin analog, then fenestration or partial hepatectomy, then transplant, with a MELD exception because synthetic function is preserved. The familial cholestatic syndromes split by GGT, with the bile salt export pump and membrane-organizing defects low GGT and the phosphatidylcholine flippase defect high GGT, and the export-pump type carries the highest pediatric liver cancer risk warranting alpha-fetoprotein surveillance. Ileal bile acid transporter inhibitors are the era-defining therapy for pruritus in the progressive intracellular-cholestasis syndromes and Alagille, combined with rifampin and naltrexone. For the full chapter with MCQs, tables, and primary-guideline references, visit www.boardpearls.com. Questions or feedback: [email protected]. (00:00) - Introduction: four diseases, one logic (00:33) - Alpha-one antitrypsin: the two-organ split (04:21) - A1AT treatment: augmentation and NSAID traps (05:57) - CF-associated liver disease: three intervention points (08:25) - Polycystic liver disease: mass effect and MELD exception (11:11) - Familial cholestatic syndromes: the GGT split (13:23) - Cholestasis treatment: IBAT inhibitors and pruritus (15:16) - Alagille syndrome (16:13) - Pulling the four together

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