Episode two works primary biliary cholangitis, the anti-mitochondrial-antibody cholestatic disease of the middle-aged woman, as a biochemical-target-driven problem. The diagnosis is usually made on labs alone, treatment starts with ursodeoxycholic acid for everyone, and escalation is driven by where the alkaline phosphatase and bilirubin sit at twelve months, because those numbers are the surrogate for survival. The second-line landscape changed when obeticholic acid left the US market, leaving elafibranor and seladelpar as the two approved PPAR-targeted agents that tend to improve rather than worsen the itch. The close is the stepped, mechanism-targeted pruritus algorithm from cholestyramine through rifampin, sertraline, naltrexone, and the emerging ileal transporter inhibitors. Topics covered Clinical picture and pathogenesis of primary biliary cholangitis Lab-based diagnosis and when biopsy is needed Florid duct lesion and staging Biphasic natural history and prognostic scores Ursodeoxycholic acid mechanism and twelve-month response Second-line agents after obeticholic acid withdrawal Fat-soluble vitamins, bone, and the lipid profile Stepped mechanism-targeted pruritus algorithm Ileal bile acid transporter inhibitors Key decisions Diagnose primary biliary cholangitis on labs alone when there is a positive anti-mitochondrial antibody, an alkaline phosphatase above one and a half times normal, and transaminases under five times normal with no alternative explanation; biopsy is unnecessary and reserved for antibody-negative disease or suspected overlap. Start every patient on ursodeoxycholic acid thirteen to fifteen milligrams per kilogram per day for life, and assess response at twelve months: the alkaline phosphatase should fall toward one and a half times normal with a normal bilirubin, and failure or intolerance triggers a second agent. Use the twelve-month continuous risk scores that combine age, bilirubin, alkaline phosphatase, albumin, and platelets to identify the roughly one third of non-responders who face higher risk of cirrhosis, transplant, and death. Obeticholic acid was withdrawn from the US market in 2025 for liver-injury signals, leaving elafibranor and seladelpar, both PPAR agonists, as the only approved second-line agents, chosen by tolerability rather than a clear efficacy difference. Do not reflexively add a statin for high total cholesterol, because the profile is dominated by lipoprotein X and HDL and is generally not atherogenic; statins are safe but reserved for patients with conventional risk factors. Run pruritus as a stepped sequence: cholestyramine first, dosed at least one hour before or four hours after other drugs, then rifampin with liver tests at four to eight weeks, then sertraline, then low-dose naltrexone. Stop rifampin at any signal of worsening transaminases or rising bilirubin, since idiosyncratic hepatotoxicity occurs in the first couple of months, rather than reducing the dose and continuing. For the full chapter with MCQs, tables, and primary-guideline references, visit www.boardpearls.com. Questions or feedback: [email protected]. (00:00) - The middle-aged woman with cholestatic labs (00:27) - Clinical picture and pathogenesis (01:23) - Lab-based diagnosis and when to biopsy (02:50) - Biphasic natural history and risk scores (04:08) - Ursodeoxycholic acid and twelve-month response (05:44) - Second-line agents after obeticholic acid (07:32) - Vitamins, bone, and the lipid trap (08:23) - The stepped pruritus algorithm

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