This document presents a case study of a 63-year-old male who developed fatal cholestatic liver failure. He had undergone surgery for bladder cancer and cholecystectomy. His liver function tests continued rising after surgery. Extensive testing found no clear cause of cholestasis. Liver biopsies showed features of obstruction or drug effect. He was exposed to imipramine and amoxicillin-clavulanic acid, both known to cause cholestasis. Literature review found rare cases of progressive cholestasis and liver failure from these drugs. The patient's declining condition was treated supportively but he ultimately died of sepsis.

1. A Case of Fatal Cholestatic Liver Failure Senior Clinicopathologic Conference Andre Cap, MD, PhD Walter Reed Army Medical Center

24. Subsequent Hospital Course (6 weeks)

39. General Mechanisms Underlying Injury Drug (xenobiotic) Stable metabolites, excretion P450 bioactivation Detoxification Reactive metabolite Immune mechanisms Nonimmune mechanisms Cell damage

40. Classification NSAIDs, Statins, Bactrim, Amoxicillin / Clavulanate, phenytoin Acetaminophen Carbon tetrachloride Examples Aberrant metabolite; Hypersensitivity Toxic Metabolite Cause Cholestatic / Mixed Hepatocellular Type of reaction Yes No Genetic No Yes Predictable No Yes Dose - dependent Idiosyncratic Intrinsic Feature

47. Acute Hepatocellular Cholestatic Chronic Hepatocellular Cholestatic Vascular Neoplastic Steatosis Phospholipidosis Fibrosis Granulomas Spectrum of Injury

48. Hepatocellular v. Cholestatic Reactions < 1 % Up to 10 % Case fatality rate Rare Yes Acute liver failure Yes No Pruritis + + / - + / - Jaundice ALP AST / ALT Enzyme elevations Cholestatic Hepatocellular Feature

49. Acute Liver Failure: Etiology Ostapowitz G et al. Ann Inter Med 2002;137:947

50. Acute Liver Failure: Definition Rapid onset of hepatic encephalopathy with severe coagulopathy occurring within weeks of symptoms or jaundice in a patient without pre-existing liver disease

53. Cholestasis: Medications Floxuridine Intralesional scolicidal agents (2% formaldehyde, 20% hypertonic saline, absolute alcohol, silver nitrate, iodine solution) Chlorpromazine Flucloxacillin and other oxypenicillins Amoxicillin-clavulanic acid Ampicillin Amitriptyline Azathioprine Barbiturates Carbamazepine Chlorthiazide Cotrimoxazole Clindamycin Chlorpromazine Cimetidine Cyproheptadine Dicloxacillin Erythromycin esters Estradiol Flucloxacillin Haloperidol Ibuprofen Imipramine D-penicillamine Phenytoin Norandrostenolone Prochlorperazine Tetracycline Terbinafine Thiabendazole Tiopronin Tolbutamide Methyl testosterone Dextropropoxyphene Flucoxacillin Carmustine Toxins: paraquat, methylene-dianiline Chlorpromazine Macrolide antibiotics Tricyclic anti-depressants Carbamazepine Amoxicillin-clavulanate Oxypenicillins NSAIDs Azathioprine Estrogens Anabolic steroids Cyclosporine Tamoxifen Azathioprine Sclerosing cholangitis-like Vanishing bile duct syndrome Cholestasis w/ bile duct injury Cholestasis w/ hepatitis Cholestasis w/o hepatitis