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Drug-Induced Acute Liver Failure in the US 2005: Results from the US Acute Liver Failure Study Group

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Drug-Induced Acute Liver Failure in the US 2005: Results from the US Acute Liver Failure Study Group

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    1. Drug-Induced Acute Liver Failure in the US 2005: Results from the US Acute Liver Failure Study Group William M. Lee, MD Meredith Mosle Chair in Liver Disease UT Southwestern Medical Center Dallas, TX www8.utsouthwestern.edu/liver

    3. Altered mentation, coagulopathy, no cirrhosis Relatively rare disease: ca. 2,000 cases/yr No one center can study the condition High mortality/morbidity Transplantation has helped – but ALF remains largely untreatable or uses large amt resources DILI ALF is the top of a larger iceberg

    4. Acute Liver Failure Study Group Funded by NIH R03, FDA Orphan Grant, Now R01 (‘00-’05) 14 sites initially 1998, now 25 Also 25 pediatric sites, since 2000 820 cases in adult, 320 in pediatric registry N-acetylcysteine trial for non-APAP ALF Numerous (38) ancillary studies in progress Provides a surveillance network for DILI cases

    13. Narcotic:APAP Combinations Is there a rationale for them? Is there really synergy between pain relievers? Isn’t it just easier to prescribe: no triplicate? How many abuse these combinations? Do we need triplicates any longer? Electronic tracking used widely to prevent multiple Rx Would separation of combinations work?

    15. Acetaminophen (APAP) adducts assay HPLC-EC detects APAP-cysteine residues Highly sensitive and specific Remains positive up to 9 days after ingestion Present in 20% of indeterminate cases, peds and adults

    17. Anti-TB drugs: 16 8 INH without other anti-TB drugs 2 with other non-TB drugs 5 INH + rifampin + pyrazinamide 1 INH + ethambutol 2 rifampin + pyrazinamide Sulfa-related drugs : 6 Septra, sulfadiazine, sulfasalazine Other antibiotics: 8 1 Augmentin, 4 nitrofurantoin, 1 ciprofloxacin, 1 doxycycline, 1 itraconazole

    19. Statins: Do They Lead to ALF? Case #1: 61 yo African American woman, survived pravastatin x 6 months Other drugs: losartan, HCTZ, metformin, ASA – 6 months paroxetine, trazodone – 12 months; TMP/SMX – 14 Days Case #2: 59 yo Caucasian woman, transplanted simvastatin x 6 months 20 mg qd, x 3 wks 40 mg qd Other drugs: Prempro, synthroid – 6 months; vitamin A ?high dose, vitamin E– 6 wks Labs: Bili 23.2, AST 649, ALT 471, Alk Phos 201, INR 4.4, ANA 1:160, ASMA 1:40 Case #3: 40 yr Caucasian woman, transplanted simvastatin x 2 months; atorvastatin x 1 month Other drugs: fexofenadine, Lo-Ovral – 24-36 months, nitrofurantoin – 12 months Case #4 62 yr Caucasian woman, died atorvastatin x 36 months Other drugs: atenolol, HCTZ, chlothalidone x 60 months’ use Labs: Bili 28.1, AST 267, ALT 477, Alk Phos 176, INR 1.6, creat 3.6

    20. Causality Assessment in DILI ALF Remains a major issue/need All reports rely on the site investigator’s judgment Medication lists are often inaccurate RUCAM requires specifics that often cannot be met Guilt by association at best DNA assays would fill a need here Adduct assays might be useful for other drugs

    21. Pediatric ALF Due to Drugs: 6% of first 189 cases

    24. Prognosis in Acute Liver Failure Good prognosis: Acetaminophen Hepatitis A Shock Bad prognosis: Drugs Indeterminate Hepatitis B Wilson Disease

    25. 6 sites contributed: Kings, London; Rigshospitalet, Copenhagen; Hannover, Germany; Aga Khan, Karachi; Royal Prince Alfred, Sydney; Queen Mary Hospital, Hong Kong 284 patients over a 2 yr period: 7/02-6/04 54% female Overall etiologies similar but striking regional differences

    27. Summary: ALF in the US An Ongoing Problem More than 60% related to drugs: APAP ~ 50% A disease of developed countries Viral hepatitis may be on the decline Indeterminate cases still not elucidated Transplantation not an option for many Much work to be done

    28. Current ancillary studies on DILI Overview of the idiosyncratic group still in process False positive APAP assays APAP adducts assays DNA studies: cytokine polymorphisms USC APAP DNA polymorphism studies: Cyp 2E1: University of Louisville Glucuronidation: Boston University

    29. Limit the number of drug-induced cases, particularly acetaminophen-related Finish testing N-acetylcysteine for non-ACM ALF Test hypothermia as treatment for ALF Internationalize the multi-center data study Broaden surveillance (different definitions)

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