Acute Liver Failure Due to Drugs

ABSTRACT

Acetaminophen overdose and idiosyncratic drug-induced liver injury (DILI) are the most commonly identified causes of acute liver failure (ALF) in the United States. Suspected acetaminophen hepatotoxicity can be effectively treated with N-acetylcysteine but still an estimated 500 patients die each year. Product labeling changes, dispensing restrictions, and reformulation of acetaminophen containing narcotic analgesics have been proposed to reduce the rising incidence of this preventable form of dose-dependent liver injury. In contrast, idiosyncratic DILI is not preventable due to our lack of understanding of host susceptibility and outcome factors. Patients with ALF due to DILI are difficult to diagnose and have a low likelihood of spontaneous recovery. Patients with severe idiosyncratic DILI should be urgently referred to a transplant center as there are no established medical treatments beyond drug discontinuation. Investigation of host variability in metabolic, regeneration, and immunological pathways may provide insights into the molecular basis of DILI as well as improved diagnostic and prognostic biomarkers.

Hepatotoxicity - acute liver failure - idiosyncratic - causality assessment

REFERENCES

• 1 Centers for Disease Control and Prevention . Nonfatal, unintentional medication exposures among young children: United States 2001-2003.  MMWR Morb Mortal Wkly Rep. 2006;  55(RR-16) 1-5
• 2 Lazarou J, Pomeranz B H, Corey P N. Incidence of adverse drug reactions in hospitalized patients: an analysis of prospective studies.  JAMA. 1998;  279 1200-1205
• 3 Lee W M, Senior J R. Recognizing drug-induced liver injury: current problems, possible solutions.  Toxicol Pathol. 2005;  33 155-164
• 4 Navarro V J, Senior J R. Drug-related hepatotoxicity.  N Engl J Med. 2006;  354 731-739
• 5 Ostapowicz G, Fontana R J, Schiødt F V et al.. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States.  Ann Intern Med. 2002;  137 947-954
• 6 Watkins P B. Idiosyncratic liver injury: challenges and approaches.  Toxicol Pathol. 2005;  33 1-5
• 7 Meier Y, Cavallaro M, Roos M et al.. Incidence of drug-induced liver injury in medical inpatients.  Eur J Clin Pharmacol. 2005;  61 135-143
• 8 Duh M S, Walker A M, Kronlund Jr K H. Descriptive epidemiology of acute liver enzyme abnormalities in the general population of central Massachusetts.  Pharmacoepidemiol Drug Saf. 1999;  8 275-283
• 9 Beard K, Belic L, Aselton P et al.. Outpatient drug-induced parenchymal liver disease requiring hospitalization.  J Clin Pharmacol. 1986;  26 633-637
• 10 Galan M V, Potts J A, Silverman A L, Gordon S C. The burden of acute non-fulminant drug-induced hepatitis in a United States tertiary referral center.  J Clin Gastroenterol. 2005;  39 64-67
• 11 Vuppalanchi R, Liangpunsakul S, Chalasani N. Etiology of new-onset jaundice: how often is it caused by idiosyncratic jaundice in the United States?.  Am J Gastroenterol. 2007;  102 558-562
• 12 De Valle M B, Klinteberg A V, Alem N, Olsson R, Bjornsson E. Drug-induced liver injury in a Swedish University hospital outpatient hepatology clinic.  Aliment Pharmacol Ther. 2006;  24 1187-1195
• 13 Sgro C, Clinard F, Ouazier K et al.. Incidence of drug-induced hepatic injuries: a French population-based study.  Hepatology. 2002;  36 451-455
• 14 Verma A, Lilienfeld D E. The need for a population-based surveillance system for liver disease in the United States.  Pharmacoepidemiol Drug Saf. 2004;  13 821-824
• 15 Hoofnagle J H. Drug-Induced Liver Injury Network (DILIN).  Hepatology. 2004;  40 773
• 16 Kaplowitz N. Causality assessment versus guilt-by-association in drug hepatotoxicity.  Hepatology. 2001;  33 308-310
• 17 Andrade R J, Lucena M I, Fernandez M C et al.. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.  Gastroenterology. 2005;  129 512-521
• 18 Ibanez L, Perez E, Vidal X, Laporte J R. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic disease: epidemiological and clinical features, and exposure to drugs.  J Hepatol. 2002;  37 592-600
• 19 Sharp J R, Ishak K G, Zimmerman H J. Chronic active hepatitis and severe hepatic necrosis associated with nitrofurantoin.  Ann Intern Med. 1980;  92 14-19
• 20 Lucena M I, Andrade R J, Fernandez M C et al.. Determinants of the clinical expression of amoxicillin-clavulanate hepatotoxicity: a prospective series from Spain.  Hepatology. 2006;  44 850-856
• 21 Lucena M I, Camargo R, Andrade R J, Perez-Sanchez C F, Sanchez De La Cuesta F. Comparison of two clinical scales for causality assessment in hepatotoxicity.  Hepatology. 2001;  33 123-130
• 22 Graham D J. Telithromycin and acute liver failure.  N Engl J Med. 2006;  355 2260-2261
• 23 Gitlin N, Neil J L, Spurr C L et al.. Two cases of severe clinical and histologic hepatotoxicity associated with troglitazone.  Ann Intern Med. 1998;  129 36-38
• 24 Kohlroser J, Mathai J, Reichheld J, Banner B F, Bonkovsky H L. Hepatotoxicity due to troglitazone: report of two cases and review of adverse events reported to the United States Food and Drug Administration.  Am J Gastroenterol. 2000;  95 272-276
• 25 Molinari M, Watt K DS, Kruszyna T et al.. Acute liver failure induced by green tea extracts: case report and review of the literature.  Liver Transpl. 2006;  12 1892-1895
• 26 Wai C T, Tan B H, Chan C L et al.. Drug-induced liver injury at an Asian center: a prospective study.  Liver Int. 2007;  27 465-474
• 27 Shapiro M A, Lewis J H. Causality assessment of drug-induced hepatotoxicity: promises and pitfalls.  Clin Liver Dis. 2007;  11 477-505
• 28 Danan G, Benichou C. Causality assessment of adverse reactions to drugs-I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries.  J Clin Epidemiol. 1993;  46 1323-1330
• 29 Rockey D C, Seeff L B, Freston J W et al.. Comparison between expert opinion and RUCAM for assignment of causality in drug-induced liver injury [abstract].  Gastroenterology. 2007;  132 M1777
• 30 Leeder J S, Xu X, Timsit Y, Gaedigk A. Non-monooxygenase cytochromes P450 as potential human autoantigens in anticonvulsant hypersensitivity reactions.  Pharmacogenetics. 1998;  8 211-225
• 31 Aithal G P, Ramsay L, Daly A K et al.. Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity.  Hepatology. 2004;  39 1430-1440
• 32 Sullivan J R, Shear N H. The drug hypersensitivity syndrome: what is the pathogenesis?.  Arch Dermatol. 2001;  137 357-364
• 33 Neuman M G, Shear N H, Malkiewicz I M et al.. Immunopathogenesis of hypersensitivity syndrome reactions to sulfonamides.  Transl Res. 2007;  149 243-253
• 34 Takikawa H, Takamori Y, Kumagi T et al.. Assessment of 287 Japanese cases of drug-induced liver injury by the diagnostic scale of the International Consensus Meeting.  Hepatol Res. 2003;  27 192-195
• 35 Davern T J, James L P, Hinson J A et al.. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure.  Gastroenterology. 2006;  130 687-694
• 36 James L P, Mayeux P R, Hinson J A. Acetaminophen-induced hepatotoxicity.  Drug Metab Dispos. 2003;  31 1499-1506
• 37 Watkins P B, Seeff L B. Drug-induced liver injury: summary of a single-topic clinical research conference.  Hepatology. 2006;  43 618-631
• 38 Wilke R A, Lin D W, Roden D M et al.. Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges.  Nat Rev Drug Discov. 2007;  6 904-916
• 39 O'Donohue J, Oien K A, Donaldson P et al.. Co-amoxiclav jaundice: clinical and histological features and HLA class II association.  Gut. 2000;  47 717-720
• 40 Andrade R J, Lucena I, Alonso A et al.. HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease.  Hepatology. 2004;  39 1603-1612
• 41 Pachkoria K, Lucena M I, Ruiz-Cabello F et al.. Genetic polymorphisms of CYP2C9 and CYP2C19 are not related to drug-induced idiosyncratic liver injury (DILI).  Br J Pharmacol. 2007;  150 808-815
• 42 Liu C, Aronow B J, Jeffa A G et al.. Novel resequencing chip customized to diagnose mutations in patients with inherited syndromes of intrahepatic cholestasis.  Gastroenterology. 2007;  132 119-126
• 43 Pauli-Magnus C, Meier P J. Hepatobiliary transporters and drug-induced cholestasis.  Hepatology. 2006;  44 778-787
• 44 Watanabe I, Tomita A, Shimizu M et al.. A study to survey susceptible genetic factors responsible for troglitazone-associated hepatotoxicity in Japanese patients with type 2 diabetes mellitus.  Clin Pharmacol Ther. 2003;  73 435-455
• 45 Kleiner D A, Chalasani N P, Conjeevaram H S et al.. Relationship of biochemical to histologic findings and the pathological pattern of injury among cases identified in the NIH Drug-Induced Liver Injury Network (DILIN) study [abstract].  Gastroenterology. 2007;  137 M1775
• 46 Bjornsson E, Kalaitzakis E, Olsson R. The impact of eosinophilia and hepatic necrosis on prognosis in patients with drug-induced liver injury.  Aliment Pharmacol Ther. 2007;  25 1411-1421
• 47 Donaldson B W, Gopinath R, Wanless I R et al.. The role of transjugular liver biopsy in fulminant liver failure: relation to other prognostic indicators.  Hepatology. 1993;  18 1370-1376
• 48 Hanau C, Munoz S J, Rubin R. Histopathological heterogeneity in fulminant hepatic failure.  Hepatology. 1995;  21 345-351
• 49 Stravitz R T, Kramer A H, Davern T et al.. Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group.  Crit Care Med. 2007;  35 2498-2508
• 50 Trey C, Davidson C S. The management of fulminant hepatic failure.  Prog Liver Dis. 1970;  3 282-298
• 51 Hoofnagle J H, Carithers R L, Shapiro C et al.. Fulminant hepatic failure: summary of a workshop.  Hepatology. 1995;  21 240-253
• 52 Dalton H R, Fellows H J, Stableforth W et al.. The role of hepatitis E virus testing in drug-induced liver injury.  Aliment Pharmacol Ther. 2007;  26 1429-1435
• 53 Teo E K, Ostapowicz G, Hussain M et al.. Hepatitis B infection in patients with acute liver failure in the United States.  Hepatology. 2001;  33 972-976
• 54 Levitsky J, Thadareddy A, Lakeman F D et al.. Quantitative measurement of herpes simplex virus before and after liver transplantation.  , [abstract] Am J Transplant. 2007;  7(suppl 2) 1388
• 55 Lee W M, Brown K E, Young N S et al.. Brief report: no evidence of parvovirus B19 or hepatitis E virus as causes of acute liver failure.  Dig Dis Sci. 2006;  51 1712-1715
• 56 Umemura T, Tanaka E, Ostapowicz G et al.. Investigation of SEN virus infection in patients with cryptogenic acute liver failure, hepatitis-associated aplastic anemia, or acute and chronic non-A-E hepatitis.  J Infect Dis. 2003;  188 1545-1552
• 57 Russo M W, Galanko J A, Shrestha R et al.. Liver transplantation for acute liver failure from drug-induced liver injury in the United States.  Liver Transpl. 2004;  10 1018-1023
• 58 Wong W M, Wu P C, Yuen M F et al.. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection.  Hepatology. 2000;  31 201-206
• 59 Mok M Y, Ng W L, Yuen M F et al.. Safety of disease-modifying anti-rheumatic agents in rheumatoid arthritis patients with chronic viral hepatitis.  Clin Exp Rheumatol. 2000;  18 363-368
• 60 Zachariae H. Liver biopsies and methotrexate: a time for reconsideration?.  J Am Acad Dermatol. 2000;  42 531-534
• 61 Rutherford A, Davern T, Hay J E et al.. Influence of high body mass index on outcome in acute liver failure.  Clin Gastroenterol Hepatol. 2006;  4 1544-1549
• 62 Lammert C, Bjornsson E, Saha C et al.. Relationship between medication dose and idiosyncratic drug-induced liver injury.  Hepatology. 2007;  46(suppl 1) A1288
• 63 Squires R H, Shneider B L, Bucuvalas J et al.. Acute liver failure in children: the first 348 patients in the Pediatric Acute Liver Failure Study Group.  J Pediatr. 2006;  148 652-658
• 64 Lewis J H. “Hy's Law,” the “Rezulin Rule,” and other predictors of severe drug-induced hepatotoxicity: putting risk-benefit into perspective.  Pharmacoepidemiol Drug Saf. 2006;  15 221-229
• 65 Zimmerman H J. Hepatoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver. 2nd ed. Philadelphia, PA; Lippincott Williams & Wilkins 1999
• 66 Bjornsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease.  Hepatology. 2005;  42 481-489
• 67 Ohmori S, Shiraki K, Inoue H et al.. Clinical characteristics and prognostic indicators of drug-induced fulminant hepatic failure.  Hepatogastroenterology. 2003;  50 1531-1534
• 68 Food and Drug Administration . Guidance for industry: drug-induced liver injury: premarketing clinical evaluation.  Fed Regist. 2007;  , October 24
• 69 O'Grady J G, Alexander G JM, Hayllar K M et al.. Early indicators of prognosis in fulminant hepatic failure.  Gastroenterology. 1989;  97 439-455
• 70 Pauwels A, Mostefa-Kara N, Florent C et al.. Emergency liver transplantation for acute liver failure: evaluation of London and Clichy criteria.  J Hepatol. 1993;  17 124-127
• 71 Bernal W, Donaldson N, Wyncoll D et al.. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study.  Lancet. 2002;  359 558-563
• 72 Larson A M, Polson J, Fontana R J et al.. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study.  Hepatology. 2005;  42 1364-1372
• 73 Schmidt L E, Dalhoff K. Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injury.  Hepatology. 2005;  41 26-31
• 74 Schmidt L E, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity.  Hepatology. 2002;  36 659-665
• 75 Makin A J, Wendon J, Williams R. A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993).  Gastroenterology. 1995;  109 1907-1916
• 76 Constantine J K, Wendon J, Safinia N et al.. Long-term outcomes for patients transplanted for acetaminophen-induced acute liver failure: no worse than for other etiologies.  , [abstract] Hepatology. 2007;  46 575
• 77 Davies M H, Harrison R F, Elias E, Hubscher S G. Antibiotic-associated acute vanishing bile duct syndrome: a pattern associated with severe, prolonged, intrahepatic cholestasis.  J Hepatol. 1994;  20 112-116
• 78 Levy C, Linder K D. Drug-induced cholestasis.  Clin Liver Dis. 2003;  7 311-330
• 79 Aithal P G, Day C P. The natural history of histologically proved drug-induced liver disease.  Gut. 1999;  44 731-735
• 80 Andrade R J, Lucena M I, Kaplowitz N et al.. Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry.  Hepatology. 2006;  44 1581-1588
• 81 Bénichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting.  J Hepatol. 1990;  11 272-276
• 82 Bjornsson E, Kalaitzakis E, Av Klintberg V, Alem N, Olsson R. Long-term follow-up of patients with mild to moderate drug-induced liver injury.  Aliment Pharmacol Ther. 2007;  26 79-85
• 83 Sterling R K, Luketic V A, Sanyal A J et al.. Treatment of fulminant hepatic failure with intravenous prostaglandin E1.  Liver Transpl Surg. 1998;  4 424-431
• 84 O'Grady J G, Gimson A E, O'Brien C J et al.. Controlled trials of charcoal hemoperfusion and prognostic factors in fulminant hepatic failure.  Gastroenterology. 1988;  94 1186-1192
• 85 Demetriou A A, Brown R S, Busuttil R W et al.. Prospective, randomized, multicenter controlled trial of a bioartificial liver in treating acute liver failure.  Ann Surg. 2004;  239 660-667
• 86 Pohle T, Menzel J, Domschke W. Minocycline and fulminant hepatic failure necessitating liver transplantation.  Am J Gastroenterol. 2000;  95 560-561
• 87 Furhoff A K. Adverse reactions with methyldopa: a decade's reports.  Acta Med Scand. 1978;  203 425-428
• 88 Gough A, Chapman S, Wagstaff K, Emery P, Elias E. Minocycline-induced autoimmune hepatitis and systemic lupus erythematous-like syndrome.  BMJ. 1996;  312 169-172
• 89 Dechene A, Treicherl U, Gerken G et al.. Effectiveness of a steroid and ursodeoxycholic acid combination therapy with drug-induced subacute liver failure.  Hepatology. 2005;  42 A358
• 90 Rakela J, Mosley J W, Edwards V M et al.. A double-blinded randomized trial of hydrocortisone in acute hepatic failure.  Dig Dis Sci. 1991;  36 1223-1228
• 91 European Association for the Study of the Liver Group . Randomized trial of steroid therapy in acute liver failure.  Gut. 1979;  20 620-623
• 92 Walsh T S, Hopton P, Philips B J et al.. The effect of n-acetylcysteine on oxygen transport and uptake in patients with fulminant hepatic failure.  Hepatology. 1998;  27 1332-1340
• 93 Sklar G E, Subramaniam M. Acetylcysteine treatment for non-acetaminophen-induced acute liver failure.  Ann Pharmacother. 2004;  38 498-501
• 94 Lee W M, Rossaro L, Fontana R J et al.. Intravenous n-acetylcysteine improves spontaneous survival in early stage non-acetaminophen acute liver failure.  , [abstract] Hepatology. 2007;  46 A79
• 95 Legras A, Bergemer-Fouquet A M, Jonville-Bera A P. Fatal hepatitis with leflunomide and itraconazole.  Am J Med. 2002;  113 352-353
• 96 Van Roon E N, Jansen T L, Houtman N M et al.. Leflunomide for the treatment of rheumatoid arthritis in clinical practice: incidence and severity of hepatotoxicity.  Drug Saf. 2004;  27 345-352
• 97 Boyer J L. Nuclear receptor ligands: rational and effective therapy for chronic cholestatic liver disease?.  Gastroenterology. 2005;  129 735-740
• 98 Zimmerman H J, Maddrey W C. Acetaminophen hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure.  Hepatology. 1995;  22 767-773
• 99 Whitcomb D C, Block G D. Association of acetaminophen hepatotoxicity with fasting and ethanol use.  JAMA. 1994;  272 1845-1850
• 100 Schmidt L E, Kalhoff K, Poulsen H E. Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity.  Hepatology. 2002;  35 876-882
• 101 Slattery J T, Nelson S D, Thummel K E. The complex interaction between ethanol and acetaminophen.  Clin Pharmacol Ther. 1996;  60 241-246
• 102 Litovitz T L, Klein-Schwartz W, White S et al.. 2000 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System.  Am J Emerg Med. 2001;  19 337-395
• 103 Bond G R, Hite L K. Population-based incidence and outcome of acetaminophen poisoning by type of ingestion.  Acad Emerg Med. 1999;  6 1115-1120
• 104 Nourjah P, Ahmad S R, Karwoski C, Willy M. Estimates of acetaminophen-associated overdoses in the United States.  Pharmacoepidemiol Drug Saf. 2006;  15 398-405
• 105 Rowden A K, Norvell J, Eldridge D L, Kirk M A. Updates on acetaminophen toxicity.  Med Clin North Am. 2005;  89 1145-1159
• 106 Schiødt F V, Rochling F A, Casey D L et al.. Acetaminophen toxicity in an urban county hospital.  N Engl J Med. 1997;  337 1112-1117
• 107 Lee W M. Acetaminophen toxicity: changing perceptions on a social/medical issue.  Hepatology. 2007;  46 966-970
• 108 Rumack B H. Acetaminophen hepatotoxicity: the first 35 years.  J Toxicol Clin Toxicol. 2002;  40 3-20
• 109 Myers R P, Li B, Fong A, Shaheen A A, Quan H. Hospitalizations for acetaminophen overdose: a Canadian population-based study from 1995-2004.  BMC Public Health. 2007;  7 143-151
• 110 Fontana R J, Adams P C. “Unintentional” acetaminophen overdose on the rise: who is responsible?.  Can J Gastroenterol. 2006;  20 319-324
• 111 Kaplowitz N. Acetaminophen hepatotoxicity: what do we know, what don't we know, and what do we do next?.  Hepatology. 2004;  40 23-26
• 112 Prince M I, Thomas S H, James O F, Hudson M. Reduction in incidence of severe paracetamol poisoning.  Lancet. 2000;  355 2047-2048
• 113 Hawton K, Simkin S, Deeks J et al.. UK legislation on analgesic packs: before and after study of long-term effect on poisonings.  BMJ. 2004;  329 1076
• 114 Food and Drug Administration .21 CRF Parts 201 and 343. Internal analgesic, antipyretic, and antirheumatic drug products for over-the-counter human use: proposed amendment of the tentative final monograph, Required warnings and other labeling. Federal Register Parts 201 and 343 (12/26/06) Available at: http://www.accessdata.fda.gov/scripts/oc/ohrms/frbydocket.cfm
• 115 Osborne Z P, Bryant S M. Patients discharged with a prescription for acetaminophen-containing narcotic analgesics do not receive appropriate written instructions.  Am J Emerg Med. 2003;  21 48-50