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hepatotoxicity

Toxic to the liver. Etiology: - hepatotoxic pharmaceutical agents include: - acetaminophen (paracetamol)* most common [3] - allopurinol - aminosalicylate - amoxicillin/clavulanate (Augmentin)* - chlorpromazine - dapsone - didanosine - erythromycin estolate - estrogens - ethionamide - glyburide - halothane - isoniazid - ketoconazole - methimazole - methotrexate - methoxyflurane - methyldopa - monoamine oxidase (MAO) inhibitors - niacin (nicotinic acid) - nifedipine - nitrofurantoin - phenytoin* - propoxyphene - propylthiouracil - pyridium - rifampin - salicylates - sulfonamides - tamoxifen - tetracyclines - trimethoprim/sulfamethoxazole - valproic acid (sodium valproate)* - vitamin A - zidovudine - >= 10 events/10,000 person years - stavudine, erlotinib, lenalidomide or thalidomide, chlorpromazine, metronidazole, prochlorperazine, isoniazid [13] - 5-10 events/10,000 person years - moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, ciprofloxacin [13] * most common culprits [2,4] Epidemiology: - single prescription medication in 73% of subjects - dietary supplement in 9% - more that 1 prescription medication (or a prescription plus a dietary supplement) in 18% - most commonly implicated drug classes were antibiotics (46%) & central nervous system agents, i.e. antiseizure or psychotropic drugs (15%) - most commonly implicated single agent was amoxicillin/clavulanate (23 cases) - nitrofurantoin, isoniazid, & trimethoprim/sulfamethoxazole were implicated in 13 cases each - as defined by specified patterns of serum ALT & serum ALP, a) 57% of cases hepatocellular b) 23% cholestatic c) 20% were mixed - 69% of patients developed jaundice, - 60% were hospitalized - 8% died within 6 months [2] Pathology: 1) acute liver injury a) acetaminophen b) isoniazid 2) chronic liver injury a) nitrofurantoin b) minocycline c) methyldopa 3) fibrosis & cirrhosis a) methotrexate b) vitamin A 4) jaundice a) erythromycin b) amoxicillin/clavulanate (Augmentin) c) chlorpromazine d) estrogens 5) hypersensitivity - phenytoin 6) fatty liver a) amiodarone b) tamoxifen c) valproic acid d) didanosine Complications: - hospitalization (59%) - liver failure requiring liver transplantation (4.5%) - acetaminophen overdose is most common cause [3] - death (4.8%) - persistent liver damage (19%) [6] Differential diagnosis: - viral hepatitis, especially acute hepatitis C infection Management: - remove offending agent - N-acetylcysteine used to treat acute liver failure due to drug-induced liver injury (including drugs other than acetaminophen) - see acetaminophen toxicity - treatment of drug induced hepatotoxicity in the absence of acute liver failure is supportive* - prognosis is generally good after removal of offending agent [3] - refer to liver transplantation center for encephalopathy, coagulopathy, or acute liver failure [3] * other than acetaminophen

Related

hepatic injury

Specific

hepatoxic botanicals

General

toxicity; poisoning; overdose liver disease

References

  1. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook, Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 829-39
  2. Chalasani N et al. for the Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008 Dec; 135:1924. PMID: 18955056
  3. Medical Knowledge Self Assessment Program (MKSAP) 15, 16, 17, 18. American College of Physicians, Philadelphia 2009, 2012, 2015, 2018.
  4. Bjornsson ES et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013 Jun; 144:1419. PMID: 23419359
  5. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006 Feb 16;354(7):731-9. PMID: 16481640
  6. Fontana RJ et al. Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology 2014 Jul; 147:96 PMID: 24681128
  7. Ghabril M, Chalasani N, Bjornsson E Drug-induced liver injury: a clinical update. Curr Opin Gastroenterol. 2010 May;26(3):222-6. PMID: 20186054
  8. Bjornsson E Review article: drug-induced liver injury in clinical practice. Aliment Pharmacol Ther. 2010 Jul;32(1):3-13 PMID: 20374223
  9. Verma S, Kaplowitz N. Diagnosis, management and prevention of drug-induced liver injury. Gut. 2009 Nov;58(11):1555-64. PMID: 19834119
  10. Lee WM, Hynan LS, Rossaro L et al Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009 Sep;137(3):856-64, 864.e1. Erratum in: Gastroenterology. 2013 Sep;145(3):695. Dosage error in article text. PMID: 19524577
  11. Chalasani NP, Hayashi PH, Bonkovsky HL et al ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014 Jul;109(7):950-66; PMID: 24935270
  12. Hoofnagle JH, Bjornsson ES. Drug-Induced Liver Injury - Types and Phenotypes. N Engl J Med 2019; 381:264-273, July 18 PMID: 31314970 https://www.nejm.org/doi/full/10.1056/NEJMra1816149
  13. Torgersen J, Mezochow AK, Newcomb CW et al Severe Acute Liver Injury After Hepatotoxic Medication Initiation in Real-World Data. JAMA Intern Med. 2024 Jun 24:e241836. PMID: 38913369 PMCID: PMC11197444 Free PMC article. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2820267