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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 - treatment of drug induced hepatotoxicity in the absence of acute liver failure is supportive* - N-acetylcysteine use is common practice for drug-induced liver injury, but is not evidence based except for acetaminphen toxicity - 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. - Medical Knowledge Self Assessment Program (MKSAP) 20 American College of Physicians, Philadelphia 2025
  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
  14. Chalasani NP, Maddur H, Russo MW, et al; Practice Parameters Committee of the American College of Gastroenterology. ACG clinical guideline: diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2021;116:878-898. PMID: 33929376