Drug-induced liver injury

Last updated: November 20, 2023

Summarytoggle arrow icon

Drug-induced liver injury (DILI) is most commonly caused by antibiotics, anticonvulsants, over-the-counter medications (e.g., NSAIDs, acetaminophen), and herbal or dietary supplements. Patients with DILI may be asymptomatic or present with a range of symptoms, from nausea and fatigue to signs of acute liver failure. Diagnosis requires a thorough clinical assessment of current and prior medication use. Laboratory studies show elevated liver enzymes with a pattern of injury that can be determined as hepatocellular, cholestatic, or mixed, based on the R-value for liver injury. DILI is a diagnosis of exclusion; other diagnoses such as viral hepatitis or biliary disease must be ruled out with laboratory studies and abdominal imaging (e.g., ultrasound). Management primarily includes immediate discontinuation of the offending agent with symptomatic and adjunctive therapies (e.g., N-acetylcysteine) as indicated.

Etiologytoggle arrow icon

Common causative agents of DILI include: [1][2][3]

Consult a comprehensive database of substances associated with liver injury if necessary (see “Tips & links”).

Classificationtoggle arrow icon

By pattern of liver injury [2]

Based on the calculation of the R-value for liver injury: R-value = (ALTSerum / ALTULN)/(ALPSerum / ALPULN) [4]

By mechanism of hepatotoxicity [1]

  • Direct hepatotoxicity (common)
  • Indirect hepatotoxicity
    • Secondary liver injury due to drug effects on the immune system
    • Onset is variable, e.g., weeks to months.
    • Mostly dose-independent
  • Idiosyncratic hepatotoxicity (rare)
    • Secondary liver injury caused by an abnormal immune reaction to the drug
    • Onset is variable, e.g., days to years.
    • Dose-independent

Clinical featurestoggle arrow icon

Patients may be asymptomatic or develop symptoms within days to a year after drug exposure. [5]

Diagnosticstoggle arrow icon

DILI is diagnosed if liver chemistry findings are abnormal, there is a history of exposure to a causative medication, and alternative diagnoses have been excluded. [3]

Approach [2][6]

  • Clinical assessment, including a detailed medication history
  • Initial laboratory studies to confirm clinically significant liver injury, i.e., either:
  • Calculate the R-value for liver injury.
  • Additional studies to rule out alternative diagnoses depending on the pattern of injury
  • Consult hepatology if the cause remains unclear.

A thorough medication history should include prescription and over-the-counter medications, herbal remedies, and dietary supplements, especially within the last 6 months.

Initial laboratory studies [1][2][7]

Elevated serum albumin and elevated INR are signs of severe liver injury. [1]

Additional studies [1][2][3]

Additional laboratory studies

Imaging [7]

Liver biopsy

  • Not routinely required
  • May be considered to:

Differential diagnosestoggle arrow icon

The differential diagnoses listed here are not exhaustive.

Treatmenttoggle arrow icon

For patients with acute liver failure, start treatment immediately: See “Management of acute liver failure.”

General principles [1]

  • Immediately discontinue the offending agent(s).
  • Consider pharmacological treatment, e.g., N-acetylcysteine or glucocorticoids.
  • Initiate inpatient care for patients with dehydration, encephalopathy, and/or coagulopathy.
  • Provide symptomatic management as needed.
  • Determine severity based on prognostic scores (e.g., MELD).
    • Consult hepatology for patients with severe disease.
    • Refer to a transplant center if necessary.
  • Report suspected cases of DILI to the FDA via MedWatch (see “Tips & Links”).

Immediately stop any potential causative agents in patients with DILI.

Drug-specific therapy [1][2][3]

Very few specific drugs provide a clear benefit.

Consider N-acetylcysteine in all patients with acute liver failure related to DILI.

Glucocorticoids [1][3]

Evidence on the use of glucocorticoids in DILI is sparse.

Symptomatic treatment

Follow up [3]

  • Frequently check liver chemistries for improvement after drug discontinuation.
  • Consider other causes if:
    • Peak ALT declines < 50% in 30–60 days
    • Peak ALP or bilirubin decline < 50% or < 2× ULN in 180 days

Recovery from cholestatic DILI is typically slower than recovery from hepatocellular DILI. [3]

Prognosistoggle arrow icon

  • Patients often recover within 6 months of stopping the offending agent.
  • 80% of patients will recover completely, with no sequelae. [1]
  • Patients with acute liver failure have a 25% chance of recovery. [1]
  • Prognostic scores (e.g., MELD, Charlson comorbidity index) can predict 6-month mortality.

Referencestoggle arrow icon

  1. Fontana RJ, Liou I, Reuben A, et al. AASLD practice guidance on drug, herbal, and dietary supplement–induced liver injury. Hepatology. 2023; 77 (3): p.1036-1065.doi: 10.1002/hep.32689 . | Open in Read by QxMD
  2. Chalasani NP, Maddur H, Russo MW, Wong RJ, Reddy KR. ACG Clinical Guideline: Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury. Am J Gastroenterol. 2021; 116 (5): p.878-898.doi: 10.14309/ajg.0000000000001259 . | Open in Read by QxMD
  3. Sandhu N, Navarro V. Drug‐Induced Liver Injury in GI Practice. Hepatol Commun. 2020; 4 (5): p.631-645.doi: 10.1002/hep4.1503 . | Open in Read by QxMD
  4. Kwo PY, Cohen SM, Lim JK. ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries. Am J Gastroenterol. 2017; 112 (1): p.18-35.doi: 10.1038/ajg.2016.517 . | Open in Read by QxMD
  5. Fontana R, Hayashi P. Clinical Features, Diagnosis, and Natural History of Drug-Induced Liver Injury. Semin Liver Dis. 2014; 34 (02): p.134-144.doi: 10.1055/s-0034-1375955 . | Open in Read by QxMD
  6. Camargo CA, Tsai CL, Sullivan AF, et al. Safety Climate and Medical Errors in 62 US Emergency Departments. Ann Emerg Med. 2012; 60 (5): p.555-563.e20.doi: 10.1016/j.annemergmed.2012.02.018 . | Open in Read by QxMD
  7. Andrade RJ, Robles‐Díaz M. Diagnostic and prognostic assessment of suspected drug‐induced liver injury in clinical practice. Liver Int. 2019; 40 (1): p.6-17.doi: 10.1111/liv.14271 . | Open in Read by QxMD
  8. Hodgman MJ, Garrard AR. A Review of Acetaminophen Poisoning. Crit Care Clin. 2012; 28 (4): p.499-516.doi: 10.1016/j.ccc.2012.07.006 . | Open in Read by QxMD
  9. Schneider BJ, Naidoo J, Santomasso BD, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. J Clin Oncol. 2021; 39 (36): p.4073-4126.doi: 10.1200/jco.21.01440 . | Open in Read by QxMD
  10. Mack CL, Adams D, Assis DN, et al. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology. 2020; 72 (2): p.671-722.doi: 10.1002/hep.31065 . | Open in Read by QxMD

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