Drug-induced liver injury

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.

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

• Analgesics: e.g., acetaminophen (in acute overdose or chronic overuse), NSAIDs
• Antimicrobials
  • Antibiotics: e.g., macrolides, trimethoprim/sulfamethoxazole, nitrofurantoin, amoxicillin/clavulanate, fluoroquinolones, doxycycline, dapsone, cephalosporins
  • Antituberculosis therapy: e.g., isoniazid, rifampin, pyrazinamide
  • Antifungals: e.g., terbinafine, itraconazole, ketoconazole
  • Antiretrovirals: e.g., efavirenz, abacavir, didanosine
• Anticonvulsants: e.g., valproic acid, carbamazepine, phenytoin
• Cardiovascular medications: e.g., statins, amiodarone, methyldopa, fibrates, labetalol, ACE inhibitors
• Immune modulators: e.g., methotrexate, leflunomide, azathioprine, sulfasalazine, immune checkpoint inhibitors (ICIs), interferon alpha and interferon beta, TNF inhibitors (e.g., etanercept)
• Antithyroid medication: e.g., propylthiouracil, methimazole
• Other drugs: inhaled anesthetics (e.g., halothane), disulfiram, allopurinol, anabolic steroids, danazol, tolcapone, dopamine antagonists (e.g., chlorpromazine, phenothiazine)
• Herbal and dietary supplements : e.g., ashwagandha, green tea extract, Chinese skullcap, kratom, garcinia cambogia, Polygonum multiflorum

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

By pattern of liver injury ^[2]

Based on the calculation of the R-value for liver injury: R-value = (ALT_Serum / ALT_ULN)/(ALP_Serum / ALP_ULN) ^[4]

• Hepatocellular liver injury: R-value > 5 (most common)
• Cholestatic liver injury: R-value < 2
• Mixed liver injury: R-value 2–5

By mechanism of hepatotoxicity ^[1]

• Direct hepatotoxicity (common)
  • Direct liver injury caused by hepatotoxic drugs
  • Onset usually within days
  • Dose-dependent
• 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

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

• Nausea
• Fatigue
• Abdominal pain
• Features associated with cholestasis (e.g., jaundice, pruritus)
• Signs of acute liver failure (e.g., ascites, encephalopathy)
• Immunoallergic symptoms, e.g., fever, rash (see “Nonimmediate drug hypersensitivity reactions”)

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:
  • AST and/or ALT > 5× ULN and/or ALP > 2× ULN on 2 separate measurements
  • Total bilirubin > 2.5 mg/dL and any elevation of AST, ALT, or ALP
  • INR > 1.5 and any elevation of AST, ALT, or ALP
• 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]

• Liver chemistries: Findings depend on the pattern of injury.
  • Normal or ↑ ALT and/or AST
  • Normal or ↑ ALP
  • Normal or ↑ bilirubin
  • Normal or ↑ albumin
• Coagulation panel: normal or ↑INR

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

Additional studies ^[1][2][3]

Additional laboratory studies

• Hepatocellular or mixed injury patterns
  • All patients
    • Viral hepatitis panel
    • ANA, ASMA: to evaluate for autoimmune hepatitis
  • Select patients based on clinical suspicion
    • HSV, EBV, and CMV PCR ^[5]
    • Serum ceruloplasmin: to assess for Wilson disease
    • Iron studies: to assess for hemochromatosis
    • Serum and/or urine drug or toxin levels (e.g., acetaminophen)
    • α1-antitrypsin: to evaluate for AATD
• Cholestatic injury pattern: AMA to assess for primary biliary cholangitis

Imaging ^[7]

• Ultrasound abdomen
  • Obtain in all patients.
  • Used to assess for cirrhosis, biliary obstruction, or other parenchymal focal lesions
• Advanced abdominal imaging (e.g., CT or MRI abdomen, MRCP): Consider based on clinical suspicion, especially in patients with a cholestatic injury pattern.

Liver biopsy

• Not routinely required
• May be considered to:
  • Increase diagnostic certainty ^[1][3]
  • Assess for alternative diagnoses, e.g., autoimmune hepatitis

• Hepatocellular or mixed injury pattern ^[1]
  • Viral infection
    • Hepatitis types A–E
    • Nonhepatotropic viruses: CMV, EBV, HSV
  • Inherited or autoimmune disorders
    • Autoimmune hepatitis
    • Wilson disease
    • Budd-Chiari syndrome
    • Hemochromatosis
    • α1-antitrypsin deficiency
  • Alcoholic liver disease
  • Nonalcoholic fatty liver disease
  • Ischemic hepatitis
  • Rhabdomyolysis
  • Thyroid disease (i.e., hypothyroidism or thyrotoxicosis)
• Cholestatic injury pattern ^[1]
  • Biliary obstruction (e.g., caused by choledocholithiasis, pancreaticobiliary tumors)
  • Primary sclerosing cholangitis
  • Primary biliary cholangitis
  • Cholestasis due to total parenteral nutrition
  • Bone disease
  • See also “Etiology of jaundice in adults.”

The differential diagnoses listed here are not exhaustive.

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.

• Acetaminophen toxicity ^[8]
  • Start N-acetylcysteine over 3 days. ^[1]
  • Consider activated charcoal and/or gastric lavage for acute acetaminophen overdose.
• Valproate toxicity: Consider L-carnitine in patients with hyperammonemia.
• Leflunomide toxicity: Cholestyramine may be considered in patients with persistent cholestasis to enhance elimination.

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.

• May be considered in patients with, e.g.:
  • Severe immune-mediated drug hypersensitivity reactions (e.g., DRESS)
  • Findings of autoimmunity
  • Hepatotoxicity due to ICIs or tyrosine kinase inhibitors
• Agents include: ^[3]
  • Methylprednisolone for severe ICI-related DILI ^[1][9]
  • Prednisone for all other patients ^[1][10]

Symptomatic treatment

• Management of nausea and vomiting
• Management of cholestasis-associated pruritus
• Management of dehydration

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]

• 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.