DILI Learning Objectives (resident)

Drug-induced liver injury is damage to the hepatobiliary system caused by a drug or dietary supplement, identified by significant liver enzyme elevations without another cause.

Define drug-induced liver injury (DILI)

- ALT > 5× ULN

- Alk Phos > 2× ULN

- ALT > 3× ULN + total bilirubin > 2× ULN

DILI diagnosis labs

- direct

- idiosyncratic

- indirect

DILI occurs through three main mechanisms

- Dose-dependent

- predictable

- Short onset (1-5 days)

- acetaminophen

- Methotrexate

- valproic acid

direct

- Not dose-dependent

- Unpredictable and rare

- Occurs weeks to months after exposure

- Due to patient-specific factors (e.g., genetics)

- augmentin

- isoniazide

- macrobid

- bactrim

- minocycline

- cefazolin

- azrithromycin

- ciprofloxacin

- levofloxacin

idiosyncratic

- Caused by drug effects (not direct toxicity)

- May trigger underlying disease or immune reactions

- Slower onset (months)

- controversial

- immunomodulatory agents, TNF alpha: immune mediated hep

- risperidone, haladol: fatty liver disease

- chemo: reactivation Hep B

indirect

- acetaminophen

- antimicrobials

- herbal supplements

List the most common causative agents of DILI

- Black cohosh

- Kava

- St. John's Wort

- Red yeast ric

herbal supplements

- lipid lowering (statins)

- isoniazid

- valproic acid

- erythromycin

- rifampin

- diclofenac

- acetaminophen/ amiodarone

- methotrexate

- Augmentin

- graves disease (PTU)

- efavirenz/nevirapin (HIV)

Medications

- Avoid high-risk or unnecessary medications

- Monitor liver enzymes for hepatotoxic drugs

- Avoid drug interactions (CYP inhibition)

- Limit alcohol use

- Use caution with herbal supplements

- Educate patients on safe dosing (especially acetaminophen)

Explain methods of prevention for DILI

- proper diagnosis

- Primary treatment: STOP the offending drug

- Avoid re-exposure

- Use antidotes when applicable

- Supportive care

- Monitor liver enzymes and symptoms of acute liver failure

- educate on prevention

- Refer for transplant in severe cases

Describe the management of DILI

N-acetylcysteine

acetaminophen antidote

L-carnitine

valproic acid antidote

hepatotoxicity

valproic acid BBW

- Confirm drug exposure before injury

- Exclude other causes

- Improvement after discontinuation

Diagnosis involves

- ALT

- AST

- ALK Phos

- Albumin

- Prothrombin (INR)

- Serium Bilirubin

LFTs

10-40

ALT normal

10-50

AST normal

30-120

Alk Phos normal

chronic DIL

can progress to cirrhosis and chronic liver failure

- pre-existing liver disease

- elevated SCr

- jaundice + bilrubin > 2 + ALT > 120

- extended exposure

risk factors for mortality

- age

- occupational exposure to toxins

- alcohol use

- malnutrition

- concurrent drug therapy

- high use of herbal supplements

- genetic presidposition

risk factors

- increase x3 ALT/AST

- increase ALK Phos

- acute hepatitis, chronic hepatitis, acute liver failure

- isoniazid

- macrobid

- diclofenac

hepatocellular

- ALT > 3x ULN

- R >5

hepatocellular

- increase ALT/AST

- increase x2 ALK Phos

- pruritic and jaundice

- augmentin

- cephalosporins

- terbinafine

- azathioprine

cholesatic

- Alk Phos > 2x ULN

- R < 2

cholesatic

- increase x2 ALT/AST

- increase x2 ALK Phos

- both occurring at once

- fluroquinolones

- macrolides

- phenytoin

- sulfonamides

mixed

- ALT > 3x ULN

- Alk Phos > 2x ULN

- R 2-5

mixed

ALT/ULN / Alk Phos/ULN

ration value (R)