Drug-induced Liver Injury - Gibson

• adverse toxic drug reaction resulting in liver injury

• Liver is exposed to all substances circulating in the body - prone to injury

• Over 1,100 meds that are considerate for heaptotoxcity

• causes 11-13% of all acute liver failures in the US

  • 2000 fulminant cases annually

• Hepatotoxicity is #1 cause for post-market drug withdrawal

DILI definition

Female

Adults

Alcohol

Malnutrition

Risk factors for DILI

Need

• Elevated Liver enzymes + Drug culprit

Drug culprit

• causality established/strongly suspected using a validated tool (RUCAM) or DILI scoring

How to diagnose DILI

• used to estimate hepatotoxic potential of drugs in trials

• Sensitive and specific predictor of a drugs potential to cause severe liver injury

• Patients have >10 % risk of mortality from DILI if TWO OR MORE of following

  • AST/ALT > 3x ULN

  • Totally bili > 2x ULN WITHOUT cholestasis

  • No alternative causes of LFT elevations

  • Some sources add jaundice

What is HY’s Law?

Direct toxicity

• Acetaminophen, amiodarone, anabolic steroids, valproic acid, statins, HAART

DILI categorization (Intrinsic)

R <2 = Cholestatic

• Amox/Clav, trimethoprim, azathioprine

R (2-5) = Mixed

• Fluoroquinolones, macrolides, phenytoin, carbamazepine

R > 5 = Hepatocellular

• Isoniazid, nitrofurantoin, lamotrigine, PPI’s, TNF-Alpha inhibitors

DILI categorization (Idiosyncratic)

Steatohepatitis

• AMio, tamoxifen, methotrexate

Neoplastic

• Anabolic steroids

Vascular

• Azathioprine

DILI categorization (Other)

• Dose dependent injury

• Onset of hours to days

• Predictable

• Lipophilic drug characteristics

• Reactive metabolites - oxidative stress (mechanism)

Intrinsic DILI categorization/symptoms

• NOT Dose dependent injury

• Onset of weeks to months

• Unpredictable

• Variable mechanism (may be allergic or non-allergy)

• Based on injury pattern or score

Idiosyncratic DILI categorization/symptoms

• Damages liver cells

• Variable reversibility

• Significant LFT elevations

  • ALT >800 U/L or >20 ULN + Bilirubin elevated

• R > 5

• General sx of liver toxicity

• impacts PT/INR

• Worse outcomes

Hepatocellular DILI points

• Damages bile flow

• Usually reversible

• AlkPhos > 3x ULN + Bilirubin elevated

• R <2

• Pruritis, jaundice, eosinophilia, etc

• Impacts PT/INR

• Less Morbid!!!

Cholestatic DILI points

R = (ALT / ALT ULN) / (ALP / ALP ULN)

• Hepatocellular DILI = R >5

• Mixed DILI - (R = 2-5)

• Cholestatic DILI = R <2

Hepatocellular vs Cholestatic DILI - R value interpretations

Discontinue Drug!!!

• Decisions guided by patient specific factors

• Spontaneous recovery usually occurs after drug D/C (and confirms it was drug caused)

Main treatment for DILI

Supportive care

• Hospitalize patients with signs of liver failure

  • Jaundice, encephalopathy, coagulopathy

• Serial measurement of LFTS for all patients

• Consider Vit K for coagulopathy

• Consider Cholestyramine or colestipol for pruritus

Additional DILI treatment

Cholestyramine

If a patient experiences DILI (hepatotoxicity) with Leflunamide OR Terbinafine, what would you give them as therapy?

Carnitine

If a patient experiences DILI (hepatotoxicity) with Valproate, what would you give them as therapy?

Leucovorin

If a patient experiences DILI (hepatotoxicity) with Methotrexate, what would you give them as therapy?

N-Acetylcysteine (NAC)

If a patient experiences DILI (hepatotoxicity) with Acetaminophen , what would you give them as therapy?

• CANNOT be resumed in FULMINANT disease

• Med rechallenge should only be considered IF:

  • Drug-induced mechanism is uncertain

  • Great need for the medication

  • Lack of of other treatment options

  • ALl sx have resolved

• Resume at HALF DOSE

• Monitor LFTS quickly + often

Points about possible rechallenge of drugs after a DILI

The Glucoronidation and Glutathione conjugation pathways that form the stable metabolites for excretion become OVERSATURATED

• Cause the covalent binding and oxidative stress that kills hepatocytes

How does Acetaminophen Overdose happen? (pathophys)

• Most effective when given promptly (within 8-10 hours) after acute ingestion

• Serves as Glutathione substitute - enhances the non-toxic sulfating conjugation of Tylenol

Easy way: Supplements stable metabolites!!!

How does NAC work and treat Acetaminophen overdose?

Chronic Toxicity of Tylenol

• Only administer if acetaminophen levels > 20 mcg/mL AND LFT elevations

NAC is ineffective for _____ and should only administer when?

• Always administer for ingestions > 30 grams

• Check Tylenol blood levels within 4-24 hours of ingestion for other patients

  • Do not allow lab delays to interfere with treatment

  • Compare levels to Rumack Matthew nomogram

Decision to administer points for NAC

1. take Tylenol level

2. plot on Axis

3. If ABOVE THE SOLID DIAGONAL LINE - Treat with NAC!!!!

Rumack-Matthew Nomogram points

Dosing goal: deliver > 300 mg/kg IV or PO in first 20-24 hours

“Three Bag regimen”

1. Load: 150 mg/kg (max 15g) IV over 1 hour

2. Second Dose: 50 mg/kg (max 5g) over 4 hours

3. Third Dose: 100 mg/kg (max 10g) over 15 hours

4. Evaluate for stopping criteria

NAC dosing goal + dosing

1. APAP level <10 mcg/mL

2. INR < 2

3. LFTS normal or reduced by 25%-50%

4. Clinical stability

What are the stopping criteria for NAC? (Must have all of them to stop NAC)

• Edema

• Facial flush

• Skin rash

• Pruritus

• Urticaria (hives)

• Hypersenstivity

• Vomiting

NAC adverse reactions