Drug-Induced Hepatotoxicity

Question 1

What is the leading cause of acute liver failure in the US and what agency intends to respond to this?

Answer 1

Drug-induced hepatoxicity / liver injury (DILI)

The DILI network called DILIN is designed to study this problem

Question 2

Are DILI’s predictable? What is associated with the highest mortality?

Answer 2

No -> no reliable way to predict or prevent at this time

Highest mortality is associated with development of jaundice.

Question 3

Why is it often difficult to implicate drugs absolutely in liver injury?

Answer 3

It is a diagnosis of exclusion, since there may be other causes which could contribute

DILIN developed criteria to assess this

Question 4

What are some of the risk factors of DILI?

Answer 4

Older females, with obesity, malnutrition, alcoholism, underlying liver disease, CYP polymorphism, or other underlying abnormalities

Question 5

What drugs are known to cause a hepatitis-like picture?

Answer 5

Acute - phenytoin

Chronic - nitrofurantoin, alpha-methyldopa

Question 6

What drugs are particularly known for a cholestatic picture?

Answer 6

Estrogen supplements / birth control pills

Question 7

What drugs are known to cause a mixed cholestatic-hepatitis picture?

Answer 7

Amoxicillin/clavulanate, chlorpromazine

Question 8

What drugs are known to cause a macrovesicular or microvesicular fatty liver?

Answer 8

Macrovesicular - corticosteroids

Microvesicular - tetracycline overdose

Question 9

What drug is known to cause fibrosis of the liver and what is the workup for its treatment?

Answer 9

Methotrexate = fibrosis / cirrhosis

This is a dose-related toxicity with an insidious onset, worse with psoriasis

Liver biopsy is primary role in follow up, as LFTs may be normal

Question 10

What drug is especially known for granulomatous liver disease?

Answer 10

Allopurinol

Question 11

What substance is known to cause hepatic malignancies?

Answer 11

Vinyl chloride from PVC -> hepatic angiosarcoma

Question 12

What liver injury does pre-marrow-transplant chemotherapy cause?

Answer 12

Hepatic veno-occlusive disease

Question 13

What is a Phase I vs Phase II reaction?

Answer 13

Phase 1 - oxidation, reduction, hydrolysis

Phase 2 - conjugation to make drug water-soluble

Question 14

Define what a “predictable” hepatotoxin is and give a couple examples.

Answer 14

Known direct toxins with dose-related severity, affecting all exposed individuals, reproducible in animals and causing distinctive liver histology

i.e. acetaminophen, carbon tetrachloride (dry-cleaning), amatoxin

Question 15

What determines if acetaminophen is toxic or not and how does the antidote work?

Answer 15

Phase I - toxic
Phase II - safe

N-acetylcysteine works to replenish intracellular glutathione stores involved in dealing with toxic NAPQI accumultation. These are also depleted in alcoholism and malnutrition

Question 16

What is the type of DILI accounted for by most hepatic drug reactions? What is the clinical course?

Answer 16

Unpredictable, idiosyncratic

-> occurs rarely for any drug, includes herbals

• > long latent period (sensitization?) for several weeks before reaction
• > rechallenge with same drug will lead to rapid reaction
• > associated with fever, rash, eosinophilia (suggesting hypersensitivity)

Question 17

What are the prevailing theories for idiosyncratic drug reactions?

Answer 17

1. Immunologic - drug metabolite + carrier protein forms hapten which induces an immune response, leading to hepatotoxicity
2. Metabolic - drug + genetic polymorphisms -> unusually toxic metabolite or large amounts of toxic metabolite, leading to hepatotoxicity

Question 18

What drug reaction does phenytoin usually cause?

Answer 18

Acute hepatitis with delayed onset

May cause DRESS syndrome though:
Drug Reaction with Eosinophilia and Systemic Symptoms
-> fever, rash, eosinophilia, lymphadenopathy
-> mechanism unclear

Question 19

What type of drug causes the most DILI’s?

Answer 19

Antimicrobials

Question 20

What is the treatment for DILI?

Answer 20

Discontinue drug -> most reactions resolve after months

May need supportive care with corticosteroids in severe reactions

Worst case scenario: Liver transplant