LIver 3

Question 1

Most commob=n cause of drug recall

Answer 1

Drug-induced hepatotocicity

Question 2

WHo is more affected by DILI’s?

Answer 2

Women

Question 3

Hepatocellular DILI

Answer 3

↑ AST/ALT (preceds incr total bilirubin and ALP)

Usually occurs w/in 1yr of starting drug

Can result in fulminant hepatitis

Question 4

Steotonecrosis DILI

Answer 4

↑ synth of FAhepatocytes engorged with FA, burst open
Inflammation

Question 5

Fibrosis DILI

Answer 5

Mild, chronic hepatitisfibrosiscirrhosis if drug not d/c

Question 6

Cholestatic DILI

Answer 6

Prevents proper elimination of bile by liveraccumulation
↑ ALP

Question 7

Definition of hepatotoxicity

Answer 7

Question 8

How can determine the pattern of injury?

Answer 8

Question 9

General mechanisms of DILI

Answer 9

Intrinsic: predictable
direct hepatotoxin, which has inherent propensity to induce injury in all individuals; dose dependent or time dependent & reproducible

Idiosyncratic: unpredictable
causes injury in a small # of uniquely susceptible patients; variable presentation
further classified into allergic or non-allergic type

Question 10

Most common type of intrinsic DILI

Answer 10

Aectaminophen - Most common cause of acute liver failure

Extremely high AST/ALT levels (>3500)

Help distinguish from other drug induced hepatotoxicity (generally 5x ULN)

Question 11

Excess actaminophen causes what?

Answer 11

With overdose, ↑ production of NAPQI exceeds capacity of glutathione stores

NAPQ Covalently binds to and modifies critical hepatic cell proteins

Results in hepatic necrosis and possibly death to the patient

Question 12

Stages of Acetaminophen Toxicity

Answer 12

Question 13

Acute toxicity Values

Answer 13

Toxic doses
Adults: >7.5g
Children: >150mg/kg

Question 14

Gut Decontamination after acet toxicity

Answer 14

Syrup of Ipecac
Not contraindicated, but effectiveness beyond 1 hour is markedly diminished
Emesis induced within 1hr reduced serum levels by 50% ; No impact at 90 minutes

Activated charcoal

Superior to ipecac in reducing serum levels
Single dose should be administered within 1hour (Effectiveness after 1hr not known)
Should be considered to all patients with potential acetaminophen od before the 4hour nomogram evaluation
Avoid other gut decontamination measures

Question 15

Anti-dote of acetaminophen toxicity?

Answer 15

Acetylcysteine

Question 16

MOA of acetycysteine

Answer 16

Enhances glutathione stores (acts as substrate)

Promotes conjugation by nontoxic pathway

Question 17

Nonogram for identifying acetaminophen toxicty

Answer 17

Rumack-Matthew nomogram(modified in North America)

Question 18

Rumack-Matthew Nonogram

Answer 18

Predicts only the likelihood of AST/ALT >1000
Does not predict survival or death
Use of nomogram > 24hrs not recommended
Identifies patients who require aggressive management
Not reliable for extended release products

Question 19

Acetycysteine Infusion Rates

Answer 19

Longer infusions may be superior if long delay in treatment (10-24hrs)

Treatment may be delayed up to 8 hours without increased risk

Question 20

Allergic Type Idosyncratic DILI

Answer 20

Some cases of hepatotoxicity present with “allergic” type sx

Fever, rash, eosinophilia, etc
May have extrahepatic involvement as well

Symptoms may occur with increasing intensity with repeated exposure (sensitization)

Question 21

Drugs associated with allergic-type idosyncratic

Answer 21

Anticonvulsants (phenytoin, phenobarb, CBZ)
Sulfonamide antibiotics
Allopurinol
Dapsone, minocycline, propythiourocil

Question 22

Non-allergic Idiosyncratic DILI

Answer 22

Likely caused by toxic metabolites

Mechanism of production not always clear

Onset 1 week to > 1 year

Rechallenge: days to weeks (accumulation must occur?)

Question 23

Drugs associated with non-allergic DILI

Answer 23

isoniazid, valproic acid, ketoconazole, methyldopa

Question 24

Onset(Latency) of drug timing approach?

Answer 24

Short = 3–30 days
Moderate = 30–90 days
Long 90 = days

Question 25

Management of suspected DILI

Answer 25

Immediate d/c of all potential hepatotoxins

Supportive care as needed
Acetylcysteine for acetaminophen poisonings

Potential other uses as well
Corticosteroids can be considered for ‘allergic’ rxns
“DRESS” [with eosinophilia & systemic sx]

No other antidotes exist

Serial biochemical measurements until the liver enzymes return to normal

Severe jaundice
significant indicator of mortality

referral to transplant center ASAP

Question 26

How can liver dysfunction be quantified?

Answer 26

Child Pugh A = 5-6 points
Child Pugh B = 7-9 points
Child Pugh C = 10-15 points (severe)