Liver 3

Question 1

What is the most common reason for drug recall?

Answer 1

drug-induced hepatoxicity
-women more commonly affected
-acute or chronic
-~50% of all acute liver failure

Question 2

What can increase the risk of hepatoxicity from herbal products?

Answer 2

exceeding recommended doses

Question 3

What risk do environmental toxins pose to the liver?

Answer 3

can predispose a patient to a hepatic reaction when a drug is added

Question 4

Why is DILI classification difficult?

Answer 4

drugs may cause > 1 pattern of damage
cause not always possible to determine
different types may occur at once
MOA not always understood

Question 5

What should be considered in the diagnosis of DILI?

Answer 5

temporal relationship to drug use
exclusion of other causes of liver damage

Question 6

What is the definition of hepatoxicity?

Answer 6

clinically significant abnormalities of liver tests
-ALT > 3x ULN and total bilirubin > 2x ULN

Question 7

How can we determine the pattern of hepatic injury?

Answer 7

evaluate the ratio of ALT to ALP to determine predominant cause
-R >/5=hepatocellular injury
-2<R>5=mixed
-R<2=cholestatic</R>

Question 8

What are the general mechanisms of DILI?

Answer 8

intrinsic: predictable
-direct hepatotoxin, 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 (allergic or non-allergenic)

Question 9

What is the most common cause of acute liver failure?

Answer 9

acetaminophen
-extremely high AST/ALT levels (>3500)
=helps distinguish from other drug induced hepatoxicity

Question 10

Describe normal metabolism of acetaminophen, and then what occurs with excessive acetaminophen.

Answer 10

normally:
-90% glucuronidated or sulfated, 2% metabolized by CYP
with excessive acetaminophen:
-glucuronidation & sulfation become saturated
-CYP becomes primary metabolic pathway
–>product of reaction=NAPQI (toxic)
–>NAPQI normally detoxified by glutathione
-with OD, NAPQI production exceeds glutathione stores
=hepatic necrosis and possible death

Question 11

What are the 4 stages of acetaminophen toxicity?

Answer 11

stage 1 (within 24h)
-GI sx
stage 2 (24-72h)
-resolution of stage 1 sx
-onset of RUQ pain, increased bilirubin, PT, transaminases
stage 3 (72-96h)
-asymptomatic to fulminant hepatic failure
-AST and ALT peak (up to 100x normal)
-death at 3-5 days after ingestion
stage 4
-recovery stage, if survive stage 3
-symptoms subside and transaminases normalize
-survivors do not have chronic hepatic dysfunction

Question 12

What are the toxic doses of acetaminophen?

Answer 12

adults: > 7.5g
children: > 150mg/kg

Question 13

True or false: the clinical presentation of acetaminophen toxicity shows a fast onset

Answer 13

false
delayed=early recognition is essential

Question 14

What is the Rumack-Matthew nomogram?

Answer 14

helps identify who should receive acetylcysteine
-does not predict survival or death
-use >24h not recommended
-not reliable for extended release products

Question 15

What is the antidote of choice for acetaminophen toxicity?

Answer 15

acetylcysteine

Question 16

What is the MOA of acetylcysteine?

Answer 16

enhances glutathione stores

Question 17

When is acetylcysteine given?

Answer 17

if serum concentration exceeds the “treatment line” on the Rumack-Matthew nomogram

Question 18

What is the benefit of acetylcysteine?

Answer 18

reduce risk of hepatoxicity
-all regimens

Question 19

How long can treatment with acetylcysteine be delayed without increased risk of hepatoxicity?

Answer 19

up to 8h

Question 20

Aside from acetylcysteine, what are some other potential options for acetaminophen toxicity?

Answer 20

Syrup of Ipecac
-not CI, but effectiveness beyond 1hr is diminished
activated charcoal:
-superior to ipecac in reducing serum levels
-no data on clinical benefit
-should be administered within 1hr, should be considered to all pts before the 4hr nomogram evaluation

Question 21

Describe allergic-type DILI.

Answer 21

presents with allergic type sx
-fever, rash, eosinophilia, etc
sx may occur with increasing intensity with repeated exposure

Question 22

What are some drugs associated with allergic-type DILI?

Answer 22

anticonvulsants
sulfonamides
allopurinol
dapsone, minocycline, PTU

Question 23

Describe non-allergic DILI.

Answer 23

likely caused by toxic metabolites
-MOA not clear
-onset: 1wk to > 1yr

Question 24

What are some drugs associated with non-allergic DILI?

Answer 24

isoniazid
valproic acid
ketoconazole
methyldopa

Question 25

What are some general steps to take if you suspect DILI?

Answer 25

take detailed medication history (Rx, OTC, herbals)
examine LETs and identify type of liver injury
what symptoms are present?
is there a possible alternate cause?
consider onset with relation to drug timing
-short=3-30d
-moderate=30-90d
-long=90d
did sx subside after drug d/c?
consult references

Question 26

What is the use of causality assessment tools?

Answer 26

help assess the probability of a drug-related cause of DILI

Question 27

What is the most commonly used causality assessment tool for DILI?

Answer 27

RUCAM
-0=drug/herb is not likely cause
-<2=unlikely to be cause
-<5=possibly caused the reaction
-<8=probably the caused the reaction
->8=highly probably caused the reaction

Question 28

What is the management of suspected DILI?

Answer 28

immediate d/c of all potential hepatotoxins
supportive care as needed
-acetylcysteine for acet poisonings
-corticosteroids for allergic reactions
-no other antidotes exist
serial biochemical measurements until liver enzymes return to normal

Question 29

What are the three categories of the Child-Pugh score?

Answer 29

A: 5-6 points
B: 7-9 points
C: 10-15 points

Question 30

Which class of agents should be used cautiously in liver injury?

Answer 30

nephrotoxins