Exam 3: Lecture 13, Drug-Induced Liver Injury

Question 1

DILI accounts for nearly….

Answer 1

50% of cases of acute liver failure in USA

Question 2

Most common drug associated with hepatotoxicity in USA?

Answer 2

Acetaminophen

Amox Clav = world wide

Question 3

How many drugs have some degree of DILI risk?

Answer 3

750 per FDA

Question 4

DILI categorized as…

Answer 4

Acute or Chronic

Hepatitis, Cholestatic, or mixed pattern injury

Question 5

Hepatitis

Answer 5

Hepatocyte necrosis and associated with poor prognosis

Question 6

Is DILI major cause of drug attrition?

Answer 6

Yes

Question 7

Cholestatic Drug-induced injury

Answer 7

has to do with issues in bile secretion

Question 8

2 mechanisms for chronic cholestasis

Answer 8

Obliteration of bile ducts

Extrahepatic biliary obstruction

Question 9

Drugs causing Cholestatic hepatitis

Answer 9

amoxicillin clav, sulfonylureas, vitamin A

Question 10

Drugs causing Hepatocellular necrosis

Answer 10

Acetaminophen, isoniazid, niacin

Question 11

Drugs causing Microvesicular Steatosis/lactic acidosis

Answer 11

Antiretrovirals, Aspirin, valproic acid

Question 12

Drugs causing Fatty liver

Answer 12

Amiodarone, corticosteroids, ethanol

Question 13

Factors of DILI

Answer 13

PK of the drug
patient age/sex/comorbidities

Hard to predict

positive correlation between age/risk

Question 14

Men or women more prone to developing hepatitis and progress to acute liver failure?

Answer 14

women

Question 15

Which oral meds have higher chance to result in DILI?

Answer 15

drugs with significant hepatic metabolism

Question 16

Mechanisms of DILI

Answer 16

direct toxicity from admin of drug and their metabolites

result from immune-mediated mechanisms

can be distinct or interconnected

Question 17

One of earliest events of DILI is…

Answer 17

inhibition of mitochondrial respiratory chain

increased ROS
depletion of ATP

Question 18

Immune-mediated injury

Answer 18

characterized by prolonged interval between admin of drug and recognized liver toxicity

Question 19

6 Mechanisms for DILI

Answer 19

Mitochondrial impairment
Inhibition of Biliary efflux
Lysosomal impairment
Reactive metabolites
ER stress
Immune system

Question 20

Symptoms of DILI

Answer 20

fever
jaundace
tired
itching
unusual weight gain
swelling of feet/legs
nausea/vomiting/pain in abdomen

Question 21

How to diagnose DILI?

Answer 21

Blood test

Biochemical test for liver enzymes AST/ALT elevation

Question 22

Management of DILI

Answer 22

based on proper diagnosis and recognition of what caused it/withdrawal

Question 23

When should drug admin be stopped DILI?

Answer 23

ALT> 8 x upper limit of normal
ALT > 5 x ULN for 3 weeks
ALT > 3 x ULN + Bilirubin > 2 X ULN
Prothrombin time/international normalized ratio > 1.5 ULN
Presence of symptoms suggesting liver injury

Question 24

antidote for DILI?

Answer 24

Nothing

reception is N-acetylcysteine for acetaminophen

Question 25

How to consider patients for liver transplant?

Answer 25

Kings College has some chart

Question 26

Acetaminophen DILI

Answer 26

fraction of drug metabolized by CYP to toxic intermediate metabolite that can interact with intracellular proteins and induce hepatocyte death

Question 27

toxic intermediate metabolite from Acetaminophen?

Answer 27

NAPQI

Question 28

Hepatotoxicity occurs when GST is…

Answer 28

depleted or NAPQI generation exceeds GST binding capacity

both Get depletion/increased NAPQI seen in alcoholics, can develop severe liver injury with low doses of acetaminophen

Question 29

How to prevent acetaminophen toxic metabolite toxicity?

Answer 29

GSH binds and prevents it from occurring

otherwise intermediate goes and binds protein

Question 30

By what mechanism does INH cause DILI?

Answer 30

direct hepatotoxic effects of INH metabolites

accumulation of acetylhydrazine/hydrazine

accumulation dependent on acetylator phenotype of patient