Module 6: Drug Induced Liver Injury (TRAT)

Question 1

How is liver function assessed?

Answer 1

-Enzymes: LFT
-Synthetic function test: tells how well the liver is functioning
-Cholestatic/Gallbladder function: help to clear Bilirubin -> if impaired it can cause elevated bilirubin -> Jaundice

Question 2

Symptoms and Signs of Drug-induced liver injury

Answer 2

-abdominal pain
-ascites
-coagulopathy (liver responsible for producing the clotting factors)
-Varices (dilated blood vessels, type of upper GI bleed)
-Jaundice
-Puritis (itching, may be due to bilirubin)
-Splenomegaly
-Hepatomegaly

Question 3

LFT test explained

Answer 3

-Enzymes: LFT
AST: Aspartate Transaminase
ALT: Alaline Aminotransferase
ALP: Alkaline Phosphatase

an acute injury of the hepatocytes will cause an increase in these enzymes in the blood

-but will not tell how severe the damage is

Question 4

Which test indicates how well the liver is functioning?

Answer 4

Synthetic Function
-Albumin
-clotting factor
-platelets
-INR

Question 5

Types of DILI

Answer 5

-Cytotoxic = Hepatocellular
directly to liver cells
drug binds protein/cellular material
immunologic: fever, rash, eosinophilia

-Cholestatic:
inhibition of bile excretion
Neoplasm: steroids, hormones

Question 6

Which levels are elevated in cytotoxic and cholestatic DILI?

Answer 6

-cytotoxic: AST and ALT (10-500x)

-cholestatic:
ALP (3-10x)
T-bili and direct bilirubin (2-20x)

Question 7

What are the drugs causing cytotoxic DILI?

Answer 7

-Isoniazid (used for TB)
-Valproic acid (use: epilepsy, seizure, bipolar)
-Acetaminophen

-Macrolides
-Nitrofurantoin
-Tetracycline
-Antivirals
-Azoles
-Analgesics

Both: Amiodarone

Question 8

What are the drugs causing cholestatic DILI?

Answer 8

-Penicillins (cephalosporins)
-Sulfonamides
-Steroids

Both: Amiodarone

Question 9

Which drugs may cause cytotoxic and cholestatic DILI?

Answer 9

-Amiodarone
-statins
-TCA

Question 10

Which drugs are known to have a long time of onset?

Answer 10

> 1 year
-Amiodarone
-Macrolides
-Nitrofurantion
-Tetracyclines

Question 11

Which drugs are known to have a shorter time of onset?

Answer 11

-3-12 weeks (1-2 months)
Isoniazid
Valproic acid

1-4 weeks (after completion)
Amox/Clav

24-72 h
Hypersensitiviy (Sulfonamides)

Question 12

What is the most common way to counter DILI?

Answer 12

1: stop the offending agent

there are not many counteracting agents

Question 13

Antidote for Cytotoxic DILI

Answer 13

-N-acetyl cysteine
decreases the risk of the need of a liver transplant

Question 14

Antidote for Immune-mediated/hypersensitivity DILI

Answer 14

20-80 mg prednisone X 8-12 weeks

Question 15

Antidote for Cholestatic DILI

Answer 15

-Ursodilol (Actigall)
promotes the excretion of bilirubin

Question 16

Which drug is an antidote for liver injury caused by Methotrexate or Bactrim?

Answer 16

Folic acid agents
-Methotrexate and Bactrim are folic acid antagonists
replenish folic acid stores, rescue cells exposed to antagonists

-Leucovorin 1 mg = Levoleucovorin 0.5 mg

Question 17

Antidote for Valproic acid-induced liver injury

Answer 17

L-Carnitine (supplement)

-MOA: repletion of deficit ( of L-Carnitine) caused by VPA injury

-dosing: 50-300 mg/kg IV q 3-6 h
-ADR:N/V, seizure risk

Question 18

Antidote for Acetaminophen-induced liver injury

Answer 18

N-acetylcysteine

-MOA: replenishes glutathione
-dosing:
IV (ACAP + other DILI): 21h regimen for acety
PO (ACAP): 72h regimen

ADR:
PO: N/V
IV: Itching, flushing, hypersensitivity reactions (due to loading dose - may pretreat with Benadryl)

Question 19

N-acetylcysteine dosing

Answer 19

-IV (ACAP + cytotoxic): 21h regimen
LD: 150 mg/kg over 1h
then 50 mg/kg over 4h
then 100 mg/kg over 16h

-PO (ACAP): 72h regimen (over 3 days)
LD: 140 mg/kg
then maintenance 70 mg/kg q 4h for 17 doses

Question 20

Which tool is used to assess the risk of a liver injury after an acetaminophen overdose?

Answer 20

Rumack-Matthew Monogram

-if below the line, the risk for a liver injury is low
-if above, they might have a liver injury -> use N-acetylcysteine

Question 21

Which enzyme produces the toxic metabolite in an acetaminophen-induced liver injury?

Answer 21

CYP2E1

-other metabolites are produced via Conjugation of sulfate or glucuronide (non-toxic)
-in an overdose, the non-toxic is saturated -> and the toxic pathway starts increasing
-glutathione is used in the toxic pathway -> depletion

Question 22

What is the role of glutathione in acetaminophen metabolism?

Answer 22

-glutathione is used to metabolize the toxic metabolite NAPQI -> conjugation of glutathione making it non-toxic

-starts accumulation after the non-toxic pathway is saturated

-NAC is a source of glutathione

Question 24

What is the antidote for cholestatic injury?

Answer 24

Ursodeoxycholic acid (not used often)

-MOA: helps to dissolve cholestatic or bile acid deposits
-not often seen due to DDIs with bile acid sequestrants (reduce Ursodilol absoprtion)

-dosing: 300 mg BID
-ADR: N/V

Question 25

Which patient population may often need a liver transplant?

Answer 25

-chronic, untreated DILI
-acute Acetaminophen toxicity (often due to Tylenol leading to liver transplant)

most patients completely recover

Question 26

Which antidote has a dosing ratio of 1:1?

Answer 26

Leucovorin 1 mg = Levoleucovorin 0.5 mg
for Methotrexate induced liver injury

Question 27

Which drug may also be used for other DILI’s than acetaminophen?

Answer 27

IV N-acetylcysteine

Question 28

Which molecule is replenished with N-acetylcysteine

Answer 28

Glutathione