Week 4 Drug induced Liver Injury

Question 1

Role of Liver

Answer 1

• Metabolism
• Synthesis
• Detoxification

Question 2

Problems associated with diseased liver

Answer 2

• Dec AA metabolism
• Dec Protein synthesis
• Inc Bili

Question 3

What are the effects of dec protein synthesis

Answer 3

• Dec clotting factors causing an inc in PT/INR
• Dec albumin conct
• Dec thrombpopoietin synthesis causing dec in platelets

Question 4

Normal AST and ALT

Answer 4

<40

Question 5

What is an inc in AST and ALT associated with?

Answer 5

Hepatocyte injury

Question 6

What is an inc in ALP associated with?

Answer 6

Cholestatic injury

Question 7

Normal ALP

Answer 7

<140

Question 8

normal Albumin

Answer 8

4

Question 9

Normal INR

Answer 9

4

Question 10

Normal bili

Answer 10

<1

Question 11

Causes of Liver Disease

Answer 11

• alcohol and hepatitis ( most common)
• biliary tract disease
• fatty liver disease
• drug induced
• genetics

Question 12

DILI clinical pearls

Answer 12

• responsible for 13% of liver failure — #1 cause of death in Acute LF
• Responsible for 16% of liver transplants

Question 13

DILI definitions (4)

Answer 13

-total bili >2.5 w/ any inc in AST, ALP, ALP
- ALT or AST >5x ULN
- ALP > 2x ULN OR
- INR >1.5 w/ any inc in AST, ALP

Question 14

What is the equation for deciding the type of DILI

Answer 14

R = (ALT/ULN) / (ALP/ULN)

Question 15

Hepatocellular injury R value

Answer 15

R >/= 5

Question 16

Mixed R value

Answer 16

R = 2-5

Question 17

Cholestatic injury R value

Answer 17

</= 2

Question 18

Augmentin DILI pearls

Answer 18

• causes both types of injury
• 2 nd most common drug to cause DILI
• GENE HLA-DRBI*15
• onset 2-45 days

Question 19

Augmentin DILI treatment

Answer 19

self resolving, supportive care

Question 20

Drugs that cause DILI (in order )

Answer 20

1. APAP
2. Antimicrobals
   
   • Augmentin
   • Isoniazid
   • Nitrofurantoin
   • Bactrim
   • Minocycline
3. NSAIDs : Diclofenac

Question 21

DILI mortality/transplants

Answer 21

• Most common with hepatocellular injury and when bili >2.5

Question 22

APAP pk

Answer 22

• rapid absorption
• during overdose MOA unchanged. total absorption w/ 4 hrs
• crosses BBB and placenta

Question 23

APAP Metabolism

Answer 23

90% undergoes glucuronidation & sulfation
5-15% oxidized by CYP2E1 to NAPQI
- Combines w/ glutathion to form non-toxic cysteine/mercaptate and is then eliminated in urine

Question 24

APAP toxicity MOA

Answer 24

• glucuronidation pa thway over saturated
• more CYP2E1 metabolism
• inc NAPQ1
• hepatocyte injury
• DEATH

Question 25

What APAP dose is toxic

Answer 25

>7.5 g adults > 150mg/kg in kids

Question 26

Predisposing factors for APAP tox

Answer 26

- CYP2E1 induction - Malnourished - dec glucuronidation & sulfation

Question 27

What drugs causes CYP2E1

Answer 27

Anticonvulsants , Isoniazid , ETOH

Question 28

What labs are seen w/in 24-36 post ingestion of APAP?

Answer 28

AST> 1000 (untreated; liver injury)

Question 29

When does maximal hepatoxicity happen and symptoms/labs associated with it?

Answer 29

- w/in 72- 96 post ingestion (untreated) - encephalopathy, coma, cerebral edema, hemorrhage - AST, ALT> 10,000 - inc INR, Bili, pH, Lactate

Question 30

APAP toxicity management options

Answer 30

- NAC - Activated charcoal - Supportive care

Question 31

When is activated charcoal used?

Answer 31

pt presents <4 hrs after ingestion

Question 32

How do we determine when to use NAC

Answer 32

- Rumack Matthew Nomogram - start w/in 8 hrs post ingestion for best efficacy

Question 33

In what patients should NAC be used after 24 hrs of therapy?

Answer 33

- AST still elevated (>1000 or above ULN and not decreasing) - APAP detectable (>10mcg/ ml) - On going liver failure - on PO therapy (72 hr duration)

Question 34

What 2 features identify liver failure

Answer 34

- inc in PT/INR and Encephalopathy

Question 35

NAC MOA

Answer 35

Precursor to glutathione, incs it production -detoxifies NAPQI

Question 36

PO NAC pearls

Answer 36

- straight to liver - super bad taste (cover it, dilute it 5%, pre-treat with antiemetics, put in NG tube)

Question 37

IV NAC pearls

Answer 37

- loading dose over 60 minutes to avoid *Anaphylactoid rxns* - pause inf, give Benadryl, resume - typically doesnt happen twice

Question 38

Who gets IV NAC

Answer 38

- pregnant - liver failure (which is...) - inability to tolerate PO