Week 4 Drug induced Liver Injury Flashcards
Role of Liver
- Metabolism
- Synthesis
- Detoxification
Problems associated with diseased liver
- Dec AA metabolism
- Dec Protein synthesis
- Inc Bili
What are the effects of dec protein synthesis
- Dec clotting factors causing an inc in PT/INR
- Dec albumin conct
- Dec thrombpopoietin synthesis causing dec in platelets
Normal AST and ALT
<40
What is an inc in AST and ALT associated with?
Hepatocyte injury
What is an inc in ALP associated with?
Cholestatic injury
Normal ALP
<140
normal Albumin
4
Normal INR
4
Normal bili
<1
Causes of Liver Disease
- alcohol and hepatitis ( most common)
- biliary tract disease
- fatty liver disease
- drug induced
- genetics
DILI clinical pearls
- responsible for 13% of liver failure — #1 cause of death in Acute LF
- Responsible for 16% of liver transplants
DILI definitions (4)
-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
What is the equation for deciding the type of DILI
R = (ALT/ULN) / (ALP/ULN)
Hepatocellular injury R value
R >/= 5
Mixed R value
R = 2-5
Cholestatic injury R value
</= 2
Augmentin DILI pearls
- causes both types of injury
- 2 nd most common drug to cause DILI
- GENE HLA-DRBI*15
- onset 2-45 days
Augmentin DILI treatment
self resolving, supportive care
Drugs that cause DILI (in order )
- APAP
- Antimicrobals
- Augmentin
- Isoniazid
- Nitrofurantoin
- Bactrim
- Minocycline
- NSAIDs : Diclofenac
DILI mortality/transplants
- Most common with hepatocellular injury and when bili >2.5
APAP pk
- rapid absorption
- during overdose MOA unchanged. total absorption w/ 4 hrs
- crosses BBB and placenta
APAP Metabolism
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
APAP toxicity MOA
- glucuronidation pa thway over saturated
- more CYP2E1 metabolism
- inc NAPQ1
- hepatocyte injury
- DEATH
What APAP dose is toxic
> 7.5 g adults
150mg/kg in kids
Predisposing factors for APAP tox
- CYP2E1 induction
- Malnourished
- dec glucuronidation & sulfation
What drugs causes CYP2E1
Anticonvulsants , Isoniazid , ETOH
What labs are seen w/in 24-36 post ingestion of APAP?
AST> 1000 (untreated; liver injury)
When does maximal hepatoxicity happen and symptoms/labs associated with it?
- w/in 72- 96 post ingestion (untreated)
- encephalopathy, coma, cerebral edema, hemorrhage
- AST, ALT> 10,000
- inc INR, Bili, pH, Lactate
APAP toxicity management options
- NAC
- Activated charcoal
- Supportive care
When is activated charcoal used?
pt presents <4 hrs after ingestion
How do we determine when to use NAC
- Rumack Matthew Nomogram
- start w/in 8 hrs post ingestion for best efficacy
In what patients should NAC be used after 24 hrs of therapy?
- AST still elevated (>1000 or above ULN and not decreasing)
- APAP detectable (>10mcg/ ml)
- On going liver failure
- on PO therapy (72 hr duration)
What 2 features identify liver failure
- inc in PT/INR and Encephalopathy
NAC MOA
Precursor to glutathione, incs it production
-detoxifies NAPQI
PO NAC pearls
- straight to liver
- super bad taste (cover it, dilute it 5%, pre-treat with antiemetics, put in NG tube)
IV NAC pearls
- loading dose over 60 minutes to avoid Anaphylactoid rxns
- pause inf, give Benadryl, resume
- typically doesnt happen twice
Who gets IV NAC
- pregnant
- liver failure (which is…)
- inability to tolerate PO
