not all drugs are good drugs: Liver Flashcards
Definition of drug-induced liver disease/impairment
- Total bili >2.5 with any ALT, AST elevation or
- ALT >5x ULN or
- AST >5x ULN or
- ALP >2x ULN or
- INR >1.5 with elevated AST, ALT, OR ALP
Normal bilirubin lab values
Just think about 1
- Total bili <1.2
- Conjugated <0.2
- Unconjugated <1.0
Normal AST and ALT values
- AST normally 5-40
- ALT normally 5-40
Normal albumin value
4
Normal INR value
1
MOA of APAP induced liver impairment/tox
In setting of high doses:
1. conjugation pathway becomes saturated →
2. CYP2E1 pathway is utilized more than it normaly is →
3. more NAPQI (toxic) production →
4. glutathione stores cannot regenerate fast enough to combine with all NAPQI to make them non toxic →
5. NAPQI starts attacking hepatocytes → hepatocyte injury and death
Predisposing factors to APAP overdose
- CYP2E1 induction (anticonvulsants, isoniazid, chronic EtOH)
- Malnourishment
- Decreased sulfation and glucoronidation
Toxic levels of APAP
- 7.5g in adults
- > 150mg/kg in children
ABX that can cause liver disase
- Augmentin: can cause cholestatic jaundice and hepatocellular injury
- Azithromycin
- Bactrim
- Cefazolin
- Cipro
- Isoniazid
- Levofloxacin
- Minocycline
- Nitrofurantoin
Can dietary supplements cause liver dsiase?
Yes
- Body building herbal dietary supplement (HDS) → usually cholestatic injury
- Non-body building HDS → usually hepatocellular injury
- More severe
Diclofenac can/cannot cause liver disease
CAN
General treatment for drug induced liver diseases
Supportive care
- IV fluids
- management of N/V
- Correction of hypoglycemia
- Vitamin K/FFP
NAC if indicated
Drug rechallenge in drug-induced liver disease
If patient had cholestatic or mixed injury (NOT soley hepatic injury), could rechallenge, but avoid doing so unless there is no other alternative
MOA of NAC in APAP overdose
NAC therapy: provides something other than human tissue for NAPQI to bind to, also possibly a precursor to glutathione.
PO vs IV NAC in APAP overdose
-
PO (72 hr protocol): bad n/v and smells really really bad
- Pre-treat with anti-emetics
-
IV (20 hr protocol): prefered in pts with liver failure, preggers, or can’t tolerate PO
- Can cause anaphylactoid reactions, just treat with steroids and Benadryl and readmin
When to start NAC in APAP overdose
- Prior to hour 4:
- Consider activated charcoal
- Wait and recheck at hour 4 to assess whether or not NAC is needed
- After hour 24 (can no longer use the nomogram to figure out if needed) → if AST is elevated regardless of APAP level
- Begin NAC
- After hour 24 or unknown late ingestion with detectable APAP level
- Begin NAC
When to continue NAC beyond the 20/72 hr protocol
- On-going liver failure present
- Elevated PT/INR
- Encephalopathy present
- Detectable APAP
- APAP >10mcg/ml
- Ongoing hepatocyte damage
- AST above ULN and not decreaseing
- AST >1000
How to calculate R value?
R = [ALT/ULN] / [ALP/ULN]
What does the R value tell you?
What kind of DILI it is
hepatocellular vs cholestatic vs mixed
R≥5 means
hepatocellular likely d/t AST/ALT elevation (hepatocytes impacted)
R = 2-5 means
Mixed presentation
R ≤2 means
cholestatic d/t ALP elevation (biliary dysfx)
ULN for ALT is
40
ULN for ALP is
140
Gamma Glutamyl Transpeptidase (GGT)
Found in hepato-billiary tree (liver)
Concurrent GGT elevation with ALP = confirm hepatic origin of ALP elevation
Causes of liver disease other than drugs
- alcohol
- hepatitis
- biliary tract disease
- NAFLD
- genetics/metabolic
- hemochromatosis
- a1 antitrypsin deficiency
- wilson’s disease
Short latency drugs
Drugs that can cause DILI shortly after iniitation
dili ≤ 7 days
azithro
cipro
levo(floxacin)
Long latency drugs
drugs that can cause dili years after initiation
dili ≥365 days
amiodarone
minocycline
(?) high intensity statin
Markers of liver function
AST
ALT
ALP
GGT
Markers of liver synthesis
Bilirubin
Albumin
PT/INR
Facts about APAP
- crosses BBB and placenta
- RAPID PO absorption 2hrs, complete by 4 hrs
- 25% via first pass
An AST of <1000 IU/L (is/ is NOT) clinically significant for APAP hepatotoxicity?
IS NOT
