Drug-Induced Liver Injury

Question 1

What are the 3 MAIN PURPOSES of the liver?

Answer 1

1. Metabolism:
   - amino acids
   - carbohydrates
   -lipids
2. Synthesis:
   - proteins (albumin, clotting factors, Igs)
   - cholesterol/triglycerides
   - platelets
3. Detoxification:
   - food, drugs, herbals

Question 2

What are some FUNCTIONAL liver indices (LFTs)?

Answer 2

Aminotransferases - AST/ALT
Alkaline phosphatase - ALP
GGT

Question 3

What are some SYNTHETIC liver indices?

Answer 3

Albumin levels
PT/INR

Question 4

Jaundice is the presence of too much WHAT? What is it the byproduct of?

Answer 4

Bilirubin - the byproduct of degraded hemoglobin from RBCs

Question 5

Aminotransferases (AST/ALTs) are mainly found in what part of the liver?

Answer 5

Hepatocytes

Question 6

Alkaline phasphatase (ALP) is mainly found WHERE?

Answer 6

Bile ducts (NOT in liver/hepatocytes!)

Question 7

What is the difference between UNCONJUGATED and CONJUGATED bilirubin?

Answer 7

Unconjugated = predominantly in blood serum, lipophilic
Conjungated = Glucuronidated in hepatocytes, moved to bile ducts after

Question 8

What are the general NORMAL VALUES for AST, ALT, ALP and bilirubin?

Answer 8

AST/ALT ≈ 40
ALP ≈ 140
Bilirubin ≈ 1.0

Question 9

What is the MOST COMMON drug that causes drug-induced liver injury? What is the next most common?

Answer 9

1 = APAP

#2 = antibiotics

Question 10

Drug-induced liver injury is defined by what lab parameters? (4 major!)

Answer 10

Total bili > 2.5 mg/dL + elevated AST/ALT/ALP
AST or ALT > 5x ULN
ALP > 2x ULN
INR > 1.5 + elevated AST/ALT/ALP

Question 11

What lab value abnormalities (equation) differentiate hepatocellular vs cholestatic vs mixed liver injury?

Answer 11

Hepatocellular (AST/ALT elevation)
R ≥ 5

Cholestatic (ALP elevation)
R ≤ 2

Mixed
R = 2-5

     ALT          ALP R = ——— ÷ ———
      40           140

Question 12

Amoxicillin-clavulanate is well-known to cause jaundice and hepatocellular injury. What allele is associated with the development of DILI from augmentin?

Answer 12

HLA-DRB1*15 (HLA affects antigen presentation)

Question 13

What disease must be ruled out when determining if a patient has drug-induced liver injury?

Answer 13

Hepatitis (all types)

Question 14

What are the top 2 CLASSES of drugs that cause DILI?

Answer 14

Antimicrobials
Herbal/Dietary supplements

Question 15

What are the top 10 DRUGS that cause DILI?

Answer 15

1. Amoxicillin/clavulanate
2. Isoniazid
3. Nitrofurantoin
4. Bactrim
5. Minocycline
6. Cefazolin
7. Azithromycin
8. Ciprofloxacin
9. Levofloxacin
10. DICLOFENAC (NSAIDs)

Question 16

Bodybuilding herbals/supplements have more _______ injury
Non-bodybuilding herbals/supplements have more _________ injury

Answer 16

Bodybuilding (herbal dietary supplements) HDS - more cholestatic injury
Non-bodybuilding HDS - hepatocellular injury (MORE SEVERE)

Question 17

Which has the best prognosis and lowest mortality: hepatocellular injury, cholestatic injury, or mixed?

Answer 17

Mixed

Question 18

When a patient ODs on APAP, what range will their AST/ALT usually look like? What other lab values may be affected?

Answer 18

AST/ALTs > 10,000!
INRs, bili, glucose, lactate, phosphate and pH may change

Question 19

What is the PK profile of APAP that makes it so dangerous for liver injury?

Answer 19

Rapid oral absorption
Even in OD, most APAP absorbs within 2 hours
Crosses BBB and placenta

Question 20

5-15% of APAP is oxidized by CYP2E1 to what?

Answer 20

N-acetyl-p-benzoquinoeimine (NAPQI)

Question 21

NAPQI (metabolite of APAP) is usually converted to non-toxic cysteine/mercaptopurine and eliminated. What causes the hepatocyte injury in an overdose then?

Answer 21

Glutathione stores become diminished in an overdose, therefore toxic NAPQI begins to attack hepatocytes leading to liver cell injury and death.

Question 22

What is a toxic dose of APAP?

Answer 22

≥ 7.5 grams

Question 23

What are some SYMPTOMS of APAP toxicity?

Answer 23

N/V
Malaise
Pallor
Diaphoresis

Question 24

What drug may be used within the first 1-2 hours post-APAP ingestion? What drug should ALWAYS be used in an APAP overdose?

Answer 24

Within 1-2 hours of ingestion: ACTIVATED CHARCOAL

Always use: N-acetylcysteine! (NAC)

Question 25

How does NAC work in an APAP overdose?

Answer 25

Acts as a substitute for glutathione in converting toxic NAPQI
Is a precursor fr glutathione, creates more
Decreases NAPQI production by promoting APAP metab. Through other mechanisms

Question 26

What window of time post-ingestion does NAC work?

Answer 26

4 - 24 hours after OD
(May still use after 24 hours if AST is elevated or detectable APAP levels)

Question 27

Compare IV and PO NAC: what are some major AEs? What is a downside of PO NAC PK? Which has benefits if liver failure is present?

Answer 27

PO (solution):
AEs - BAD TASTE, N/V so use antiemetics
Administers directly to liver but is first-pass metab causes much lower concentration NAC

IV:
AEs- anaphylactoid reaction (not real anaphylaxis) - rash, flushing, bronchospasm
administer slowly to avoid
PREFERRED if liver failure or pregnant
Is much more expensive

Question 28

How long should treatment for APAP overdose continue?

Answer 28

Until PT/INR stabilizes and no encephalopathy present
Until no more detectable APAP and no more hepatocyte damage
AST at ULN or decreasing
AST < 1000
APAP < 10 mcg/mL