Drug-Induced Liver Disease

Question 1

Diseased Liver - Changes in Function

Answer 1

decreased amino acid metabolism (-> increased ammonia)
decreased protein synthesis (-> increased INR, decreased albumin)
increased bilirubin
altered carbohydrate metabolism (-> hypoglycemia)
reduced cholesterol production
reduced detoxification (-> impaired drug metabolism)

Question 2

Hepatic Labs - Liver Function Tests

Answer 2

aminotransferases (ALT & AST)
GGT
ALP

Question 3

Hepatic Labs - Synthetic Function

Answer 3

albumin
PT / INR

Question 4

Hepatic Labs - Jaundice

Answer 4

bilirubin

Question 5

Aminotransferases - Values

Answer 5

AST and ALT - 5-40 U/L

Question 6

Alkaline Phosphatase - Values

Answer 6

30-140 U/L

Question 7

Bilirubin - Values

Answer 7

total < 1.2 mg/dL
conjugated < 0.2 mg/dL
unconjugated < 1 mg/dL

Question 8

Drug-Induced Liver Injury - Criteria

Answer 8

• total bilirubin > 2.5 with elevated ALT / AST / ALP
• ALT > 5x ULN
• AST > 5x ULN
• ALP > 2x ULN
• INR > 1.5 with elevated AST / ALT / ALP

Question 9

DI Liver Injury - Types

Answer 9

hepatocellular (AST & ALT elevation)
cholestatic (ALP elevation)
mixed

Question 10

DILI - Hepatocellular R

Answer 10

R = [ALT / ULN] / [ALP / ULN] is 5 or greater

Question 11

DILI - Cholestatic R

Answer 11

R = [ALT / ULN] / [ALP / ULN] is 2 or less

Question 12

DILI - Mixed R

Answer 12

R = [ALT / ULN] / [ALP / ULN] is greater than 2 but less than 5

Question 13

DILIN - Agents

Answer 13

1. amoxicillin-clavulanate
2. isoniazid
3. nitrofurantoin
4. SMX / TMP
5. minocycline
6. cefazolin
7. azithromycin
8. ciprofloxacin
9. levofloxacin
10. diclofenac

Question 14

DILI - Herbal & Dietary Supplements - Patterns

Answer 14

bodybuilding HDS -> cholestatic injury
non-bodybuilding HDS -> hepatocellular injury (more death & transplantation)

Question 15

Acetaminophen - PK

Answer 15

rapid PO absorption - complete by hour 4
crosses BBB & placenta

Question 16

Acetaminophen - Metabolism

Answer 16

25% extracted through first-pass metabolism
of remaining 75%:
- 90% - glucuronidation & sulfation to inactive metabolites
- < 5% unchanged in urine
- 5-15% oxidized by CYP2E1 to NAPQI

Question 17

NAPQI - Further Metabolism

Answer 17

toxic NAPQI combines with glutathione and is converted to non-toxic cysteine, then eliminated in urine

Question 18

Acetaminophen - Toxicity Mechanism

Answer 18

conjugation metabolic pathways become saturated -> more APAP goes through CYP2E1 pathway -> more NAPQI -> glutathione stores are diminished -> NAPQI attacks hepatocytes

Question 19

Acetaminophen - Toxic Dose

Answer 19

adults: 7.5 grams or more
children: 150 mg/kg or more

Question 20

Acetaminophen Toxicity - Risk Factors

Answer 20

CYP2E1 induction (anticonvulsants, isoniazid, chronic EtOH)
reduced glutathione stores (malnourishment)

Question 21

Acetaminophen Toxicity - Manifestations

Answer 21

Sx: NV, malaise, pallor, diaphoresis
24-36 hrs post-ingestion: peak AST > 1000
72-96 hrs post-ingestion: AST & ALT > 10,000; changes in INR, bilirubin, glucose, lactate, pH, renal failure

death from acute overdose will generally occur within 3-5 days post-ingestion

Question 22

Acetaminophen Toxicity - Management

Answer 22

activated charcoal (only if within 1-2 hrs post-ingestion)
NAC
IV fluids
management of NV
hypoglycemia correction
Vitamin K
FFP

Question 23

N-Acetylcysteine - Mechanism of Action

Answer 23

acts as glutathione substitute -> detoxifies NAPQI
also a precursor to glutathione -> increased production
also increases sulfation -> less NAPQI production

Question 24

NAC - Oral Administration

Answer 24

72 hrs
AE: bad taste, NV (need pre-treatment with anti-emetics)
delayed absorption
change to IV if liver failure develops
140 mg/kg loading dose, then 70 mg/kg q4h x 17 doses to a total dose of 1330 mg/kg

Question 25

NAC - IV administration

Answer 25

20 hours
AE: anaphylactoid reaction, angioedema, urticaria
preferred in liver failure, pregnancy
150 mg/kg loading dose, then 50 mg/kg over 4 hrs, then 100 mg/kg over 16 hrs to a total dose of 300 mg/kg

Question 26

NAC - Treatment Duration

Answer 26

continue post-protocol if:
- elevated PT / INR
- encephalopathy present
- detectable APAP > 10 mcg/mL
- AST above ULN and not decreasing
- AST > 1,000 U/L

Question 27

Liver Transplant - Criteria

Answer 27

• pH < 7.3 despite fluid and hemodynamic resuscitation
• PT > 100 sec + SCr > 3.3 mg/dL + grade III or IV encephalopathy
• lactate > 3 mmol/L after fluids
• phosphate > 1.2 mmol/L 48-82 hrs post-ingestion