Drug-Induced Liver Disease Flashcards
Diseased Liver - Changes in Function
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)
Hepatic Labs - Liver Function Tests
aminotransferases (ALT & AST)
GGT
ALP
Hepatic Labs - Synthetic Function
albumin
PT / INR
Hepatic Labs - Jaundice
bilirubin
Aminotransferases - Values
AST and ALT - 5-40 U/L
Alkaline Phosphatase - Values
30-140 U/L
Bilirubin - Values
total < 1.2 mg/dL
conjugated < 0.2 mg/dL
unconjugated < 1 mg/dL
Drug-Induced Liver Injury - Criteria
- 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
DI Liver Injury - Types
hepatocellular (AST & ALT elevation)
cholestatic (ALP elevation)
mixed
DILI - Hepatocellular R
R = [ALT / ULN] / [ALP / ULN] is 5 or greater
DILI - Cholestatic R
R = [ALT / ULN] / [ALP / ULN] is 2 or less
DILI - Mixed R
R = [ALT / ULN] / [ALP / ULN] is greater than 2 but less than 5
DILIN - Agents
- amoxicillin-clavulanate
- isoniazid
- nitrofurantoin
- SMX / TMP
- minocycline
- cefazolin
- azithromycin
- ciprofloxacin
- levofloxacin
- diclofenac
DILI - Herbal & Dietary Supplements - Patterns
bodybuilding HDS -> cholestatic injury
non-bodybuilding HDS -> hepatocellular injury (more death & transplantation)
Acetaminophen - PK
rapid PO absorption - complete by hour 4
crosses BBB & placenta
Acetaminophen - Metabolism
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
NAPQI - Further Metabolism
toxic NAPQI combines with glutathione and is converted to non-toxic cysteine, then eliminated in urine
Acetaminophen - Toxicity Mechanism
conjugation metabolic pathways become saturated -> more APAP goes through CYP2E1 pathway -> more NAPQI -> glutathione stores are diminished -> NAPQI attacks hepatocytes
Acetaminophen - Toxic Dose
adults: 7.5 grams or more
children: 150 mg/kg or more
Acetaminophen Toxicity - Risk Factors
CYP2E1 induction (anticonvulsants, isoniazid, chronic EtOH)
reduced glutathione stores (malnourishment)
Acetaminophen Toxicity - Manifestations
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
Acetaminophen Toxicity - Management
activated charcoal (only if within 1-2 hrs post-ingestion)
NAC
IV fluids
management of NV
hypoglycemia correction
Vitamin K
FFP
N-Acetylcysteine - Mechanism of Action
acts as glutathione substitute -> detoxifies NAPQI
also a precursor to glutathione -> increased production
also increases sulfation -> less NAPQI production
NAC - Oral Administration
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
NAC - IV administration
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
NAC - Treatment Duration
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
Liver Transplant - Criteria
- 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
