Exam 3: Lecture 13, Drug-Induced Liver Injury Flashcards
DILI accounts for nearly….
50% of cases of acute liver failure in USA
Most common drug associated with hepatotoxicity in USA?
Acetaminophen
Amox Clav = world wide
How many drugs have some degree of DILI risk?
750 per FDA
DILI categorized as…
Acute or Chronic
Hepatitis, Cholestatic, or mixed pattern injury
Hepatitis
Hepatocyte necrosis and associated with poor prognosis
Is DILI major cause of drug attrition?
Yes
Cholestatic Drug-induced injury
has to do with issues in bile secretion
2 mechanisms for chronic cholestasis
Obliteration of bile ducts
Extrahepatic biliary obstruction
Drugs causing Cholestatic hepatitis
amoxicillin clav, sulfonylureas, vitamin A
Drugs causing Hepatocellular necrosis
Acetaminophen, isoniazid, niacin
Drugs causing Microvesicular Steatosis/lactic acidosis
Antiretrovirals, Aspirin, valproic acid
Drugs causing Fatty liver
Amiodarone, corticosteroids, ethanol
Factors of DILI
PK of the drug
patient age/sex/comorbidities
Hard to predict
positive correlation between age/risk
Men or women more prone to developing hepatitis and progress to acute liver failure?
women
Which oral meds have higher chance to result in DILI?
drugs with significant hepatic metabolism
Mechanisms of DILI
direct toxicity from admin of drug and their metabolites
result from immune-mediated mechanisms
can be distinct or interconnected
One of earliest events of DILI is…
inhibition of mitochondrial respiratory chain
increased ROS
depletion of ATP
Immune-mediated injury
characterized by prolonged interval between admin of drug and recognized liver toxicity
6 Mechanisms for DILI
Mitochondrial impairment Inhibition of Biliary efflux Lysosomal impairment Reactive metabolites ER stress Immune system
Symptoms of DILI
fever jaundace tired itching unusual weight gain swelling of feet/legs nausea/vomiting/pain in abdomen
How to diagnose DILI?
Blood test
Biochemical test for liver enzymes AST/ALT elevation
Management of DILI
based on proper diagnosis and recognition of what caused it/withdrawal
When should drug admin be stopped DILI?
ALT> 8 x upper limit of normal
ALT > 5 x ULN for 3 weeks
ALT > 3 x ULN + Bilirubin > 2 X ULN
Prothrombin time/international normalized ratio > 1.5 ULN
Presence of symptoms suggesting liver injury
antidote for DILI?
Nothing
reception is N-acetylcysteine for acetaminophen
How to consider patients for liver transplant?
Kings College has some chart
Acetaminophen DILI
fraction of drug metabolized by CYP to toxic intermediate metabolite that can interact with intracellular proteins and induce hepatocyte death
toxic intermediate metabolite from Acetaminophen?
NAPQI
Hepatotoxicity occurs when GST is…
depleted or NAPQI generation exceeds GST binding capacity
both Get depletion/increased NAPQI seen in alcoholics, can develop severe liver injury with low doses of acetaminophen
How to prevent acetaminophen toxic metabolite toxicity?
GSH binds and prevents it from occurring
otherwise intermediate goes and binds protein
By what mechanism does INH cause DILI?
direct hepatotoxic effects of INH metabolites
accumulation of acetylhydrazine/hydrazine
accumulation dependent on acetylator phenotype of patient
