Drug induced liver injury Flashcards
1
Q
Clinical significance of DILI
A
- # 1 cause of ALF, can mimic all forms of liver disease (cholestatic, hepatocellular, mixed)
- Acetaminophen OD is most common cause of ALF and DILI
- Most adverse drug rxns in liver present as acute hepatitis/cholestasis/mixed
- Acute drug-induced hepatitis w/ jaundice and R≥5 has 10% mortality (Hy’s law)
- Cholestatic/mixed reactions resolve slowly
2
Q
Types of injury from various drugs
A
- Acute hepatocellular injury: acetaminophen, INH
- Acute cholestatic/mixed: erythromycin, rifampin
- Some antibios like amoxicillin-clavulanate (augmentin) has onset delayed 1-2 mo after course of Rx
- Very important: do not tolerate cholestasis rxns from drugs as they can be irreversible
- Rifampin: prevents uptake of unconjugated bili
3
Q
Chronic DILI
A
- Acute hepatitis caused by drug-> stop drug-> either resolves or pt goes into ALF
- Acute hepatitis caused by drug-> do not stop drug-> cirrhosis
- Acute cholestasis-> stop drug-> slowly resolves or goes to chronic ductopenia (and then cirrhosis)
4
Q
Classification of DILI
A
- Predictable rxns: dose-related, frequent injury
- Acetaminophen, cyclosporin
- Unpredictable (idiosyncratic): there is a threshold dose to cause damage, but not dose dependent (different for each person)
- For idiosyncratic hepatotoxicity there are some ( 3xULN but ASx) but this injury reverses w/ continued use (adaptation, Temple’s corollary)
- For these pts do not have to stop drug
- A subset of those pts will have overt liver disease (elevated transaminases, jaundice, Sxs) and the drug must be stopped
- A subgroup of these pts will have acute liver failure from the drug and will die or get Tx
5
Q
Risk factors in DILI
A
- Age
- Gender: F for hepatitis, M for cholestasis
- Diseases: HBV, HCV, HIV
- ETOH
- Concomitant drugs
- Obesity/DM
- Genetics
6
Q
Allergic vs non-allergic
A
- Allergic: fever, rash, eosinophilia, autoAbs
- Appears after 1-4 wks of being on drug
- Non-allergic: absence of immune features, often long latency (up to 1 yr)
7
Q
Pathogenesis of DILI
A
- Direct toxicity from drug leading to DNA damage or mito impairment (inhibits ETC causing ROS generation)
- Drug metabolized and metabolite has toxicity on the hepatocytes
- Covalent binding of the metabolite causes oxidative stress, leading to cytotoxicity or allergy
- Metabolite or actual drug causes immune response/apoptosis
- Combination of toxicity and inflammation leads to liver injury
- Massive immune responses also can cause multi-organ damage
8
Q
Pathogenesis of cholestatic DILI
A
- 2 mechanisms
- The drug may directly inhibit the excretion of bile acids
- Drug or metabolites damage cholangiocytes and cause inflammation which blocks or destroys bile ducts
9
Q
Acetaminophen toxicity
A
- Severe toxicity occurs when sufficient dose to deplete glutathione (usually >7g)
- Lower doses can cause damage when there is starvation (decreased GSH and glucuronic acid) or CYP2E1 inducers (INH, etoh)
- Presentation: very high transaminases begin at day 2, INR abnormal, minimal hyperbili
- Poor prognosis: pH 100 sec (INR>6), Cr >3.4, coma, serum phosphate >1.2 (phosphate should be low when hepatocyte are regenerating- if its high then little regeneration)
- Rx is N-acetylcysteine (NAC)
10
Q
Pathogenesis of acetaminophen toxicity 1
A
- Tylenol broken down by 3 possible pathways
- Sulfation takes care of low amounts, but gets overwhelmed quickly
- Glucuronidation takes care of most of the metabolism once sulfation is overwhelmed
- On really high doses even glucuronidation is overwhelmed, and CYP2E1 takes care of the rest
- But when CYP2E1 metabolizes acetaminophen it creates NAPQI (a reactive intermediate) which uses up glutathione, thus depleting glutathione stores
11
Q
Pathogenesis of acetaminophen toxicity 2
A
- Low glutathione leads to ROS generation and up regulation of JNK (causes more ROS) leading to apoptosis and necrosis
- Fasting decreases glucuronic acid and glutathione, increasing risk of damage
- Chronic etoh and INH induce CYP2E1 and thus increase flux thru that pathway increasing risk of damage
- Acute etoh will compete for CYP2E1 and thus doesn’t increase risk for OD
12
Q
INH hepatotoxicity 1
A
- Classic idiosyncratic nonallergic hepatotoxin
- Clinical: most don’t have hepatotoxicity, but 10% develop ASx ALT elevation (>3xULN)
- 1% get jaundice and have Sxs (overt hepatitis) w/ 50% of these cases being a delayed onset (after 2mo)
- Always stop INH if AST is >5xULN or AST >3xULN + Sxs
- If INH alone and 35 (or other risk factors) then monthly LFTs
- If ALT rises but <5xULN then monitor more frequently and look for adaptation
13
Q
INH hepatotoxicity 2
A
- If on a multi drug regimen everyone should get 8 wks of LFTs ever 2 wks, followed by monthly LFTs
- Increased risks: alcoholics, contomitant TB meds (rifampin), chronic HCV/HBV/HIV, >35yo, slow acetylators (these pts get more production of toxic metabolites instead of benign metabolites)
- Rifampin increases INH toxicity by inducing amidase (produces hydrazine) and a CYP, leading to more production of a toxic metabolite
14
Q
Augmentin (amoxicillin-clavilanate) toxicity
A
- Most common cause of idiosyncratic DILI, does have allergic features
- Has a broad signature: can be cholestatic/hepatitis/mixed
- 50% of cases have delayed onset: put to 8 wks after cessation
- Early onset usually in females 55 and cholestatic/mixed picture
