DILI/ALI Flashcards
Hepatotoxicity Causers
- > 1000 medications/supplements known to cause it
- Many cases are idiosyncratic where patients are on multiple medications
- Diet supplements and OTCs are also often the cause in many cases
Risk Factors for Hepatotoxicity
- Advanced age
- Sex
- Alchohol use
- Pregnancy
- Genetic predisposition
Diagnosing DILI
- Can be difficult
- Patients range from asymptomatic elevations in enzymes to fulminant hepatic failure
ALF + Severe Complications
- INR >= 1.5
- Hepatic encephalopathy
- <26 weeks of illness without apparent CLD
- Common causes: DILI, viral hepatitis, autoimmune liver disease, shock, hypoperfusion
Things to Consider for DILI
- Time to onset
- Time to recovery
- Clinical pattern
- Exclusion to other causes of liver injruy
- If a drug is known to be the cause
- Response to re-exposure
Time to Onset
- Typically between 5 day to 3 months of starting a medication
- Can be 24-72 hours for allergic reactions
- Exceptions can occur 3-12 months or even years after starting (isoniazid, amiodarone)
Time to Recovery
- Time to FULL recovery
- Typically see improvement within days to weeks
- FULL improvement seen in 2-3 months
- Tylenol and niacin are examples that have rapid improvement
Clinical Pattern of Injury
- Refers to histological features of injury
- Described with patterns of liver enzymes
- Hepatocellular, cholestatic, or mixed
Hepatocellular Injury
- ALT > 2x ULN or ALT:ALK ratio > 5
- EX: isoniazid, methyldopa
Cholestatic Injury
- ALK > 2x ULN or ALT:ALK ratio <2
- EX: Augmentin, erythromycin
Mixed Injury
- ALT and ALK elevated, ALT > 8x ULN
- EX: Phenytoin, Enalapril
Exclusions to Other Causes
- Viral Hepatitis (A, B, or C)
- Alcohol use
- Weight gain
- History of autoimmune diseases
- History of cardiac failure, shock, or septicemia
- History of ALL drug intake within last 3 months
Re-exposure
- Usually not recommended since rapid injury and potentially fatal outcomes can occur
- If multiple medications are suspected, reintroduce in order of least likely to cause the outcome
- Inadvertent re-exposure is also possible on the patient’s part
Medication Categories with Hepatotoxic Effects
- Antibiotics
- Antituberculosis Drugs
- Tylenol
- Statins
- Anticonvulsants
- Metformin
Antibiotics
- Rare, usually asymptoatic, transient, and cause mild impairment
- Augmentin is most common to cause liver injury
- Injury usually occurs days to weeks after use
- Host factors can increase likelihood, like Bactrim-induced injury is more likely in HIV patients
- Initial injury may be transient but reexposures may increase liver injury risk
Antituberculosis Drugs
-Well known for hepatotoxic effects
-Ranges from asymptomatic to fulminant hepatic failure
-EX: isoniazid, pyrazinamide, and rifampicin
-Occurs within first few weeks of therapy and main cause for early TB treatment termination
-Host factors increase susceptibility: age (>60), female, malnutrition
-Possible factors: pre-existing liver disease, HIV, acetylator status,
CYP2E1 polymorphisms, alcohol consumption, concomitant hepatotoxic
meds
-Combo therapies also increase the risk
-Ethambutol and streptomycin are not associated with hepatotoxicity
Tylenol
- Enzyme elevations are common with concurrent use
- Usually asymptomatic and resolve rapidly with stopping therapy, reducing dose, or even when continuing the dose sometimes
- STILL the preferred analgesic with liver disease since it is safer than alternatives
Tylenol + Toxic Metabolite
-5-9% of Tylenol is converted to a toxic metabolic, N-acetyl-p-benzoquinone
imine
-Usually rapidly metabolized/conjugated with glutathione and excreted
-N-acetylcysteine = antidote, prevents toxicity if used early
-Glutathione availability, alcohol use, and other medications that induce P450 enzymes increase risk for toxicity
Statins
- Vague recommendations against use in patients with liver disease
- Fat deposits on the liver that these patients have would make them benefit from statins
- Liver transaminase elevations are rare (<1%)
- No data suggesting to avoid statins in patients with liver disease
Anticonvulsants
- Rare, idiosyncratic, and often accompanied by signs of allergic reaction
- May be a genetic predisposition
Anticonvulsant Drug Examples
- Phenytoin: reactive metabolite leads to immune reaction mostly in adults, can be severe and lead to ALF/death
- Carbemazepine: asymptomatic rises in liver enzymes (Oxcarb. is less toxic)
- Lamotrigine: one of the most common causers of DILI, can also cause allergic reactions
- Valproic acid: Can cause many distinct forms of DILI
Valproic Acid Risk Factors
- <2 children
- Combo therapy with enzyme inducer anticonvulsant
- Developmental delay
- Carnitine deficiency
Metformin
- Historically avoided due to concerns about lactic acidosis
- Metformin may decrease liver enzymes
- Data overall says that patients with liver disease may benefit from it and experience lower risk of cancer and higher survival in HCV
DILI General Management
- D/C offending agent
- In ALF, hold/discontinue all unnecessary medications
- Administer antidote if possible
- Offer supportive care, steroids are helpful for autoimmune hepatitis
- UDSA can help reduce itching in cholestatic injury patients
- Give tenofovir for HBV
Drugs Known to Cause Liver Disease
- Do not necessary need to be avoided
- Usually not predominantly metabolized by liver
Furosemide
- Concern: electrolyte abnormalities
- Effect in Cirrhotic Patients: electrolyte disturbances, hepatorenal syndrome
ACE-I
- Concern: + RAS effect
- Effect in Cirrhotic Patients: hypotension
NSAIDs
- Concern: renal failure, increased bleeding risk
- Effect in Cirrhotic Patients: hepatorenal syndrome, fatal GI bleeds, anemia
Aminoglycosides
- Concern: renal failure
- Effect in Cirrhotic Patients: hepatorenal syndrome
