Drug-Induced Liver Injury (DILI) Professor Kassim Al-Saudi M.B.,Ch.B.,Ph.D.
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Transcript of Drug-Induced Liver Injury (DILI) Professor Kassim Al-Saudi M.B.,Ch.B.,Ph.D.
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Drug-Induced Liver Injury(DILI)
Professor Kassim Al-Saudi
M.B.,Ch.B.,Ph.D
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Importance
• Prognosis may be worse than for viral hepatitis
• Responsible for 3% to 10% of all adverse drug reactions; frequency appears to be increasing
• Drugs and toxins responsible for 1/3 of cases of fulminant hepatic failure
• Drug injury can mimic all forms of liver disease
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BOO EZ
DR UG
COKE
Burger BLOOD
Obesity/diabetes
Abnormallivertests
HCVHBV
FOURTH CAUSE
9%**Bagheri,Br J Clin Pharmac2000;50:479.
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Risk Factors
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Chronic Ethanol Use Increases Sensitivity of Liver to Hepatotoxins
• Anesthetic agents• Acetaminophen• Isoniazide• Cocaine• Vitamin A• Aflatoxins• Methotrexate• Carbon Tetrachloride
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Youngadults
DILI and age
High drugconsumption
Old Children
Exceptions: Reye’s syndrome with
aspirin and Reye-like syndrome with
valproate
> >
Susceptibility(e.g., isoniazid)
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(Same in females and males before 50)
DILI and gender
Incidence of DILI: 2.6-fold higher in females than males
in persons aged 50 years or more
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CIRRHOSIS
- Does not change the incidence of DILI
- but worsens it outcome
(The same degree of liver injury, which is well tolerated in a normal subject, can trigger liver failure, complications and
death in patients with an already impaired liver function)
DILI in cirrhosis
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DIAGNOSIS
DILI is most often a diagnosis of exclusion.
• All the known causes of liver disease have to be excluded.• Common diseases to be excluded are viral hepatitis, autoimmune disorders, Alcohol intake, Metabolic and genetic disorders, hemodynamic dysfunction and billiary abnormalities.• Perform relevant investigations.
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Clinicopathologic Classification of Drug-Induced Liver Disease
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General Mechanism
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Acetaminophen Liver Toxicity
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• Acetaminophen is hepatotoxic in large doses and often used to commit suicide
• Acetaminophen metabolism creates toxic metabolites that cause zone 3 necrosis when present at levels exceeding the liver’s detoxification capacity
Acetaminophen Hepatotoxicity
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• Evolution of injury in three phases
– Phase I –acute GI symptoms (1-4 hours) – Phase II –latent (1-3 days) – Phase III –liver damage/failure (3-10 days) • About 15% of patients with overt liver injury die
Acetaminophen Hepatotoxicity
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FULMINANT HEPATITIS IN THE USA
OTHER CAUSES: 48%
OTHER DRUGS: 12%
PARACETAMOL: 40%
DRUGS: 52% Intentional overdoses Self medication withexcessive doses in the USA
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In overdose situations, liver enzymes become saturated, glutathione is depleted, NAPQI
(N-acetyl-p-benzoquinoneimine) accumulates, and hepatic necrosis occurs
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• Toxic dose
– In adults, threshold for liver damage is 150 to 250 mg/kg
– Children under 10 appear to be more resistant
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• Potential liver damage
– Adults: > 150 mg/kg in acute dose
– Adults: > 7.5 Grams in 24 hours (chronic)
– Children (<10 yrs): > 200 mg/kg
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Glutathione: Role in Acetaminophen-Induced Liver Disease
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Treatment of Acetaminophen Toxicity
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• GI decontamination– Syrup of Ipecac
• return usually 30-40% at best• best if used early (first 1-2 hours)
– Gastric lavage• effectiveness diminishes with time
Treatment of Acetaminophen Toxicity
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• Activated charcoal– Should not be witheld– dose 50-100 Grams
• Cathartic– utilized to speed transit time
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• Hemodialysis– Limited benefit– Damage occurs quickly
• Hemoperfusion– No benefit
• Peritoneal dialysis– No benefit
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•4 hour post ingestion APAP level–levels drawn earlier may be
erroneous
–levels may be accurate up to 18 hours
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N-acetylcysteine (NAC)
• Mechanism of action– glutathione substitute– may supply inorganic sulfur, altering
metabolism
• Route of administration– Orally or IV
• IV not approved in the U.S.
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• NAC dosing
– Oral 72 hour protocol• Loading dose is 140 mg/kg
• Maintenance doses: 70 mg/kg– Given every 4 hours x 17 doses starting 4 hours
after loading dose
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• NAC supplied as 10 or 20% oral solution– dilute to 5% final concentration with juice or
soft drink
– May be administered via NG tube
– If emesis occurs within 1 hour of administration, repeat the dose
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• If emesis persists, antiemetics may be used
– Reglan® (metoclopramide)• 0.1 to 1.0 mg/kg iv is often effective
– If emesis is refractory, may consider
Zofran® (ondansetron) or Kytril® (granisetron)
• Expensive, but very effective
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NAC side effects
• Relatively free of side effects when given orally
• Emesis may occur– extremely offensive sulfur odor
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Points to remember
• APAP is present in many poly drug overdoses • No symptoms may be present…screen• 150 mcg/ml at 4 hours is a “treat” level• NAC loading dose is 140 mg/kg• NAC maintenance doses are 70 mg/kg• Once NAC is started, DO NOT DC• Metoclopramide 0.1-1.0 mg/kg is very
effective in controlling nausea/vomiting associated with APAP toxicity
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CONCLUSION
TWO GOLDEN RULES1. Always consider
the possibility of DILI
2. Immediately withdrawall suspected drugs
in severe cases
DILI: Difficult to avoid, predict and diagnose
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The End
And Happy Eid