Drug-Induced Liver Injury (DILI) Professor Kassim Al-Saudi M.B.,Ch.B.,Ph.D

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

B O O E Z D R U G C O K E Burger B L O O D Obesity/ diabetes Abnormal liver tests HCV HBV FOURTH CAUSE 9%* * Bagheri, Br J Clin Pharmac 2000;50:479.

Risk Factors

Chronic Ethanol Use Increases Sensitivity of Liver to Hepatotoxins Anesthetic agents Acetaminophen Isoniazide Cocaine Vitamin A Aflatoxins Methotrexate Carbon Tetrachloride

Young adults DILI and age High drug consumption Old Children Exceptions: Reye’s syndrome with aspirin and Reye-like syndrome with valproate > >  Susceptibility (e.g., isoniazid)

(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

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

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.

Clinicopathologic Classification of Drug-Induced Liver Disease

General Mechanism

Acetaminophen Liver Toxicity

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

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

FULMINANT HEPATITIS IN THE USA OTHER CAUSES: 48% OTHER DRUGS: 12% PARACETAMOL: 40% DRUGS: 52% Intentional overdoses Self medication with excessive doses in the USA

In overdose situations, liver enzymes become saturated, glutathione is depleted, NAPQI (N-acetyl-p-benzoquinoneimine) accumulates, and hepatic necrosis occurs

Toxic dose –In adults, threshold for liver damage is 150 to 250 mg/kg –Children under 10 appear to be more resistant

Potential liver damage –Adults: > 150 mg/kg in acute dose –Adults: > 7.5 Grams in 24 hours (chronic) –Children ( 200 mg/kg

Glutathione: Role in Acetaminophen- Induced Liver Disease

Treatment of Acetaminophen Toxicity

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

Activated charcoal –Should not be witheld –dose Grams Cathartic –utilized to speed transit time

Hemodialysis –Limited benefit –Damage occurs quickly Hemoperfusion –No benefit Peritoneal dialysis –No benefit

4 hour post ingestion APAP level –levels drawn earlier may be erroneous –levels may be accurate up to 18 hours

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.

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

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

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

NAC side effects Relatively free of side effects when given orally Emesis may occur –extremely offensive sulfur odor

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 mg/kg is very effective in controlling nausea/vomiting associated with APAP toxicity

CONCLUSION TWO GOLDEN RULES 1. Always consider the possibility of DILI 2. Immediately withdraw all suspected drugs in severe cases DILI: Difficult to avoid, predict and diagnose

The End And Happy Eid