Drug-induced Liver Disease (DILD)

DR. IZHARULLAH
ASSISTANT PROFESSOR
MIIPS
 Occurrence of DILD
 10% of cases of hepatitis in a major hepatology center in France

 20% of instances of jaundice among aged persons in USA

 10 fold increase in No. of reported cases between 1964-1973 in

Japan

 25%-40% of fulminent hepatic failure

 Major Types of DILD
 Predictable
 Dose related
 Intrinsically hepatotoxic drugs
 Acute (hours)
 Injury pattern is usually necrosis Clinically → Fulminant (Acute Hepatitis)
Example: Acetaminophine
 Unpredictable
 Not dose related
 Rare 0.01-1.0 %
 Weeks to months after ingestion of drug
 Idiosyncratic
 Immune mediated idiosyncrasy (Hypersensitivity)
 Rash
 Fever
 Arthralgia
 Eosinophilia
 Example: Phenytoin, Sulfonamides, Valproate
 Metabolic idiosyncrasy (Production of toxic metabolites)
 Example: INH, Ketoconazole, and Diclofenac
Histological Classification

 Hepatocellular ------› Hepatocytes

 Cholestatic -------› Bile ducts or canaliculi

 Mixed
Diagnosis of (DILD)
 High index of suspicion
 Abnormalities in hepatic associated enzymes
 Hepatitis like symptoms
 Jaundice
 Drug history
 Dose
 Duration of therapy
 Time between initiating therapy and the development of
hepatic injury (latency)
 Exclusion of other causes of liver diseases
 Hepatitis B 2%-5% of
general
 Hepatitis C
population
 Alcoholic liver diseases
 Non alcoholic fatty liver diseases
 Haemochromatosis
Diagnosis of (DILD)

Progressive relationship

 Most cases of acute DILD occurring within 1 week to 3 months of

exposure
 Positive response to discontinuing the agent (Dechallenge)
 In acute hepatocelluler injury
 50% reduction in hepatic –associated enzymes after 2 weeks
 Return to normal by 4 weeks
 In cholestatic injury
 May have prolonged recovery time
Diagnosis of (DILD)
Extrahepatic signs

 Hypersensitivity reactions
 Fever
 Rash
 Arthralgia
 Esinophelia
Risk Factors For DILD

 Methotrexate  Acetaminophen
 Alcohol  Alcohol
 Obesity  Fasting
 D.M  INH
 Chronic hepatitis

 Valproate
 INH  Young age
 HBV,HCV,HIV  Anticonvulsants
 Alcohol
 Older age  Diclofenac
 Female  Female
 Osteoarthritis
Continued

 Sulfonamide  Rifampicin
 HIV  Slow acetylators
 Slow acetylator  INH
 Genetic defect in defense
 Pyrazinamide
 Anticonvulsants  Slow acetylators
 Genetic defect in  INH
detoxification
 ALT: L-alanine to α-ketoglutarate

 AST catalyzes the reversible transfer of an

α-amino group between aspartate and
glutamate and, as such, is an important
enzyme in amino acid metabolism.

Alkaline phosphatase responsible for

removing phosphate groups from many
types of molecules,
including nucleotides, proteins,
and alkaloids
Acute Hepatocelluler Injury
(Direct toxic reaction)

 Characterized by
 Marked elevation in ALT (Alanin Amino transferase)and AST
(Aspartate Aminotransferase)
 Normal or minimally elevated alkaline phosphatase
 Bilirubin variably increased
 Comprise 1/3 of all cases of acute hepatic failure in the US.
 20% due to Acetominophen
 12%-15% due to other drugs
Acute Hepatocelluler Injury
(Direct toxic reaction)
 Alcohol
 AST (10-40 normal range) is always 2-3 times higher than ALT (7-
56)

 Immense elevation of ALT&AST(5000-10000 IU)

 Drugs (acetaminophen)
 Differential:
 Chemical toxins
 Toxic Mushrooms
 Shock liver
 Unusual with other causes of liver diseases including Viral Hepatitis.
Acute Hepatocelluler Injury
(Direct toxic reaction)
Examples
 Anesthetics  NSAIDS & analgesics
 Halothane  Acetaminophen
 Isoflurane  Piroxicam,Diclofenac

 Antimicrobials  Miscellaneous
 INH  Labetalol
 Rifampin  Nicotinic acid
 Ketoconazole  Propylthiouracil
 Sulfonamides

 Anticonvulsants
 Phenytoin
 Valproic acid
 Carbamazipine
Cholestatic Injury

Definition: Reduction in bile flow due to

 Reduced secretion
 Obstruction

Biochemically:
 Elevated Alkaline phosphatase
 Elevated GGT (Gamma-Glutamyltransferase (GGT)
 Elevated 5 NT (5′ -Nucleotidase)

Acute illness that diminishes when the offending drug is

withdrawn.
Cholestatic Injury

Clinical presentation

Jaundice

Pruritis
 Drugs causing chronic cholestasis
and the vanishing bile duct syndrome

Antibiotics Psychotropic Miscellaneous

•Aprindine

• Azathioprine
 Ampicillin  Amitriptyline • Carbutamide
• Ciproheptadine
 Augmentin  Barbiturates • Chlorthiazide

 Clindamycin  Carbamazipine • cyamemazine

• Ibuprphen
 Erythromycin  Chlorpromazine
• Cimetidine
 Haloperidol Prochlorperazine
 Organic arsenicals •

• Terbinafine
 Imipramide
 Tetracycline • Terfenadine
 phenothiazines • Tolbutamide
 thiabendazole
• Ticlodipine
• Xenalamine
•Ethenyl estradiol
Natural History and Prognosis

 When recognized promptly and the offending agent is discontinued most

cases resolve

 Mortality principally depend on the degree of hepatocelluler injury.

 10% mortality for agents causing fulminant hepatitis or toxic steatosis's

 Agents that cause cholestatic injury rarely , if ever , produce acute fatalities

 The prognosis is worse whenever jaundice accompanies hepatocelluler

injury.