Drug-Induced Liver Injury

Drug-Induced Liver Injury (DILI)
Presented by:
Sumiya Shahid
MPhil Pharmacy practice
case
53 years old male shifted to ER from his dialysis center following the episodes of
tachycardia.
Medical history:
ESRD (on dialysis thrice weekly)
Hypertension (on Metoprolol)
Seizures (on phenobarbitone and phenytoin)
CAD (on Aspirin and rosuvastatin)
Afib (on diltiazem)
Presenting compliants:
Fatigue, abdominal pain and vomiting
Vitals:
Afebrile, pulse 150bpm, BP 136/95mmHg
Physical Examination:
Decrease breath sounds
Bilateral lower extremity edema
case
ECG revealed atrial flutter and started on IV diltiazem. However patient continue to have
a persistent atrial flutter. Then patient was started on Amiodarone infusion. Shortly after
amiodarone administration, patient LFTs started to deteriorate with worsening
coagulopathy
Ultrasound shows hepatomegagly
Repeated ECG showed severe systolic heart failure
Labs:
ALT 1500IU/L, AST 3000IU/L, INR 24
All cultures were reported negative
What is your intervention at this stage??
LFTs further deteriorate… multiple organ dysfunction… cardiac arrest… death
Diagnosis??
Culprit drugs???
Drug-induced Liver Injury (DILI)
 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
• Arthragia
• Eosinophilia
• Example: Phenytoin, Sulfonamides, Valproate
 Metabolic idiosyncrasy (Production of toxic metabolites)

• Example: INH, Ketoconazole, and Diclofenac
Overview of Drug induced Liver Injury
 Types of Drug Reactions
 Approach to the patient
 Natural History
Histological Classification
 Hepatocellular ------› Hepatocytes
 Cholestatic -------› Bile ducts or canaliculi
 Mixed
Categorization according to type of reaction
 Direct toxic reactions

 Idiosyncratic reactions
 Combined toxic/Allergic reactions
 Allergic hepatitis
 Cholestatic reactions
 Granulomatous reactions
 Chronic hepatitis and cirrhosis
 Fatty liver /NASH
 Veno-Occlusive disease
 Neoplastic
Diagnosis of (DILI)
 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
• Hepatitis C 2%-5% of
• Alcoholic liver diseases general
• Non alcoholic fatty liver diseases population
• Hemochromatosis
Diagnosis of (DILD)
Temporal relationship
• Most cases of acute DILI occurring within 1 week to 3

months of exposure
• Positive response to discontinuing the agent

 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 (DILI)
Extrahepatic manifestations
• Hypersensitivity reactions
 Fever
 Rash
 Arthralgias
 Esinophelia
Risk Factors For Susceptibility to DILI
 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
Risk Factors For Susceptibility to DILI
 Sulfonamide  Rifampicin
• HIV • Slow acetylators
• Slow acetylator • INH
• Genetic defect in
defense  Pyrazinamide
• Slow acetylators
 Anticonvulsats • INH
• Genetic defect in
detoxification
Clinical Presentations
Asymptomatic elevation in hepatic enzymes
No progress despite Progression to

Continued use of the Hepatic injury with
Medication. Continued use of the
(Drug tolerance) medication
AST & ALT 3-5 times

Upper limit of normal
•INH
•Phenytoin May progress to
•Chlopromazine Hepatic failure
Acute Hepatocelluler Injury
(Direct toxic reaction)
 Characterized by
• Marked elevation in ALT and AST
• Normal or minimally elevated alkaline phosphatase
• Bilirubin variably increased-----›worse prognosis.
 Comprise 1/3 of all cases of fulminant hepatic

failure
• 20% due to Acetominophen
• 12%-15% due to other drugs
 Alcohol
• AST is always 2-3 times higher than ALT
• AST remains less than 300 IU.
• ALT is almost always less than 100 IU.
 Towering elevation of ALT&AST(5000-10000 IU)

• Drugs (acetaminophen)
• Differential:
 Chemical toxins
 Toxic Mushrooms
• Unusual with other causes of liver diseases including
Viral Hepatitis.
Examples
 Anesthetics  NSAIDS & analgesics
• Halothane • Acetaminophen
• Isoflurane • Piroxicam,Diclofenac
• Sulindac
 Antimicrobials
• INH  Miscellaneous
• Rifampin • Labetalol
• Ketoconazole • Nicotinic acid
• Sulfonamides • Propylthiouracil
 Anticonvulsants
• Phenytoin
• Valproic acid
Cholestatic Injury
Definition: Reduction in bile flow due to

• Reduced secretion
• Obstruction
Biochemically:
• Elevated Alk phosphatase
• Elevated GGT
Acute illness that subsides 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
• Azathioprine
 Ampicillin  Amitriptyline
Barbiturates • Chlorthiazide
 Augmentin 
 Carbamazipine • Ibuprphen
 Clindamycin
 Chlorpromazine • Cimetidine
 Erythromycin
 Haloperidol • Prochlorperazine
 Organic arsenicals  Imipramide • Terbinafine
 Septran  phenothiazines • Terfenadine
 Tetracycline
• Tolbutamide
 Thiabebdazole
• Ticlodipine
• Ethenyl estradiol
Granulamatous Hepatitis
 A form of hepatic injury characterized by :
• Fever
• Diaphoresis
• Malaise
• Anorexia
• Jaundice
• Rt upper quadrant discomfort
• Granuloma on liver biopsy
• Illness usually occurs within the first 2 months of therapy
 Examples:
• Quinidine
• Carbamazipine
• Allopurinol
• Hydralazine
• Phenytoin
• Gold
• Mineral oil ingestion
• Phenylbutazone
Drug induced chronic hepatitis
 Can resemble chronic active hepatitis including cirrhosis as well as
a form of chronic autoimmune hepatitis
 Characteristics of drug- induced autoimmune hepatitis

Duration of drug intake ≥ 2-24 months
Female predominance > 80%
Onset Insidious, gradual
Clinical Fatigue, anorexia, wt loss, jaundice,
ascites, hepatosplenomegaly, and portal
hypertension
Biochemical AST, ALT= 5-50 × ULN
Increased gamma globulin level
Histology  Very active necro-inflammatory lesion
 Prominent plasma cells
Usual course Resolution on withdrawal of drug
Drugs leading to a syndrome resembling
type I autoimmune chronic hepatitis
Multiple cases
Methyldopa
Minocycline
Nitrofurantoin
Oxyphenisatin
Few cases
Benzarone
Diclofenac
Fenofibrate
Papverine
Pemoline
Propylthiouracil
Captopril
Flucloxacillin
Procainamide
Vascular injury
 May involve all of the vascular components of the liver,
including the sinusoids, hepatic veins, and hepatic arteries.
 Veno-occlusive disease (VOD):

• May be caused by:
 Toxic plant alkaloids (certain herbal tea)
 A serious complication complication of bone marrow transplant
• Azathioprine is probably the calprit
• Clinically presents as
 Mild viral-like illness →→ Fulminent hepatic failure
 Rapid weight gain
 Ascites
 Jaundice
 Evidance of portal hypertension
 Chronic form of VOD may also exist.

Neoplastic lesions
Neoplastic lesions Clinical findings Examples
Focal noduler  Hepatic mass Contraceptive steroids
hyperplasia
Adenoma  Hepatic mass  Contraceptive steroids
 Hemoperitoneum  Anabolic steroids
 Danazole
Hepatocelluler  Malignant mass  Anabolic steroids

carcinoma  Contraceptive steroids
 Venyl chloride
 Thorium dioxide
(Thorotrast)
Angiosarcoma  Malignant mass Anabolic steroids

Inorganic arsenicals
Thorium
dioxide(Thorotrast)
Natural History and Prognosis
 When recognized promptly and the offending agent is

discontinued most cases resolve without chronic sequalae
 Mortality principally depend on the degree of hepatocelluler

injury.
 10% mortality for agents causing fulminant hepatitis or

toxic steatosis.
 Agents that cause cholestatic injury rarely , if ever ,

produce acute fatalities
 The prognosis is worse whenever jaundice accompanies

hepatocelluler injury.
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Drug-Induced Liver Injury (DILI)

What is your intervention at this stage??

LFTs further deteriorate… multiple organ dysfunction… cardiac arrest… death

 Metabolic idiosyncrasy (Production of toxic metabolites)

 Types of Drug Reactions

 Approach to the patient

 Hepatocellular ------› Hepatocytes

 Cholestatic -------› Bile ducts or canaliculi

 Direct toxic reactions

• Most cases of acute DILI occurring within 1 week to 3

• Positive response to discontinuing the agent

Asymptomatic elevation in hepatic enzymes

No progress despite Progression to

AST & ALT 3-5 times

 Comprise 1/3 of all cases of fulminant hepatic

 Towering elevation of ALT&AST(5000-10000 IU)

Definition: Reduction in bile flow due to

Acute illness that subsides when the offending drug

 Characteristics of drug- induced autoimmune hepatitis

 Veno-occlusive disease (VOD):

• Azathioprine is probably the calprit

 Chronic form of VOD may also exist.

Hepatocelluler  Malignant mass  Anabolic steroids

Angiosarcoma  Malignant mass Anabolic steroids

 When recognized promptly and the offending agent is

 Mortality principally depend on the degree of hepatocelluler

 10% mortality for agents causing fulminant hepatitis or

 Agents that cause cholestatic injury rarely , if ever ,

 The prognosis is worse whenever jaundice accompanies

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