Therapeutics: Drug induced liver disease
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What type of immune cells are present at a high percentage in the liver due to the large amount of toxins present?
Macrophages (Kupffer cells and KC) and Natural Killer cells
If a T cell mounts an inflammatory response against a liver cell, what cytokines will be released?
If a T cell mounts hepatoprotective response against a liver cell, what cytokines will be released?
What is Hapten or p-i theory?
- Pharmacological interaction of drugs with immune receptors
- Drugs or their reactive metabolites covalently bind to endogenous hepatic proteins to form immunogenic drug-protein adducts
What are the clinincal feature suggesting an adaptive immune response has occurred?
- Rash, fever, eosinophila
- Delay of reaction (1-8 weeks)
- Follows repeat drug exposure
- Presence of antibodies specific for the drug
Is anaphylaxis an adaptive immune response?
No, can happen after a single exposure
What is Centrolubular necrosis
- Direct cell damage usually due to toxic metabolite
- Often dose related
What drugs cause Centrolubular necrosis?
APAP, Street drugs ecstasy and cocaine
What is Steatohepatitis and Phospholipidosis?
Accumulation of fatty acids or phospholipids in hepatocyte
What drugs cause steatohepatitis?
ETOH, Tetracycline, Valproic Acid
What drugs cause phospholipidosis?
What constitutes a hepatic vascular disorder?
Lesions form in hepatic venules, sinusoids, or portal vein
What drugs cause hepatic vascular disorders?
Androgens, Estrogens, Tamoxifen, Azathioprine
What is Generalized necrosis?
- Mimics changes characteristic of viral hepatitis
- Symptoms usually delayed a week or more from exposure to drug
What drug causes generalized necrosis?
What is Toxic cirrhosis?
Drug causes eventual fibrosis
What drugs cause toxic cirrhosis?
Methotrexate, High-dose Vitamin A
What is Cholestatic disease?
Prevents movement of bile (containing toxic excretion products) from liver into gallbladder for excretion
What drugs cause Cholestatic disease?
Chlorpromazine, Augmentin, Carbamazepine
What laboratory test would you use to evaluate liver injury?
- Alk Phos
- (1st 4 are the main ones)
What type of drugs are most likely to cause elevated bilirubin?
Those that cause Cholestatic liver disease(Chlorpromazine, Augmentin and Carbemazapine)
What is DILIN?
Drug induced liver injury network
What OTC drugs were listed as examples of “strongly associated with liver disease”?
- Felbamate (Felbatol)
- Tolcapone (Tasmar)
- Propylthiouracil (PTU)
- Kava Kava
What Rx drugs were listed as examples of “strongly associated with liver disease”?
- Telithromycin (Ketek)
- Amiodarone and Dronadarone (Multaq)
- Maraviroc (Selzentry)
- Valproic Acid (Depakote)
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