Drug & Toxic Induced Liver Disease

DEFINITION:

More than 600 medicines have been reported to cause liver injury; Two most common: Acetaminophen and Alcohol; See also Liver- Alcoholic Liver Disease (Chapter 4.04)

EPIDEMIOLOGY:

Drug-induced liver disease accounts for 2-5% of hospital admissions for jaundice in the U.S. and 10-20% of cases of fulminant liver failure

PATHOPHYSIOLOGY:

Intrinsic injury (hepatotoxin with direct or indirect toxicity of hepatocytes): direct damage by covalently binding to cellular macromolecules
- Example: Acetaminophen, Chloroform, Carbon Tetracholoride, Phosphorus
Idiosyncratic injury (hyperimmune reaction): dose-dependent and hepatic injury cannot be reproduced in animal models
- Clinical features of hypersensitivity common (rash, fever, eosinophilia)
- Example: Phenytoin, Isoniazid, Ticrynafen, Halothane, Valproic Acid
Patterns of injury: Cholestatic and Hepatocellular liver injury typically occurs 5-90 days after initial exposure
- Drug stopped, biochemical improvement begins: Hepatocellular usually within 2 weeks, Cholestatic/Mixed up to 4 weeks
- Persistence beyond these intervals suggests coexistent or independent cause of liver disease: Viral, AIH, PBC, PSC, etc
Drugs causing:
- Chronic Hepatitis and Cirrhosis: Isoniazid, Methotrexate, Methyldopa, Nitrofurantoin, Oxyphenisatin, Trazodone
- Mixed injury: Amitriptyline, Amoxicillin, Ampicillin, Captopril, Carbamazepine, Cimetidine, Flutamide, Imipramine, Nitrofurantoin, Phenylbutazone, Quinidine, Rantidine, Sulfonamides, Sulindac, Bactrim, NSAIDs
- Cholestasis: Allopurinol, Amitriptyline, Azathioprine/6MP, Captopril, Carbamazepine, Phenytoin, OCP, Androgens/Anabolic Steroids
- Granulomas causes: Allopurinol, Aspirin, Chlorpromazine, Diazepam, Diltiazem, Gold, Isoniazid, Mineral Oil, Nitrofurantoin, OCP, Oxacillin, Penicillin, Phenytoin, Phenylbutazone, Quinidine, Quinine, Tolbutamide
- Drug-induced Steatosis (fatty liver):
  - Microvesicular Steatosis: Aspirin (Reye’s), Ketoprofen, Tetracycline, Valproic Acid, Zidovudine (AZT), Valproic Acid
  - Macrovesicular Steatosis: ETOH, Acetaminophen, Cisplatin, Corticosteroids, Methotrexate, Tamoxifen
  - Phospholipidosis Steatosis: 4′4′-diethylamino ethyl hexestrol, Perhexiline maleate, Amiodarone, Bactrim, TPN
- See also Liver- Histopathology of Liver (Chapter 4.19)

LABORATORY STUDIES/DIAGNOSTIC STUDIES:

▪	Patterns of drug-induced liver injury:		ALT	Aφ	ALT:Aφ Ratio
		Hepatocellular	≥2-fold ↑	Normal	High (≥5)	Aminotransferases
		Cholestatic	Normal	≥2-fold ↑	Low (≤2)	>1000 and ↑↑↑ LDH:
		Mixed Injury	≥2-fold ↑	≥2-fold ↑	2-5	‘Shock Liver’ (Ischemia)

Diagnosis of drug-induced liver injury requires exclusion of viral, toxic, cardiovascular, inheritable, and malignant causes
Biopsy indications: medication stoppage not followed by improvement, cause still in question, severity necessitates intervention (i.e. OLT)

ETOH: