Ans. B: Acetaminophen Patterns of liver injuries A. Zonal Necrosis This is the most common type of drug induced liver cell necrosis where the injury is largely confined to a paicular zone of the liver lobule. It may manifest as very high level of ALT and severe disturbance of liver function leading to acute liver failure. Causes include: Carbon tetrachloride Paracetamol Acetaminophen (paracetamol) is usually well tolerated in prescribed dose but overdose is the most common cause of drug induced liver disease and acute liver failure worldwide. Damage to the liver is not due to the drug itself but to a toxic metabolite (N-acetyl- p-benzoquinone imine NAPQI, or NABQI) which is produced by cytochrome P450 enzymes in the liver. In normal circumstances this metabolite is detoxified by conjugating with glutathione in phase 2 reaction. In overdose large amount of NAPQI is generated which overwhelm the detoxification process and lead to damage to liver cells. Administration of Acetylcysteine, a precursor of glutathione, can limit the severity of the liver damage by capturing the toxic NAPQI. B. Hepatitis In this pattern hepatocellular necrosis is associated with infiltration of inflammatory cells. There can be three types of drug induced hepatitis. Viral hepatitis type picture is the commonest, where histological features are similar to acute viral hepatitis. Causes include: Halothane, isoniazid, phenytoin In the focal or non specific hepatitis scattered foci of cell necrosis may accompany lymphocytic infiltrate. Causes include: Aspirin Chronic hepatitis type is very similar to autoimmune hepatitis clinically, serologically as well as histologically. Causes include: Methyldopa, diclofenac C. Cholestasis Liver injury leads to impairment of bile flow and clinical picture is predominated by itching and jaundice. Histology may show inflammation (cholestatic hepatitis) or it can be bland without any parenchymal inflammation. In rare occasions it can produce features similar to primary biliary cirrhosis due to progressive destruction of small bile ducts (Vanishing duct syndrome). Causes include: Bland: Oral contraceptive pills, anabolic steroid, androgens Inflammatory: Allopurinol, co-amoxiclav, carbamazepine Ductal: Chlorpromazine, flucloxacillin D. Steatosis Hepatotoxicity may manifest as triglyceride accumulation which leads to either small droplet (microvesicular) or large droplet (macrovesicular) fatty liver. There is a separate type of steatosis where phospholipid accumulation leads to a pattern similar to the diseases with inherited phospholipid metabolism defects (e.g. Tay-Sachs disease). Causes include: Microvesicular: Aspirin (Reye's syndrome), ketoprofen, tetracycline Macrovesicular: Acetamenophen, methotrexate Phospholipidosis: Amiodarone, total parenteral nutrition E. Granuloma Drug induced hepatic granulomas are usually associated with granulomas in other tissues and patients typically have features of systemic vasculitis and hypersensitivity. Causes include: Allopurinol, phenytoin, isoniazid, quinine, penicillin, quinidine F. Vascular lesions They result from injury to the vascular endothelium. Peliosis hepatis: anabolic steroid Hepatic vein thrombosis: Oral contraceptives G. Neoplasm Neoplasms have been described with prolonged exposure to some medications or toxins. Hepatocellular carcinoma, angiosarcoma and liver adenomas are the ones usually repoed. Causes include: Vinyl chloride, combined oral contraceptive pill, anabolic steroid, arsenic, thorotrast