Drug & Toxin-Induced Hepatic Disease Mechanism of injury: Direct toxicity (Drugs are often divided into dose-dependent, or predictable, hepatotoxins and dose-independent, or unpredictable (idiosyncratic), hepatotoxins) Hepatic conversion of a xenobiotic to an actual toxin Immune mechanisms  drug or metabolite acts as hapten Types of injury: Hepatocyte necrosis Cholestasis Insidious liver dysfunction Reye syndrome – children given ASA; extensive accumulation of fat droplets within hepatocytes (microvesicular steatosis)

Drug & Toxin-Induced Hepatic Disease Reye syndrome Usually in children < 4 years of age Often follows a chickenpox or influenza infection Mitochondrial damage (? virus, salicylates) Disruption of urea cycle  increased serum ammonia Defective beta-oxidation of fatty acids

Drug & Toxin-Induced Hepatic Disease Reye syndrome Microvesicular steatosis (? Salicylate effect) Clinical findings: Encephalopathy Hepatomegaly  liver failure Laboratory findings: Transaminasemia Normal to slight inc. total bilirubin Increased serum ammonia

ACETAMINOPHEN Acetaminophen (paracetamol) is a widely used analgesic available without prescription. It is safe when taken in the recommended therapeutic dose of 1 to 4 g daily, but hepatotoxicity produced by self-poisoning with acetaminophen has been recognized since the 1960s. Despite the effectiveness of thiol-based antidotes, acetaminophen remains the most common cause of drug-induced liver injury in most countries and an important cause of acute liver failure.Parasuicide and suicide are the usual reasons for overdose. Single doses of acetaminophen that exceed 7 to 10 g (140 mg/kg body weight in children) may cause liver injury, but this outcome is not inevitable. Severe liver injury (serum ALT level greater than 1000 U/L) or fatal cases usually involve doses of at least 15 to 25 g, Among heavy drinkers and chronic liver diseases, daily acetaminophen doses of 2 to 6 g have been associated with fatal hepatotoxicity.

Self-poisoning with acetaminophen is most common in young women, but fatalities are most frequent in men, possibly because of alcoholism and late presentation. In the first two days after acetaminophen self-poisoning, features of liver injury are not present. Nausea, vomiting, and drowsiness are often caused by concomitant ingestion of alcohol and other drugs. After 48 to 72 hours, serum ALT levels may be elevated, and symptoms such as anorexia, nausea and vomiting, fatigue, and malaise may occur. Hepatic pain may be pronounced. In severe cases, the course is characterized by repeated vomiting, jaundice, hypoglycemia, and other features of acute liver failure, particularly coagulopathy and hepatic encephalopathy. Indicators of a poor outcome include grade IV hepatic coma, acidosis, severe and sustained impairment of coagulation factor synthesis, renal failure, and a pattern of falling serum ALT levels in conjunction with a worsening prothrombin time.

Management : In patients who present within four hours of ingesting an excessive amount of acetaminophen, the stomach should be emptied with a wide-bore gastric tube. Osmotic cathartics or binding agents have little if any role in management. Charcoal hemoperfusion has no established role. The focus of management is on identifying patients who should receive thiol-based antidote therapy and, in those with established severe liver injury, assessing the patient's candidacy for liver transplantation. Cases of acetaminophen-induced severe liver injury are virtually abolished if N acetyl cysteine ( NAC ) is administered within 12 hours and possibly within 16 hours of acetaminophen ingestion. After 16 hours, thiol donation is unlikely to affect the development of liver injury because oxidation of acetaminophen to NAPQI with consequent oxidation of thiol groups is complete and mitochondrial injury and activation of cell death pathways are likely to be established.

NAC DOSE AND ADMINISTERATION : Oral administration is preferred in the United States,with a loading dose of 140 mg/kg followed by administration of 70 mg/kg every 4 hours for 72 hours. This regimen is highly effective, despite the theoretical disadvantage that delayed gastric emptying and vomiting may reduce intestinal absorption of NAC. In Europe and Australia, NAC is administered by slow bolus intravenous injection followed by infusion (150 mg/kg over 15 minutes in 200 mL of 5% dextrose, with a second dose of 50 mg/kg 4 hours later, if the blood acetaminophen levels indicate a high risk of hepatoxicity, and a total dose over 24 hours of 300 mg/kg).The intravenous route may be associated with a higher rate of hypersensitivity reactions because of the higher systemic blood levels achieved.