Pharmacology
Mechanisms of Acetaminophen-lnduced Liver Necrosis
By Jack A. Hinson, Dean W. Roberts, and Laura P. James
Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is widely used as analgesic and antipyretic drug. At therapeutic doses, acetaminophen is safe to be used. Acetaminophen other than aspirin and ibuprofen has only weak anti-inflammatory properties. At higher doses, acetaminophen produces a centrilobular hepatic necrosis that can be fatal.
Acetaminophen-lnduced Hepatotoxicity
Observation/ Microscopic Examination
Sign and Symptoms
1. Indicated fulminating hepatic necrosis
2. Eosinophilic degeneration of cells with pyknosis of nuclearmaterial in hepatocytes
3. Vacuolization and early degenerative changes surrounding the portal areas
4. Mild polymorphonuclear leukocytic infiltration
5. Necrosis in the cells of the proximal tubules of the kidney
1. Nausea and vomiting within 2-3 hour of ingestion
2. Abdominal pain in the right upper quadrant
3. Liver dysfunction occurred within 24 hour
4. Dramatic increase in serum alanine aminofiansferase (ALT) and asparatate aminotransferase (AST) levels
5. Mild hyperbilirubinemia
6. Increased prothrombin time nephrotoxicity
Histological Observation
1. Glycogen loss and vacuolization of centrilobular hepatocytes by 2 hours
2. Clear demarcation of the centrilobular areas from the rest of the liver
3. Nuclear changes in centrilobular hepatocytes and single cell necrosis with pycnotic cells by 3 hours
4. Gross necrosis of the entire centrilobular areas by 6 hours
5. Hepatic congestion
.
Metabolism in Acetaminophen Toxicity
1. Drug metabolizing enzymes convert acetaminophen to a reactive metabolite that bound to proteins covalently
2. Glutathione detoxify the metabolite and form acetaminophen-glutathione conjugate at nontoxic dose. However, the metabolite depleted hepatic glutathione and covalently bound to protein at toxic dose. Since diethylmaleate depleted hepatic glutathione without
By Jack A. Hinson, Dean W. Roberts, and Laura P. James
Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is widely used as analgesic and antipyretic drug. At therapeutic doses, acetaminophen is safe to be used. Acetaminophen other than aspirin and ibuprofen has only weak anti-inflammatory properties. At higher doses, acetaminophen produces a centrilobular hepatic necrosis that can be fatal.
Acetaminophen-lnduced Hepatotoxicity
Observation/ Microscopic Examination
Sign and Symptoms
1. Indicated fulminating hepatic necrosis
2. Eosinophilic degeneration of cells with pyknosis of nuclearmaterial in hepatocytes
3. Vacuolization and early degenerative changes surrounding the portal areas
4. Mild polymorphonuclear leukocytic infiltration
5. Necrosis in the cells of the proximal tubules of the kidney
1. Nausea and vomiting within 2-3 hour of ingestion
2. Abdominal pain in the right upper quadrant
3. Liver dysfunction occurred within 24 hour
4. Dramatic increase in serum alanine aminofiansferase (ALT) and asparatate aminotransferase (AST) levels
5. Mild hyperbilirubinemia
6. Increased prothrombin time nephrotoxicity
Histological Observation
1. Glycogen loss and vacuolization of centrilobular hepatocytes by 2 hours
2. Clear demarcation of the centrilobular areas from the rest of the liver
3. Nuclear changes in centrilobular hepatocytes and single cell necrosis with pycnotic cells by 3 hours
4. Gross necrosis of the entire centrilobular areas by 6 hours
5. Hepatic congestion
.
Metabolism in Acetaminophen Toxicity
1. Drug metabolizing enzymes convert acetaminophen to a reactive metabolite that bound to proteins covalently
2. Glutathione detoxify the metabolite and form acetaminophen-glutathione conjugate at nontoxic dose. However, the metabolite depleted hepatic glutathione and covalently bound to protein at toxic dose. Since diethylmaleate depleted hepatic glutathione without