Acetaminophen Toxicity at Therapeutic Doses

Cesar Yaghi1 Yaghi Cesar Yaghi, Antoine Assaf


Acetaminophen is the first line choice for pain management. Also, it is the most important pharmacological cause of liver injury. It is considered safe at doses of 4g/day. However, acetaminophen at therapeutic dosage should be considered in the differential diagnosis of the acute liver injury. Alcoholic patients may have increased CYP2E1 activity and lower concentration of glutathione. This leads to higher levels of NAPQI, responsible for liver toxicity. Some drugs, like phenytoin and Simvastatin, are also well-known inducers of the CYP 450 pathway. Malnutrition and prolonged fasting shunt glucose precursors toward gluconeogenesis instead of glucuronidation. Centrilobular zones of the liver, essential site of glucuronidation and reservoir of liver CYP2E1, are the most vulnerable to low oxygen delivery in cardiopulmonary disease. In the absence of sufficient oxygen necessary for glucuronidation, more acetaminophen is metabolized through the CYP450 pathway leading to higher NAPQI concentrations and therefore acetaminophen toxicity with centrilobular necrosis. The induced activity of CYP2E1 in obesity and NAFLD can favor acetaminophen hepatotoxicity in these situations. Diagnosis of liver injury with therapeutic doses of acetaminophen is challenging and requires a high index of suspicion. Acetaminophen level should be measured whenever the diagnosis is suspected. Acetaminophen related liver injury is dose dependent and may be prevented by reducing daily drug dose to 2 to 3 g/day in the presence of risk factors for liver toxicity. 


(Acetaminophen; Paracetamol; Liver toxicity; liver function tests; therapeutic doses)

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