Individuals with alcoholic cirrhosis of liver may develop severe hepatotoxicity after doses of acetaminophen that are not toxic to individuals with normal liver function. This increased sensitivity to acetaminophen’s toxicity is due to:
## **Core Concept**
Alcoholic cirrhosis of the liver leads to increased sensitivity to acetaminophen toxicity due to alterations in liver function and enzyme activity. Acetaminophen is primarily metabolized in the liver, and its toxicity is closely related to the formation of a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI).
## **Why the Correct Answer is Right**
The correct answer, **C. depletion of glutathione stores and induction of CYP2E1**, explains the increased sensitivity to acetaminophen toxicity in individuals with alcoholic cirrhosis. Chronic alcohol consumption leads to the induction of cytochrome P450 2E1 (CYP2E1), an enzyme involved in the metabolism of acetaminophen to NAPQI. At the same time, alcohol consumption depletes glutathione stores in the liver. Glutathione is crucial for detoxifying NAPQI; when its levels are low, NAPQI accumulates and causes liver damage.
## **Why Each Wrong Option is Incorrect**
- **Option A:** Increased levels of glutathione would actually protect against acetaminophen toxicity, not increase sensitivity.
- **Option B:** While induction of CYP2E1 does contribute to increased formation of NAPQI, it is not the sole reason; the depletion of glutathione stores is equally critical for the increased toxicity.
- **Option D:** Reduced activity of CYP2E1 would decrease, not increase, the formation of the toxic NAPQI metabolite.
## **Clinical Pearl / High-Yield Fact**
A key point to remember is that patients with chronic alcohol abuse and liver disease are at increased risk of acetaminophen-induced hepatotoxicity, even at doses that are considered therapeutic for individuals with normal liver function. Therefore, caution and dose adjustment are advised when prescribing acetaminophen to such patients.
## **Correct Answer:** . C. depletion of glutathione stores and induction of CYP2E1