USMLE PRACTICE QUESTION #123
TOPIC: Liver Pathology
USMLE practice question #123 will test your ability to identify the cause(s) of a patient’s liver pathology.
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A 42-year-old woman presents to the emergency department with confusion, jaundice, and abdominal pain. She has a history of depression and was recently treated for a viral upper respiratory infection. Physical examination reveals scleral icterus, hepatomegaly, and asterixis. Laboratory studies show elevated transaminases (AST 3200 U/L, ALT 3400 U/L), elevated bilirubin, and prolonged prothrombin time. Her family reports that she has been consuming over-the-counter cold medications for the past week. Which of the following best explains the pathophysiology of her condition?
A) Excessive glutathione conjugation depletes the availability of hepatic antioxidants
B) Cytochrome P450-mediated production of a toxic intermediate causing hepatocyte damage
C) Direct oxidative damage to hepatocytes caused by reactive oxygen species
D) Mitochondrial dysfunction induced by toxic bile salt accumulation
E) Impaired beta-oxidation of fatty acids causing microvesicular steatosis
Detailed Breakdown of Answers + Correct Answer Below ⏬
ANSWER + QUESTION BREAKDOWN
It’s important to adopt the correct MENTAL MODEL when answering USMLE questions; it saves time and increases accuracy. The mental model outlined below is a foundational component of our test-taking skills masterclass (check it out if you want to elevate your skills). Here’s how to think through this question:
Step 1. Read the last line to get to the heart of the question: “Which of the following best explains the pathophysiology of her condition?”
Step 2: Is this a first-, second-, or third-order question?
Answer: 3rd order. 1st: Correctly diagnose the condition; 2nd: Correctly identify the underlying cause; 3rd: Correctly identify the mechanism linked to that underlying cause.
Step 3: Read the vignette carefully and ask yourself: “Based on the given information, she likely has ________________, caused by _____________________, whose pathophysiology is _____________________________.”
Step 4. Look at the answer choices and select the option most closely resembling your final thought from “Step 3” above.
GENERAL ANALYSIS
This 42-year-old woman presents with confusion, jaundice, abdominal pain, and laboratory findings of markedly elevated transaminases, elevated bilirubin, and prolonged prothrombin time, consistent with acute liver failure (ALF). Her family reports recent use of over-the-counter cold medications, which commonly contain acetaminophen. The clinical presentation, combined with the history of acetaminophen use, strongly suggests acetaminophen-induced hepatotoxicity, the most common cause of ALF in the United States.
ANSWER CHOICES:
CHOICE A: Excessive glutathione conjugation depletes the availability of hepatic antioxidants
Explanation: Glutathione conjugation is a protective mechanism that detoxifies NAPQI by converting it into non-toxic metabolites. However, in acetaminophen overdose, glutathione stores are overwhelmed and depleted, allowing NAPQI to accumulate and cause hepatocyte damage.
While glutathione depletion is a key step in acetaminophen hepatotoxicity, the primary mechanism involves the cytochrome P450-mediated production of NAPQI, not excessive glutathione conjugation itself.
CHOICE B: Cytochrome P450-mediated production of a toxic intermediate causing hepatocyte damage
Explanation: Acetaminophen is metabolized in the liver primarily by glucuronidation and sulfation pathways. However, a small fraction is metabolized by cytochrome P450 enzymes (mainly CYP2E1) into the highly reactive intermediate NAPQI. Under normal conditions, NAPQI is detoxified by conjugation with glutathione. In cases of overdose or chronic use, excessive NAPQI overwhelms glutathione stores, leading to direct binding of NAPQI to cellular proteins and lipids, resulting in oxidative stress, mitochondrial dysfunction, and centrilobular necrosis.
CHOICE C: Direct oxidative damage to hepatocytes caused by reactive oxygen species
Explanation: Reactive oxygen species (ROS) can cause oxidative damage to hepatocytes in various conditions, such as ischemia-reperfusion injury or alcoholic hepatitis. While oxidative stress plays a role in NAPQI-induced hepatocyte damage, it is secondary to the formation of NAPQI via cytochrome P450 metabolism. ROS alone does not explain acetaminophen toxicity.
CHOICE D: Mitochondrial dysfunction induced by toxic bile salt accumulation
Explanation: Mitochondrial dysfunction can occur in cholestatic liver diseases due to toxic bile salt accumulation. This mechanism is not relevant to acetaminophen toxicity.
CHOICE E: Impaired beta-oxidation of fatty acids causing microvesicular steatosis
Explanation: Impaired beta-oxidation and microvesicular steatosis are seen in conditions such as Reye syndrome or mitochondrial disorders. Acetaminophen toxicity causes centrilobular necrosis rather than microvesicular steatosis.
FINAL VERDICT…
CORRECT ANSWER: B) Cytochrome P450-mediated production of a toxic intermediate causing hepatocyte damage
Acetaminophen hepatotoxicity occurs when excessive metabolism by cytochrome P450 enzymes produces high levels of the toxic intermediate NAPQI. When hepatic glutathione stores are depleted, NAPQI binds covalently to cellular proteins and lipids, causing oxidative stress, mitochondrial dysfunction, and centrilobular necrosis. This process leads to acute liver failure if untreated.
KEY CONCEPTS:
Acetaminophen Metabolism:
Normally metabolized via glucuronidation and sulfation pathways.
A small fraction is metabolized by cytochrome P450 enzymes (mainly CYP2E1) into NAPQI.
NAPQI is detoxified by conjugation with glutathione under normal conditions.
Pathophysiology of Toxicity:
Overdose or chronic use overwhelms detoxification pathways.
Excessive NAPQI depletes glutathione stores.
Free NAPQI binds cellular proteins and lipids, causing oxidative stress and centrilobular necrosis.
Clinical Features of Acetaminophen Toxicity:
Symptoms include nausea, vomiting, abdominal pain, jaundice, confusion (encephalopathy), and coagulopathy.
Laboratory findings show markedly elevated transaminases (AST/ALT), hyperbilirubinemia, prolonged prothrombin time (PT/INR), and hypoglycemia.
Histopathology:
Centrilobular (zone 3) necrosis without significant inflammation or steatosis.
Management:
Early administration of N-acetylcysteine (NAC) replenishes glutathione stores and prevents progression to liver failure.
Severe cases may require liver transplantation.
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