USMLE® Step 1 Question of the Day: Lower extremity pain

USMLE® Step 1 Question of the Day: Lower extremity pain

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Discover the case of a 57-year-old man with acute-onset right lower extremity pain in the emergency department. Explore the medical history and symptoms that led to a concerning diagnosis. Learn about the histological findings that indicate irreversible cellular injury in the affected extremity. Find out more here.

A 57-year-old man presents to the emergency department due to acute-onset right lower extremity pain. The symptoms began two hours ago. Past medical history is notable for atrial fibrillation and hypercholesterolemia. Temperature is 37.0°C (98.6°F), blood pressure is 158/83 mmHg, and pulse is 117/min. The right lower extremity is cold to touch below the knee on physical examination. The suitable posterior tibial and dorsalis pedis pulses are absent. Which of the following histological findings, if present, is most suggestive of irreversible cellular injury in the affected extremity?

A. Detachment of ribosomes from the endoplasmic reticulum

B. Loss of microvilli on the cellular surface

C. Rupture of the lysosomal membranes

D. Clumping of chromatin within the nucleus

E. Swelling of the mitochondri

Scroll down for the correct answer!

The correct answer to today’s USMLE® Step 1 Question is…

C. Rupture of the lysosomal membranes

Before we get to the Main Explanation, let’s look at the incorrect answer explanations. Skip to the bottom if you want to see the correct answer right away!

Incorrect answer explanations

A. Detachment of ribosomes from the endoplasmic reticulum

Incorrect: During cellular hypoxia, the Na+/K+ ATPase pumps stop working. Sodium and water accumulate intracellularly, and the cell begins to swell. These changes can damage the endoplasmic reticulum and cause the ribosomes to detach.

B. Loss of microvilli on the cellular surface

Incorrect: During cellular hypoxia, the Na+/K+ ATPase pumps stop working, which causes water and sodium to accumulate within the cell. These changes lead to cellular swelling and loss of microvilli on the plasma membrane. However, this is a reversible process.

D.  Clumping of chromatin within the nucleus

Incorrect: Clumping chromatin within the nucleus signifies reversible cell damage. In contrast, symptoms of membrane damage (e.g. mitochondrial or lysosomal membrane rupture) are more suggestive of irreversible damage. 

E. Swelling of the mitochondria

Incorrect: Mitochondrial swelling is a sign of reversible cell damage. In contrast, signs of membrane damage (e.g. mitochondrial or lysosomal membrane rupture) suggest irreversible damage.

Main Explanation

This patient has findings suggestive of acute limb ischemia. The condition can lead to tissue hypoxia, and the presence of ruptured lysosomal membranes is consistent with the irreversible cellular injury. 

Hypoxia develops when cells receive insufficient oxygen. As a result, the cells fail to generate adequate ATP. Reversible and irreversible findings of cellular damage can subsequently create.

A common reversible finding is cellular swelling, which develops since the Na+/K+ ATPase pumps stop working. Sodium and water accumulate intracellularly, which expands the cytosol and causes mitochondrial swelling. These changes lead to ribosomal detachment from the endoplasmic reticulum and plasma membrane changes (e.g., loss of microvilli, blebbing). Similarly, calcium pumps stop working, and intracellular calcium levels become elevated. Furthermore, cells will increase anaerobic respiration to produce more ATP. This process leads to lactic acid accumulation and decreased intracellular pH, resulting in chromatin clumping and protein denaturation.

Over time, the damage becomes irreversible. This transition is partly caused by elevated intracellular calcium levels, which activate enzymes (e.g., endonuclease, phospholipase) and precipitate further cellular injury. The hallmark of irreversible injury is membrane damage, manifesting as plasma membrane breakdown, increased mitochondrial permeability, and lysosomal rupture.

table of findings suggestive of cellular injury

Major Takeaway

Hypoxia can lead to reversible and irreversible cellular damage. Reversible damage is characterized by cellular swelling, increased intracellular calcium levels, and chromatin clumping. In contrast, irreversible injury is characterized by membrane damage

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