In familial hypercholesterolemia with very high total cholesterol, which mechanism best explains a total cholesterol in the 700–1000 mg/dL range?

• A. Absence of functional LDL receptors on hepatocytes
• B. LDL receptor deficiency
• C. Overproduction of HDL
• D. Increased LDL clearance

Answer: (A)

The main idea is that plasma cholesterol levels are driven by how effectively the liver clears LDL from the blood. In familial hypercholesterolemia, mutations cause the LDL receptors on liver cells to be absent or nonfunctional. With no functional LDL receptors, hepatocytes can’t bind and internalize circulating LDL, so LDL clearance drops dramatically. That leaves LDL—which carries most of the cholesterol in the blood—trapped in circulation, pushing total cholesterol into the very high range (700–1000 mg/dL).

Other options don’t fit as well: overproduction of HDL would raise HDL cholesterol, not drive up total cholesterol; increased LDL clearance would lower LDL and total cholesterol; and simply saying LDL receptor deficiency conveys the idea of reduced clearance but the absence of functional receptors captures the mechanism most directly.