A patient with homozygous familial hypercholesterolemia (HoFH) fails to respond to high-dose statins because:

• A HMG-CoA reductase is constitutively overexpressed and cannot be inhibited
• B PCSK9 is overproduced, degrading all LDL receptors
• C LDL receptor is absent or nonfunctional; hepatic LDL uptake is absent regardless of receptor upregulation ✓
• D Cholesterol absorption from gut is maximally increased

Explanation

Statins inhibit HMG-CoA reductase, reducing intracellular cholesterol, which upregulates LDL receptor expression — the mechanism by which they lower plasma LDL. In HoFH, both LDL receptor alleles are mutated (absent, non-functional, or defective in transport); upregulating a non-functional or absent receptor has no effect on LDL clearance. Treatment requires receptor-independent approaches such as LDL apheresis, lomitapide, or PCSK9 inhibitors (which have limited effect without receptors).

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.