1. A 22 years old man is referred for evaluation of premature coronary artery disease. He has one elder brother and a paternal uncle who had similar problems. On examination he has rounded swellings on the extensor tendons of his hands. There are small yellowish speckles around his eyes. The fasting lipid profile showed a calculated LDL of 340 mg/dL. All other lipoprotein components were normal. What is the most likely pathophysiology in this patient?

1. Defective receptor mediated endocytosis of LDL in the liver
2. Defective ligand mediated reverse cholesterol transport
3. Exaggerated enterohepatic circulation.
4. Uncontrolled transcription of the Apo B mRNA.

Answer: The clinical scenario described is Familial Hypercholesterolemia, which is an autosomal dominant disease with variable penetrance. Patients with complete penetrance have very high LDL levels and very early CAD. Those with reduced penetrance have variety of high levels of LDL but which are not as high. The heterozygotes have milder form of disease compared to the homozygotes. The pathophysiology behind FH is defective receptor mediated endocytosis of the LDL and Apo B100 rich lipoprotein molecules by the liver for metabolism.