Genetics · MU Sofia

21. Diseases of Impaired Lipoprotein Metabolism: Familial Hypercholesterolemia (FH)

Covers familial hypercholesterolaemia as an inherited lipid disorder, moving from its inheritance pattern and frequency to the genes involved (LDLR, APOB and PCSK9) and how raised LDL leads to atherosclerosis and xanthomas. It then contrasts the heterozygous and homozygous forms, outlines diagnostic criteria such as Dutch Lipid Clinic Network, Simon Broome and MEDPED, and summarises lifestyle and drug treatments, including options for the severe form. Six pictures accompany the text.

Inside: 9 sections · 6 labelled pictures · 15 flashcards · 3 min

Topic 21 of 65 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 9 sections, about 407 words (3 min of reading), with 15 flashcards.

In this note

  1. Introduction
  2. Diseases of Impaired Lipoprotein Metabolism: Familial Hypercholesterolemia (FH)
  3. I. Introduction
  4. II. Molecular Basis
  5. III. Pathogenesis
  6. IV. Clinical Features
  7. V. Diagnosis
  8. VI. Management
  9. VII. Clinical Relevance

I. Introduction

Familial hypercholesterolemia (FH) is a common inherited disorder of lipid metabolism, characterized by very high LDL cholesterol levels and early-onset atherosclerotic cardiovascular disease (ASCVD).

  • Inheritance: usually autosomal dominant.
  • Frequency: ~1 in 250 for heterozygous FH (HeFH); ~1 in 300,000–1,000,000 for homozygous FH (HoFH).
  • Pathogenesis: impaired clearance of LDL particles from plasma due to mutations affecting the LDL receptor pathway.

II. Molecular Basis

FH is caused by mutations in genes regulating LDL uptake:

  1. 1. LDLR gene (most common) → defective or absent LDL receptors → reduced clearance of LDL cholesterol.
  2. 2. APOB gene → defective apolipoprotein B-100 (ligand for LDLR).
  3. 3. PCSK9 gene → gain-of-function mutations → increased degradation of LDL receptors.

Result: elevated plasma LDL cholesterol, accelerated atherosclerosis.

III. Pathogenesis

  1. 1. Mutations impair binding or recycling of LDL receptors.
  2. 2. LDL particles remain in circulation → plasma LDL cholesterol ↑↑.
  3. 3. Excess LDL infiltrates arterial intima → foam cell formation, atherosclerotic plaques.
  4. 4. Cholesterol deposition also occurs in skin and tendons → xanthomas.
  5. 5. Severe premature atherosclerosis → early myocardial infarction and stroke.

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