U01.01.128 Familial dyslipidemias

Familial Dyslipidemia genetic disorders affecting lipid metabolism, classified based on inheritance pattern, pathogenesis, lipid profile, and clinical presentation. These disorders are important for USMLE Step 1 preparation as they highlight lipid physiology and its clinical consequences.

Classification of Familial Dyslipidemia

Overview Table

Type	Inheritance	Pathogenesis	Blood Lipid Levels	Clinical Features
I – Hyperchylomicronemia	AR	Deficiency in lipoprotein lipase (LPL) or Apo C-II	↑ Chylomicrons, triglycerides (TG), cholesterol	Pancreatitis, hepatosplenomegaly, eruptive/pruritic xanthomas, creamy layer in supernatant; no ↑ atherosclerosis risk
II – Familial Hypercholesterolemia	AD	Absent/defective LDL receptors or defective ApoB-100	IIa: ↑ LDL, cholesterol IIb: ↑ LDL, cholesterol, VLDL	Accelerated atherosclerosis, tendon xanthomas (e.g., Achilles), corneal arcus; early MI (homozygotes: cholesterol ≥ 700 mg/dL)
III – Dysbetalipoproteinemia	AR	Defective ApoE	↑ Chylomicrons, VLDL	Premature atherosclerosis, Tuberoeruptive xanthomas, palmar xanthomas
IV – Hypertriglyceridemia	AD	Hepatic overproduction of VLDL	↑ VLDL, TG	Hypertriglyceridemia (> 1000 mg/dL), acute pancreatitis; associated with insulin resistance

Detailed Description of Each Type

Type I – Hyperchylomicronemia

Inheritance: Autosomal recessive
Pathogenesis: Lipoprotein lipase or apolipoprotein C-II deficiency impairs chylomicron clearance.
Blood Lipid Levels: Elevated chylomicrons, triglycerides, and cholesterol.
Clinical Features:
- Pancreatitis
- Hepatosplenomegaly
- Eruptive/pruritic xanthomas
- Distinctive Sign: Creamy supernatant layer; no increased atherosclerosis risk.

Type II – Familial Hypercholesterolemia

Inheritance: Autosomal dominant
Pathogenesis: LDL receptors or ApoB-100 dysfunction causes impaired LDL uptake.
Blood Lipid Levels:
- Type IIa: Elevated LDL and cholesterol
- Type IIb: Elevated LDL, cholesterol, and VLDL
Clinical Features:
- Heterozygotes: Cholesterol ≈ 300 mg/dL
- Homozygotes: Cholesterol ≥ 700 mg/dL
- Tendon xanthomas (Achilles), corneal arcus, and early-onset MI (< age 20).

Type III – Dysbetalipoproteinemia

Inheritance: Autosomal recessive
Pathogenesis: Defective ApoE impairs remnant clearance.
Blood Lipid Levels: Elevated chylomicrons and VLDL.
Clinical Features:
- Premature atherosclerosis
- Tuberoeruptive xanthomas
- Palmar xanthomas

Type IV – Hypertriglyceridemia

Inheritance: Autosomal dominant
Pathogenesis: Overproduction of VLDL by the liver.
Blood Lipid Levels: Elevated VLDL and triglycerides.
Clinical Features:
- Hypertriglyceridemia (> 1000 mg/dL)
- Acute pancreatitis
- Associated with insulin resistance.

Key Points to Remember

Inheritance Patterns: Autosomal recessive (Type I, III) and autosomal dominant (Type II, IV).
Pathogenesis: Each type involves a specific defect in lipid metabolism, leading to the accumulation of particular lipoproteins.
Clinical Features: Types I and IV often lead to pancreatitis, while Types II and III are associated with atherosclerosis.
Laboratory Clues:
- Type I: Creamy supernatant layer.
- Type II: High LDL or combined LDL/VLDL elevations.
- Type III: Palmar xanthomas.
- Type IV: Very high triglycerides.

Bibliography Reference Links

Robbins Basic Pathology, 10th Edition.
First Aid for the USMLE Step 1, 2024 Edition.
NIH: Familial Hypercholesterolemia Overview (Link).

USMLE Step 1 Review Series

Curriculum