Disorders of lipid metabolism

Lipoprotein Metabolism - The Lipid Taxi System

Transports insoluble lipids (triglycerides, cholesterol) through blood.

• Chylomicron: Delivers dietary TGs to periphery.
• VLDL: Delivers hepatic TGs to periphery.
• LDL: Delivers hepatic cholesterol to tissues. (📌 Lousy)
• HDL: Reverse cholesterol transport from tissues to liver. (📌 Healthy)

Key Enzymes & Apoproteins:

• Lipoprotein Lipase (LPL): Degrades TGs in chylomicrons/VLDL. Activated by ApoC-II.
• ApoB-100: Ligand for LDL receptor binding.
• ApoE: Mediates remnant uptake by liver.

⭐ Familial hypercholesterolemia is commonly caused by defects in the LDL receptor (coded by the LDLR gene), leading to elevated LDL levels and premature atherosclerosis.

Familial Dyslipidemias - Cholesterol Chaos

• Type I: Hyperchylomicronemia (AR)

  • Defect: ↓ Lipoprotein Lipase (LPL) or ApoC-II deficiency.
  • Labs: ↑↑ Chylomicrons, ↑ Triglycerides (>1000 mg/dL).
  • Clinical: Acute pancreatitis, eruptive xanthomas, creamy supernatant in blood sample. No increased risk for atherosclerosis.

• Type IIa: Familial Hypercholesterolemia (AD)

  • Defect: ↓ or absent LDL receptors.
  • Labs: ↑↑ LDL, ↑ Cholesterol (Het: >300 mg/dL; Hom: >700 mg/dL).
  • Clinical: Tendinous xanthomas (Achilles), corneal arcus. Leads to premature atherosclerosis and MI.

• Type IV: Hypertriglyceridemia (AD)

  • Defect: Hepatic overproduction of VLDL.
  • Labs: ↑ VLDL, ↑ Triglycerides.
  • Clinical: Mostly asymptomatic; can cause pancreatitis at high levels. Associated with insulin resistance.

⭐ Type IIa (Familial Hypercholesterolemia) is infamous for causing myocardial infarction in patients before the age of 20 in its homozygous form.

Lysosomal Storage Diseases - Cellular Traffic Jams

• Pathophysiology: Inherited lysosomal enzyme deficiencies → accumulation of undigested substrates → organ damage.
• Inheritance: Mostly Autosomal Recessive (AR), except Fabry disease (X-linked).

• Key Sphingolipidoses:
  • Tay-Sachs: ↓ Hexosaminidase A → GM2 ganglioside buildup.
    • Features: "Cherry-red" macula, neurodegeneration, onion-skin lysosomes. No hepatosplenomegaly.
  • Fabry Disease: ↓ α-galactosidase A → Ceramide trihexoside buildup.
    • Features: Peripheral neuropathy, angiokeratomas, renal/heart failure.
  • Gaucher Disease: ↓ Glucocerebrosidase → Glucocerebroside buildup.
    • Features: Hepatosplenomegaly, pancytopenia, bone crises. Gaucher cells (lipid-laden macrophages).
  • Niemann-Pick Disease: ↓ Sphingomyelinase → Sphingomyelin buildup.
    • Features: "Cherry-red" macula, hepatosplenomegaly, neurodegeneration. Foam cells.

⭐ Gaucher disease is the most common lysosomal storage disease.

• Type I (Familial Chylomicronemia): LPL or ApoC-II deficiency leads to ↑ chylomicrons, causing pancreatitis and eruptive xanthomas.
• Type IIa (Familial Hypercholesterolemia): Absent LDL receptors cause ↑ LDL, leading to tendon xanthomas and premature CAD.
• Type III (Dysbetalipoproteinemia): Defective ApoE results in ↑ chylomicron and VLDL remnants, with pathognomonic palmar xanthomas.
• Type IV (Hypertriglyceridemia): Hepatic overproduction of VLDL increases triglycerides, raising the risk of acute pancreatitis.
• Abetalipoproteinemia: MTP gene defect impairs ApoB formation, causing fat malabsorption and spinocerebellar degeneration.