Disorders of Lipid Metabolism

Lipid Basics & Dyslipidemia Overview - Fat Facts & Freaky Flows

• Lipids: Triglycerides (TG) for energy; Cholesterol (Chol) for membranes, steroids.
• Lipoproteins: Lipid transporters.
  • Chylomicrons: Dietary TG transport. ApoB48.
  • VLDL: Liver's endogenous TG. ApoB100.
  • LDL ("Bad"): Chol to tissues. ApoB100. Target < 100 mg/dL.
  • HDL ("Good"): Reverse Chol transport. ApoA1. Target > 40 (M), > 50 (F) mg/dL.
• Dyslipidemia: Abnormal lipids (↑LDL, ↑TG, ↓HDL); atherosclerosis risk.
• ⭐ Friedewald formula: $LDL-C = TC - HDL-C - (TG/5)$ (TG < 400 mg/dL).

⭐ Statins, HMG-CoA reductase inhibitors, are first-line drugs for lowering LDL cholesterol.

Hypercholesterolemias - Cholesterol Chaos Crew

• Group of disorders characterized by elevated LDL cholesterol (LDL-C, "bad cholesterol") & total cholesterol.
• Familial Hypercholesterolemia (FH):
  • Autosomal dominant; common defect in LDLR (LDL receptor) gene.
  • Results in ↓ LDL clearance, causing markedly ↑ LDL-C from birth.
  • Signs: Tendon xanthomas (Achilles, knuckles), xanthelasmas, premature arcus cornealis.
  • High risk of early atherosclerosis & coronary artery disease (CAD).
  • Treatment: Lifestyle modification, statins, ezetimibe, PCSK9 inhibitors.
• Polygenic Hypercholesterolemia:
  • Most common form; multiple genetic predispositions + environmental factors.
  • Milder LDL-C elevation compared to FH.

⭐ In Familial Hypercholesterolemia, untreated LDL cholesterol levels are typically >190 mg/dL in heterozygotes and often >400-500 mg/dL in homozygotes, leading to very early cardiovascular disease if not managed aggressively from childhood or adolescence for homozygotes, and early adulthood for heterozygotes.

Hypertriglyceridemias & Deficiencies - Triglyceride Turmoil Tales

• Primary Hypertriglyceridemias: Genetic causes of elevated triglycerides.
  • Familial Hypertriglyceridemia (Type IV): Common. ↑ VLDL, ↑ TGs. Autosomal Dominant. Risk: Pancreatitis (TGs > 1000 mg/dL), CAD. Eruptive xanthomas.
  • Familial Chylomicronemia (Type I): Rare. Lipoprotein Lipase (LPL) or ApoC-II deficiency. ↑ Chylomicrons, massive ↑ TGs (often > 2000 mg/dL). Infancy: recurrent pancreatitis, eruptive xanthomas, lipemia retinalis. Creamy layer in spun plasma. 📌 LPL: Lots of Pancreatitis, Lipemia.
  • Dysbetalipoproteinemia (Type III): Defective ApoE (typically E2/E2). ↑ IDL (remnants), leading to ↑ TGs & Cholesterol. Palmar xanthomas (xanthoma striatum palmare), tuberous xanthomas. Premature atherosclerosis.

⭐ Palmar xanthomas (xanthoma striatum palmare) are virtually pathognomonic for Type III hyperlipoproteinemia (Dysbetalipoproteinemia).

Lysosomal Lipidoses - Lipid Locker Lockdowns

• Mostly AR (Fabry X-LR). Lysosomal lipid buildup.
• Gaucher Disease:
  • Enzyme: ↓ Glucocerebrosidase
  • Substrate: Glucocerebroside
  • Features: Hepatosplenomegaly, pancytopenia, bone crises, Gaucher cells ("crinkled paper" cytoplasm).
• Niemann-Pick Disease (Types A&B):
  • Enzyme: ↓ Sphingomyelinase
  • Substrate: Sphingomyelin
  • Features: Hepatosplenomegaly. Type A: neurodegeneration, cherry-red spot. Foam cells.
• Tay-Sachs Disease:
  • Enzyme: ↓ Hexosaminidase A
  • Substrate: GM2 ganglioside
  • Features: Progressive neurodegeneration, cherry-red spot. NO hepatosplenomegaly.
• Fabry Disease (X-LR):
  • Enzyme: ↓ α-galactosidase A
  • Substrate: Ceramide trihexoside (Gb3)
  • Features: Pain (acroparesthesias), angiokeratomas, hypohidrosis. Late: renal/cardiac failure.

⭐ Cherry-red spot on macula is seen in Tay-Sachs, Niemann-Pick Type A, Sandhoff disease, and GM1 gangliosidosis (Central Retinal Artery Occlusion also causes it but is not a lysosomal lipidosis).

High‑Yield Points - ⚡ Biggest Takeaways

• Familial Hypercholesterolemia (FH): Autosomal Dominant, LDL receptor defect; causes high LDL-C, tendon xanthomas, early CAD.
• Lipoprotein Lipase (LPL) Deficiency (Type I): AR; leads to severe hypertriglyceridemia (chylomicrons), pancreatitis, eruptive xanthomas.
• Dysbetalipoproteinemia (Type III): ApoE2/E2 genotype; results in ↑ VLDL remnants (IDL), palmar xanthomas, tuberous xanthomas.
• Abetalipoproteinemia: AR, MTP gene defect; causes absent ApoB-lipoproteins, fat malabsorption, acanthocytes, retinitis pigmentosa.
• Tangier Disease: AR, ABCA1 defect; presents with markedly low HDL, orange tonsils, splenomegaly, neuropathy.
• Niemann-Pick Disease Type C: NPC1/2 gene defect; causes impaired cholesterol trafficking, hepatosplenomegaly, progressive neurodegeneration.
• Gaucher Disease: Glucocerebrosidase (GBA) deficiency; leads to glucocerebroside accumulation, hepatosplenomegaly, bone disease, pancytopenia.
• Tay-Sachs Disease: HEXA gene defect (β-Hexosaminidase A deficiency); causes GM2 ganglioside accumulation, cherry-red spot, neurodegeneration.
• Fabry Disease: X-linked recessive, GLA gene defect (α-galactosidase A deficiency); Gb3 accumulation, angiokeratomas, pain crises, renal failure.
• Wolman Disease/Cholesteryl Ester Storage Disease (CESD): LIPA gene defect (lysosomal acid lipase deficiency); hepatomegaly, calcified adrenals (Wolman), dyslipidemia (CESD).