Lipid Disorders

Lipid Disorders

Lipid disorders (dyslipidemias) are abnormalities in plasma lipid levels. They are major risk factors for cardiovascular disease (CVD) — the leading cause of death worldwide.

Hyperlipoproteinemias (Fredrickson Classification)

  • Type I: ↑Chylomicrons. LPL or ApoC-II deficiency. Presents: Pancreatitis, eruptive xanthomas, creamy plasma. No ↑CVD risk. Treatment: Very low fat diet.
  • Type IIa (Familial Hypercholesterolemia): ↑LDL only. LDL receptor mutation (autosomal dominant). Presents: Tendon xanthomas (Achilles), xanthelasma, premature CAD. Treatment: Statins, PCSK9 inhibitors.
  • Type IIb: ↑LDL + ↑VLDL. Combined hyperlipidemia. High CVD risk.
  • Type III: ↑IDL (remnant particles). ApoE2/E2 homozygosity. Palmar xanthomas, premature CAD. Treatment: Fibrates, Statins.
  • Type IV: ↑VLDL (endogenous hypertriglyceridemia). Associated with obesity, DM, alcohol. ↑Pancreatitis risk. Treatment: Fibrates, Niacin, lifestyle.
  • Type V: ↑Chylomicrons + ↑VLDL. Severe hypertriglyceridemia; pancreatitis risk.

Atherosclerosis

Atherosclerosis is the underlying process of coronary artery disease, stroke, and peripheral artery disease. Pathogenesis: Endothelial injury (hypertension, smoking, hyperglycemia) → LDL accumulation in intima → oxidation → foam cell formation (macrophages engulf oxLDL) → Fatty streak → Fibrous plaque → Complicated plaque (ulceration, thrombosis, calcification).

  • Risk factors: ↑LDL, ↓HDL, hypertension, diabetes, smoking, obesity, family history
  • Reverse cholesterol transport (HDL) is protective
  • Lipoprotein(a) [Lp(a)]: Independent CVD risk factor; structurally similar to LDL with ApoA attached to ApoB

Fatty Liver Disease (Hepatic Steatosis)

Accumulation of TG in hepatocytes (>5% of liver weight).

  • NAFLD/NASH: Non-alcoholic fatty liver disease; associated with obesity, insulin resistance, metabolic syndrome
  • Alcoholic Fatty Liver: Alcohol → ↑NADH/NAD+ ratio → ↓FAO + ↑FA synthesis + ↑TG synthesis → steatosis; VLDL export impaired
  • Can progress: Steatosis → Steatohepatitis → Fibrosis → Cirrhosis → HCC

Treatment of Dyslipidemias

  • Statins (HMG-CoA Reductase inhibitors): First-line for ↑LDL. Also anti-inflammatory effects.
  • Fibrates (PPAR-α agonists): Best for ↑TG (↑LPL activity, ↓VLDL production). Fenofibrate, Gemfibrozil.
  • Niacin (B3): ↑HDL most effectively; ↓TG, ↓LDL. Side effects: Flushing (PGE-mediated). ↑Uric acid.
  • Bile acid sequestrants: Cholestyramine; bind bile acids in gut → ↓recycling → liver converts cholesterol to bile acids → ↓LDL. Constipation; may ↑TG.
  • Ezetimibe: Blocks intestinal NPC1L1 transporter → ↓cholesterol absorption → ↓LDL. Used with statins.
  • PCSK9 inhibitors: Monoclonal antibodies (Evolocumab, Alirocumab); greatly ↓LDL (up to 60%) by preventing LDL receptor degradation.

Sphingolipidoses (Lysosomal Storage Diseases)

  • Gaucher's (Glucocerebrosidase def.) — Most common; bone, spleen, liver
  • Niemann-Pick (Sphingomyelinase def.) — Foam cells, cherry-red spot
  • Tay-Sachs (Hexosaminidase A def.) — GM2 gangliosidosis; cherry-red spot, neurodegeneration; no organomegaly
  • Fabry's (α-Galactosidase A def.) — X-linked; kidney failure, painful neuropathy, skin lesions (angiokeratomas)
  • Krabbe's (Galactocerebrosidase def.) — White matter; globoid cells; infantile onset