DEFINITIONS AND RISK STRATIFICATION

• Serum Triglyceride Concentrations (mg/dL):
  • Normal: <150
  • Borderline high: 150–199
  • High: 200–499
  • Very high: ≥500
• Hypertriglyceridemia:
  • Defined as serum triglyceride >199 mg/dL.
  • Associated with increased risk of cardiovascular disease.
  • Can be caused or exacerbated by:
    • Obesity
    • Poorly controlled diabetes mellitus
    • Nephrotic syndrome
    • Hypothyroidism
    • Oral estrogen therapy

METABOLIC BASIS

• Trapping of Triglyceride-Rich Lipoproteins:
  • Hypertriglyceridemia = accumulation of VLDL, VLDL remnants, and/or chylomicrons.
  • Often coupled with variable hypercholesterolemia because these lipoproteins also carry cholesterol.
• Role of Lipoprotein Lipase (LPL):
  • Hydrolyzes triglycerides in chylomicrons and VLDL into free fatty acids for energy usage or storage.
  • Facilitates transfer of cholesterol to HDL.
  • Deficient LPL activity → hypertriglyceridemia + low HDL.

FREDRICKSON PHENOTYPE CLASSIFICATION

1. Type I: LPL Deficiency
   • Increased chylomicrons, markedly high triglycerides.
   • Serum can show a creamy top layer.
2. Type IIa: Familial Hypercholesterolemia
   • Increased LDL, high total cholesterol.
   • Serum appears clear.
3. Type IIb
   • Increased LDL and VLDL.
   • Serum appears clear.
4. Type III: Familial Dysbetalipoproteinemia
   • Increased VLDL remnants + chylomicrons.
   • Serum appears turbid.
5. Type IV: Familial Hypertriglyceridemia
   • Increased VLDL.
   • Serum appears turbid.
6. Type V: Mixed Hypertriglyceridemia
   • Increased chylomicrons + VLDL.
   • Serum has creamy top layer and turbid lower layer.

SPECIFIC CAUSES

Type I Hyperlipoproteinemia (LPL or Apo CII Deficiency)

• Rare recessive disorders:
  • Absent LPL activity or absent apo CII (cofactor for LPL).
• Severe hypertriglyceridemia due to blocked clearance of triglyceride-rich particles.
• Chylomicronemia syndrome is common (see below).

Type IIa Hyperlipoproteinemia

• Familial Hypercholesterolemia:
  • Defect in LDL receptor, leading to high LDL.

Type IIb Hyperlipoproteinemia

• Combined hyperlipidemia:
  • Decreased LDL receptor function + increased apo B → high LDL + VLDL.

Type III Hyperlipoproteinemia (Familial Dysbetalipoproteinemia)

• Apo E isoform defect → poor clearance of VLDL & chylomicron remnants.
• Typical genotype: homozygous E2/E2.
• Leads to premature CHD + tuberoeruptive xanthomas.

Type IV Hyperlipoproteinemia (Familial Hypertriglyceridemia)

• Autosomal dominant:
  • Overproduction of VLDL; moderate hypertriglyceridemia (200–500 mg/dL).
  • Low HDL and normal LDL are common.
  • Aggravated by alcohol, estrogens, etc.
  • Typically associated with obesity, insulin resistance, hyperglycemia, and hypertension.

Type V Hyperlipoproteinemia (Mixed Hypertriglyceridemia)

• Very high triglycerides (>99th percentile).
• Increased chylomicrons + VLDL.
• Serum has a creamy supernatant and turbid infranatant.
• May include hepatosplenomegaly, eruptive xanthomas.

Familial Combined Hyperlipidemia

• Genetically heterogeneous disorder.
• Overproduction of apo B100 in VLDL.
• Presents with hypercholesterolemia + hypertriglyceridemia.

Apo C Proteins in Triglyceride Metabolism

• Apo CI and apo CIII: regulate uptake of triglyceride-rich lipoproteins by interfering with apo E binding at lipoprotein receptors.
• Apo CII: an LPL cofactor; deficiency leads to severe hypertriglyceridemia.

CLINICAL PRESENTATIONS

Chylomicronemia Syndrome (Triglycerides >1000 mg/dL)

• Abdominal pain and acute pancreatitis (can be life-threatening).
• Eruptive xanthomas.
• Flushing with alcohol.
• Memory loss and lipemia retinalis.
• Usually seen in LPL deficiency or apo CII deficiency.

Physical and Laboratory Findings

• Eruptive xanthomas occur if TG > 1000 mg/dL.
• Plasma or serum becomes turbid (>2000 mg/dL) or milky with high chylomicrons.
• Very low in volume weighting may cause measurement artifacts in electrolytes.

TREATMENT APPROACH

1. Lifestyle Modifications:
   • Weight loss (if obese).
   • Regular isotonic exercise.
   • Optimize glycemic control (in diabetics).
   • Limit alcohol intake.
   • Avoid free/simple carbohydrates.
2. Pharmacologic Interventions:
   • Statins (HMG-CoA reductase inhibitors):
     • Best if both LDL and TG are elevated.
   • Fibrates (gemfibrozil, fenofibrate):
     • Lower triglycerides by up to ~50%; good for predominant hypertriglyceridemia.
     • Gemfibrozil can increase risk of statin-related myopathy.
   • Niacin:
     • Lowers TG but may cause hyperglycemia; caution in impaired glucose tolerance.
   • Omega-3 Fatty Acids (fish oil):
     • High doses (≥3 g/day) can reduce TG by ~50%.
   • Orlistat:
     • Consider for type V hyperlipoproteinemia refractory to standard therapies, as it reduces GI fat absorption.
3. Preventing Pancreatitis
   • When TG ≥500 mg/dL, first goal = avoid pancreatitis.
   • Rapid intervention using fibrates or niacin to reduce TG below 500 mg/dL.