What is mixed hyperlipidemia?

Definition of Mixed Hyperlipidemia

Mixed hyperlipidemia is characterized by elevations in both LDL cholesterol and triglycerides, often accompanied by decreased HDL cholesterol levels, creating an atherogenic lipid profile that significantly increases cardiovascular risk. 1

Key Characteristics

• Mixed hyperlipidemia typically presents with LDL-C ≥130 mg/dL and triglycerides ≥150 mg/dL, creating a pattern that increases cardiovascular disease risk 1
• The condition can be either primary (genetic) or secondary (due to underlying conditions like diabetes, obesity, metabolic syndrome) 1
• The lipid abnormalities result from multiple mechanisms including overproduction of apoB-containing lipoproteins and impaired clearance of triglyceride-rich lipoproteins 2

Types of Mixed Hyperlipidemia

Familial Combined Hyperlipidemia (FCHL)

• Most common primary form of mixed hyperlipidemia with autosomal-dominant inheritance 2
• Characterized by hepatic overproduction of apoB-containing VLDL, IDL, and LDL particles 2
• Multiple phenotypes may be present within the same family, with varying patterns of lipid abnormalities 2
• The underlying mechanism involves overproduction of VLDL particles, reduced free fatty acid trapping, and decreased clearance of chylomicrons and remnants 2

Type III Dysbetalipoproteinemia (Familial Dysbetalipoproteinemia)

• Characterized by elevations of both cholesterol and triglycerides with a cholesterol-to-triglyceride ratio of approximately 1:1 2
• Associated with autosomal-recessive inheritance and homozygosity for apolipoprotein E2 or other polymorphisms 2
• May present with palmar xanthomas, tuberous and eruptive xanthomata when manifesting in pediatric age groups 2

Clinical Significance

• Mixed hyperlipidemia significantly increases cardiovascular disease risk through multiple mechanisms 1
• Triglyceride-rich lipoproteins (TRLs) contribute to atherogenesis by:
  • Impairing endothelial cell-dependent vasodilation 2
  • Enhancing recruitment and attachment of monocytes to endothelium 2
  • Interfering with HDL's anti-inflammatory functions 2
• When triglycerides are severely elevated (>1000 mg/dL), there is also increased risk of pancreatitis 2

Diagnostic Criteria

• Diagnosis is based on fasting serum lipid profile showing elevated LDL-C, total cholesterol, and triglycerides 2
• The Endocrine Society defines the following triglyceride cutoffs:
  • 150-199 mg/dL: mild hypertriglyceridemia
  • 200-999 mg/dL: moderate hypertriglyceridemia
  • 1,000-1,999 mg/dL: severe hypertriglyceridemia
  • ≥2,000 mg/dL: very severe hypertriglyceridemia 2
• Non-HDL cholesterol (total cholesterol minus HDL cholesterol) is a valuable marker in mixed dyslipidemia 1
• Apolipoprotein B levels are useful as they reflect the total number of atherogenic particles 1

Treatment Implications

• Fenofibrate is FDA-approved as adjunctive therapy to diet for mixed dyslipidemia to reduce elevated LDL-C, total cholesterol, triglycerides, and apolipoprotein B, and to increase HDL-C 3
• For patients with both elevated LDL cholesterol and triglycerides, the level of non-HDL cholesterol or apolipoprotein B might guide decisions about initiation of drug therapy 2
• Combination therapy may be required in some cases, with fibrates and statins being commonly used together for more severe forms 4
• Initial treatment should include dietary counseling and weight loss in patients who are overweight or obese 2

Clinical Pitfalls and Caveats

• Mixed hyperlipidemia may be secondary to other conditions including diabetes, hypothyroidism, obesity, excessive alcohol intake, or certain medications (thiazides, beta-blockers, estrogen, corticosteroids) 2
• Always evaluate for secondary causes before attributing to primary genetic disorders 2
• When triglycerides exceed 500 mg/dL, patients are at risk for pancreatitis, which should be addressed as a priority 2
• Combination therapy with statins and fibrates requires careful monitoring due to increased risk of myopathy, particularly with gemfibrozil 5