What is Mixed Hyperlipidemia
Mixed hyperlipidemia is a lipid disorder characterized by simultaneous elevations in both LDL cholesterol (≥130 mg/dL) and triglycerides (≥150 mg/dL), often accompanied by decreased HDL cholesterol, creating a highly atherogenic lipid profile that significantly increases cardiovascular disease risk. 1
Definition and Lipid Profile Characteristics
The hallmark lipid pattern shows elevations in total cholesterol, LDL cholesterol, and triglycerides occurring together, distinguishing it from isolated hypercholesterolemia or isolated hypertriglyceridemia. 1 This combination creates small, dense, highly atherogenic LDL particles that are particularly damaging to blood vessels. 1
The condition presents with:
- LDL-C typically ≥130 mg/dL 1
- Triglycerides ≥150 mg/dL 1
- Often reduced HDL cholesterol levels 2
- Elevated apolipoprotein B levels (reflecting total atherogenic particle burden) 2
Primary vs. Secondary Forms
Mixed hyperlipidemia can arise from two distinct pathways:
Primary (genetic) forms include familial combined hyperlipidemia (FCHL), the most common inherited dyslipidemia with 5-10% population prevalence. 1 FCHL results from hepatic overproduction of apoB-containing VLDL, IDL, and LDL particles, with apoB levels exceeding the 90th percentile. 3 Multiple phenotypes may appear within the same family due to autosomal-dominant inheritance. 2
Secondary forms develop from underlying metabolic conditions including diabetes mellitus, obesity, metabolic syndrome, hypothyroidism, or medications (estrogen therapy, thiazide diuretics, beta-blockers). 1, 4
Pathophysiology and Atherogenic Mechanisms
The underlying mechanism involves overproduction of VLDL particles, reduced free fatty acid trapping, and decreased clearance of chylomicrons and remnants. 2
Triglyceride-rich lipoproteins (TRLs) drive atherogenesis through multiple pathways: 2
- Impairment of endothelial cell-dependent vasodilation 2
- Enhanced recruitment and attachment of monocytes to endothelium 2
- Interference with HDL's anti-inflammatory and cholesterol efflux functions 2
- Direct cytotoxicity and apoptosis induction in vessel wall cells 2
- Increased expression of inflammatory proteins, adhesion molecules, and coagulation factors 2
Cardiovascular Risk
Mixed hyperlipidemia confers a moderately to significantly increased risk of premature cardiovascular disease. 2, 1 The combination of elevated triglycerides and low HDL creates a particularly dangerous atherogenic environment beyond what LDL elevation alone would produce. 1
In patients with diabetes and mixed dyslipidemia, 50% of mortality stems from coronary artery disease, making aggressive lipid management crucial. 1
Diagnostic Approach
Diagnosis requires a complete fasting lipid profile demonstrating simultaneous elevations in LDL-C, total cholesterol, and triglycerides. 1
Non-HDL cholesterol (total cholesterol minus HDL cholesterol) serves as a valuable marker because it captures all atherogenic particles in a single measurement. 2, 1 For patients with both elevated LDL and triglycerides, non-HDL cholesterol or apolipoprotein B can guide treatment decisions. 2
Family history assessment is critical to distinguish primary genetic forms (FCHL) from secondary causes. 3 The diagnosis of FCHL is confirmed when at least 2 lipid abnormalities (elevated cholesterol, triglycerides, or apoB) segregate among first-degree relatives across successive generations. 3
Critical Clinical Distinctions
Mixed hyperlipidemia differs from familial hypercholesterolemia (FH), which shows isolated LDL-C elevations >190 mg/dL without significant triglyceride elevation, often with tendon xanthomas. 3
It also differs from familial chylomicronemia syndrome, which presents with extreme triglycerides >1000 mg/dL, eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and acute pancreatitis risk. 2, 3
Type III dysbetalipoproteinemia (familial dysbetalipoproteinemia) represents a specific subtype with cholesterol-to-triglyceride ratio approximately 1:1, associated with apolipoprotein E2 homozygosity, and may present with palmar xanthomas and tuberous/eruptive xanthomata. 2, 1
Special Populations and Considerations
In pediatric patients, concomitant overweight exacerbates lipid abnormalities, and management should focus on fat-, cholesterol-, and simple carbohydrate-restricted diet with cardiovascular lifestyle changes. 2
When triglycerides exceed 1000 mg/dL, the immediate priority shifts to preventing acute pancreatitis rather than cardiovascular risk reduction. 1 Patients with fasting triglycerides >4 mmol/L (350 mg/dL) or random levels >8 mmol/L (700 mg/dL) require therapy primarily aimed at pancreatitis prevention. 2
Post-transplant patients commonly develop mixed hyperlipidemia, with immunosuppressive therapy being the most likely explanation. 2