What is the significance of a High-Density Lipoprotein (HDL) level greater than 100?

From the Guidelines

An HDL level greater than 100 mg/dL is unusually high and warrants medical evaluation, though it's not always harmful. While HDL is typically considered "good cholesterol" with levels above 60 mg/dL generally deemed protective against heart disease, extremely elevated levels (above 100 mg/dL) may indicate underlying conditions requiring attention. These could include genetic disorders like hyperalphalipoproteinemia, certain medications (especially estrogen or statins), excessive alcohol consumption, or liver and thyroid diseases. Some research suggests that very high HDL levels might paradoxically increase cardiovascular risk in certain individuals, possibly due to dysfunctional HDL particles that don't properly remove cholesterol from arteries.

Key Considerations

• Extremely high HDL levels can be associated with various conditions, including genetic disorders and certain medications 1.
• The relationship between very high HDL levels and cardiovascular risk is complex and may depend on the functionality of HDL particles.
• Regular physical activity has been shown to improve HDL cholesterol levels, with a mean increase of 4.6% reported in a review of 51 papers describing physical activity interventions 1.

Recommendations

• If you have HDL above 100 mg/dL, consult your healthcare provider for a comprehensive evaluation including additional lipid testing, liver function tests, and assessment of other cardiovascular risk factors.
• Addressing any underlying condition is important, rather than solely focusing on lowering high HDL levels.
• Your doctor will focus on your overall cardiovascular risk profile rather than treating the HDL number in isolation.

Important Factors

• The mechanisms underlying the effect of exercise on the lipid profile are unclear, but exercise appears to enhance the ability of skeletal muscles to utilize lipids as opposed to glycogen, thus reducing plasma lipid levels 1.
• The process of cholesterol removal is known as ‘reverse cholesterol transport’, which removes cholesterol from circulation for disposal as a result of increases in LCAT and reductions in CETP following acute and chronic exercise 1.

From the Research

Significance of High-Density Lipoprotein (HDL) Levels

The significance of HDL levels greater than 100 can be understood by examining the relationship between HDL cholesterol and cardiovascular risk.

• HDL cholesterol is considered a protective factor against coronary heart disease, with higher levels associated with lower risk 2.
• Studies have shown that HDL cholesterol levels are a strong inverse predictor of cardiovascular events, even at very low levels of low-density lipoprotein (LDL) cholesterol 3.
• However, extremely high HDL-C levels (≥100 mg/dl) have been associated with a higher risk of mortalities, including total, coronary heart disease, and stroke mortality 4.

Relationship Between HDL Levels and Cardiovascular Risk

The relationship between HDL levels and cardiovascular risk is complex, with both low and extremely high HDL levels associated with increased risk.

• Low HDL-C levels (<30 mg/dl) have been linked to a greater risk of total mortality, coronary heart disease, and stroke mortality 4.
• In contrast, extremely high HDL-C levels (≥100 mg/dl) have been associated with a higher risk of mortalities, although the mechanisms underlying this association are not fully understood 4.
• The use of PCSK9 inhibitors, which can increase HDL-C levels, has been shown to result in a more atheroprotective HDL particle profile, particularly in patients not concomitantly treated with ezetimibe 5.

Inflammatory Factors and HDL Levels

The relationship between HDL levels and inflammatory factors is also complex, with both low and extremely high HDL levels associated with increased levels of inflammatory factors.

• Concentrations of C-reactive protein, fibrinogen, and white blood count have been shown to decrease as HDL-C levels increase, although this relationship is attenuated at extremely high HDL-C levels 4.
• Extremely high HDL-C levels (≥100 mg/dl) have been associated with higher levels of inflammatory factors, which may contribute to the increased risk of mortalities observed in this group 4.