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Quick Reference
  • Low HDL (Men): <40 mg/dL
  • Low HDL (Women): <50 mg/dL
  • Desirable (Protective): ≥60 mg/dL
  • Primary Use: Cardiovascular risk assessment; HDL ≥60 mg/dL is protective (negative risk factor)
  • Sample Type: Serum or plasma (fasting not required)
  • Key Point: Higher is generally better - HDL removes cholesterol from arterial walls and reduces cardiovascular risk

Test Description

What is HDL Cholesterol?

High-density lipoprotein (HDL) cholesterol, commonly called "good cholesterol," is a lipoprotein that transports cholesterol from peripheral tissues back to the liver for excretion or recycling. Unlike LDL, which deposits cholesterol in arterial walls, HDL actively removes it - providing cardiovascular protection.

Why is HDL Called "Good Cholesterol"?

HDL earns its "good" reputation through multiple protective mechanisms:

  • Reverse cholesterol transport: HDL removes excess cholesterol from arterial plaques and peripheral tissues, transporting it to liver for excretion in bile
  • Anti-inflammatory effects: HDL reduces endothelial inflammation and oxidative stress
  • Antioxidant properties: HDL particles contain enzymes (paraoxonase, LCAT) that prevent LDL oxidation
  • Antiplatelet and antithrombotic effects: HDL reduces platelet aggregation and clot formation
  • Endothelial protection: HDL promotes nitric oxide production, improving endothelial function and vasodilation

Reverse Cholesterol Transport

The primary protective mechanism of HDL is reverse cholesterol transport (RCT):

  • Step 1 - HDL formation: Liver and intestine secrete nascent HDL particles (lipid-poor apoA-I)
  • Step 2 - Cholesterol acquisition: HDL acquires cholesterol from peripheral cells (including arterial macrophages/foam cells) via ABCA1 and ABCG1 transporters
  • Step 3 - Cholesterol esterification: LCAT (lecithin-cholesterol acyltransferase) esterifies free cholesterol, allowing HDL to accept more cholesterol
  • Step 4 - Maturation: HDL particles grow larger as they accumulate cholesterol, becoming mature spherical HDL
  • Step 5 - Hepatic uptake: Liver takes up cholesterol from HDL via SR-B1 receptor
  • Step 6 - Excretion: Liver converts cholesterol to bile acids and excretes in bile, removing it from body
HDL as Negative Risk Factor: The Framingham Heart Study established that HDL ≥60 mg/dL reduces cardiovascular risk so significantly that it counts as a "negative risk factor" - allowing subtraction of one risk factor when calculating 10-year cardiovascular risk. Each 1 mg/dL increase in HDL reduces cardiovascular risk by approximately 2-3%.

HDL Subfractions

HDL is heterogeneous, containing multiple subpopulations with different functions:

  • HDL2 (large, buoyant): More protective; better at cholesterol efflux; higher in women and with exercise
  • HDL3 (small, dense): Less protective; predominates in metabolic syndrome and diabetes
  • Pre-beta HDL: Nascent HDL; most active in cholesterol efflux from cells

While total HDL-C is routinely measured, HDL functionality (cholesterol efflux capacity) may be more important than absolute HDL level. This explains why very high HDL is not always protective.

How is HDL Measured?

HDL cholesterol is directly measured after precipitation or separation of other lipoproteins (LDL, VLDL). Modern automated assays use direct enzymatic methods. Fasting is not required as HDL varies minimally with food intake.

Normal Ranges

HDL levels are classified based on cardiovascular risk. Higher HDL generally confers greater protection, though very high HDL (>100 mg/dL) may not always be beneficial.

Swipe to see more
Category HDL Cholesterol Cardiovascular Risk
Low (Men) <40 mg/dL Increased cardiovascular risk; major risk factor
Low (Women) <50 mg/dL Increased cardiovascular risk; major risk factor
Average (Men) 40-50 mg/dL Moderate protection
Average (Women) 50-59 mg/dL Moderate protection
Desirable/Protective ≥60 mg/dL Strong cardiovascular protection; negative risk factor
Very High >100 mg/dL Variable - may indicate genetic variant; not always protective
Important Considerations:
  • Sex differences: Women naturally have higher HDL (~10 mg/dL higher) due to estrogen effects; different thresholds for low HDL reflect this
  • Low HDL is common: ~25% of US adults have low HDL; often part of metabolic syndrome
  • Ratio matters: Total cholesterol/HDL ratio or LDL/HDL ratio may be better risk predictors than absolute HDL
  • Very high HDL caveat: HDL >100 mg/dL may reflect dysfunctional HDL or genetic variants (CETP deficiency) that don't provide expected protection
Clinical Significance

Low HDL Cholesterol (Hypoalphalipoproteinemia)

Low HDL is a major independent risk factor for cardiovascular disease. Causes include:

Metabolic Syndrome and Insulin Resistance

  • Metabolic syndrome: Low HDL (<40 men, <50 women) is one of five diagnostic criteria; associated with insulin resistance, hypertriglyceridemia, central obesity
  • Type 2 diabetes: Insulin resistance alters lipid metabolism; typically low HDL + high triglycerides + small dense LDL
  • Obesity: Adipose tissue dysfunction and inflammation reduce HDL; visceral obesity worse than subcutaneous
  • Polycystic ovary syndrome (PCOS): Insulin resistance causes low HDL in women with PCOS

Lifestyle Factors

  • Smoking: Reduces HDL by 5-10 mg/dL; quitting increases HDL
  • Sedentary lifestyle: Physical inactivity associated with lower HDL; exercise increases HDL
  • High carbohydrate diet: Especially refined carbohydrates; lowers HDL and raises triglycerides
  • Trans fats: Uniquely harmful - raise LDL AND lower HDL
  • Obesity and weight gain: Each 3 kg weight gain associated with ~1 mg/dL HDL decrease

Medications That Lower HDL

  • Beta-blockers (non-selective): May reduce HDL by 5-10%
  • Thiazide diuretics: Small HDL reduction
  • Anabolic steroids and androgens: Marked HDL reduction (can drop to <20 mg/dL)
  • Progestins (some oral contraceptives): Variable effects on HDL
  • Protease inhibitors: HIV medications often reduce HDL

Genetic Causes of Low HDL

  • Familial hypoalphalipoproteinemia: Autosomal dominant; HDL typically 20-35 mg/dL; premature CAD common
  • Tangier disease: Rare autosomal recessive; ABCA1 mutation; HDL near zero; orange tonsils, hepatosplenomegaly, peripheral neuropathy
  • LCAT deficiency: Cannot esterify cholesterol; very low HDL with corneal opacities
  • ApoA-I mutations: Various mutations in apoA-I gene cause low HDL

Other Medical Conditions

  • Chronic kidney disease: HDL dysfunction and reduced levels
  • Liver disease: Reduced HDL synthesis
  • Inflammatory conditions: Chronic inflammation (RA, lupus) reduces HDL
  • Hypertriglyceridemia: High triglycerides inversely related to HDL (VLDL and HDL compete for lipase)

High HDL Cholesterol (Hyperalphalipoproteinemia)

Elevated HDL is usually protective, though very high levels (>100 mg/dL) may not always confer additional benefit:

Beneficial Causes of High HDL

  • Regular aerobic exercise: Most effective lifestyle intervention; can increase HDL 5-10%
  • Moderate alcohol consumption: 1-2 drinks/day increases HDL ~4 mg/dL (benefits must be weighed against alcohol risks)
  • Weight loss: Especially loss of visceral fat; ~1 mg/dL increase per 3 kg weight loss
  • Estrogen: Women have higher HDL; estrogen therapy increases HDL
  • Mediterranean diet: Omega-3 fatty acids, nuts, olive oil modestly increase HDL

Genetic Causes of High HDL

  • CETP deficiency: Cholesteryl ester transfer protein deficiency; HDL often >100 mg/dL; variable cardiovascular protection (may not be beneficial despite high HDL)
  • Familial hyperalphalipoproteinemia: Genetic variants causing high HDL; usually protective
  • ApoA-I variants: Some mutations increase HDL production

Medications That Increase HDL

  • Statins: Modest increase (5-10%); LDL reduction is primary benefit
  • Fibrates: Increase HDL 10-25%; also reduce triglycerides; most effective for low HDL
  • Niacin: Increases HDL 15-35%; most effective HDL-raising drug but limited cardiovascular benefit in statin era and significant side effects
  • SGLT2 inhibitors: Diabetes medications; modest HDL increase
Important Concept - HDL Functionality vs. Level: Recent trials of HDL-raising drugs (niacin, CETP inhibitors) showed that increasing HDL cholesterol does NOT necessarily reduce cardiovascular events. HDL functionality (cholesterol efflux capacity, anti-inflammatory effects) matters more than absolute HDL level. Very high HDL from CETP deficiency may be dysfunctional. Focus on proven interventions (statins, lifestyle) rather than chasing high HDL numbers.
Interpretation Guidelines

HDL in Risk Assessment

HDL is incorporated into cardiovascular risk calculators and risk factor counting:

Framingham Risk Score:

  • HDL <40 mg/dL: Adds 1 risk factor point
  • HDL 40-59 mg/dL: Neutral (0 points)
  • HDL ≥60 mg/dL: Negative risk factor (subtract 1 point from total risk score)

Cholesterol Ratios:

Total Cholesterol/HDL Ratio:
Optimal: <3.5
Average: 3.5-5.0
High risk: >5.0

LDL/HDL Ratio:
Optimal: <2.0
Average: 2.0-3.0
High risk: >3.0

These ratios may be better risk predictors than isolated cholesterol values, especially in patients with metabolic syndrome.

Metabolic Syndrome Criteria

Low HDL is one of five criteria for metabolic syndrome (need 3 of 5 for diagnosis):

  • Waist circumference: >40 inches (men), >35 inches (women)
  • Triglycerides: ≥150 mg/dL
  • HDL cholesterol: <40 mg/dL (men), <50 mg/dL (women)
  • Blood pressure: ≥130/85 mmHg or on antihypertensive medication
  • Fasting glucose: ≥100 mg/dL or known diabetes

Strategies to Raise HDL

Evidence-based approaches to increasing HDL:

Lifestyle Modifications (Most Effective):

  • Aerobic exercise: 150 min/week moderate or 75 min/week vigorous; increases HDL 5-10%; most effective intervention
  • Weight loss: Lose 5-10% body weight; ~1 mg/dL increase per 3 kg lost; focus on visceral fat
  • Smoking cessation: HDL increases 5-10 mg/dL within weeks of quitting
  • Reduce refined carbohydrates: High-carb diets lower HDL; replace with healthy fats (nuts, olive oil, avocado)
  • Moderate alcohol: 1-2 drinks/day increases HDL ~4 mg/dL, but risks may outweigh benefits
  • Replace trans fats and saturated fats with unsaturated fats: Improves HDL and overall lipid profile
  • Add omega-3 fatty acids: Fish, flaxseed, walnuts; modest HDL benefit

Pharmacologic Options:

  • Fibrates (gemfibrozil, fenofibrate): Increase HDL 10-25%; best for low HDL + high triglycerides; monitor for myopathy if combined with statin
  • Niacin (nicotinic acid): Increases HDL 15-35%; limited use due to flushing, glucose intolerance, lack of cardiovascular benefit in recent trials
  • Statins: Modest HDL increase 5-10%; primary benefit is LDL reduction
Treatment Priority: While low HDL increases cardiovascular risk, current guidelines prioritize LDL lowering (with statins) over HDL raising. Focus on: 1) Statin for LDL reduction, 2) Lifestyle modifications (exercise, weight loss, smoking cessation) to improve all lipid parameters, 3) Consider fibrate if HDL remains <40 mg/dL and triglycerides >200 mg/dL despite lifestyle changes.
Interfering Factors

Factors That Decrease HDL

  • Lifestyle: Smoking, sedentary lifestyle, obesity, high refined carbohydrate diet, trans fats
  • Medications: Beta-blockers (non-selective), thiazide diuretics, anabolic steroids, androgens, protease inhibitors, progestins
  • Medical conditions: Metabolic syndrome, type 2 diabetes, hypertriglyceridemia, chronic kidney disease, liver disease, inflammatory conditions
  • Genetic: Familial hypoalphalipoproteinemia, Tangier disease, LCAT deficiency
  • Acute illness: HDL drops during acute infection, MI, surgery (similar to LDL decrease)

Factors That Increase HDL

  • Lifestyle: Regular aerobic exercise, weight loss, smoking cessation, moderate alcohol (1-2 drinks/day), healthy fats (olive oil, nuts, fish)
  • Medications: Fibrates, niacin, statins (modest), estrogen, SGLT2 inhibitors
  • Hormonal: Female sex, estrogen, pregnancy
  • Genetic: CETP deficiency, familial hyperalphalipoproteinemia

Analytical Considerations

  • Fasting not required: HDL changes minimally (<5%) with meals; non-fasting HDL is acceptable
  • Biological variation: HDL varies ±7-8% day-to-day; average multiple measurements for baseline
  • Acute illness: HDL decreases during acute illness, stress, or hospitalization; wait 6-8 weeks after acute event for accurate baseline
  • Recent weight change: Rapid weight loss (crash diets) transiently lowers HDL; stabilizes after weight maintenance
  • Alcohol timing: Acute alcohol intake may transiently affect HDL; chronic moderate use increases HDL
Clinical Pearls
Clinical Pearl
"HDL ≥60 is a negative risk factor": Framingham data showed HDL ≥60 mg/dL reduces cardiovascular risk enough to subtract one risk factor from total count. Each 1 mg/dL increase in HDL reduces CV risk by ~2-3%. Higher is generally better, though very high HDL (>100) may not always be protective.
Clinical Pearl
Exercise is most effective HDL intervention: Regular aerobic exercise (150 min/week moderate or 75 min/week vigorous) is the single most effective way to raise HDL, typically increasing it 5-10%. More effective than any medication and has numerous other benefits. Resistance training also helps, especially in metabolic syndrome.
Clinical Pearl
Low HDL + high triglycerides = metabolic syndrome: This combination is a hallmark of metabolic syndrome and insulin resistance. Often accompanies central obesity, pre-diabetes, and hypertension. Signals need for aggressive lifestyle modification (weight loss, exercise) and screening for diabetes.
Raising HDL doesn't always reduce cardiovascular events: While observational studies show inverse relationship between HDL and CV risk, randomized trials of HDL-raising drugs (niacin, CETP inhibitors) failed to reduce events when added to statins. HDL functionality matters more than absolute level. Focus on proven therapies (statins, lifestyle) rather than chasing high HDL.
Total/HDL ratio may be better than isolated values: Total cholesterol/HDL ratio <3.5 is optimal, >5.0 is high risk. This ratio captures the balance between atherogenic (total cholesterol) and protective (HDL) lipoproteins. Similarly, LDL/HDL ratio <2.0 is optimal. Useful when individual values are borderline.
Clinical Pearl
Women naturally have higher HDL than men (~10 mg/dL): Estrogen increases HDL, explaining higher levels in women and different thresholds for "low HDL" (men <40, women <50). HDL drops after menopause unless on hormone replacement. Trans men on testosterone see HDL decrease; trans women on estrogen see HDL increase.
Clinical Pearl
Smoking cessation rapidly increases HDL: HDL rises 5-10 mg/dL within weeks of quitting smoking. One of the fastest lipid benefits of cessation (along with reduced thrombotic risk). Quantify this benefit when counseling patients on smoking cessation.
Niacin is not recommended in statin era: Despite raising HDL 15-35%, niacin failed to reduce cardiovascular events when added to statins in AIM-HIGH and HPS2-THRIVE trials. Side effects (flushing, glucose intolerance, GI symptoms) outweigh benefits. Not recommended for routine use.
Clinical Pearl
Fibrates best for low HDL + high triglycerides: Fibrates (fenofibrate, gemfibrozil) increase HDL 10-25% and reduce triglycerides 30-50%. Most beneficial in patients with metabolic syndrome pattern (HDL <40, TG >200). Gemfibrozil has more drug interactions than fenofibrate if combining with statin.
Very high HDL (>100 mg/dL) is not always protective: While usually beneficial, some genetic causes of very high HDL (CETP deficiency) produce dysfunctional HDL that doesn't provide expected cardiovascular protection. If HDL >100 mg/dL without obvious cause (extreme exercise, genetics), consider cholesterol efflux capacity testing (research setting).
Clinical Pearl
Moderate alcohol increases HDL but risks may outweigh benefits: 1-2 drinks/day increases HDL ~4 mg/dL and may reduce CV risk in observational studies. However, alcohol has numerous health risks (liver disease, cancer, accidents, addiction). Don't recommend starting alcohol for HDL benefit - exercise is safer and more effective.
Clinical Pearl
Weight loss raises HDL (~1 mg/dL per 3 kg lost): Losing 5-10% body weight improves all lipid parameters. HDL increases as visceral fat decreases. Effect is sustained with weight maintenance but reversed with weight regain. Combine with exercise for maximal benefit.
References
  1. Kratz, A., Ferraro, M., Sluss, P. M., & Lewandrowski, K. B. (2004). Laboratory reference values. New England Journal of Medicine, 351, 1548-1564.
  2. Lee, M. (Ed.). (2009). Basic skills in interpreting laboratory data. Ashp.
  3. Farinde, A. (2021). Lab values, normal adult: Laboratory reference ranges in healthy adults. Medscape. https://emedicine.medscape.com/article/2172316-overview?form=fpf
  4. Nickson, C. (n.d.). Critical Care Compendium. Life in the Fast Lane • LITFL. https://litfl.com/ccc-critical-care-compendium/
  5. Farkas, Josh MD. (2015). Table of Contents - EMCrit Project. EMCrit Project. https://emcrit.org/ibcc/toc/
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