What are the causes of extremely low high‑density lipoprotein (HDL) cholesterol?

Causes of Extremely Low HDL Cholesterol

Extremely low HDL cholesterol (<20 mg/dL) results from primary genetic disorders, secondary causes including androgen use and malignancy, or severe hypertriglyceridemia—and requires systematic evaluation to identify the underlying etiology. 1

Primary Genetic Disorders

The most important causes of extremely low HDL are rare monogenic disorders that directly impair HDL metabolism:

• Apolipoprotein A-I mutations disrupt the primary structural protein of HDL particles, leading to profoundly low HDL-C levels 1
• Tangier disease (ABCA1 mutations) prevents cellular cholesterol efflux to HDL, resulting in near-absent HDL cholesterol and characteristic orange tonsils 1
• Lecithin-cholesterol acyltransferase (LCAT) deficiency blocks HDL maturation, causing extremely low HDL-C with corneal opacities and renal disease 1
• Familial hypobetalipoproteinemia can present with very low HDL-C alongside low LDL cholesterol 2

These genetic conditions provide natural experiments demonstrating that humans can tolerate lifelong very low HDL without necessarily developing premature atherosclerosis, challenging the simple "HDL is protective" paradigm. 1

Secondary Causes

After confirming HDL-C <20 mg/dL, systematically evaluate for reversible secondary causes:

• Androgen use or abuse (testosterone, anabolic steroids) potently suppresses HDL production 1
• Malignancy, particularly hematologic cancers, can lower HDL through inflammatory mechanisms 1
• Severe hypertriglyceridemia (>500 mg/dL) mathematically reduces measured HDL-C due to the inverse relationship between triglycerides and HDL 3, 4
• Metabolic syndrome components including insulin resistance, obesity, and physical inactivity commonly produce low HDL as part of atherogenic dyslipidemia 3, 4

Genetic Variants and Polygenic Influences

Beyond rare monogenic disorders, common genetic variation substantially influences HDL levels:

• CETP gene variants are strongly associated with higher or lower HDL-C across populations 5
• Hepatic and endothelial lipase gene mutations directly modify HDL metabolism 5
• Apolipoprotein A-I gene variants affect HDL particle size and concentration 5
• Paraoxonase-1 (PON1) polymorphisms influence HDL activity in a genotype-dependent manner 5

These genetic factors explain why baseline HDL levels vary widely among individuals and why some people have constitutionally low HDL without identifiable disease. 6

Critical Clinical Context: HDL-C Is Not Causally Protective

Mendelian randomization studies definitively demonstrate that low HDL cholesterol per se does not cause atherosclerotic cardiovascular disease. 2, 5 When genetically determined low HDL is adjusted for triglycerides and LDL cholesterol, the apparent association with cardiovascular risk disappears. 2 This means:

• Elevated triglyceride-rich lipoproteins (remnant cholesterol) are causally associated with cardiovascular disease, independent of HDL levels 2, 3
• The observational inverse relationship between HDL-C and cardiovascular risk reflects confounding, not causation 2, 5
• Focus cardiovascular risk management on LDL cholesterol reduction, not HDL raising 5, 3

Diagnostic Approach

When encountering HDL-C <20 mg/dL:

1. Confirm the result with repeat fasting lipid panel to exclude laboratory error 1
2. Measure triglycerides to determine if severe hypertriglyceridemia is present 1, 4
3. Obtain detailed medication history focusing on androgens, beta-blockers, and thiazide diuretics 1
4. Screen for malignancy if clinically indicated by other symptoms 1
5. Assess for metabolic syndrome components (waist circumference, blood pressure, glucose, triglycerides) 4
6. Consider genetic testing for monogenic disorders if family history suggests inherited disease or if physical findings (corneal opacities, hepatosplenomegaly, neuropathy) are present 1

Management Priorities

Address reversible secondary causes first (discontinue offending medications, treat underlying malignancy, optimize metabolic syndrome components). 1 However, recognize that:

• No pharmacologic therapy is indicated solely to raise HDL cholesterol 5
• Cardiovascular risk reduction should target LDL cholesterol with statins to evidence-based goals (<70 mg/dL for high-risk patients, <55 mg/dL for very high-risk) 3, 7
• Manage other cardiovascular risk factors (hypertension, diabetes, smoking cessation) regardless of HDL level 5

The key pitfall is overemphasizing HDL-C as a therapeutic target when genetic evidence proves it is a biomarker, not a causal factor in atherosclerosis. 2, 5