Introduction

High-density lipoprotein (HDL) cholesterol is a class of lipoproteins characterized by a dense protein structure and a diameter of approximately 8 to 12 nanometers.[1] HDL particles are composed of a hydrophobic core consisting largely of esters and triglycerides, surrounded by a layer of phospholipids, free cholesterol, and apolipoproteins. HDL levels are routinely measured using enzymatic assays that quantify the cholesterol content of HDL particles after precipitation or inhibition of other lipoprotein classes. Additionally, different methods have been used to subclassify HDL particle number by size and density via ultracentrifugal flotation, and by lipoprotein mass concentration.[2] Further, HDL can be subcategorized by gel electrophoresis and by apolipoprotein composition.

HDL cholesterol has many antiatherogenic properties, including reverse cholesterol transport, a process that removes cholesterol from peripheral tissues and transports it to the liver for clearance by macrophages.[3] Moreover, HDL has many anti-inflammatory, antioxidative, and endothelial-protective functions.[3] Due to these characteristics, HDL particles play a role in reducing cardiovascular risk.

Etiology

Low HDL cholesterol levels can have a wide range of etiologies, including lifestyle factors, metabolic and endocrine disorders, genetic causes, medication-related effects, and diseases associated with chronic inflammation. One of the most common etiologies of low HDL cholesterol levels is lifestyle. Specifically, obesity, smoking, and physical inactivity contribute to low HDL levels.[4][5] Furthermore, research indicates that diets high in simple sugars and trans fats are inversely associated with HDL cholesterol levels. Considering diet, exercise, and other lifestyle factors is essential when a patient has low HDL cholesterol levels.

Additionally, metabolic and endocrine disorders can lead to low HDL cholesterol levels. Insulin resistance, as in type 2 diabetes, reduces HDL by promoting the overproduction of very-low-density lipoprotein in the liver.[6] Moreover, hypothyroidism and liver disease can lead to reduced HDL cholesterol levels due to altered apolipoprotein metabolism rates and decreased HDL cholesterol synthesis, respectively.[7][8] Thus, a thorough evaluation for metabolic syndrome and polyglandular autoimmune syndromes is paramount in determining the etiology of low HDL levels. 

Genetic defects in cholesterol production can result in syndromes, eg, Fish-Eye disease, familial hypoalphalipoproteinemia, familial HDL deficiency, and Tangier disease. A mutation in the apolipoprotein A-I gene causes familial hypoalphalipoproteinemia. Familial HDL deficiency shares genetic links with Tangier disease, an autosomal codominant condition characterized by the absence of HDL cholesterol in homozygous individuals.[9] The low HDL concentration leads to premature coronary artery disease and cholesteryl ester deposition in the reticuloendothelial system, causing organomegaly and xanthoma production.[10] 

Lastly, a deficiency in lecithin cholesterol acyltransferase (LCAT) impairs HDL maturation, ultimately leading to low HDL cholesterol levels, as in Fish Eye disease.[11] Corneal opacities, nephropathy, and proteinuria characterize this disease. Typically, early-onset cardiovascular disease is absent in LCAT deficiency. Medications, specifically beta blockers and anabolic steroids, may also lead to a decrease in specific subtypes of HDL cholesterol.[12] Therefore, it is crucial for clinicians to properly review a patient's medication history when considering etiologies of low HDL cholesterol. 

Epidemiology

Approximately 20% of the adult population has low HDL cholesterol, with a significantly higher prevalence in men (29% of men versus 9% of women).[CDC. Total and High-density Lipoprotein Cholesterol in Adults: United States, 2015–2018] Additionally, low HDL cholesterol levels are more common in White and Asian adults.[CDC. Total and High-density Lipoprotein Cholesterol in Adults: United States, 2015–2018] The case prevalence of hereditary low HDL cholesterol is not well established, but most genetic etiologies are rare. 

Pathophysiology

The pathophysiology of low HDL cholesterol depends upon the etiology. For example, in patients with hypoalphalipoproteinemia, specific mutations result in distinct phenotypes. In children with identified mutations in apolipoprotein A-I (the principal component of HDL), heterozygote levels are reduced by approximately 50%. Conversely, the homozygotes are deficient in plasma HDL, consistent with an autosomal dominant genetic pattern. Additionally, adenosine triphosphate-binding cassette transporter (ABC1) mutations are common in both familial HDL deficiency and Tangier disease.[12][13] These ABC1 mutations impair macrophage cholesterol clearance, predisposing patients to an increased risk of early atherosclerotic disease. These macrophages transform into foam cells, contributing to the development of early-onset coronary artery disease.

Familial combined hypolipidemia patients have mutations in ANGPTL3 (encoding the angiopoietin-like 3 protein). ANGPTL3 inhibits lipoprotein lipase (LPL), leading to reduced cholesterol levels. Patients who are heterozygous or homozygous for these mutations have lower HDL cholesterol concentrations than noncarriers. Despite the low HDL level associated with these mutations, affected individuals have a lower cardiac risk because their low-density lipoprotein levels are also low. However, complete LPL deficiency, seen in homozygotes of lipoprotein lipase gene mutations, leads to severe hypertriglyceridemia and chylomicronemia.[14][15]

Additionally, low HDL cholesterol states can result from increased HDL catabolism or increased clearance. Specifically, elevated triglyceride-rich lipoproteins promote cholesteryl ester transfer protein (CETP) activity, leading to decreased HDL levels through the transfer of cholesteryl esters in exchange for triglycerides.[16] Conditions, eg, insulin resistance, accelerate CETP transfer.[16] Furthermore, inflammation and oxidative stress can enhance HDL catabolism via the hepatic scavenger receptor class B type 1, a receptor involved in HDL clearance.[17]

History and Physical

Most patients with low HDL do not exhibit symptoms or have physical findings. However, some of the syndromes mentioned above have clinical findings that offer clues to the diagnosis. For patients with insulin resistance, physical examination can reveal acanthosis nigricans, skin tags, and central obesity.[18] Diseases characterized by elevated low-density lipoprotein and triglyceride levels can manifest as xanthomas and xanthelasma, yellow lipid deposits that accumulate in macrophages beneath the skin. Furthermore, Fish Eye disease is phenotypically characterized by severe corneal opacities. Patients with Tangier disease may exhibit hepatosplenomegaly, enlarged tonsils or lymph nodes, or arcus corneae (lipid deposits in the eye).[19] 

Evaluation

Fasting lipid panels will reveal the levels of total cholesterol, low-density lipoprotein cholesterol, HDL cholesterol, and triglycerides. Additionally, nuclear magnetic resonance (NMR) can be used to measure particle numbers. However, quantification via NMR is not standardized and is often difficult to interpret.[2][20] Additionally, certain diseases (eg, Fish Eye disease) are associated with proteinuria and nephropathy; assessing kidney function with a basic metabolic panel and urinalysis is reasonable if this disease is suspected. Furthermore, blood sugar quantification is reasonable if HDL abnormalities associated with metabolic syndrome are taken into account. 

Treatment / Management

HDL levels are generally inversely proportional to cardiovascular disease risk. However, the clinical correlation between elevated HDL cholesterol and cardiac disease remains incompletely understood. While results from several studies have shown that higher HDL levels are associated with a lower risk of cardiovascular disease, a 2009 meta-analysis failed to find this association after adjusting for changes in LDL cholesterol.[21] Furthermore, results from a 2022 cohort study demonstrated that very high HDL cholesterol levels are paradoxically associated with higher mortality in patients with coronary artery disease. Thus, the need to treat HDL levels is unclear and is not currently a standard of care in cholesterol management.[22]

Despite the lack of evidence for HDL-targeted medications, multiple pharmacological options are available that raise HDL levels and lower LDL and triglyceride levels. Among the medications that raise HDL cholesterol, niacin has the most significant effect, increasing serum HDL by 15% to 30%.[23] Although niacin raises HDL in the absence of any other lipid abnormality, there is little evidence that the addition of niacin to statin therapy has any cardiovascular benefit.[23] In the AIM High trial, adding niacin to statins in patients with well-controlled LDL cholesterol showed no cardiovascular benefit despite a significant increase in HDL levels.

The infusion of apolipoprotein A-I (apoA-I) has been investigated for its potential cardiovascular benefits, as apoA-I levels are strongly associated with reduced cardiovascular disease risk in patients already on statin therapy.[24] A large study examined the effects of consecutive weekly infusions of apoA-I versus placebo after a recent myocardial infarction to determine the benefits of apoA-I infusion therapy.[25] Patients who received the apoA-I infusion had an increase in cholesterol efflux capacity. However, further research is needed to determine if this therapy will translate to a reduction in major adverse cardiovascular events.

Therefore, no specific treatment is recommended solely to increase HDL cholesterol levels as a means to reduce cardiovascular disease risk. In patients with increased cardiovascular risk and low HDL cholesterol, regular exercise, adequate fruit and vegetable intake, reaching target body weight, and smoking/substance use cessation improve HDL cholesterol and decrease cardiovascular disease risk.[26][27][28] Thus, clinicians should focus on counseling patients with low HDL on the importance of lifestyle modification.

Differential Diagnosis

The differential diagnosis of low HDL cholesterol can include lifestyle factors, eg, poor diet or lack of exercise. Additionally, type 2 diabetes and hypothyroidism can be associated with low HDL levels. Rare causes, eg, genetic disorders, can manifest with physical examination findings, eg, subcutaneous lipid deposits in Tangier disease or Fish Eye disease. Certain medications can also lower HDL levels, eg, both antihypertensive medications and diuretics can decrease HDL cholesterol and increase triglycerides, with the magnitude of the effect proportional to the dose. Beta-blockers decrease HDL levels secondary to increased triglycerides, although cardioselective beta-blockers have a smaller effect; alpha-blockers decrease triglycerides and increase HDL levels.[29][30]

Prognosis

According to the Framingham Heart Study, the risk of myocardial infarction increases by approximately 25% for every 5 mg/dL decrease in serum HDL cholesterol below median values.[31] Furthermore, a low HDL cholesterol level is an independent risk factor for myocardial infarction in patients with established cardiovascular disease. Moreover, the SMART (Secondary Manifestations of Arterial Disease) study demonstrated that elevated HDL cholesterol is protective against future cardiac events in patients on statin therapy. Thus, patients have a better cardiovascular prognosis when HDL cholesterol levels are higher.[32]

Complications

Complications of low HDL cholesterol include an increased risk of atherosclerotic cardiovascular disease, impaired glucose metabolism and insulin resistance, increased inflammation/oxidative stress, and a higher risk of cognitive decline due to vascular and neuroinflammatory effects.[33][34][35]

Deterrence and Patient Education

A healthy diet and regular exercise can treat low HDL cholesterol levels. Educating patients about healthy dietary choices, such as the Mediterranean diet, which reduces cardiovascular and overall mortality, is essential. Further counseling on weight loss and exercise is also necessary. Foods high in saturated fats tend to increase LDL and HDL cholesterol while decreasing the triglyceride-rich lipoproteins. Furthermore, monounsaturated fats reduce insulin resistance and may indirectly increase HDL cholesterol levels. Continued yearly visits with the patient's primary care clinician remain the most effective way to screen for and improve low HDL cholesterol levels. 

Enhancing Healthcare Team Outcomes

Addressing low HDL cholesterol and other lipid abnormalities requires an interdisciplinary care team. Other members of the healthcare team can assist the clinician in counseling the patient on diet, exercise, and weight loss.[36] Referrals to weight loss programs, nutrition consultations, physical therapy for functionally limiting orthopedic concerns, pharmacy services, and social work can improve patient outcomes.

The average primary care clinician's median visit length is only 10 minutes, which often limits discussions on the root cause of low HDL levels.[37] Many members of the health care team can assist in counseling patients and supporting them over multiple visits to optimize lifestyle modifications. Moreover, licensed therapists can assist with behavioral modification strategies, including smoking and alcohol cessation, and improved eating habits. Dietitians are also beneficial for individual consultations and for teaching patient classes about healthier cooking habits. 

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References

1.

Ding Y, Wang Y, Opoku-Damoah Y, Wang C, Shen L, Yin L, Zhou J. Dual-functional bio-derived nanoparticulates for apoptotic antitumor therapy. Biomaterials. 2015 Dec;72:90-103. [PubMed: 26344366]

2.

Rosenson RS, Brewer HB, Ansell B, Barter P, Chapman MJ, Heinecke JW, Kontush A, Tall AR, Webb NR. Translation of high-density lipoprotein function into clinical practice: current prospects and future challenges. Circulation. 2013 Sep 10;128(11):1256-67. [PubMed: 24019446]

3.

Feingold KR, Grunfeld C. Effect of Inflammation and Infection on Lipids and Lipoproteins. In: Feingold KR, Adler RA, Ahmed SF, Anawalt B, Blackman MR, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hamilton E, Hofland J, Jan de Beur S, Kalra S, Kaltsas G, Kapoor N, Kim M, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Muzumdar R, Purnell J, Rey R, Sahay R, Shah AS, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. MDText.com, Inc.; South Dartmouth (MA): Jun 18, 2025. [PubMed: 26561701]

4.

Gaggini M, Saponaro C, Gastaldelli A. Not all fats are created equal: adipose vs. ectopic fat, implication in cardiometabolic diseases. Horm Mol Biol Clin Investig. 2015 Apr;22(1):7-18. [PubMed: 25816312]

5.

Ma B, Chen Y, Wang X, Zhang R, Niu S, Ni L, Di X, Han Q, Liu C. Cigarette smoke exposure impairs lipid metabolism by decreasing low-density lipoprotein receptor expression in hepatocytes. Lipids Health Dis. 2020 May 08;19(1):88. [PMC free article: PMC7210682] [PubMed: 32384892]

6.

Taskinen MR. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia. 2003 Jun;46(6):733-49. [PubMed: 12774165]

7.

Duntas LH. Thyroid disease and lipids. Thyroid. 2002 Apr;12(4):287-93. [PubMed: 12034052]

8.

Lewis GF, Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res. 2005 Jun 24;96(12):1221-32. [PubMed: 15976321]

9.

Moudian I, Bakkach J, Zian Z, Ghailani Nourouti N, Barakat A, Bennani Mechita M. Genetic Underpinnings of Mitochondrial Cardiomyopathy: A Scoping 2010-2024 Update. DNA Cell Biol. 2025 Sep;44(9):473-485. [PubMed: 40600299]

10.

Koseki M, Yamashita S, Ogura M, Ishigaki Y, Ono K, Tsukamoto K, Hori M, Matsuki K, Yokoyama S, Harada-Shiba M. Current Diagnosis and Management of Tangier Disease. J Atheroscler Thromb. 2021 Aug 01;28(8):802-810. [PMC free article: PMC8326168] [PubMed: 33994407]

11.

Pavanello C, Calabresi L. Genetic, biochemical, and clinical features of LCAT deficiency: update for 2020. Curr Opin Lipidol. 2020 Aug;31(4):232-237. [PubMed: 32618730]

12.

Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, Yu L, Brewer C, Collins JA, Molhuizen HO, Loubser O, Ouelette BF, Fichter K, Ashbourne-Excoffon KJ, Sensen CW, Scherer S, Mott S, Denis M, Martindale D, Frohlich J, Morgan K, Koop B, Pimstone S, Kastelein JJ, Genest J, Hayden MR. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet. 1999 Aug;22(4):336-45. [PubMed: 10431236]

13.

Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, Deleuze JF, Brewer HB, Duverger N, Denèfle P, Assmann G. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet. 1999 Aug;22(4):352-5. [PubMed: 10431238]

14.

Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C, Garimella KV, Fisher S, Abreu J, Barry AJ, Fennell T, Banks E, Ambrogio L, Cibulskis K, Kernytsky A, Gonzalez E, Rudzicz N, Engert JC, DePristo MA, Daly MJ, Cohen JC, Hobbs HH, Altshuler D, Schonfeld G, Gabriel SB, Yue P, Kathiresan S. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010 Dec 02;363(23):2220-7. [PMC free article: PMC3008575] [PubMed: 20942659]

15.

Genest JJ, Martin-Munley SS, McNamara JR, Ordovas JM, Jenner J, Myers RH, Silberman SR, Wilson PW, Salem DN, Schaefer EJ. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation. 1992 Jun;85(6):2025-33. [PubMed: 1534286]

16.

Tall AR. Plasma cholesteryl ester transfer protein. J Lipid Res. 1993 Aug;34(8):1255-74. [PubMed: 8409761]

17.

Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science. 1996 Jan 26;271(5248):518-20. [PubMed: 8560269]

18.

Rafique S, Dihowm H, Parveen S, Jakoby M. Insulin-Induced Acanthosis Nigricans. Cureus. 2025 May;17(5):e83424. [PMC free article: PMC12129569] [PubMed: 40458329]

19.

Winder AF, Alexander R, Garner A, Johnston D, Vallance D, McCreanor G, Frohlich J. The pathology of cornea in Tangier disease (familial high density lipoprotein deficiency). J Clin Pathol. 1996 May;49(5):407-10. [PMC free article: PMC500482] [PubMed: 8707957]

20.

Vaisar T, Heinecke J. Quantification of high-density lipoprotein particle number by proton nuclear magnetic resonance: don't believe the numbers. Curr Opin Lipidol. 2024 Oct 01;35(5):228-233. [PMC free article: PMC11527121] [PubMed: 39162237]

21.

Ghali WA, Rodondi N. HDL cholesterol and cardiovascular risk. BMJ. 2009 Feb 16;338:a3065. [PubMed: 19221138]

22.

Liu C, Dhindsa D, Almuwaqqat Z, Ko YA, Mehta A, Alkhoder AA, Alras Z, Desai SR, Patel KJ, Hooda A, Wehbe M, Sperling LS, Sun YV, Quyyumi AA. Association Between High-Density Lipoprotein Cholesterol Levels and Adverse Cardiovascular Outcomes in High-risk Populations. JAMA Cardiol. 2022 Jul 01;7(7):672-680. [PMC free article: PMC9118072] [PubMed: 35583863]

23.

AIM-HIGH Investigators. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011 Dec 15;365(24):2255-67. [PubMed: 22085343]

24.

Boekholdt SM, Arsenault BJ, Hovingh GK, Mora S, Pedersen TR, Larosa JC, Welch KM, Amarenco P, Demicco DA, Tonkin AM, Sullivan DR, Kirby A, Colhoun HM, Hitman GA, Betteridge DJ, Durrington PN, Clearfield MB, Downs JR, Gotto AM, Ridker PM, Kastelein JJ. Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis. Circulation. 2013 Oct 01;128(14):1504-12. [PMC free article: PMC3807966] [PubMed: 23965489]

25.

Michael Gibson C, Korjian S, Tricoci P, Daaboul Y, Yee M, Jain P, Alexander JH, Steg PG, Lincoff AM, Kastelein JJ, Mehran R, D'Andrea DM, Deckelbaum LI, Merkely B, Zarebinski M, Ophuis TO, Harrington RA. Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction: The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I). Circulation. 2016 Dec 13;134(24):1918-1930. [PMC free article: PMC5147036] [PubMed: 27881559]

26.

Moffatt RJ. Effects of cessation of smoking on serum lipids and high density lipoprotein-cholesterol. Atherosclerosis. 1988 Nov;74(1-2):85-9. [PubMed: 3214483]

27.

Wood PD, Stefanick ML, Dreon DM, Frey-Hewitt B, Garay SC, Williams PT, Superko HR, Fortmann SP, Albers JJ, Vranizan KM. Changes in plasma lipids and lipoproteins in overweight men during weight loss through dieting as compared with exercise. N Engl J Med. 1988 Nov 03;319(18):1173-9. [PubMed: 3173455]

28.

Wood PD, Stefanick ML, Williams PT, Haskell WL. The effects on plasma lipoproteins of a prudent weight-reducing diet, with or without exercise, in overweight men and women. N Engl J Med. 1991 Aug 15;325(7):461-6. [PubMed: 1852180]

29.

Kasiske BL, Ma JZ, Kalil RS, Louis TA. Effects of antihypertensive therapy on serum lipids. Ann Intern Med. 1995 Jan 15;122(2):133-41. [PubMed: 7992988]

30.

Wolinsky H. The effects of beta-adrenergic blocking agents on blood lipid levels. Clin Cardiol. 1987 Oct;10(10):561-6. [PubMed: 2889552]

31.

Castelli WP. Cardiovascular disease and multifactorial risk: challenge of the 1980s. Am Heart J. 1983 Nov;106(5 Pt 2):1191-200. [PubMed: 6637784]

32.

van de Woestijne AP, van der Graaf Y, Liem AH, Cramer MJ, Westerink J, Visseren FL., SMART Study Group. Low high-density lipoprotein cholesterol is not a risk factor for recurrent vascular events in patients with vascular disease on intensive lipid-lowering medication. J Am Coll Cardiol. 2013 Nov 12;62(20):1834-41. [PubMed: 23948286]

33.

Drew BG, Duffy SJ, Formosa MF, Natoli AK, Henstridge DC, Penfold SA, Thomas WG, Mukhamedova N, de Courten B, Forbes JM, Yap FY, Kaye DM, van Hall G, Febbraio MA, Kemp BE, Sviridov D, Steinberg GR, Kingwell BA. High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus. Circulation. 2009 Apr 21;119(15):2103-11. [PubMed: 19349317]

34.

Kao YC, Ho PC, Tu YK, Jou IM, Tsai KJ. Lipids and Alzheimer's Disease. Int J Mol Sci. 2020 Feb 22;21(4) [PMC free article: PMC7073164] [PubMed: 32098382]

35.

Tabet F, Rye KA. High-density lipoproteins, inflammation and oxidative stress. Clin Sci (Lond). 2009 Jan;116(2):87-98. [PubMed: 19076062]

36.

Valero-Elizondo J, Aneni EC, Osondu CU, Grandhi GR, Virani SS, Nasir K. Gaps in provider lifestyle counseling and its adherence among obese adults with prediabetes and diabetes in the United States. Prev Med. 2019 Dec;129:105815. [PubMed: 31454663]

37.

Tai-Seale M, McGuire TG, Zhang W. Time allocation in primary care office visits. Health Serv Res. 2007 Oct;42(5):1871-94. [PMC free article: PMC2254573] [PubMed: 17850524]

Disclosure: Jonathan Van Name declares no relevant financial relationships with ineligible companies.

Disclosure: Saurabh Sharma declares no relevant financial relationships with ineligible companies.