History

Persons with low high-density lipoprotein (HDL) cholesterol levels, except those patients with a deficiency syndrome, have no symptoms specific to the condition. However, they may have a history of premature atherosclerosis, as well as a history consistent with coronary heart disease (CHD), peripheral artery disease, or other such conditions, including the following:

Premature atherosclerosis
- CHD - A history of angina or myocardial infarction (MI) in a person below age 60 years, a history of premature heart disease in a patient's siblings and first-degree relatives, sequelae of MI
- Congestive heart failure
- Peripheral vascular disease - A history of claudication
Cerebrovascular disease
- History of stroke
- History of transient ischemic attack
- History of carotid endarterectomy
Xanthomas (tendinous, cutaneous)
History consistent with secondary causes
- Cigarette smoking
- Physical inactivity
- Hypertriglyceridemia
- Renal disease
- Obesity
- Medications
- Androgens
- Progestins
- Probucol
- High-dose thiazides
- High-dose beta blockers
Corneal opacification

Physical Examination

Persons with the common low high-density lipoprotein (HDL) syndromes have no specific physical findings. If atherosclerosis is present, the examination may reveal findings consistent with the affected arterial bed. These may include the following:

Tendon xanthomas
Cutaneous xanthomas
Findings of ischemic coronary heart disease or peripheral vascular disease
- S₄ gallop consistent with ischemic left ventricular dysfunction
- Signs of congestive heart failure, such as a raised jugular distension, crackles at the lung bases, edema, and hepatomegaly
- Arrhythmias
Corneal opacification

Workup

Yamakawa-Kobayashi K, Yanagi H, Fukayama H, et al. Frequent occurrence of hypoalphalipoproteinemia due to mutant apolipoprotein A-I gene in the population: a population-based survey. Hum Mol Genet. 1999 Feb. 8(2):331-6. [QxMD MEDLINE Link]. [Full Text].
Gebauer SK, Destaillats F, Dionisi F, Krauss RM, Baer DJ. Vaccenic acid and trans fatty acid isomers from partially hydrogenated oil both adversely affect LDL cholesterol: a double-blind, randomized controlled trial. Am J Clin Nutr. 2015 Nov 11. [QxMD MEDLINE Link].
Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001 May 16. 285(19):2486-97. [QxMD MEDLINE Link].
Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III Final Report). May 2001. Available at http://www.nhlbi.nih.gov/guidelines/cholesterol/.
Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004 Jul 13. 110(2):227-39. [QxMD MEDLINE Link]. [Full Text].
Singh VN. New ATP III lipid guidelines update for patients at high risk for cardiovascular events. Medscape Reference Feature Series - Lipid Newsletter. Jul 21, 2005. series 1(9):[Full Text].
Dioguardi N, Vergani C. [Familial alpha lipoprotein deficiency. Tangier disease, familial hypoalphalipoproteinemia and familial deficiency of lecithin cholesterol acyltransferase deficiency]. Minerva Med. 1983 Mar 24. 74(12):585-94. [QxMD MEDLINE Link].
Sorrenson B, Suetani RJ, Bickley VM, George PM, Williams MJ, Scott RS, et al. An ABCA1 truncation shows no dominant negative effect in a familial hypoalphalipoproteinemia pedigree with three ABCA1 mutations. Biochem Biophys Res Commun. 2011 Jun 10. 409(3):400-5. [QxMD MEDLINE Link].
Bartlett J, Predazzi IM, Williams SM, Bush WS, Kim Y, Havas S, et al. Is Isolated Low High-Density Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor? New Insights From the Framingham Offspring Study. Circ Cardiovasc Qual Outcomes. 2016 May. 9 (3):206-12. [QxMD MEDLINE Link].
Hackethal V. Framingham: Low HDL, in Isolation, Not a CV Risk Predictor. http://www.medscape.com/viewarticle/863880. Available at http://www.medscape.com/viewarticle/863880. May 26, 2016; Accessed: November 3, 2016.
Chien KL, Chen MF, Hsu HC, et al. Genetic association study of APOA1/C3/A4/A5 gene cluster and haplotypes on triglyceride and HDL cholesterol in a community-based population. Clin Chim Acta. 2008 Feb. 388(1-2):78-83. [QxMD MEDLINE Link].
van den Bogaard B, Holleboom AG, Duivenvoorden R, Hutten BA, Kastelein JJ, Hovingh GK, et al. Patients with low HDL-cholesterol caused by mutations in LCAT have increased arterial stiffness. Atherosclerosis. 2012 Dec. 225(2):481-5. [QxMD MEDLINE Link].
Savel J, Lafitte M, Pucheu Y, Pradeau V, Tabarin A, Couffinhal T. Very low levels of HDL cholesterol and atherosclerosis, a variable relationship--a review of LCAT deficiency. Vasc Health Risk Manag. 2012. 8:357-61. [QxMD MEDLINE Link]. [Full Text].
Asztalos BF, Schaefer EJ, Horvath KV, et al. Role of LCAT in HDL remodeling: investigation of LCAT deficiency states. J Lipid Res. 2007 Mar. 48(3):592-9. [QxMD MEDLINE Link]. [Full Text].
Tietjen I, Hovingh GK, Singaraja R, Radomski C, McEwen J, Chan E, et al. Increased self-reported risk of coronary artery disease in Caucasians with extremely low HDL cholesterol due to mutations in ABCA1, APOA1, and LCAT. Biochim Biophys Acta. 2011 Aug 19. [QxMD MEDLINE Link].
Santamarina-Fojo S, Hoeg JM, Assmann G. Lecithin cholesterol acyltransferase deficiency and fish eye disease. Scriver CR, Sly WS, Childs B, et al, eds. Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001. vol 2: 2817-33.
Asada S, Kuroda M, Aoyagi Y, Bujo H, Tanaka S, Konno S, et al. Disturbed apolipoprotein A-I-containing lipoproteins in fish-eye disease are improved by the lecithin:cholesterol acyltransferase produced by gene-transduced adipocytes in vitro. Mol Genet Metab. 2011 Feb. 102(2):229-31. [QxMD MEDLINE Link].
Uehara Y, Tsuboi Y, Zhang B, et al. POPC/apoA-I discs as a potent lipoprotein modulator in Tangier disease. Atherosclerosis. 2008 Mar. 197(1):283-9. [QxMD MEDLINE Link].
Nicholls SJ, Ruotolo G, Brewer HB, Kane JP, Wang MD, Krueger KA, et al. Cholesterol Efflux Capacity and Pre-Beta-1 HDL Concentrations Are Increased in Dyslipidemic Patients Treated With Evacetrapib. J Am Coll Cardiol. 2015 Nov 17. 66 (20):2201-10. [QxMD MEDLINE Link].
Assmann G, von Eckardstein A, Brewer HB Jr. Familial analphalipoproteinemia: Tangier disease. Scriver CR, Sly WS, Childs B, et al, eds. Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001. Vol 2: 2937-60.
Herbert PN, Assmann G, Gotto AM Jr, et al. Familial lipoprotein deficiency (abetalipoproteinemia and Tangier disease). Stanbury JB, Wyngaarden JB, Fredrickson DS, et al, eds. The Metabolic Basis of Inherited Disease. New York, NY: McGraw-Hill; 1982.
Brites FD, Bonavita CD, De Geitere C, et al. Alterations in the main steps of reverse cholesterol transport in male patients with primary hypertriglyceridemia and low HDL-cholesterol levels. Atherosclerosis. 2000 Sep. 152(1):181-92. [QxMD MEDLINE Link].
Satta MA, Scoppola A, Melina D, et al. [The relationship between high-density lipoproteins, thromboxane B2 and arteriosclerosis in a case of primary hypoalphalipoproteinemia]. Minerva Med. 1989 Dec. 80(12):1345-9. [QxMD MEDLINE Link].
Carroll MD, Fryar CD, Kit BK. Total and High-density Lipoprotein Cholesterol in Adults: United States, 2011-2014. NCHS Data Brief. 2015 Dec. 1-8. [QxMD MEDLINE Link].
DeLong DM, DeLong ER, Wood PD, et al. A comparison of methods for the estimation of plasma low- and very low-density lipoprotein cholesterol. The Lipid Research Clinics Prevalence Study. JAMA. 1986 Nov 7. 256(17):2372-7. [QxMD MEDLINE Link].
Ordovas JM, Schaefer EJ, Salem D, et al. Apolipoprotein A-I gene polymorphism associated with premature coronary artery disease and familial hypoalphalipoproteinemia. N Engl J Med. 1986 Mar 13. 314(11):671-7. [QxMD MEDLINE Link].
Frohlich J, Westerlund J, Sparks D, et al. Familial hypoalphalipoproteinemias. Clin Invest Med. 1990 Aug. 13(4):202-10. [QxMD MEDLINE Link].
Godin DV, Garnett ME, Hoag G, et al. Erythrocyte abnormalities in a hypoalphalipoproteinemia syndrome resembling fish eye disease. Eur J Haematol. 1988 Aug. 41(2):176-81. [QxMD MEDLINE Link].
Rader DJ, deGoma EM. Approach to the patient with extremely low HDL-cholesterol. J Clin Endocrinol Metab. 2012 Oct. 97(10):3399-407. [QxMD MEDLINE Link]. [Full Text].
Barkowski RS, Frishman WH. HDL metabolism and CETP inhibition. Cardiol Rev. 2008 May-Jun. 16(3):154-62. [QxMD MEDLINE Link].
Barter PJ, Brewer HB Jr, Chapman MJ, et al. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol. 2003 Feb 1. 23(2):160-7. [QxMD MEDLINE Link]. [Full Text].
de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, et al. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation. 2002 May 7. 105(18):2159-65. [QxMD MEDLINE Link]. [Full Text].
Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003 Nov 5. 290(17):2292-300. [QxMD MEDLINE Link]. [Full Text].
Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998 Aug 19. 280(7):605-13. [QxMD MEDLINE Link]. [Full Text].
Lamon-Fava S, Postfai B, Diffenderfer M, et al. Role of the estrogen and progestin in hormonal replacement therapy on apolipoprotein A-I kinetics in postmenopausal women. Arterioscler Thromb Vasc Biol. 2006 Feb. 26(2):385-91. [QxMD MEDLINE Link]. [Full Text].
Eslick GD, Howe PR, Smith C, et al. Benefits of fish oil supplementation in hyperlipidemia: a systematic review and meta-analysis. Int J Cardiol. 2008 Sep 5. [QxMD MEDLINE Link].
AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011 Dec 15. 365 (24):2255-67. [QxMD MEDLINE Link]. [Full Text].
HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014 Jul 17. 371 (3):203-12. [QxMD MEDLINE Link]. [Full Text].
Patrice Wending. FDA Pulls Approval of Niacin, Fibrate in Combo with Statins. Heartwire from Medscape Medical News. 2016 Apr 15. Available at http://www.medscape.com/viewarticle/862022.
HDL-Atherosclerosis Treatment Study (HATS). Cardiosource: American College of Cardiology. Available at http://www.cardiosource.com/clinicaltrials/trial.asp?trialID=486. Accessed: 2/10/09.
Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 2 (ARBITER 2). Cardiosource: American College of Cardiology. Available at http://www.cardiosource.com/clinicaltrials/trial.asp?trialID=1144. Accessed: 2/10/09.
Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007 Nov 22. 357(21):2109-22. [QxMD MEDLINE Link]. [Full Text].
Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis inpatients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003 Nov 5. 290(17):2292-300. [QxMD MEDLINE Link]. [Full Text].
Parolini C, Marchesi M, Lorenzon P, et al. Dose-related effects of repeated ETC-216 (recombinant apolipoprotein A-I Milano/1-palmitoyl-2-oleoyl phosphatidylcholine complexes) administrations on rabbit lipid-rich soft plaques: in vivo assessment by intravascular ultrasound and magnetic resonance imaging. J Am Coll Cardiol. 2008 Mar 18. 51(11):1098-103. [QxMD MEDLINE Link].
Ibanez B, Vilahur G, Cimmino G, et al. Rapid change in plaque size, composition, and molecular footprint after recombinant apolipoprotein A-I Milano (ETC-216) administration: magnetic resonance imaging study in an experimental model of atherosclerosis. J Am Coll Cardiol. 2008 Mar 18. 51(11):1104-9. [QxMD MEDLINE Link].
Hernáez Á, Soria-Florido MT, Castañer O, et al. Leisure time physical activity is associated with improved HDL functionality in high cardiovascular risk individuals: a cohort study. Eur J Prev Cardiol. 2020 Jun 2. 2047487320925625. [QxMD MEDLINE Link].
Vega GL, Grundy SM. Comparison of lovastatin and gemfibrozil in normolipidemic patients with hypoalphalipoproteinemia. JAMA. 1989 Dec 8. 262(22):3148-53. [QxMD MEDLINE Link].
Ahumada Ayala M, Jimenez Villanueva C, Cardoso Saldana G, et al. [Hypoalphalipoproteinemia and atherosclerosis. Genetic and biochemical profile of 10 families]. Arch Inst Cardiol Mex. 1989 Jan-Feb. 59(1):9-18. [QxMD MEDLINE Link].
Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011 Dec 15. 365(24):2255-67. [QxMD MEDLINE Link].
Daum U, Leren TP, Langer C, et al. Multiple dysfunctions of two apolipoprotein A-I variants, apoA- I(R160L)Oslo and apoA-I(P165R), that are associated with hypoalphalipoproteinemia in heterozygous carriers. J Lipid Res. 1999 Mar. 40(3):486-94. [QxMD MEDLINE Link]. [Full Text].
Dioguardi N. [Familial hypoalphalipoproteinemia. Vergani's disease]. Minerva Med. 1983 Nov 16. 74(44):2659-64. [QxMD MEDLINE Link].
Hersberger M, von Eckardstein A. Low high-density lipoprotein cholesterol: physiological background, clinical importance and drug treatment. Drugs. 2003. 63(18):1907-45. [QxMD MEDLINE Link].
Jones PJ, Ntanios FY, Raeini-Sarjaz M, et al. Cholesterol-lowering efficacy of a sitostanol-containing phytosterol mixture with a prudent diet in hyperlipidemic men. Am J Clin Nutr. 1999 Jun. 69(6):1144-50. [QxMD MEDLINE Link].
Kort EN, Ballinger DG, Ding W, et al. Evidence of linkage of familial hypoalphalipoproteinemia to a novel locus on chromosome 11q23. Am J Hum Genet. 2000 Jun. 66(6):1845-56. [QxMD MEDLINE Link]. [Full Text].
Meco JF, Pinto X, Quintana E, et al. [Efficacy of hygienic and dietary therapy in coronary patients with isolated hypoalphalipoproteinemia]. An Med Interna. 1999 Dec. 16(12):620-5. [QxMD MEDLINE Link].
Mingpeng S, Zongli W. The protective role of high-density lipoproteins in atherosclerosis. Exp Gerontol. 1999. 34(4):539-48. [QxMD MEDLINE Link].
Mora S, Buring JE, Ridker PM, Cui Y. Association of high-density lipoprotein cholesterol with incident cardiovascular events in women, by low-density lipoprotein cholesterol and apolipoprotein b100 levels: a cohort study. Ann Intern Med. 2011 Dec 6. 155(11):742-50. [QxMD MEDLINE Link]. [Full Text].
Mott S, Yu L, Marcil M, et al. Decreased cellular cholesterol efflux is a common cause of familial hypoalphalipoproteinemia: role of the ABCA1 gene mutations. Atherosclerosis. 2000 Oct. 152(2):457-68. [QxMD MEDLINE Link].
Rader DJ. High-density lipoproteins as an emerging therapeutic target for atherosclerosis. JAMA. 2003 Nov 5. 290(17):2322-4. [QxMD MEDLINE Link].
Saku K, Zhang B, Shirai K, et al. Hyperinsulinemic hypoalphalipoproteinemia as a new indicator for coronary heart disease. J Am Coll Cardiol. 1999 Nov 1. 34(5):1443-51. [QxMD MEDLINE Link].
Schaefer EJ. Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency. Arteriosclerosis. 1984 Jul-Aug. 4(4):303-22. [QxMD MEDLINE Link].
Singh VN. Need for more aggressive statin use in various ethnic groups: Latino, Asian, and African American populations. Medscape Reference Feature Series - Lipid Newsletter. Oct 20, 2005. series 1(12):[Full Text].
Singh VN. The USDA "Food Pyramid" needs to go on a diet. Pinellas County Medical Society (PICOMESO) Journal. 2004. 43(4):3, 18-19.
Tall AR. Plasma high density lipoproteins. Metabolism and relationship to atherogenesis. J Clin Invest. 1990 Aug. 86(2):379-84. [QxMD MEDLINE Link]. [Full Text].
Third JL, Montag J, Flynn M, et al. Primary and familial hypoalphalipoproteinemia. Metabolism. 1984 Feb. 33(2):136-46. [QxMD MEDLINE Link].
Zema MJ. Gemfibrozil, nicotinic acid and combination therapy in patients with isolated hypoalphalipoproteinemia: a randomized, open-label, crossover study. J Am Coll Cardiol. 2000. 35(3):640-6. [QxMD MEDLINE Link].

Media Gallery

of 0

Author

Vibhuti N Singh, MD, MPH, FACC, FSCAI Clinical Assistant Professor, Division of Cardiology, University of South Florida College of Medicine; Director, Cardiology Division and Cardiac Catheterization Lab, Chair, Department of Medicine, Bayfront Medical Center, Bayfront Cardiovascular Associates; President, Suncoast Cardiovascular Research

Vibhuti N Singh, MD, MPH, FACC, FSCAI is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, Florida Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Yoram Shenker, MD Chief of Endocrinology Section, Veterans Affairs Medical Center of Madison; Interim Chief, Associate Professor, Department of Internal Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Wisconsin at Madison

Yoram Shenker, MD is a member of the following medical societies: American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for Physician Leadership, American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society, International Society for Clinical Densitometry, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Ghassem Pourmotabbed, MD, MD

Ghassem Pourmotabbed, MD, MD is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, Endocrine Society

Disclosure: Nothing to disclose.

Sections Low HDL Cholesterol (Hypoalphalipoproteinemia)
Overview
Presentation
Workup
Treatment
Medication
Follow-up
Questions & Answers
Tables
References

Variant	Molecular Defect	Inheritance	Metabolic Defect	Lipoprotein Abnormality	Clinical Features	Premature Atherosclerosis
Familial apo A-I	Apo deficiency	Autosomal codominant	Absent apo A-1 biosynthesis	HDL < 5 mg/dL; TGs normal	Planar xanthomas, corneal opacities	Yes
Familial apo A-I structural mutations	Abnormal apo A-I	Autosomal dominant	Rapid apo A-1 catabolism	HDL 15-30 mg/dL; TGs increased	Often none; sometimes corneal opacities	No
Familial LCAT	LCAT deficiency (complete)	Autosomal recessive	Rapid HDL catabolism	HDL < 10 mg/dL; TGs increased	Corneal opacities, anemia, proteinuria, renal insufficiency	No
Fish-eye disease	LCAT deficiency (partial)	Autosomal recessive	Rapid HDL catabolism	HDL < 10 mg/dL; TGs increased	Corneal opacities	No
Tangier disease	Unknown	Autosomal codominant	Very rapid HDL catabolism	HDL < 5 mg/dL; TGs usually increased	Corneal opacities, enlarged orange tonsils, hepatosplenomegaly, peripheral neuropathy	No to yes
Familial HA	Unknown	Autosomal dominant	Usually rapid HDL catabolism	HDL 15-35 mg/dL; TGs normal	Often none; sometimes corneal opacities	No to yes

Low HDL Cholesterol (Hypoalphalipoproteinemia) Clinical Presentation

History

Physical Examination

References

Tables

Contributor Information and Disclosures

What would you like to print?