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High HDL Cholesterol (Hyperalphalipoproteinemia)

  • Author: Vibhuti N Singh, MD, MPH, FACC, FSCAI; Chief Editor: George T Griffing, MD  more...
 
Updated: Jul 14, 2016
 

Background

High-density lipoprotein (HDL) is positively associated with a decreased risk of coronary heart disease (CHD). As defined by the US National Cholesterol Education Program Adult Treatment Panel III guidelines, an HDL cholesterol level (HDL-C) of 60 mg/dL or greater is a negative (protective) risk factor.[1] On the other hand, a high-risk HDL cholesterol level is described as one that is below 40 mg/dL. Randomized, controlled clinical trials have demonstrated that interventions to raise HDL cholesterol levels are associated with reduced CHD events. A prospective analysis by Mora et al investigated the link between cholesterol and cardiovascular events in women and found baseline HDL-C level was consistently and inversely associated with incident coronary and coronary vascular disease events across a range of low-density lipoprotein-cholesterol (LDL-C) values.[2]

The major apolipoproteins of HDL are apolipoprotein (apo) A-I and apo A-II, the alpha lipoproteins. An elevated concentration of apo A-I and apo A-II is called hyperalphalipoproteinemia (HALP), which is associated with a lower risk CHD. Conversely, hypoalphalipoproteinemia increases the risk of CHD. The levels at which HDL confers benefit or risk are not discrete, and the cut points are somewhat arbitrary, especially considering that HDL levels are, on average, higher in US women compared with men and higher in blacks compared with whites.

Elevated HDL levels are associated with low levels of very low-density lipoprotein cholesterol (VLDL) and triglyceride (TG) levels. LDL-C levels may be within the reference range or elevated. Persons with HALP do not have any unusual clinical features, and the condition should not be considered a disease entity but rather a fortuitous condition that can increase longevity because of the associated decreased incidence of CHD.[3]

HDL is more tightly controlled by genetic factors than are the other lipoproteins (ie, LDL, VLDL, intermediate-density lipoprotein [IDL], and chylomicrons). For example, in certain families, especially some families with Japanese ancestry, a genetic deficiency of cholesteryl ester transfer protein (CETP) is associated with strikingly elevated HDL cholesterol levels.[4]

However, environmental factors also have a significant impact on HDL levels. Factors that elevate HDL concentrations include chronic alcoholism, treatment with oral estrogen replacement therapy, extensive aerobic exercise, and treatment with niacin, statins, or fibrates.[5, 6, 7] On the other hand, smoking reduces levels of HDL cholesterol, while quitting smoking leads to a rise in the plasma HDL level.

Very high levels of HDL cholesterol have been reported to be atherogenic. The mechanism of this paradoxical effect is not entirely clear.

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Pathophysiology

Hyperalphalipoproteinemia (HALP) may be familial, including primary (without CETP deficiency) and otherwise (with CETP deficiency), or secondary.[8] Familial HALP (aside from the primary form) is a well-documented genetic form of hypercholesterolemia characterized by a deficiency of CETP, a key protein in the reverse cholesterol transport system that facilitates the transfer of cholesteryl esters from high-density lipoprotein (HDL) to beta lipoproteins. Primary HALP is a term used for familial elevated HDL cholesterol levels that are not due to CETP deficiency and for which the cause is unknown. Secondary HALP is due to environmental factors or medications.

Physiology

Plasma HDL is a small, spherical, dense lipid-protein complex that is half lipid and half protein. The lipid component consists of phospholipids, free cholesterol, cholesteryl esters, and triglycerides. The protein component includes apo A-I (molecular weight, 28,000) and apo A-II (molecular weight, 17,000). Other minor, but important, proteins are apo E and apo C, including apo C-I, apo C-II, and apo C-III.

HDL particles are heterogeneous. They can be classified as a larger, less dense HDL2 or a smaller, denser HDL3.[9] Normally, most of the plasma HDL is found in HDL3.[10] To add to the complexity of HDL classification, HDL is composed of 4 apolipoproteins per particle. HDL may be composed of apo A-I and apo A-II or of apo A-I alone. HDL2 is usually made up only of apo A-I, while HDL3 contains a combination of apo A-I and apo A-II. HDL particles that are less dense than HDL2 are rich in apo E.

The reverse cholesterol transport system

HDL serves as a chemical shuttle that transports excess cholesterol from peripheral tissues to the liver. This pathway is called the reverse cholesterol transport system. In this system, plasma HDL takes up cholesterol from the peripheral tissues, such as fibroblasts and macrophages. (A study by El Khoury et al indicated that in persons with HALP, macrophages have an increased plasma cholesterol efflux capacity.[11] ) This may occur by passive diffusion or may be mediated by the adenosine triphosphate (ATP) – binding cassette transporter 1. The latter interacts directly with free apo A-1, generating nascent, or so-called discoidal, HDL. Cholesterol undergoes esterification by lecithin-cholesterol acyltransferase (LCAT) to produce cholesteryl ester, which results in the production of the mature spherical HDL. Cholesterol is also taken up from triglyceride-rich lipoproteins in a process mediated by a phospholipid transfer protein (ie, CETP).[12, 13, 14, 15]

Cholesterol is then returned to the liver by multiple routes. In the first route, cholesterol esters may be transferred from HDL to the apo B–containing lipoproteins, such as very low-density lipoprotein (VLDL) or intermediate-density lipoprotein (IDL), by CETP. These lipoproteins undergo metabolism and subsequent uptake by the liver, primarily by a process mediated by the B,E receptor. In the second route, HDL particles may be taken up directly by the liver. In the third, free cholesterol may be taken up directly by the liver. Finally, HDL cholesterol esters may be selectively taken up via the scavenger receptor SR-B1.

If the hepatic uptake of VLDL and IDL is impaired, their cholesterol may be delivered back to peripheral tissues.

See Causes.

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Epidemiology

Frequency

United States

Hyperalphalipoproteinemia (HALP) is a common entity in the general population. A correct diagnosis would help to avoid unnecessary treatment of hypercholesterolemia in 5% of the population. The overall prevalence rate is 7.8%. In persons with HALP, primary HALP accounts for 92% of cases, and secondary HALP accounts for 7.9% of cases.

International

The incidence of hyperalphalipoproteinemia is unknown. The condition has been described in most populations, but few population-wide data are available.

Mortality/Morbidity

Hyperalphalipoproteinemia (HALP) may be associated with a decreased risk of coronary heart disease (CHD), as well as reduced morbidity and mortality.

The plasma high-density lipoprotein (HDL) level is inversely correlated with the prevalence of and mortality rates for CHD. Despite having HALP, however, some patients may still develop lesions in their coronary arteries. HDL with apo A-I is considered the most reliable parameter for predicting a reduced risk of atherosclerosis.[16, 17]

The most important mechanism by which HDL exerts its antiatherogenic role is the removal of excess cholesterol from peripheral cells and its transport to the liver, a process commonly termed the reverse cholesterol transport system. Several proteins are involved in this process, including ATP-binding cassette transporter 1, LCAT, CETP, and hepatic triglyceride lipase (see Pathophysiology).[18]

HDL also has antioxidant properties that may directly slow the atherogenic process.

Race

A somewhat lower prevalence of hyperalphalipoproteinemia (HALP) has been reported in Asian persons and Asian Indian populations.[19] Population studies (Lipid Research Clinic data) in the United States demonstrate racial differences in the prevalence of HALP, as follows[20] :

  • In randomly screened children aged 6-19 years who had age-, race-, and sex-specific total plasma cholesterol levels greater than or equal to 95th percentile levels, 7.8% of white males, 12.8% of white females, 25% of black males, and 17.2% of black females had hypercholesterolemia due to elevated high-density lipoprotein [HDL] cholesterol levels (but not due to elevated low-density lipoprotein [LDL] cholesterol levels) greater than age-, sex-, and race-specific 95th percentile levels. That is, they had HALP.
  • For adults aged 20-79 years, 4% of white men, 6.9% of white women, 13.3% of black men, and 13.3% of black women had predominant HALP, which accounted for their hypercholesterolemia.

Sex

Population studies have demonstrated a female predominance for hyperalphalipoproteinemia (Lipid Research Clinic data).[20, 21]

Age

The incidence of hyperalphalipoproteinemia appears to decrease with age. In a population survey, the following rates were reported:

  • In persons aged 20-29 years, the prevalence rate was 15.8%.
  • In persons aged 30-39 years, the prevalence rate was 8.4%.
  • In persons older than 40 years, the prevalence rate averaged 7.8%.
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Contributor Information and Disclosures
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.

Don S Schalch, MD Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics

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

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.

References
  1. 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. [Medline].

  2. 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. [Medline]. [Full Text].

  3. Ron D, Aviram M, Brook JG. High density lipoprotein in octogenarians. Biochem Med. 1983 Oct. 30(2):253-60. [Medline].

  4. Yamashita S, Maruyama T, Hirano K, et al. Molecular mechanisms, lipoprotein abnormalities and atherogenicity of hyperalphalipoproteinemia. Atherosclerosis. 2000. 152(2):271-85. [Medline].

  5. Miller M. Raising an isolated low HDL-C level: why, how, and when?. Cleve Clin J Med. 2003 Jun. 70(6):553-60. [Medline].

  6. Kakafika A, Athyros VG, Tziomalos K, et al. High density lipoprotein cholesterol and statin trials. Curr Med Chem. 2008. 15(22):2265-70. [Medline].

  7. Bermudez V, Cano R, Cano C, et al. Pharmacologic management of isolated low high-density lipoprotein syndrome. Am J Ther. 2008 Jul-Aug. 15(4):377-88. [Medline].

  8. Plengpanich W, Tongkobpetch S, Shotelersuk V, Le Goff W, Khovidhunkit W. Functional characterization of novel variants in the CETP promoter and the LIPC gene in subjects with hyperalphalipoproteinemia. Clin Chim Acta. 2013 Feb 1. 416:92-5. [Medline].

  9. Mendoza S, Lutmer RF, Glueck CJ. Composition of HDL-2 and HDL-3 in familial hyperalphalipoproteinemia. Atherosclerosis. 1976 Oct. 25(1):131-6. [Medline].

  10. Sich D, Saïdi Y, Giral P, et al. Hyperalphalipoproteinemia: characterization of a cardioprotective profile associating increased high-density lipoprotein2 levels and decreased hepatic lipase activity. Metabolism. 1998 Aug. 47(8):965-73. [Medline].

  11. El Khoury P, Plengpanich W, Frisdal E, Le Goff W, Khovidhunkit W, Guerin M. Improved plasma cholesterol efflux capacity from human macrophages in patients with hyperalphalipoproteinemia. Atherosclerosis. 2014 May. 234 (1):193-9. [Medline].

  12. Arai T, Tsukada T, Murase T, et al. Particle size analysis of high density lipoproteins in patients with genetic cholesteryl ester transfer protein deficiency. Clin Chim Acta. 2000. 301(1-2):103-17. [Medline].

  13. Ye D, Kraaijeveld AO, Grauss RW, et al. Reduced leucocyte cholesteryl ester transfer protein expression in acute coronary syndromes. J Intern Med. 2008 Sep 6. [Medline].

  14. Plengpanich W, Tongkobpetch S, Shotelersuk V, Le Goff W, Khovidhunkit W. Functional characterization of novel variants in the CETP promoter and the LIPC gene in subjects with hyperalphalipoproteinemia. Clin Chim Acta. 2013 Feb 1. 416:92-5. [Medline].

  15. Tietjen I, Hovingh GK, Singaraja RR, Radomski C, Barhdadi A, McEwen J, et al. Segregation of LIPG, CETP, and GALNT2 mutations in Caucasian families with extremely high HDL cholesterol. PLoS One. 2012. 7(8):e37437. [Medline]. [Full Text].

  16. Mingpeng S, Zongli W. The protective role of high-density lipoproteins in atherosclerosis. Exp Gerontol. 1999. 34(4):539-48. [Medline].

  17. Vigna GB, Satta E, Bernini F, Boarini S, Bosi C, Giusto L, et al. Flow-mediated dilation, carotid wall thickness and HDL function in subjects with hyperalphalipoproteinemia. Nutr Metab Cardiovasc Dis. 2014 Jul. 24(7):777-83. [Medline].

  18. Hirano K, Yamashita S, Kuga Y. Atherosclerotic disease in marked hyperalphalipoproteinemia. Combined reduction of cholesteryl ester transfer protein and hepatic triglyceride lipase. Arterioscler Thromb Vasc Biol. 1995 Nov. 15(11):1849-56. [Medline]. [Full Text].

  19. Shanker J, Perumal G, Rao VS, et al. Genetic studies on the APOA1-C3-A5 gene cluster in Asian Indians with premature coronary artery disease. Lipids Health Dis. 2008 Sep 19. 7(1):33. [Medline]. [Full Text].

  20. Marquez Contreras E, Casado Martinez JJ, Sanchez Ramos JL, et al. [Prevalence of hyperalphalipoproteinemia in the general population]. Med Clin (Barc). 1993 May 8. 100(18):699-701. [Medline].

  21. Kucharska-Newton AM, Rosamond WD, Mink PJ, et al. HDL-cholesterol and incidence of breast cancer in the ARIC cohort study. Ann Epidemiol. 2008 Sep. 18(9):671-7. [Medline].

  22. Deiana L, Pes GM, Carru C, et al. Extremely high HDL levels in a patient with multiple symmetric lipomatosis. Clin Chim Acta. 1993 Dec 31. 223(1-2):143-7. [Medline].

  23. Patsch W, Kuisk I, Glueck C. Lipoproteins in familial hyperalphalipoproteinemia. Arteriosclerosis. 1981 Mar-Apr. 1(2):156-61. [Medline].

  24. Glueck CJ, Fallat RW, Millett F. Familial hyperalphalipoproteinemia. Arch Intern Med. 1975 Aug. 135(8):1025-8. [Medline].

  25. van der Steeg WA, Hovingh GK, Klerkx AH, et al. Cholesteryl ester transfer protein and hyperalphalipoproteinemia in Caucasians. J Lipid Res. 2007 Mar. 48(3):674-82. [Medline]. [Full Text].

  26. Brousseau ME, Santamarina-Fojo S, Zech LA. Hyperalphalipoproteinemia in human lecithin cholesterol acyltransferase transgenic rabbits. In vivo apolipoprotein A-I catabolism is delayed in a gene dose-dependent manner. J Clin Invest. 1996 Apr 15. 97(8):1844-51. [Medline]. [Full Text].

  27. Gehrisch S, Kostka H, Tiebel M, et al. Mutations of the human hepatic lipase gene in patients with combined hypertriglyceridemia/hyperalphalipoproteinemia and in patients with familial combined hyperlipidemia. J Mol Med. 1999. 77(10):728-34. [Medline].

  28. Morrison JA, Khoury P, Laskarzewski P. Hyperalphalipoproteinemia in hypercholesterolemic adults and children. Trans Assoc Am Physicians. 1980. 93:230-43. [Medline].

  29. Saito F. A pedigree of homozygous familial hyperalphalipoproteinemia. Metabolism. 1984 Jul. 33(7):629-33. [Medline].

  30. Tall AR. Plasma high density lipoproteins. Metabolism and relationship to atherogenesis. J Clin Invest. 1990 Aug. 86(2):379-84. [Medline]. [Full Text].

 
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