Laboratory Studies

Several studies have found that the vascular effects of high-density lipoprotein (HDL) vary widely and do not always correlate with HDL concentrations in blood. In contrast to healthy individuals’ HDL, research found that HDL in patients with CHD, kidney disease, or diabetes demonstrated no protective vascular effects and was even thought to have some harmful effects. In acute and chronic diseases, the HDL composition itself changes, undergoing modification in complex ways. This needs to be remembered when interpreting lipid panel results, as it may be misleading to assume an equivalence between HDL levels and “good cholesterol.”^[2]Currently available blood assays cannot determine the functionality of HDL cholesterol (HDL-C) but can only quantify it in plasma; they may in future be replaced by assays that can assess the composition and functionality of HDL-C.

Prior consumption of food has little effect on the determination of HDL, with postprandial blood samples usually yielding results that can be well interpreted.^{[2, 15]}

Plasma fasting lipid profile

A plasma fasting lipid profile measures low-density lipoprotein (LDL), HDL, total cholesterol, and triglyceride levels.

Lipids in plasma and in isolated lipoprotein fractions are quantified by enzymatic methods. HDL cholesterol levels are determined using a phosphotungstic/magnesium chloride reagent to precipitate the apo B–containing lipoproteins; cholesterol is enzymatically measured in the supernatant. LDL cholesterol levels are calculated using the Friedewald formula or may be measured directly using enzymatic methods.

Plasma HDL apolipoproteins

Studies of HDL apolipoproteins are not routinely performed clinically, but they may be useful research assays. Some clinicians use ratios of apo A-I to apo B-100 for risk assessment, but these measurements are quite expensive and have proven to be no more accurate than the measurement of the ratio of total cholesterol to HDL cholesterol. Measurement of apo C, apo D, and apo E concentrations is not clinically useful.

Apo A lipoproteins include apo A-I, apo A-II, and apo A-IV. Apo C lipoproteins include apo C-I, apo C-II, and apo C-III.

Other apolipoproteins

Other apolipoproteins include apo D and apo E.

Imaging Studies

Whether or not imaging studies are appropriate depends on the clinical manifestations associated with hyperalphalipoproteinemia (HALP), if any. Patients with HALP-related corneal opacification may require ophthalmoscopic examination and corneal or intraocular imaging.

Other Tests

Studies to assess CTEP or hepatic lipase activity are not routinely performed clinically, but they may be useful research assays.

Density ultracentrifugation can be used to isolate and measure high-density lipoprotein (HDL) levels directly.

Nuclear magnetic resonance measurements of HDL levels are used in some specialized laboratories. HDL2 and HDL3 subfraction measurements can also be performed in the specialized laboratories involved in research studies.

A study by Minhas et al suggested that in patients with hyperalphalipoproteinemia, evaluation of cardiovascular disease risk using the QRISK2 calculator be performed using standard population mean HDL values rather than actual measured HDL to avoid underestimation of disease risk. The report found a statistically significant difference between scores using the two types of measurements.^[40]

Procedures

No procedures are usually required.

Histologic Findings

In rare cases of hyperalphalipoproteinemia in which patients have multiple lipomatosis syndrome, histologic examinations may be performed on biopsy specimens. The findings are usually consistent with lipoma.

Treatment & Management

Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989 Jan. 79 (1):8-15. [QxMD MEDLINE Link].
Marz W, Kleber ME, Scharnagl H, et al. HDL cholesterol: reappraisal of its clinical relevance. Clin Res Cardiol. 2017 Sep. 106 (9):663-75. [QxMD MEDLINE Link]. [Full Text].
Giammanco A, Noto D, Barbagallo CM, et al. Hyperalphalipoproteinemia and Beyond: The Role of HDL in Cardiovascular Diseases. Life (Basel). 2021 Jun 18. 11 (6):[QxMD MEDLINE Link]. [Full Text].
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].
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].
Emerging Risk Factors Collaboration, Di Angelantonio E, Sarwar N, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009 Nov 11. 302 (18):1993-2000. [QxMD MEDLINE Link]. [Full Text].
van der Steeg WA, Holme I, Boekholdt SM, et al. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies. J Am Coll Cardiol. 2008 Feb 12. 51 (6):634-42. [QxMD MEDLINE Link]. [Full Text].
Bowe B, Xie Y, Xian H, Balasubramanian S, Zayed MA, Al-Aly Z. High Density Lipoprotein Cholesterol and the Risk of All-Cause Mortality among U.S. Veterans. Clin J Am Soc Nephrol. 2016 Oct 7. 11 (10):1784-93. [QxMD MEDLINE Link]. [Full Text].
Bartlett J, Predazzi IM, Williams SM, 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]. [Full Text].
Ron D, Aviram M, Brook JG. High density lipoprotein in octogenarians. Biochem Med. 1983 Oct. 30(2):253-60. [QxMD MEDLINE Link].
Yamashita S, Maruyama T, Hirano K, et al. Molecular mechanisms, lipoprotein abnormalities and atherogenicity of hyperalphalipoproteinemia. Atherosclerosis. 2000. 152(2):271-85. [QxMD MEDLINE Link].
Miller M. Raising an isolated low HDL-C level: why, how, and when?. Cleve Clin J Med. 2003 Jun. 70(6):553-60. [QxMD MEDLINE Link].
Kakafika A, Athyros VG, Tziomalos K, et al. High density lipoprotein cholesterol and statin trials. Curr Med Chem. 2008. 15(22):2265-70. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Nordestgaard BG, Langsted A, Mora S, et al. Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentration cut-points-a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. Eur Heart J. 2016 Jul 1. 37 (25):1944-58. [QxMD MEDLINE Link]. [Full Text].
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. [QxMD MEDLINE Link].
Mendoza S, Lutmer RF, Glueck CJ. Composition of HDL-2 and HDL-3 in familial hyperalphalipoproteinemia. Atherosclerosis. 1976 Oct. 25(1):131-6. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [Full Text].
NCD Risk Factor Collaboration . National trends in total cholesterol obscure heterogeneous changes in HDL and non-HDL cholesterol and total-to-HDL cholesterol ratio: a pooled analysis of 458 population-based studies in Asian and Western countries. Int J Epidemiol. 2019 Jul 18. [QxMD MEDLINE Link]. [Full Text].
Mingpeng S, Zongli W. The protective role of high-density lipoproteins in atherosclerosis. Exp Gerontol. 1999. 34(4):539-48. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [Full Text].
Takaeko Y, Matsui S, Kajikawa M, et al. Association of extremely high levels of high-density lipoprotein cholesterol with endothelial dysfunction in men. J Clin Lipidol. 2019 Jun 20. [QxMD MEDLINE Link]. [Full Text].
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. [QxMD MEDLINE Link]. [Full Text].
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. [QxMD MEDLINE Link].
Ozaki A, Bravo-Jaimes K, Smotherman C, Kraemer DF, Samura A, Velarde GP. Sex and Racial Differences in High-Density Lipoprotein Levels in Acute Coronary Syndromes. Am J Med Sci. 2021 May 4. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Patsch W, Kuisk I, Glueck C. Lipoproteins in familial hyperalphalipoproteinemia. Arteriosclerosis. 1981 Mar-Apr. 1(2):156-61. [QxMD MEDLINE Link].
Glueck CJ, Fallat RW, Millett F. Familial hyperalphalipoproteinemia. Arch Intern Med. 1975 Aug. 135(8):1025-8. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [Full Text].
Wakabayashi I. Difference in sensitivities of blood HDL cholesterol and LDL cholesterol levels to alcohol in middle-aged Japanese men. Alcohol. 2018 Mar. 67:45-50. [QxMD MEDLINE Link].
Jan CF, Chang HC, Tantoh DM, et al. Duration-response association between exercise and HDL in both male and female Taiwanese adults aged 40 years and above. Oncotarget. 2018 Jan 5. 9 (2):2120-7. [QxMD MEDLINE Link].
Pitanga FJG, Griep RH, Almeida MDC, et al. Association between Leisure Time Physical Activity and HDL-C in the Elsa-Brasil Study Participants: Are There Any Gender Differences in the Dose-Response Effect?. Arq Bras Cardiol. 2021 Jul 2. [QxMD MEDLINE Link]. [Full Text].
Minhas JS, Patel P, Gupta PK. Limitations of a Cardiac Risk (QRISK2) Calculator in Patients with High Density Lipoprotein (HDL). High Blood Press Cardiovasc Prev. 2016 Mar. 23 (1):47-50. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [Full Text].
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. [QxMD MEDLINE Link].
Morrison JA, Khoury P, Laskarzewski P. Hyperalphalipoproteinemia in hypercholesterolemic adults and children. Trans Assoc Am Physicians. 1980. 93:230-43. [QxMD MEDLINE Link].
Saito F. A pedigree of homozygous familial hyperalphalipoproteinemia. Metabolism. 1984 Jul. 33(7):629-33. [QxMD MEDLINE Link].
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].

Media Gallery

of 0

Author

Basma Abdulhadi, MD Fellow, Department of Medicine, Division of Endocrinology, University of Alabama School of Medicine

Basma Abdulhadi, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Clinical Endocrinologists, Endocrine Society

Disclosure: Nothing to disclose.

Coauthor(s)

Catherine Anastasopoulou, MD, PhD, FACE Associate Professor of Medicine, The Steven, Daniel and Douglas Altman Chair of Endocrinology, Sidney Kimmel Medical College of Thomas Jefferson University; Einstein Endocrine Associates, Einstein Medical Center

Catherine Anastasopoulou, MD, PhD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American Society for Bone and Mineral Research, Endocrine Society, Philadelphia Endocrine Society

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 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.

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.