High HDL Cholesterol (Hyperalphalipoproteinemia)

Updated: Mar 22, 2017
  • Author: Vibhuti N Singh, MD, MPH, FACC, FSCAI; Chief Editor: George T Griffing, MD  more...
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Practice Essentials

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.

Workup and management

A plasma fasting lipid profile measures LDL, HDL, total cholesterol, and triglyceride levels. Lipids in plasma and in isolated lipoprotein fractions are quantified by enzymatic methods.

Whether or not imaging studies are appropriate depends on the clinical manifestations associated with HALP, if any.

Generally, patients with HALP are asymptomatic and require no medical therapy. However, patients with the corneal opacity sometimes associated with HALP may need an ophthalmologic evaluation.



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.


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.




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.


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


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.


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.


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


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%.