eMedicine Specialties > Endocrinology > Metabolic Disorders

High HDL Cholesterol (Hyperalphalipoproteinemia)

Author: Vibhuti N Singh, MD, MPH, FACC, FSCAI, Director, Suncoast Cardiovascular Center; Chair, Cardiology Division and Cath Labs, Department of Medicine, Bayfront Medical Center; Clinical Assistant Professor, Division of Cardiology, University of South Florida College of Medicine
Coauthor(s): Elena Citkowitz, MD, PhD, FACP, Clinical Professor of Medicine, Yale University School of Medicine; Director, Cholesterol Management Center, Director, Cardiac Rehabilitation, Department of Medicine, Hospital of St Raphael
Contributor Information and Disclosures

Updated: Oct 17, 2008

Introduction

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 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.

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. Low-density lipoprotein (LDL) cholesterol 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.²

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.³

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.^4,5,6 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.

Pathophysiology

Hyperalphalipoproteinemia (HALP) may be familial — including primary (without CETP deficiency) and otherwise (with CETP deficiency) — or secondary. 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 HDL3.⁷ Normally, most of the plasma HDL is found in HDL3.⁸ 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. 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).^9,10

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.

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.¹¹

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).¹²

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.¹³ Population studies (Lipid Research Clinic data) in the United States demonstrate racial differences in the prevalence of HALP, as follows¹⁴ :

• 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).^14,15

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%.

Clinical

History

Hyperalphalipoproteinemia (HALP) has no specific symptoms. It is usually identified through the routine assessment of a lipid profile. Another member of a patient's family may have been found to have elevated high-density lipoprotein (HDL) cholesterol levels. Aside from its cardioprotective role, HALP is occasionally associated with the following symptoms and signs:

• Juvenile corneal opacification
• Multiple symmetric lipomatosis¹⁶
• History related to secondary causes
  • History of alcohol abuse
  • Treatment with medications such as oral estrogens, statins, niacin (ie, nicotinic acid), phenytoin, or fibrates (eg, bezafibrate, clofibrate, fenofibrate, gemfibrozil)^4,6
  • History of vigorous, sustained aerobic exercise (eg, long-distance running)

Physical

Patients with asymptomatic hyperalphalipoproteinemia (HALP) do not present with any significant physical findings. Rare patients may exhibit the following:

• Juvenile corneal opacification - This is described in patients with marked HALP.
• Multiple systemic lipomatosis - In rare cases, the development of multiple lipomas has been reported.

Causes

• Primary causes
  • Familial HALP - Familial HALP includes CETP deficiency, familial hepatic lipase deficiency, and primary HALP. A selective up-regulation of apo A-I production is one metabolic cause of familial HALP and leads to high plasma concentrations of HDL cholesterol, apo A-I, and lipoprotein A-I. It possibly may also result in protection from atherosclerotic coronary heart disease (CHD).^17,18 Familial HALP can involve premature corneal opacity, reduced hepatic lipase activity, and reduced uptake of HDL by lymphocytes.
  • Primary HALP - This is a term used for familial elevated HDL cholesterol levels that are not due to CETP deficiency. Epidemiologic studies have suggested that this syndrome is associated with a decreased risk for coronary artery disease and with increased longevity.
  • CETP deficiency - This asymptomatic, hereditary syndrome is caused by low CETP levels. Decreased CETP activity slows the transport of cholesteryl esters from HDL to apo B–containing lipoproteins. The condition is frequently observed in Japanese Americans. Clinical features include marked elevations of plasma HDL cholesterol in homozygotes (usually >100 mg/dL) and probably lower rates of CHD. In heterozygotes, the HDL levels are only moderately elevated. CETP deficiency has not yet been demonstrated to be associated with a decreased risk for atherosclerotic cardiovascular disease, and some experts do not consider this condition protective against cardiovascular disease.¹⁹
  • LCAT overexpression - Rarely, HALP has been reported to be due to LCAT overexpression. The activity of LCAT is increased in blood plasma and is associated with high levels of HDL. Reduction in the fractional catabolic rate of HDL is considered to be the predominant mechanism by which LCAT overexpression modulates HDL concentrations. Such patients may have reduced risk of developing CHD.
  • Up-regulation of apo A-I production - Selective up-regulation of apo A-I production is another cause of familial HALP. Affected individuals have elevated HDL cholesterol and apo A-I levels. Additionally, many patients have a reduced risk of atherosclerotic CHD.
• Secondary causes^4,6
  • Vigorous and sustained aerobic exercise (eg, long-distance running)
  • Regular, substantial alcohol consumption
  • Treatment with oral estrogens, particularly if not opposed by progestins
  • Treatment with statins
  • Treatment with nicotinic acid (niacin) at doses greater than 1 g/d
  • Treatment with phenytoin
  • Primary biliary cirrhosis
  • Treatment with fibrates (eg, bezafibrate, clofibrate, fenofibrate, gemfibrozil)

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