Practice Essentials
While it has been proven via multiple studies that elevated levels of low-density lipoprotein (LDL) contribute to the development of atherosclerosis, high-density lipoprotein (HDL) is widely thought to have atheroprotective effects. Results from multiple epidemiologic studies of healthy populations (most importantly, from the Framingham Heart Study) have given rise to the idea that high HDL levels protect against coronary heart disease (CHD). Patients with known CHD have been found to have lower levels of HDL. [1, 2, 3] 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.
As defined by the US National Cholesterol Education Program Adult Treatment Panel III guidelines, an HDL-C level of 60 mg/dL or greater is a negative (protective) risk factor. [4] On the other hand, a high-risk HDL-C level is described as being below 40 mg/dL. Randomized, controlled clinical trials have demonstrated that interventions to raise HDL-C 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 that the baseline HDL-C level was consistently and inversely associated with incident coronary and coronary vascular disease events across a range of LDL-C values. [5]
Evidence from animal experiments indicates that HDL has anti-atherosclerotic effects. Fatty-streak formation was inhibited by HDL administration in rabbits fed an atherogenic diet. Inhibition of atherogenesis was also found in cholesterol-fed rabbits who received an infusion of apolipoprotein (apo) A-I Milano. [2]
However, although low levels of HDL predict increased cardiovascular risk, particularly in healthy individuals with no history of cardiovascular events, the relationship between HDL and CHD risk is complex, with HDL-C and cardiovascular disease having a nonlinear relationship. For example, research found that HDL levels above approximately 60 mg/dL showed no further improvement in prognosis, and the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk and IDEAL (Incremental Decrease in End Points through Aggressive Lipid Lowering) studies showed that very high levels of HDL may actually be associated with an increased risk of atherosclerotic disease. [6, 7, 2]
A study of over 1 million US veterans showed a U-shaped relationship between HDL and total mortality, with 50 mg/dL as the level associated with the lowest mortality. [8, 2] In addition, an analysis of the Framingham study demonstrated that LDL and triglyceride levels modify HDL’s predictive value; CHD risk was found to be higher when low HDL was combined with high LDL and/or triglycerides as compared with the presence of low HDL levels alone. [9, 2]
With mounting research suggesting that HDL cholesterol has a U-shaped association with mortality risk, a retrospective study by Ishibashi et al indicated that the relationship between HDL cholesterol and cardiovascular disease outcomes (specifically, myocardial infarction, stroke, and all-cause death) is linked to the presence of diabetes mellitus. In persons with diabetes, an HDL cholesterol level of 90 mg/dL or above was associated with an increased likelihood of cardiovascular disease outcomes, while in individuals with a normal fasting plasma glucose (FPG) or prediabetes, no such relationship was seen. With regard to low HDL cholesterol levels, the investigators found that the association with increased cardiovascular disease outcomes existed no matter what the FPG level was but that the relationship was more pronounced as FPG levels increased. [10]
The relationship between HDL and CHD risk is also confounded by the presence of pro-atherogenic and inflammatory markers. [2] Moreover, 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 than in men and higher in blacks than in whites.
Therefore, the practice of measuring HDL levels and using them to predict CHD risk is not accurate, because a high HDL level may not necessarily mean reduced risk. [2]
HDL is plasma’s smallest and densest lipoprotein. The major apolipoproteins of HDL are apo A-I and apo A-II, the alpha lipoproteins. An elevated concentration of apo A-I and apo A-II, known as hyperalphalipoproteinemia (HALP), is associated with a lower risk of CHD. Conversely, hypoalphalipoproteinemia increases the chances of CHD development. [2] HALP generally does not produce any unusual clinical features (although corneal opacity has been associated with the condition), and it should not be considered a disease entity but rather a fortuitous condition that can increase longevity because of the related decrease in CHD incidence. [11]
HDL plays an important role in transporting cholesterol from the peripheral tissues to the liver, where it can be excreted; this process is known as reverse cholesterol transport (RCT). (The liver is the main organ for excretion of cholesterol, doing so either directly or by converting cholesterol into bile acids.) It is important to remember that most HDL measured in the blood is derived from the liver and intestine. Therefore, the concentration of HDL in plasma does not reflect cholesterol efflux from blood vessels or the efficiency of RCT. Moreover, HDL function in RCT is not mirrored by HDL measurements. [2]
HDL is more tightly controlled by genetic factors than are the other lipoproteins (ie, LDL, very–low-density lipoprotein (VLDL), intermediate-density lipoprotein [IDL], 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-C levels. [12]
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. [13, 14, 15] On the other hand, smoking reduces levels of HDL-C, while quitting smoking leads to a rise in the plasma HDL level.
Workup and management
Typically, a fasting plasma lipid profile is ordered to measure LDL, HDL, total cholesterol, and triglyceride levels. Lipids in plasma and in isolated lipoprotein fractions are quantified by enzymatic methods. Prior consumption of food has little effect on the determination of HDL, with postprandial blood samples usually yielding results that can be well interpreted. [16, 2] Current clinically available techniques can determine the cholesterol content, but not the biologic function, of HDL particles. [2]
Additional testing, for metabolic and inflammatory pathologies, should be triggered by the presence of low HDL levels. [2]
Whether or not imaging studies are appropriate depends on the clinical manifestations, if any, associated with HALP.
As previously stated, patients with HALP generally are asymptomatic and require no medical therapy. However, patients with the corneal opacity sometimes associated with the condition may need an ophthalmologic evaluation.
Pathophysiology
Hyperalphalipoproteinemia (HALP) may be familial, including primary (without CETP deficiency) and otherwise (with CETP deficiency), or secondary. [17] 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 (RCT) 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. [18] Normally, most of the plasma HDL is found in HDL3. [19] 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 RCT 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. [20] ) 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-I, 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). [21, 22, 23, 24]
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.
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.
A pooled analysis by the NCD Risk Factor Collaboration of 458 population-based studies covering 23 Asian and Western countries determined that in a number of Western nations, as well as in Japan and South Korea, the mean ratio of total-to-HDL cholesterol has declined since 1980, with the reduction in Swiss men being approximately 0.7 per decade between 1980 and 2015. (In contrast, China saw an increase in the ratio.) Also from about 1980 to 2015, HDL-C levels in Japan and South Korea saw a per-decade rise of between 0.04 mmol/L (South Korean men) and 0.17 mmol/L (Japanese women). [25]
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. [26, 27]
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 (RCT). Several proteins are involved in this process, including ATP-binding cassette transporter 1, LCAT, CETP, and hepatic triglyceride lipase (see Pathophysiology). [28]
HDL also has antioxidant properties that may directly slow the atherogenic process.
Despite HDL-C’s link to reduced CHD risk, a study by Takaeko et al suggested that extremely high HDL-C levels (80 mg/dL or above) can actually harm vascular function. The report, which involved adult males, found an association between such HDL-C concentrations and a significant decrease in flow-mediated vasodilation. [29]
Race
A somewhat lower prevalence of hyperalphalipoproteinemia (HALP) has been reported in Asian persons and Asian Indian populations. [30] Population studies (Lipid Research Clinic data) in the United States demonstrate racial differences in the prevalence of HALP, as follows [31] :
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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.
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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.
A study by Ozaki et al of emergency department patients with an acute coronary syndrome found high HDL cholesterol levels (>40 mg/dL; measured within 72 hours of presentation) to occur more frequently in women and Blacks than in men and Whites. [32]
Sex
Population studies have demonstrated a female predominance for hyperalphalipoproteinemia (Lipid Research Clinic data). [31, 33]
The aforementioned study by Ozaki and colleagues of emergency department patients with an acute coronary syndrome found that although in Whites, HDL cholesterol levels differed significantly between males and females, the same was not true for Blacks. Higher HDL cholesterol levels were also associated with the absence coronary artery disease and diabetes in the study subjects. [32]
Age
The incidence of hyperalphalipoproteinemia appears to decrease with age. In a population survey, the following rates were reported:
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In persons aged 20-29 years, the prevalence rate was 15.8%.
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In persons aged 30-39 years, the prevalence rate was 8.4%.
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In persons older than 40 years, the prevalence rate averaged 7.8%.
