Low levels of high-density lipoprotein cholesterol (HDL), or hypoalphalipoproteinemia (HA), includes a variety of conditions, ranging from mild to severe, in which concentrations of alpha lipoproteins or high-density lipoprotein (HDL) are reduced. The etiology of HDL deficiencies ranges from secondary causes, such as smoking, to specific genetic mutations, such as Tangier disease and fish-eye disease.
HA has no clear-cut definition. An arbitrary cutoff is the 10th percentile of HDL cholesterol levels. A more practical definition derives from the theoretical cardioprotective role of HDL. The US National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) redefined the HDL cholesterol level that constitutes a formal coronary heart disease (CHD) risk factor. The level was raised from 35 mg/dL to 40 mg/dL for men and women. 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 CVD events across a range of LDL-C values. [1, 2]
For the metabolic syndrome in which multiple mild abnormalities in lipids, waist size (abdominal circumference), blood pressure, and blood sugar increase the risk of CHD, the designated HDL cholesterol levels that contribute to the syndrome are sex-specific. For men, a high-risk HDL cholesterol level is still less than 40 mg/dL, but for women, the high-risk HDL cholesterol level is less than 50 mg/dL. [3, 4, 5, 6]
A low HDL cholesterol level is thought to accelerate the development of atherosclerosis because of impaired reverse cholesterol transport and possibly because of the absence of other protective effects of HDL, such as decreased oxidation of other lipoproteins.
The common, mild forms of HA have no characteristic physical findings, but patients may have premature coronary heart or peripheral vascular disease, as well as a family history of low HDL cholesterol levels and premature CHD.
Therapy to raise the concentration of HDL cholesterol includes weight loss, smoking cessation, aerobic exercise, and pharmacologic management with niacin and fibrates.
This review addresses the pathogenesis and presenting features of, and the diagnostic tests, therapeutic interventions, and follow-up strategies for, low HDL cholesterol levels.
Plasma lipoproteins are macromolecular complexes of lipids and proteins that are classified by density and electrophoretic mobility. The structure of all lipoproteins is the same. The nonpolar lipids (ie, cholesterol ester, triglycerides [TGs]) reside in a core surrounded by more polar components (eg, free cholesterol, phospholipids, proteins). The proteins, termed apolipoproteins, play an important role in lipoprotein metabolism.
The major apolipoproteins of high-density lipoprotein (HDL) are alpha lipoproteins (ie, apolipoprotein A-I [apo A-I], apo A-II, apo A-IV), which are soluble and can move between different classes of lipoproteins. The beta lipoproteins are structural, are never complexed with HDL, and remain throughout the metabolism of the lipoproteins with which they are associated. Apo B-450 is associated with chylomicrons and their remnants, and apo B-100 is associated with low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), VLDL remnants, and intermediate-density lipoprotein.
HDL plays a major role in reverse cholesterol transport, mobilizing cholesterol from the periphery to promote return to the liver. In the general population, lower-than-normal HDL cholesterol levels are closely correlated with coronary heart disease (CHD); the risk of a coronary event is thought to increase 2% for every 1% decrease in HDL cholesterol. However, extreme HDL deficiencies caused by rare autosomal recessive disorders, including familial hypoalphalipoproteinemia (HA), familial lecithin-cholesterol acetyltransferase (LCAT) deficiency, and Tangier disease, do not always correlate with more frequent CHD. [7, 8]
Results from the Framingham Heart Study offspring cohort, where 3590 individuals without known cardiovascular disease were studied from 1987 to 2011, found that cardiovascular risk was not only associated with high-density lipoprotein cholesterol but also was associated with a combination HDL levels and levels of low-density lipoprotein cholesterol and triglycerides. [9, 10]
Familial hypoalphalipoproteinemia or familial apo A-I deficiency
Criteria for the definition of familial HAs are (1) a low HDL cholesterol level in the presence of normal VLDL cholesterol and LDL cholesterol levels, (2) an absence of diseases or factors to which HA may be secondary, and (3) the presence of a similar lipoprotein pattern in a first-degree relative.
Familial HA is a relatively common disorder and is frequently associated with decreased apo A-I production or increased apo A-I catabolism. Severe HDL deficiency can also be associated with a heterogeneous group of rare, autosomal-recessive lipoprotein disorders. The underlying molecular defects involve apo A-I, apo C-III, or apo A-IV. HDL in plasma is almost undetectable in persons with the familial apo A-I deficiency caused by deletions of the APOA1 gene, the HDL level being less than 10 mg/dL. Heterozygotes tend to have less severe reductions in HDL. 
Some patients with severe genetic HDL reductions manifest corneal opacities and xanthomas and have an increased risk of developing premature coronary atherosclerosis (ie, CHD). [12, 13] The molecular diagnosis can be made by specialized analysis, including electrophoresis of the plasma apolipoproteins and deoxyribonucleic acid (DNA) analysis to determine the mutation. Because raising plasma apo A-I or HDL-C levels is usually difficult in persons with these disorders, treatment should be directed toward lowering the level of non-HDL cholesterol.
In some patients, this condition occurs as a result of certain nonsense mutations that affect the generation of the apo A-I molecule. These mutations are a very rare cause of low HDL cholesterol levels (usually 15-30 mg/dL). An example is APOA1 Milano, inherited as an autosomal dominant trait, which is not associated with an increased risk of premature CHD despite low HDL levels. Other than corneal opacities, most of these patients do not exhibit many clinical sequelae related to the APOA1 mutations. Certain other APOA1 mutations have been found in association with systemic amyloidosis, and the mutant APOA1 gene has been located within the amyloid plaque.
Familial lecithin-cholesterol acyltransferase (LCAT) deficiency
This is a very rare autosomal recessive disorder characterized by corneal opacities, normochromic anemia, and renal failure in young adults. Approximately 30 kindreds and a number of mutations have been reported. LCAT deficiency results in decreased esterification of cholesterol to cholesteryl esters on HDL particles. This in turn results in an accumulation of free cholesterol on lipoprotein particles and in peripheral tissues, such as the cornea, red blood cells, renal glomeruli, and vascular walls. At present, no effective method has been found to increase plasma LCAT levels; therefore, therapy is limited to (1) dietary restriction of fat to prevent the development of complications and (2) management of complications (eg, renal transplant for advanced renal disease). [14, 15]
Two kinds of genetic LCAT deficiencies have been reported. The first is complete (or classic) LCAT deficiency. Complete LCAT deficiency is manifested by anemia, increased proteinuria, and renal failure. The diagnosis can be made based on the results of LCAT quantification and cholesterol esterification activity in the plasma in certain specialized laboratories. The second type of deficiency is partial LCAT deficiency (fish-eye disease). [16, 17] Partial LCAT deficiency has known clinical sequelae. Progressive corneal opacification, very low plasma levels of HDL cholesterol (usually < 10 mg/dL), and variable hypertriglyceridemia are characteristic of partial and classic LCAT deficiency. 
The risk of atherosclerosis is not usually associated with an increased risk of CHD. Similarly, LCAT-deficient animal models do not demonstrate an increased prevalence of atherosclerosis.
Tangier disease is an autosomal codominant disorder that causes a complete absence or extreme deficiency of HDL. LDL cholesterol levels are also usually reduced. The disease is characterized by the presence of orange tonsils, peripheral neuropathy, splenomegaly, discoloration of the rectal mucosa, hepatomegaly, opacities, premature CHD, and other abnormalities. Although the underlying mutation is not yet well defined, in some subjects the condition is caused by mutations of the adenosine triphosphate (ATP) – binding cassette transporter 1, which is involved in the passage of cholesterol from within the cells to outside the cells (efflux). [18, 19] Cholesteryl esters are deposited in the reticuloendothelial system.
Patients with Tangier disease also may exhibit accelerated HDL catabolism. Their HDL cholesterol levels are usually lower than 5 mg/dL. Their apo A-I levels are also very low. This condition has no specific treatment. [20, 21]
Components of plasma high-density lipoprotein
Plasma HDL is a small, dense, spherical lipid-protein complex, with the lipid and protein components each making up half. The major lipids are phospholipid, cholesterol, cholesteryl esters, and TGs. The major proteins include apo A-I (molecular weight, 28,000) and apo A-II (molecular weight, 17,000). Other minor, albeit 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 into larger, less dense HDL2 and smaller, denser HDL3. Normally, most HDL is present as HDL3. However, individual variability in HDL levels in humans is usually due to different amounts of HDL2.
Reverse cholesterol transport system
HDL removes cholesterol from the peripheral tissues, such as fibroblasts and macrophages, and it is esterified by LCAT. The cholesteryl ester thus produced is transferred from the HDL to apo B – containing lipoproteins, such as VLDL, intermediate-density lipoprotein, and LDL, by a key protein termed cholesteryl ester transport protein in the liver. The HDL itself becomes enriched with TGs and subsequently becomes hydrolyzed by hepatic lipase. By this mechanism, the HDL finally becomes smaller again and is ready to scavenge more cholesterol. This pathway is called the reverse cholesterol transport system.
Therefore, HA represents a clinical condition in which the reverse cholesterol transport system functions suboptimally, causing an increased tendency to develop atherosclerotic lesions. 
Table. Hypoalphalipoproteinemia (Open Table in a new window)
|Variant||Molecular Defect||Inheritance||Metabolic Defect||Lipoprotein Abnormality||Clinical Features||Premature Atherosclerosis|
|Familial apo A-I||Apo deficiency||Autosomal codominant||Absent apo A-1 biosynthesis||HDL < 5 mg/dL; TGs normal||Planar xanthomas, corneal opacities||Yes|
|Familial apo A-I structural mutations||Abnormal apo A-I||Autosomal dominant||Rapid apo A-1 catabolism||HDL 15-30 mg/dL; TGs increased||Often none; sometimes corneal opacities||No|
|Familial LCAT||LCAT deficiency (complete)||
|Rapid HDL catabolism||HDL < 10 mg/dL; TGs increased||Corneal opacities, anemia, proteinuria, renal insufficiency||No|
|Fish-eye disease||LCAT deficiency (partial)||Autosomal recessive||Rapid HDL catabolism||HDL < 10 mg/dL; TGs increased||Corneal opacities||No|
|Tangier disease||Unknown||Autosomal codominant||Very rapid HDL catabolism||HDL < 5 mg/dL; TGs usually increased||Corneal opacities, enlarged orange tonsils, hepatosplenomegaly, peripheral neuropathy||No to yes|
|Familial HA||Unknown||Autosomal dominant||Usually rapid HDL catabolism||HDL 15-35 mg/dL; TGs normal||Often none; sometimes corneal opacities||No to yes|
The variant apo A-I Milano, as well as the less well-known variants apo A-I Marburg, apo A-I Giessen, apo A-I Munster, and apo A-I Paris, cause HA but do not seem to increase the risk of atherosclerosis.
Hypoalphalipoproteinemia is frequently found in patients with coronary heart disease (CHD). Research indicates that 58% of patients with CHD have high-density lipoprotein (HDL) cholesterol levels below the 10th percentile of normal values.
A National Center for Health Statistics (NCHS) data brief found that the percentage of adults with low HDL cholesterol dropped from 21.3% between 2009 and 2010 to approximately 20% between 2011 and 2014. 
At present, the prevalence of inheritance and of underlying defects in the familial disorder are unknown. Overall, however, primary and secondary hypoalphalipoproteinemia are common.
Hypoalphalipoproteinemia (HA) is associated with an increased risk of recurrent coronary episodes and mortality caused by coronary heart disease (CHD), and it constitutes a significant risk factor for the development of premature (accelerated) atherosclerosis.
In general, approximately 14 million people in the United States have CHD, many of whom exhibit associated HA. CHD remains the most common cause of death in the industrialized world. Approximately 1.5 million acute myocardial infarctions (MIs) occur each year in the United States; of patients experiencing acute MI, 500,000 die (almost 33%). Survivors experience an ever-increasing incidence of congestive heart failure, arrhythmias, and other forms of morbidity.
The incidence of stroke is also quite high. An estimated 600,000 new and recurrent cases of stroke occur each year, with 160,000 deaths per year. Stroke has become a leading cause of serious, long-term disability. Approximately 4.4 million stroke survivors live in the United States today; stroke not only exacts a huge cost in human suffering, it takes a financial toll as well, with the care of patients who have suffered a stroke reaching approximately $45.3 billion.
Peripheral vascular disease also affects many individuals. Approximately 50% of patients who report claudication have peripheral vascular disease.
Hypoalphalipoproteinemia (HA) has been described in persons of all races. While no particular race predilection has been noted, some literature suggests that a higher prevalence of HA exists in Asian Indians.
Women tend to have a somewhat lower frequency of hypoalphalipoproteinemia than do men. Whether this finding is a reflection of hormonal differences is not clear.
Young boys and girls have similar high-density lipoprotein (HDL) cholesterol levels, but after male puberty, these levels decrease in males, remaining lower than those in females for all subsequent age groups.
What would you like to print?