Low HDL Cholesterol (Hypoalphalipoproteinemia)

Updated: May 21, 2021
Author: Vibhuti N Singh, MD, MPH, FACC, FSCAI; Chief Editor: George T Griffing, MD 


Practice Essentials

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.

Signs and symptoms

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.

See Presentation for more detail.


Laboratory studies

Laboratory studies used in the workup of HA include the following:

  • Routine blood tests (eg, chemistry profile)

  • Liver function tests

  • Thyroid profile

  • Plasma fasting lipid profile

  • Plasma lipid subfractions

Imaging studies

Patients with corneal opacification may require ophthalmoscopic examination and corneal or intraocular imaging.

Patients with premature coronary atherosclerosis may need the following:

  • Chest radiograph

  • Echocardiogram

  • Nuclear (radionuclide) stress test

  • Stress echocardiography

  • Electron beam (ultrafast) computed tomography (CT) scan

  • Coronary angiography by cardiac catheterization

Other tests

Other tests that may be included in the workup of HA are as follows:

  • Electrocardiogram (ECG)

  • Exercise (treadmill) stress test

  • Evaluation of HDL subfractions

  • Measurement of the LCAT enzymatic activity

  • Apo A-I, apo A-II, and HDL subfractions

  • Genetic studies, including chromosomal studies

  • Thromboxane A2 levels

  • Decreased erythrocyte osmotic fragility

See Workup for more detail.


Therapy to raise the concentration of HDL cholesterol includes weight loss, smoking cessation, aerobic exercise, and pharmacologic management with niacin and fibrates.

See Treatment and Medication for more detail.

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

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.[11]

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.[14]

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

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.[22]

Table. Hypoalphalipoproteinemia (Open Table in a new window)


Molecular Defect


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


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


Familial LCAT

LCAT deficiency (complete)



Rapid HDL catabolism

HDL < 10 mg/dL; TGs increased

Corneal opacities, anemia, proteinuria, renal insufficiency


Fish-eye disease

LCAT deficiency (partial)

Autosomal recessive

Rapid HDL catabolism

HDL < 10 mg/dL; TGs increased

Corneal opacities


Tangier disease


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


Autosomal dominant

Usually rapid HDL catabolism

HDL 15-35 mg/dL; TGs normal

Often none; sometimes corneal opacities

No to yes


Variant apolipoproteins

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 (HA) may be caused by familial or primary and secondary disorders that are associated with low plasma levels of high-density lipoprotein (HDL) cholesterol.

Familial or primary causes

Decreased or absent synthesis of apo A-I due to a gene defect is the cause of apo A-I/apo C-III and apo A-I/apo C-III/apo A-IV deficiency. However, the etiology of the low levels of HDL is unclear for most of the remaining familial HAs. Increased catabolism, decreased synthesis, and altered equilibration of HDL between intravascular and extravascular spaces have all been suggested as underlying causes of low plasma HDL levels. Whatever the cause, these disorders are associated with altered HDL composition and altered equilibration of cholesterol, among the various lipoprotein classes. Familial or primary causes include the following:

  • Familial apo A-I deficiency and structural mutations

  • Familial lecithin-cholesterol acetyltransferase (LCAT) deficiency

  • Tangier disease

  • Miscellaneous

    • Familial HDL deficiency

    • Familial apo A-I and apo C-III deficiency (formerly known as apo A-I absence)

    • Familial deficiency of apo A-I and apo C-III

    • Fish eye disease (partial LCAT deficiency)

    • Familial HA

    • Apo A-I variants (apo A-I Milano, apo A-I Marburg, apo A-I Giessen, apo A-I Munster)

Secondary causes

Secondary causes of HA include the following:

  • Obesity

  • Physical inactivity

  • Type 2 diabetes

  • Cigarette smoking

  • End-stage renal disease

  • Hypertriglyceridemia

  • Probucol

  • Androgens

  • Progestins

  • High-dose thiazide diuretics

  • High-dose beta blockers

  • Very low-fat diet

  • Dysglobulinemia

  • Severe liver disease

  • Malabsorption

  • Malnutrition

  • Severe inflammatory disease

Miscellaneous causes

Data in the literature suggest that some cases of HA involve an increase in thromboxane B2 together with an increased risk of atherosclerosis. Satta and colleagues described a 32-year-old man who revealed clinical and biochemical features strongly indicative of this pathology (see Histologic Findings).[23]


United States statistics

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.[24]

International statistics

At present, the prevalence of inheritance and of underlying defects in the familial disorder are unknown. Overall, however, primary and secondary hypoalphalipoproteinemia are common.

Race-, sex-, and age-related demographics

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.


If hypoalphalipoproteinemia (HA) is diagnosed early and monitored closely, the prognosis for patients with HA is generally reasonably good. The risk derives from the development of complications.


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.


Complications of HA include the following:

  • Premature atherosclerosis
  • Corneal opacification

Patient Education

Pursue aggressive dietary modification with patients. Discuss medications and their potential adverse effects, and monitor for adverse effects.

For excellent patient education resources, visit eMedicineHealth's Cholesterol Center. Also, see eMedicineHealth's patient education articles High Cholesterol, Cholesterol Charts, Lifestyle Cholesterol Management, and Cholesterol-Lowering Medications.




Persons with low high-density lipoprotein (HDL) cholesterol levels, except those patients with a deficiency syndrome, have no symptoms specific to the condition. However, they may have a history of premature atherosclerosis, as well as a history consistent with coronary heart disease (CHD), peripheral artery disease, or other such conditions, including the following:

  • Premature atherosclerosis

    • CHD - A history of angina or myocardial infarction (MI) in a person below age 60 years, a history of premature heart disease in a patient's siblings and first-degree relatives, sequelae of MI

    • Congestive heart failure

    • Peripheral vascular disease - A history of claudication

  • Cerebrovascular disease

    • History of stroke

    • History of transient ischemic attack

    • History of carotid endarterectomy

  • Xanthomas (tendinous, cutaneous)

  • History consistent with secondary causes

    • Cigarette smoking

    • Physical inactivity

    • Hypertriglyceridemia

    • Renal disease

    • Obesity

    • Medications

    • Androgens

    • Progestins

    • Probucol

    • High-dose thiazides

    • High-dose beta blockers

  • Corneal opacification

Physical Examination

Persons with the common low high-density lipoprotein (HDL) syndromes have no specific physical findings. If atherosclerosis is present, the examination may reveal findings consistent with the affected arterial bed. These may include the following:

  • Tendon xanthomas

  • Cutaneous xanthomas

  • Findings of ischemic coronary heart disease or peripheral vascular disease

    • S4 gallop consistent with ischemic left ventricular dysfunction

    • Signs of congestive heart failure, such as a raised jugular distension, crackles at the lung bases, edema, and hepatomegaly

    • Arrhythmias

  • Corneal opacification



Laboratory Studies

Laboratory studies used in the workup of hypoalphalipoproteinemia (HA) are as follows:

  • Routine blood tests - Included among these is a chemistry profile.

  • Additional tests - These include liver function tests and a thyroid profile.

  • Plasma fasting lipid profile - After a 12-hour fast, plasma samples are obtained for lipid analysis. Total cholesterol and triglyceride (TG) levels are measured by enzymatic methods. The low-density lipoprotein (LDL) cholesterol level is determined in the supernatant after plasma precipitation with magnesium chloride–phosphotungstic acid. LDL cholesterol levels are estimated using the formula proposed by DeLong and colleagues.[25] Values obtained include LDL, HDL, total cholesterol, and TG levels.

  • Plasma lipid subfractions - Apo A-I, apo A-II, apo B, and lipoprotein Lp(a) are measured, using immunoassays for apo A-II and nephelometric assays employing antibodies for apo A-I, apo B, and Lp(a). Subfractions include apo A, apo A-I, apo A-II, apo A-III, apo B, apo C, and apo E.

Imaging Studies

Whether imaging studies are needed depends on the clinical manifestations of hypoalphalipoproteinemia (HA). Imaging studies that may be used are as follows:

  • Patients with corneal opacification may require ophthalmoscopic examination and corneal or intraocular imaging.

  • Patients with premature coronary atherosclerosis may need the following:

    • Chest radiograph - A chest radiograph may show alteration in the size of the cardiac silhouette; calcification or congestion of the lung fields, including interstitial edema; and Kerley B lines, indicating congestive heart failure.

    • Echocardiogram - Two-dimensional, ultrasonographic images of the heart can show chamber-size alterations, regional wall motion abnormalities, and valvular regurgitations consistent with the presence of atherosclerosis.

    • Nuclear (radionuclide) stress test - The quantity of blood that flows to different parts of the myocardium can be evaluated, using a nuclear (gamma single-photon emission computed tomography) camera to reveal the presence of a hot spot (good flow) or a cold spot (diminished flow). A radioactive isotope, such as thallium, sestamibi, or tetrofosmin, is used, and the image is produced once with patient exercise and then in the absence of exercise. If a patient cannot exercise, pharmacologic agents (eg, adenosine [Adenocard], dipyridamole [Persantine], dobutamine [Dobutrex]) can be used to stimulate the heart muscle for the stress test. This test is expensive but noninvasive, and its accuracy is quite high (>93%).

    • Stress echocardiography - Instead of using a radionuclide agent, echocardiographic (ultrasonographic) images can be obtained immediately following incremental exercise on the treadmill or after the administration of intravenous dobutamine. In this test, the ventricular wall motion during stress is compared with that at rest. Wall motion decreases during stress in a coronary artery that has significant obstruction.

    • Electron beam (ultrafast) computed tomography (CT) scan - This test is noninvasive but somewhat controversial. By measuring the amount of calcium deposited in the plaques of coronary arteries, it can detect even 10-20% blockages, which other tests may not reveal. The only recommendations for such insignificant blockages are lifestyle changes and risk-factor modification. Also, because elderly people frequently have calcium in their coronary arteries without significant narrowing, electron beam CT is of limited value for persons in this age group. The advantage of electron beam CT is that it can be used to noninvasively screen young people with 1 or more heart disease risk factors.

    • Coronary angiography by cardiac catheterization - Performed in the hospital, this test involves intravenous placement of long, thin, plastic catheters into the opening of the coronary arteries, starting from either the groin (femoral artery) or the arm (brachial artery). Once the catheter reaches the opening of the coronary artery, a small amount of radiographic iodine dye is injected, which makes the coronary arteries visible on radiographs. Pictures of the coronary arteries are recorded for later review. The images show the diameter of the coronary arteries and reveal any blockages that are narrowing them. Coronary angiography is an invasive test. In experienced hands, the risk of complications from the procedure is less than 1%. It is the only test that helps a cardiologist to determine precisely whether to treat a patient using bypass surgery, through-the-skin intervention (percutaneous coronary interventions) such as angioplasty or stent placement, or medicines alone.

  • Some imaging studies may be included in the workup for exploring secondary causes of HA.

Other Tests

Other tests that may be included in the workup of HA are as follows:

  • Electrocardiograph (ECG)

    • The 12-lead resting ECG tracings are obtained by placing 6 limb and 6 chest electrodes on the patient.

    • ECG findings consistent with the presence of coronary atherosclerosis may include ST-segment shift or T-wave changes.

  • Exercise (treadmill) stress test

    • The presence of physiologically significant atherosclerotic plaque in 1 or more major coronary arteries may be detected by stressing the heart with continuous ECG monitoring.

    • The patient walks on a treadmill while ECG heart monitoring wires are placed on the chest and tracings are recorded at 2- to 3-minute intervals. The speed and elevation are gradually increased.

    • The treadmill stress test has a predictive accuracy of 60-70%. Sometimes, its readings may be falsely abnormal in people with baseline ECG changes, electrolyte abnormalities, electrical conduction abnormalities, digitalis use, enlarged heart, or mitral valve problems.

  • Evaluation of HDL subfractions

  • Measurement of the LCAT enzymatic activity

  • Apo A-I, apo A-II, and HDL subfractions

  • Genetic studies, including chromosomal studies

    • In a 1986 report, Ordovas and colleagues identified a PstI restriction-endonuclease site adjacent to the human APOA1 gene at its 3' end that is polymorphic.[26]

    • The absence and presence of this site, as determined by genomic blotting analysis of PstI-digested chromosomal DNA with the use of an APOA1 gene probe, were associated with 3.3-kilobase (kb) and 2.2-kb hybridization bands, respectively.

    • The 3.3-kb band appeared in 4.1% of 123 randomly selected control subjects and in 3.3% of 30 subjects with no angiographic evidence of coronary artery disease. In contrast, among 88 subjects who had severe coronary disease when younger than 60 years, as documented by angiography, the 3.3-kb band occurred in 32% (P< .001). It was also found in 8 of 12 index cases (P< .001) of kindreds with familial HA.

  • Thromboxane A2 levels

  • Decreased erythrocyte osmotic fragility

    • Frohlich and colleagues in 1990 and Godin and coauthors in 1988 described erythrocyte membrane abnormalities.[27, 28]

    • The observed changes in a number of structural and functional properties of erythrocytes in this disorder are indistinguishable from those previously described in homozygotes for LCAT deficiency.

    • Thus, in both of these disorders, an abnormality of plasma LCAT activity possibly causes functional and structural changes in the erythrocyte membrane, either directly or indirectly.


Procedures that may be used in the assessment of patients with HA are as follows:

  • Patients with HA need monitoring for the development of premature atherosclerosis. Some procedures that may be useful include the following:

    • Noninvasive cardiac procedures

      • Stress-nuclear testing

      • Rest and stress echocardiography

      • Electron beam computed tomography

      • Cardiac catheterization and coronary angiography

      • Percutaneous coronary interventions

      • Coronary artery bypass grafting surgery

    • Carotid atherosclerosis

      • Carotid Doppler studies

      • Carotid artery angiograms

      • Carotid endarterectomy

    • Peripheral vascular and renal vascular disease

      • Ankle-brachial index

      • Peripheral arterial angiography

      • Percutaneous interventions

      • Peripheral vascular bypass surgery

Histologic Findings

In 1988, Godin and colleagues described a case of erythrocyte membrane abnormalities in a 16-year-old boy with HA resembling fish-eye disease.[28] The proband's erythrocytes had markedly decreased osmotic fragility, with target cells observed in the peripheral film. Analysis of the patient's erythrocyte membrane lipids revealed normal cholesterol and phospholipid content but a marked increase in phosphatidylcholine with concomitant decreases in phosphatidylethanolamine and sphingomyelin.

Of the erythrocyte membrane enzymes examined, acetylcholinesterase and superoxide dismutase activities were decreased, while those of Na+/K+ -ATPase, catalase, and glutathione reductase were normal. In this patient, chromium Cr 51–labeled erythrocyte survival was slightly decreased. The observed changes in a number of structural and functional properties of erythrocytes in this disorder are indistinguishable from those described in homozygotes for familial LCAT deficiency.

In 1989, Satta and colleagues noted that the data in the literature suggest that cases of HA involve an increase in thromboxane B2 together with an increased risk of atherosclerosis. A detailed examination of a 32-year-old man revealed clinical and biochemical features strongly indicative of that pathology. The case presented several unusual features, including (1) marked infiltration of the skin and mesenteric lymph nodes by histiocytic lipids, with hyperplasia sufficient to induce acute intestinal occlusion and (2) an in vivo thromboxane B2 generation curve, subsequently inhibited by aspirin, that was comparable to the curves of the control subjects.[23]



Medical Care

Most individuals are diagnosed with hypoalphalipoproteinemia (HA) based on the results of a routine lipid profile measurement. This finding of a low high-density lipoprotein (HDL) cholesterol level can be useful as an independent factor in assessing coronary artery disease (CAD) risk and further management. Guidelines in the ATP III report emphasized the importance of HDL cholesterol; the level of HDL considered to be a significant risk factor was changed from less than 35 mg/dL to less than 40 mg/dL.[3, 4, 5, 6, 29]

The basic purpose of the management of HA and related lipid abnormalities is to reduce the risk of atherosclerosis, which is the main mechanism of increased morbidity and mortality. With regard to HA, the ATP III report stated, "Low HDL cholesterol is a strong independent predictor of CHD [coronary heart disease]. In ATP III, low HDL cholesterol is defined categorically as a level < 40 mg/dL, a change from the level of < 35 mg/dL in ATP II [1993]. In the present guidelines, low HDL cholesterol both modifies the goal for LDL-lowering therapy and is used as a risk factor to estimate 10-year risk for CHD."[3, 4, 5, 6]

The document also reported that there are several causes of low HDL cholesterol levels and that a number of these—including type II diabetes, overweight, obesity, elevated triglycerides (TGs), and a lack of physical activity—are associated with insulin resistance. The study also cited cigarette smoking, a very high carbohydrate intake (>60% of calories), and certain agents (such as progestational drugs, anabolic steroids, and beta blockers) as causes of low HDL levels.

  • Follow an appropriate management strategy. The ATP III report did not provide a specific level to which a low HDL concentration should be raised. According to the study's executive summary, "Although clinical trial results suggest that raising HDL will reduce risk, the evidence is insufficient to specify a goal of therapy. Furthermore, currently available drugs do not robustly raise HDL cholesterol." The panel stated that low HDL levels should be managed in the following manner:

    • Reducing low-density lipoprotein (LDL) levels is the primary goal.

    • Metabolic syndrome is the second target. According to the ATP III executive summary, "After the LDL goal has been reached, emphasis shifts to weight reduction and increased physical activity (when the metabolic syndrome is present)." Metabolic syndrome is diagnosed in patients with at least 3 of the following risk factors:

      • Abdominal obesity, with a waist circumference of over 35 inches (females) or above 40 inches (males)

      • TG levels of 15 mg/dL or greater

      • HDL cholesterol levels of below 40 mg/dL (males) or less than 50 mg/dL (females)

      • Blood pressure at or above 130 mm Hg systolic and greater than or equal to 85 mm Hg diastolic

      • Fasting glucose levels at or above 110 mg/dL

    • An association between low HDL and hypertriglyceridemia requires attention. The ATP III reported, "When a low HDL cholesterol is associated with high triglycerides (200-499 mg/dL), secondary priority goes to achieving the non-HDL cholesterol goal." For example:

      • In the patients with established CHD or a CHD risk equivalent (10-year risk for CHD >20%), the LDL goal is under 100 mg/dL, and the goal for non-HDL cholesterol (LDL plus very–low-density lipoprotein [VLDL]) is below 130 mg/dL.

      • In persons with multiple (2+) risk factors and 10-year risk of equal to or less than 20%, the LDL goal is < 130 mg/dL, while the non-HDL goal is < 160 mg/dL.

      • In persons with 0-1 risk factor, the LDL goal is < 160 mg/dL, and that for the non-HDL is < 190 mg/dL.

    • Managing isolated low HDL cholesterol is also important. According to the ATP III, if a patient's TG levels are below 200 mg/dL (isolated low HDL cholesterol), the administration of drugs that increase HDL (fibrates or nicotinic acid) can be considered. Statins have only a modest effect. Treatment for isolated low HDL cholesterol is provided mainly to patients with CHD and CHD risk equivalents.

  • Identify patients whose diet is very low in fat. A low HDL cholesterol level in this setting is rarely associated with an increased risk for premature CHD.

  • Identify and correct secondary factors. Instruct patients who smoke to stop smoking, tell persons who are overweight to manage their weight, and encourage individuals who are sedentary to engage in regular exercise. Whenever possible, eliminate medications associated with low HDL cholesterol levels. Control diabetes optimally, and aggressively treat LDL cholesterol, regardless of HDL cholesterol levels.

  • Consider estrogen replacement therapy for postmenopausal women, because this can substantially raise HDL cholesterol levels.

  • It is unclear whether pharmacologic agents should be used to raise the HDL cholesterol level in otherwise healthy persons, because no published clinical trials are available that demonstrate a benefit. Nonetheless, individuals at high risk require further assessment for CHD risk, with an evaluation that includes a family history, measurements of apo and lipoprotein Lp(a), and electron beam CT scanning.

    • Niacin is the most effective agent currently available. However, many patients with isolated HA do not respond well to niacin. Most patients who receive niacin also have high LDL cholesterol levels that are being managed pharmacologically, and niacin is added to raise their HDL cholesterol level if it is low.

    • Gemfibrozil and fenofibrate modestly raise the HDL cholesterol level. They are most effective in the setting of concomitant hypertriglyceridemia.

    • Statins only mildly raise HDL cholesterol levels. They are not recommended for this purpose alone.

    • Alcohol tends to raise some HDL subfractions. However, no clinical trial data are available to demonstrate any positive role for raising HDL levels with alcohol in order to reduce cardiovascular events in patients with CHD.

HDL-raising therapies

Low HDL levels often reflect a genetic abnormality, although they can also be pushed downward by a high blood level of TGs or by cigarette smoking, inactivity, or hypertension, as well as by a diet very high in carbohydrates or polyunsaturated fats.

Another pharmacologic approach geared towards raising HDL levels involves inhibiting cholesteryl ester transfer protein (CETP). CETP helps to exchange cholesterol between lipoproteins and can transfer it from HDL to LDL and VLDL. Individuals with a genetic mutation that causes the loss of all CETP activity have very high levels of HDL cholesterol. These individuals appear to be at lower risk of coronary disease.[30, 31]

A small study in 2004 involving the CETP inhibitor torcetrapib showed that the drug markedly increased HDL levels and decreased LDL levels when taken alone and also when taken in combination with a statin. The increases in HDL levels were much higher than can be achieved with existing lipid drugs. Although this points researchers in a promising direction, therapy with torcetrapib needs to be tested in a larger population; it must be shown through outcome studies that the drug not only to increases HDL levels, but that it also prevents heart problems.[32]

HDL infusion therapy studied in a group of 40 Italian villagers led to the discovery of a rare type of HDL that seemed to protect against heart disease even when the levels of HDL were not very high. People in the study had a protein in their HDL, the aforementioned apo A-I Milano, that seemed to be better at stimulating the removal of cholesterol from plaques than was HDL containing the normal protein, called apo A-I.

Nissen and colleagues tested whether a synthetic version of apo A-I Milano (recombinant apo A-1 Milano/phospholipid complexes, ETC-216) infused into the blood of people who did not naturally have this protein would have the same effect.[33] The small trial randomly assigned 47 people who had recently had a heart attack to receive either a placebo or a low or high dose of the synthetic protein.

Studying ultrasonograms of the arteries, the researchers found that from the beginning to the end of the 5-week trial, the plaque in the treatment groups shrank by 4%, while that of the placebo group increased by a small amount. Although these were exciting results, a larger trial employing synthetic HDL infusion therapy is needed.

Estrogen replacement or hormone replacement therapy (HRT) raises HDL by about 8% in postmenopausal women, but its use is controversial; such treatment is not recommended for CAD prevention due to a demonstrated lack of benefit and the possible risk of increased thrombosis.

The Heart and Estrogen/progestin Replacement Study (HERS) found no net decrease in secondary prevention of CHD events over 4 years.[34] Events increased 50% with HRT during year 1 but then progressively decreased to 33% lower by the study's end. The early increase may have resulted from prothrombotic and/or pro-inflammatory effects of HRT, while the later decrease may have reflected the 8% increase in HDL cholesterol and/or other antiatherosclerotic mechanisms.[35] Results of HRT in primary prevention await completion of the Women's Health Initiative in 2007.

Because an increase in the consumption of cold-water fish (eg, salmon) rich in polyunsaturated fats may help to raise HDL, fish oil capsules (capsules containing omega-3 fatty acids, ie, 1.48 grams of docosahexaenoic acid and 1.88 grams of eicosapentaenoic acid) have been studied in small trials. In a study in patients with familial combined hyperlipidemia, treatment with this formulation for 8 weeks increased HDL by 8%, particularly the more buoyant HDL-2 subfraction. levels of paraoxonase, an HDL-associated, antioxidant enzyme, were also increased by 10%.[36]

None of these HDL-raising therapies have been studied in Asian Indians. Therefore, no particular treatment recommendations can be made at this juncture. Nonetheless, the treatment strategies appear to be well suited for this subpopulation, which has a high prevalence of HA.

Niacin, fibrates, and statins

Multiple studies have shown that niacin, fibrates, and statins can decrease the risk of cardiovascular disease and atherosclerosis progression by affecting multiple lipid parameters. In a study by AIM-HIGH Investigators et al, the addition of niacin to statin therapy did not provide any clear benefit to patients with cardiovascular disease and low HDL levels.[37] The much larger HPS2-THRIVE study (N=25,673) confirmed these findings. Additionally, adding niacin to statins increased risk for serious adverse events.[38]

Overall, fibrates reduce the risk for major coronary events by 25%, whereas currently available data for niacin suggest about a 27% reduction. Statins do have modest affects on HDL, increasing concentrations by 5% to 10%, providing a secondary benefit to this therapy beyond LDL reduction.

Completion of trials with clinical endpoints (eg, AIM-HIGH and HPS2-THRIVE clinical trials) have shown that the addition of niacin that decreased TGs and/or increased HDL-C levels in statin-treated patients does not cause further reduction in risk of CV events. Consistent with this conclusion, the FDA has determined that the benefits of niacin ER tablets for coadministration with statins no longer outweigh the risks, and the approval for this indication should be withdrawn. Additionally, the combination products that include simvastatin or lovastatin plus long-acting niacin (ie, Advicor, Simcor) were withdrawn from the U.S. market at the beginning of 2016 and are no longer available.[39]


In the ADvicor Versus Other Cholesterol-Modulating Agents Trial Evaluation (ADVOCATE), 315 patients with high LDL (≥160 mg/dL without CAD, or ≥130 mg/dL with CAD) and low HDL (< 45 mg/dL in men, and < 50 mg/dL in women) were randomized to 16 weeks of a combination of niacin/lovastatin versus standard doses of atorvastatin or simvastatin. Niacin/lovastatin increased HDL significantly more than did statin alone at all dose combinations (P< 0.001). In addition, a significant decrease in LDL (42% vs 34%; P< 0.001) and significant improvements in TGs, lipoprotein(a), apo A-I, and apo B were seen in those patients receiving niacin/lovastatin (no longer on U.S. market).

HATS study

A niacin/statin combination was also evaluated in the HDL-Atherosclerosis Treatment Study (HATS).[40] In this investigation, LDL levels fell by 42% (P< 0.001) and HDL levels increased by 26% (P< 0.001). Angiographic analysis revealed that the combination therapy significantly enhanced stenosis regression. The statin/niacin combination also resulted in a 60-90% reduction in the incidence of major coronary events.

ARBITER 2 study

In the ARterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2) study, a double-blind, placebo-controlled trial was performed on an extended-release niacin/statin therapy.[41] One group of patients received the combination therapy, while another group received only statin. HDL levels in the combination group rose 21% higher (P = 0.002) than they did in the statin-only group, and TGs decreased significantly (P = 0.009). The primary endpoint of ARBITER 2 was change in common carotid intima-media thickness (CIMT). CIMT progression was 68% lower in the niacin/statin group than in the other patients. The end result was a 50% reduction in the composite cardiovascular endpoint for the niacin/statin patients.

Emerging treatment strategies

Several novel approaches to increasing HDL cholesterol that have been under investigation include the following:

  • The aforementioned partial CETP inhibitor, torcetrapib, may increase HDL by as much as 46%.

  • The glitazones, which are PPAR (peroxisome proliferator-activated receptor) agonists, act by lowering free fatty acid (FFA) and TG levels and by raising HDL. Rosiglitazone appears to increase the size of small LDL particles.

  • Recombinant apo A-1 Milano mimics the activity of nascent HDL and has shown promise in early trials in patients with acute coronary syndromes.

CETP inhibition therapy

CETP mediates the transfer of cholesteryl ester for TGs from HDL to VLDL and LDL. It may be proatherogenic if the VLDL-LDL cholesteryl ester is taken up by arterial macrophages. Blocking CETP prevents the transfer of cholesterol from HDL2 to the apo B–containing lipoproteins, and therefore, the HDL concentration in terms of cholesterol rises.

Two pharmacologic inhibitors of CETP have undergone phase 3 clinical trials: torcetrapib and JTT-705. The 2 drugs differ in chemical structure. With torcetrapib, the CETP activity is inhibited by only about 50% to 60%, to avoid the fact that patients with complete CETP deficiency, mostly found in Japan, exhibit a paradoxically increased risk of CAD. The effect of torcetrapib is dose-dependent; for example, increasing the dose from 10 mg to 120 mg twice daily is associated with an almost 90% CETP inhibition and a greater rise in HDL. In addition, LDL is reduced by torcetrapib, by as much as 40%.

Torcetrapib was looked at in a phase 3 global study called the Investigation of Lipid level management to Understand its iMpact IN ATherosclerotic Events (ILLUMINATE) trial. The study utilized 15,067 patients (mean age 61 years; 78% male, 93% white) with CHD or CHD risk equivalent (type 2 diabetes).[42] Patients received either torcetrapib and atorvastatin or atorvastatin alone.

At 12 months follow-up, patients who received torcetrapib demonstrated a mean increase of 72.1% in HDL cholesterol and a mean decrease of 24.9% in LDL cholesterol, as well as a mean decrease of 9% in TGs compared with baseline (all P< .001 vs atorvastatin-only patients). Beginning early in the trial, however, the 2 patient groups diverged with regard to the study's primary endpoint, a composite of first major cardiovascular events (CHD death, nonfatal myocardial infarction, stroke, and hospitalization for unstable angina).

By the study's termination, the torcetrapib group demonstrated a 25% elevation in risk over the patients who received only atorvastatin (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.09-1.44; P = .001). This included a greater risk of death from cardiovascular causes (49 in the torcetrapib group in comparison with 35 in the atorvastatin-only patients) and from noncardiovascular causes (40 in the torcetrapib group vs 20 in the atorvastatin-only patients). At 12 months follow-up, systolic blood pressure (SBP) in the torcetrapib patients had risen from baseline by a mean of 5.4 mm Hg, a significantly greater increase than that (0.9 mm Hg) found in the atorvastatin group (P< .001).

A significant (albeit small) change in serum electrolytes—a reduction in potassium and increases in sodium and serum bicarbonate—was also found in the torcetrapib patients. These changes may have indicated that mineralocorticoid excess accounted for the blood pressure increase.

A trial by Roche Pharmaceuticals using an agent similar to torcetrapib is underway. This drug reportedly does not raise blood pressure. The study's results should be available within a few years.

ApoA-1 Milano complexes

Apo A-I Milano, an apo A-I variant identified in a rural Italian population, is associated with cardioprotection due to its "super-HDL" properties. Individuals possessing apo Milano were found to have very low levels of HDL and yet, as a group, had a very low prevalence of atherosclerotic disease because most of their HDL was apo A-I Milano.

In a study, ETC-216, a recombinant form of apo A-I Milano–phospholipid complex, was found to be effective in reducing coronary atheroma volume as measured by intravascular ultrasonography. The investigation showed that the atherosclerosis in the coronary vessel wall could be modified in a much shorter time than anticipated, ie, within 5-6 weeks.[43, 44, 45]

An apo A-I mimetic peptide under development, D-4F, is targeted not at raising HDL but at changing pro-inflammatory HDL into anti-inflammatory HDL in high-risk patients.

Surgical Care

Hypoalphalipoproteinemia (HA) may not require any surgical intervention. However, its association with and promotion of atherosclerosis may require a variety of surgical interventions, as follows:

  • Cardiac catheterization, coronary angiography, and various percutaneous interventions for coronary heart disease (CHD)

  • Coronary bypass grafting surgery for patients with CHD

  • Percutaneous interventions and bypass procedures for peripheral vascular disease

  • Carotid endarterectomy for carotid disease

  • Gastric stapling and other related intestinal surgeries for weight reduction and the management of metabolic syndrome


Always consider secondary causes of low HDL levels, especially medications, smoking habits, dietary patterns, and physical activity. Patients with elevated triglyceride levels (>500 mg/dL) commonly have low HDL cholesterol levels; address hypertriglyceridemia first in such patients. Patients with moderately reduced HDL levels (20-35 mg/dL) usually have secondary causes that should be addressed. Individuals with severely reduced HDL levels (< 20 mg/dL) may have a specific genetic etiology, such as familial lecithin-cholesterol acetyltransferase (LCAT) deficiency, Tangier disease, or mutations in apo A-I. Ironically, these disorders are not commonly associated with an increased risk of atherosclerosis. Refer patients who may possibly have one of these diagnoses to a specialized lipid center for advanced management. Consultation with the following specialists may be required:

  • Lipidologist

  • Endocrinologist

  • Cardiologist

  • Vascular specialist

  • Cardiovascular surgeon

  • Dietitian

Diet and Activity


Diets that are very low in fat are associated with low high-density lipoprotein (HDL) cholesterol levels. However, because no data are available that show a reduction in the risk of coronary heart disease (CHD) upon raising HDL cholesterol levels, no particular dietary interventions are needed for this specific purpose. In fact, increasing the fat content of a patient's diet is not recommended. Dietary management should follow the NCEP guidelines for lowering frequently associated low-density lipoprotein (LDL) cholesterol, which is the primary target in lipid management[3, 4, 5, 6] ; lowering LDL levels has been demonstrated to reduce CHD morbidity and mortality in multiple randomized clinical trials.

The NCEP has recommended a therapeutic lifestyle-change diet, which should be incorporated in the treatment of all patients. The following are recommendations:

  • Patients should reduce their intake of saturated fats to less than 7% of their total calorie (energy) intake. Their cholesterol intake should be reduced to less than 200 mg/d. Trans fatty acids (the HDL-lowering, LDL-raising fats) should be kept to a minimum. Polyunsaturated fats should constitute up to 10% of total energy intake, and monounsaturated fats, up to 20% of total energy intake. Total fat intake, therefore, should be in the range of 25-35% of total energy intake.

  • Carbohydrates (complex carbohydrates from grains, whole grains, fruits, and vegetables) should constitute 50-60% of total energy intake.

  • Patients should consume 20-30 g/d of fiber.

  • The protein content should be approximately 15% of total energy intake.

  • In order to maintain a desirable body weight and to prevent weight gain, the total amount of energy consumed must be balanced in terms of energy intake and expenditure.


Strongly encourage increased physical activity, especially in persons with sedentary habits. According to the NCEP guidelines, daily activity and energy expenditure should include at least moderate physical activity, with the patient expending approximately 840 kJ/d.

In a Spanish study that included 296 adults at high cardiovascular risk, leisure-time physical activity was associated with increased circulating levels of HDL, as well as improvement in several markers of HDL functionality.[46]



Medication Summary

Currently, clinical trial results suggest that raising high-density lipoprotein (HDL) levels reduces risk. However, the evidence does not support a recommendation of therapy for hypoalphalipoproteinemia (HA). Additionally, drugs available for cholesterol management do not raise HDL cholesterol levels as much as desired. However, physicians should pay reasonable attention to low HDL cholesterol levels and their management.

According to NCEP ATP III guidelines, the primary goal of therapy is to lower low-density lipoprotein (LDL) cholesterol levels.[3, 4, 5, 6] Once the LDL target has been reached, emphasize therapeutic lifestyle changes, such as weight management and increased exercise, especially if the patient has a metabolic syndrome.

If triglyceride (TG) levels are lower than 200 mg/dL (ie, isolated HA), drugs for raising HDL (eg, fibrates, nicotinic acid) can be considered. Statins have only a modest effect. Treatment for isolated low HDL cholesterol levels is reserved mostly for individuals with established coronary heart disease (CHD) and for patients with risk factors for CHD.

Antilipemic agents

Class Summary

These medications usually lower low-density lipoprotein (LDL) cholesterol levels. In addition, they sometimes lower triglyceride (TG) levels and may modestly elevate high-density lipoprotein (HDL) cholesterol levels. Antilipemic agents may be of value to patients with hypoalphalipoproteinemia (HA).

Niacin, nicotinic acid (Niacor, Nicobid, Nicolar, Niaspan)

Source of niacin used in tissue respiration, lipid metabolism, and glycogenolysis. Nicotinic acid has lipid-lowering properties, but nicotinamide and niacinamide do not.

Gemfibrozil (Lopid)

Fibric acid antilipemic agent that effectively reduces serum TGs and favorably alters lipoprotein levels; the mechanism of action is unknown, but gemfibrozil may inhibit lipolysis, the secretion of VLDL, and hepatic fatty acid uptake.

Fenofibrate (Tricor)

Fibric acid antilipemic agent that lowers LDL cholesterol more effectively than do older fibrates (ie, clofibrate, gemfibrozil). Fenofibrate is primarily indicated for TG reduction and for use in mixed dyslipidemia. This agent increases plasma catabolism and the clearance of TG-rich particles by lipoprotein lipase induction and the suppression of the hepatic production of apo C-III through the activation of PPARs. Fenofibrate activates acetyl-CoA and other enzymes, increasing fatty acid oxidation. TG production is also decreased via the inhibition of acetyl-CoA carboxylase and fatty acid synthase. Clinically, a marked reduction in plasma TGs and VLDL is observed, as is an increase in HDL cholesterol levels.

HMG-CoA reductase inhibitors

Class Summary

Statins are used to lower LDL cholesterol, but they also modestly raise HDL cholesterol.

Atorvastatin (Lipitor)

Selective competitive inhibition of HMG-CoA reductase decreases cholesterol synthesis and increases cholesterol metabolism. Atorvastatin may modestly elevate HDL cholesterol levels. Clinically, reduced levels of circulating total cholesterol, LDL cholesterol, and serum TGs are observed.

Simvastatin (Zocor)

Inhibits HMG-CoA reductase, which, in turn, inhibits cholesterol synthesis and increases cholesterol metabolism.

Pravastatin (Pravachol)

Competitively inhibits HMG-CoA reductase, which catalyzes the rate-limiting step in cholesterol synthesis. Before initiating therapy, place patients on a cholesterol-lowering diet for 3-6 mo, and continue the diet indefinitely.

Lovastatin (Mevacor)

Competitively inhibits HMG-CoA reductase, which catalyzes the rate-limiting step in cholesterol synthesis. Before initiating therapy, place patients on a cholesterol-lowering diet for 3-6 mo, and continue the diet indefinitely.

Fluvastatin (Lescol)

Synthetically prepared HMG-CoA reductase inhibitor with some similarities to lovastatin, simvastatin, and pravastatin. However, fluvastatin is structurally distinct and has a different biopharmaceutical profile (eg, no active metabolites, extensive protein binding, minimal CSF penetration).

Rosuvastatin (Crestor)

Competitively inhibits HMG-CoA reductase, which catalyzes the rate-limiting step in cholesterol synthesis.

Pitavastatin (Livalo)

HMG-CoA reductase inhibitor (statin) indicated for primary or mixed hyperlipidemia. In clinical trials, 2 mg/d reduced total cholesterol and LDL cholesterol similar to atorvastatin 10 mg/d and simvastatin 20 mg/d.



Further Inpatient and Outpatient Care

Further inpatient care

Generally, patients with hypoalphalipoproteinemia (HA) are discovered during routine lipid profile testing. Such patients are ambulatory and do not usually require hospitalization or inpatient care.

Inpatient care is usually required for complications arising from accelerated atherosclerosis. In patients with secondary causes of HA, inpatient care may become necessary based on the primary pathology.


Patients with hypoalphalipoproteinemia (HA) rarely require transfer, and no specific recommendations are available for this purpose. In patients who are admitted to a health care facility, transfer depends mainly on the underlying condition or on complications of HA or premature atherosclerosis, such as myocardial infarction, arrhythmia, or hypotension.

Further outpatient care

Provide outpatient care at regular intervals, especially clinical evaluation, lipid profile assessment, and follow-up evaluations for complications (such as coronary heart disease).

Monitor patients frequently to ascertain the effectiveness of medical treatment and to determine whether complications are arising from drug therapy. For example, monitor liver function tests and eye function when treating patients with lipid-lowering agents.

Inpatient and Outpatient Medications

Inpatient and outpatient medications include the following:

  • Niacin or nicotinic acid

  • Gemfibrozil (Lopid) or fenofibrate (Tricor)

  • Statins

    • Atorvastatin (Lipitor)

    • Simvastatin (Zocor)

    • Pravastatin (Pravachol)


Familial or genetically inheritable forms of HA are not amenable to prevention. Genetic counseling and screening may be applicable in rare cases.

Hypoalphalipoproteinemia resulting from secondary causes can frequently be managed by treating those causes. Examples include quitting smoking and initiating regular physical activity.


Questions & Answers


What is low HDL cholesterol (hypoalphalipoproteinemia)?

What is the role of plasma lipoproteins in the pathophysiology of low HDL cholesterol (hypoalphalipoproteinemia)?

What is the pathophysiology of familial low HDL cholesterol (hypoalphalipoproteinemia)?

What is the pathophysiology of familial LCAT deficiency?

What is the pathophysiology of Tangier disease?

What is the role of plasma HDL in the pathophysiology of low HDL cholesterol (hypoalphalipoproteinemia)?

What is the reverse cholesterol transport system in the pathophysiology of low HDL cholesterol (hypoalphalipoproteinemia)?

What are the variants of low HDL cholesterol (hypoalphalipoproteinemia)?

What is the US prevalence of low HDL cholesterol (hypoalphalipoproteinemia)?

What is the global prevalence of low HDL cholesterol (hypoalphalipoproteinemia)?

What is the mortality and morbidity associated with low HDL cholesterol (hypoalphalipoproteinemia)?

What are the racial predilections of low HDL cholesterol (hypoalphalipoproteinemia)?

What are the sexual predilections of low HDL cholesterol (hypoalphalipoproteinemia)?


Which clinical history findings are associated with secondary causes of low HDL cholesterol (hypoalphalipoproteinemia)?

Which clinical history findings are characteristic of low HDL cholesterol (hypoalphalipoproteinemia)?

Which physical findings are characteristic of low HDL cholesterol (hypoalphalipoproteinemia)?

What are the primary or familial causes of low HDL cholesterol (hypoalphalipoproteinemia)?

What are the secondary causes of low HDL cholesterol (hypoalphalipoproteinemia)?

What causes low HDL cholesterol (hypoalphalipoproteinemia)?


What is the role of lab tests in the workup of low HDL cholesterol (hypoalphalipoproteinemia)?

What is the role of imaging studies in the workup of low HDL cholesterol (hypoalphalipoproteinemia)?

Which specialized lab tests may be included in the workup of low HDL cholesterol (hypoalphalipoproteinemia)?

What is the role of cardiac testing in the workup of low HDL cholesterol (hypoalphalipoproteinemia)?

How are patients with low HDL cholesterol (hypoalphalipoproteinemia) monitored for premature atherosclerosis?

Which histologic findings are characteristic of low HDL cholesterol (hypoalphalipoproteinemia)?


What are the guidelines in the ATP III report on management of low HDL cholesterol (hypoalphalipoproteinemia)?

Which HDL-raising therapies are used in the treatment of low HDL cholesterol (hypoalphalipoproteinemia)?

What is the role of niacin, fibrates and statins in the treatment of low HDL cholesterol (hypoalphalipoproteinemia)?

What were the results of the ADVOCATE study on cholesterol-modulating agents for the treatment of low HDL cholesterol (hypoalphalipoproteinemia)?

What is the efficacy of combined niacin/statin for the treatment of low HDL cholesterol (hypoalphalipoproteinemia)?

Which medications are being investigated as possible treatments for low HDL cholesterol (hypoalphalipoproteinemia)?

What is the role of CETP inhibition therapy in the treatment of low HDL cholesterol (hypoalphalipoproteinemia)?

How are low HDL cholesterol (hypoalphalipoproteinemia) variants treated?

What is the role of surgery in the treatment of low HDL cholesterol (hypoalphalipoproteinemia)?

Which specialist consultations are beneficial to patients with low HDL cholesterol (hypoalphalipoproteinemia)?

Which dietary modifications are used in the treatment of low HDL cholesterol (hypoalphalipoproteinemia)?

Which activity modifications are used in the treatment of low HDL cholesterol (hypoalphalipoproteinemia)?


What is the role of medications in the treatment of low HDL cholesterol (hypoalphalipoproteinemia)?

Which medications in the drug class HMG-CoA reductase inhibitors are used in the treatment of Low HDL Cholesterol (Hypoalphalipoproteinemia)?

Which medications in the drug class Antilipemic agents are used in the treatment of Low HDL Cholesterol (Hypoalphalipoproteinemia)?


What is included in the long-term monitoring of low HDL cholesterol (hypoalphalipoproteinemia)?

How is low HDL cholesterol (hypoalphalipoproteinemia) prevented?

What are the possible complications of low HDL cholesterol (hypoalphalipoproteinemia)?

What is the prognosis of low HDL cholesterol (hypoalphalipoproteinemia)?

What is included in patient education about low HDL cholesterol (hypoalphalipoproteinemia)?

When is inpatient care indicated for the treatment of low HDL cholesterol (hypoalphalipoproteinemia)?

Which medications are used in the treatment of low HDL cholesterol (hypoalphalipoproteinemia)?

When is patient transfer indicated for the treatment of low HDL cholesterol (hypoalphalipoproteinemia)?