Apolipoprotein A deficiency

Lipid Disorders Main Page
Overview
Causes
Classification Abetalipoproteinemia Hypobetalipoproteinemia Familial hypoalphalipoproteinemia LCAT Deficiency Chylomicron retention disease Tangier disease Familial combined hypolipidemia
Differential Diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2] Synonyms and keywords: Familial hypoalphalipoproteinemia, FHA, familial HDL deficiency, FHD, high density lipoprotein deficiency, HDLD

Overview

Familial hypoalphalipoproteinemia is defined as a reduction in the synthesis of HDL-cholesterol or "good" cholesterol (< 35 mg/dl) for men and < 45 mg/dL for women). 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 clearcut definition. An arbitrary cutoff is the 10th percentile of HDL cholesterol (HDL-C) 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) recently redefined the HDL-C level that constitutes a formal coronary heart disease (CHD) risk factor. The level was raised from 35 mg/dL to 40 mg/dL for both men and women. 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-C levels that contribute to the syndrome are sex-specific. For men, a high-risk HDL-C level is still less than 40 mg/dL, but for women, the high-risk HDL-C level is less than 50 mg/dL. [[Category:]] A low HDL-C 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 and a family history of low HDL-C levels and premature CHD.

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

This review addresses the pathogenesis, presenting features, diagnostic tests, therapeutic interventions, and follow-up strategies for low HDL-C levels (i.e., HA).

Frequency

United States

HA is frequently found in patients with CHD. Among patients with CHD, 58% had HDL-C levels below the 10th percentile of normal values.

International

At present, the prevalence of inheritance and underlying defects in the familial disorder are unknown. However, overall, both secondary and primary HA are common.

Mortality / Morbidity

• Hypoalphalipoproteinemia is associated with an increased risk of recurrent coronary episodes and mortality caused by CHD and 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, and care of these patients costs approximately $45.3 billion, in addition to a huge cost in human suffering.
• Peripheral vascular disease also affects many individuals. Approximately 50% of patients who report claudication have peripheral vascular disease.

Demographics

Race

HA has been described in persons of all races. While no particular predilection has been noted, some literature suggests a higher prevalence of HA in Asian Indians.

Gender

Women tend to have a somewhat lower frequency of HA than men. Whether this finding is a reflection of hormonal differences is not clear.

Age

Young boys and girls have similar HDL-C levels, but after male puberty, HDL-C levels in males decrease and remain lower than those in females for all subsequent age groups.

Pathophysiology

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 (i.e., cholesterol ester, triglycerides [TGs]) reside in a core surrounded by more polar components (eg, free cholesterol, phospholipids, proteins). The protein, termed apolipoprotein (apo), plays an important role in lipoprotein metabolism. The major apolipoproteins of HDL are alpha-apolipoproteins (i.e., 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 very low-density lipoprotein (VLDL), VLDL remnants, intermediate-density lipoprotein, and low-density lipoprotein (LDL).

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-C levels are closely correlated with CHD; the risk of a coronary event is thought to increase 2% for every 1% decrease in HDL-C. However, extreme HDL deficiencies caused by rare autosomal recessive disorders, including familial HA, familial lecithin-cholesterol acetyltransferase (LCAT) deficiency, and Tangier disease, do not always correlate with more frequent CHD.

Familial hypoalphalipoproteinemia or familial apolipoprotein A-I deficiency

Criteria for the definition of familial HAs are (1) a low HDL-C level in the presence of normal VLDL cholesterol and LDL cholesterol (LDL-C) 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-1 production or increased apo A-1 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 because of deletions of the APOA1 gene (level <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). The molecular diagnosis can be made by specialized analysis, including electrophoresis of the plasma apolipoproteins and 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-C.

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-C levels (usually 15-30 mg/dL). An example is APOA1 Milano, inherited as 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 types 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 the plasma LCAT levels; therefore, therapy is limited to (1) dietary restriction of fat to prevent the development of complications and (2) management of complications (e.g., renal transplant for advanced renal disease).

Two kinds of genetic LCAT deficiencies have been reported. The first is complete (or classic) LCAT deficiency. Complete LCAT deficiency is manifested by anemia, increasing proteinuria, and renal failure. The diagnosis can be made based on results of LCAT quantification and cholesterol esterification activity in the plasma in certain specialized laboratories. The second is partial LCAT deficiency (fish eye disease). Partial LCAT deficiency has known clinical sequelae. Progressive corneal opacification, very low plasma levels of HDL-C (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

Tangier disease is an autosomal codominant disorder that causes a complete absence or extreme deficiency of HDL. LDL-C 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 ATP-binding cassette transporter 1, which is involved in the passage of cholesterol from within the cells to outside the cells (efflux). Cholesteryl esters are deposited in the reticuloendothelial system. Patients with Tangier disease also may exhibit accelerated HDL catabolism. Their HDL-C levels are usually lower than 5 mg/dL. Their apo A-I levels are also very low. This condition has no specific treatment.

Components of plasma high-density lipoprotein

Plasma HDL is a small, spherical, dense lipid-protein complex that consists of half lipid and half protein. 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 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 into larger, less dense HDL2 or smaller, more dense HDL3. Most HDL is normally 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.

Variant apolipoproteins

The variant apo A-I Milano and 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.

Causes

HA may be caused by familial or primary and secondary disorders that are associated with low plasma HDL-C levels.

• 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 apo A-I deficiency and structural mutations
• Familial 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

• 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: Data in the literature suggest that some cases of HA involve an increase in thromboxane B2 together with an increased risk of atherosclerosis. Satta et al described a 32-year-old man who revealed clinical and biochemical features strongly indicative of this pathology.

History and Symptoms

Persons with low HDL-C levels, except those with a deficiency syndrome, have no symptoms specific to the condition. However, they may have a history of premature atherosclerosis and a history consistent with CHD, peripheral artery disease, or other such conditions.

• Premature atherosclerosis

• Coronary heart disease - History of angina or MI when younger than 60 years, history of premature heart disease in siblings and first-degree relatives, sequelae of MI
• Congestive heart failure
• Peripheral vascular disease - 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 Findings

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

• Tendon xanthomas
• Cutaneous xanthomas
• Findings of ischemic CHD or peripheral vascular disease

• S4 gallop consistent with ischemic left ventricular dysfunction
• Signs of congestive heart failure, such as raised jugular distension, crackles at lung bases, edema, and hepatomegaly
• Arrhythmias

• Corneal opacification

Laboratory Studies

• 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 TG levels are measured by enzymatic methods. The LDL-C level is determined in the supernatant after plasma precipitation with magnesium chloride–phosphotungstic acid. LDL-C levels are estimated using the formula proposed by DeLong et al. 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 with nephelometric assays using antibodies for apo A-I, apo B, and lipoprotein Lp(a) and by immunoassays for apo A-II. 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 HA.
• Patients with corneal opacification may require ophthalmoscopic examination and corneal or intraocular imaging.
• Patients with premature coronary atherosclerosis may need the following:

Chest x-ray

A chest x-ray film 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

Ultrasound images of the heart (2-dimensional images) 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 with a nuclear (gamma single-photon emission computed tomography) camera as a hot spot (good flow) or cold spot (diminished flow) by using a radioactive isotope, such as thallium, sestamibi, or tetrofosmin, once with exercise and then without.

If a patient cannot exercise, pharmacologic agents (e.g., adenosine [Adenocard], dipyridamole [Persantine], dobutamine [Dobutrex]) can be used to stimulate the heart muscle for the stress test. This test is expensive but non-invasive, and its accuracy is quite high (>93%).

Stress echocardiography

Instead of using a radionuclide agent, echocardiographic (ultrasound) images can be obtained immediately following incremental exercise on the treadmill or following 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) CT scan

This new 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 in screening young people with one or more heart disease risk factors in a noninvasive manner.

Coronary angiography

Performed in the hospital, this test involves intravenous placement of long, thin, specifically designed 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 x-ray film. Pictures of the coronary arteries are recorded for later review. The images show the diameter of the coronary arteries and any blockages narrowing them.

Coronary angiography is an invasive test. In experienced hands, the risk of complications 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

• Electrocardiogram

• 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.

• treadmill

• The presence of physiologically significant atherosclerotic plaque in one 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

• Reported in 1986, Ordovas et al identified a PstI restriction-endonuclease site adjacent to the human APOA1 gene at its 3' end that is polymorphic.
• 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 <0.001). It was also found in 8 of 12 index cases (p <0.001) of kindreds with familial HA.

• Thromboxane A2 levels
• Decreased erythrocyte osmotic fragility

• Frohlich et al in 1990 and Godin et al in 1988 described erythrocyte membrane abnormalities.
• 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

• 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 et al described a case of erythrocyte membrane abnormalities in a 16-year-old boy with HA resembling fish eye disease. 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 et al 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.

Treatment

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

According to NCEP ATP III guidelines, the primary goal of therapy is to lower LDL-C levels. Once the LDL target is reached, emphasize therapeutic lifestyle changes, such as weight management and increased exercise, especially if the patient has a metabolic syndrome.

If TG levels are lower than 200 mg/dL (i.e., isolated HA), drugs for raising HDL (e.g., fibrates, nicotinic acid) can be considered. Statins have only a modest effect. Treatment for isolated low HDL-C levels is reserved mostly for individuals with established CHD and for patients with risk factors for CHD.

Pharmacotherapy

Most individuals are diagnosed with HA based on the results of a routine lipid profile measurement. This finding of a low HDL-C level can be useful as an independent factor in assessing coronary artery disease risk and further management. Recently, the third report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults ATP III published its guidelines on the US National Heart, Lung and Blood Institute Web site (see www.nhlbi.org) and in the Journal of the American Medical Association. In these guidelines, the importance of HDL-C was emphasized and 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.

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 panel stated "Low HDL-C is a strong independent predictor of Coronary heart disease (CHD). In ATP III, low HDL-C is defined categorically as a level <40 mg/dl, a change from the level of <35 mg/dl in ATP II (published in 1993). In the present guidelines, low HDL-C both modifies the goal for LDL-lowering therapy and is used as a risk factor to estimate 10-year risk for CHD."

According to the ATP III document, "Low HDL cholesterol levels have several causes, many of which are associated with insulin resistance, i.e., elevated triglycerides, overweight, and obesity, physical inactivity, and type 2 diabetes. Other causes are cigarette smoking, very high carbohydrate intake (>60% of calories), and certain drugs (e.g., beta-blockers, anabolic steroids, and progestational agents)."

• Management strategy: As specified in the current NCEP guidelines, "ATP III does not specify a goal for HDL raising. 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. Nonetheless, a low HDL should receive clinical attention and management according to the following sequence:"

• LDL is the primary target. "In all persons with low HDL cholesterol, the primary goal of therapy is to lower LDL (low density lipoprotein) cholesterol. ATP III guidelines should be followed to achieve the LDL cholesterol goal."
• Metabolic syndrome is the second target. "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 when three or more of the following risk factors are present: 1. Abdominal obesity, with waist circumference of >102 cm or >40" for men, and >88 cm or >35" for women, 2. Triglycerides equal to or >150 mg/dl, 3. HDL cholesterol <40 mg/dl for men, and <50 mg/dl for women, 4. Blood pressure equal to or >130 systolic, and equal to or >85 mm hg diastolic, and 5. Fasting glucose equal to or >110 mg/dl)."
• Association with hypertriglyceridemia needs attention. "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, 1. In the patients with established CHD, or CHD risk equivalent (10-year risk for CHD >20%), the 'LDL' goal is <100 mg/dl; or the 'non-HDL cholesterol' goal is <130 mg/dl. 2. 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. 3. 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: "If the triglycerides are <200 mg/dl (isolated low-HDL cholesterol), drugs for raising HDL (fibrates or nicotinic acid) can be considered. Statins have only modest effect. Treatment for isolated low HDL cholesterol is mostly reserved for persons with CHD and CHD risk equivalents."

• Identify persons who eat a very low-fat diet. A low HDL-C level in this setting is rarely associated with 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-C levels. Control diabetes optimally, and aggressively treat LDL-C, regardless of the HDL-C levels.
• Consider estrogen replacement therapy for postmenopausal women because this can substantially raise HDL-C levels.
• Whether to use pharmacologic agents to raise the HDL-C level in otherwise healthy persons is unclear 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 including a family history, measurements of apolipoprotein and lipoprotein Lp(a), and electron beam computed tomography.

• 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-C levels that are being managed pharmacologically, and niacin is added to raise their HDL-C level if it is low.
• Gemfibrozil and fenofibrate modestly raise the HDL-C level. They are most effective in the setting of concomitant hypertriglyceridemia.
• Statins only mildly raise HDL-C 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 triglycerides or by cigarette smoking, inactivity, hypertension, or a diet very high in carbohydrates or polyunsaturated fats.

CETP Inhibition Therapy

Another pharmacologic approach geared towards raising HDL levels involves inhibiting cholesteryl ester transfer protein (CETP). The CETP helps exchange cholesterol between lipoproteins and can transfer it from HDL to the LDL and VLDL. Individuals with a genetic mutation that causes loss of all CETP activity have very high levels of HDL cholesterol. They appear to be at lower risk of coronary disease. A small study in 2004 involving 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, and shown not only to increase HDL levels, but also to prevent heart problems through outcome studies.

HDL-infusion therapy

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. These people had a protein in their HDL, now called apo A-I Milano, that seemed to be better at stimulating the removal of cholesterol from plaques than did HDL containing the normal protein, called apo A-I. Researchers recently tested whether a synthetic version of apo A-I Milano (recombinant ApoA-1 Milano/ phospho-lipid complexes, ETC-216) infused into the blood of people who didn’t naturally have this protein would have the same effect. The small trial randomly assigned 47 people who had recently had heart attacks to receive either a placebo or a low or high dose of thischemical. Through ultrasounds of the arteries, researchers found that from the beginning to the end of the five-week trial, the plaque in the treatment groups shrank by 4%, while that of the placebo group increased by a small amount. Although these are exciting results, a larger trial with such 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, and is not recommended for CAD prevention due to demonstrated lack of benefit and 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. Events increased 50% with HRT during year 1 but then progressively decreased to 33% lower by study end. The early increase may have resulted from pro-thrombotic and/or pro-inflammatory effects of HRT, while the later decrease may have reflected the 8% increase in HDL-C and/or other antiatherosclerotic mechanisms. Results of HRT in primary prevention await completion of the Women's Health Initiative in 2007.

Fish Oil Capsules

Since dietary modification to increase the consumption of cold-water fish (e.g., salmon) rich in polyunsaturated fats may help to raise HDL, capsules containing omega-3 fatty acids (1.48 grams of docosahexaenoic acid and 1.88 grams of eicosa-pentaenoic acid) have been studied in small trials. In a recent 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 the antioxidant HDL-associated enzyme paraoxonase were also increased by 10%.

None of these HDL-raising therapies have been studied in the Asian Indians. And, therefore, no particular treatment recommendations can be made at this juncture. The treatment strategies, nonetheless, appear well suited for this subpopulation with high prevalence of hypoalphalipoproteinemia (Low HDL-cholesterol).

Surgical Therapy

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 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 management of the metabolic syndrome

Additional Consultations

Always consider secondary causes of low HDL levels, especially medications, smoking habits, dietary patterns, and physical activity. Patients with elevated TG levels (>500 mg/dL) commonly have low HDL-C 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 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 Requirements

Very low-fat diets are associated with low HDL-C levels. However, because no data are available that show reduction of the risk of CHD upon raising the HDL-C levels, no particular dietary interventions are needed for this specific purpose. In fact, increasing the fat content in the patient's diet is not recommended. Dietary management should follow the NCEP guidelines for lowering frequently associated LDL-C, which is the primary target in lipid management, and lowering of 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 total calories (energy). Cholesterol intake should be reduced to less than 200 mg/d. Keep trans fatty acids (the HDL-lowering, LDL-raising fats) 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.
• The total amount of energy consumed must be balanced in terms of energy intake and expenditure to maintain desirable body weight and to prevent weight gain.

Daily Physical Activity

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, expending approximately 840 kJ/d.

References

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