Low HDL Cholesterol (Hypoalphalipoproteinemia) Workup

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