Low HDL Cholesterol (Hypoalphalipoproteinemia)

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 esters, 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 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 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 acyltransferase (LCAT) deficiency, and Tangier disease, do not always correlate with more frequent CHD. ^{[8, 9]}

Results from the Framingham Heart Study offspring cohort, in which 3590 individuals without known cardiovascular disease were studied from 1987 to 2011, found that cardiovascular risk was not only associated with HDL cholesterol alone but also was associated with a combination of HDL levels and levels of LDL cholesterol and triglycerides. ^[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 cholesterol 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.

In a whole-exome sequencing study of 204 patients with low HDL cholesterol levels (mean, 27.8 mg/dL), researchers identified 120 occurrences of probably damaging variants among 45 of 104 recognized HDL candidate genes, with ABCA1 (n=20) and LDLR showing genome-wide significance. The findings highlight the genetic complexity of HA. ^[14]

Familial lecithin-cholesterol acyltransferase (LCAT) deficiency

LCAT is a lipoprotein-associated enzyme that plays a large role in the esterification of free cholesterol, the maturation of HDL particles, and the intravascular stage of reverse cholesterol transport (described below). LCAT, which is bound to HDL and LDL cholesterol in the plasma, catalyzes the formation of cholesterol esters in lipoproteins as follows:

• Unesterified cholesterol + phosphatidylcholine → cholesterol ester + lysophosphatidylcholine

Familial LCAT deficiency is a very rare autosomal recessive disorder characterized by corneal opacities, normochromic anemia, and renal failure in young adults, 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). ^{[15, 16]}

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). ^{[17, 18]} 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. ^[15]

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). ^{[19, 20]} 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. ^{[21, 22]}

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 the cholesterol is then 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. ^[23]

Table. Hypoalphalipoproteinemia (Open Table in a new window)

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 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 acyltransferase (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, and 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). ^[24]

United States statistics

Hypoalphalipoproteinemia is frequently found in patients with CHD. Research indicates that 58% of patients with CHD have HDL cholesterol levels below the 10th percentile of normal values.

National Center for Health Statistics (NCHS) data briefs 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 to 13.8% between August 2021 and August 2023. ^{[25, 26]}

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 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.

Morbidity/mortality

HA is associated with an increased risk of recurrent coronary episodes and mortality caused by CHD, and it constitutes a significant risk factor for the development of premature (accelerated) atherosclerosis.

Although some documented cases of premature atherosclerosis have been reported in individuals with familial LCAT deficiency and fish-eye disease (partial LCAT deficiency), premature atherosclerosis in these conditions remains a controversial topic. ^{[27, 28, 29]} Ossoli et al reviewed several studies on the role of LCAT in atherosclerosis. They concluded that the available data is contradictory but that it clearly supports the concept that reduced plasma LCAT concentrations are not necessarily associated with increased atherosclerosis, despite the low HDL cholesterol levels. They speculated that the preserved macrophage cholesterol removal associated with decreased LCAT function may be the reason why atherogenesis is not increased in these patients. ^[30]

The major morbidity and mortality in familial LCAT deficiency is related to renal failure, with proteinuria manifesting in childhood and end-stage renal disease in adulthood, requiring renal replacement. ^{[31, 32]} In fish-eye disease, the major morbidity is visual impairment from corneal opacities.

Complications

Complications of HA include the following:

• Premature atherosclerosis
• Corneal opacification