Marked HDL deficiency and premature coronary heart disease

Abstract

Purpose of review: Our purpose is to review recent publications in the area of marked human HDL deficiency, HDL particles, coronary heart disease (CHD), amyloidosis, the immune response, and kidney disease.

Recent findings: Lack of detectable plasma apolipoprotein (apo) A-I can be due to DNA deletions, rearrangements, or nonsense or frameshift mutations within the APOA1 gene resulting in a lack of apoA-I secretion. Such patients have marked HDL deficiency, normal levels of triglycerides and LDL cholesterol, and can have xanthomas and premature CHD. ApoA-I variants with amino acid substitutions, especially in the region of amino acid residues 50-93 and 170-178, have been associated with amyloidosis. Patients with homozygous Tangier disease have defective cellular cholesterol efflux due to mutations in the adenosine triphosphate-binding cassette transporter A1, detectable plasma apoA-I levels and prebeta-1 HDL in their plasma. They have decreased LDL cholesterol levels and can develop neuropathy and premature CHD. Patients with lecithin: cholesterol acyltransferase deficiency have both prebeta-1 and alpha-4 HDL present in their plasma and develop corneal opacities, anemia, proteinuria, and kidney failure.

Summary: Patients with marked HDL deficiency can have great differences in their clinical phenotype depending on the underlying defect.

Figures

Figure 1. In the left panel the plasma apoA-I pattern obtained after two-dimensional gel electrophoresis is shown. To the right a schematic diagram of all the A-I containing HDL particles is shown

Particles are separated by size (diameter in nm) in the vertical dimension and by charge in the horizontal dimension into particles of preβ, α, and preα mobility.

Figure 2. A composite of the HDL gel patterns is shown

A composite is shown of the HDL gel patterns observed in a normal subject (far left), a homozygote with apoA-I deficiency (second gel from left), a Tangier homozygote (third gel from left), and a homozygote with LCAT deficiency (fourth from left). Also shown are gels from patients with lipoprotein lipase (LPL) deficiency (fifth from left), hepatic lipase deficiency (second from right), and cholesteryl ester transfer protein (CETP) deficiency (farthest to the right).

Figure 3

In this figure we have depicted results obtained when apoA-I HDL gels are also immunoblotted with antibodies containing apoA-II (far left), apoA-IV (second from left), apoC-I (third from left), apoC-III (second from right) and apoE (far right)

Figure 4. Models of apoA-I containing HDL particles are shown

The two small particles, preβ-1 and α-4 HDL are discs containing apoA-I without apoA-II. Medium-sized α-3 and α-2 HDL are shown, which are spherical particles containing both apoA-I and apoA-II, with α-2 HDL also containing serum amyloid A protein. The large spherical α-1 HDL particle is also shown

Figure 5

Findings in homozygous familial apolipoprotein deficiency are shown: tubo-eruptive xanthomas (upper left), with microscopy (lower right); planar xanthomas in the wrist area (upper right), moderate corneal opacification (lower left), and a normal eye fundus (lower middle)

Figure 6

Computed tomographic image of the heart of a 39-year-old patient with homozygous familial apolipoprotein A-I deficiency indicating marked coronary calcification in the left anterior descending coronary artery is shown

Figure 7

Coronary angiography of a 39-year-old patient with homozygous apoA-I deficiency is shown documenting complete obstruction of the left anterior descending coronary artery

Figure 8. A multidetector 64 slice computed tomographic angiographic image of a 39-year-old patient with homozygous familial apoA-I deficiency with premature coronary artery is shown

The aorta was normal, but significant narrowing of the left anterior descending coronary artery and the diagonal branches were noted, and the right coronary artery was totally obstructed, with a vein graft to the distal right coronary artery

Figure 9

A photograph of the enlarged orange tonsils from a patient with homozygous Tangier disease is shown

Figure 10

Electron micrographs of the cholesteryl ester deposition in the macrophages in the tonsils, bone marrow, nerve cells, and smooth muscle cells in a patient with homozygous Tangier disease are shown

Figure 11

A coronary angiogram in a 56-year-old patient with homozygous Tangier disease is shown documenting the presence of significant coronary artery disease in the right and left anterior descending coronary arteries

Figure 12

A diagram depicting our view of HDL particle metabolism is shown