Our purpose is to provide a framework for diagnosing the inherited causes of marked
high-density lipoprotein (HDL) deficiency (
HDL cholesterol levels <10 mg/dL in the absence of severe
hypertriglyceridemia or
liver disease) and to provide information about
coronary heart disease (CHD) risk for such cases. Published articles in the literature on severe HDL deficiencies were used as sources. If
apolipoprotein (
Apo) A-I is not present in plasma, then three forms of
ApoA-I deficiency, all with premature CHD,and normal
low-density lipoprotein (
LDL) cholesterol levels have been described:
ApoA-I/C-III/A-IV deficiency with fat malabsorption,
ApoA-I/C-III deficiency with planar
xanthomas, and
ApoA-I deficiency with planar and tubero-eruptive
xanthomas (pictured in this review for the first time). If
ApoA-I is present in plasma at a concentration <10 mg/dL, with
LDL cholesterol that is about 50% of normal and mild
hypertriglyceridemia, a possible diagnosis is
Tangier disease due to mutations at the
adenosine triphosphate binding cassette
protein A1 (ABCA1) gene locus. These patients may develop premature CHD and
peripheral neuropathy, and have evidence of
cholesteryl ester-laden macrophages in their liver, spleen, tonsils, and Schwann cells, as well as other tissues. The third form of severe HDL deficiency is characterized by plasma
ApoA-I levels <40 mg/dL, moderate
hypertriglyceridemia, and decreased
LDL cholesterol, and the finding that most of the
cholesterol in plasma is in the free rather than the esterified form, due to a deficiency in
lecithin:cholesterol acyltransferase activity. These patients have marked corneal opacification and
splenomegaly, and are at increased risk of developing
renal failure, but have no clear evidence of premature CHD. Marked HDL deficiency has different etiologies and is generally associated with early CHD risk.