Clinical presentation, laboratory values, and coronary heart disease risk in marked high-density lipoprotein–deficiency states

Abstract

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.

Genetic causes of high and low serum HDL-cholesterol

“…clinical symptoms ( 41,42 ). Approximately 25 patients with apoAI defi ciency owing to nonsense mutations, a chromosomal aberration or deletion, have been reported thus far ( 41,(43)(44)(45)(46)(47).…”

“…Approximately 25 patients with apoAI defi ciency owing to nonsense mutations, a chromosomal aberration or deletion, have been reported thus far ( 41,(43)(44)(45)(46)(47). Structural mutations in the APOA1 gene such as missense mutations are a frequent cause of FHA (15-35 mg/dl) ( 48,49 ).…”

“…However, because cholesterol accumulates in many tissues throughout the body (tonsils, liver, spleen, Schwann cells), the major clinical fi ndings are enlarged orange tonsils, hepatomegaly, splenomegaly, and occasionally mild corneal opacifi cation ( Table 1 ) ( 41,42 ). Furthermore, about 50% of the cases present peripheral neuropathy, a life quality-limiting symptom ( 41,55 ), and several present hematological fi ndings, mainly thrombocytopenia ( 42 ). Fibroblasts from patients show a defective cholesterol and phospholipid effl ux to apolipoproteins ( 21,56 ).…”

“…A complete loss of apoAI (apoAI defi ciency [MIM 604091]) results in a profound decrease in HDL-C (<5 mg/dl) and an increased risk of premature CAD ( Table 1 ) ( 15,20,41 ). ApoAI defi ciency patients can be distinguished from other causes of HDL defi ciency by the complete absence of plasma apoAI (0 mg/dl, undetectable) and normal levels of LDL-C and TGs ( Table 1 ).…”

“…In LCAT disorders, free cholesterol is greatly increased in the plasma and peripheral tissues, because it cannot be converted to cholesterol esters, which leads to the inability to form mature HDL particles (i.e., large spherical) and thus to rapid clearance of apoAI with only discoidal HDL particles present in plasma (pre-␤ HDL and ␣ -4 HDL) ( 21,41 ). FLD patients also present highly abnormal apoB-containing lipoproteins, hemolytic anemia associated with an increased content of cholesterol in red cells, proteinuria, and progressive renal disease ( 42 ).…”