Disorders of High-Density Lipoprotein (HDL)

A 35-year-old healthy woman is seen at the endocrine clinic for above-normal high-density lipoprotein (HDL). Her triglyceride level is 200mg/dl, and low- density lipoprotein (LDL) is 90mg/dl, with HDL of 129mg/dl. She has no risk factors for coronary artery disease (CAD), except that her father died of premature coronary artery disease at the age of 42.

How does one approach a patient with abnormal HDL? When is HDL protective and when is it not? How do we treat low HDL? This editorial discusses those questions as well as when to consider genetic testing in patients with HDL disorders.

HDL mobilizes cellular cholesterol and transport of cholesterol for hepatic uptake.1 Cholesterol carried by HDL is sometimes referred to as “atheroprotective cholesterol,” because it transports cholesterol away from lipid-laden cells (macrophages) known as foam cells in arteries and tissues to the liver for excretion and reutilization.1 Therefore, HDL may help prevent atherosclerosis and reduce macrophage accumulation.

HDL-cholesterol (HDL-C) refers to free cholesterol and cholesterol ester carried by HDL in the circulation. In practice, the terms HDL and HDL-C often are used interchangeably. Lipoproteins Apo A-I and Apo A-II are the major structural components of HDL.2 In healthy individuals, around 30 percent of cholesterol is carried by HDL.1 HDL-C has an inherited basis in 40 to 80 percent of cases.3 Extreme levels of HDL-C can have a polygenic origin.3

U.S. National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines define an HDL-C of 60 mg/dL or greater as a negative risk factor.4 Low HDL-C level is below 40 mg/dL in men and less than 50mg/dL in women.4

Factors that increase HDL-C include female gender5 and moderate alcohol intake.6 Age is positively correlated with HDL-C.7 Elevated HDL-C usually correlates with decreased cardiovascular risk in observational analyses.1 However, high HDL-C levels caused by genetic disorders such as cholesteryl ester transfer protein (CETP) deficiency, primary familial hyperalphalipoproteinemia and endothelial lipase deficiency may not protect against cardiovascular disease.8,9,10 Patients with promoter variants of hepatic lipase(LIPC) have elevated HDL-C and, paradoxically, increased cardiovascular risk.11

Secondary causes of high HDL-C include primary biliary cirrhosis and thyroid disorders, possibly because of increased phospholipid to protein ratio and effect on hepatic lipase, respectively.12,13 High HDL-C in patients not taking lipid-lowering drugs should prompt a diagnostic evaluation, including hepatic function and thyroid-stimulating hormone levels.

Primary causes of high HDL-C are genetic mutations causing overproduction or decreased HDL clearance. CETP deficiency is an autosomal recessive disorder caused by CETP gene mutation.14 CETP facilitates transfer of cholesterol esters from HDL to other lipoproteins. Affected patients have asymptomatic elevation of HDL cholesterol above 150 mg/dL.14

Primary familial hyperalphalipoproteinemia is an autosomal-dominant condition caused by genetic mutations of Apo protein A-I overproduction or Apo protein C-III variants. It is diagnosed incidentally with plasma HDL-C levels above 80 mg/dL9.

Even though high HDL does not need to be treated, per se, the patient needs counseling to avoid risk factors such as smoking in light of her family’s CAD history. It has to be considered that the high HDL, in her case, is not likely to protect against CAD.

Low HDL, in general, is associated with increased CAD risk.15 Obesity, a high- fat diet, a lack of physical activity, and smoking are among the modifiable risk factors low HDL-C levels.16,17 Type 2 diabetes mellitus is also associated with reduced HDL-C levels.16

Multiple epidemiological studies and the landmark Framingham Heart Study have shown that low HDL-C represents a significant and independent predictor of cardiovascular disease (CVD).15,18,19,20

Genetic disorders causing low HDL are Apo lipoprotein A-1 (Apo A-I) deficiency, lecithin: cholesterol acyltransferase (LCAT) deficiency, and ATP-Binding Cassette Transporter A1 (ABCA1) deficiency, all of which are rare and autosomal-recessive.21 Apo A-I mutations cause the most elevation in cardiovascular risk compared with other gene mutations in HDL metabolism. Not all genetic forms of very low HDL-C are associated with increased risk of CVD.22

Apo A-I deficiency is characterized by the absence of apoA-I, whereas LDL-C and triglyceride levels are not affected.23 Symptoms include xanthomas and corneal opacities. Heterozygotes of the Apo A-I Milano variant exhibit low HDL-C levels but reduced CAD,22 whereas carriers of the Apo A-I Paris variant are protected against CAD.22 LCAT converts free cholesterol into cholesteryl ester.

LCAT deficiency causes accelerated catabolism of Apo A-I and ApoA-II and low HDL. Heterozygotes have 40 percent reductions in HDL- C. Symptoms include corneal opacity in partial LCAT deficiency (fish eye), proteinuria, and anemia. Both partial LCAT deficiency and familial LCAT deficiency increase the risk of premature CAD.23,24

Patients with ABCA1 gene mutations (Tangier disease), are not at increased cardiovascular risk as these patients can have cholesterol delivered onto more mature HDL via the ABCG1 (ATP- Binding Cassette G1) Transporter.25,26 In Tangier disease, ABCA1 function is impaired. Apo A-I cannot be lipidated, leading to rapid clearance that results in significantly reduced levels of Apo A-I and the presence of small pre–β-HDL particles. Symptoms include peripheral neuropathy, hepatosplenomegaly, corneal opacities, and thrombocytopenia and intracellular accumulation of cholesterol ester deposition in lymphoid organs.25,26 Plasma levels of Apo A-I are reduced to about 3 percent of normal, and triglyceride levels are increased along with reduced LDL-C (50 percent of normal).26

Treatments for LDL cholesterol and triglycerides often increase HDL cholesterol, and the three objectives can sometimes be achieved simultaneously. The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study27 and the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/ High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH)28 trial failed to demonstrate that an increase in HDL-C with niacin in statin-treated patients resulted in a reduced CAD risk. Fibrates and CETP inhibitors (dalcetrapib) have failed to demonstrate cardiovascular outcome benefits, in spite of increasing HDL-C levels.14,29

Recombinant HDL (Apo protein A-1 Milano) is a possible future treatment option for atherosclerosis.

A patient with high or low HDL and a family history of cardiovascular disorders makes a case for genetic testing. A family history of longevity is reassuring in a patient with extremes of HDL levels with no other risk factors.

Disclosure statement: Dr. Ramachandra Pai has no disclosures to report.

References are listed on page 36 of the PDF.


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