Causes and Natural History of Dyslipidemias

This study will evaluate people with dyslipidemias - disorders that affect the fat content in the blood. Fats, or lipids, such as cholesterol and triglycerides, are carried in the blood in particles called lipoproteins. These particles are involved in causing blood vessel diseases that can lead to conditions like atherosclerosis (hardening of the arteries) or heart attack. Participants will undergo accepted medical tests and procedures to evaluate their condition. Most of the test results are helpful in making a diagnosis and in guiding treatment.

People with lipid disorders are eligible for this study. Representative types of patients include those with:

• Plasma cholesterol levels greater than 200 mg/dl or less than 120 mg/dl
• Plasma LDL-C levels greater than 130 mg/dl or less than 70 mg/dl
• Plasma HDL-C levels greater than 70 mg/dl or less than 25 mg/dl
• Unusual cholesterol deposits or xanthomas (nodules of lipid deposits on the skin)

Children under 2 years of age are excluded from the study.

Participants will undergo some or all of the following procedures:

• Plasma evaluation. Apolipoproteins (plasma proteins involved in metabolism of cholesterol, triglycerides, phospholipids, and proteins in the blood) and enzymes involved in lipid metabolism are measured.
• Fat biopsy. A small sample of fat tissue is collected for examination. For this test, an area on the buttock or abdominal wall is numbed. A needle is inserted into the fat, and a small amount of tissue is sucked out by a syringe.
• Leukapheresis. White blood cells are collected to help diagnose the lipid disorder. For this test, blood is collected through a needle in an arm vein, similar to donating blood. The blood circulates through a machine that separates it into its components, and the white cells are removed. The rest of the blood is returned to the body, either through the same needle or through another needle in the other arm.
• Skin biopsy. Skin cells are collected for study. The cells are grown in the laboratory and the amount of cholesterol that enters or leaves the cells is measured, providing information on abnormalities in cholesterol transport. For this test, an area of skin is numbed with an anesthetic and a small circular area is removed, using a skin punch instrument similar to a sharp cookie cutter.
• Heparin infusion study. Heparin, a blood thinner, releases enzymes that break down fat in the blood. Lipase activity (breakdown of fats) in the blood is measured following the injection of heparin into a vein.

The lipoprotein transport system is vital to the delivery of the hydrophobic fats that are carried in the aqueous environment of the blood. The lipoprotein particles that comprise this system are polydisperse and contain triglycerides, free and esterified cholesterol, phospholipids and proteins. Inborn errors in the lipoprotein transport system lead to alterations in both the steady state concentrations of the various lipoproteins and in the metabolism of these particles. These inborn errors lead to both hyperlipoproteinemia and hypolipoproteinemia. Profound changes in the ambient lipoprotein concentrations have a variety of clinical manifestations. The present study protocol is designed to permit a full evaluation of the lipids, lipoproteins and apolipoproteins, in patients with potential genetic defects in these processes. We will use a variety of diagnostic procedures and assays that represent standard of care in tertiary referral hospitals but which are not standardized or CLIA-Certified and, in some cases, require isolation of tissue and blood cell samples. These specialized assays are necessary to correctly diagnose and treat patients that present with the more unusual disorders of lipid metabolism; these patients cannot be diagnosed by standard, CLIA-Certified assays and may require tissue or blood cells for diagnosis and adequate treatment. The study population will include patients which are referred to the Molecular Disease Branch from private care providers, academic institutions or the NHLBI-MDB website, with any of the following potential lipid abnormalities or clinical stigmata associated with dyslipoproteinemias: a) increased plasma levels of cholesterol, triglycerides, HDL-cholesterol or LDL-cholesterol; b) decreased plasma concentrations of cholesterol and HDL-cholesterol; c) postprandial hyperlipidemia or d) eruptive xanthomas, xanthelasma, tuberous or tendinous xanthomas, or corneal opacities.

• Iverius PH, Ostlund-Lindqvist AM. Preparation, characterization, and measurement of lipoprotein lipase. Methods Enzymol. 1986;129:691-704. No abstract available.
• Santamarina-Fojo S, Brewer HB Jr. The familial hyperchylomicronemia syndrome. New insights into underlying genetic defects. JAMA. 1991 Feb 20;265(7):904-8. No abstract available.
• Chait A, Iverius PH, Brunzell JD. Lipoprotein lipase secretion by human monocyte-derived macrophages. J Clin Invest. 1982 Feb;69(2):490-3.

• INCLUSION CRITERIA:

The following is a representative list of the types of patient presentations and potential diagnoses eligible for this protocol:

1. Plasma cholesterol levels greater than 200 mg/dl or less than 120 mg/dl - includes patients with diagnoses such as familial hypercholesterolemia, familial combined hyperlipidemia, sitosterolemia, lipoprotein lipase, hepatic lipase or apo-CII deficiency, and dysbetalipoproteinemia.
2. Plasma LDL-C levels greater than 130 mg/dl or less than 70 mg/dl - includes patients with diagnoses such as familial hypercholesterolemia, familial combined hyperlipidemia, lipoprotein lipase, hepatic lipase or apo-CII deficiency, sitosterolemia, dysbetalipoproteinemia, abetalipoproteinemia and hypobetalipoproteinemia.
3. Plasma HDL-C levels greater than 70 mg/dl or less than 25 mg/dl - includes patients with deficiency of cholesteryl ester transfer protein, lecithin cholesterol acyltransferase, phospholipid transfer protein, lipoprotein lipase, hepatic lipase, or apo-CII, and Tangier disease.
4. Plasma triglyceride levels greater than 150 mg/dl - includes patients with deficiency of lipoprotein lipase, hepatic lipase or apoC-II, dysbetalipoproteinemia, Type IV and Type V hyperlipidemia.

EXCLUSION CRITERIA

1. Inability to provide informed consent. In order for cognitively impaired individuals to participate in this protocol, consent will be obtained from the patient's legal guardian. Participating in this protocol will benefit this population of patients since it will facilitate the accurate diagnosis and treatment of their dyslipidemia. Since all of the procedures and assays listed in this protocol are not of an experimental nature, but represent standard of care in tertiary referral hospitals, no further protections need to be in place.
2. Prisoners or other institutionalized persons will be not be allowed to participate because of the possible need for prolonged stay in the Clinical Center.
3. Children less than 2 years of age.