Causes and Natural History of Dyslipidemias

Conditions:High Cholesterol, Peripheral Vascular Disease, Cardiology
Therapuetic Areas:Cardiology / Vascular Diseases
Age Range:2 - 100
Start Date:January 1, 2004
Contact:Robert D Shamburek, M.D.
Phone:(301) 496-3460

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Disease Pathogenesis and Natural History of Lipid Disorders

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

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.


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

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.


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.
We found this trial at
9000 Rockville Pike
Bethesda, Maryland 20892
Phone: 800-411-1222
Bethesda, MD
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