Causes and Natural History of Dyslipidemias

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 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.

Study Overview

• Status: Recruiting
• Conditions: Atherosclerosis; Hypercholesterolemia

Detailed Description

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 plasma evaluation of the lipids, lipoproteins and apolipoproteins, in patients with potential genetic defects in these processes. We will use a variety of research plasma assays. These specialized plasma 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 Lipid Service, Cardiovascular Branch, NHLBI 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.

• Study Type: Observational
• Enrollment (Estimated): 2000

Contacts and Locations

• Study Contact: Name: Robert D Shamburek, M.D.; Phone Number: (301) 496-3460; Email: bobs@mail.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 100 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Unlimited

Description

• INCLUSION CRITERIA:
• Children >= 2 years of age and >12 kg and adults
• Dyslipidemia subjects of interest the group

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

• Plasma cholesterol levels >200 mg/dl or <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.
• Plasma LDL-C levels >130 mg/dl or <70 mg/dl includes patients with diagnoses such as familial hypercholesterolemia, PCSK9, apo3500, familial combined hyperlipidemia, sitosterolemia, dysbetalipoproteinemia, abetalipoproteinemia and hypobetalipoproteinemia.
• Plasma HDL-C levels >70 mg/dl or <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, ANGPTL3, and Tangier disease.
• Plasma triglyceride levels >150 mg/dl includes patients with deficiency of lipoprotein lipase, hepatic lipase or apoC-II, GPIHBP1, LMF1, dysbetalipoproteinemia, Type I, Type IV and Type V hyperlipidemia.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Dyslipidemia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
permit a full evaluation of the lipoproteins, apolipoproteins, and cellular enzymes and receptors relevant to lipoprotein metabolism in order to accurately diagnose and treat patients with potential genetic defects in these processes	Evaluate Lipids	25 years

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Robert D Shamburek, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Iverius PH, Ostlund-Lindqvist AM. Preparation, characterization, and measurement of lipoprotein lipase. Methods Enzymol. 1986;129:691-704. doi: 10.1016/0076-6879(86)29099-0. 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. doi: 10.1172/jci110473.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): October 14, 2003

Study Registration Dates

• First Submitted: July 18, 2006
• First Submitted That Met QC Criteria: July 18, 2006
• First Posted (Estimated): July 19, 2006

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: March 12, 2024

More Information

Terms related to this study

• Keywords: Natural History; Triglyceride; Phospholipids; Free and Esterfied Cholesterol; Polydisperse; Lipoprotein Transport System
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia; Atherosclerosis
• Other Study ID Numbers: 030280; 03-H-0280

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No