Familial Hypercholesterolemia

National Organization for Rare Disorders, Inc.

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It is possible that the main title of the report Familial Hypercholesterolemia is not the name you expected.

Disorder Subdivisions

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General Discussion

Familial hypercholesterolemia (FH) is a diagnosis which refers to individuals with very significantly elevated low-density lipoprotein (LDL) cholesterol (LDL-C) or "bad cholesterol". In heterozygous familial hypercholesterolemia (HeFH), an individual inherits a mutation (alteration) for FH from one (affected) parent. In homozygous familial hypercholesterolemia (HoFH), an individual inherits a causal FH mutation from both parents. For the purposes of this report, "FH" will refer to HeFH unless otherwise stated.

FH is one of the most common genetic diseases and affects at least 1 in 500 individuals. This may be an underestimate as recent genetic studies indicate that FH may be as common as 1 in 250 in European Caucasian populations. If DNA testing is performed, most (60-80%) will be found to have a mutation in one of three relevant genes. Others may express these clinical findings for other reasons or may carry a mutation in a gene or genes that have yet to be discovered.

FH is characterized by very high levels of LDL-C, as well as of total cholesterol. The condition greatly increases the risk of hardening of the arteries (atherosclerosis), which can lead to heart attacks, strokes and other vascular conditions. Individuals with FH have a 20-fold increased risk for coronary heart disease (CHD). Untreated men have a 50% risk of a nonfatal or fatal coronary event by age 50 years; untreated women have a 30% risk by age 60 years. If one or more other risk factors for CHD are present, especially cigarette smoking or diabetes mellitus, the risk of developing symptomatic CHD is even higher.

FH is treatable and the associated cardiovascular disease is largely preventable with early and intensive treatment, using statins, additional drugs, and other means. Family members of an affected individual found through "cascade screening" or "family tracing" who have not yet exhibited symptoms and who are appropriately treated are likely to live a normal lifespan.

HoFH is very rare (~ 1 in 250,000 to 1 in 1 million). LDL-C levels are usually, though not always, > 400 mg/dl. Severe vascular disease including CHD and aortic stenosis are often seen by the teenage years. Without very aggressive treatment including LDL-C apheresis and HoFH specific medications, mortality is common before age 30.
In 1973, Joseph Goldstein and Michael Brown identified and characterized a cell membrane protein they called the LDL receptor and the mutations in the low-density lipoprotein receptor gene (LDLR) that interfered with its function. Normally functioning receptors lower the blood levels of LDL-C by taking up the lipoproteins that carry LDL-C in the liver. Mutations in this gene cause a decrease either in the number or function of the receptors, resulting in the extreme LDL-C elevations seen in FH. Goldstein and Brown became the first investigators to identify a mutation that caused a metabolic disorder when only a single abnormal gene was present. In 1985 they won the Nobel Prize in Medicine for this work. Their pioneering work and the subsequent studies of LDL-C metabolism in FH patients greatly contributed to our knowledge about the link between cholesterol and heart disease and led to the development of numerous therapeutic agents that benefit a very large number of individuals with high cholesterol. Since that time, other genes causing FH such as the apolipoprotein B-100 gene (APOB) and the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) have been identified (see below).

Importantly, there is a great deal of evidence showing that early diagnosis and intensive treatment can prevent illness and death due to FH.

Supporting Organizations

American Heart Association

7272 Greenville Avenue
Dallas, TX 75231
Tel: (214)784-7212
Fax: (214)784-1307
Tel: (800)242-8721
Email: Review.personal.info@heart.org
Website: http://www.heart.org

FH Foundation

1515 Hope Street
Suite 204
South Pasandena, CA 91030
Tel: (626)465-1234
Fax: (626)628-2146
Email: info@theFHfoundation.org
Website: http://www.thefhfoundation.org

Genetic and Rare Diseases (GARD) Information Center

PO Box 8126
Gaithersburg, MD 20898-8126
Tel: (301)251-4925
Fax: (301)251-4911
Tel: (888)205-2311
Website: http://rarediseases.info.nih.gov/GARD/

International FH Foundation

St. Andrews Court
Wellington St.
Oxfordshire, OX9 3WT
Tel: 01235 531 203
Email: ask@fh-foundation.org
Website: http://www.fh-foundation.org

NIH/National Heart, Lung and Blood Institute

P.O. Box 30105
Bethesda, MD 20892-0105
Tel: (301)592-8573
Fax: (301)251-1223
Email: nhlbiinfo@rover.nhlbi.nih.gov
Website: http://www.nhlbi.nih.gov/

For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders (NORD). For a full-text version of this report, go to www.rarediseases.org and click on Rare Disease Database under "Rare Disease Information".

The information provided in this report is not intended for diagnostic purposes. It is provided for informational purposes only.

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This disease entry is based upon medical information available through the date at the end of the topic. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder.

Last Updated:  10/19/2015
Copyright  2014 National Organization for Rare Disorders, Inc.