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Lipoprotein Disorders Microchapters
Patient Information
Overview
Causes
Classification Hyperlipoproteinemia Hypolipoproteinemia
Treatment

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: Broad beta disease; broad beta hyperlipoproteinemia; broad-beta hyperlipoproteinemia; dysbetalipoproteinemia; familial dysbetalipoproteinemia; familial hypercholesterolemia with hyperlipemia; type III hyperlipoproteinemia

Overview

Familial dysbetalipoproteinemia is a disorder passed down through families in which there are high amounts of cholesterol and triglycerides in the blood. This form is due to high chylomicrons and IDL (intermediate density lipoprotein). Also known as broad beta disease or dysbetalipoproteinemia, the most common cause for this form is the presence of ApoE E2/E2 genotype. It is due to cholesterol-rich VLDL (β-VLDL). Prevalence is 0.02% of the population.

Hyperlipoproteinemia type III, also known as dysbetalipoproteinemia or broad beta disease, is a rare genetic disorder characterized by improper breakdown (metabolism) of certain fatty materials known as lipids, specifically cholesterol and triglycerides. This results in the abnormal accumulation of lipids in the body (hyperlipidemia). Affected individuals may develop multiple yellowish, lipid-filled bumps (papules) or plaques on the skin (xanthomas). Affected individuals may also develop the buildup of fatty materials in the blood vessels (artherosclerosis) potentially obstructing blood flow and resulting in coronary heart disease or peripheral vascular disease. Most cases of hyperlipoproteinemia type III are inherited as an autosomal recessive trait.

Causes

A genetic defect causes this condition. The defect results in the build up of large lipoprotein particles that contain both cholesterol and triglycerides, a type of fat. The disease is linked to defects in the gene for apolipoprotein E in many cases.

Hypothyroidism, obesity, or diabetes can make the condition worse. Risk factors for familial dysbetalipoproteinemia include a family history of the disorder or coronary artery disease.

Most cases of hyperlipoproteinemia type III are inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.

Symptoms of hyperlipoproteinemia type III develop due to the improper function or imbalance of special proteins in the blood (protein-lipid molecules known as apo E) that transport cholesterol and other fats from one area of the body to another and help clear fats from the blood.

The gene that is responsible for the production of apo E is located on the long arm of chromosome 19 (19q13). The gene occurs in many forms (alleles), the three most common of which are known as e2, e3 and e4. Every person had two apo E genes in some combination of these various forms. Physicians consider apo e3 the “normal” form of the gene; others are considered mutations of the apo E gene.

Most cases of recessively inherited hyperlipoproteinemia type III result from inheritance of two genes that code for apo e2. Apo e2 clears dietary fats from the body at a slower rate than apo e3. However, the presence of two apo e2-coding genes by itself usually does not result in the development of symptoms of hyperlipoproteinemia type III. In fact, fewer than 10 percent of individuals with two genes coding for apo e2 ever develop outward symptoms of hyperlipoproteinemia type III. Researchers believe that additional genetic, environmental, or hormonal factors play a role in the development of the disorder. These factors may include the presence of other disorders (e.g., hypothyroidism, diabetes), obesity, or age. In women, low estrogen levels may contribute to the development of symptoms, which is why the disorder occurs in women after menopause.

There are approximately 25 additional, extremely rare variants of apo E, some of which also cause hyperlipoproteinemia type III. These rare variants of the apo E gene are inherited as autosomal dominant traits.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Individuals with the dominant forms of hyperlipoproteinemia type III may experience symptoms from birth. Additional genetic, environmental and hormonal factors may determine the severity of the disorder.

Differential Diagnosis

Symptoms of the following disorders can be similar to those of hyperlipoproteinemia type III. Comparisons may be useful for a differential diagnosis:

Hyperlipoproteinemias are a group of inherited lipid storage and transport diseases that are characterized by excessive levels of certain fats (lipoproteins) in the blood. In addition to hyperlipoproteinemia type III, this group of disorders includes hyperlipoproteinemia type I (familial hyperchylomicronemia); hyperlipoproteinemia type II (familial hyperbetalipoproteinemia); familial hyperlipoproteinemia type IV (carbohydrate induced hyperlipemia); and hyperlipoproteinemia type V (fat and carbohydrate hyperlipemia). Symptoms of all of these forms of hyperlipoproteinemia include the abnormal accumulation of fatty material in the walls that line medium and large arteries and the presence of multiple yellow fatty deposits (xanthomas) on certain areas of the skin. (For more information on these disorders, choose “Hyperlipoproteinemia” as your search term in the Rare Disease Database.)

Hyperlipoproteinemia type IV is an inborn error of metabolism characterized by an abnormal increase in the blood level of certain fats called triglycerides. The body’s ability to use sugar (glucose tolerance) may also be impaired. Symptoms include fatty nodules or plaques (xanthomas) on the arms, legs, and/or buttocks. Hyperlipoproteinemia type IV usually leads to the degeneration of blood vessels and heart disease. The liver and spleen may also be enlarged (hepatosplenomegaly). Hyperlipoproteinemia type IV is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Hyperlipoproteinemia Type IV” as your search term in the Rare Disease Database.)

Hyperlipoproteinemia type I (familial hyperchylomicronemia) is a rare inherited disorder that prevents children born with it from transporting dietary cholesterol and/or triglycerides properly. (Chylomicrons are another lipoprotein-complex essential to the transport of fat from the stomach to various organs of the body.) In this case, the presence of extremely high levels of triglycerides does not commonly lead to hardening of the arteries (atherosclerosis) but potentially serious inflammation of the pancreas (pancreatitis) may accompany the symptoms of this disorder. Severe abdominal pain is experienced after eating fatty foods. Fatty growths on the skin (eruptive xanthomas) are not uncommon. People with this form must minimize the eating of dietary fats of any kind.

Related Disorders

Symptoms of the following disorders can be similar to those of hyperlipoproteinemia type III. Comparisons may be useful for a differential diagnosis:

Hyperlipoproteinemias are a group of inherited lipid storage and transport diseases that are characterized by excessive levels of certain fats (lipoproteins) in the blood. In addition to hyperlipoproteinemia type III, this group of disorders includes hyperlipoproteinemia type I (familial hyperchylomicronemia); hyperlipoproteinemia type II (familial hyperbetalipoproteinemia); familial hyperlipoproteinemia type IV (carbohydrate induced hyperlipemia); and hyperlipoproteinemia type V (fat and carbohydrate hyperlipemia). Symptoms of all of these forms of hyperlipoproteinemia include the abnormal accumulation of fatty material in the walls that line medium and large arteries and the presence of multiple yellow fatty deposits (xanthomas) on certain areas of the skin. (For more information on these disorders, choose “Hyperlipoproteinemia” as your search term in the Rare Disease Database.)

Hyperlipoproteinemia type IV is an inborn error of metabolism characterized by an abnormal increase in the blood level of certain fats called triglycerides. The body’s ability to use sugar (glucose tolerance) may also be impaired. Symptoms include fatty nodules or plaques (xanthomas) on the arms, legs, and/or buttocks. Hyperlipoproteinemia type IV usually leads to the degeneration of blood vessels and heart disease. The liver and spleen may also be enlarged (hepatosplenomegaly). Hyperlipoproteinemia type IV is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Hyperlipoproteinemia Type IV” as your search term in the Rare Disease Database.)

Hyperlipoproteinemia type I (familial hyperchylomicronemia) is a rare inherited disorder that prevents children born with it from transporting dietary cholesterol and/or triglycerides properly. (Chylomicrons are another lipoprotein-complex essential to the transport of fat from the stomach to various organs of the body.) In this case, the presence of extremely high levels of triglycerides does not commonly lead to hardening of the arteries (atherosclerosis) but potentially serious inflammation of the pancreas (pancreatitis) may accompany the symptoms of this disorder. Severe abdominal pain is experienced after eating fatty foods. Fatty growths on the skin (eruptive xanthomas) are not uncommon. People with this form must minimize the eating of dietary fats of any kind.

Diagnosis

There is no specific diagnostic test for hyperlipoproteinemia type III. A diagnosis is made based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings such as xanthoma striata palmaris. Tests may be performed that demonstrate elevated levels of cholesterol and triglycerides (hyperlipidemia), which occurs after fasting; reveal the presence of very low density lipoproteins (VLDLs), a type of lipoprotein that is elevated in individuals with hyperlipoproteinemia type III; and demonstrate an increased ratio between VLDLs to plasma triglycerides. A test known as electrophoresis may be used to demonstrate abnormal lipoproteins. Electrophoresis is a laboratory test that measures protein levels in the blood or urine by using an electric current to separate proteins by molecular size.

Genotyping is a test that determines what form (allele) of gene is present. A simple blood test can determine whether an individual has two apo e2 genes. When these genes are found a person with characteristic symptoms, it is diagnostic of hyperlipoproteinemia type III.

Standard Therapies

Treatment

Most individuals with hyperlipoproteinemia type III respond to dietary therapy that consists of a diet that is low in cholesterol and saturated fat. The reduction of the intake of dietary cholesterol and other fats generally prevents xanthomas and high lipid levels in the blood (hyperlipidemia). Exercise in addition to dietary therapy may help lower lipid levels.

In individuals in whom dietary modification does not lower lipid levels, certain drugs may be used. These drugs include niacin, gemfibrozil, clofibrate, and/or lovastatin. Other drugs, such as cholestyramine and colestipol are not effective for the treatment of Broad Beta Disease; they may actually raise blood levels of beta-lipoproteins.

Xanthomas can sometimes be removed surgically. Treatment of cardiovascular disease is symptomatic. Because estrogen improves the clearance of specific lipids associated with hyperlipoproteinemia type III, estrogen therapy may help some postmenopausal women with this disorder.

Genetic counseling may be of benefit for people with hyperlipoproteinemia type III and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Affected Populations

Hyperlipoproteinemia type III affects males more often than females. The majority of cases occur during early adulthood, although cases have been reported in children and the elderly. Women are rarely affected until after menopause.

The incidence of hyperlipoproteinemia is unknown. It is estimated to affect approximately 1 in 5,000-10,000 people in the general population.

Symptoms

Symptoms may not be seen until age 20 or older.

Yellow deposits of fatty material in the skin called xanthomas may appear on the eyelids, palms of the hands, soles of the feet, or on the tendons of the knees and elbows.

Atherosclerosis develops. There may be early chest pain (angina) or decreased blood flow to specific parts of the body, causing transient ischemic attacks of the brain or peripheral artery disease.

Exams and Tests

Tests that may be done to diagnose this condition include:

• Angiogram
• Genetic testing for apolipoprotein E (apoE)
• Heart stress test
• Total cholesterol
• Triglyceride level
• Very low density lipoprotein (VLDL) test

Treatment

The goal of treatment is to control underlying conditions such as obesity, hypothyroidism, and diabetes.

Reducing calories, saturated fats, and cholesterol may significantly reduce cholesterol levels.

If high cholesterol and triglyceride levels continue despite diet changes, your doctor may recommend medicine to lower your cholesterol. Medicine to lower cholesterol levels include:

• Bile acid-sequestering resins
• Fibrates
• Nicotinic acid
• Statins

Treatment

Most individuals with hyperlipoproteinemia type III respond to dietary therapy that consists of a diet that is low in cholesterol and saturated fat. The reduction of the intake of dietary cholesterol and other fats generally prevents xanthomas and high lipid levels in the blood (hyperlipidemia). Exercise in addition to dietary therapy may help lower lipid levels.

In individuals in whom dietary modification does not lower lipid levels, certain drugs may be used. These drugs include niacin, gemfibrozil, clofibrate, and/or lovastatin. Other drugs, such as cholestyramine and colestipol are not effective for the treatment of Broad Beta Disease; they may actually raise blood levels of beta-lipoproteins.

Xanthomas can sometimes be removed surgically. Treatment of cardiovascular disease is symptomatic. Because estrogen improves the clearance of specific lipids associated with hyperlipoproteinemia type III, estrogen therapy may help some postmenopausal women with this disorder.

Genetic counseling may be of benefit for people with hyperlipoproteinemia type III and their families. Other treatment is symptomatic and supportive.

Prognosis

Persons with this condition have an increased risk for coronary artery disease and peripheral vascular disease.

With treatment, most people show a significant reduction in lipid levels.

Possible Complications

• Heart attack
• Stroke
• Peripheral vascular disease
• Intermittent claudication
• Gangrene of the lower extremities

Prevention

Screening the family members of those with familial dysbetalipoproteinemia may lead to early detection and treatment.

Early treatment and avoiding other risk factors for vascular disease (such as smoking) are crucial to preventing early heart attacks, strokes, and blocked blood vessels.