Dysbetalipoproteinemia
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Synonyms and keywords: Broad beta disease; Broad beta hyperlipoproteinemia; Broad-beta hyperlipoproteinemia; Dysbetalipoproteinemia; Familial dysbetalipoproteinemia; Familial hypercholesterolemia with hyperlipemia; Type III hyperlipoproteinemia; Type 3 hyperlipoproteinemia

# Overview
Familial dysbetalipoproteinemia is an inheritable, autosomal recessive disorder in which there are high amounts of cholesterol and triglycerides in the blood.  This form of hyperlipoproteinemia, also known as broad beta disease or dysbetalipoproteinemia, occurs due to high levels of chylomicrons and IDL (intermediate density lipoprotein). The most common genetic cause of this disease is the presence of the ApoE E2/E2 genotype. It is due to cholesterol-rich VLDL (-VLDL). The prevalence of familial dysbetalipoproteinemia is 1 in 5,000-10,000 people in the general population.

# Historical perspective
In 1967, Fredrickson classified lipoprotein disorder using paper electrophoresis.

# Classification
There is no established classification system for dysbetalipoproteinemia.
For a detailed classification of hyperlipoproteinemia click here.

# Pathophysiology
Dysbetalipoproteinemia is an autosomal recessive disorder caused by mutations in Apo E gene, which is located on the long arm of chromosome 19(19q13).

## Genetics
- Homozygosity for the ApoE2 isoform, which contains two cysteine residues and has lower binding capacity for the LDL receptor, is associated with majority of cases with dysbetalipoproteinemia.
- Besides Apo E2, naturally occurring Apo E mutations have also been found to be associated with dysbetalipoproteinemia. These are inherited in a dominant mode and expressed at an early age.

## Pathogenesis
- Remnants of chylomicrons and VLDL are cleared from circulation by Apolipoprotein E
- Apolipoprotein E, serving as a ligand for the low-density lipoprotein receptor, mediates hepatic clearance of chylomicrons and VLDL remnants from circulation.
- The most common Apo E isoform is E 3/3, which contains cysteine at position 112 and arginine at position 158.
- VLDL and chylomicron remnants that contains Apo E2 on their surface are not cleared as efficiently from the plasma, resulting in the formation of dense VLDL particles known as beta-VLDL.
- The accumulation of VLDL and chylomicrons results in atherosclerosis and dyslipidemia.

# Causes
The cause of type 3 hyperlipidemia is genetic.

# Differential Diagnosis
Dysbetalipoproteinemia must be differentiated from all other kinds of hyperlipidemias. On the basis of high triglyceride levels it can be differentiated from:
- Familial hyperchylomicronemia
- Familial hypercholesterolemia
- Familial combined hyperlipidemia
- Primary hypertriglyceridemia/ Primary hypertriglyceridemia
- Drugs causing high triglyceride levels:
Atypical antipsychotic drugs (fluperlapine, clozapine, olanzapine), beta-blockers (especially non-beta 1-selective), bile acid sequestrants, cyclophosphamide, glucocorticoids, Immunosuppressive drugs (cyclosporine, sirolimus), interferon, L-asparaginase, oral estrogens, protease inhibitors, raloxifene, retinoids, rosiglitazone, tamoxifen, thiazide diuretics.
- Atypical antipsychotic drugs (fluperlapine, clozapine, olanzapine), beta-blockers (especially non-beta 1-selective), bile acid sequestrants, cyclophosphamide, glucocorticoids, Immunosuppressive drugs (cyclosporine, sirolimus), interferon, L-asparaginase, oral estrogens, protease inhibitors, raloxifene, retinoids, rosiglitazone, tamoxifen, thiazide diuretics.
For a detailed differential diagnosis of hyperlipoproteinemia click here.

# Epidemiology and Demographics
The prevalence of dysbetalipoproteinemia is approximately 1 in 5,000-10,000 people in the general population.

## Age
The majority of cases occur during early adulthood. Rarely, cases have been described in children and the elderly.
- Women are usually affected after menopause.

## Gender
Males are more commonly affected than females.

## Race
There is no racial predilection for familial dysbetalipoproteinemia.

# Risk Factors
Common risk factors in the development of dysbetalipoproteinemia are:
- Family history (most important)
- Hypothyroidism
- Obesity
- Diabetes
- Coronary heart disease
- Kidney disease
- Alcohol abuse

# Screening
There are no established screening recommendations for dysbetalipoproteinemia.

# Natural History, Complication, Prognosis

## Natural History
If left untreated, dysbetalipoproteinemia can lead to chronic pancreatitis, atherosclerosis, stroke, and intermittent claudication.

## Complications
Dysbetalipoproteinemia is associated with the following complications: 
- Atherosclerotic complications (e.g., coronary artery disease)
- Pancreatitis
- Stroke
- Peripheral vascular disease
- Intermittent claudication
- Glomerulopathy leading to Renal Failure

## Prognosis
Patients with dysbetalipoproteinemia have an increased risk for coronary artery disease and peripheral vascular disease. With treatment, most people show a significant reduction in lipid levels and thus associated complications.

# Diagnosis

## Symptoms
A detailed history, complete with a focused family history, must be obtained in order to ensure an accurate diagnosis is made. Symptoms of dysbetalipoprotenemia include:
- Yellow papules (Xanthomas) involving skin and tendons may be present.
- Chest pain can be the presenting complaint signifying cardiac involvement
- Leg pain (due to peripheral vascular disease)

## Physical Exam
A detailed physical exam is required for patients suspected to have dysbetalipoproteinemia. Physical examination in dysbetalipoproteinemia may range from being normal to being remarkable for the following findings:

### Dermatological
- Xanthoma Striatum palmare-consisting of yellow streaks in the palmar creases
- Tuberoeruptive xanthomas on the elbow or tibial tuberosities
- Cutaneous xanthomas

### Musculoskeletal
- Tendon xanthomas may also be seen in rare cases

### Vascular
- Peripheral vascular disease

## Laboratory Findings
The laboratory findings consistent with a diagnosis of dysbetalipoprotenemia include the following:

## Molecular Genetic Testing
A diagnosis of dysbetalipoproteinemia can be confirmed by presence of two Apo E2 genes, in the presence of characteristic symptoms.

# Treatment
Options for the treatment of dysbetalipoprotenemia include both medical and non-medical approaches, as described below.

## Non-pharmacological Therapy
- Exercise and dietary therapy involving a low-cholesterol and low-fat diet have been shown to be effective.
- Patients may also be counseled to avoid other risk factors responsible for complications, such as smoking.
- Inappropriate or subnormal control of the disease with the implementation of non-pharmacological therapies requires pharmacological treatment.

## Medical Therapy
- Bile acid binding agents are an option if triglyceride levels are <200 mg/dL.
- Statins can be used if triglyceride levels are <500 mg/dL.
- Fibrates and nicotinic acid can also be used.

# Prevention

## Primary Prevention
- Genetic counseling is recommended for patients and their family members.

## Secondary Prevention
Measures for the secondary prevention for dysbetalipoproteinemia include:
- Lifestyle modifications
- Screening family members to increase the likelihood of early detection and treatment
- Early treatment and avoidance of other risk factors for vascular disease (e.g., smoking) to prevention of complications