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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
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 (β-VLDL). The prevalence of familial dysbetalipoproteinemia is 1 in 5,000-10,000 people in the general population.
- 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.
- 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.
The cause of type 3 hyperlipidemia is genetic.
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.
Epidemiology and Demographics
The majority of cases occur during early adulthood. Rarely, cases have been described in children and the elderly.
- Women are usually affected after menopause.
Males are more commonly affected than females.
There is no racial predilection for familial dysbetalipoproteinemia.
- Family history (most important)
- Coronary heart disease
- Kidney disease
- Alcohol abuse
There are no established screening recommendations for dysbetalipoproteinemia.
Natural History, Complication, Prognosis
- Atherosclerotic complications (e.g., coronary artery disease)
- Peripheral vascular disease
- Intermittent claudication
- Glomerulopathy leading to Renal Failure
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.
Dermatological and musculoskeletal
- Chest pain can be the presenting complaint signifying cardiac involvement
- Leg pain (due to peripheral vascular disease)
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:
- Xanthoma Striatum palmare-consisting of yellow streaks in the palmar creases
- Tuberoeruptive xanthomas on the elbow or tibial tuberosities
- Cutaneous xanthomas
- Tendon xanthomas may also be seen in rare cases
|Appearance||Lipid Profile||VLDL cholesterol||Isoelectric focusing|
VLDL triglyceride >0.35
Molecular Genetic Testing
A diagnosis of dysbetalipoproteinemia can be confirmed by presence of two Apo E2 genes, in the presence of characteristic symptoms.
- 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.
- 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.
- 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
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