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{{Lipoprotein disorders}}
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{{CMG}}; {{AE}} {{USAMA}}, {{VD}}


{{SK}} Broad beta disease; broad beta hyperlipoproteinemia; broad-beta hyperlipoproteinemia; dysbetalipoproteinemia; familial dysbetalipoproteinemia; familial hypercholesterolemia with hyperlipemia; type III hyperlipoproteinemia  
'''To view Lipoprotein disorders main page [[ Lipoprotein disorders | Click here]]'''<br>
'''To view Hyperlipoproteinemia main page [[ Hyperlipoproteinemia | Click here]]''' <br>
 
{{SK}} Broad beta disease; Broad beta hyperlipoproteinemia; Broad-beta hyperlipoproteinemia; Dysbetalipoproteinemia; Familial dysbetalipoproteinemia; Familial hypercholesterolemia with hyperlipemia; Type III hyperlipoproteinemia; Type 3 hyperlipoproteinemia


==Overview==
==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 [[chylomicron]]s and [[IDL]] (intermediate density lipoprotein). Also known as broad beta disease or dysbetalipoproteinemia, the most common cause for this form is the presence of [[Apolipoprotein E|ApoE]] E2/E2 genotype. It is due to cholesterol-rich VLDL (β-VLDL). Prevalence is 0.02% of the population.
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 [[Apolipoprotein E|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.
 
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==
==Historical perspective==
A genetic defect causes this condition. The defect results in the build up of large lipoprotein particles that contain both [[cholesterol]] and [[triglyceride]]s, a type of fat. The disease is linked to defects in the gene for [[apolipoprotein E]] in many cases.
In 1967, Fredrickson classified lipoprotein disorder using paper [[electrophoresis]].<ref name="pmid32961932">{{cite journal| author=Culliton BJ| title=Fredrickson's bitter end at Hughes. | journal=Science | year= 1987 | volume= 236 | issue= 4807 | pages= 1417-8 | pmid=3296193 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3296193  }}</ref>


[[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]].
==Classification==
There is no established classification system for dysbetalipoproteinemia.
For a detailed classification of [[hyperlipoproteinemia]] click '''[[Hyperlipoproteinemia#Classification|here]]'''.


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.
==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).
<ref name="pmid22069485">{{cite journal| author=Georgiadou D, Chroni A, Vezeridis A, Zannis VI, Stratikos E| title=Biophysical analysis of apolipoprotein E3 variants linked with development of type III hyperlipoproteinemia. | journal=PLoS One | year= 2011 | volume= 6 | issue= 11 | pages= e27037 | pmid=22069485 | doi=10.1371/journal.pone.0027037 | pmc=3206067 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22069485}}</ref><ref name="pmid8304363">{{cite journal| author=Zhao SP, Smelt AH, Leuven JA, Vroom TF, van der Laarse A, van 't Hooft FM| title=Changes of lipoprotein profile in familial dysbetalipoproteinemia with gemfibrozil. | journal=Am J Med | year= 1994 | volume= 96 | issue= 1 | pages= 49-56 | pmid=8304363 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8304363  }} </ref><ref name="medline">{{https://medlineplus.gov/ency/article/000402.html}}</ref><ref name="pmid10552997">{{cite journal| author=Mahley RW, Huang Y, Rall SC| title=Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes. | journal=J Lipid Res | year= 1999 | volume= 40 | issue= 11 | pages= 1933-49 | pmid=10552997 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10552997  }} </ref><ref name="pmid8185134">{{cite journal| author=Walden CC, Hegele RA| title=Apolipoprotein E in hyperlipidemia. | journal=Ann Intern Med | year= 1994 | volume= 120 | issue= 12 | pages= 1026-36 | pmid=8185134 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8185134  }} </ref>


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%.
=== 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 [[Autosomal dominant|dominant mode]] and expressed at an early age.


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.
===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]].


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.
==Causes==
 
The cause of type 3 hyperlipidemia is genetic.
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==
==Differential Diagnosis==
Symptoms of the following disorders can be similar to those of hyperlipoproteinemia type III. Comparisons may be useful for a 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]]
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.)
*[[Familial hypercholesterolemia]]
 
*[[Familial combined hyperlipidemia]]
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.)
*[[Primary hypertriglyceridemia]]/ [[Primary hypertriglyceridemia]]
 
*Drugs causing high triglyceride levels:<ref name="pmid25234560">Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH et al. (2014) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=25234560 National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 - executive summary.] ''J Clin Lipidol'' 8 (5):473-88. [http://dx.doi.org/10.1016/j.jacl.2014.07.007 DOI:10.1016/j.jacl.2014.07.007] PMID: [https://pubmed.gov/25234560 25234560]</ref>
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.
**[[Atypical antipsychotic drugs]] ([[Atypical antipsychotic|fluperlapine]], [[clozapine]], [[olanzapine]]), [[beta-blockers]] (especially non-beta 1-selective), [[bile acid sequestrants]], [[cyclophosphamide]], [[glucocorticoids]], [[Immunosuppressive drugs]] ([[cyclosporine]], [[sirolimus]]), [[interferon]], [[L-asparaginase]], [[Estrogens|oral estrogens]], [[protease inhibitors]], [[raloxifene]], [[retinoids]], [[rosiglitazone]], [[tamoxifen]], [[thiazide diuretics]].
 
==== 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 ====
For a detailed differential diagnosis of [[hyperlipoproteinemia]] click '''[[Hyperlipoproteinemia#Differential Diagnosis|here]]'''.
'''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.
==Epidemiology and Demographics==
The prevalence of dysbetalipoproteinemia is approximately 1 in 5,000-10,000 people in the general population.<ref name="pmid8304363" /><ref name="medline" />
===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.


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.
==Risk Factors==
Common risk factors in the development of dysbetalipoproteinemia are:<ref name="pmid8304363" /><ref name="medline" />
*Family history (most important)
*[[Hypothyroidism]]
*[[Obesity]]
*[[Diabetes mellitus|Diabetes]]
*[[Coronary heart disease]]
*[[Kidney disease]]
*[[Alcohol abuse]]


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.
==Screening==
There are no established screening recommendations for dysbetalipoproteinemia.


Genetic counseling may be of benefit for people with hyperlipoproteinemia type III and their families. Other treatment is symptomatic and supportive.
==Natural History, Complication, Prognosis==
===Natural History===
If left untreated, dysbetalipoproteinemia can lead to [[chronic pancreatitis]], [[atherosclerosis]], [[stroke]], and [[intermittent claudication]].


==== Investigational Therapies ====
===Complications===
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.
Dysbetalipoproteinemia is associated with the following complications:<ref name="pmid12506591">{{cite journal| author=Blom DJ, Byrnes P, Jones S, Marais AD| title=Dysbetalipoproteinaemia--clinical and pathophysiological features. | journal=S Afr Med J | year= 2002 | volume= 92 | issue= 11 | pages= 892-7 | pmid=12506591 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12506591  }} </ref> <ref name="pmid244053722">{{cite journal| author=Marais AD, Solomon GA, Blom DJ| title=Dysbetalipoproteinaemia: a mixed hyperlipidaemia of remnant lipoproteins due to mutations in apolipoprotein E. | journal=Crit Rev Clin Lab Sci | year= 2014 | volume= 51 | issue= 1 | pages= 46-62 | pmid=24405372 | doi=10.3109/10408363.2013.870526 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24405372  }}</ref>
*Atherosclerotic complications (e.g., [[coronary artery disease]])
*[[Pancreatitis]]
*[[Stroke]]
*[[Peripheral vascular disease]]
*[[Intermittent claudication]]
*[[Glomerulopathy]] leading to [[Renal Failure]]


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


==== Affected Populations ====
==Diagnosis==
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.
===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:<ref name="pmid12506591">{{cite journal| author=Blom DJ, Byrnes P, Jones S, Marais AD| title=Dysbetalipoproteinaemia--clinical and pathophysiological features. | journal=S Afr Med J | year= 2002 | volume= 92 | issue= 11 | pages= 892-7 | pmid=12506591 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12506591  }} </ref><ref name="pmid3042820">{{cite journal| author=Cruz PD, East C, Bergstresser PR| title=Dermal, subcutaneous, and tendon xanthomas: diagnostic markers for specific lipoprotein disorders. | journal=J Am Acad Dermatol | year= 1988 | volume= 19 | issue= 1 Pt 1 | pages= 95-111 | pmid=3042820 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3042820  }} </ref><ref name="pmid24205719">{{cite journal| author=Eto M, Saito M| title=[Familial type III hyperlipoproteinemia]. | journal=Nihon Rinsho | year= 2013 | volume= 71 | issue= 9 | pages= 1590-4 | pmid=24205719 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24205719  }} </ref>


The incidence of hyperlipoproteinemia is unknown. It is estimated to affect approximately 1 in 5,000-10,000 people in the general population.
====== Dermatological and musculoskeletal ======
*Yellow papules [[Xanthomas|(Xanthomas]]) involving [[skin]] and [[tendon]]s may be present.


==Symptoms==
===== Cardiac =====
*[[Chest pain]] can be the presenting complaint signifying cardiac involvement


Symptoms may not be seen until age 20 or older.
===== Vascular =====
*Leg pain (due to [[peripheral vascular disease]])


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.
===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:<ref name="pmid12506591">{{cite journal| author=Blom DJ, Byrnes P, Jones S, Marais AD| title=Dysbetalipoproteinaemia--clinical and pathophysiological features. | journal=S Afr Med J | year= 2002 | volume= 92 | issue= 11 | pages= 892-7 | pmid=12506591 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12506591  }} </ref>
====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


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.
====Vascular====
*[[Peripheral vascular disease]]


==Exams and Tests==
===Laboratory Findings===
The laboratory findings consistent with a diagnosis of dysbetalipoprotenemia include the following:<ref name="pmid10552997">{{cite journal| author=Mahley RW, Huang Y, Rall SC| title=Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes. | journal=J Lipid Res | year= 1999 | volume= 40 | issue= 11 | pages= 1933-49 | pmid=10552997 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10552997  }} </ref><ref name="Heart Disease">{{cite book |last=Braunwald |first=Eugene |date= |title=Heart Disease- Fourth Edition |location= Harvard Medical School |publisher=W. B. SAUNDERS COMPANY |page=1137 |isbn=0-7216-3097-9}}​</ref>
{| class="wikitable"
! rowspan="2" |Appearance
! colspan="4" |Lipid Profile
! rowspan="2" |VLDL cholesterol
! rowspan="2" |Isoelectric focusing
|-
!Total Cholesterol
!Triglycerides
!LDL
!HDL
|-
|Floating
beta lipoproteins
|Elevated
|Elevated
|Decreaesd
|Normal
|[[VLDL]] cholesterol/
VLDL triglyceride >0.35
|[[ApoE2]] homozygote
|}


Tests that may be done to diagnose this condition include:
=== Molecular Genetic Testing ===
* Angiogram
A diagnosis of dysbetalipoproteinemia can be confirmed by presence of two Apo E2 genes, in the presence of characteristic symptoms.<ref name="pmid27603268">{{cite journal| author=Rothschild M, Duhon G, Riaz R, Jetty V, Goldenberg N, Glueck CJ et al.| title=Pathognomonic Palmar Crease Xanthomas of Apolipoprotein E2 Homozygosity-Familial Dysbetalipoproteinemia. | journal=JAMA Dermatol | year= 2016 | volume= 152 | issue= 11 | pages= 1275-1276 | pmid=27603268 | doi=10.1001/jamadermatol.2016.2223 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27603268  }} </ref>
* Genetic testing for apolipoprotein E (apoE)
* Heart stress test
* Total cholesterol
* Triglyceride level
* Very low density lipoprotein (VLDL) test


==Treatment==
==Treatment==
Options for the treatment of dysbetalipoprotenemia include both medical and non-medical approaches, as described below.<ref>The Measurement of Lipids, Lipoproteins, Apolipoproteins, Fatty Acids, and Sterols, and Next Generation Sequencing for the Diagnosis and Treatment of Lipid Disorders.
Schaefer EJ, Tsunoda F, Diffenderfer M, Polisecki E, Thai N, Asztalos B.</ref><ref name="pmid17100406">{{cite journal| author=Hachem SB, Mooradian AD| title=Familial dyslipidaemias: an overview of genetics, pathophysiology and management. | journal=Drugs | year= 2006 | volume= 66 | issue= 15 | pages= 1949-69 | pmid=17100406 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17100406  }} </ref>


The goal of treatment is to control underlying conditions such as obesity, hypothyroidism, and diabetes.
===Non-pharmacological Therapy===
 
*[[Exercise]] and dietary therapy involving a low-[[cholesterol]] and low-fat diet have been shown to be effective.
Reducing calories, saturated fats, and cholesterol may significantly reduce cholesterol levels.
*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.
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
===Medical Therapy===
* Stroke
*[[Bile acid]] binding agents are an option if [[triglyceride]] levels are <200 mg/dL.
* Peripheral vascular disease
*[[Statins]] can be used if [[triglyceride]] levels are <500 mg/dL.
* Intermittent claudication
*[[Fibrates]] and [[nicotinic acid]] can also be used.
* Gangrene of the lower extremities


==Prevention==
==Prevention==
===Primary Prevention===
*[[Genetic counseling]] is recommended for patients and their family members.<ref name="pmid244053722">{{cite journal| author=Marais AD, Solomon GA, Blom DJ| title=Dysbetalipoproteinaemia: a mixed hyperlipidaemia of remnant lipoproteins due to mutations in apolipoprotein E. | journal=Crit Rev Clin Lab Sci | year= 2014 | volume= 51 | issue= 1 | pages= 46-62 | pmid=24405372 | doi=10.3109/10408363.2013.870526 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24405372  }}</ref>


Screening the family members of those with familial dysbetalipoproteinemia may lead to early detection and treatment.
===Secondary Prevention===
 
Measures for the [[secondary prevention]] for dysbetalipoproteinemia include:<ref name="pmid17100406">{{cite journal| author=Hachem SB, Mooradian AD| title=Familial dyslipidaemias: an overview of genetics, pathophysiology and management. | journal=Drugs | year= 2006 | volume= 66 | issue= 15 | pages= 1949-69 | pmid=17100406 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17100406  }} </ref>
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.
*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


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
{{Lipopedia}}
{{Lipopedia}}
[[Category:Cardiology]]
[[Category:Cardiology]]
[[Category:Disease]]
[[Category:Lipopedia]]
[[Category:Lipids]]
[[Category:Up-To-Date]]
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2], Vishal Devarkonda, M.B.B.S[3]

To view Lipoprotein disorders main page Click here
To view Hyperlipoproteinemia main page Click here

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 (β-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.[1]

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). [2][3][4][5][6]

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

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:

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.[3][4]

Age

The majority of cases occur during early adulthood. Rarely, cases have been described in children and the elderly.

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:[3][4]

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:[8] [9]

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:[8][10][11]

Dermatological and musculoskeletal
Cardiac
  • Chest pain can be the presenting complaint signifying cardiac involvement
Vascular

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:[8]

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

Laboratory Findings

The laboratory findings consistent with a diagnosis of dysbetalipoprotenemia include the following:[5][12]

Appearance Lipid Profile VLDL cholesterol Isoelectric focusing
Total Cholesterol Triglycerides LDL HDL
Floating

beta lipoproteins

Elevated Elevated Decreaesd Normal VLDL cholesterol/

VLDL triglyceride >0.35

ApoE2 homozygote

Molecular Genetic Testing

A diagnosis of dysbetalipoproteinemia can be confirmed by presence of two Apo E2 genes, in the presence of characteristic symptoms.[13]

Treatment

Options for the treatment of dysbetalipoprotenemia include both medical and non-medical approaches, as described below.[14][15]

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

Prevention

Primary Prevention

Secondary Prevention

Measures for the secondary prevention for dysbetalipoproteinemia include:[15]

  • 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

References

  1. ↑ Culliton BJ (1987). "Fredrickson's bitter end at Hughes". Science. 236 (4807): 1417–8. PMID 3296193.
  2. ↑ Georgiadou D, Chroni A, Vezeridis A, Zannis VI, Stratikos E (2011). "Biophysical analysis of apolipoprotein E3 variants linked with development of type III hyperlipoproteinemia". PLoS One. 6 (11): e27037. doi:10.1371/journal.pone.0027037. PMC 3206067. PMID 22069485.
  3. ↑ 3.0 3.1 3.2 Zhao SP, Smelt AH, Leuven JA, Vroom TF, van der Laarse A, van 't Hooft FM (1994). "Changes of lipoprotein profile in familial dysbetalipoproteinemia with gemfibrozil". Am J Med. 96 (1): 49–56. PMID 8304363.
  4. ↑ 4.0 4.1 4.2 Template:Https://medlineplus.gov/ency/article/000402.html
  5. ↑ 5.0 5.1 Mahley RW, Huang Y, Rall SC (1999). "Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes". J Lipid Res. 40 (11): 1933–49. PMID 10552997.
  6. ↑ Walden CC, Hegele RA (1994). "Apolipoprotein E in hyperlipidemia". Ann Intern Med. 120 (12): 1026–36. PMID 8185134.
  7. ↑ Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH et al. (2014) National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 - executive summary. J Clin Lipidol 8 (5):473-88. DOI:10.1016/j.jacl.2014.07.007 PMID: 25234560
  8. ↑ 8.0 8.1 8.2 Blom DJ, Byrnes P, Jones S, Marais AD (2002). "Dysbetalipoproteinaemia--clinical and pathophysiological features". S Afr Med J. 92 (11): 892–7. PMID 12506591.
  9. ↑ 9.0 9.1 Marais AD, Solomon GA, Blom DJ (2014). "Dysbetalipoproteinaemia: a mixed hyperlipidaemia of remnant lipoproteins due to mutations in apolipoprotein E." Crit Rev Clin Lab Sci. 51 (1): 46–62. doi:10.3109/10408363.2013.870526. PMID 24405372.
  10. ↑ Cruz PD, East C, Bergstresser PR (1988). "Dermal, subcutaneous, and tendon xanthomas: diagnostic markers for specific lipoprotein disorders". J Am Acad Dermatol. 19 (1 Pt 1): 95–111. PMID 3042820.
  11. ↑ Eto M, Saito M (2013). "[Familial type III hyperlipoproteinemia]". Nihon Rinsho. 71 (9): 1590–4. PMID 24205719.
  12. ↑ Braunwald, Eugene. Heart Disease- Fourth Edition. Harvard Medical School: W. B. SAUNDERS COMPANY. p. 1137. ISBN 0-7216-3097-9.​
  13. ↑ Rothschild M, Duhon G, Riaz R, Jetty V, Goldenberg N, Glueck CJ; et al. (2016). "Pathognomonic Palmar Crease Xanthomas of Apolipoprotein E2 Homozygosity-Familial Dysbetalipoproteinemia". JAMA Dermatol. 152 (11): 1275–1276. doi:10.1001/jamadermatol.2016.2223. PMID 27603268.
  14. ↑ The Measurement of Lipids, Lipoproteins, Apolipoproteins, Fatty Acids, and Sterols, and Next Generation Sequencing for the Diagnosis and Treatment of Lipid Disorders. Schaefer EJ, Tsunoda F, Diffenderfer M, Polisecki E, Thai N, Asztalos B.
  15. ↑ 15.0 15.1 Hachem SB, Mooradian AD (2006). "Familial dyslipidaemias: an overview of genetics, pathophysiology and management". Drugs. 66 (15): 1949–69. PMID 17100406.

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