Dysbetalipoproteinemia: Difference between revisions

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{{SI}}
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{{CMG}} {{AE}} {{USAMA}}{{VD}}
{{CMG}}; {{AE}} {{USAMA}}, {{VD}}
 
'''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


{{SK}} [[Dysbetalipoproteinemia|Broad beta disease]]; [[Dysbetalipoproteinemia|Broad beta hyperlipoproteinemia]]; [[Dysbetalipoproteinemia|Broad-beta hyperlipoproteinemia]]; [[Dysbetalipoproteinemia]]; [[Dysbetalipoproteinemia|Familial dysbetalipoproteinemia]]; [[Dysbetalipoproteinemia|Familial hypercholesterolemia with hyperlipemia]]; [[Dysbetalipoproteinemia|Type III hyperlipoproteinemia]].
==Overview==
==Overview==
Familial dysbetalipoproteinemia is a autosomal recessive 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 1 in 5,000-10,000 people in the general 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.
 
==Historical perspective==
==Historical perspective==
*In 1967, Fredrickson using paper [[electrophoresis]], classified lipoprotein disorder<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>
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>
 
==Classification==
==Classification==
*There is no established classification system for dysbetalipoproteinemia
There is no established classification system for dysbetalipoproteinemia.
For a detailed classification of [[hyperlipoproteinemia]] click '''[[Hyperlipoproteinemia#Classification|here]]'''.
 
==Pathophysiology==
==Pathophysiology==
*Dysbetalipoproteinemia is an [[autosomal recessive disorder]] caused by mutations in [[Apo E gene]]:<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>
Dysbetalipoproteinemia is an [[autosomal recessive disorder]] caused by mutations in [[Apo E gene]], which is located on the long arm of chromosome 19(19q13).
**[[Apo E gene]] 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>
 
=== 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.
 
===Pathogenesis===
===Pathogenesis===
*Remnants of [[chylomicrons]] and [[VLDL]] are cleared from circulation by [[Apolipoprotein E]]
*Remnants of [[chylomicrons]] and [[VLDL]] are cleared from circulation by [[Apolipoprotein E]]
*Apolipoprotein E serving as a ligand for the low-density lipoprotien receptor, mediates hepatic clearance of [[chylomicrons]] and [[VLDL remnants]] from circulation.  
*[[Apolipoprotein E]], serving as a [[ligand]] for the [[low-density lipoprotein]] receptor, mediates hepatic clearance of [[chylomicrons]] and [[VLDL remnants]] from circulation.  
*Most common Apo E isoform is E 3/3, containing  cysteine at position 112 and arginine at position 158
*The most common Apo E isoform is E 3/3, which contains [[cysteine]] at position 112 and [[arginine]] at position 158.
*[[Homozygosity]] for the ApoE2 isoform , containing two [[cysteine]] residues, which has lower binding capacity for [[LDL]] receptor, is associated with majority of cases with dysbetalipoproteinemia.
*[[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.
*Besides Apo E2, naturally occurring Apo E mutations have also been describe to be associated with dysbetalipoproteinemia. These are inherited in a [[Autosomal dominant|dominant mode]] and expressed early in age.
*The accumulation of [[VLDL]] and [[chylomicrons]] results in [[atherosclerosis]] and [[dyslipidemia]].
*VLDL and [[chylomicron remnants]] that contains Apo E2 on their surface are not cleared as efficiently from the plasma. Resulting in formation of dense VLDL particle known as beta-VLDL.
 
*Accumulation of VLDL and chylomicrons results in atherosclerosis and [[dyslipidemia]].
==Causes==
==Causes==
The cause of type 3 hyperlipidemia remains genetic
The cause of type 3 hyperlipidemia is genetic.
==Differential Diagnoses==
 
==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:<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>
**[[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]].
 
For a detailed differential diagnosis of [[hyperlipoproteinemia]] click '''[[Hyperlipoproteinemia#Differential Diagnosis|here]]'''.
 
==Epidemiology and Demographics==
==Epidemiology and Demographics==
*Epidemiological and demographics of dysbetalipoproteinemia are discussed below:-<ref name="pmid8304363" /><ref name="medline" />
The prevalence of dysbetalipoproteinemia is approximately 1 in 5,000-10,000 people in the general population.<ref name="pmid8304363" /><ref name="medline" />
===Prevalence ===
===Age===
*The disease has been described in all races
The majority of cases occur during early adulthood. Rarely, cases have been described in children and the elderly.  
*The prevalence of dysbetalipoproteinemia is approximately 1 in 5,000-10,000 people in the general population
*Women are usually affected after [[menopause]].
===Demographics===
===Gender===
====Age====
Males are more commonly affected than females.
*Majority of cases occur during early adulthood. Rarely, cases have been described in children and the elderly.  
===Race===
*Women are usually affected after [[menopause]]
There is no racial predilection for familial dysbetalipoproteinemia.
====Gender====
 
*Males are more often affected then females
==Risk Factors==
==Risk Factors==
*The risk factors for [[dysbetalipoproteinemia]] are:<ref name="pmid8304363" /><ref name="medline" />
Common risk factors in the development of dysbetalipoproteinemia are:<ref name="pmid8304363" /><ref name="medline" />
**Family history (most important)
*Family history (most important)
**[[Hypothyroidism]]
*[[Hypothyroidism]]
**[[Obesity]]
*[[Obesity]]
**[[Diabetes mellitus|Diabetes]]
*[[Diabetes mellitus|Diabetes]]
**[[Coronary heart disease|coronary artery disease]]
*[[Coronary heart disease]]
*[[Kidney disease]]
*[[Alcohol abuse]]
 
==Screening==
==Screening==
There are no known screening recommendations for dysbetalipoprotenemia
There are no established screening recommendations for dysbetalipoproteinemia.
 
==Natural History, Complication, Prognosis==
==Natural History, Complication, Prognosis==
===Natural History===
===Natural History===
*If left untreated dysbetalipoprotenemia can lead to [[chronic pancreatitis]], [[atherosclerosis]], [[stroke]] and [[intermittent claudication]]
If left untreated, dysbetalipoproteinemia can lead to [[chronic pancreatitis]], [[atherosclerosis]], [[stroke]], and [[intermittent claudication]].
 
===Complications===
===Complications===
Dysbetalipoprtenemia can cause 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>  
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 like [[coronary artery disease]]
*Atherosclerotic complications (e.g., [[coronary artery disease]])
*[[Pancreatitis]]
*[[Pancreatitis]]
* [[Stroke]]
*[[Stroke]]
* [[Peripheral vascular disease]]
*[[Peripheral vascular disease]]
* [[Intermittent claudication]]
*[[Intermittent claudication]]
*[[Glomerulopathy]] leading to [[Renal Failure]]
 
===Prognosis===
===Prognosis===
*Patients with [[dysbetalipoproteinemia]] have an increased risk for [[coronary artery disease]] and [[peripheral vascular disease]]
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.
*With treatment, most people show a significant reduction in lipid levels and thus the complications
 
==Diagnosis==
==Diagnosis==
===History and Symptoms===
===Symptoms===
A detailed history along with a focused family history must be obtained
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>
 
====== Dermatological and musculoskeletal ======
*Yellow papules [[Xanthomas|(Xanthomas]]) involving [[skin]] and [[tendon]]s may be present.


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


===== Dermatological and musculoskeletal =====
===== Vascular =====
*Yellow papules [[Xanthomas|(Xanthomas]]) involving skin and tendons may be seen
==== Cardiac ====
*Chest pain can be the presenting compliant signifying cardiac involvement
==== Vascular ====
*Leg pain (due to [[peripheral vascular disease]])
*Leg pain (due to [[peripheral vascular disease]])
===Physical Exam===
===Physical Exam===
A detailed physical exam is required for patients suspected to have dysbetalipoproteinemia. Physical examination in dysbetalipoproteinemia may range from being normal to the presence of 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>
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====
====Dermatological====
*[[Xanthoma]] Striatum palmare-consisting of yellow streaks in the palmar creases
*[[Xanthoma]] Striatum palmare-consisting of yellow streaks in the palmar creases
Line 76: Line 106:
*Cutaneous [[xanthomas]]
*Cutaneous [[xanthomas]]
====Musculoskeletal====
====Musculoskeletal====
*Tendon [[xanthomas]] may also be seen rarely
*Tendon [[xanthomas]] may also be seen in rare cases
 
====Vascular====
====Vascular====
*[[Peripheral vascular disease]]
*[[Peripheral vascular disease]]
===Laboratory Findings===
===Laboratory Findings===
The laboratory findings consistent with [[Dysbetalipoproteinemia|dysbetalipoprotenemia]] include the following:<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>  
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"
{| class="wikitable"
!Appearance
! rowspan="2" |Appearance
!VLDL cholesterol
! colspan="4" |Lipid Profile
!Cholesterol
! rowspan="2" |VLDL cholesterol
! rowspan="2" |Isoelectric focusing
|-
!Total Cholesterol
!Triglycerides
!Triglycerides
!Isoelectric focusing
!LDL
!HDL
|-
|-
|Floating  
|Floating  
beta lipoproteins
beta lipoproteins
|Elevated
|Elevated
|Decreaesd
|Normal
|[[VLDL]] cholesterol/
|[[VLDL]] cholesterol/
VLDL triglyceride >0.35
VLDL triglyceride >0.35
|Elevated
|Elevated
|[[ApoE2]] homozygote
|[[ApoE2]] homozygote
|}
|}


=== Molecular Genetic Testing ===
=== Molecular Genetic Testing ===
*Diagnosis 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>
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>


==Treatment==
==Treatment==
Treatment of [[Dysbetalipoproteinemia|dysbetalipoprotenemia]] include:- <ref>The Measurement of Lipids, Lipoproteins, Apolipoproteins, Fatty Acids, and Sterols, and Next Generation Sequencing for the Diagnosis and Treatment of Lipid Disorders.
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>


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>
===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.


===Non-pharmacological therapy===
*Exercise and dietary therapy with low [[cholesterol]] and fat diet have been shown to be effective
*Avoiding other risk factors responsible for the complications, to decrease severity such as avoiding smoking
Inappropriate or subnormal control with non pharmacological therapies requires pharmacological treatment.
===Medical Therapy===
===Medical Therapy===
*[[Bile acid]] binding agents are an option if [[triglyceride]] levels are <200mg/dL
*[[Bile acid]] binding agents are an option if [[triglyceride]] levels are <200 mg/dL.
*[[Statins]] can be used if [[triglyceride]] levels are <500mg/dL
*[[Statins]] can be used if [[triglyceride]] levels are <500 mg/dL.
*[[Fibrates]] and [[Nicotinic acid]] can also be used
*[[Fibrates]] and [[nicotinic acid]] can also be used.
 
==Prevention==
==Prevention==
* There is no way to prevent someone from inheriting this syndrome
===Primary Prevention===
* [[Genetic counseling]] is recommended for patients and family members as well<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>
*[[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>


===Secondary prevention===
===Secondary Prevention===
The [[secondary prevention]] for dysbetalipoproteinemia includes:-
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>
*Lifestyle modifications  
*Lifestyle modifications  
*Screening the family members may lead to early detection and treatment
*Screening family members to increase the likelihood of early detection and treatment
*Early treatment and avoiding other risk factors for [[vascular disease]] (such as [[smoking]]) are crucial to prevent complications
*Early treatment and avoidance of other risk factors for [[vascular disease]] (e.g., [[smoking]]) to prevention of complications
 
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

Latest revision as of 16:02, 9 August 2017

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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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