Familial combined hyperlipidemia: Difference between revisions

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__NOTOC__
__NOTOC__
{{Lipoprotein disorders}}
{{SI}}
{{CMG}}
{{CMG}}{{AE}}{{USAMA}}, {{PTD}}, {{VD}}


{{SK}} Type IIB hyperlipoproteinemia
'''To view Lipoprotein disorders main page [[ Lipoprotein disorders | Click here]]'''<br>
'''To view Hyperlipoproteinemia main page [[ Hyperlipoproteinemia | Click here]]''' <br>
 
{{SK}} Type IIB hyperlipoproteinemia, Multiple phenotype familial hyperlipidemia, Familial combined hyperlipoproteinemia, and Familial combined hypercholesterolemia-hypertriglyceridemia.


==Overview==
==Overview==
Based on old and recent definitions, Familial combined hyperlipidemia is a common metabolic disorder charaterized by following:-
Familial combined hyperlipidemia is a common metabolic disorder charaterized by  increase in [[cholesterol]] and/or [[triglycerides]] in at least two members of the family, variable  intra-individual and intrafamilial [[lipid]] [[phenotype]], and increased risk of premature [[coronary heart disease]]. Several theories have been postulated about the development of familial combined hyperlipidemia. Its [[prevalence]] is estimated to be 0.5-2% in general population annually.<ref name="pmid182008072" />
*An increased cholesterol and/or triglycerides in at least to members of the same family.
*An intra-individual and intrafamilial variability of the lipid phenotype
*An increased risk of premature coronary heart disease.
The high [[VLDL]] levels are due to overproduction of substrates, including triglycerides, [[acetyl-CoA]], and an increase in B-100 synthesis.
 
==Historical perspective==
==Historical perspective==
*In 1967, Fredrickson using paper electrophosresis , 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 using paper [[electrophosresis]], classified [[lipoprotein disorders]].<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 1973, Familial combined hyperlipidemia (FCHL) for the first time in medical literature was described by Goldstein.
*In 1973, familial combined hyperlipidemia (FCHL) for the first time in medical literature was described by Goldstein.


==Classification==
==Classification==
*There is no established classification for familial combined hyperlipidemia.
*There is no established classification for familial combined hyperlipidemia.
For a detailed classification of [[hyperlipoproteinemia]] click '''[[Hyperlipoproteinemia#Classification|here]]'''.
==Pathophysiology==
==Pathophysiology==
===Pathogenesis===
===Pathogenesis===
The exact pathogenesis of Familial combined hyperlipidemia remains unknown. Several theories have been postulated about the development of a familial combined hyperlipidemia. The underlying mechanisms of the disease involves the following:-
The exact pathogenesis of familial combined hyperlipidemia remains (FCHL) is unknown. Several theories have been postulated about the development of familial combined hyperlipidemia. The underlying mechanisms of the disease involves the following:<ref name="pmid182008072">{{cite journal| author=Gaddi A, Cicero AF, Odoo FO, Poli AA, Paoletti R, Atherosclerosis and Metabolic Diseases Study Group| title=Practical guidelines for familial combined hyperlipidemia diagnosis: an up-date. | journal=Vasc Health Risk Manag | year= 2007 | volume= 3 | issue= 6 | pages= 877-86 | pmid=18200807 | doi= | pmc=2350131 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18200807  }}</ref>
====VLDL abnormalities====
====VLDL abnormalities====
*In many cases, FCHL is caused by overproduction of VLDL-apo B.
*In many cases, FCHL is caused by overproduction of [[VLDL]]-[[apo B]].
*Overproduction of VLDL-apo B could be do to the following:-
*Overproduction of [[VLDL]]-[[apo B]] could be do to the following:<ref name="pmid8318511">{{cite journal| author=Venkatesan S, Cullen P, Pacy P, Halliday D, Scott J| title=Stable isotopes show a direct relation between VLDL apoB overproduction and serum triglyceride levels and indicate a metabolically and biochemically coherent basis for familial combined hyperlipidemia. | journal=Arterioscler Thromb | year= 1993 | volume= 13 | issue= 7 | pages= 1110-8 | pmid=8318511 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8318511  }} </ref><ref name="pmid11932285">{{cite journal| author=Meijssen S, Derksen RJ, Bilecen S, Erkelens DW, Cabezas MC| title=In vivo modulation of plasma free fatty acids in patients with familial combined hyperlipidemia using lipid-lowering medication. | journal=J Clin Endocrinol Metab | year= 2002 | volume= 87 | issue= 4 | pages= 1576-80 | pmid=11932285 | doi=10.1210/jcem.87.4.8408 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11932285  }} </ref><ref name="pmid17466309">{{cite journal| author=Evans K, Burdge GC, Wootton SA, Collins JM, Clark ML, Tan GD et al.| title=Tissue-specific stable isotope measurements of postprandial lipid metabolism in familial combined hyperlipidaemia. | journal=Atherosclerosis | year= 2008 | volume= 197 | issue= 1 | pages= 164-70 | pmid=17466309 | doi=10.1016/j.atherosclerosis.2007.03.009 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17466309  }} </ref><ref name="pmid10894818">{{cite journal| author=Pihlajamäki J, Karjalainen L, Karhapää P, Vauhkonen I, Taskinen MR, Deeb SS et al.| title=G-250A substitution in promoter of hepatic lipase gene is associated with dyslipidemia and insulin resistance in healthy control subjects and in members of families with familial combined hyperlipidemia. | journal=Arterioscler Thromb Vasc Biol | year= 2000 | volume= 20 | issue= 7 | pages= 1789-95 | pmid=10894818 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10894818  }} </ref>
**Alterations to incorporations of fatty acids in the TG  
**Alterations to incorporations of [[fatty acids]] in the [[triglyceride]](TG).
**Alterations in postprandial metabolism of VLDLs
**Alterations in postprandial metabolism of [[VLDL]]s.
**Defects in activity of Lipoprotein lipase, lecithin:cholesterol acyltransferase, and/or hepatic lipase.
**Defects in activity of [[lipoprotein lipase]], [[LCAT|lecithin:cholesterol acyltransferase]], and/or [[hepatic lipase]].
**Decreased fatty acid oxidation in liver, results in overproduction of triacylglycerol(TAG), with fatty acids directed to TG synthesis.  
**Decreased fatty acid oxidation in [[liver]], results in overproduction of [[triacylglycerol]](TAG), with [[fatty acids]] directed to [[triglyceride]](TG) synthesis.
**Imparied postprandial C3 response, would result in impaired peripheral postprandial FFA uptake, which leads to increased hepatic FFA flux and VLDL overproduction.
**Imparied postprandial [[C3]] response, would result in impaired peripheral postprandial [[FFA]] uptake, which leads to increased hepatic free fatty acids([[FFA]]) flux and [[VLDL]] overproduction.


====LDL abnormalities====
====LDL abnormalities====
*In many cases, FCHL is caused by predominance of atherogenic LDL "B" pattern.
*In many cases, FCHL is caused by predominance of [[Atherosclerosis|atherogenic]] [[LDL]] "B"(atherogenic) pattern
*LDL "B" pattern could be due to following:-
*LDL "B" pattern could be due to following:<ref name="pmid12173032">{{cite journal| author=Vakkilainen J, Pajukanta P, Cantor RM, Nuotio IO, Lahdenperä S, Ylitalo K et al.| title=Genetic influences contributing to LDL particle size in familial combined hyperlipidaemia. | journal=Eur J Hum Genet | year= 2002 | volume= 10 | issue= 9 | pages= 547-52 | pmid=12173032 | doi=10.1038/sj.ejhg.5200844 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12173032  }} </ref><ref name="pmid16011471">{{cite journal| author=Corella D, Ordovas JM| title=SINGLE NUCLEOTIDE POLYMORPHISMS THAT INFLUENCE LIPID METABOLISM: Interaction with Dietary Factors. | journal=Annu Rev Nutr | year= 2005 | volume= 25 | issue=  | pages= 341-90 | pmid=16011471 | doi=10.1146/annurev.nutr.25.050304.092656 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16011471  }} </ref>
**Uncontrolled overproduction of apo B.
**Overproduction of [[apo B]].
**Relative deficit of hepatic lipoprotein lipase can reduce the liver uptake of apo B, leading to increase synthesis of apolipoproteins.
**Relative deficit of [[hepatic lipoprotein lipase]] can reduce the [[liver]] uptake of [[apo B]], leading to increase synthesis of [[apolipoproteins]].
**An increase LDL susceptibility  oxidation.
**An increase [[LDL]] susceptibility  [[oxidation]].


====HDLs abnormalities====
====HDLs abnormalities====
*In many cases, FCHL is associated with reduced levels of HDL-C
*In many cases, FCHL is associated with reduced levels of [[HDL-C]].
*Low HDL-C, could be due to the following:-
*Low [[HDL]]-C, could be due to the following:<ref name="pmid12777471">{{cite journal| author=Soro A, Jauhiainen M, Ehnholm C, Taskinen MR| title=Determinants of low HDL levels in familial combined hyperlipidemia. | journal=J Lipid Res | year= 2003 | volume= 44 | issue= 8 | pages= 1536-44 | pmid=12777471 | doi=10.1194/jlr.M300069-JLR200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12777471  }} </ref><ref name="pmid14751815">{{cite journal| author=Georgieva AM, van Greevenbroek MM, Krauss RM, Brouwers MC, Vermeulen VM, Robertus-Teunissen MG et al.| title=Subclasses of low-density lipoprotein and very low-density lipoprotein in familial combined hyperlipidemia: relationship to multiple lipoprotein phenotype. | journal=Arterioscler Thromb Vasc Biol | year= 2004 | volume= 24 | issue= 4 | pages= 744-9 | pmid=14751815 | doi=10.1161/01.ATV.0000119681.47218.a4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14751815  }} </ref>
**TG-enrichment of HDL particles.
**[[TG]]-enrichment of [[HDL-cholesterol|HDL]] particles
**Enhanced hepatic lipase (HL).
**Enhanced [[hepatic lipase]] (HL)
**Very high concentration of VLDL-1
**Very high concentration of [[VLDL]]-1
 
=== Genetics ===
*The following [[Gene|genes]] were found to be associated with familial combined hyperlipidemia:<ref name="pmid2369363">{{cite journal| author=Austin MA, Brunzell JD, Fitch WL, Krauss RM| title=Inheritance of low density lipoprotein subclass patterns in familial combined hyperlipidemia. | journal=Arteriosclerosis | year= 1990 | volume= 10 | issue= 4 | pages= 520-30 | pmid=2369363 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2369363  }} </ref><ref name="pmid11031215">{{cite journal| author=Coon H, Myers RH, Borecki IB, Arnett DK, Hunt SC, Province MA et al.| title=Replication of linkage of familial combined hyperlipidemia to chromosome 1q with additional heterogeneous effect of apolipoprotein A-I/C-III/A-IV locus. The NHLBI Family Heart Study. | journal=Arterioscler Thromb Vasc Biol | year= 2000 | volume= 20 | issue= 10 | pages= 2275-80 | pmid=11031215 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11031215  }} </ref><ref name="pmid14551155">{{cite journal| author=Eichenbaum-Voline S, Olivier M, Jones EL, Naoumova RP, Jones B, Gau B et al.| title=Linkage and association between distinct variants of the APOA1/C3/A4/A5 gene cluster and familial combined hyperlipidemia. | journal=Arterioscler Thromb Vasc Biol | year= 2004 | volume= 24 | issue= 1 | pages= 167-74 | pmid=14551155 | doi=10.1161/01.ATV.0000099881.83261.D4 | pmc=2773540 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14551155  }} </ref><ref name="pmid15331429">{{cite journal| author=Badzioch MD, Igo RP, Gagnon F, Brunzell JD, Krauss RM, Motulsky AG et al.| title=Low-density lipoprotein particle size loci in familial combined hyperlipidemia: evidence for multiple loci from a genome scan. | journal=Arterioscler Thromb Vasc Biol | year= 2004 | volume= 24 | issue= 10 | pages= 1942-50 | pmid=15331429 | doi=10.1161/01.ATV.0000143499.09575.93 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15331429  }} </ref>
**[[Locus (genetics)|Locus]] 1q21-q23, is linked to be associated with familial combined hyperlipidemia and [[Diabetes mellitus|diabetes]].
**Newly discovered apo AV gene with APOAI/CIII/AIV cluster was to be associated with FCH transmission.
**Few studies found FCH trait is influenced by multiple loci located to 9p, 16q, and 11.
**[[Gene]] encoding upstream transcription factor 1 (USF1) has appeared to be linked to FCH.
 
== Causes ==
*The cause of familial combined hyperlipidemia is genetic, with complex inheritance to explain the variability in the [[phenotype]].


==Causes==
*[[Gene]]-[[envirnoment]] interaction strongly influence the laboratory and clinical features of familial combined hyperlipidemia.
The cause of familial combined hyperlipidemia remains genetic.


==Differential diagnosis==
==Differential diagnosis==
Familial combined hyperlipidemia 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]]
*[[Dysbetalipoproteinemia|Dysbetalipoprotenemia]]
*[[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==
===Epidemiology===
===Epidemiology===
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==Screening==
==Screening==
The USPSTF has no screening guidelines for the detection of familial combined hyperlipidemia.
===Screening in children and adolescents===
The USPSTF has no screening guidelines for the detection of familial combined hyperlipidemia however, early detection of lipid disorders in childhood has benefit of reducing the risk and severity of [[cardiovascular disease]] (CVD) in adulthood. The pediatric dyslipidemia screening guidelines from the 2011 expert panel integrated Guidelines for cardiovascular health and risk reduction in children and adolescents has therefore outlined the following:<ref name="pmid22084329">{{cite journal| author=Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. National Heart, Lung, and Blood Institute| title=Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. | journal=Pediatrics | year= 2011 | volume= 128 Suppl 5 | issue=  | pages= S213-56 | pmid=22084329 | doi=10.1542/peds.2009-2107C | pmc=4536582 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22084329  }} </ref><ref name="pmid25845026">{{cite journal| author=Gooding HC, Rodday AM, Wong JB, Gillman MW, Lloyd-Jones DM, Leslie LK et al.| title=Application of Pediatric and Adult Guidelines for Treatment of Lipid Levels Among US Adolescents Transitioning to Young Adulthood. | journal=JAMA Pediatr | year= 2015 | volume= 169 | issue= 6 | pages= 569-74 | pmid=25845026 | doi=10.1001/jamapediatrics.2015.0168 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25845026  }} </ref> <ref name=screening> Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents http://www.nhlbi.nih.gov/guidelines/cvd_ped/peds_guidelines_full.pdf.</ref>
 
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 120px;" colspan="3" | {{fontcolor|#FFF|'''
Pediatric dyslipidemia screening guidelines from the 2011 Expert Panel Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents'''}}
|-
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Age}}
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Screening recommendation}}
! style="background: #4479BA; width: 50px;" | {{fontcolor|#FFF|Reommendation level}}
|-
| style="padding: 5px 5px; background: #DCDCDC;" rowspan="1" | '''birth- <2years'''
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | No lipid screening
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | C
|-
| style="padding: 5px 5px; background: #DCDCDC;" rowspan="4" | '''2-8years (''' No routine lipid screening,
however screen if one of the following is present using  FLP two times)
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |Parent, grandparent, aunt/uncle, or sibling with myocardial infarction (MI), angina, stroke, coronary artery bypass graft Strongly recommend (CABG)/stent/angioplasty at <55 years in males, <65 years in females
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |Parent with TC ≥ 240 mg/dL or known dyslipidemia
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |Child has diabetes, hypertension, BMI ≥ 95th percentile or smokes cigarettes
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | Child has a moderate- or high-risk medical condition (eg. Diabetes mellitus type 1 and type 2, chronic renal disease/end-stage renal disease/ postrenal transplant, Postorthotopic heart transplant, Kawasaki disease with current aneurysms)
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
|-
| style="padding: 5px 5px; background: #DCDCDC;" rowspan="2" | '''9-11years  ('''Universal Screening)
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | Universal screening with a non-FLP screening using non-HDL-C levels ( Non-HDL–C = TC – HDL–C) when Non-HDL ≥ 145 mg/dL, HDL < 40 mg/dL check FLP × 2
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | Do further FLP if LDL–C ≥ 130 mg/dL, non-HDL–C ≥ 145 mg/dL HDL–C < 40 mg/dL, TG ≥ 100 mg/dL if < 10 years; ≥ 130 mg/dL if ≥ 10 years.  Repeat FLP after 2 weeks but within 3 months
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
|-
| style="padding: 5px 5px; background: #DCDCDC;" rowspan="5" |'''12-16years ('''Selective screening using FLP x 2)
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | Lipid screening is not recommended for those ages 12–16 years because of significantly decreased sensitivity and specificity for predicting adult LDL–C levels and significantly increased false-negative results in this age group. Selective screening ( Interval between FLP measurements: after 2 weeks but within 3 months)  is recommended for those with the clinical indications outlined below:
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | Parent, grandparent, aunt/uncle or sibling with MI, angina, stroke, CABG/stent/ Strongly recommend angioplasty, sudden death at < 55 years in males, < 65 years in females
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | • Parent with TC ≥ 240 mg/dL or known dyslipidemia
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |Patient has diabetes, hypertension, BMI ≥ 85th pr\ercentile or smokes cigarettes
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |Patient has a moderate- or high-risk medical condition (eg. Diabetes mellitus type 1 and type 2, chronic renal disease/end-stage renal disease/ postrenal transplant, Postorthotopic heart transplant, Kawasaki disease with current aneurysms)
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
|-
| style="padding: 5px 5px; background: #DCDCDC;" rowspan="1" | '''17-19years'''
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | Universal screening once during this time period with a nonfasting lipid screening using non-HDL-C levels. If  Non-HDL-C ≥ 145 mg/dL, HDL-C < 40 mg/dL do FLP × 2, Further screening with FLP if LDL-C ≥ 130 mg/dL, non-HDL-C ≥ 145 mg/dL HDL-C < 40 mg/dL, TG ≥ 130 mg/dL repeat FLP after 2 weeks but within 3 months
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
|-
| rowspan="1" style="padding: 5px 5px; background: #DCDCDC;" | '''17-21years'''
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | Universal screening once during this time period with a nonfasting lipid screening using non-HDL-C levels. If Non-HDL-C ≥ 190 mg/dL, HDL-C < 40 mg/dL  do FLP × 2, Further screening with  FLP when LDL-C ≥ 160 mg/dL, non-HDL-C ≥ 190 mg/dL,  HDL-C < 40 mg/dL, TG ≥ 150 mg/dL repeat FLP after 2 weeks but within 3 months
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
|}


==Natural History, Complications, and Prognosis==
==Natural History, Complications, and Prognosis==
===Natural History===
===Natural History===
If left untreated, familial combined hyperlipidemia leads to increased carotid artery initima-media thickness and an increased risk of cardiovascular disease.<ref name="pmid11834529">{{cite journal| author=Keulen ET, Kruijshoop M, Schaper NC, Hoeks AP, de Bruin TW| title=Increased intima-media thickness in familial combined hyperlipidemia associated with apolipoprotein B. | journal=Arterioscler Thromb Vasc Biol | year= 2002 | volume= 22 | issue= 2 | pages= 283-8 | pmid=11834529 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11834529  }} </ref>
If left untreated, familial combined hyperlipidemia leads to increased carotid artery initima-media thickness and an increased risk of [[cardiovascular disease]].<ref name="pmid11834529">{{cite journal| author=Keulen ET, Kruijshoop M, Schaper NC, Hoeks AP, de Bruin TW| title=Increased intima-media thickness in familial combined hyperlipidemia associated with apolipoprotein B. | journal=Arterioscler Thromb Vasc Biol | year= 2002 | volume= 22 | issue= 2 | pages= 283-8 | pmid=11834529 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11834529  }} </ref>
 
===Complications===
===Complications===
Complications that can develop in patients with familial combined hyperlipidemia include<ref name="pmid4718953">{{cite journal| author=Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG| title=Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. | journal=J Clin Invest | year= 1973 | volume= 52 | issue= 7 | pages= 1544-68 | pmid=4718953 | doi=10.1172/JCI107332 | pmc=302426 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4718953  }} </ref><ref name="pmid11895451">{{cite journal| author=Sniderman AD, Castro Cabezas M, Ribalta J, Carmena R, de Bruin TW, de Graaf J et al.| title=A proposal to redefine familial combined hyperlipidaemia -- third workshop on FCHL held in Barcelona from 3 to 5 May 2001, during the scientific sessions of the European Society for Clinical Investigation. | journal=Eur J Clin Invest | year= 2002 | volume= 32 | issue= 2 | pages= 71-3 | pmid=11895451 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11895451  }} </ref><ref name="pmid12957324">{{cite journal| author=Ayyobi AF, Brunzell JD| title=Lipoprotein distribution in the metabolic syndrome, type 2 diabetes mellitus, and familial combined hyperlipidemia. | journal=Am J Cardiol | year= 2003 | volume= 92 | issue= 4A | pages= 27J-33J | pmid=12957324 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12957324  }} </ref>
Complications that can develop in patients with familial combined hyperlipidemia include:<ref name="pmid19402225">{{cite journal| author=Brouwers MC, Reesink KD, van Greevenbroek MM, Meinders JM, van der Kallen CJ, Schaper N et al.| title=Increased arterial stiffness in familial combined hyperlipidemia. | journal=J Hypertens | year= 2009 | volume= 27 | issue= 5 | pages= 1009-16 | pmid=19402225 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19402225  }} </ref><ref name="pmid4718953">{{cite journal| author=Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG| title=Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. | journal=J Clin Invest | year= 1973 | volume= 52 | issue= 7 | pages= 1544-68 | pmid=4718953 | doi=10.1172/JCI107332 | pmc=302426 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4718953  }} </ref><ref name="pmid11895451">{{cite journal| author=Sniderman AD, Castro Cabezas M, Ribalta J, Carmena R, de Bruin TW, de Graaf J et al.| title=A proposal to redefine familial combined hyperlipidaemia -- third workshop on FCHL held in Barcelona from 3 to 5 May 2001, during the scientific sessions of the European Society for Clinical Investigation. | journal=Eur J Clin Invest | year= 2002 | volume= 32 | issue= 2 | pages= 71-3 | pmid=11895451 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11895451  }} </ref><ref name="pmid12957324">{{cite journal| author=Ayyobi AF, Brunzell JD| title=Lipoprotein distribution in the metabolic syndrome, type 2 diabetes mellitus, and familial combined hyperlipidemia. | journal=Am J Cardiol | year= 2003 | volume= 92 | issue= 4A | pages= 27J-33J | pmid=12957324 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12957324  }} </ref>  
*Coronary heart disease
*[[Atherosclerosis]]
*Coronary vasuclar disease
*[[Coronary artery disease]]
*Peripheral vascular disease
*[[Peripheral artery disease]]
*Gangrene of the extremities
*[[Gangrene]]


===Prognosis===
===Prognosis===
Line 79: Line 159:
==Diagnosis==
==Diagnosis==
===History and symptoms===
===History and symptoms===
History is usually suggestive of:
*Premature [[cardiovascular disease]], such as:
**[[Angina pectoris]], leading to [[PTCA]] or [[CABG]]
**[[Myocardial infarction]]
**[[Transient ischemic attack]]s ([[TIA]])
**[[Cerebrovascular accident]]s/[[Stroke]]s
**[[Peripheral artery disease]] ([[PAD]])
*[[Family history]] of premature [[atherosclerosis]]


Symptoms of 
===Physical examination===
===Physical examination===
*Signs of Type
Ptients with familial combined hyperlipidemia may present with the following:
 
====Eyes====
 
*[[Xanthelasma|Xanthelasma palpabrum]] (yellowish patches above the eyelids)
 
*[[Arcus senilis]] corneae, whitish discoloration of the iris
 
====Extremities====
 
*Tendon [[xanthoma]]s
 
 
 
 
 
 
 
 
 
 
 


====Non-specific signs====
The following non-specific signs may also be seen in patients with familial combined hyperlipidemia:
* Obesity and insulin resistance<ref name="pmid16285998">{{cite journal| author=van der Vleuten GM, Veerkamp MJ, van Tits LJ, Toenhake H, den Heijer M, Stalenhoef AF et al.| title=Elevated leptin levels in subjects with familial combined hyperlipidemia are associated with the increased risk for CVD. | journal=Atherosclerosis | year= 2005 | volume= 183 | issue= 2 | pages= 355-60 | pmid=16285998 | doi=10.1016/j.atherosclerosis.2005.03.019 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16285998  }} </ref>
*waist-to-hip ratio appears to be the best determinant of [[hyperlipidemia]], particularly [[hypertriglyceridemia]] in FCHL patients.<ref name="pmid18200807">{{cite journal| author=Gaddi A, Cicero AF, Odoo FO, Poli AA, Paoletti R, Atherosclerosis and Metabolic Diseases Study Group| title=Practical guidelines for familial combined hyperlipidemia diagnosis: an up-date. | journal=Vasc Health Risk Manag | year= 2007 | volume= 3 | issue= 6 | pages= 877-86 | pmid=18200807 | doi= | pmc=2350131 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18200807  }} </ref>


===Laboratory findings===
===Laboratory findings===


===Molecular Genetic Testing===
Assessment of the [[lipid profile]]s of at least three first-degree relatives is necessary.<ref name="pmid15478042">{{cite journal| author=Aguilar Salinas CA, Zamora M, Gómez-Díaz RA, Mehta R, Gómez Pérez FJ, Rull JA| title=Familial combined hyperlipidemia: controversial aspects of its diagnosis and pathogenesis. | journal=Semin Vasc Med | year= 2004 | volume= 4 | issue= 2 | pages= 203-9 | pmid=15478042 | doi=10.1055/s-2004-835379 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15478042  }} </ref>


A high degree of diagnostic uncertainty exists in the categorization as normal or abnormal of members of FCHL.<ref name="pmid18200807">{{cite journal| author=Gaddi A, Cicero AF, Odoo FO, Poli AA, Paoletti R, Atherosclerosis and Metabolic Diseases Study Group| title=Practical guidelines for familial combined hyperlipidemia diagnosis: an up-date. | journal=Vasc Health Risk Manag | year= 2007 | volume= 3 | issue= 6 | pages= 877-86 | pmid=18200807 | doi= | pmc=2350131 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18200807  }} </ref>
Its manifestations include:<ref name="pmid15478042">{{cite journal| author=Aguilar Salinas CA, Zamora M, Gómez-Díaz RA, Mehta R, Gómez Pérez FJ, Rull JA| title=Familial combined hyperlipidemia: controversial aspects of its diagnosis and pathogenesis. | journal=Semin Vasc Med | year= 2004 | volume= 4 | issue= 2 | pages= 203-9 | pmid=15478042 | doi=10.1055/s-2004-835379 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15478042  }} </ref><ref name="pmid8318511">{{cite journal| author=Venkatesan S, Cullen P, Pacy P, Halliday D, Scott J| title=Stable isotopes show a direct relation between VLDL apoB overproduction and serum triglyceride levels and indicate a metabolically and biochemically coherent basis for familial combined hyperlipidemia. | journal=Arterioscler Thromb | year= 1993 | volume= 13 | issue= 7 | pages= 1110-8 | pmid=8318511 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8318511  }} </ref><ref name="pmid12777471">{{cite journal| author=Soro A, Jauhiainen M, Ehnholm C, Taskinen MR| title=Determinants of low HDL levels in familial combined hyperlipidemia. | journal=J Lipid Res | year= 2003 | volume= 44 | issue= 8 | pages= 1536-44 | pmid=12777471 | doi=10.1194/jlr.M300069-JLR200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12777471  }} </ref>
*[[Hypercholesterolemia]]
*[[Hypertriglyceridemia]]
*Combination of above
* Increased circulating [[very-low-density lipoprotein]] (VLDL) [[apolipoprotein]] (apo) B
*Reduced levels of [[HDL]] [[cholesterol]]
*Children with [[apolipoprotein]] B level exceeding the 95th percentile may be diagnostic of familial combined hyperlipidemia (FCHL).<ref name="pmid15557711">{{cite journal| author=Sveger T, Nordborg K| title=Apolipoprotein B as a marker of familial hyperlipoproteinemia. | journal=J Atheroscler Thromb | year= 2004 | volume= 11 | issue= 5 | pages= 286-92 | pmid=15557711 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15557711  }} </ref>
*Familial combined hyperlipidemia (FCHL) is traditionally diagnosed by total plasma [[cholesterol]] and/or [[triglyceride]] levels above the 90th percentile adjusted for age and gender. However, recent studies suggest that the diagnosis of FCHL is best predicted by absolute [[apoB]] levels combined with [[triglyceride]] and total [[cholesterol]] levels adjusted for age and gender and may accurately be calculated by a nomogram.<ref name="pmid11834528">{{cite journal| author=Veerkamp MJ, de Graaf J, Bredie SJ, Hendriks JC, Demacker PN, Stalenhoef AF| title=Diagnosis of familial combined hyperlipidemia based on lipid phenotype expression in 32 families: results of a 5-year follow-up study. | journal=Arterioscler Thromb Vasc Biol | year= 2002 | volume= 22 | issue= 2 | pages= 274-82 | pmid=11834528 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11834528  }} </ref>


==Treatment==
==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 (example smoke cessation).
*Subnormal control with non pharmacological therapies requires pharmacological treatment.


===Pregnancy Management===
===Medical Therapy===
 
Familial combined hyperlipidemia can be treated with the following options:<ref name="pmid18200807">{{cite journal| author=Gaddi A, Cicero AF, Odoo FO, Poli AA, Paoletti R, Atherosclerosis and Metabolic Diseases Study Group| title=Practical guidelines for familial combined hyperlipidemia diagnosis: an up-date. | journal=Vasc Health Risk Manag | year= 2007 | volume= 3 | issue= 6 | pages= 877-86 | pmid=18200807 | doi= | pmc=2350131 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18200807  }} </ref>
===Investigative Therapies===
*[[Bile acid]] binding agents are an option if [[triglyceride]] levels are <200mg/dL.
 
*[[Statins]] can be used if [[triglyceride]] levels are <500mg/dL.
===Gene Therapy===
*[[Fibrates]] and [[Nicotinic acid]] can otherwise be used.


==Prevention==
==Prevention==
===Secondary prevention===
===Prevention of complications===
===Prevention of complications===
Disease prevention in familial combined hyperlipidemia is mainly towards prevention of complications as shown below:<ref name="pmid27089599">{{cite journal| author=Brun N, Aubert CE, Nanchen D, Rodondi N| title=[New guidelines for screening and management of familial dyslipidemia]. | journal=Rev Med Suisse | year= 2016 | volume= 12 | issue= 508 | pages= 435-9 | pmid=27089599 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27089599  }} </ref>
*Early screening in childhood in case of family history of premature cardiovascular disease or severe hyperlipidemia in first degree relatives
*Lifestyle modifications
*Control of cardiovascular risk factors


==References==  
==References==  

Latest revision as of 19:45, 5 April 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], Prince Tano Djan, BSc, MBChB [3], Vishal Devarkonda, M.B.B.S[4]

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

Synonyms and keywords: Type IIB hyperlipoproteinemia, Multiple phenotype familial hyperlipidemia, Familial combined hyperlipoproteinemia, and Familial combined hypercholesterolemia-hypertriglyceridemia.

Overview

Familial combined hyperlipidemia is a common metabolic disorder charaterized by increase in cholesterol and/or triglycerides in at least two members of the family, variable intra-individual and intrafamilial lipid phenotype, and increased risk of premature coronary heart disease. Several theories have been postulated about the development of familial combined hyperlipidemia. Its prevalence is estimated to be 0.5-2% in general population annually.[1]

Historical perspective

  • In 1967, Fredrickson using paper electrophosresis, classified lipoprotein disorders.[2]
  • In 1973, familial combined hyperlipidemia (FCHL) for the first time in medical literature was described by Goldstein.

Classification

  • There is no established classification for familial combined hyperlipidemia.

For a detailed classification of hyperlipoproteinemia click here.

Pathophysiology

Pathogenesis

The exact pathogenesis of familial combined hyperlipidemia remains (FCHL) is unknown. Several theories have been postulated about the development of familial combined hyperlipidemia. The underlying mechanisms of the disease involves the following:[1]

VLDL abnormalities

LDL abnormalities

HDLs abnormalities

  • In many cases, FCHL is associated with reduced levels of HDL-C.
  • Low HDL-C, could be due to the following:[9][10]

Genetics

  • The following genes were found to be associated with familial combined hyperlipidemia:[11][12][13][14]
    • Locus 1q21-q23, is linked to be associated with familial combined hyperlipidemia and diabetes.
    • Newly discovered apo AV gene with APOAI/CIII/AIV cluster was to be associated with FCH transmission.
    • Few studies found FCH trait is influenced by multiple loci located to 9p, 16q, and 11.
    • Gene encoding upstream transcription factor 1 (USF1) has appeared to be linked to FCH.

Causes

  • The cause of familial combined hyperlipidemia is genetic, with complex inheritance to explain the variability in the phenotype.
  • Gene-envirnoment interaction strongly influence the laboratory and clinical features of familial combined hyperlipidemia.

Differential diagnosis

Familial combined hyperlipidemia 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

Epidemiology

Familial combined hyperlipidemia is a a very common genetic hyperlipidemia . The prevalence is estimated to be 0.5-2% in general population annually. Familial combined hyperlipidemia is commonly seen in patients with coronary disease( 10%) , patients less than 60 years of age who have survived an acute infarct (11.3%) and upto 40% in all myocardial infarction survivors. [16][17] More than 3.5 million people in EU and 2.7 million in the US suffer from familial combined hyperlipidemia.[16]

Demographics

Geographical distribution can not be estimated so far as most of the studies conducted on familial combined hyperlipidemia consist of Caucasian population living the United States and Europe.[18]

Age

Familial combined hyperlipidemia is commonly seen in all ages in myocardial infarction survivors.[17] Dr. Iwata in 2003 explained that many patients with familial combined hyperlipidemia present during their childhood.[19]

Gender

Familial combined hyperlipidemia affects men and women equally.

Screening

Screening in children and adolescents

The USPSTF has no screening guidelines for the detection of familial combined hyperlipidemia however, early detection of lipid disorders in childhood has benefit of reducing the risk and severity of cardiovascular disease (CVD) in adulthood. The pediatric dyslipidemia screening guidelines from the 2011 expert panel integrated Guidelines for cardiovascular health and risk reduction in children and adolescents has therefore outlined the following:[20][21] [22]

Pediatric dyslipidemia screening guidelines from the 2011 Expert Panel Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents

Age Screening recommendation Reommendation level
birth- <2years No lipid screening C
2-8years ( No routine lipid screening,

however screen if one of the following is present using  FLP two times)

Parent, grandparent, aunt/uncle, or sibling with myocardial infarction (MI), angina, stroke, coronary artery bypass graft Strongly recommend (CABG)/stent/angioplasty at <55 years in males, <65 years in females B
Parent with TC ≥ 240 mg/dL or known dyslipidemia B
Child has diabetes, hypertension, BMI ≥ 95th percentile or smokes cigarettes B
Child has a moderate- or high-risk medical condition (eg. Diabetes mellitus type 1 and type 2, chronic renal disease/end-stage renal disease/ postrenal transplant, Postorthotopic heart transplant, Kawasaki disease with current aneurysms) B
9-11years (Universal Screening) Universal screening with a non-FLP screening using non-HDL-C levels ( Non-HDL–C = TC – HDL–C) when Non-HDL ≥ 145 mg/dL, HDL < 40 mg/dL check FLP × 2 B
Do further FLP if LDL–C ≥ 130 mg/dL, non-HDL–C ≥ 145 mg/dL HDL–C < 40 mg/dL, TG ≥ 100 mg/dL if < 10 years; ≥ 130 mg/dL if ≥ 10 years. Repeat FLP after 2 weeks but within 3 months B
12-16years (Selective screening using FLP x 2) Lipid screening is not recommended for those ages 12–16 years because of significantly decreased sensitivity and specificity for predicting adult LDL–C levels and significantly increased false-negative results in this age group. Selective screening ( Interval between FLP measurements: after 2 weeks but within 3 months) is recommended for those with the clinical indications outlined below: B
Parent, grandparent, aunt/uncle or sibling with MI, angina, stroke, CABG/stent/ Strongly recommend angioplasty, sudden death at < 55 years in males, < 65 years in females B
• Parent with TC ≥ 240 mg/dL or known dyslipidemia B
Patient has diabetes, hypertension, BMI ≥ 85th pr\ercentile or smokes cigarettes B
Patient has a moderate- or high-risk medical condition (eg. Diabetes mellitus type 1 and type 2, chronic renal disease/end-stage renal disease/ postrenal transplant, Postorthotopic heart transplant, Kawasaki disease with current aneurysms) B
17-19years Universal screening once during this time period with a nonfasting lipid screening using non-HDL-C levels. If Non-HDL-C ≥ 145 mg/dL, HDL-C < 40 mg/dL do FLP × 2, Further screening with FLP if LDL-C ≥ 130 mg/dL, non-HDL-C ≥ 145 mg/dL HDL-C < 40 mg/dL, TG ≥ 130 mg/dL repeat FLP after 2 weeks but within 3 months B
17-21years Universal screening once during this time period with a nonfasting lipid screening using non-HDL-C levels. If Non-HDL-C ≥ 190 mg/dL, HDL-C < 40 mg/dL do FLP × 2, Further screening with FLP when LDL-C ≥ 160 mg/dL, non-HDL-C ≥ 190 mg/dL, HDL-C < 40 mg/dL, TG ≥ 150 mg/dL repeat FLP after 2 weeks but within 3 months B

Natural History, Complications, and Prognosis

Natural History

If left untreated, familial combined hyperlipidemia leads to increased carotid artery initima-media thickness and an increased risk of cardiovascular disease.[23]

Complications

Complications that can develop in patients with familial combined hyperlipidemia include:[24][25][26][27]

Prognosis

The presence of hypertriglyceridemia along with hypercholesterolemia is a poor prognostic factor. The coronary flow reserve in young patients is decreased in the presence of this combination.[28]

Diagnosis

History and symptoms

History is usually suggestive of:

Physical examination

Ptients with familial combined hyperlipidemia may present with the following:

Eyes

Extremities

Non-specific signs

The following non-specific signs may also be seen in patients with familial combined hyperlipidemia:

Laboratory findings

Assessment of the lipid profiles of at least three first-degree relatives is necessary.[30]

A high degree of diagnostic uncertainty exists in the categorization as normal or abnormal of members of FCHL.[18] Its manifestations include:[30][3][9]

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 (example smoke cessation).
  • Subnormal control with non pharmacological therapies requires pharmacological treatment.

Medical Therapy

Familial combined hyperlipidemia can be treated with the following options:[18]

Prevention

Prevention of complications

Disease prevention in familial combined hyperlipidemia is mainly towards prevention of complications as shown below:[33]

  • Early screening in childhood in case of family history of premature cardiovascular disease or severe hyperlipidemia in first degree relatives
  • Lifestyle modifications
  • Control of cardiovascular risk factors

References

  1. 1.0 1.1 Gaddi A, Cicero AF, Odoo FO, Poli AA, Paoletti R, Atherosclerosis and Metabolic Diseases Study Group (2007). "Practical guidelines for familial combined hyperlipidemia diagnosis: an up-date". Vasc Health Risk Manag. 3 (6): 877–86. PMC 2350131. PMID 18200807.
  2. Culliton BJ (1987). "Fredrickson's bitter end at Hughes". Science. 236 (4807): 1417–8. PMID 3296193.
  3. 3.0 3.1 Venkatesan S, Cullen P, Pacy P, Halliday D, Scott J (1993). "Stable isotopes show a direct relation between VLDL apoB overproduction and serum triglyceride levels and indicate a metabolically and biochemically coherent basis for familial combined hyperlipidemia". Arterioscler Thromb. 13 (7): 1110–8. PMID 8318511.
  4. Meijssen S, Derksen RJ, Bilecen S, Erkelens DW, Cabezas MC (2002). "In vivo modulation of plasma free fatty acids in patients with familial combined hyperlipidemia using lipid-lowering medication". J Clin Endocrinol Metab. 87 (4): 1576–80. doi:10.1210/jcem.87.4.8408. PMID 11932285.
  5. Evans K, Burdge GC, Wootton SA, Collins JM, Clark ML, Tan GD; et al. (2008). "Tissue-specific stable isotope measurements of postprandial lipid metabolism in familial combined hyperlipidaemia". Atherosclerosis. 197 (1): 164–70. doi:10.1016/j.atherosclerosis.2007.03.009. PMID 17466309.
  6. Pihlajamäki J, Karjalainen L, Karhapää P, Vauhkonen I, Taskinen MR, Deeb SS; et al. (2000). "G-250A substitution in promoter of hepatic lipase gene is associated with dyslipidemia and insulin resistance in healthy control subjects and in members of families with familial combined hyperlipidemia". Arterioscler Thromb Vasc Biol. 20 (7): 1789–95. PMID 10894818.
  7. Vakkilainen J, Pajukanta P, Cantor RM, Nuotio IO, Lahdenperä S, Ylitalo K; et al. (2002). "Genetic influences contributing to LDL particle size in familial combined hyperlipidaemia". Eur J Hum Genet. 10 (9): 547–52. doi:10.1038/sj.ejhg.5200844. PMID 12173032.
  8. Corella D, Ordovas JM (2005). "SINGLE NUCLEOTIDE POLYMORPHISMS THAT INFLUENCE LIPID METABOLISM: Interaction with Dietary Factors". Annu Rev Nutr. 25: 341–90. doi:10.1146/annurev.nutr.25.050304.092656. PMID 16011471.
  9. 9.0 9.1 Soro A, Jauhiainen M, Ehnholm C, Taskinen MR (2003). "Determinants of low HDL levels in familial combined hyperlipidemia". J Lipid Res. 44 (8): 1536–44. doi:10.1194/jlr.M300069-JLR200. PMID 12777471.
  10. Georgieva AM, van Greevenbroek MM, Krauss RM, Brouwers MC, Vermeulen VM, Robertus-Teunissen MG; et al. (2004). "Subclasses of low-density lipoprotein and very low-density lipoprotein in familial combined hyperlipidemia: relationship to multiple lipoprotein phenotype". Arterioscler Thromb Vasc Biol. 24 (4): 744–9. doi:10.1161/01.ATV.0000119681.47218.a4. PMID 14751815.
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Template:WikiDoc Sources rance of LDL. Prevalence in the population is 10%.


References

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