Familial hypercholesterolemia: Difference between revisions

Jump to navigation Jump to search
No edit summary
No edit summary
 
(75 intermediate revisions by 5 users not shown)
Line 2: Line 2:
{{SI}}
{{SI}}
{{CMG}}; {{AE}} {{PTD}}
{{CMG}}; {{AE}} {{PTD}}
'''To view Lipoprotein disorders main page [[ Lipoprotein disorders | Click here]]'''<br>
'''To view Hyperlipoproteinemia main page [[ Hyperlipoproteinemia | Click here]]''' <br>


{{SK}} FHC; FH; type IIA hyperlipoproteinemia; hyper-low-density-lipoproteinemia; familial hypercholesterolemic xanthomatosis; LDL receptor disorder
{{SK}} FHC; FH; type IIA hyperlipoproteinemia; hyper-low-density-lipoproteinemia; familial hypercholesterolemic xanthomatosis; LDL receptor disorder


==Overview==
==Overview==
'''Familial hypercholesterolemia''' (also spelled '''familial hypercholesterolaemia''') is a rare [[genetic disorder]] characterized by very high [[LDL]] cholesterol and early [[cardiovascular disease]] running in families.
Familial hypercholesterolemia is most commonly [[autosomal dominant]]<ref name="pmid18516203">{{cite journal| author=Marais AD| title=Familial hypercholesterolaemia. | journal=Clin Biochem Rev | year= 2004 | volume= 25 | issue= 1 | pages= 49-68 | pmid=18516203 | doi= | pmc=1853359 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18516203  }} </ref><ref name="pmid15321837">{{cite journal| author=Austin MA, Hutter CM, Zimmern RL, Humphries SE| title=Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. | journal=Am J Epidemiol | year= 2004 | volume= 160 | issue= 5 | pages= 407-20 | pmid=15321837 | doi=10.1093/aje/kwh236 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15321837  }} </ref><ref name="pmid21382890">{{cite journal| author=van der Graaf A, Avis HJ, Kusters DM, Vissers MN, Hutten BA, Defesche JC et al.| title=Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. | journal=Circulation | year= 2011 | volume= 123 | issue= 11 | pages= 1167-73 | pmid=21382890 | doi=10.1161/CIRCULATIONAHA.110.979450 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21382890  }} </ref> disorder caused by mutations involving three genes<ref name="pmid21382890">{{cite journal| author=van der Graaf A, Avis HJ, Kusters DM, Vissers MN, Hutten BA, Defesche JC et al.| title=Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. | journal=Circulation | year= 2011 | volume= 123 | issue= 11 | pages= 1167-73 | pmid=21382890 | doi=10.1161/CIRCULATIONAHA.110.979450 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21382890  }} </ref><ref name="pmid15321837">{{cite journal| author=Austin MA, Hutter CM, Zimmern RL, Humphries SE| title=Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. | journal=Am J Epidemiol | year= 2004 | volume= 160 | issue= 5 | pages= 407-20 | pmid=15321837 | doi=10.1093/aje/kwh236 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15321837  }} </ref> and rarely an [[autosomal recessive]] disorder involving hypercholesterolemia adaptor protein.<ref name="pmid18516203">{{cite journal| author=Marais AD| title=Familial hypercholesterolaemia. | journal=Clin Biochem Rev | year= 2004 | volume= 25 | issue= 1 | pages= 49-68 | pmid=18516203 | doi= | pmc=1853359 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18516203  }} </ref>  It is characterized by very high [[LDL]] cholesterol with associated atherosclerotic plaque deposition in arteries and a markedly increased risk of premature coronary artery disease.
 
==Historical perspective==
==Historical perspective==
The Norwegian physician Dr C Müller first associated the physical signs, high cholesterol levels and autosomal dominant inheritance in 1938. In the early 1970s and 1980s, the genetic cause for FH was described by Dr [[Joseph L. Goldstein]] and Dr Michael S. Brown of Dallas, Texas [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=4355366].
* The Norwegian physician Dr C Müller first associated the physical signs, high cholesterol levels and [[autosomal dominant]] inheritance in 1938.  
* In the early 1970s and 1980s, the genetic cause for familial hypercholesterolemia was described by Dr [[Joseph L. Goldstein]] and Dr Michael S. Brown of Dallas, Texas [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=4355366].


==Classification==
==Classification==
Line 14: Line 19:


*'''Heterozygous''' vs '''homozygous'''<ref name="pmid7584986">{{cite journal| author=Grossman M, Rader DJ, Muller DW, Kolansky DM, Kozarsky K, Clark BJ et al.| title=A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia. | journal=Nat Med | year= 1995 | volume= 1 | issue= 11 | pages= 1148-54 | pmid=7584986 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7584986  }} </ref><ref name="pmid15321837">{{cite journal| author=Austin MA, Hutter CM, Zimmern RL, Humphries SE| title=Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. | journal=Am J Epidemiol | year= 2004 | volume= 160 | issue= 5 | pages= 407-20 | pmid=15321837 | doi=10.1093/aje/kwh236 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15321837  }} </ref>
*'''Heterozygous''' vs '''homozygous'''<ref name="pmid7584986">{{cite journal| author=Grossman M, Rader DJ, Muller DW, Kolansky DM, Kozarsky K, Clark BJ et al.| title=A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia. | journal=Nat Med | year= 1995 | volume= 1 | issue= 11 | pages= 1148-54 | pmid=7584986 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7584986  }} </ref><ref name="pmid15321837">{{cite journal| author=Austin MA, Hutter CM, Zimmern RL, Humphries SE| title=Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. | journal=Am J Epidemiol | year= 2004 | volume= 160 | issue= 5 | pages= 407-20 | pmid=15321837 | doi=10.1093/aje/kwh236 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15321837  }} </ref>
**This is particularly important because, phenotypically, familial hypercholesterolemia (FH) is characterized by increased [[plasma]] levels of [[total cholesterol]] and [[low-density lipoprotein cholesterol]], tendinous [[xanthomata]], and premature symptoms of [[coronary heart disease]]. These are more pronounced in homozygous than heterozygous individuals.
**This is particularly important because, phenotypically, familial hypercholesterolemia (FH) is characterized by increased [[plasma]] levels of [[total cholesterol]] and [[low-density lipoprotein cholesterol]], tendinous [[xanthomata]], and premature symptoms of [[coronary heart disease]].  
***These are more pronounced in homozygous than heterozygous individuals.


*'''Polygenic''' vs '''monogenic'''
*'''Polygenic''' vs '''monogenic'''
**Polygenic hypercholesterolemia is a major source of atherosclerotic [[cardiovascular disease]]. [[Xanthelasma]], premature [[CHD]], tendon [[xanthomata]], and [[obesity|childhood obesity]] are common in monogenic hypercholesterolemia. Tendon [[xanthomata]] and [[obesity|childhood obesity]] are not observed in polygenic hypercholesterolemia.
**Polygenic hypercholesterolemia is a major source of atherosclerotic [[cardiovascular disease]].  
**[[Xanthelasma]], premature [[CHD]], tendon [[xanthomata]], and [[obesity|childhood obesity]] are common in monogenic hypercholesterolemia.  
**Tendon [[xanthomata]] and [[obesity|childhood obesity]] are not observed in polygenic hypercholesterolemia.


==Pathophysiology==
==Pathophysiology==
Both forms of FH are caused by the same problem: a mutation in either the [[LDL]] receptor or the [[ApoB]] protein. There is one known ApoB defect (R3500Q) and a multitude of [[LDL receptor]] defects, the frequency of which is different for each population. The [[LDL receptor]] [[gene]] is located on the short arm of [[chromosome]] 19 (19p13.1-13.3). It comprises 18 [[exons]] and spans 45kb, and the gene product contains 839 [[amino acids]] in mature form.
===Genetics===
* Familial hypercholesterolemia is a most commonly [[autosomal dominant]]<ref name="pmid18516203">{{cite journal| author=Marais AD| title=Familial hypercholesterolaemia. | journal=Clin Biochem Rev | year= 2004 | volume= 25 | issue= 1 | pages= 49-68 | pmid=18516203 | doi= | pmc=1853359 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18516203  }} </ref><ref name="pmid15321837">{{cite journal| author=Austin MA, Hutter CM, Zimmern RL, Humphries SE| title=Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. | journal=Am J Epidemiol | year= 2004 | volume= 160 | issue= 5 | pages= 407-20 | pmid=15321837 | doi=10.1093/aje/kwh236 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15321837  }} </ref><ref name="pmid21382890">{{cite journal| author=van der Graaf A, Avis HJ, Kusters DM, Vissers MN, Hutten BA, Defesche JC et al.| title=Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. | journal=Circulation | year= 2011 | volume= 123 | issue= 11 | pages= 1167-73 | pmid=21382890 | doi=10.1161/CIRCULATIONAHA.110.979450 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21382890  }} </ref> disorder caused by mutations involving three genes:<ref name="pmid21382890">{{cite journal| author=van der Graaf A, Avis HJ, Kusters DM, Vissers MN, Hutten BA, Defesche JC et al.| title=Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. | journal=Circulation | year= 2011 | volume= 123 | issue= 11 | pages= 1167-73 | pmid=21382890 | doi=10.1161/CIRCULATIONAHA.110.979450 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21382890  }} </ref><ref name="pmid15321837">{{cite journal| author=Austin MA, Hutter CM, Zimmern RL, Humphries SE| title=Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. | journal=Am J Epidemiol | year= 2004 | volume= 160 | issue= 5 | pages= 407-20 | pmid=15321837 | doi=10.1093/aje/kwh236 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15321837  }} </ref>
**The [[LDL receptor]]
**The [[apolipoprotein B]] gene ([[ApoB]])
*** [[ApoB]] is necessary for binding of [[LDL]] particles to the [[LDL receptor]]. Mutation in this gene leads to impaired binding to the [[LDL receptor]].
**[[Proprotein convertase subtilisin/kexin type 9]] gene
*** Mutation in this gene leads to decreased [[LDL]] [[metabolism]]<ref name="pmid21382890">{{cite journal| author=van der Graaf A, Avis HJ, Kusters DM, Vissers MN, Hutten BA, Defesche JC et al.| title=Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. | journal=Circulation | year= 2011 | volume= 123 | issue= 11 | pages= 1167-73 | pmid=21382890 | doi=10.1161/CIRCULATIONAHA.110.979450 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21382890  }} </ref>
*There are over 1600 known mutations of the LDL receptor gene documented to cause familial hypercholesterolemia, accounting for about 85 to 90% of familial hypercholesterolemia cases.
*The [[apolipoprotein B]] gene mutation (Arg3500Gln mutation in APOB) is mostly observed in Northern European population but rare in other populations. It accounts for 5 to 10% of familial hypercholesterolemia cases.
*Mutations involving [[Proprotein convertase subtilisin/kexin type 9]] gene is a gain-of-function mutation causing fewer than 5% of familial hypercholesterolemia cases.
* The [[LDL receptor]] [[gene]] is located on the short arm of [[chromosome]] 19 (19p13.1-13.3). It comprises 18 [[exons]] and spans 45kb, and the gene product contains 839 [[amino acids]] in mature form.
*Familial hypercholesterolemia is rarely an [[autosomal recessive]] disorder involving hypercholesterolemia adaptor protein. This adaptor protein contains a phosphotyrosine binding domain, which in other proteins binds LDL receptor. Hypercholesterolemia adaptor protein appears to have a tissue-specific role in LDL receptor function, as it is required in liver but not in fibroblasts.<ref name="pmid18516203">{{cite journal| author=Marais AD| title=Familial hypercholesterolaemia. | journal=Clin Biochem Rev | year= 2004 | volume= 25 | issue= 1 | pages= 49-68 | pmid=18516203 | doi= | pmc=1853359 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18516203  }} </ref><ref name="pmid11326085">{{cite journal| author=Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M et al.| title=Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. | journal=Science | year= 2001 | volume= 292 | issue= 5520 | pages= 1394-8 | pmid=11326085 | doi=10.1126/science.1060458 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11326085  }} </ref>


Familial disorders of cholesterol metabolism may result from one of the following:  
===Pathogenesis===
*Overproduction of lipoproteins
* Familial disorders of [[cholesterol]] metabolism may result from one of the following:  
*Impaired removal of lipoproteins (this may result from primary defect with the lipoprotein or its receptor).
**Overproduction of [[lipoproteins]]
**Impaired removal of [[lipoproteins]] (this may result from primary defect with the [[lipoprotein]] or its [[receptor]]) as described above.
* [[Low density lipoprotein|LDL]] [[cholesterol]] normally circulates in the body for 2.5 days, after which it is cleared by the [[liver]].
* In Familial hypercholesterolemia (FH), the [[half-life]] of an [[LDL]] particle is almost doubled to 4.5 days.
** This leads to markedly elevated [[LDL]] levels, with the other forms of [[cholesterol]] remaining normal, most notably [[High density lipoprotein|HDL]].
* The classic form of familial hypercholesterolemia results from defects in the [[cell surface receptor]] that normally removes LDL particles from the [[blood plasma]].<ref name="pmid4368448">{{cite journal| author=Goldstein JL, Brown MS| title=Binding and degradation of [[low density lipoproteins]] by cultured human [[fibroblasts]]. Comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia. | journal=J Biol Chem | year= 1974 | volume= 249 | issue= 16 | pages= 5153-62 | pmid=4368448 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4368448  }} </ref>


[[Low density lipoprotein|LDL]] cholesterol normally circulates in the body for 2.5 days, after which it is cleared by the [[liver]]. In FH, the half-life of an LDL particle is almost doubled to ''4.5 days''. This leads to markedly elevated LDL levels, with the other forms of cholesterol remaining normal, most notably [[High density lipoprotein|HDL]]. Goldstein and Brown (1974) showed that the classic form of familial hypercholesterolemia results from defects in the cell surface receptor that normally removes LDL particles from the blood plasma.
* The excess circulating [[LDL]] is taken up by cells all over the body&mdash;most notably, by [[macrophages]], and particularly the ones in a primary streak (the earliest stage of [[atherosclerosis]]).  
* [[Oxidation]] of [[LDL]] increases its uptake by [[foam cells]].


The excess circulating LDL is taken up by cells all over the body but most notably by [[macrophages]] and especially the ones in a primary streak (the earliest stage of [[atherosclerosis]]). [[Oxidation]] of LDL increases its uptake by [[foam cells]].
* Although [[atherosclerosis]] can occur in all people, many familial hypercholesterolemia patients develop accelerated atherosclerosis due to the presence of excess [[LDL]]. Some studies of familial hypercholesterolemia cohorts suggest that additional risk factors are generally present when a familial hypercholesterolemic patient develops [[atherosclerosis]].<ref>Scientific Steering Committee on behalf of the Simon Broome Register Group (Ratcliffe Infirmary, Oxford, England), "Risk of fatal coronary heart disease in familial hypercholesterolaemia", ''British Medical Journal'' 303 (1991), pp. 893-896.</ref><ref>E.J.G. Sijbrands, et al., "Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study", ''British Medical Journal'' 322 (2001), pp. 1019-1023.</ref>
 
**The degree of atherosclerosis roughly depends of the amount of LDL receptors still expressed by the cells in the body, as well as the functionality of these receptors. In heterozygous FH, there is at least 50% of the normal LDL receptor activity however, in homozygous FH, both alleles are damaged to some degree, which may lead to extremely high levels of LDL. Children with this form of FH may develop severe premature heart disease. A further complication is the ineffectiveness of statins.
Although atherosclerosis can occur in all people, many FH patients develop accelerated atherosclerosis due to the excess LDL. Some studies of FH cohorts suggest that additional risk factors are generally at play when an FH patient develops atherosclerosis.<ref>Scientific Steering Committee on behalf of the Simon Broome Register Group (Ratcliffe Infirmary, Oxford, England), "Risk of fatal coronary heart disease in familial hypercholesterolaemia", ''British Medical Journal'' 303 (1991), pp. 893-896.</ref><ref>E.J.G. Sijbrands, et al., "Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study", ''British Medical Journal'' 322 (2001), pp. 1019-1023.</ref>
 
The degree of atherosclerosis roughly depends of the ''amount'' of LDL receptors still expressed by the cells in the body and the ''functionality'' of these receptors. In the hetrozygous forms of FH, the receptor function is only mildly impaired, and LDL levels will remain relatively low. In more serious forms, the homozygouse form, the "broken" receptor is not expressed at all.
 
In ''heterozygous'' FH, only one of the two [[DNA]] copies ([[allele]]s) is damaged, and there will be at least 50% of the normal LDL receptor activity (the "healthy" copy and whatever the "broken" copy can still contribute).
 
In ''homozygous'' FH, however, both alleles are damaged in some degree, which can lead to extremely high levels of LDL, and to children with extremely premature heart disease. A further complication is the lack of effect of [[statin]]s (see below).


==Causes==
==Causes==
Familial hypercholesterolemia is predominantly an autosomal dorminant  but rarely autosomal recessive disease caused by mutations involving three genes (LDL receptor gene, apolipoprotein B gene and [[Proprotein convertase subtilisin/kexin type 9]] gene) .


==Differentiating familial hypercholesterolemia from other diseases==
==Epidemiology and demographics==
===Prevalence===
Homozygous familial hypercholesterolemiai is less prevalent (prevalence 1:160,000 to 1:1,000,000) compared to heterozygous hypercholesterolemia.<ref>{{Cite journal| author = [[Emily Youngblom]] & [[Joshua W. Knowles]]| title = Familial Hypercholesterolemia| year = 1993| month = | pmid = 24404629}}</ref>
The prevalence of familial hypercholesterolemia varies dependeing on the population under study as shown below:<ref name="pmid8792826">{{cite journal| author=Steyn K, Goldberg YP, Kotze MJ, Steyn M, Swanepoel AS, Fourie JM et al.| title=Estimation of the prevalence of familial hypercholesterolaemia in a rural Afrikaner community by direct screening for three Afrikaner founder low density lipoprotein receptor gene mutations. | journal=Hum Genet | year= 1996 | volume= 98 | issue= 4 | pages= 479-84 | pmid=8792826 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8792826  }} </ref><ref name="pmid18516203">{{cite journal| author=Marais AD| title=Familial hypercholesterolaemia. | journal=Clin Biochem Rev | year= 2004 | volume= 25 | issue= 1 | pages= 49-68 | pmid=18516203 | doi= | pmc=1853359 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18516203  }} </ref>
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 120px;" colspan="2" | {{fontcolor|#FFF|'''Prevalence of FH in Select Populations'''}}
|-
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Population}}
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Prevalence}}
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |General population
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |1:200-500
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | French Canadian
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |1:270
|-
|style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | Christian Lebanese
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |1:85
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |Tunisia
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |1:165
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |South African Afrikaner
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |1:72 to 1:100
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |South African Ashkenazi Jews
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |1:67
|-
|}


==Epidemiology and demographics==
===Age===


==Risk factors==
Most individuals with homozygous FH experience severe CHD by their mid-20s. The rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common.
===Race===
There is no racial predilection to acquiring FH however some individuals are found to have higher prevalence of the disease as shown in the table of prevalence above.


==Screening==
==Screening==
Line 58: Line 108:


Although not present in many individuals with familial hypercholesterolemia (FH), the following physical findings should prompt the clinician to strongly suspect FH and obtain necessary lipid measurements if not already available:
Although not present in many individuals with familial hypercholesterolemia (FH), the following physical findings should prompt the clinician to strongly suspect FH and obtain necessary lipid measurements if not already available:
*Tendon xanthomas at any age (most common in Achilles tendon and finger extensor tendons, but can also occur in patellar and triceps tendons). B Arcus corneae in a patient under age 45)
*Tendon [[xanthomas]] at any age (most common in Achilles tendon and finger extensor tendons, but can also occur in patellar and triceps tendons). [[Arcus corneae|B Arcus corneae]] in a patient under age 45.
*Tuberous xanthomas or xanthelasma in a patient under age 20 to 25
*Tuberous xanthomas or [[xanthelasma]] in a patient under age 20 to 25
At the LDL cholesterol levels listed below the probability of FH is approximately 80% in the setting of general population screening.
At the LDL cholesterol levels listed below the probability of FH is approximately 80% in the setting of general population screening.
*These LDL cholesterol levels should prompt the clinician to strongly consider a diagnosis of FH and obtain further family information:
*These LDL cholesterol levels should prompt the clinician to strongly consider a diagnosis of FH and obtain further family information:
Line 65: Line 115:
**LDL cholesterol ≥ 220 mg/dL for patients aged 20 to 29
**LDL cholesterol ≥ 220 mg/dL for patients aged 20 to 29
**LDL cholesterol ≥ 190 mg/dL in patients under age 20
**LDL cholesterol ≥ 190 mg/dL in patients under age 20
===Screening in children===
===Screening in children and adolescents===
Lipid screening recommnedations for familial hypercholesterolemia in children are varies by age and their risk factors.<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>
Lipid screening recommendations for familial hypercholesterolemia in children varies by age and risk factors as shown below:<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>
====Child-parent familial hypercholesterolemia screening in primary care====
 
*Recent study shows the feasibility and efficacy of child-parent familial hypercholesterolemia screening in primary care setting.  
{| 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
|}
 
===Child-parent familial hypercholesterolemia screening in primary care===
*Recent studies show the feasibility and efficacy of child-parent familial hypercholesterolemia screening in primary care setting.  
*The conclusion remains that child–parent familial hypercholesterolemia screening is a simple, practical, and effective way of screening the population to identify and prevent a common inherited cause of premature cardiovascular disease.<ref name="pmid27783906">{{cite journal| author=Wald DS, Bestwick JP, Morris JK, Whyte K, Jenkins L, Wald NJ| title=Child-Parent Familial Hypercholesterolemia Screening in Primary Care. | journal=N Engl J Med | year= 2016 | volume= 375 | issue= 17 | pages= 1628-1637 | pmid=27783906 | doi=10.1056/NEJMoa1602777 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27783906  }} </ref>
*The conclusion remains that child–parent familial hypercholesterolemia screening is a simple, practical, and effective way of screening the population to identify and prevent a common inherited cause of premature cardiovascular disease.<ref name="pmid27783906">{{cite journal| author=Wald DS, Bestwick JP, Morris JK, Whyte K, Jenkins L, Wald NJ| title=Child-Parent Familial Hypercholesterolemia Screening in Primary Care. | journal=N Engl J Med | year= 2016 | volume= 375 | issue= 17 | pages= 1628-1637 | pmid=27783906 | doi=10.1056/NEJMoa1602777 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27783906  }} </ref>


==Natural history, complication and prognosis==
==Natural history, complication and prognosis==
If left untreated, the majority of affected individuals will have symptomatic [[coronary artery disease]] by 50-60 years and half of the men and 15%-30% of the women will have died. On the other hand, patients who start attending a lipid clinic before they develop clinical [[CAD]] may enjoy a normal life expectancy if well managed.<ref name="pmid18840879">{{cite journal| author=Neil A, Cooper J, Betteridge J, Capps N, McDowell I, Durrington P et al.| title=Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. | journal=Eur Heart J | year= 2008 | volume= 29 | issue= 21 | pages= 2625-33 | pmid=18840879 | doi=10.1093/eurheartj/ehn422 | pmc=2577142 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18840879  }} </ref><ref name="pmid27594540">{{cite journal| author=Authors/Task Force Members:. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ et al.| title=2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). | journal=Atherosclerosis | year= 2016 | volume= 253 | issue=  | pages= 281-344 | pmid=27594540 | doi=10.1016/j.atherosclerosis.2016.08.018 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27594540  }} </ref><ref>{{Cite journal| author = [[Emily Youngblom]] & [[Joshua W. Knowles]]| title = Familial Hypercholesterolemia| year = 1993 | month = | pmid = 24404629}}</ref>


==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's)
**[[Cerebrovascular accident]]s/[[Stroke]]s
**[[Peripheral artery disease]] (PAD)
*[[Family history]] of premature [[atherosclerosis]]
===Physical examinations===
===Physical examinations===
Ptients with familial hypercholesterolemia 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 (thickening of [[tendon]]s due to accumulation of [[macrophage]]s filled with [[cholesterol]]).
===Laboratory findings===
===Laboratory findings===




In FH, a genetic diagnosis is important for family screening, to establish the diagnosis in patients with borderline [[LDL-C]] and to improve patient adherence to therapy.<ref name="pmid23956253">{{cite journal| author=Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS et al.| title=Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. | journal=Eur Heart J | year= 2013 | volume= 34 | issue= 45 | pages= 3478-90a | pmid=23956253 | doi=10.1093/eurheartj/eht273 | pmc=3844152 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23956253  }} </ref>
Genetic testing is generally undertaken when:
* A family member has been shown to have a mutation
* High cholesterol is found in a young patient with [[atherosclerosis|atherosclerotic]] disease
* [[Tendon xanthomas]] are found in a patient with high cholesterol
FH are best identified by a definite or probable phenotypic diagnosis of FH based on the DLCN criteria<ref name="pmid26908947">{{cite journal| author=Benn M, Watts GF, Tybjærg-Hansen A, Nordestgaard BG| title=Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217. | journal=Eur Heart J | year= 2016 | volume= 37 | issue= 17 | pages= 1384-94 | pmid=26908947 | doi=10.1093/eurheartj/ehw028 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26908947  }} </ref> as shown below:
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 120px;" colspan="3" | {{fontcolor|#FFF|'''Dutch Lipid Clinic Network (DLCN) diagnostic criteria for familial hypercholesterolaemia'''}}
|-
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Variable}}
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Criteria}}
! style="background: #4479BA; width: 50px;" | {{fontcolor|#FFF|Score}}
|-
| style="padding: 5px 5px; background: #DCDCDC;" rowspan="4" | '''Family History'''
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |First-degree relative with known premature (i.e men < 55 years, or  women < 60 years) [[coronary heart disease]] [[(CHD)]]
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | 1
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |First-degree relative with known [[LDL-C]] > 95th percentile by age and sex for country
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | 1
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |First-degree relative with [[tendon xanthoma]] and/or [[corneal arcus]]
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | 2
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | Child/children aged < 18 years with [[LDL-C]] > 95th percentile by age and sex for country
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | 2
|-
| style="padding: 5px 5px; background: #DCDCDC;" rowspan="2"| '''Clinical History'''
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | Premature [[CHD]] (i.e men < 55 years, or  women < 60 years)
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | 2
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | Premature (i.e men < 55 years, or  women < 60 years) cerebral or peripheral vascular disease
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | 1
|-
| style="padding: 5px 5px; background: #DCDCDC;" rowspan="2" | '''Physical Examination'''
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | The presence of tendon xanthoma
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | 6
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | Corneal arcus in a person aged < 45 years
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | 4
|-
| style="padding: 5px 5px; background: #DCDCDC;" rowspan="4" |'''LDL Cholesterol Level'''
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | LDL-C concentrations: ≥ 8.5 mmol/L (≥ 330 mg/dL)
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | 8
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | ≥ 6.5 to < 8.5 mmol/L (≥ 250 to < 330 mg/dL)
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | 5
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | ≥ 5.0 to < 6.5 mmol/L (≥ 190 to < 250 mg/dL)
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | 3
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |≥ 4.0 to < 5.0 mmol/L (≥ 155 to < 190 mg/dL)
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | 1
|-
| style="padding: 5px 5px; background: #DCDCDC;" rowspan="1" | '''DNA Analysis'''
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | Deoxyribonucleic acid (DNA) analysis and the finding of a causative mutation inolving LDLR, apoB, or [[PCSK9]] gene
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | 8
|-
|}
The table below shows the interpretation of the DLCN diagnostic criteria.
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 120px;" colspan="2" | {{fontcolor|#FFF|'''Interpretation of DLCN score'''}}
|-
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Score}}
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Diagnosis}}
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | >8
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |Definite FH diagnosis
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | 6-8
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |Probable FH diagnosis
|-
|style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | 3-5
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |Possible FH diagnosis
|-
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | 0-2
| style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |Unlikely FH diagnosis
|-
|}
==Treatment==
===Medical therapy===
====Heterozygous FH====
The initial drug of choice are high-dose statin therapy especially atorvastatin, simvastatin or rosuvastatin. <ref name="pmid11558482">{{cite journal| author=Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF| title=Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. | journal=Lancet | year= 2001 | volume= 357 | issue= 9256 | pages= 577-81 | pmid=11558482 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11558482  }} </ref><ref name="pmid9024733">{{cite journal| author=Davidson MH, Stein EA, Dujovne CA, Hunninghake DB, Weiss SR, Knopp RH et al.| title=The efficacy and six-week tolerability of simvastatin 80 and 160 mg/day. | journal=Am J Cardiol | year= 1997 | volume= 79 | issue= 1 | pages= 38-42 | pmid=9024733 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9024733  }} </ref><ref name="pmid9514454">{{cite journal| author=Jones P, Kafonek S, Laurora I, Hunninghake D| title=Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study) | journal=Am J Cardiol | year= 1998 | volume= 81 | issue= 5 | pages= 582-7 | pmid=9514454 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9514454  }} </ref>
Statins work by forcing the liver to produce more LDL receptor to maintain the amount of cholesterol in the cell. This requires at least one functioning copy of the gene.
In cases where monotherapy with statins are ineffective, combination therapy with statin and other lipid lowering medication can be considered although their utility is not well established.
The following can be added to statins:<ref name="pmid17215532">{{cite journal| author=Cuchel M, Bloedon LT, Szapary PO, Kolansky DM, Wolfe ML, Sarkis A et al.| title=Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. | journal=N Engl J Med | year= 2007 | volume= 356 | issue= 2 | pages= 148-56 | pmid=17215532 | doi=10.1056/NEJMoa061189 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17215532  }} </ref>
* Ezetimibe<ref name="pmid18376000">{{cite journal| author=Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF et al.| title=Simvastatin with or without ezetimibe in familial hypercholesterolemia. | journal=N Engl J Med | year= 2008 | volume= 358 | issue= 14 | pages= 1431-43 | pmid=18376000 | doi=10.1056/NEJMoa0800742 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18376000  }} </ref>
* [[Fibrate]]
The combination of fibrates and statins is associated with a markedly increased risk of [[myopathy]] and [[rhabdomyolysis]] (breakdown of muscle tissue, leading to [[acute renal failure]]), so patients must be monitored closely.
*[[Bile acid sequestrant]] 
*[[Niacin]]/[[acipimox]]<ref name="pmid8031206">{{cite journal| author=Illingworth DR, Stein EA, Mitchel YB, Dujovne CA, Frost PH, Knopp RH et al.| title=Comparative effects of lovastatin and niacin in primary hypercholesterolemia. A prospective trial. | journal=Arch Intern Med | year= 1994 | volume= 154 | issue= 14 | pages= 1586-95 | pmid=8031206 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8031206  }} </ref>
====Homozygous FH====
According to the 2015 AHA scientific statement on FH, early diagnosis of homozygous FH and prompt initiation of diet and lipid-lowering therapy are critical.<ref name="pmid26510694">{{cite journal| author=Gidding SS, Champagne MA, de Ferranti SD, Defesche J, Ito MK, Knowles JW et al.| title=The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association. | journal=Circulation | year= 2015 | volume= 132 | issue= 22 | pages= 2167-92 | pmid=26510694 | doi=10.1161/CIR.0000000000000297 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26510694  }} </ref><ref name="pmid25053660">{{cite journal| author=Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA et al.| title=Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. | journal=Eur Heart J | year= 2014 | volume= 35 | issue= 32 | pages= 2146-57 | pmid=25053660 | doi=10.1093/eurheartj/ehu274 | pmc=4139706 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25053660  }} </ref>
As previously mentioned, the LDL levels are much higher and the most effective treatments (statins) require at least one copy of the functional LDL receptor gene. In this case, high amounts of bile acid sequestrants are often given. Occasionally, high-dosed statins can help express a dysfunctional (but some times working) LDL receptor. Other treatments used are [[LDL apheresis]] (clearing LDL by blood filtration, similar to [[dialysis]]) with [[liver transplant]]  as last result. The last option will introduce liver cells with working LDL receptors, effectively curing the condition.
=== National Lipid Association Guidelines for Identifying Patients Eligible for Apheresis:<ref>{{Cite journal
| author = [[Matthew K. Ito]], [[Mary P. McGowan]] & [[Patrick M. Moriarty]] | title = Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia | journal = [[Journal of clinical lipidology]] | volume = 5 | issue = 3 Suppl | pages = S38–S45 | year = 2011 | month = June | doi = 10.1016/j.jacl.2011.04.001 | pmid = 21600528 }}</ref> ===
In patients who, after six months, do not have an adequate response to maximum tolerated drug therapy, LDL apheresis is indicated according to these guidelines:
1.Functional homozygous FH patients with LDL cholesterol ≥300 mg/dL (or non-HDL cholesterol ≥330 mg/dL).
2.Functional heterozygous FH patients with LDL cholesterol ≥300 mg/dL (or non-HDL cholesterol ≥330 mg/dL) and 0-1 risk factors.
3.Functional heterozygous FH patients with LDL cholesterol ≥200 mg/dL (or non-HDL cholesterol ≥230 mg/dL) and high risk characteristics such as ≥2 risk factors or high lipoprotein (a) ≥50 mg/dL using an isoform insensitive assay.
4. Functional heterozygotes with LDL cholesterol ≥160 mg/dL (or non-HDL cholesterol ≥190 mg/dL) and very high risk characteristics (established CHD, other cardiovascular disease, or diabetes).
==Prevention==
Prevention of complications of familial hypercholesterolemia are as follows:<ref name="pmid18840879">{{cite journal| author=Neil A, Cooper J, Betteridge J, Capps N, McDowell I, Durrington P et al.| title=Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. | journal=Eur Heart J | year= 2008 | volume= 29 | issue= 21 | pages= 2625-33 | pmid=18840879 | doi=10.1093/eurheartj/ehn422 | pmc=2577142 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18840879  }} </ref><ref name="pmid27594540">{{cite journal| author=Authors/Task Force Members:. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ et al.| title=2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). | journal=Atherosclerosis | year= 2016 | volume= 253 | issue=  | pages= 281-344 | pmid=27594540 | doi=10.1016/j.atherosclerosis.2016.08.018 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27594540  }} </ref><ref>{{Cite journal| author = [[Emily Youngblom]] & [[Joshua W. Knowles]]| title = Familial Hypercholesterolemia| year = 1993 | month = | pmid = 24404629}}</ref><ref name="pmid23956253">{{cite journal| author=Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS et al.| title=Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. | journal=Eur Heart J | year= 2013 | volume= 34 | issue= 45 | pages= 3478-90a | pmid=23956253 | doi=10.1093/eurheartj/eht273 | pmc=3844152 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23956253  }} </ref>
*Early genetic diagnosis
*Early attendance at a lipid clinic before they develop clinical [[CAD]]
*Adherence to therapy


==References==
==References==

Latest revision as of 19:02, 2 March 2017

WikiDoc Resources for Familial hypercholesterolemia

Articles

Most recent articles on Familial hypercholesterolemia

Most cited articles on Familial hypercholesterolemia

Review articles on Familial hypercholesterolemia

Articles on Familial hypercholesterolemia in N Eng J Med, Lancet, BMJ

Media

Powerpoint slides on Familial hypercholesterolemia

Images of Familial hypercholesterolemia

Photos of Familial hypercholesterolemia

Podcasts & MP3s on Familial hypercholesterolemia

Videos on Familial hypercholesterolemia

Evidence Based Medicine

Cochrane Collaboration on Familial hypercholesterolemia

Bandolier on Familial hypercholesterolemia

TRIP on Familial hypercholesterolemia

Clinical Trials

Ongoing Trials on Familial hypercholesterolemia at Clinical Trials.gov

Trial results on Familial hypercholesterolemia

Clinical Trials on Familial hypercholesterolemia at Google

Guidelines / Policies / Govt

US National Guidelines Clearinghouse on Familial hypercholesterolemia

NICE Guidance on Familial hypercholesterolemia

NHS PRODIGY Guidance

FDA on Familial hypercholesterolemia

CDC on Familial hypercholesterolemia

Books

Books on Familial hypercholesterolemia

News

Familial hypercholesterolemia in the news

Be alerted to news on Familial hypercholesterolemia

News trends on Familial hypercholesterolemia

Commentary

Blogs on Familial hypercholesterolemia

Definitions

Definitions of Familial hypercholesterolemia

Patient Resources / Community

Patient resources on Familial hypercholesterolemia

Discussion groups on Familial hypercholesterolemia

Patient Handouts on Familial hypercholesterolemia

Directions to Hospitals Treating Familial hypercholesterolemia

Risk calculators and risk factors for Familial hypercholesterolemia

Healthcare Provider Resources

Symptoms of Familial hypercholesterolemia

Causes & Risk Factors for Familial hypercholesterolemia

Diagnostic studies for Familial hypercholesterolemia

Treatment of Familial hypercholesterolemia

Continuing Medical Education (CME)

CME Programs on Familial hypercholesterolemia

International

Familial hypercholesterolemia en Espanol

Familial hypercholesterolemia en Francais

Business

Familial hypercholesterolemia in the Marketplace

Patents on Familial hypercholesterolemia

Experimental / Informatics

List of terms related to Familial hypercholesterolemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2]

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

Synonyms and keywords: FHC; FH; type IIA hyperlipoproteinemia; hyper-low-density-lipoproteinemia; familial hypercholesterolemic xanthomatosis; LDL receptor disorder

Overview

Familial hypercholesterolemia is most commonly autosomal dominant[1][2][3] disorder caused by mutations involving three genes[3][2] and rarely an autosomal recessive disorder involving hypercholesterolemia adaptor protein.[1] It is characterized by very high LDL cholesterol with associated atherosclerotic plaque deposition in arteries and a markedly increased risk of premature coronary artery disease.

Historical perspective

  • The Norwegian physician Dr C Müller first associated the physical signs, high cholesterol levels and autosomal dominant inheritance in 1938.
  • In the early 1970s and 1980s, the genetic cause for familial hypercholesterolemia was described by Dr Joseph L. Goldstein and Dr Michael S. Brown of Dallas, Texas [3].

Classification

Familial hypercholesterolemia may be classified according to the severity of the mutation involving the LDL-cholesterol (LDL-C) receptor or depending on the mode of inheritance as follows:

Pathophysiology

Genetics

  • Familial hypercholesterolemia is a most commonly autosomal dominant[1][2][3] disorder caused by mutations involving three genes:[3][2]
  • There are over 1600 known mutations of the LDL receptor gene documented to cause familial hypercholesterolemia, accounting for about 85 to 90% of familial hypercholesterolemia cases.
  • The apolipoprotein B gene mutation (Arg3500Gln mutation in APOB) is mostly observed in Northern European population but rare in other populations. It accounts for 5 to 10% of familial hypercholesterolemia cases.
  • Mutations involving Proprotein convertase subtilisin/kexin type 9 gene is a gain-of-function mutation causing fewer than 5% of familial hypercholesterolemia cases.
  • The LDL receptor gene is located on the short arm of chromosome 19 (19p13.1-13.3). It comprises 18 exons and spans 45kb, and the gene product contains 839 amino acids in mature form.
  • Familial hypercholesterolemia is rarely an autosomal recessive disorder involving hypercholesterolemia adaptor protein. This adaptor protein contains a phosphotyrosine binding domain, which in other proteins binds LDL receptor. Hypercholesterolemia adaptor protein appears to have a tissue-specific role in LDL receptor function, as it is required in liver but not in fibroblasts.[1][5]

Pathogenesis

  • Familial disorders of cholesterol metabolism may result from one of the following:
  • LDL cholesterol normally circulates in the body for 2.5 days, after which it is cleared by the liver.
  • In Familial hypercholesterolemia (FH), the half-life of an LDL particle is almost doubled to 4.5 days.
    • This leads to markedly elevated LDL levels, with the other forms of cholesterol remaining normal, most notably HDL.
  • The classic form of familial hypercholesterolemia results from defects in the cell surface receptor that normally removes LDL particles from the blood plasma.[6]
  • Although atherosclerosis can occur in all people, many familial hypercholesterolemia patients develop accelerated atherosclerosis due to the presence of excess LDL. Some studies of familial hypercholesterolemia cohorts suggest that additional risk factors are generally present when a familial hypercholesterolemic patient develops atherosclerosis.[7][8]
    • The degree of atherosclerosis roughly depends of the amount of LDL receptors still expressed by the cells in the body, as well as the functionality of these receptors. In heterozygous FH, there is at least 50% of the normal LDL receptor activity however, in homozygous FH, both alleles are damaged to some degree, which may lead to extremely high levels of LDL. Children with this form of FH may develop severe premature heart disease. A further complication is the ineffectiveness of statins.

Causes

Familial hypercholesterolemia is predominantly an autosomal dorminant but rarely autosomal recessive disease caused by mutations involving three genes (LDL receptor gene, apolipoprotein B gene and Proprotein convertase subtilisin/kexin type 9 gene) .

Epidemiology and demographics

Prevalence

Homozygous familial hypercholesterolemiai is less prevalent (prevalence 1:160,000 to 1:1,000,000) compared to heterozygous hypercholesterolemia.[9] The prevalence of familial hypercholesterolemia varies dependeing on the population under study as shown below:[10][1]

Prevalence of FH in Select Populations
Population Prevalence
General population 1:200-500
French Canadian 1:270
Christian Lebanese 1:85
Tunisia 1:165
South African Afrikaner 1:72 to 1:100
South African Ashkenazi Jews 1:67

Age

Most individuals with homozygous FH experience severe CHD by their mid-20s. The rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common.

Race

There is no racial predilection to acquiring FH however some individuals are found to have higher prevalence of the disease as shown in the table of prevalence above.

Screening

Universal screening for elevated serum cholesterol is recommended.[11]

General population screening

Familial hypercholesterolemia (FH) should be suspected when untreated fasting LDL cholesterol or non HDL cholesterol levels are at or above the following:

  • Adults (≥ 20 years):
    • LDL cholesterol ≥ 190 mg/dL or non-HDL cholesterol ≥ 220 mg/dL
  • Children, adolescents and young adults (< 20 years):
    • LDL cholesterol ≥160 mg/dL or non- HDL cholesterol ≥ 190 mg/dL

Cholesterol screening should be considered beginning at age 2 for children with a family history of premature cardiovascular disease or elevated cholesterol. All individuals should be screened by age 20.

Although not present in many individuals with familial hypercholesterolemia (FH), the following physical findings should prompt the clinician to strongly suspect FH and obtain necessary lipid measurements if not already available:

  • Tendon xanthomas at any age (most common in Achilles tendon and finger extensor tendons, but can also occur in patellar and triceps tendons). B Arcus corneae in a patient under age 45.
  • Tuberous xanthomas or xanthelasma in a patient under age 20 to 25

At the LDL cholesterol levels listed below the probability of FH is approximately 80% in the setting of general population screening.

  • These LDL cholesterol levels should prompt the clinician to strongly consider a diagnosis of FH and obtain further family information:
    • LDL cholesterol ≥ 250 mg/dL in a patient aged 30 or more
    • LDL cholesterol ≥ 220 mg/dL for patients aged 20 to 29
    • LDL cholesterol ≥ 190 mg/dL in patients under age 20

Screening in children and adolescents

Lipid screening recommendations for familial hypercholesterolemia in children varies by age and risk factors as shown below:[12][13] [14]

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

Child-parent familial hypercholesterolemia screening in primary care

  • Recent studies show the feasibility and efficacy of child-parent familial hypercholesterolemia screening in primary care setting.
  • The conclusion remains that child–parent familial hypercholesterolemia screening is a simple, practical, and effective way of screening the population to identify and prevent a common inherited cause of premature cardiovascular disease.[15]

Natural history, complication and prognosis

If left untreated, the majority of affected individuals will have symptomatic coronary artery disease by 50-60 years and half of the men and 15%-30% of the women will have died. On the other hand, patients who start attending a lipid clinic before they develop clinical CAD may enjoy a normal life expectancy if well managed.[16][17][18]

Diagnosis

History and Symptoms

History is usually suggestive of:

Physical examinations

Ptients with familial hypercholesterolemia may present with the following:

Eyes

Extremities

Laboratory findings

In FH, a genetic diagnosis is important for family screening, to establish the diagnosis in patients with borderline LDL-C and to improve patient adherence to therapy.[19]

Genetic testing is generally undertaken when:

  • A family member has been shown to have a mutation
  • High cholesterol is found in a young patient with atherosclerotic disease
  • Tendon xanthomas are found in a patient with high cholesterol

FH are best identified by a definite or probable phenotypic diagnosis of FH based on the DLCN criteria[20] as shown below:

Dutch Lipid Clinic Network (DLCN) diagnostic criteria for familial hypercholesterolaemia
Variable Criteria Score
Family History First-degree relative with known premature (i.e men < 55 years, or women < 60 years) coronary heart disease (CHD) 1
First-degree relative with known LDL-C > 95th percentile by age and sex for country 1
First-degree relative with tendon xanthoma and/or corneal arcus 2
Child/children aged < 18 years with LDL-C > 95th percentile by age and sex for country 2
Clinical History Premature CHD (i.e men < 55 years, or women < 60 years) 2
Premature (i.e men < 55 years, or women < 60 years) cerebral or peripheral vascular disease 1
Physical Examination The presence of tendon xanthoma 6
Corneal arcus in a person aged < 45 years 4
LDL Cholesterol Level LDL-C concentrations: ≥ 8.5 mmol/L (≥ 330 mg/dL) 8
≥ 6.5 to < 8.5 mmol/L (≥ 250 to < 330 mg/dL) 5
≥ 5.0 to < 6.5 mmol/L (≥ 190 to < 250 mg/dL) 3
≥ 4.0 to < 5.0 mmol/L (≥ 155 to < 190 mg/dL) 1
DNA Analysis Deoxyribonucleic acid (DNA) analysis and the finding of a causative mutation inolving LDLR, apoB, or PCSK9 gene 8


The table below shows the interpretation of the DLCN diagnostic criteria.


Interpretation of DLCN score
Score Diagnosis
>8 Definite FH diagnosis
6-8 Probable FH diagnosis
3-5 Possible FH diagnosis
0-2 Unlikely FH diagnosis

Treatment

Medical therapy

Heterozygous FH

The initial drug of choice are high-dose statin therapy especially atorvastatin, simvastatin or rosuvastatin. [21][22][23] Statins work by forcing the liver to produce more LDL receptor to maintain the amount of cholesterol in the cell. This requires at least one functioning copy of the gene. In cases where monotherapy with statins are ineffective, combination therapy with statin and other lipid lowering medication can be considered although their utility is not well established. The following can be added to statins:[24]

The combination of fibrates and statins is associated with a markedly increased risk of myopathy and rhabdomyolysis (breakdown of muscle tissue, leading to acute renal failure), so patients must be monitored closely.

Homozygous FH

According to the 2015 AHA scientific statement on FH, early diagnosis of homozygous FH and prompt initiation of diet and lipid-lowering therapy are critical.[27][28]

As previously mentioned, the LDL levels are much higher and the most effective treatments (statins) require at least one copy of the functional LDL receptor gene. In this case, high amounts of bile acid sequestrants are often given. Occasionally, high-dosed statins can help express a dysfunctional (but some times working) LDL receptor. Other treatments used are LDL apheresis (clearing LDL by blood filtration, similar to dialysis) with liver transplant as last result. The last option will introduce liver cells with working LDL receptors, effectively curing the condition.

National Lipid Association Guidelines for Identifying Patients Eligible for Apheresis:[29]

In patients who, after six months, do not have an adequate response to maximum tolerated drug therapy, LDL apheresis is indicated according to these guidelines:

1.Functional homozygous FH patients with LDL cholesterol ≥300 mg/dL (or non-HDL cholesterol ≥330 mg/dL).

2.Functional heterozygous FH patients with LDL cholesterol ≥300 mg/dL (or non-HDL cholesterol ≥330 mg/dL) and 0-1 risk factors.

3.Functional heterozygous FH patients with LDL cholesterol ≥200 mg/dL (or non-HDL cholesterol ≥230 mg/dL) and high risk characteristics such as ≥2 risk factors or high lipoprotein (a) ≥50 mg/dL using an isoform insensitive assay.

4. Functional heterozygotes with LDL cholesterol ≥160 mg/dL (or non-HDL cholesterol ≥190 mg/dL) and very high risk characteristics (established CHD, other cardiovascular disease, or diabetes).

Prevention

Prevention of complications of familial hypercholesterolemia are as follows:[16][17][30][19]

  • Early genetic diagnosis
  • Early attendance at a lipid clinic before they develop clinical CAD
  • Adherence to therapy

References

  1. 1.0 1.1 1.2 1.3 1.4 Marais AD (2004). "Familial hypercholesterolaemia". Clin Biochem Rev. 25 (1): 49–68. PMC 1853359. PMID 18516203.
  2. 2.0 2.1 2.2 2.3 2.4 Austin MA, Hutter CM, Zimmern RL, Humphries SE (2004). "Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review". Am J Epidemiol. 160 (5): 407–20. doi:10.1093/aje/kwh236. PMID 15321837.
  3. 3.0 3.1 3.2 3.3 3.4 van der Graaf A, Avis HJ, Kusters DM, Vissers MN, Hutten BA, Defesche JC; et al. (2011). "Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children". Circulation. 123 (11): 1167–73. doi:10.1161/CIRCULATIONAHA.110.979450. PMID 21382890.
  4. Grossman M, Rader DJ, Muller DW, Kolansky DM, Kozarsky K, Clark BJ; et al. (1995). "A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia". Nat Med. 1 (11): 1148–54. PMID 7584986.
  5. Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M; et al. (2001). "Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein". Science. 292 (5520): 1394–8. doi:10.1126/science.1060458. PMID 11326085.
  6. Goldstein JL, Brown MS (1974). "Binding and degradation of [[low density lipoproteins]] by cultured human [[fibroblasts]]. Comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia". J Biol Chem. 249 (16): 5153–62. PMID 4368448. URL–wikilink conflict (help)
  7. Scientific Steering Committee on behalf of the Simon Broome Register Group (Ratcliffe Infirmary, Oxford, England), "Risk of fatal coronary heart disease in familial hypercholesterolaemia", British Medical Journal 303 (1991), pp. 893-896.
  8. E.J.G. Sijbrands, et al., "Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study", British Medical Journal 322 (2001), pp. 1019-1023.
  9. Emily Youngblom & Joshua W. Knowles (1993). "Familial Hypercholesterolemia". PMID 24404629.
  10. Steyn K, Goldberg YP, Kotze MJ, Steyn M, Swanepoel AS, Fourie JM; et al. (1996). "Estimation of the prevalence of familial hypercholesterolaemia in a rural Afrikaner community by direct screening for three Afrikaner founder low density lipoprotein receptor gene mutations". Hum Genet. 98 (4): 479–84. PMID 8792826.
  11. Journal of Clinical Lipidology. Clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial Hypercholesterolemia: Screening, diagnosis and management of pediatric and adult patients. (2011) https://www.lipid.org/sites/default/files/articles/familial_hypercholesterolemia_1.pdf Accessed on October 27 2016
  12. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. National Heart, Lung, and Blood Institute (2011). "Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report". Pediatrics. 128 Suppl 5: S213–56. doi:10.1542/peds.2009-2107C. PMC 4536582. PMID 22084329.
  13. Gooding HC, Rodday AM, Wong JB, Gillman MW, Lloyd-Jones DM, Leslie LK; et al. (2015). "Application of Pediatric and Adult Guidelines for Treatment of Lipid Levels Among US Adolescents Transitioning to Young Adulthood". JAMA Pediatr. 169 (6): 569–74. doi:10.1001/jamapediatrics.2015.0168. PMID 25845026.
  14. 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.
  15. Wald DS, Bestwick JP, Morris JK, Whyte K, Jenkins L, Wald NJ (2016). "Child-Parent Familial Hypercholesterolemia Screening in Primary Care". N Engl J Med. 375 (17): 1628–1637. doi:10.1056/NEJMoa1602777. PMID 27783906.
  16. 16.0 16.1 Neil A, Cooper J, Betteridge J, Capps N, McDowell I, Durrington P; et al. (2008). "Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study". Eur Heart J. 29 (21): 2625–33. doi:10.1093/eurheartj/ehn422. PMC 2577142. PMID 18840879.
  17. 17.0 17.1 Authors/Task Force Members:. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ; et al. (2016). "2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR)". Atherosclerosis. 253: 281–344. doi:10.1016/j.atherosclerosis.2016.08.018. PMID 27594540.
  18. Emily Youngblom & Joshua W. Knowles (1993). "Familial Hypercholesterolemia". PMID 24404629.
  19. 19.0 19.1 Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS; et al. (2013). "Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society". Eur Heart J. 34 (45): 3478–90a. doi:10.1093/eurheartj/eht273. PMC 3844152. PMID 23956253.
  20. Benn M, Watts GF, Tybjærg-Hansen A, Nordestgaard BG (2016). "Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217". Eur Heart J. 37 (17): 1384–94. doi:10.1093/eurheartj/ehw028. PMID 26908947.
  21. Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF (2001). "Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial". Lancet. 357 (9256): 577–81. PMID 11558482.
  22. Davidson MH, Stein EA, Dujovne CA, Hunninghake DB, Weiss SR, Knopp RH; et al. (1997). "The efficacy and six-week tolerability of simvastatin 80 and 160 mg/day". Am J Cardiol. 79 (1): 38–42. PMID 9024733.
  23. Jones P, Kafonek S, Laurora I, Hunninghake D (1998). "Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study)". Am J Cardiol. 81 (5): 582–7. PMID 9514454.
  24. Cuchel M, Bloedon LT, Szapary PO, Kolansky DM, Wolfe ML, Sarkis A; et al. (2007). "Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia". N Engl J Med. 356 (2): 148–56. doi:10.1056/NEJMoa061189. PMID 17215532.
  25. Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF; et al. (2008). "Simvastatin with or without ezetimibe in familial hypercholesterolemia". N Engl J Med. 358 (14): 1431–43. doi:10.1056/NEJMoa0800742. PMID 18376000.
  26. Illingworth DR, Stein EA, Mitchel YB, Dujovne CA, Frost PH, Knopp RH; et al. (1994). "Comparative effects of lovastatin and niacin in primary hypercholesterolemia. A prospective trial". Arch Intern Med. 154 (14): 1586–95. PMID 8031206.
  27. Gidding SS, Champagne MA, de Ferranti SD, Defesche J, Ito MK, Knowles JW; et al. (2015). "The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association". Circulation. 132 (22): 2167–92. doi:10.1161/CIR.0000000000000297. PMID 26510694.
  28. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA; et al. (2014). "Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society". Eur Heart J. 35 (32): 2146–57. doi:10.1093/eurheartj/ehu274. PMC 4139706. PMID 25053660.
  29. Matthew K. Ito, Mary P. McGowan & Patrick M. Moriarty (2011). "Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia". Journal of clinical lipidology. 5 (3 Suppl): S38–S45. doi:10.1016/j.jacl.2011.04.001. PMID 21600528. Unknown parameter |month= ignored (help)
  30. Emily Youngblom & Joshua W. Knowles (1993). "Familial Hypercholesterolemia". PMID 24404629.

External links

  • MEDPED (Make Early Diagnosis to Prevent Early Deaths)
  • NCBI (Familial Hypercholesterolemia Page at National Center for Biotechnology Information)
  • H·E·A·R·T UK (H·E·A·R·T UK, Familial Hypercholesterolemia charity based in the United Kingdom)

Template:Endocrine, nutritional and metabolic pathology


Template:WikiDoc Sources