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| ==Pathophysiology==
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| Familial hypercholesterolemia is a common [[autosomal dominant]]<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.
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| These mutations include the following:<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>
| | '''Von Willebrand disease''' (vWD) is the most common genetic coagulation disorder described in humans. It affects up to 1% of the population, although most cases are mild. Symptomatic vWD is much rare, ~1 in 10000. Von Willebrand disease arises from a qualitative or quantitative deficiency of [[von Willebrand factor]] (vWF), a large glycoprotein protein that is required for [[platelet]]<nowiki/>s to bind to collagen. vWF is therefore important in primary hemostasis. When the disease comes to medical attention, it usually presents in the typical manner for platelet disorders: mucosal bleeding and easy bruising. The disease is usually inherited in an autosomal dominant manner, although there are recessive forms as well, and it can also be acquired secondary to another disease. <ref>Ng et al. Diagnostic Approach to von Willebrand Disease. Blood 2015; 125(13): 2029-2037.</ref><ref>Blomback et al. Von Willebrand Disease Biology Hemophilia 2012; 18: 141-147.</ref><ref>Favarolo et al. Von Willebrand Disease and Platelet Disorders. Hemophilia 2014; 20: 59-64.</ref> |
| *The [[LDL receptor]]
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| *The [[apolipoprotein B]] gene, which impairs binding of [[LDL]] particles to the [[LDL receptor]]
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| *[[Proprotein convertase subtilisin/kexin type 9]] gene, which leads to decreased [[LDL]] metabolism
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| Familial hypercholesterolemia has 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.
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| Familial disorders of [[cholesterol]] metabolism may result from one of the following:
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| *Overproduction of [[lipoproteins]]
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| *Impaired removal of [[lipoproteins]] (this may result from primary defect with the [[lipoprotein]] or its [[receptor]])
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| [[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]]. 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>
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| The excess circulating [[LDL]] is taken up by cells all over the body—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]].
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| Although [[atherosclerosis]] can occur in all people, many FH patients develop accelerated atherosclerosis due to the presence of excess [[LDL]]. Some studies of FH cohorts suggest that additional risk factors are generally present 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>
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| 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 the heterozygous forms of FH, the receptor function is only mildly impaired, and [[LDL]] levels will remain relatively low. In more serious form (i.e., the homozygous form), the "broken" receptor is not expressed at all.
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| In '''heterozygous FH''', only one of the two [[DNA]] copies ([[alleles]]) is damaged, and there will be at least 50% of the normal [[LDL receptor]] activity (i.e., the "healthy" copy and whatever the "broken" copy can still contribute).
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| In '''homozygous FH''', however, both alleles are damaged to some degree, which can lead to extremely high levels of [[LDL]]. Children with this form of FH may develop extremely premature [[heart disease]]. A further complication is the ineffectiveness of [[statins]].
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| Historical Perspective
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| Classification
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| Pathophysiology
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| Causes
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| Differentiating Familial hypercholesterolemia from other Diseases
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| Epidemiology and Demographics
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| Familial hypercholesterolaemia-causing mutations are estimated to occur in 1:217 in the general population <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>
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| Risk Factors
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| smoking cesation <ref name="pmid14507483">{{cite journal| author=Maeda K, Noguchi Y, Fukui T| title=The effects of cessation from cigarette smoking on the lipid and lipoprotein profiles: a meta-analysis. | journal=Prev Med | year= 2003 | volume= 37 | issue= 4 | pages= 283-90 | pmid=14507483 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14507483 }} </ref>
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| weight/lack of exercise <ref name="pmid22795291">{{cite journal| author=Huffman KM, Hawk VH, Henes ST, Ocampo CI, Orenduff MC, Slentz CA et al.| title=Exercise effects on lipids in persons with varying dietary patterns-does diet matter if they exercise? Responses in Studies of a Targeted Risk Reduction Intervention through Defined Exercise I. | journal=Am Heart J | year= 2012 | volume= 164 | issue= 1 | pages= 117-24 | pmid=22795291 | doi=10.1016/j.ahj.2012.04.014 | pmc=3399760 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22795291 }} </ref><ref name="pmid17395756">{{cite journal| author=Slentz CA, Houmard JA, Johnson JL, Bateman LA, Tanner CJ, McCartney JS et al.| title=Inactivity, exercise training and detraining, and plasma lipoproteins. STRRIDE: a randomized, controlled study of exercise intensity and amount. | journal=J Appl Physiol (1985) | year= 2007 | volume= 103 | issue= 2 | pages= 432-42 | pmid=17395756 | doi=10.1152/japplphysiol.01314.2006 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17395756 }} </ref><ref name="pmid12421890">{{cite journal| author=Kraus WE, Houmard JA, Duscha BD, Knetzger KJ, Wharton MB, McCartney JS et al.| title=Effects of the amount and intensity of exercise on plasma lipoproteins. | journal=N Engl J Med | year= 2002 | volume= 347 | issue= 19 | pages= 1483-92 | pmid=12421890 | doi=10.1056/NEJMoa020194 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12421890 }} </ref>
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| t2dm <ref name="pmid11237932">{{cite journal| author=Liu S, Manson JE, Stampfer MJ, Holmes MD, Hu FB, Hankinson SE et al.| title=Dietary glycemic load assessed by food-frequency questionnaire in relation to plasma high-density-lipoprotein cholesterol and fasting plasma triacylglycerols in postmenopausal women. | journal=Am J Clin Nutr | year= 2001 | volume= 73 | issue= 3 | pages= 560-6 | pmid=11237932 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11237932 }} </ref>
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| high fat diet <ref name="pmid12716665">{{cite journal| author=Mensink RP, Zock PL, Kester AD, Katan MB| title=Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. | journal=Am J Clin Nutr | year= 2003 | volume= 77 | issue= 5 | pages= 1146-55 | pmid=12716665 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12716665 }} </ref><ref name="pmid16476868">{{cite journal| author=Nordmann AJ, Nordmann A, Briel M, Keller U, Yancy WS, Brehm BJ et al.| title=Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials. | journal=Arch Intern Med | year= 2006 | volume= 166 | issue= 3 | pages= 285-93 | pmid=16476868 | doi=10.1001/archinte.166.3.285 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16476868 }} </ref>
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| ==Screening==
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| {| style="border: 0px; font-size: 90%; margin: 3px;" align=center
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| |+
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| ! style="background: #4479BA; width: 120px;" colspan="3" | {{fontcolor|#FFF|'''
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| Pediatric dyslipidemia screening guidelines from the 2011 Expert Panel Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents'''}}
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| |-
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| ! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Age}}
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| ! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Screening recommendation}}
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| ! style="background: #4479BA; width: 50px;" | {{fontcolor|#FFF|Reommendation level}}
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| |-
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| | style="padding: 5px 5px; background: #DCDCDC;" rowspan="1" | '''birth- <2years'''
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | No lipid screening
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | C
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| |-
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| | style="padding: 5px 5px; background: #DCDCDC;" rowspan="4" | '''2-8years (''' No routine lipid screening,
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| however screen if one of the following is present using FLP two times)
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| | 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
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
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| |-
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |Parent with TC ≥ 240 mg/dL or known dyslipidemia
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
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| |-
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |Child has diabetes, hypertension, BMI ≥ 95th percentile or smokes cigarettes
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
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| |-
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| | 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)
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
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| | style="padding: 5px 5px; background: #DCDCDC;" rowspan="2" | '''9-11years ('''Universal Screening)
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| | 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
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
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| |-
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| | 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
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
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| |-
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| | style="padding: 5px 5px; background: #DCDCDC;" rowspan="5" |'''12-16years ('''Selective screening using FLP x 2)
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| | 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:
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
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| |-
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| | 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
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
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| |-
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | • Parent with TC ≥ 240 mg/dL or known dyslipidemia
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
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| |-
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" |Patient has diabetes, hypertension, BMI ≥ 85th pr\ercentile or smokes cigarettes
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
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| |-
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| | 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)
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
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| |-
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| | style="padding: 5px 5px; background: #DCDCDC;" rowspan="1" | '''17-19years'''
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| | 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
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
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| |-
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| | rowspan="1" style="padding: 5px 5px; background: #DCDCDC;" | '''17-21years'''
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| | 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
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| | style="padding: 5px 5px; background: #F5F5F5; text-align:center;" | B
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| |}
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| ==hgghg==
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| The original 1992 National
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| Cholesterol Education Program (NCEP) report
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| National Cholesterol Education Program: Report
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| of the Expert Panel on Blood Cholesterol Levels
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| in Children and Adolescents (NCEP Pediatric
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| Guidelines) recommended screening for elevated
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| cholesterol levels only among children with either
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| a family history of early CVD or elevated TC | |
| levels.8
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| The Expert Panel recommends two complementary
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| strategies to reduce future risk for clinical CVD.
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| Primordial prevention seeks to prevent the
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| acquisition of risk factors by optimizing CV health
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| for all, beginning in infancy. Primary prevention
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| requires screening to identify children at increased
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| risk for CVD. This section focused on screening
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| and reviewed the limitations of current knowledge
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| within the requirements for a useful screening
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| program. Taking these factors into account, the
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| Expert Panel recommends routine measurement
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| of length/height and weight beginning in infancy,
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| with calculation of BMI annually beginning
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| at age 2 years to identify growth trends; yearly
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| assessment of BP from age 3 years; and universal
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| screening for lipid abnormalities by a nonfasting
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| non-HDL–C level at age 10 years. These screening
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| strategies, described in detail in the respective risk
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| factor sections of these Guidelines, will identify | |
| a relatively large number of children for whom
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| the Expert Panel recommends intensified lifestyle
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| intervention. Only a small number of children
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| will require pharmacologic therapy. While they
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| await the results of future research, the Expert
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| Panel members conclude that recommending these
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| assessments, followed by interventions as part of
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| routine pediatric care, represents the best current
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| primary prevention strategy to lower lifetime risk
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| of atherosclerotic vascular disease.
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| Natural History, Complications and Prognosis
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| Diagnosis
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| History and Symptoms
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| Physical Examination
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| Laboratory Findings
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| http://www.nhlbi.nih.gov/files/docs/guidelines/peds_guidelines_full.pdf
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| Primary Lipid Disorders Lipid/Lipoprotein Abnormality
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| Familial hypercholesterolemia Homozygous: hhLDL–C
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| Heterozygous: hLDL–C*
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| Familial defective apolipoprotein B hLDL–C
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| Familial combined hyperlipidemia* Type IIa: hLDL–C
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| Type IV: h VLDL–C, hTG
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| Type IIb: hLDL–C, hVLDL–C, hTG
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| Types IIb and IV often with iHDL–C
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| Polygenic hypercholesterolemia hLDL–C
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| Familial hypertriglyceridemia (200–1,000 mg/dL) hVLDL-C, hTG
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| Severe hypertriglyceridemia (≥1,000 mg/dL) hChylomicrons, hVLDL–C, hhTG
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| Familial hypoalphalipoproteinemia iHDL–C
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| Dysbetalipoproteinemia (TC: 250–500 mg/dL; hIDL–C, hchylomicron remnants
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| 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>
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| FH are best identified by a definite or probable phenotypic diagnosis of FH based on the DLCN criteria or an LDL-cholesterol above 4.4 mmol/L. <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>
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| Electrocardiogram
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| Chest X Ray
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| CT
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| MRI
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| Echocardiography or Ultrasound
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| Other Imaging Findings
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| Other Diagnostic Studies
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| Treatment
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| Medical Therapy
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| Lomitapide is a microsomal triglyceride transfer protein inhibitor currently approved for treatment of homozygous familial hypercholesterolemia that may be useful in the management of severe hypertriglyceridemia.<ref name="pmid27785928">{{cite journal| author=Brahm AJ, Hegele RA| title=Lomitapide for the treatment of hypertriglyceridemia. | journal=Expert Opin Investig Drugs | year= 2016 | volume= | issue= | pages= | pmid=27785928 | doi=10.1080/13543784.2016.1254187 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27785928 }} </ref>
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| Surgery
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| Prevention
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| ==References==
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| {{reflist|2}}
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| __NOTOC__
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| {{SI}}
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| {{CMG}}; {{AE}} {{PTD}}
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| {{SK}} FHC; FH; type IIA hyperlipoproteinemia; hyper-low-density-lipoproteinemia; familial hypercholesterolemic xanthomatosis; LDL receptor disorder
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| ==Overview==
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| '''Familial hypercholesterolemia''' (also spelled '''familial hypercholesterolaemia''') is a rare [[genetic disorder]] characterized by very high [[LDL]] cholesterol and early [[cardiovascular disease]] running in families.
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| ==Classification==
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| Familial hypercholesterolemia may be classified according to the severity of the mutation involving the [[LDL-cholesterol]] (LDL-C) receptor or depending on the [[inheritance|mode of inheritance]] as follows:
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| *'''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>
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| **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.
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| *'''Polygenic''' vs '''monogenic'''
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| **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.
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| | |
| ==Pathophysiology==
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| 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.
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| Familial disorders of cholesterol metabolism may result from one of the following:
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| *Overproduction of lipoproteins
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| *Impaired removal of lipoproteins (this may result from primary defect with the lipoprotein or its receptor).
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| | |
| [[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.
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| 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]].
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| 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>
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| 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.
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| 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).
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| 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).
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| ==Epidemiology==
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| ===Prevalence===
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| *The prevalence of FH is 1 in 300 to 500 in many populations, making FH among the most common of serious genetic disorders
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| ===Ethnicity===
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| *In a few populations (such as French Canadians and Dutch Afrikaners), the prevalence of FH may be as high as 1 in 100
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| ===United States===
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| *There are approximately 620,000 FH patients currently living in the United States
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| ==Screening==
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| Universal screening for elevated serum cholesterol is recommended.<ref name=FH-Screening>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</ref>
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| ===General population screening===
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| Familial hypercholesterolemia (FH) should be suspected when untreated fasting LDL cholesterol or non HDL cholesterol levels are at or above the following:
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| *Adults (≥ 20 years):
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| **LDL cholesterol ≥ 190 mg/dL or non-HDL cholesterol ≥ 220 mg/dL
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| *Children, adolescents and young adults (< 20 years):
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| **LDL cholesterol ≥160 mg/dL or non- HDL cholesterol ≥ 190 mg/dL
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| 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.
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| 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:
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| *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)
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| *Tuberous xanthomas or xanthelasma in a patient under age 20 to 25
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| At the LDL cholesterol levels listed below the probability of FH is approximately 80% in the setting of general population screening.
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| *These LDL cholesterol levels should prompt the clinician to strongly consider a diagnosis of FH and obtain further family information:
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| **LDL cholesterol ≥ 250 mg/dL in a patient aged 30 or more
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| **LDL cholesterol ≥ 220 mg/dL for patients aged 20 to 29
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| **LDL cholesterol ≥ 190 mg/dL in patients under age 20
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| ===Screening in children===
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| 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>
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| ====Child-parent familial hypercholesterolemia screening in primary care====
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| *Recent study shows the feasibility and efficacy of child-parent familial hypercholesterolemia screening in primary care setting.
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| *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>
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| ==Prognosis==
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| *Approximately 1 in one million persons is [[homozygous]] (or compound heterozygous) for LDLR mutations and has extreme hypercholesterolemia with rapidly accelerated atherosclerosis when left untreated.
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| ==Diagnosis==
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| == Signs and symptoms ==
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| *Elevated serum [[cholesterol]], most notably the [[LDL]] fraction ([[VLDL]] and [[triglyceride]]s are typically normal)
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| ** on lipoprotein [[electrophoresis]] (rarely done), a [[hyperlipoproteinemia type II]] pattern is recognised
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| *Premature [[cardiovascular disease]], such as:
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| **[[Angina pectoris]], leading to [[PTCA]] or [[CABG]]
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| **[[Myocardial infarction]]
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| **[[Transient ischemic attack]]s (TIA's)
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| **[[Cerebrovascular accident]]s/[[Stroke]]s
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| **[[Peripheral artery disease]] (PAOD)
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| *A ''[[family history]]'' of premature [[atherosclerosis]]
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| ===Physical Examination===
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| The following signs are not always present:
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| ====Eyes====
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| *[[Xanthelasma|Xanthelasma palpabrum]] (yellowish patches above the eyelids)
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| *[[Arcus senilis]] corneae, whitish discoloration of the iris
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| ====Extremities====
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| *Tendon [[xanthoma]]s (thickening of [[tendon]]s due to accumulation of [[macrophage]]s filled with [[cholesterol]]).
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| ===Laboratory Studies===
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| LDL-receptor gene defects can be identified with genetic testing. Testing is generally undertaken when:
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| * A family member has been shown to have a mutation;
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| * High cholesterol is found in a young patient with [[atherosclerosis|atherosclerotic]] disease;
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| * [[Tendon xanthomas]] are found in a patient with high cholesterol.
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| ==Treatment==
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| === Heterozygous FH ===
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| Heterozygous FH can be treated effectively with [[statins]]. These are drugs that inhibit the body's ability to produce [[cholesterol]] by blocking the enzyme [[HMG-CoA reductase|hydroxymethylglutaryl CoA reductase]] (HMG-CoA-reductase). Maximum doses are often necessary. 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 (see below).
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| In case statins are not effective, either a drug from the [[fibrate]] or [[bile acid sequestrant]] class can be added, as well as [[niacin]]/[[acipimox]]. As 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]]), these patients are monitored closely.
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| === Homozygous FH ===
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| Homozygous FH is a different story. 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]]) and - as a last resort - a [[liver transplant]]. The last option will introduce liver cells with working LDL receptors, effectively curing the condition.
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| ==History==
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| 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].
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| == Differential Diagnosis ==
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| {| class="wikitable"
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| ! rowspan="3" |
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| ! rowspan="3" |Diseases
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| ! rowspan="3" |Mode of Inheritance
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| ! colspan="8" |Laboratory Findings
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| ! rowspan="3" |Other Findings
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| ! rowspan="3" |Management
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| ! rowspan="3" |Complications
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| ! rowspan="3" |Prognosis
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| |-
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| ! colspan="5" |Lipid Profile
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| ! colspan="3" |Other Laboratory Findings
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| |-
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| !Total Cholesterol
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| !LDL
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| !HDL
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| !Triglycerides
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| !Plasma Appearance
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| !Chylomicrons
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| !VLDL
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| !Genetic mutations
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| |-
| |
| | rowspan="6" |'''Primary Hyperlipoprotenemia'''
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| |[[Familial hyperchylomicronemia|Type I]]
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| |Autosomal Recessive
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| &
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| Autosomal Dominant(Rare)
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| |Normal or '''↑'''
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| |'''↓'''
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| |'''↓↓↓'''
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| |'''↑↑↑↑'''
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| |Milky
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| |'''↑↑↑↑'''
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| |'''↓'''
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| | -LPL gene mutation
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| | -Fat tolerance markedly abnormal
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| -Carbohydrate inducibility may be abnormal
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| |Treatment for hyperlipoproteinemia type 1 is intended to control blood triglyceride levels with a very low-fat diet
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| |<nowiki>-Recurrent Pancreatitis</nowiki>
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| | |
| -Rarely life threatening
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| |Good
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| |-
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| |Type IIA
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| |
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| |
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| |
| |
| |
| |
| |
| |
| |-
| |
| |Type IIB
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| |
| |
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| |
| |
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| |
| |
| |
| |
| |
| |
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| |
| |
| |
| |
| |
| |
| |
| |
| |
| |-
| |
| |Type III
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| |
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| |
| |
| |
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| |
| |
| |
| |
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| |
| |
| |
| |
| |
| |
| |-
| |
| |Type IV
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| |Autosomal Recessive
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| &
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| | |
| Autosomal Dominant
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| |Normal or '''↑'''
| |
| |
| |
| |Prebeta-HDL '''↑'''
| |
| | |
| &
| |
| | |
| HDL-C '''↓'''
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| | '''↑↑'''
| |
| |Clear or Cloudy
| |
| |Normal
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| | '''↑'''
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| |<nowiki>-LPL genes (Gly188Glu,Asp9Asn, Asn291Ser,Ser447Ter)</nowiki>
| |
| | |
| -APOA5
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| | |
| -LMF1
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| | |
| -GPIHBP1
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| |Hyperglycemia, Pancytopneia and pseudo-Niemann
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| | |
| pick cells
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| |<nowiki>-Weight reduction</nowiki>
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| | |
| -Niacin or Fibrates
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| | |
| -Gene therapy
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| |<nowiki>-Ischemic Heart Disea</nowiki>
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| | |
| -Recurrent Pancreatitis
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| | |
| -NIDDM
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| | |
| -NAFLD
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| |
| |
| |-
| |
| |Type V
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| |Variable
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| |{{Center|'''↑''' to '''↑↑'''}}
| |
| |{{Center|'''↓'''}}
| |
| |{{Center|'''↓↓↓'''}}
| |
| |{{Center|'''↑↑↑↑'''}}
| |
| |Creamy supernatant and turbid infranatant
| |
| |{{Center|'''↑'''}}
| |
| |{{Center|'''↑↑↑'''}}
| |
| |❑ Apo E, Apo A5 mutations<br> ❑ LPL gene mutation in 10% of western population patients
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| |❑ Restriction of dietary fat eliminates Chylomicrons and reverts to type IV HLP <br> ❑ When triglyceride levels are >1000mg/dl given the rarity of type I it is almost always type V HLP
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| |❑ Weight reduction<br>❑ [[Niacin]] or [[Fibrates]] or [[Statins|Strong statins]]<br>❑ Low fat diet
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| |❑ Recurrent Pancreatitis
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| |❑ {{Center|Good}}
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| |-
| |
| |}
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|
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|
| ==References== | | ==References== |
| {{Reflist|2}} | | {{Reflist|2}} |
|
| |
| ==External links==
| |
| *[http://www.medped.org MEDPED] (Make Early Diagnosis to Prevent Early Deaths)
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| *[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=144010 NCBI] (Familial Hypercholesterolemia Page at National Center for Biotechnology Information)
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| *[http://www.heartuk.org.uk/index.html H·E·A·R·T UK] (H·E·A·R·T UK, Familial Hypercholesterolemia charity based in the United Kingdom)
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|
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| {{Endocrine, nutritional and metabolic pathology}}
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| [[Category:Cardiology]]
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| [[Category:Inborn errors of metabolism]]
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