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Familial hypercholesterolemias

MedGen UID:
468437
Concept ID:
CN118841
Disease or Syndrome
 
Related genes: PCSK9, LDLRAP1, PPP1R17, LDLR, ITIH4, GHR, EPHX2, APOB, APOA2, ABCA1

Definition

Familial hypercholesterolemia (FH) is characterized by severely elevated LDL cholesterol (LDL-C) levels that lead to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age, leading to an increased risk for cardiovascular disease. Xanthomas (patches of yellowish cholesterol buildup) may worsen with age as a result of extremely high cholesterol levels. Xanthomas can occur around the eyelids and within the tendons of the elbows, hands, knees, and feet. In FH, the more common cardiovascular disease is coronary artery disease (CAD), which may manifest as angina and myocardial infarction; stroke occurs more rarely. Untreated men are at a 50% risk for a fatal or non-fatal coronary event by age 50 years; untreated women are at a 30% risk by age 60 years. An estimated 70%-95% of FH results from a heterozygous pathogenic variant in one of three genes (APOB, LDLR, PCSK9). FH is the most common inherited cardiovascular disease, with a prevalence of 1:200-250. FH likely accounts for 2%-3% of myocardial infarctions in individuals younger than age 60 years. In contrast, homozygous FH (HoFH) results from biallelic (homozygous or compound heterozygous) pathogenic variants in one of these known genes (APOB, LDLR, PCSK9). Most individuals with HoFH experience severe CAD by their mid-20s and the rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common. [from GTR]

Additional descriptions

From GeneReviews
Familial hypercholesterolemia (FH) is characterized by severely elevated LDL cholesterol (LDL-C) levels that lead to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age, leading to an increased risk for cardiovascular disease. Xanthomas (patches of yellowish cholesterol buildup) may worsen with age as a result of extremely high cholesterol levels. Xanthomas can occur around the eyelids and within the tendons of the elbows, hands, knees, and feet. In FH, the more common cardiovascular disease is coronary artery disease (CAD), which may manifest as angina and myocardial infarction; stroke occurs more rarely. Untreated men are at a 50% risk for a fatal or non-fatal coronary event by age 50 years; untreated women are at a 30% risk by age 60 years. An estimated 70%-95% of FH results from a heterozygous pathogenic variant in one of three genes (APOB, LDLR, PCSK9). FH is the most common inherited cardiovascular disease, with a prevalence of 1:200-250. FH likely accounts for 2%-3% of myocardial infarctions in individuals younger than age 60 years. In contrast, homozygous FH (HoFH) results from biallelic (homozygous or compound heterozygous) pathogenic variants in one of these known genes (APOB, LDLR, PCSK9). Most individuals with HoFH experience severe CAD by their mid-20s and the rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common.  https://www.ncbi.nlm.nih.gov/books/NBK174884
From NCBI curation
Familial hypercholesterolemia (FH) is characterized by severely elevated LDL cholesterol (LDL-C) levels that lead to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age, leading to an increased risk for cardiovascular disease. Xanthomas (patches of yellowish cholesterol buildup) may worsen with age as a result of extremely high cholesterol levels. Xanthomas can occur around the eyelids and within the tendons of the elbows, hands, knees, and feet. In FH, the more common cardiovascular disease is coronary artery disease (CAD), which may manifest as angina and myocardial infarction; stroke occurs more rarely. Untreated men are at a 50% risk for a fatal or non-fatal coronary event by age 50 years; untreated women are at a 30% risk by age 60 years. An estimated 70%-95% of FH results from a heterozygous pathogenic variant in one of three genes (APOB, LDLR, PCSK9). FH is the most common inherited cardiovascular disease, with a prevalence of 1:200-250. FH likely accounts for 2%-3% of myocardial infarctions in individuals younger than age 60 years. In contrast, homozygous FH (HoFH) results from biallelic (homozygous or compound heterozygous) pathogenic variants in one of these known genes (APOB, LDLR, PCSK9). Most individuals with HoFH experience severe CAD by their mid-20s and the rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common.

Recent clinical studies

Etiology

Marbach JA, Thapa J, Goldenberg E, Duffy D
Del Med J 2015 Aug;87(8):238-43. PMID: 26402926
Marbach JA, McKeon JL, Ross JL, Duffy D
Pharmacotherapy 2014 Sep;34(9):961-72. Epub 2014 Jun 5 doi: 10.1002/phar.1441. PMID: 24899514
McDonough A, Matura LA, Carroll D
Nurs Womens Health 2013 Oct;17(5):443-7. doi: 10.1111/1751-486X.12068. PMID: 24138664
Daniels SR, Gidding SS, de Ferranti SD; National Lipid Association Expert Panel on Familial Hypercholesterolemia.
J Clin Lipidol 2011 Jun;5(3 Suppl):S30-7. Epub 2011 Apr 5 doi: 10.1016/j.jacl.2011.03.453. PMID: 21600527
Górski B, Kubalska J, Naruszewicz M, Lubiński J
Hum Genet 1998 May;102(5):562-5. PMID: 9654205

Diagnosis

Marbach JA, Thapa J, Goldenberg E, Duffy D
Del Med J 2015 Aug;87(8):238-43. PMID: 26402926
Mendiara I, Bentayeb K, Nerín C, Domeño C
Talanta 2015 Jan;132:690-7. Epub 2014 Oct 23 doi: 10.1016/j.talanta.2014.10.029. PMID: 25476366
Hopkins PN, Toth PP, Ballantyne CM, Rader DJ; National Lipid Association Expert Panel on Familial Hypercholesterolemia.
J Clin Lipidol 2011 Jun;5(3 Suppl):S9-17. Epub 2011 Apr 3 doi: 10.1016/j.jacl.2011.03.452. PMID: 21600530
Goldberg AC, Robinson JG, Cromwell WC, Ross JL, Ziajka PE
J Clin Lipidol 2011 Jun;5(3 Suppl):S46-51. Epub 2011 Apr 8 doi: 10.1016/j.jacl.2011.04.002. PMID: 21600529
Daniels SR, Gidding SS, de Ferranti SD; National Lipid Association Expert Panel on Familial Hypercholesterolemia.
J Clin Lipidol 2011 Jun;5(3 Suppl):S30-7. Epub 2011 Apr 5 doi: 10.1016/j.jacl.2011.03.453. PMID: 21600527

Therapy

Marbach JA, Thapa J, Goldenberg E, Duffy D
Del Med J 2015 Aug;87(8):238-43. PMID: 26402926
Marbach JA, McKeon JL, Ross JL, Duffy D
Pharmacotherapy 2014 Sep;34(9):961-72. Epub 2014 Jun 5 doi: 10.1002/phar.1441. PMID: 24899514
McDonough A, Matura LA, Carroll D
Nurs Womens Health 2013 Oct;17(5):443-7. doi: 10.1111/1751-486X.12068. PMID: 24138664
Ito MK, McGowan MP, Moriarty PM; National Lipid Association Expert Panel on Familial Hypercholesterolemia.
J Clin Lipidol 2011 Jun;5(3 Suppl):S38-45. Epub 2011 Apr 8 doi: 10.1016/j.jacl.2011.04.001. PMID: 21600528
Daniels SR, Gidding SS, de Ferranti SD; National Lipid Association Expert Panel on Familial Hypercholesterolemia.
J Clin Lipidol 2011 Jun;5(3 Suppl):S30-7. Epub 2011 Apr 5 doi: 10.1016/j.jacl.2011.03.453. PMID: 21600527

Prognosis

Anderson BR, Rhee D, Abellar RG, Glickstein JS
Pediatr Cardiol 2013 Jun;34(5):1247-9. Epub 2012 May 24 doi: 10.1007/s00246-012-0368-7. PMID: 22622686

Recent systematic reviews

Ito MK, McGowan MP, Moriarty PM; National Lipid Association Expert Panel on Familial Hypercholesterolemia.
J Clin Lipidol 2011 Jun;5(3 Suppl):S38-45. Epub 2011 Apr 8 doi: 10.1016/j.jacl.2011.04.001. PMID: 21600528
Daniels SR, Gidding SS, de Ferranti SD; National Lipid Association Expert Panel on Familial Hypercholesterolemia.
J Clin Lipidol 2011 Jun;5(3 Suppl):S30-7. Epub 2011 Apr 5 doi: 10.1016/j.jacl.2011.03.453. PMID: 21600527
Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, Daniels SR, Gidding SS, de Ferranti SD, Ito MK, McGowan MP, Moriarty PM, Cromwell WC, Ross JL, Ziajka PE; National Lipid Association Expert Panel on Familial Hypercholesterolemia.
J Clin Lipidol 2011 Jun;5(3 Suppl):S1-8. Epub 2011 Apr 12 doi: 10.1016/j.jacl.2011.04.003. PMID: 21600525

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