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Familial Hypercholesterolemia: Background Information
Specialist
James A. Underberg, MD, MS, FACPM, FACP, FASH, FNLA
Clinical Assistant Professor of Medicine NYU School of MedicineNYU Langone Center for Cardiovascular Disease Prevention
Director, Bellevue Hospital Lipid Clinic, New York,NY
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Disclosures• Honoraria for Speakers Bureau (Pharma) : AstraZeneca, Abbott,
Forest, GlaxoSmithKline, Daiichi-Sankyo, Kowa, Novartis, Pfizer, Liposcience, diaDexus, Merck, Eli Lilly
• Honoraria for CME Programs :American Heart Association, National Lipid Association, American College of Reproductive Medicine, PriMed, Primary Care Network
• Consulting Income: Liposcience, Amarin, Genzyme,News Corporation, Publicis Inc., Summer Street Consulting Inc. Guidepoint Global
• Advisory Boards: Kowa, Abbott, Merck, Genzyme, Amarin• Clinical Research Funding: Genzyme, GlaxoSmithKline, Kowa• Medical Education Committee Member : ASH, NLA• Editorial Board Member: Journal of Clinical Lipidology• Scientific Advisory Board: FH Foundation• Board of Directors: NLA, Foundation of the NLA, ASH Foundation
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FH: A Clinically Recognizable Genetic Disorder• Inheritable, autosomal dominant disorder1
• Usually due to mutations in LDL receptor gene2,3 that result in decreased clearance of LDL particles from plasma1
– Other mutations include those in the Apo B and PCSK9 genes
• Clinical manifestations include1,2
– Severe hypercholesterolemia due to accumulation of plasma LDL
– May be accompanied by cholesterol deposition in tendons and skin (xanthomas) and in the eyes
– Evidence of CVD early in life
1. Marais AD. Clin Biochem Rev. 2004;25:49-68.2. Mahley RW, et al. In: Kronenberg: Williams Textbook of Endocrinology. 2008.3. Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.
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Visible Signs of FH
A- Xanthelasma
B – Corneal arcus (Arcus senilis)
C - Achilles tendon xanthomas
D - Tendon xanthomas
E - Tuberous xanthomas
F - Palmar xanthomas
Mahley RW et al. In Kronenberg: Williams Textbook of Endocrinology 2008
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Genetics• Mutations in a gene on one of the first 22 non-sex
chromosomes can cause autosomal disorders• Autosomal Dominant
– Only one copy of the abnormal gene is adequate to cause the disorder
– The abnormal gene dominates the pair of genes– A child has 50% of chance of inheriting the disorder even if
only one parent has the dominant gene• Autosomal Recessive
– Two copies of an abnormal gene must be present to cause the disorder
– People with only one defective gene are considered carriers
– A child has a 25% chance of inheriting the disorder if both parents carry an autosomal recessive mutation
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The Phenotype of FH May Reflect LDL-R, Apo B, or PCSK9 Mutations
Apo B (site where receptor binds to LDL particle)
LDL receptor
Image reproduced from: http://www.dls.ym.edu.tw/ol_biology2/ultranet/Endocytosis.html.
Cytosol
Cell membrane
Extracellular Fluid
• LDLR codes for the LDL Receptor, which clears LDL particles from the circulation by binding to surface Apo B
• PCSK9 induces degradation of LDLR• FH may be caused by mutations in Apo B, LDL-R, or PCSK9
PCSK9
1. Kumar: Robbins and Cotran. Pathologic Basis of Disease, 2009.2. Rader DJ et al. J Clin Invest. 2003;111:1795-1803
LDL Particle:
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FH Is Not a Rare Genetic Disease: Prevalence is 2x Other Inherited Conditions
1. Genetic Alliance UK. Available at http://www.geneticalliance.org.uk/education3.htm.2. Streetly A, et al. J Clin Path. 2010;63:626-629.
Neuro-fibromatosis
1Familial combined hyperlipidemia has a frequency of 1:200 births; however, the genetic cause is unknown.2Sickle cell disease varies greatly by ethnicity.
Frequency per 1,000 Births of Common Genetic Disorders1
2
FH
2.0
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Prevalence Is Much Higher in Specific Sub-populations or “Founder Groups”
North America and Europe:HeFH ~1:500 HoFH ~<1:106
Higher incidence of HoFH:Québec, Tunisia, South Africa, Lebanon
Naoumova RP, et al. Curr Opin Lipidol. 2004;15:413-422.
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Austin MA, et al. Am J Epidemiol. 2004;160:407–420.
In Founder Groups, FH Prevalence Can Be 8x Greater vs. General Population
1:100 to 1:72
1:67
1:1651:270
1:170
1:500
Comparison of FH Prevalence Rates Across Populations
HeFH(US &
Europe)
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Patients With FH Are at Very High CVD Risk Before Age 40, Relative to the General Population
Scientific Steering Committee. Atherosclerosis. 1999;142:105-112.
*
*
*
*
**
*
Men (n = 605)
* P <0.01 vs general population.
Women (n = 580)
Risk of CHD in FH patients / risk of CHD in general population
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Despite the Importance of Early Detection, FH Is Under-diagnosed (US)
• The WHO estimated in 1999 that <10% of US patients with FH were diagnosed
World Health Organization Human Genetics Program. http://whqlibdoc.who.int/hq/1999/WHO_HGN_FH_CONS_99.2.pdf.
Perc
enta
ge o
f pati
ents
<<
Percentage of FH patients diagnosed
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MI Rates in FH patients vs. Non-Statin Rx and Normals
Versmissen J, et al. BMJ. 2008;337:a2423.
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Reduction in Mortality in Subjects With HomozygousFamilial Hypercholesterolemia Associated With Advances in Lipid-
Lowering Therapy
Circulation. 2011;124:2202-2207
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FH “Scoring Methods” for Clinical Diagnosis Require LDL Levels and Family History
Simon Broome Register1 MEDPED2 Dutch Lipid Clinic Network1
Definite FH• TC or LDL levels• Tendon xanthoma in
patient or relative
Probable FH• TC or LDL levels• Family history of early
MI or high TC/LDL
• TC or LDL levels based on family history and age (eg, age <20 y, with an FH relative)
• Score based on :
Family history of premature CHD, high LDL, or xanthoma
Clinical history of premature CAD or vascular disease
Presence of xanthoma or arcus cornealis
LDL panel
1. As summarized in: Marks D, et al. Atherosclerosis. 2003;168:1-14.2. As summarized in: Civiera F, et al. Circulation. 2004;173:55-68.
Comparison of FH Clinical Diagnostic Criteria by Method
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MEDPED criteria for the diagnosis of familial hypercholesterolemia. Total and LDL cholesterol (mmol/l)band {mg/dl} criteria for diagnosing
probable heterozygous familial hypercholesterolemia
Curr Opin Lipidol 2012, 23:282–289
Williams RR, Hunt SC, Schumacher C, et al. Am J Cardiol 1993; 72:171–176.
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Simon Broome Criteria
Curr Opin Lipidol 2012, 23:282–289
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Dutch lipid clinic network criteria for familial hypercholesterolemia
Curr Opin Lipidol 2012, 23:282–289World Health Organization. Familial hypercholesterolaemia. Report of asecond WHO consultation. Geneva: World Health Organization; 1999.
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Role for Genetic testing in screening varies worldwide
• Testing used as a significant part of algorithms for screening and diagnosis in many countries such as Spain, Wales, the Netherlands, UK (NICE Guidelines) but not currently in the US
• Use differs from country to country• One study done in the Netherlands suggests that
with extensive screening the proportion of those with a genetic mutation is unknown may be as low as 5%.
Curr Opin Lipidol 2012, 23:282–289van der Graaf A, Avis HJ, Kusters DM, et al. Circulation 2011; 123:1167–1173.
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Screening Varies From Country to Country
• US : NLA Recommendations (2011)Index case identified from one of three available diagnostic criteria with universal screening, then cascade screening of relatives in primary care setting- genetic testing not recommended routinely
• UK: NICE guidelines (2008) Index case identified clinically using Simon Broome followed by genetic testing and then cascade targeted genetic screening of relatives .
• Netherlands: DLCN identification followed by genetic testing. If mutation identified, registry in Foundation for Detection of Hereditary Hypercholesterolemia. Then first degree family members are genetically screened by home health nurses followed by other family member testing.
Goldberg AC, Hopkins PN, Toth PP, et al. J Clin Lipidol 2011; 5:133–140.
DeMott K, Nherera L, Shaw EJ, et al. London: National CollaboratingCentre for Primary Care and Royal College of General Practitioners; 2008.
Aarden E, Van Hoyweghen I, Horstman K. Scand J Public Health 2011; 39:634–639.
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National Collaborating Centre for Primary Care (UK). (2008). NICE clinical guideline 71: Identification and management of familial hypercholesterolaemia, London
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Family Screening Has Dramatically Increased Treatment Rates in the Netherlands
Umans-Eckenhausen MAW, et al. Lancet. 2001;357:165–168.
Effects of Family-Based Screening on Treatment Rates in People with FH
N = 5,442
• 37% identified as HeFH (based on LDL-R mutations)
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Role of Genetic Typing in FH
Journal of Clinical Lipidology, Vol 6, No 3, June 2012
Highlights from this discussion include the role of genetic typing for diagnosis
Understanding disease mechanism
Potential guidance in treatment algorithms
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Highlights• “Some studies have suggested that the individuals with gain-
of-function mutations in PKSK9 have greater levels of LDL-C, and although they are decreased with statin therapy, they remain greater than in patients with low-density lipoprotein receptor (LDLR) mutations.”
• “Today, this might influence expectations of therapeutic effectiveness, but tomorrow might indicate which class of cholesterol lowering drugs might be most effective.”
• Potential role for increasing treatment rates in children with mutations identified in parents with FH – “big benefit is for the family of someone with a known
mutation.”
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“The clinical validity and utility of cascade screening for FH is dependent on a number of factors, including the criterion used to diagnose the disorder in the index case, the use of DNA testing in the index case and in relatives, and the nature of the benefit and possible harms of identifying and pharmacologically treating the disorder in childhood. Nevertheless, cascade screening is a straightforward and highly effective way to identify persons who have FH.”
Ned, R. M., & Sijbrands, E. J. (2011). Cascade screening for familial hypercholesterolemia (FH). PLoS Curr., 3 doi:10.1371/currents.RRN1238
CASCADE SCREENING
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Screening of Children• 2008 American Academy of Pediatrics- Family history of
premature CVD screen at age 2• 2011 NLA- Screen all children age 9-11, and at age 2 if
family history of premature CVD• 2012 NHLBI- screen all children between ages 9-11 and
again between ages 17-21 with earlier screening in high risk children
• Recommendations have generated controversy- long term effects, no hard outcome studies, anxiety, missed diagnosis
• Australia- Universal Screening not recommended, screen those with family history or as part of cascade testing
• UK, Netherlands, Norway- Children screened as part of cascade testing, not universally .
Curr Opin Lipidol 2012, 23:282–289
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Summary
• Heterozygous FH is a common disorder associated with a significantly increased risk of CVD
• Observational data suggests those treated with statins have reduce risk to unaffected levels
• Disease is underdiagnosed • Screening promotes treatment• Screening in US is based on clinical criteria with no
current recommendations for routine genetic testing• Role for genetic testing varies internationally, and may
increase with reductions in cost