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Familial Hypercholesterolemia: Background Information

Familial Hypercholesterolemia: Background Information . Clinical Assistant Professor of Medicine NYU School of Medicine NYU Langone Center for Cardiovascular Disease Prevention Director, Bellevue Hospital Lipid Clinic, New York,NY. James A. Underberg, MD, MS, FACPM, FACP, FASH, FNLA.

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Familial Hypercholesterolemia: Background Information

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  1. Familial Hypercholesterolemia: Background Information Clinical Assistant Professor of Medicine NYU School of Medicine NYU Langone Center for Cardiovascular Disease Prevention Director, Bellevue Hospital Lipid Clinic, New York,NY James A. Underberg, MD, MS, FACPM, FACP, FASH, FNLA Specialist

  2. 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

  3. 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 • Marais AD. Clin Biochem Rev. 2004;25:49-68. • Mahley RW, et al. In: Kronenberg: Williams Textbook of Endocrinology. 2008. • Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.

  4. 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

  5. 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

  6. The Phenotype of FH May Reflect LDL-R, Apo B, or PCSK9 Mutations • 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 Extracellular Fluid Apo B (site where receptor binds to LDL particle) LDL Particle: Cell membrane PCSK9 Cytosol LDL receptor • Kumar: Robbins and Cotran. Pathologic Basis of Disease, 2009. • Rader DJ et al. J Clin Invest. 2003;111:1795-1803 Image reproduced from: http://www.dls.ym.edu.tw/ol_biology2/ultranet/Endocytosis.html.

  7. FH Is Not a Rare Genetic Disease: Prevalence is 2x Other Inherited Conditions Frequency per 1,000 Births of Common Genetic Disorders1 2.0 2 Neuro-fibromatosis FH 1Familial combined hyperlipidemia has a frequency of 1:200 births; however, the genetic cause is unknown. 2Sickle cell disease varies greatly by ethnicity. • Genetic Alliance UK. Available at http://www.geneticalliance.org.uk/education3.htm. • Streetly A, et al. J Clin Path. 2010;63:626-629.

  8. 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.

  9. In Founder Groups, FH Prevalence Can Be 8x Greater vs. General Population Comparison of FH Prevalence Rates Across Populations 1:67 1:100 to 1:72 1:165 1:170 1:270 1:500 HeFH (US & Europe) Austin MA, et al. Am J Epidemiol. 2004;160:407–420.

  10. Patients With FH Are at Very High CVD Risk Before Age 40, Relative to the General Population Risk of CHD in FH patients / risk of CHD in general population Women (n = 580) Men (n = 605) * * * P <0.01 vs general population. * * * * * Scientific Steering Committee. Atherosclerosis. 1999;142:105-112.

  11. Despite the Importance of Early Detection, FH Is Under-diagnosed (US) Percentage of FH patients diagnosed Percentage of patients < < 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.

  12. MI Rates in FH patients vs. Non-Statin Rx and Normals Versmissen J, et al. BMJ. 2008;337:a2423.

  13. Reduction in Mortality in Subjects With HomozygousFamilial Hypercholesterolemia Associated With Advances in Lipid-Lowering Therapy Circulation. 2011;124:2202-2207

  14. FH “Scoring Methods” for Clinical Diagnosis Require LDL Levels and Family History Comparison of FH Clinical Diagnostic Criteria by Method • As summarized in: Marks D, et al. Atherosclerosis. 2003;168:1-14. • As summarized in: Civiera F, et al. Circulation. 2004;173:55-68.

  15. MEDPED criteria for the diagnosis of familial hypercholesterolemia. Total and LDL cholesterol (mmol/l)band {mg/dl} criteria for diagnosing probable heterozygous familial hypercholesterolemia Williams RR, Hunt SC, Schumacher C, et al. Am J Cardiol 1993; 72:171–176. Curr Opin Lipidol 2012, 23:282–289

  16. Simon Broome Criteria Curr Opin Lipidol 2012, 23:282–289

  17. Dutch lipid clinic network criteria for familial hypercholesterolemia World Health Organization. Familial hypercholesterolaemia. Report of a second WHO consultation. Geneva: World Health Organization; 1999. Curr Opin Lipidol 2012, 23:282–289

  18. 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, 23:282–289 van der Graaf A, Avis HJ, Kusters DM, et al. Circulation 2011; 123:1167–1173.

  19. 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. Aarden E, Van Hoyweghen I, Horstman K. Scand J Public Health 2011; 39:634–639. DeMott K, Nherera L, Shaw EJ, et al. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners; 2008. Goldberg AC, Hopkins PN, Toth PP, et al. J Clin Lipidol 2011; 5:133–140.

  20. National Collaborating Centre for Primary Care (UK). (2008). NICE clinical guideline 71: Identification and management of familial hypercholesterolaemia, London

  21. Family Screening Has Dramatically Increased Treatment Rates in the Netherlands Effects of Family-Based Screening on Treatment Rates in People with FH N = 5,442 37% identified as HeFH (based on LDL-R mutations) Umans-Eckenhausen MAW, et al. Lancet. 2001;357:165–168.

  22. Role of Genetic Typing in FH Highlights from this discussion include the role of genetic typing for diagnosis Understanding disease mechanism Potential guidance in treatment algorithms Journal of Clinical Lipidology, Vol 6, No 3, June 2012

  23. 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.”

  24. CASCADE SCREENING “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

  25. 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

  26. 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

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