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

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

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.

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

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

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:

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

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.

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)

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

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

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f pati

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Percentage of FH patients diagnosed

MI Rates in FH patients vs. Non-Statin Rx and Normals

Versmissen J, et al. BMJ. 2008;337:a2423.

Reduction in Mortality in Subjects With HomozygousFamilial Hypercholesterolemia Associated With Advances in Lipid-

Lowering Therapy

Circulation. 2011;124:2202-2207

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

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.

Simon Broome Criteria

Curr Opin Lipidol 2012, 23:282–289

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.

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.

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.

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

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)

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

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.”

“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

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

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