1. Familial Hypercholesterolemia: Background Information
FH Presentations
Familial Hypercholesterolemia: Background Information
James A. Underberg, MD, MS, FACPM, FACP, FASH, FNLA
Clinical Assistant Professor of Medicine NYU School of Medicine
NYU Langone Center for Cardiovascular Disease Prevention
Director, Bellevue Hospital Lipid Clinic, New York,NY
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
FH Presentations
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
Familial hypercholesterolemia (FH) can be defined as a heritable disorder, caused by mutations in the LDL-receptor gene that result in receptor absence or malfunction.1,2 Inheritance may be autosomal dominant or recessive. Over 900 mutations in the LDL-receptor gene have been identified as causing FH.3
The common consequence of the possible genetic mutations is a decreased clearance of LDL from the plasma, resulting in a clinically recognisable pattern of severe hypercholesterolemia, cholesterol deposition in the tendons and skin, and high risk of atherosclerosis, which manifests mainly as coronary artery disease (CAD).2
Marais/50/col 1/para 1
Mahley/19/para 1
Rader/1797/col 2/para 1
Marais AD. Clin Biochem Rev. 2004;25:49-68.
Mahley RW, et al. In: Kronenberg: Williams Textbook of Endocrinology
Rader DJ, et al. J Clin Invest. 2003;111:

4. Visible Signs of FH A- Xanthelasma B – Corneal arcus (Arcus senilis)
FH Presentations
Visible Signs of FH
A- Xanthelasma
B – Corneal arcus (Arcus senilis)
C - Achilles tendon xanthomas
D - Tendon xanthomas
E - Tuberous xanthomas
F - Palmar xanthomas
Maley/19/Figure 36-22
What about arcus cornealis? Also can we note that tendon xanthomas [in asterix] may not be visible but detected through physical exam?
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
FH Presentations
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
REDO this slide. Animate it! Mention that it is a “Gain of Function” mutation in PCSK9 that leads to FH.
>1000 mutations in the LDL receptor have been identified in FH patients and different mutations lead to variations in phenotype (LDL-C levels, risk of CAD). Other mutations that lead to increased LDL-C include those in the Apo B and PCSK9 genes. PCSK9 down-regulates LDLR.
PCSK9
Cytosol
LDL receptor
Kumar: Robbins and Cotran. Pathologic Basis of Disease, 2009.
Rader DJ et al. J Clin Invest. 2003;111:
Image reproduced from:

7. Frequency per 1,000 Births of Common Genetic Disorders1
FH Presentations
FH Is Not a Rare Genetic Disease: Prevalence is 2x Other Inherited Conditions
Frequency per 1,000 Births of
Common Genetic Disorders1
2.0
Mutations in Apo B and PCSK9 are less common that those in LDLR (1:2,500 and 1:1,000, respectively).2 2 FH
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.
Genetic Alliance UK. Available at
Streetly A, et al. J Clin Path. 2010;63:

8. FH Presentations
Prevalence Is Much Higher in Specific Sub-populations or “Founder Groups”
North America and Europe:
HeFH ~1: HoFH ~<1:106
In North America and Europe the prevalence of heterozygous FH is approximately 1:500, while the incidence of homozygous FH is very rare (<1:106). In certain areas, such as the Lebanon, South Africa, and Quebec, homozygous FH occurs at a higher frequency due to a founder gene effect.
Naoumova/414/col 1/para 2
Higher incidence of HoFH:
Québec, Tunisia, South Africa, Lebanon
Naoumova RP, et al. Curr Opin Lipidol. 2004;15:

9. Comparison of FH Prevalence Rates Across Populations
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
1:170
1:165
1:270
1:500
HeFH
(US & Europe)
Austin MA, et al. Am J Epidemiol. 2004;160:407–420.

10. Risk of CHD in FH patients / risk of CHD in general population
FH Presentations
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
Men (n = 605)
Women (n = 580) * *
* P <0.01 vs general population. *
In this study, a cohort of 1,185 patients with heterozygous FH aged years being treated at UK lipid clinics were prospectively followed from 1980 to Most patients (86%) were prescribed statin therapy. Observed mortality due to CHD in the FH cohort was expressed as relative risk compared with expected mortality in the general population of England and Wales.
Despite lipid-lowering treatment, in patients aged years, the risk of coronary mortality was elevated 125-fold in women and 48-fold in men. The relative risk compared with the general population decreased with age, but was still significantly elevated in older women.
Scientific Steering Committee/105/abstract
Scientific Steering Committee/108/Table 2 * * * *
Scientific Steering Committee. Atherosclerosis. 1999;142:

11. Despite the Importance of Early Detection, FH Is Under-diagnosed (US)
FH Presentations
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
Percentage of FH patients diagnosed
Percentage of patients
<
<
Data out of date!
World Health Organization Human Genetics Program.

13. MI Rates in FH patients vs. Non-Statin Rx and Normals
FH Presentations
MI Rates in FH patients vs. Non-Statin Rx and Normals
Kaplan-Meier curve estimates of cumulative myocardial
infarct-free survival among patients with familial
hypercholesterolaemia older than 55 years according to statin
treatment compared with a sample from the general
population (Rotterdam study). (P<0.001 for difference between
untreated patients and general population; P=0.07 for
difference between treated patients and general population)
Versmissen J, et al. BMJ. 2008;337:a2423.

14. Reduction in Mortality in Subjects With Homozygous Familial Hypercholesterolemia Associated With Advances in Lipid-Lowering Therapy
FH Presentations
Cox proportional hazards model with time-varying benefit
from statin therapy comparing treated and untreated personyears
for (A) survival and (B) first major adverse cardiovascular
event (MACE) in patients with homozygous familial hypercholesterolemia,
with year of birth fixed as mean year of birth.
Circulation. 2011;124:

15. FH Presentations
FH “Scoring Methods” for Clinical Diagnosis Require LDL Levels and Family History
Comparison of FH Clinical Diagnostic Criteria by Method
Simon Broome Register1
MEDPED2
Dutch Lipid Clinic Network1
Definite FH
TC or LDL levels
Tendon xanthoma in patient or relative
Probable FH
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
As summarized in: Marks D, et al. Atherosclerosis. 2003;168:1-14.
As summarized in: Civiera F, et al. Circulation. 2004;173:55-68.

16. MEDPED criteria for the diagnosis of familial hypercholesterolemia
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

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

18. 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

19. 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.

20. 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.

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

22. Effects of Family-Based Screening on Treatment Rates in People with FH
FH Presentations
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
5,442 relatives of 237 FH patients screened (DNA analysis and total cholesterol levels)
37% identified as HeFH (based on LDL-R mutations)
Family screening increased treatment rates from 39% to 93% in 1 year
18% would not have been diagnosed with FH using total cholesterol levels alone (false negatives)
18% would have been improperly diagnosed with FH using total cholesterol levels alone (false positives)
37% identified as HeFH (based on LDL-R mutations)
Umans-Eckenhausen MAW, et al. Lancet. 2001;357:165–168. 22

23. Role of Genetic Typing in FH
FH Presentations
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

24. 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.”

25. 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: /currents.RRN1238

26. 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 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

27. 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