Familial Hypercholesterolemia: Background Information

1
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

• 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. 20042549-68.
2. Mahley RW, et al. In Kronenberg Williams
   Textbook of Endocrinology. 2008.
3. Rader DJ, et al. J Clin Invest.
   20031111795-1803.

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

1. Kumar Robbins and Cotran. Pathologic Basis of
   Disease, 2009.
2. Rader DJ et al. J Clin Invest. 20031111795-1803

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 1200 births however, the genetic cause is
unknown. 2Sickle cell disease varies greatly by
ethnicity.

1. Genetic Alliance UK. Available at
   http//www.geneticalliance.org.uk/education3.htm.
2. Streetly A, et al. J Clin Path. 201063626-629.

8
Prevalence Is Much Higher in Specific
Sub-populations or Founder Groups
North America and Europe HeFH 1500 HoFH
lt1106
Higher incidence of HoFH Québec, Tunisia, South
Africa, Lebanon
Naoumova RP, et al. Curr Opin Lipidol.
200415413-422.
9
In Founder Groups, FH Prevalence Can Be 8x
Greater vs. General Population
Comparison of FH Prevalence Rates Across
Populations
167
1100 to 172
1165
1170
1270
1500
HeFH (US Europe)
Austin MA, et al. Am J Epidemiol.
2004160407420.
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


P lt0.01 vs general population.





Scientific Steering Committee. Atherosclerosis.
1999142105-112.
11
Despite the Importance of Early Detection, FH Is
Under-diagnosed (US)

• The WHO estimated in 1999 that lt10 of US
  patients with FH were diagnosed

Percentage of FH patients diagnosed
Percentage of patients
lt
lt
World Health Organization Human Genetics Program.
http//whqlibdoc.who.int/hq/1999/WHO_HGN_FH_CONS_9
9.2.pdf.
12
(No Transcript)
13
MI Rates in FH patients vs. Non-Statin Rx and
Normals
Versmissen J, et al. BMJ. 2008337a2423.
14
Reduction in Mortality in Subjects With
HomozygousFamilial Hypercholesterolemia
Associated With Advances in Lipid-Lowering Therapy
Circulation. 20111242202-2207
15
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 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 lt20 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. 20031681-14.
2. As summarized in Civiera F, et al. Circulation.
   200417355-68.

16
MEDPED criteria for the diagnosis of familial
hypercholesterolemia. Total and LDL cholesterol
(mmol/l)band mg/dl criteria for diagnosing
probable heterozygous familial hypercholesterolemi
a
Williams RR, Hunt SC, Schumacher C, et al. Am J
Cardiol 1993 72171176.
Curr Opin Lipidol 2012, 23282289
17
Simon Broome Criteria
Curr Opin Lipidol 2012, 23282289
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, 23282289
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, 23282289
van der Graaf A, Avis HJ, Kusters DM, et al.
Circulation 2011 12311671173.
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 39634639.
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 5133140.
21
National Collaborating Centre for Primary Care
(UK). (2008). NICE clinical guideline 71
Identification and management of familial
hypercholesterolaemia, London
22
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.
2001357165168.
23
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 doi10.1371/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 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, 23282289
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