Transcript APOB - FH Foundation

Familial
Hypercholesterolemia
KEY POINTS

FH is an autosomal dominant genetic condition that leads to severe elevations in
cholesterol levels.
◦ Average LDL is 220mg/dl in HeFH and > 500mg/dl in HoFH

Lifetime burden of high cholesterol leads to huge increased risk of cardiovascular disease.
◦ 20 fold increased risk of premature cardiovascular disease (CVD)

FH is among the most common inherited conditions:
◦ Prevalence of heterozygous FH (HeFH) is 1:300-1:500.
◦ Homozygous FH is rare at 1:1,000,000 but has terrible consequences
◦ FH affects all race/ethnic groups

FH can be diagnosed based on a combination of lipid levels, family history, physical exam
findings and genetic testing.

FH is massively underdiagnosed and undertreated.
◦ There are > 600,000 people in the US with FH but only 10% have been diagnosed.

FH is treatable
◦ With statin-based therapy, risk of CVD can be greatly reduced

Because of the genetic nature of the disease, once one person in a family is diagnosed with
FH, it is mandatory to screen the rest of the family members (so called “cascade
screening”)
OVERVIEW
Familial Hypercholesterolemia
Overview of FH
1.
2.
3.
4.

FH is almost always inherited as an autosomal dominant disorder with a
very rare autosomal recessive form1,2

Low-density lipoprotein cholesterol (LDL-C) generally exceed the 95th
percentile during childhood in patients with FH2,3

LDL-C concentrations are generally 2- to 3 fold higher in people with HeFH
and 3- to 6-fold higher than normal in HoFH.4

Patients with FH have heightened risk of CVD due to life-long exposure to
elevated cholesterol 5,6

If left untreated, individuals with HoFH often develop symptomatic CVD before
age 25. Those with untreated HeFH often experience the same by age 55.1

A small fraction of treated FH patients have cardiovascular disease (CVD) and
persistently elevated LDL-C levels >200 mg/dL (5.17 mmol/L) or have no CVD
but persistently elevated LDL-C levels >300 mg/dL (7.75 mmol/L) despite
maximally tolerated lipid-lowering therapy. These FH patients are referred to
as severe FH and are currently eligible for LDL apheresis in the United States.
Marais AD. Clin Biochem Rev. 2004;25(1):49-68.
Mahley RW, et al. In: Kronenberg: Williams Textbook of Endocrinology; 2008.
Graaf et al . Circulation. 2011;123:1167-1173.).
Vella A, et al. Mayo Clin Proc. 2001;76(10):1039-1046.
5.
6.
7.
Goldberg AC, et al. J Clin Lipidol. 2011:5:S1-S8.
Rader DJ, et al. J Clin Invest. 2003;111(12):1795-1803.
Thompsen J, Thompson PD. Atherosclerosis. 2006;189:31-38.
Characteristics of HoFH, HeFH, and Severe FH1
HoFH
HeFH
Severe FH1
Untreated LDL-C (mg/dL)
Generally >465 mg/dL2
Average >220 mg/dL
N/A
Treated LDL-C
>300 mg/dL after max
tolerated drug therapy3
Mean 135 +/- 38 mg/dL
after treatment with high
dose statins
>200 mg/dL with CVD
after max drug therapy
or >300 mg/dL after max
drug therapy1
Tendon xanthomas
Xanthelasma
Tuberous xanthomas
Planar xanthomas
Tendon xanthomas
Xanthelasma
Tendon xanthomas
Xanthelasma
Possible before age 20
Common after age 40
Common after age 40
Within 2nd decade
Within 4th-5th decade
Within 4th-5th
decade or earlier
Clinical characteristic
Cutaneous features
Corneal arcus
Symptomatic
Atherosclerosis
Table adapted from Vella A, et al. Mayo Clin Proc. 2001;76:1039-1046.
1.
2.
3.
Thompsen J, Thompson PD. Atherosclerosis. 2006;189:31-38.
Raal FJ, et al. Atherosclerosis. 2000;150(2):421-428.
Ito MK, et al. J Clin Lipidol. 5(3):S38-S45.
FH is due to impaired LDL clearance and
increased secretion of ApoB particles
Atherosclerosis and
tissue damage
Increased plasma
LDL
Impaired LDLRmediated clearance
Increased LDL uptake by
non-LDLR-mediated pathways
Decreased
degradation of ApoB
and increased
production and
secretion of
ApoB-containing
lipoproteins
into the circulation
Figure adapted from data and concepts in adjacent references.
1.
2.
3.
4.
5.
6.
Barrett PH, Watts GF. Atheroscler Suppl. 2002;2(3):1-4.
Sniderman AD, et al. Clin Sci (Lond). 2009;118(5):333-339.
Fisher WR, et al. Arterioscler Thromb. 1994;14(4):501-510.
Cummings MH, et al. Atherosclerosis. 1995;113(1):79-89.
Tremblay AJ, et al. J Lipid Res. 2004;45(5):866-872.
Twisk J, et al. J Clin. Invest. 2000;105(4):521-532.
GENETIC BASIS
Familial Hypercholesterolemia
FH is almost always autosomal
dominant




1.
2.
3.
4.
Most common FH-causing
mutations are in the LDL receptor
gene (LDLR). Less common
defects include mutations in APOB
or PCSK9 genes1
Heterozygotes inherit a single
abnormal gene from one parent,
Given the dominant mode of
inheritance, these individuals
manifest the disorder.2
Heterozygotes have approximately
2- to 3-fold higher serum LDLcholesterol levels than normal2
Homozygotes inherit an abnormal
gene from both parents. They
typically have an LDL- cholesterol
level 3- to 6-fold higher than
normal2
Marais AD. Clin Biochem Rev. 2004;25(1):49-68.
Vella A, et al. Mayo Clin Proc. 2001;76(10):1039-1046.
Pisciotta L, et al. Atherosclerosis. 2006;186(2):433-440.
Tai ES, et al. Clin Chem. 2001;47(3):438-443.
Autosomal Dominant
LDLR, ApoB, and PCSK9 mutations
Affected or
predisposed
mother with
autosomal
dominant
faulty gene
Eggs
dd
Dd
d
Affected or
predisposed
father with
autosomal
dominant
faulty genes
Dd
D
d
Dd
Dd
D
Sperm
DD
Unaffected
Affected
Severely affected
1 out of 4
chances 25%
2 out of 4
chances 50%
1 out of 4
chances 25%
A small spectrum of affected heterozygotes may have unusually severe
phenotypes; unusually severe phenotypes may also be seen in compound
heterozygotes that have mutations in 2 different genes (1 from each parent
or both from the same parent)3,4
Image adapted from www.genetics.edu.au/pdf/factsheets/fs09.pdf.
FH is very rarely autosomal
recessive




Mutations in the LDLRAP1 gene
result in a very rare autosomal
recessive form of homozygous FH
called autosomal recessive
hypercholesterolemia (ARH)1
The clinical phenotype of
homozygous ARH is similar to that of
classic homozygous familial
hypercholesterolemia but it is
somewhat milder in terms of serum
total cholesterol and LDL-C levels1,2
Because it is a recessive disorder,
most ARH patients are homozygous
for the same allele inherited from
consanguineous or related parents1
Because ARH is an autosomal
recessive disorder, the heterozygotes
are unaffected1
Autosomal Recessive
ARH/LDLRAP1 mutations
Unaffected
genetic
carrier
mother
Eggs
RR
R
Unaffected
genetic
carrier
father
Rr
Rr
r
r
R
Rr
Rr
Sperm
rr
Non-carrier
(unaffected)
Genetic
carriers
(unaffected)
Severely affected
1 out of 4
chances 25%
2 out of 4
chances 50%
1 out of 4
chances 25%
Image adapted from www.genetics.edu.au/pdf/factsheets/fs09.pdf.
1.
2.
Soutar AK, et al. Arterioscler Thromb Vasc Biol. 2003;23(11):1963-1970.
Pisciotta L, et al. Atherosclerosis. 2006;188(2):398-405.
FH can be caused by mutations in 4
known genes
FH is typically caused by mutations in LDLR, ApoB, PCSK9,
LDLRAP1 or other as yet other unidentified genes1
Apo B
acts as ligand, binding LDL
particle to receptor
LDL Particle
Circulation
Liver cell
LDL Receptor
on hepatocyte, binds to Apo B on LDL
particle, inducing endocytosis of LDL
PCSK9 Enzyme
degrades LDL receptors
Image reproduced from http://www.dls.ym.edu.tw/ol_biology2/ultranet/Endocytosis.html.
1.
De Castro-Oros I, et al. Appl Clin Genet. 2010;3:53-64.
LDLRAP1 (ARH)
mediates internalization via
clathrin coated pits
FH-related mutations
Gene
Defect
Genotype
Plasma
LDL-C level
Prevalence
Heterozygote
+++
1:500
Metabolic defect
↓ LDL clearance (1°)4
60%-80%1
LDLR
Phenotype of FH
Frequency1
↑ LDL production (2o)4
Homozygote
+++++
1:1,000,000
↑ ApoB production (2o)2
Heterozygote
++
1:1000
↓ LDL clearance (1°)4
↑ LDL production (2o)5
1%-5%1
ApoB
Homozygote
+++
1:4,000,000
1:4,000,000
↑ ApoB production (2o)5
Heterozygote
+++
<1:2,500
↓ LDL clearance (1°)6
↑ LDL production (2o)6
Homozygote
++++2
N/A
LDLRAP1
Homozygote
++++3
Very rare
Very rare
↓ LDL clearance (1°)3
Unknown
N/A
+++
N/A
20%–40%
Unknown
PCSK9
0%-3%1
↑ ApoB production (2o)6
Table adapted from Rader DJ, et al. J Clin Invest. 2003;111:1795-1803 and De Castro-Oros I, et al. Appl Clin Genet. 2010;3:53-64.
1.
2.
3.
De Castro-Oros I, et al. Appl Clin Genet. 2010;3:53-64.
Noguchi T, et al. Atherosclerosis. 2010;210(1):166-172.
Soutar AK, et al. Arterioscler Thromb Vasc Biol. 2003;23(11):1963-1970.
4.
5.
6.
Rader DJ, et al. J Clin Invest. 2003;111(12):1795-1803.
Zulewski H, et al. J Lipid Res. 1998;39(2):380-387.
Ouguerram K, et al. Arterioscler Thromb Vasc Biol. 2004;24(8):1448-1453.
PATHOPHYSIOLOGY
Familial Hypercholesterolemia
The atherosclerotic burden of FH reflects
the lifelong accumulation of LDL and all
ApoB-containing lipoproteins
ApoB 100
ApoBcontaining
lipoproteins:
Non-HDL-C:
Apo(a)
VLDL
IDL
Cholesterol
concentration
measures:
Adapted from Robinson JG* J Am Coll Cardiol. 2010;55(1):42-44.
LDL
LDL-C
Non-HDL-C
Lp(a)
plasma cholesterol
concentration
of ApoB-containing
particles
LDL accumulates to cause CHD early in
life in FH
Age Patients Meet CHD Threshold
HoFH
HeFH
Cumulative LDL-C
(g/dL-years)
10
Normal
Female
Threshold
for CHD
Male Hypertension
Diabetes
Smoking
5
0
1
20
40
Age (years)

Threshold for CHD reached by:
–
Age 15 y in HoFH patients
–
Age 40 y in HeFH patients
–
Age >60 y in healthy individuals
Adapted from Horton JD, et al. J Lipid Res. 2009;50(Suppl):S172-S177.
60
80
Arterial Intima-media Thickness in
children with FH
Significant differences in intima-media thickness (IMT) were noted
by age 12 in children with FH versus unaffected siblings (P =
0.002)
0.08
FH – control IMT (mm)

0.06
Child with
FH
0.04
0.02
Significant difference in IMT
Unaffected
sibling
0
–0.02
–0.04
8
10
12
14
Age (y)
Adapted from Wiegman A, et al. Lancet. 2004;363(9406):369-370.
16
18
Carotid IMT in FH versus non-FH
patients
1.6
1.4
FH patients: ~45 y
Healthy non-FH: ~80 y
cIMT (mm)
1.2
1.0
FH individuals
0.8
Linear (pooled FH
individuals)
Non-FH individuals
Linear (pooled non-FH
individuals)
0.6
0.4
10
20
30
40
50
Age (y)
Adapted from De Groot E, et al. Circulation. 2004;109[ suppl III]:III33–III38.
60
70
80
LDL-C concentrations and physical
signs in untreated FH patients
Cumulative Prevalence of Physical
Signs in Adult FH Patients3
LDL-C Distribution in Untreated
Patients With Definite FH3
Cumulative prevalence, %
Tendon xanthomas
Mean = 7.22 mmol
(279.2 mg/dL)
Relative frequency
Median = 6.95 mmol/L
(268.76 mg/dL)
100
75
50
25
0
15
LDL-C (mmol/L) in untreated patients
1.
2.
3.
Marais AD. Clin Biochem Rev. 2004;25(1):49-68.
Raal FJ, et al. Atherosclerosis. 2000;150(2):421-428.
Blom DJ, et al. S Afr Fam Pract. 2011;53(1):11-18.
Xanthelasma
Arcus cornealis
25
35
45
55
Age (y)
65
75
85
EPIDEMIOLOGY
Familial Hypercholesterolemia
FH is a common inherited disorder

The prevalence of HeFH is ~1:5001-3

The prevalence of HoFH is ~1:1,000,0002,3
Frequency per 1000 births
2.5
2.0
2.0 per 1000
1.5
1.0
1.0
0.8
0.5
0.5
0.0
FH
Dominant
otosclerosis
Adult
PCKD
Sickle cell
disease
0.5
0.5
Multiple
Huntington's Fragile X
exostoses
disease
syndrome
PCKD, polycystic kidney disease.
Figure adapted from Genetic Alliance UK. Available at http://www.geneticalliance.org.uk/education3.htm.
1.
2.
3.
0.5
Citkowitz E. Familial Hypercholesterolemia. http://emedicine.medscape.com/article/121298-overview#a0199.
Vella A, et al. Mayo Clin Proc. 2001;76(10):1039-1046.
Austin MA, et al. Am J Epidemiol. 2004;160(5):407-420.
0.4
0.4
Neurofibromatosis
Cystic
fibrosis
0.3
Duchenne
muscular
dystrophy
In some populations FH is even more
common
Founder Populations
Percentage of total population
3.0
2.5
2.0
1:67
1.5
1:72 to
1:100
1.0
1:85
1:165
Christian
Lebanese
Tunisia
1:270
0.5
1:500
0.0
General
population
French
Canadian
Adapted from Austin MA, et al. Am J Epidemiol. 2004;160(5):407-420.
South Africa - South Africa Afrikaners
Ashkenazi
Jews
CLINICAL PRESENTATION
Familial Hypercholesterolemia
Heterozygous FH
20-fold increased risk of CVD
 If untreated:
◦ Men have 50% risk of CVD by age 50
◦ Women have 30% risk of CVD by age 60
 Many HeFH patients present with
established CVD (angina, MI)

Physical exam findings in FH
A.
B.
C.
D.
E.
F.
Xanthelasma
Corneal arcusa
Achilles tendon xanthomas
Tendon xanthomasb,1-3
Tuberous xanthomasc
Planar xanthomasc
A
B
C
D
A Common
in older individuals (even non-FH); definitive of FH in younger
individuals.
B 30%-50% of the HeFH population have tendon xanthomas.
C Seen mostly in HoFH, and not as often in HeFH
1.
2.
3.
Ferrières J, et al. Circulation. 1995;92(3):290-295.
Bertolini S, et al. Arterioscler Thromb Vasc Biol. 2000;20(9):E41-E52.
Descamps OS, et al. Atherosclerosis. 2001;157(2):514-518.
E
Figure adapted from Mahley RW, et al. In: Kronenberg HM. Williams Textbook of
Endocrinology. 11th ed. Philadelphia: Saunders; 2008.
F
Clinical presentation of
HoFH





Cutaneous xanthomas at birth
or by early childhood1
Planar xanthomas
(on hands, elbows, buttocks,
or knees), which are
diagnostic for the homozygous
state1
Tuberous xanthomas
(on hands, elbows, or knees)1
Tendon xanthomas (especially
on extensor tendons of hands
or Achilles tendon)1
Valve affection murmur of
aortic stenosis may be
heard1,2
A
Six-year-old girl with HoFH. Bumps on skin are deposits of cholesterol
derived from LDL.
B
C
• Image A reproduced from Brown/Goldstein Lab. Department of Molecular Genetics at UT
Southwestern. http://www4.utsouthwestern.edu/moleculargenetics/pages/gold/past.html.
• Image B reproduced from Li SG, et al. N Engl J Med. 2009;360(18):1885.
• Image C reproduced from Thappa DM, Karthikeyan K. Indian Pediatr. 2003;40(6):574-575.
1.
2.
Citkowitz E. Familial Hypercholesterolemia. http://emedicine.medscape.com/article/121298-overview#a0199.
Allen JM, et al. Br Heart J. 1980;44(4):361-368.
HoFH clinical course
Severe vascular disease at an early age.
 Numerous case reports of CABG or death
before age 10.
◦ Severe aortic stenosis common
 Untreated, usually results in death before
age 30.
 Almost all HoFH patients require LDL
apheresis but even with maximal medical
therapy there is disease progression.

DIAGNOSIS AND
SCREENING
Familial Hypercholesterolemia
LDL-C categories often used for FH
diagnosis
The diagnosis of FH is largely based on
◦ Extreme hypercholesterolemia early in life (LDL-C ≥190 mg/dL [adults] or ≥160
mg/dL [children or adolescents])1
◦ Clinical evidence of premature CVD and/or family history of hyperlipidemia2
 According to National Lipid Association (NLA) criteria, FH should be suspected in
the following cases1
◦ Children, adolescents, young adults (<20 y) with LDL-C ≥160 mg/dL or nonhigh-density lipoprotein cholesterol (HDL-C) ≥190 mg/dL
◦ Adults (≥20 y) with LDL-C ≥190 mg/dL or non-HDL-C ≥220 mg/dL
 Formal diagnosis through MEDPED, Simon-Broome or Dutch criteria

LDL-C Categories Often Used for FH Diagnosis3
Minimum LDL-C, mg/dL
Category
1.
2.
3.
Description
Age <20 y
Age 20-29 y
Age 30+ y
1
General population 95th percentile
130
160
190
2
80% have FH in first-degree relativesa
150
170
200
3
80% have FH in general population
190
220
260
4
99% have FH in general population
220
240
280
5
99.9% have FH in general population
240
260
300
Goldberg AC, et al. J Clin Lipidol. 2011:5(3 Suppl):S1-S8.
Rader DJ, et al. J Clin Invest. 2003;111(12):1795-1803.
Hopkins PN, et al. J Clin Lipidol. 2011;5(Suppl 3):S9-S17.
aThis
category is relevant for diagnosis of FH patients who are first-degree relatives of a known
FH case. At the LDL-C level shown, ~ 80% of first-degree relatives can be expected to have FH.
High cholesterol screening
recommendations from the NLA



Universal screening for serum cholesterol levels is recommended
◦ Cholesterol screening should be considered starting at age 2 for
children with a family history of premature CVD or high
cholesterol.
◦ All children should be screened between the ages of 9 – 11
regardless of family history.
For all children with an LDL-C ≥160 mg/dL after adequate lifestyle
interventions lipid altering medications are recommended.
“Cascade screening” of all first-degree relatives of diagnosed FH
patients should be performed; newly identified FH cases may
reveal additional relatives who should be screened
Goldberg AC, et al. J Clin Lipidol. 2011:5(3 Suppl):S1-S8.
Genetic testing for FH




In the US, the diagnosis of FH is usually made on clinical
grounds.
However, genetic testing is the gold-standard for the
diagnosis of FH and is widely used in many countries.
◦ Genetic testing can be used in cases where the diagnosis
is unclear.
Testing generally involves sequencing 3 genes (LDLR, APOB
and PCSK9).
◦ The yield on genetic testing is ~85% in “definite” FH cases
and ~50% in “possible” FH.
As genetic testing becomes cheaper it is probable that this
method will be used more widely.
◦ May be particularly useful for cascade screening.
The CDC has classified genetic testing for FH
as a “Tier 1” application (Best evidence to
support use)
CURRENT TREATMENT
Familial Hypercholesterolemia
Management




Diet/lifestyle changes important
◦ Reduce saturated fat
◦ High soluble fiber: 10-20g/day
◦ Dietician referral
Statins are the mainstay of therapy
◦ Many will require 2 or more drugs
◦ Goal to reduce LDL ≥ 50% (or LDL < 100 ideal)
Treat other risk factors (HTN, smoking)
DO NOT USE STANDARD RISK ASSESSMENT TOOLS
TO ESTIMATE RISK
◦ Framingham score is not valid in FH patients
Goals of therapy

FH patients are considered “high risk”
based on NCEP, AHA/ACC guidelines
◦ Rule of thumb to try to cut LDL by 50%
◦ Ultimate goal LDL < 100
 Many would try to get LDL < 70
Unlike “garden variety” HLD, non-statin
agents are standard of care.
 With proper therapy can reduce risk of
CHD by 80%.

NCEP ATP Guidelines, Circ 2002
Current therapeutic options for FH:
statins

Statins competitively inhibit HMG CoA reductase,
reducing endogenous cholesterol synthesis
LDL
ApoB
Lipid corecholesteryl esters
LDL receptor
Reduced cholesterol
synthesis
Statin
Fatty Acids
Acetyl-CoA
HMG CoA
=
Cholesterol
ACAT2
Cholesterol Esters
MTP
ApoB-100
Triglycerides
Increased receptor
expression
Figure adapted from Stancu C, Sima A. J Cell Mol Med. 2001;5(4):378-387.
VLDL
ApoB100
VLDL LDL LDL
ApoBApoB100
100
Increased ApoB-LDL
uptake
Effect of statins and lipid-lowering
therapy in FH
Statins have demonstrated significant
MI-free survival benefits in HeFH patients

Figure 1
Figure 2
A.
80
Survival probability
Cumulative event-free survival (%)
100
60
40
Statin treatment HeFH
1.0
0.6
0.4
0.2
0
5.0
7.5
10.0
10
20
30
40
50
60
70
Age (y)
0
2.5
Yes
No
0.8
No statin treatment –general population
0
Benefit From Lipid Therapy (Endpoint: Death)
0
No statin treatment HeFH
20
Delayed CV events and prolonged survival
in HoFH patients have altered the disease
spectrum of HoFH from a fatal disease in
childhood to that seen in untreated HeFH

12.5
B.
Survival probability
Follow-up (y)
1.0
Benefit From Lipid Therapy (Endpoint: MACE)
Yes
No
0.8
0.6
0.4
0.2
0
Figure 1 adapted from Versmissen J, et al. BMJ. 2008;337:a2423.
Figure 2 adapted from Raal FJ, et al. Circulation. 2011;124(20):2202-2207.
0
10
20
30
Age (y)
40
50
60
Mechanism of action of
current therapies

In FH patients, statins are highly effective but the LDL-cholesterol responsiveness to statins is influenced by the
nature of the LDL receptor gene mutation and some LDLR mutations tend to render statins less effective 4,5

Because most current therapies directly increase LDL-C clearance via the LDLR or decrease LDL-C via other
clearance mechanisms that secondarily up-regulates the LDLR, their effectiveness in FH patients can be limited

Current therapies with the exception of niacin, do not significantly impact LDL/ApoB production
Class
Primary and secondary
mechanism of action
Statins
LDL-lowering response
HeFH
HoFH
↑ LDLR activity (1O)
>35%1
Up to 28%2
Bile acid sequestrants
↓ Bile acid re-absorption (1O), ↑ LDLR activity (2O)
15%
<10%
Cholesterol absorption
inhibitors
↓ Cholesterol absorption (1O), ↑ LDLR activity (2O)
15%
<10%
Stanol esters
↓ Cholesterol absorption (1O), ↑ LDLR activity (2O)
10%
<10%
Nicotinic acid
↓ VLDL synthesis (1O)
20%
<10%
LDL apheresis
Removes LDL
20-40% (up to 76% acutely)6,7
Table adapted from Radar DJ, et al. J Clin Invest. 2003;111(12):1796-1803.
1.
2.
3.
4.
Kastelein JJ, et al. N Engl J Med. 2008;358(14);1431-1443.
Raal FJ, et al. Atherosclerosis. 2000;150(2):421-428.
Konrad RJ, et al. Lipids Health Dis. 2011;10:38.
Vohl et al, Atherosclerosis 160 (2002) 361–368
5.
6.
7.
Chaves et al. lin Endocrinol Metab 86: 4926–4932,2001
Gordon BR, et al. Am J of Card. 1998;81(4):407-411.
Ito MK, et al. J Clin Lipidol. 2011;5(3 Suppl):S38-S45.
For the worst affected FH patients LDL
apheresis is added
Cholesterol Rebound After Receiving LDL Apheresis
LDL-C reductions with
apheresis:
LDL-C (mg/dL)
• Acute: Up to 76%1
• Time averaged: 20-40%2
1
2
3
4
5
Treatments
Reproduced from Thompson GR. Curr Opin Lipidol. 2010.
1.
2.
Gordon BR, et al. Am J of Card. 1998;81(4):407-411.
Ito MK, et al. J Clin Lipidol. 2011;5(3 Suppl):S38-S45.
6
7
8
9
10
Treatment algorithm for the
worst affected FH patients



All HeFH patients require
lipid-lowering drugs to
reach target LDL-C levels1,2
Adult Treatment Panel
(ATP) III guidelines indicate
that most FH patients will
require combination
therapy1,2
LDL apheresis and/or liver
transplant is only required
in rare cases1,2
HoFH and severe
FH patients
Lifestyle changes
Proper diet, reduction in body weight if overweight,
smoking cessation, and exercise
Statin treatment
Combination therapy
LDL apheresis or
liver transplant
Schematic adapted from adjacent references
1 - NIH. NCEP, Final Report. Pub No. 02-5215. September 2002..
2 – Ito et al. Management of Familial Hypercholesterolemias in adult patients: Recommendations from the National Lipid Association Expert Panel on Familial
Hypercholesterolemia Journal of Clinical Lipidology (2011) 5, S38–S45
ADDITIONAL RISK
FACTORS TO CONSIDER
Familial Hypercholesterolemia
Additional CVD risk factors to consider
in HeFH






−
Lipoprotein(a) [Lp(a)]
−
≥50 mg/dL1,3,4
Tendon xanthomas1-3
Men: ≥30 y1
Women: ≥45 y or postmenopausal1
Cigarette smoking: active smokers1
Family history of premature CVD1
Independent CVD risk factors3,4
In FH, independent CVD risk factors could
potentially interact with lifelong high LDL-C
levels to compound risk5
◦ CVD in male first-degree relative <55 y
or in female first-degree relative <65 y
HDL-C <40 mg/dL (1.0 mmol/L)1
 Blood pressure >140/90 mmHg1
 Diabetes mellitus1

1.
2.
3.
Goldberg AC, et al. J Clin Lipidol. 2011:5(2 Suppl):S1-S8.
Neil HA, et al. Atherosclerosis. 2003;170(1):73-78.
Civeira F, et al. Arterioscler Thromb Vasc Biol. 2005;25(9):1960-1965.
4.
5.
Holmes DT, et al. Clin Chem. 2005;51(11):2067-2073.
Mbewu AD, et al. Arterioscler Thromb. 1991;11(4):940-946.
Risk factors in FH
independent of LDL-C

Tendon xanthomas
◦ Tendon xanthomas in FH are associated with CV risk independently of the
LDLR gene mutation1
◦ Approximately 30%-50% of heterozygous FH patients with genetic
diagnosis have tendon xanthomas2-4

Lipoprotein(a)
◦ Elevated serum Lp(a) concentrations may be regarded as a component of
the clinical syndrome of FH5
◦ In homozygous or heterozygous FH, mutations in the LDLR show clear
gene-dose effect on Lp(a) plasma levels6
◦ Lp(a) is an independent risk factor for CVD in heterozygous FH7
◦ Potential interactions between high plasma concentration of Lp(a) as seen
in FH and additional risk factors for CVD (such as elevated life long
accumulations of LDL-c as seen in FH) may also potentiate the very high
CVD risk of FH patients5
1.
2.
3.
4.
5.
6.
7.
Civeira F, et al. Arterioscler Thromb Vasc Biol. 2005;25(9):1960-1965.
Ferrières J, et al. Circulation. 1995;92(3):290-295.
Bertolini S, et al. Arterioscler Thromb Vasc Biol. 2000;20(9):E41-E52.
Descamps OS, et al. Atherosclerosis. 2001;157(2):514-518.
Mbewu AD, et al. Arterioscler Thromb. 1991;11(4):940-946.
Kraft HG, et al. Arterioscler Thromb Vasc Biol. 2000;20(2):522-528.
Holmes DT, et al. Clin Chem. 2005;51(11):2067-2073.
Lp(a): An independent and causal risk
factor

Lp(a) consists of an LDL-like particle and
the specific Apo(a), which is covalently
bound to the ApoB of the LDL-like particle1,3

Because Apo(a) is structurally homologous
to plasminogen, Lp(a)1,3
◦
Competitively inhibits plasmin
generation – antifibrinolytic1,3
◦
Can bind to plasmin and fibrinogen,
promoting atherosclerosis1,3
◦
Deposits oxidized phospholipids,
increasing inflammation leading to
atherosclerosis1,3
◦
Promotes plaque inflammation and
instability1,3

Lp(a) has a causal relationship to increased
CV risk2 and is recognized to predict
atherosclerosis, MI1

2011 NLA Expert Panel cited Lp(a) as an
independent driver of very high risk in FH4
Apo(a)
ApoB-100
LDL
particle
Lipoprotein(a)
1.
2.
3.
4.
Kiechl S, Willeit J, J Am Coll Cardiol. 2010;55(19):2168-2170.
Clarke R, et al. N Engl J Med. 2009;361(26):2518-2528.
Kathiresan S. N Engl J Med. 2009;361(26):2573-2574.
Goldberg AC, et al. J Clin Lipidol. 2011;5(3 Suppl):S1-S8.
Figure adapted from Brown WV, et al. J Clin Lipidol. 2010;4(4):240-247.
Lp(a) elevations more
frequent in FH
In FH, Lp(a) levels increased 3-fold vs controls
 Across Lp(a) LMW range, levels are higher in FH versus
controls

70
.
.
Low Molecular Weight
High Molecular Weight
Lp(a) (mg/dL)
60
Controls
50
FH
40
30
20
10
0
All
S1
S2
S2/S3
S2/S4
Apo(a) Isoforms
Utermann G, et al. Proc Natl Acad Sci U S A. 1989;86(11):4171-4174.
S3
S4
S3/S4
UNMET MEDICAL NEED
Familial Hypercholesterolemia
FH is an unmet medical
need

Huge healthcare burden
◦ Both in terms of morbidity and mortality
and health care expenditures
Hugely underdiagnosed
 Hugely undertreated
 Research efforts for FH funded poorly
considering prevalence of disease
 No national patient registry

The FH Foundation
Our mission is to raise awareness of
Familial Hypercholesterolemia (FH)
through education, advocacy, and
research.
Our goal is to save lives by increasing
the rate of early diagnosis and
encouraging proactive treatment.
For more information, please contact us:
[email protected]
www.TheFHFoundation.org
Facebook and Twitter: The FH Foundation
Summary: FH

FH is an inherited disorder that is characterized by high levels of LDL
from early childhood1,2

The diagnosis of FH is based primarily on
◦ Extreme hypercholesterolemia early in life (untreated LDL-C ≥190
mg/dL in early adulthood or ≥160 mg/dL in childhood or
adolescence)3
◦ Clinical evidence of premature CVD and/or family history of
hyperlipidemia4
1.
2.
3.

Patients with FH have a high risk of CVD related to elevated
LDL levels4,5

FH is primarily a problem of lipoprotein clearance and secondarily of
increased ApoB particle production6,7

FH is an autosomal dominant condition so once a family member with
FH is identified, ‘cascade’ screening in the rest of the family is
mandatory.
Marais AD. Clin Biochem Rev. 2004;25(1):49-68.
Mahley RW, et al. In: Kronenberg HM. Williams Textbook of Endocrinology.
11th ed. Philadelphia: Saunders; 2008.
Goldberg AC, et al. J Clin Lipidol. 2011;5(3 Suppl):S1-S8.
4.
5.
6.
7.
Rader DJ, et al. J Clin Invest. 2003;111(12):1795-1803.
Williams RR, et al. JAMA. 1986;255(2):219-224.
Barrett PH, Watts GF. Atheroscler Suppl. 2002;2(3):1-4.
Sniderman AD, et al. Clin Sci (Lond). 2009;118(5):333-339.
Summary: FH (cont.)





Statin based therapies have demonstrated significant MI free survival
benefits in HeFH patients1
Advances in lipid-lowering treatment, predominantly statin therapy, are
associated with delayed CV events and prolonged survival in HoFH
patients and have altered their disease spectrum of HoFH from a fatal
disease in childhood to that seen in untreated heterozygous FH2
Despite these advances in lipid-lowering therapy, all HoFH patients and
a significant proportion of heterozygous FH patients remain far from
desired LDL-C goals1,2
There is a need for additional ApoB and LDL lowering therapies
Emerging therapies include3
◦ ApoB inhibitors
◦ MTP inhibitors
◦ PCSK9 inhibitors
1.
2.
3.
Versmissen J, et al. BMJ. 2008;337:a2423.
Raal FJ, et al. Circulation. 2011;124(20):2202-2207.
Costet P, et al. Pharmacol Ther. 2010;126(3):263-278.