Developed by Ms Shawna Morrison Dr Judith Allanson and Dr June Carroll Last updated October 2016 Disclaimer This presentation is for educational purposes only and should not be used as a substitute for clinical judgement GECKO aims to aid the practicing clinician by providing ID: 593863
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Slide1
Familial Hypercholesterolemia
Developed by
Ms
. Shawna
Morrison, Dr. Judith
Allanson
and Dr. June Carroll
Last updated
October 2016Slide2
Disclaimer
This presentation is for educational purposes only and should not be used as a substitute for clinical judgement. GEC-KO aims to aid the practicing clinician by providing informed opinions regarding genetic services that have been developed in a rigorous and evidence-based manner. Physicians must use their own clinical judgement in addition to published articles and the information presented herein. GEC-KO assumes no responsibility or liability resulting from the use of information contained herein. Slide3
Objectives
Following this session the learner will be able to:
Identify and appropriately refer individuals who may benefit from consultation with lipid specialist and/or genetic consultation
Discuss and address patient concerns regarding family history of familial hypercholesterolemia
Find high quality genomics educational resources appropriate for primary careSlide4
Common autosomal dominant disorder resulting in 20x increased risk of cardiovascular disease CVD) and death
Key features:
Pearls
Cascade screening of family members allows for early identification and treatment of at-risk individuals
Early diagnosis and treatment (statin+) can normalize life expectancy
Elevated LDL-C [
≥
5mmol/L with
other features]
E
arly
onset CVD (<55 years in men, <65 years in women
)
C
holesterol
deposition in the tendons (
xanthomata)
A
rcus
cornealis
onset <
45years
F
amily
history of early onset CVD or
hyperlipidemia
requiring treatment
Familial HypercholesterolemiaSlide5
Case 1: Jason
A healthy
38-year-old
male
He has been training for half marathon
Complaining of bilateral heel pain
Motivated
by his brother’s heart attack and death at age
42 years, about 6 months ago
Wondering if he sustained an injury during training
Excellent healthNon smokerSocial drinker (~ 10/week)Healthy BMINo medications
Case: NCHPEGSlide6
Case 1: Jason
d.42
MI @50y
Treated for dyslipidemia
Jason
64
HTN
IDDM
MI @42y
66
39
38
Case:
NCHPEGSlide7
What is familial hypercholesterolemia?
Familial hypercholesterolemia (FH) is an autosomal dominant genetic
condition
Results
in lifetime exposure to very high levels of LDL-C
The
uptake of low-density lipoprotein cholesterol (LDL-C) into cells is either decreased or inhibited
FH is the most
common genetic disorder causing premature cardiovascular disease and death in both men and women
FH is underdiagnosed: estimated <15% of affected Canadians have been diagnosed
At least 1 in 500 Canadians is thought to have FHMore common in certain populations due to founder effects(e.g. 1/270 in French Canadians, 1/67 in Ashkenazi Jews)Slide8
What do I need to know about the genetics of familial hypercholesterolemia?
Can
be present in a heterozygous
form (
HeFH
)
Can be present in
a homozygous form (HoFH)All individuals with HoFH have an extremely high risk of early onset cardiovascular disease
Where an individual has a mutation in
one copy of a FH-causing geneWhere an individual has a mutation in
both copies of a FH-causing geneMost cases (80-90%) of FH are caused by mutations in the LDL receptor gene LDLRSlide9
Clinical features of familial hypercholesterolemia
Clinical features
HeFH
HoFH
Genetics
Mutation in one FH gene
Mutation in both copies of
a
FH gene
LDL-C levels
≥ 5mmol/L with at least one of the additional features (see below)
>12
mmol
/L lower LDL-C levels, especially in children or in treated patients, do not exclude dxCardiovascular disease onset
<55 years of age in men<65 years of age in women
<20 years of age (can be as early as the first year of life)
Physical findings
Cholesterol deposits in the tendons (xanthomata) and/or around the eyes (xanthelasma)
Arcus cornealis (white, grey, or blue opaque ring in the corneal margin) onset <45years
Family historyEarly onset CVDHyperlipidemia, often requiring treatmentSlide10
Likelihood
of FH diagnosis
LDL-C
≥
5mmol/L
AND
at least one other
red flagPossibleLDL-C ≥ 5mmol/L AND 2 other red flagsProbable
Familial hypercholesterolemia Red Flags which should prompt specialist referral
Personal or family history of clinical stigmata of FH Personal or family history of premature CVDFamily history of significant hypercholesterolemia, often requiring treatmentSlide11
Who should be offered genetic testing?
Heterozygous FH (
HeFH
)
Individuals
meeting FH
definite
or probable or possible diagnostic criteria
First-, second- and third-degree family members of an individual with a known mutation in an FH gene
Homozygous FH (HoFH)Individuals where both parents have known mutations in FH causing genes (at 25% risk for
HoFH)ORAn untreated LDL-C >12mmol/L or treated LDL-C ≥8mmol/L*lower LDL-C levels do not exclude HoFH, especially in children or in individuals who are treated for hyperlipidemiaWITH eitherCutaneous or tendon xanthomata before age 10 years
OR
Both parents have elevated LDL-C levels consistent with HeFHSlide12
Diagnosis of familial hypercholesterolemia
The
Canadian Cardiovascular Society (CCS) recommends using those published by the Dutch Lipid Clinic
NetworkSlide13
Cascade screening and familial hypercholesterolemia
Screen
first-, second- and third-degree relatives of
the first
individual with a confirmed
diagnosis
(known as the index case)The most cost-effective approach for identification of new FH Screening can be done by:Genetic testing for a known familial gene mutation
LDL-C measurements
Use of diagnostic criteriaSlide14
What do the genetic test results mean?
Positive test result: Pathogenic gene mutation found
Confers
a
definite
diagnosis
Offers
the opportunity for cascade
screening (1
st
, 2nd, 3rd degree relatives)Individuals with HeFH have a 20-fold higher risk of premature CVDUntreated, a fatal or non-fatal coronary event will occur in about 50% of males by age 50 and about 30% of females by age
60
~100% of individuals will develop hypercholesterolemiaSlide15
What do the genetic test results mean?
Familial
mutation
not
found
Negative test results
True negative
No further testing indicated
Reassurance for offspringSlide16
What do the genetic test results mean?
Affected individual
,
no mutation
identified
and
no known familial mutation
Negative test results
This result is
uninformativeFor individuals who meet definite, probable or possible FH criteria FH diagnosis is not ruled out
Chance of diagnosis based on Dutch Lipid
Network ClinicChance of finding a gene mutation
Definite
70%Probable29%Possible11%Slide17
Surveillance and Management
Medications and Healthy Lifestyle
Observational studies have shown a dramatic decrease in cardiac events in statin-treated
individuals
Statins are the drug class of choice
The CCS recommends a
>50% reduction of LDL-C from baseline
beginning at age 18 as primary prevention and that an ideal goal of LDL-C <2.0mmol/L is recommended for secondary
prevention
Refer to specialist if statin therapy alone is insufficient for LDL-C reductionSlide18
Case 1: Jason
A healthy
38-year-old
male
Complaining of bilateral heel pain
d.42
MI @50y
Treated for hyperlipidemia
Jason
64
HTN
IDDM
MI @42y
66
39
38
Case:
NCHPEGSlide19
Case 1: Jason
On examination:
You notice yellowish bumps over knuckles
Jason reports the size and number have been increasing
He also reports that his father has the same bumps
Case:
NCHPEG
Image:
Genest
Can J Cardio 2014Slide20
Case 1: Jason
On examination:
Tenderness over Achilles tendons
Papulonodular
changes like on hands
Apparent thickening of tendons
Case:
NCHPEG
Image:
Genest Can J Cardio 2014Slide21
Case 1: Jason
Jason has evidence of xanthoma on hands and feet
Family history of premature CVD
Family history
of significant
hypercholesterolemia
LDL-C is ordered. LDL-C = 6.9mmol/L
Definite diagnosis of familial hypercholesterolemia
Begin statin treatment
Refer to lipid specialist
and genetic specialistScreen family members (1st, 2nd, 3rd degree)Slide22
Common autosomal dominant disorder resulting in 20x increased risk of cardiovascular disease CVD) and death
Key features:
Pearls
Cascade screening of family members allows for early identification and treatment of at-risk individuals
Early diagnosis and treatment (statin+) can normalize life expectancy
Elevated LDL-C [
≥
5mmol/L with
other features]
E
arly
onset CVD (<55 years in men, <65 years in women
)
C
holesterol
deposition in the tendons (
xanthomata)
A
rcus
cornealis
onset <
45years
F
amily
history of early onset CVD or
hyperlipidemia
requiring treatment
Familial Hypercholesterolemia