Familial Hypercholesterolemia - PowerPoint Presentation

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