In The Name Of GOD Familial - PowerPoint Presentation

Slide1

In The Name Of GOD

Slide2

Familial

hypercholestrolemia and pregnancy

Soheila

S

adeghi

Slide3

What is our patient’s diagnosis ?

Is her treatment appropriate ?

Is it necessary to evaluate the patient for CAD ?

Pregnancy outcome in mother and fetus ?

What is the pharmacologic management of the patient if she does not plan for pregnancy ?

Slide4

Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease :European Heart Journal (2013) - Consensus Statement of the European Atherosclerosis Society

Familial

hypercholesterolaemia

(FH) is a common genetic cause of premature coronary heart disease

If left untreated

men and women with heterozygous FH with total cholesterol levels of 8–15

mmol

/L (310–580 mg/

dL

) typically develop CHD before age 55 and 60

while

homozygotes

with total cholesterol levels of 12–30

mmol

/L (460–1160 mg/

dL

) typically develop CHD very early in life and if untreated die before age 20

1/500 are heterozygous for FH

and 1/1 000 000 are homozygous

Slide5

prevalences

for definite or probable FH were similar for women and men below age 60

in contrast, above age 60, more women than men were in this category. These findings suggest that many men with FH had died at an earlier age

Familial

hypercholesterolaemia

is

underdiagnosed

and undertreated in the general population: guidance for clinicians to prevent coronary heart disease :European Heart Journal (2013) - Consensus Statement of the European Atherosclerosis Society

Slide6

the prevalence of CHD among definite/probable FH participants was 33%; only 48% of subjects with FH received

statins. The risk of CHD was increased 13-fold among individuals with definite/probable FH not receiving

statins

the corresponding increase in risk for CHD among individuals with FH on

statin

was ten-fold (8- to 14-fold), suggesting that the dose of

statin

therapy provided resulted in insufficient cholesterol-lowering medication, and was introduced too late in life, when severe atherosclerosis had already developed

Familial

hypercholesterolaemia

is

underdiagnosed

and undertreated in the general population: guidance for clinicians to prevent coronary heart disease :European Heart Journal (2013) - Consensus Statement of the European Atherosclerosis Society

Slide7

Familial

hypercholesterolaemia

is

underdiagnosed

and undertreated in the general population: guidance for clinicians to prevent coronary heart disease :European Heart Journal (2013) - Consensus Statement of the European Atherosclerosis Society

Slide8

The cumulative LDL cholesterol burden (a burden sufficient for CHD to develop)

55-year-old person without FH is typically 160

mmol

For an individual with heterozygous FH is reached by age 35 if untreated, by age 48 if treated since age 18, and by age 53 if treated since age 10

An untreated subject with homozygous FH will reach this level at age 12.5

Familial

hypercholesterolaemia

is

underdiagnosed

and undertreated in the general population: guidance for clinicians to prevent coronary heart disease :European Heart Journal (2013) - Consensus Statement of the European Atherosclerosis Society

Slide9

Whom to screen

: how do we recognize index cases?should be identified according to the following criteria:

(

i

) plasma total cholesterol ≥8 mmol

/L (≥310 mg/

dL

) in an adult

or adult family member(s) (or > 95th percentile by age and gender for country)(ii) premature CHD in the subject or family member(s)

(iii) tendon

xanthomas

in the subject or family member(s)

(iv) sudden premature cardiac death in a family member

Initial family members to be tested are biological first-degree relatives, namely parents, siblings, and children

Familial

hypercholesterolaemia

is

underdiagnosed

and undertreated in the general population: guidance for clinicians to prevent coronary heart disease :European Heart Journal (2013) - Consensus Statement of the European Atherosclerosis Society

Slide10

Secondary causes of

hyperlipidaemia must be excluded by determining that liver enzymes, renal function, and thyroid hormones are normal

Among individuals with a definite or probable diagnosis of FH (DLCN >5)

molecular genetic testing

is strongly recommended

We recommend the following

LDL cholesterol targets

in FH, in accordance with recent ESC/EAS guidelines:

(i

) children < 3.5

mmol

/L (< 135 mg/dL

)

(ii)

Adults

< 2.5

mmol

/L (< 100 mg/

dL

)

(iii) adults with CHD or diabetes < 1.8

mmol/L (< 70 mg/dL)

Familial

hypercholesterolaemia

is

underdiagnosed

and undertreated in the general population: guidance for clinicians to prevent coronary heart disease :European Heart Journal (2013) - Consensus Statement of the European Atherosclerosis Society

Slide11

Slide12

Patients with FH, in particular

those with elevated Lp

(a) levels and a severe

phenotype (defined as hoFH or

heFH

with

an untreated LDL-C level >310 mg/dL), should be screened for

valvular

and

supravalvular

aortic

stenosis

using auscultation and

echocardiography

There is no consensus on screening

for myocardial ischemia in patients with

asymptomatic FHStress testing could be considered in patients with asymptomatic

heFH

(1) with late initiation of lipid-lowering treatment (2) with a family history of early ASCVD (3) who intend to participate in competitive sports

My Approach to the Patient With Familial

Hypercholesterolemia

:

Mayo

Clin

Proc

. n June 2016

Slide13

My Approach to the Patient With Familial

Hypercholesterolemia :

Mayo

Clin

Proc. n June 2016

The FDA-approved

criteria for

apheresis

in patients receiving

maximally tolerated lipid-lowering therapy

are

(1) an LDL-C level greater than 500 mg/

dL

in patients with

hoFH

(2) an LDL-C level

greater than 300 mg/dL in patients with

heFH

(3) an LDL-C level greater than 200 mg/dL in patients with heFH with ASCVD

Slide14

My Approach to the Patient With Familial

Hypercholesterolemia :

Mayo

Clin

Proc. n June 2016

Slide15

Guidelines for Diagnosis and Treatment of Familial

Hypercholesterolemia 2017

)

J

Atheroscler

Thromb

, 2018

(

FH Causative Genes

Mutations in causative genes are found in 60– 80% of clinically diagnosed

HeFH

1

.

LDL Receptor

:

80% or

more

2

.

Apo B-100 : patients with apo

B-100 mutations,

which is called familial defective apolipoprotein B-100 (FDB), have a similar clinical manifestation to classical FH with LDL receptor mutations. Serum lipid levels are usually lower in FDB patients than in those with LDL receptor mutations. FH prevalence is higher than FDB.3. PCSK9 : As PCSK9 is involved in the degradation of the LDL receptor, a gain-of-function mutation will decrease LDL receptors4.LDL Receptor Adapter Protein 1 (

LDLRAP1

) : LDLRAP1 is involved in the

endocytosis

of the LDL receptor. Mutations in the LDLRAP1 gene inherited from both parents cause

autosomal

recessive hypercholesterolemia (ARH), an extremely rare disease.

Slide16

Familial Hypercholesterolemia and Pregnancy

May 14, 2018   

 

Gina Price Lundberg, MD, FACC

;

Laxmi

S. Mehta, MD, FACC

Expert Analysis

It is estimated that 90% of FH carriers are still undiagnosed

All childbearing-age women with FH on lipid lowering therapy should receive pre-pregnancy counseling as well as contraception advice

The preferred methods for contraception in women with FH are low-dose estrogen oral agents, intrauterine devices and barrier techniques

Women with FH need counseling on risk reduction and management with particular attention on therapy during pre-conception, pregnancy, childbirth and lactation

With early identification of FH in women and proper planning, most women with FH can have healthy pregnancies and healthy children

Slide17

Familial Hypercholesterolemia and Pregnancy

May 14, 2018   

 

Gina Price Lundberg, MD, FACC

; Laxmi

S. Mehta, MD, FACC

Expert Analysis

statins

are contraindicated during pregnancy and lactation.

Non-

statins

such as

ezetimibe

,

niacin

and

fibrates

have also been associated with

teratogenicity

.

PCSK9 inhibitors

have not been tested for safety during pregnancy and are not currently approved during pregnancy

The only medications currently acceptable during pregnancy are

bile acid

sequestrants. Use is limited due to side effects of elevated triglycerides and constipationMipomersen, an antisense inhibitor of APoB synthesis, is an injection that may be considered during pregnancy in HoFH womenLomitapide, in capsule form, is contraindicated during pregnancy as there is a risk of embryo-fetal toxicity

Lipoprotein

apheresis

is also approved during pregnancy and considered safe for very high risk women with known significant atherosclerotic disease or

HoFH

Slide18

Familial Hypercholesterolemia and Pregnancy

May 14, 2018   

 

Gina Price Lundberg, MD, FACC

; Laxmi

S. Mehta, MD, FACC

Expert Analysis

When a woman with FH is ready to conceive,

statins

,

ezetimibe

and niacin should be

stopped at least 4 weeks

prior to discontinuing contraception

others recommend discontinuing

statins

approximately three months

prior to attempting conception

Women who become pregnant while on

statin

therapy should stop the

statin

immediately

may also be reassured that the likelihood is low for fetal complications

More recent observational studies reviewing multiple clinical studies and case reports did not report an increased risk of congenital anomalies with statin exposure in pregnancy when compared to control groups or the prevalence of congenital anomalies in the general population

Slide19

Familial Hypercholesterolemia and Pregnancy

May 14, 2018   

 

Gina Price Lundberg, MD, FACC

; Laxmi

S. Mehta, MD, FACC

Expert Analysis

Women with FH may have more conditions associated with pregnancy-related complications such as diabetes, hypertension disorders, renal dysfunction and polycystic ovarian syndrome, which is also associated with infertility

Women with FH have similar fertility rates compared to women without FH

Women with FH who receive fertility treatments should be followed closely by their cardiologist or lipid specialist as these drugs can increase cholesterol and triglyceride levels

Slide20

Familial Hypercholesterolemia and Pregnancy

May 14, 2018   

 

Gina Price Lundberg, MD, FACC

; Laxmi

S. Mehta, MD, FACC

Expert Analysis

During pregnancy in the general population, total cholesterol can increase 25 to 50% while LDL-C can increase up to 66%

Triglycerides can increase up to 200 to 400% during pregnancy

Pregnancy in women with FH and no atherosclerotic CVD is relatively safe.

women with FH and previous myocardial infarction, myocardial ischemia or left ventricular dysfunction should have counseling on risk of CVD during pregnancy

Slide21

Familial Hypercholesterolemia and Pregnancy

May 14, 2018   

 

Gina Price Lundberg, MD, FACC

; Laxmi

S. Mehta, MD, FACC

Expert Analysis

There is no increase in risk of preterm delivery, low birth weight or congenital malformation in infants born to women with FH. There is also no increased risk for preeclampsia, gestational diabetes or pregnancy-induced hypertension in pregnant women with FH

All children of FH mothers should undergo lipid screening by age 2

Women with

HoFH

will pass the FH gene to all their children who will be

HeFH

carriers if the father is not a FH carrier

Women with

HeFH

have a 50% chance of passing the FH gene to each child if the father is not a FH carrier

Slide22

Familial Hypercholesterolemia and Pregnancy: Risk and

Management (

Mombelli

and

Mombelli. Obstet

Gynecol

cases Rev 2015,

2:8)

Total cholesterol (TC) and triglycerides levels increase during gestation. Proposed biological explanations for these changes include a metabolic shift from carbohydrates to lipids for maternal energy production in order to make glucose available for the fetus and an increase of cholesterol as a precursor for the production of steroid hormones in the placenta

In

the

second and

third

trimester HDL-C shows

a 55%

increase

Triglycerides decreases rapidly to normal

values after

delivery

cholesterol

levels remain

elevated for approximately 6 weeks after

birth

It

has been also observed an increase in Lipoprotein (a) and PCSK9Furthermore, FH women develop a prothrombotic and proinflammatory phenotype, during pregnancy due to increased concentrations of several prothrombotic and inflammatory mediators

compared to

non-FH women

Slide23

Familial Hypercholesterolemia and Pregnancy: Risk and

Management (

Mombelli

and

Mombelli. Obstet

Gynecol

cases Rev 2015,

2:8)

Discontinuation of lipid-lowering medications for the relatively

short duration

of pregnancy is thought to have little impact on

long-term therapy for primary

hypercholesterolaemia

and is unlikely

to affect

outcomes

of CHD

It is not known whether

lomitapide

or

mipomersen is excreted in breast milkThe safety or contraindication for evolocumab

in pregnancy, have not yet been evaluated

Evidence-based guidelines for FH from the National Lipid Association (NLA) recommend that treatment goals should focus on reducing LDL-C levels by 50% from pretreatment levels if target LDL-C levels cannot be achieved

Slide24

Association of lipid levels during gestation with preeclampsia

and gestational diabetes mellitus: a population-based study

)

American Journal of Obstetrics

& Gynecology NOVEMBER 2009

(

Slide25

Associations of lipid levels during

gestation with hypertensive disorders

of pregnancy and gestational diabetes

mellitus: a prospective longitudinal

cohort study

)

Shen H, et al. BMJ Open 2016

(1310 eligible women

were assessed in the first (10–13 weeks), second

(22–28 weeks) and third (30–35 weeks) trimesters

consecutively. Associations of lipid profiles with HDP

and/or GDM outcomes were assessed

Compared with the normal group, maternal TG

concentrations were higher in the HDP/GDM groups

across the three trimestersTC and LDL-c amounts were only higher in the first trimester for the

HDP and GDM groups

HDL-c levels were similar in the three groups

Slide26

TG

elevation was positively correlated with weight gain

during

gestation

Compared with intermediate

TG levels (25–75th

centile

), higher TG amounts (>75

th

centile

) were associated with increased risk of HDP/GDM

in each trimester with

aORs

of 2.04, 1.81 and 1.78,

respectively

Maternal age, pre-pregnancy body mass index,

weight gain, fasting glucose levels, gestational age and fasting state are associated with lipidlevels, and were adjusted in this study.

Associations of lipid levels during

gestation with hypertensive disorders

of pregnancy and gestational diabetes

mellitus: a prospective longitudinal

cohort study

)

Shen H, et al. BMJ Open 2016

(

Slide27

Associations of lipid levels during

gestation with hypertensive disorders

of pregnancy and gestational diabetes

mellitus: a prospective longitudinal

cohort study

)

Shen H, et al. BMJ Open 2016

(

Slide28

Pregnancy Outcomes in Familial Hypercholesterolemia : A Registry-Based Study (Circulation. 2011 )

1869 FH women (14 years) from the Medical Genetics Laboratory and about 2 million (general population) from the Medical Birth Registry of Norway during the period 1967 to 2006

2319 births of 1093 women with heterozygous FH

This registry study demonstrates that the frequency of preterm delivery (birth < 37 weeks of gestation), low birth weight ( < 2500 g), and congenital malformations were apparently similar to those in the general population of women of childbearing age in Norway

Slide29

Maternal lipid profile and the relation with spontaneous preterm delivery: a systematic review (Arch

Gynecol

Obstet

(2017)

Nine cohort studies and five case–control studies were analyzed

reporting on 1466 cases with

sPTD

and 11296 controls with term delivery

The studies suggest a possible elevated risk of

sPTD

in woman with high TG levels

no association of high and low density lipoprotein cholesterol with the risk of

sPTD

was found

High

homocysteine

levels are associated with

sPTD

in the second trimester

Slide30

2018 Guideline on the Management of Blood Cholesterol

A report of the American College of Cardiology/American Heart Association

Slide31

Predicting Cardiovascular Events in

Familial Hypercholesterolemia: The SAFEHEART Registry (CIRCULATIONAHA2017 )

2404 adult patients with FH who were followed-up for a mean period

5.5 years

The

risk of incident ASCVD may be estimated in familial

hypercholesterolaemia

patients

using simple

clinical estimates including

: age

, gender, history of atherosclerotic cardiovascular disease, blood

pressure, body mass index, smoking, and plasma LDL-C and

Lp

(a)

levels

Slide32

Slide33

Slide34

Cholestyramine

Dyslipidemia

:

  Oral: Initial: 4 g 1 to 2 times/day

increase gradually over ≥1-month intervals

maintenance: 8 to 16 g/day divided in 2 doses

maximum: 24 g/day

Slide35