Famil ilia ial l Hyperchole lesterola laemia ia in children - - PowerPoint PPT Presentation

Albert Wiegman Amsterdam University Medical Centers The Netherlands June 11th 2020

Famil ilia ial l Hyperchole lesterola laemia ia in children and adolescents: gaining decades of f life by optimizing detection and treatment

• No disclosure

Homozygous FH FH

Case report:

• 5-year-old boy with HoFH
• Treated with colestyramine
• LDL 26 mmol/L

Macchiaiolo M e.a. Lancet, 2012;379:1330

Homozygous FH FH

Case report, continued:

• Acute ischaemic cardiac event; complete obstruction of

the left coronary artery

• After stent replacement; start LDL apheresis
• Died from second MI after three months

Macchiaiolo M e.a. Lancet, 2012;379:1330

Homozygous FH FH

Case report 2:

• 4-year-old boy with HoFH
• LDL 20 mmol/L
• atorvastatin + ezetimibe; no substantial effect
• Died suddenly at age of 4;

98% occlusion of left coronary artery

Widhalm K e.a. J Pediatr, 2011;158:167

2% left where all the blood went through

Homoz vs vs heteroz vs vs nonFH

• In homozygous FH (LDL-c 15 to 30 mmol/L)

heart attacked between 3 and 6 years

LD LDL-aferese

Conclusions systematic review

• LDL-apheresis seems a safe therapy and leads to a significant

reduction in both LDL-C and xanthomata in HoFH children.

• The efficacy with respect to CVD protection is unclear and

needs to be evaluated by an international prospective cohort study.

Luirink IK e.a. J Clin Lipidol 2019;13:31-9

Heterozygous FH in childhood a dis . . . . ?

Why screening of children with heterozygous FH?

Heterozygous FH in childhood a disease ?

Why screening of children with heterozygous FH?

Heterozygous FH in childhood a disorder ?

Why screening of children with heterozygous FH?

Heterozygous FH in childhood a disaster !

Why screening of children with heterozygous FH?

Heterozygous FH in childhood cause 100 fold RR on coronary event in age 20-40 yrs !

Simon Broome Register Group BMJ 1991;303:893-6

Why screening of children with heterozygous FH?

Heterozygous FH in childhood cause 11.1 (7.1-17.5) fold RR on CHD in men and 17.3 (9.6-31.2) fold RR on CHD in women in age 25-40 yrs !

Mundal LJ e.a. Heart 2018;104:1600-7

Why screening of children with heterozygous FH?

Raal F e.a. Atherosclerosis 2012;223:262-8

Cardiovascular risk FH

Lifelong elevation of cholesterol levels on a genetic basis imposes substantially greater risk than acquired hyperlipidemia in midlife. Compared with persons with a normal LDL-C and no genetic mutation associated with FH, those with high LDL-C (>5 mmolL) and no mutation have a 6-fold increase in CVD, whereas those with high LDL-C and a known mutation have a 22-fold higher risk.

Khera e.a. J Am Coll Cardiol 2016; 67:2578-89

Lifelong elevation of cholesterol levels on a genetic basis imposes substantially greater risk than acquired hyperlipidemia in midlife. Compared with persons with a normal LDL-C and no genetic mutation associated with FH, those with high LDL-C (>5 mmolL) and no mutation have a 6-fold increase in CVD, whereas those with high LDL-C and a known mutation have a 22-fold higher risk.

Khera e.a. J Am Coll Cardiol 2016; 67:2578-89

• Physical characteristics
• Family history
• Molecular diagnosis
• Laboratory data
• Prevention
• Ultrasound
• Intervention

Gaining decades of f lif life by optimizing detection and tr treatment

• Physical characteristics
• Family history
• Molecular diagnosis
• Laboratory data
• Prevention
• Ultrasound
• Intervention

Gaining decades of f lif life by optimizing detection and tr treatment

17 children with xanthelasmata

15 children with arcus cornealis

• Physical characteristics
• Family history
• Molecular diagnosis
• Laboratory data
• Prevention
• Ultrasound
• Intervention

Gaining decades of f lif life by optimizing detection and tr treatment

Case 1: Ju June 2016

smoking + D206E 1y

TC 18.4 HDL 0.7 LDL 16.6 Trig. 2.2

4y 1y W23X W23X W23X/D206E † 23y MI smoking +

†

TC 8.9 HDL 1.3 LDL 7.2 Trig. 1.3 TC 7.5 HDL 1.1 LDL 6.1 Trig. 0.7

Case 2: Ju June 2004/June 2015

† 52y MI smoking + 48y smoking -

TC 9.2 HDL 1.8 LDL 6.7 Trig 1.5

17y † 28y MI smoking + G186G

† †

G186G G186G 20y 12y

TC 3.6 HDL 1.6 LDL 1.8 Trig 0.4

+31y MI

†

Case 3: Ju June 2014

37y MI 4 bypasses smoking + 10kb dupl 21y CVA 33y 2nd CVA smoking + 10kb dupl

6y TC 9.4 HDL 0.8 LDL 7.8 Trig. 1.8 10kb dupl

17y † 26y MI smoking -

TC 11.1 HDL 1.1 LDL 9.4

• Trig. 1.1

10kb dupl † †

† 32y MI smoking + smoking + smoking -

Genetic Field Work

Genetic Field Work: collecting family history/drawing pedigree

Nordestgaard B e.a. Eur Heart J 2013 34:3478-90

am

Nordestgaard B e.a. Eur Heart J 2013 34:3478-90

Five publications wit ithin one year: : fr frequency of f heFH 1 in in 187-244 244

Sjouke B ea Eur Heart J 2015;36:560-5 Homozygous Autosomal Dominant Hypercholesterolemia in the Netherlands: prevalence, genotype-phenotype relationship and clinical outcome. Pang J ea J Atheroscler Thromb 2016;23:505-19 International developments in the care of familial hypercholesterolemia: where now and where to next. West Australia Khera A ea J Am Coll Cardiol 2016;67:2578-89 Diagnostic yield of sequencing familial hypercholesterolemia genes in patients with severe

• hypercholesterolemia. USA

Benn M ea Eur Heart J 2016;37:1384-94 Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copen- hagen General Population Study estimated a prevalence of 1 in 217. Wald DS ea N Engl J Med 2016;375:1628-37 Child-parent familial hypercholesterolemia screening in primary care. UK

Higher prevalence of familial hypercholesterolemia than expected in adult patients of four family practices in Netherlands

Lansberg PJ e.a. Ned Tijdschr Geneeskd 2000; 144:1437-41

• autosomal dominant disorder
• 70.000 heterozygous FH
• 70 homozyg or compound heterozyg FH
• 1 in every 232 births
• 16.8 * 106 people

FH is is a common in inherited condition

Wiegman A e.a. Eur Heart J 2015;36:2425-37

• Physical characteristics
• Family history
• Molecular diagnosis
• Laboratory data
• Prevention
• Ultrasound
• Intervention

Gaining decades of f lif life by optimizing detection and tr treatment

Molecular diagnosis

Amino acid sequence of LDL receptor

• Human
• Cow
• Rabbit
• Hamster
• Swine
• Shark

Receptor was assembled > 450.000.000 years ago!

Mehta KD e.a. J Mol Evol 1996; 42:264 Yamamoto e.a. Cell 1984; 39:27

Sharks have FH as well

E.R. Golgi Endosome Liver-cell LDL-Receptor LDL

Mutatie-klasse 1 2 3 4 5 Synthesis Transport Binding Clustering Recycling

X X X X X

1 2 3 4 5

1 2 3 4 5 Mutation class

Molecular diagnosis

Family History and Cardiovascular Risk in Familial Hypercholesterolemia: data in more than 1000 children

Wiegman A, Rodenburg J, DeJongh S, Defesche JC, Bakker HD, Kastelein JJP, Sijbrands EJG Circulation 2003; 107:1473-8

Dia iagnosis of f FH in in chil ildren & adolescents

Family history of premature CHD plus high LDL-C levels are the two key selective screening criteria: (F + H =FH).

• LDL-C >5 mmol/L (190 mg/dL) twice and secondary causes

ruled out: highly probable FH

• LDL-C >4 mmol/L (160 mg/dL) twice and premature CHD in

relative or high cholesterol in parent: highly probable FH

• LDL-C >3.5 mmol/L (130 mg/dL) twice and genetic

diagnosis in parent: definite FH

• Proven pathogenic mutation in child: definite FH

Wiegman e.a. Eur Heart J 2015; 36:2425-37

Wiegman e.a. Eur Heart J 2015; 36:2425-37

• Physical characteristics
• Family history
• Molecular diagnosis
• Laboratory data
• Prevention
• Ultrasound
• Intervention

Gaining decades of f lif life by optimizing detection and tr treatment

CVD Prevention & Children?

SURGEON GENERAL’S WARNING Smoking may Stunt Your Growth

• Physical characteristics
• Family history
• Molecular diagnosis
• Laboratory data
• Prevention
• Ultrasound
• Intervention

Gaining decades of f lif life by optimizing detection and tr treatment

Arterial intima-media thickness in childhood: study in familial hypercholesterolemia heterozygotes and their siblings

Wiegman A, De Groot E, Hutten BA, Rodenburg J, Gort J, Bakker HD, Sijbrands EJG, Kastelein JJP Lancet 2004; 363:369-70

281 children (8-18 yr) 134 families 201 children with FH 80 non-affected silbings

Arterial intima-media thickness in childhood: study in familial hypercholesterolemia heterozygotes and their siblings

AGE (years)

20 18 16 14 12 10 8

Mean carotid IMT (mm)

.60 .55 .50 .45 .40 .35

fh controls  0.0044 mm/year

• est. IMT increase = 0.0003 mm/year
• est. IMT increase = 0.0047 mm/year

p= 0.004

80 70 60 50 40 30 20 10 1.1 1.0 .9 .8 .7 .6 .5 .4

0.010 mm/year 0.004 mm/year  0.006mm/year LDL-C 7.2 mmol/L LDL-C 3.4 mmol/L AGE (years) IMT (mm)

De Groot E e.a. Circulation 2004; 109(S):III33-8

0.8

40 80

T T T

10

AGE (years) IMT (mm)

De Groot E e.a. Circulation 2004; 109(S):III33-8

In Increased cIM IMT is is alr lready evid ident at t age 7 years in in FH chil ildren

Kusters DM e.a. Circ Res 2014;114:307-10

• Physical characteristics
• Family history
• Molecular diagnosis
• Laboratory data
• Prevention
• Ultrasound
• Intervention

Gaining decades of f lif life by optimizing detection and tr treatment

Lipids Trial

• Results:
• 211 of 214 children finished two-year trial
• LDL-C reduction of 25% (prava) vs 0% (p<0.0001)
• Excellent tolerability and safety

Wiegman e.a. JAMA 2004;292:331-7

• 15
• 10
• 5

5 10 15 nonFH (95) placebo (108) prava (106)

1 year 2 years *

• -^--

delta IMT in um

* p=0.019

Efficacy and safety of statin therapy in children with familial hypercholesterolemia

Wiegman e.a. JAMA 2004;292:331-7

Statin use AfterTen years of follow up

• 86% is on statin therapy (vs. 0% in sibs)
• 24% is still on pravastatin
• 30% statin + ezetimibe / cholestagel

Kusters e.a. JAMA 2014;312:1055-7

Carotid IMT in statin-treated FH children and their unaffected siblings at baseline (when statins were initiated in the FH group) and 10 years after this initiation

Kusters e.a. JAMA 2014;312:1055-7

Mean c-IMT (mm) over time in 6-17 year olds who are treated with rosuvastatin

Braamskamp e.a. Circulation 2017; 136:359-66

IK Luirink et al. N Engl J Med 2019;381:1547-1556.

Low-Density Lipoprotein (LDL) Cholesterol Levels of Patients with Familial Hypercholesterolemia and Their Unaffected Siblings at Baseline and at Follow-up.

IK Luirink et al. N Engl J Med 2019;381:1547-1556.

Kaplan–Meier Curves for Patients with Familial Hypercholesterolemia (FH) Who Began Receiving Statin Therapy during Childhood and Their Affected Parents for Whom Statins Were Available Much Later in Life.

Paediatric guidelines in the Netherlands: Medical treatment in children with heterozygous FH

• ≥ 10 yr** : low dose statin (if not effective:)
• ≥ 10 yr** : high dose statin or
• ≥ 10 yr**:

low dose statin + ezetimibe 10 mg or

• ≥ 10 yr**:

low dose statin + colesevalam 2dd 1875

• ** if LDL-c twice >3.5 mmol/L and proven mutation or

LDL-c twice > 4 mmol/L and premature CVD in relative or LDL-c twice > 5 mmol/L

Sam Gidding Eric Sijbrands Gerald Watts John Chapman Henry Ginsberg Marina Cuchel Leiv Ose Steve Humphries Olov Wiklund Olivier Descamps Alberico Catapano Raoul Santos Eric Bruckert Frederic Raal Lotte de Boer John Kastelein Henk Bakker Frits Wijburg Barbara Hutten Joep Defesche Eric de Groot Saskia de Jongh Jessica Rodenburg Anouk van der Graaf Hans Avis Meeike Kusters Marjet Braamskamp Ilse Luirink Eric Stroes Kees Hovingh