Famil ilia ial l Hyperchole lesterola laemia ia in children and adolescents: gaining decades of f life by optimizing detection and treatment Albert Wiegman Amsterdam University Medical Centers The Netherlands June 11 th 2020
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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 2% left where all the blood went through Widhalm K e.a. J Pediatr, 2011;158:167
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
Why screening of children with heterozygous FH? 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
Cardiovascular risk FH Raal F e.a. Atherosclerosis 2012;223:262-8
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
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 • Physical characteristics • Family history • Molecular diagnosis • Laboratory data • Prevention • Ultrasound • Intervention
17 children with xanthelasmata
15 children with arcus cornealis
Gaining decades of f lif life by optimizing detection and tr treatment • Physical characteristics • Family history • Molecular diagnosis • Laboratory data • Prevention • Ultrasound • Intervention
Case 1: Ju June 2016 † † 23y MI smoking + TC 7.5 smoking + HDL 1.1 D206E LDL 6.1 1y Trig. 0.7 W23X TC 8.9 TC 18.4 HDL 1.3 HDL 0.7 LDL 7.2 LDL 16.6 4y 1y Trig. 1.3 Trig. 2.2 W23X W23X/D206E
Case 2: Ju June 2004/June 2015 † 52 y MI † smoking + 48y † smoking - † 28y MI G186G smoking + TC 9.2 TC 3.6 † HDL 1.6 HDL 1.8 LDL 6.7 LDL 1.8 17y 20y 12y Trig 1.5 Trig 0.4 G186G G186G +31y MI
Case 3: Ju June 2014 † † 32y MI smoking + † 37y MI 21y CVA 4 bypasses 33y 2nd CVA † 26y MI smoking + smoking + smoking - 10kb dupl 10kb dupl TC 11.1 TC 9.4 HDL 0.8 HDL 1.1 LDL 7.8 LDL 9.4 17y 6y Trig. 1.8 Trig. 1.1 smoking + 10kb dupl 10kb dupl smoking -
Genetic Field Work
Genetic Field Work: collecting family history/drawing pedigree
am Nordestgaard B e.a. Eur Heart J 2013 34:3478-90
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 - 1 in every 232 births - 16.8 * 106 people - autosomal dominant disorder - 70.000 heterozygous FH - 70 homozyg or compound heterozyg FH
FH is is a common in inherited condition Wiegman A e.a. Eur Heart J 2015;36:2425-37
Gaining decades of f lif life by optimizing detection and tr treatment • Physical characteristics • Family history • Molecular diagnosis • Laboratory data • Prevention • Ultrasound • Intervention
Molecular diagnosis
Amino acid sequence of LDL receptor Sharks have FH as well • Human • Cow • Rabbit • Hamster • Swine • Shark Receptor was assembled > 450.000.000 years ago! Yamamoto e.a. Cell 1984; 39:27 Mehta KD e.a. J Mol Evol 1996; 42:264
LDL-Receptor LDL Molecular diagnosis Liver-cell 3 2 4 Golgi 1 5 E.R. Endosome Synthesis Transport Binding Mutation class Mutatie-klasse Clustering Recycling 1 1 X 2 X 2 X 3 3 X 4 4 X 5 5
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
Gaining decades of f lif life by optimizing detection and tr treatment • Physical characteristics • Family history • Molecular diagnosis • Laboratory data • Prevention • Ultrasound • Intervention
CVD Prevention & Children?
SURGEON GENERAL’S WARNING Smoking may Stunt Your Growth
Gaining decades of f lif life by optimizing detection and tr treatment • Physical characteristics • Family history • Molecular diagnosis • Laboratory data • Prevention • Ultrasound • Intervention
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
Arterial intima-media thickness in childhood: study in familial hypercholesterolemia heterozygotes and their siblings 281 children (8-18 yr) 134 families 201 children with FH 80 non-affected silbings
.60 Mean carotid IMT (mm) .55 est. IMT increase = 0.0047 mm/year .50 0.0044 mm/year p= 0.004 .45 est. IMT increase = 0.0003 mm/year .40 fh controls .35 8 10 12 14 16 18 20 AGE (years)
1.1 IMT (mm) 0.010 mm/year 1.0 LDL-C 7.2 mmol/L .9 0.006mm/year .8 .7 0.004 mm/year .6 .5 LDL-C 3.4 mmol/L .4 10 20 30 40 50 60 70 80 AGE (years) De Groot E e.a. Circulation 2004; 109(S):III33-8
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