LIPID CLUB Rome, 2014 June the 6h 6th Hyperlipidaemia in FH Children Ornella Guardamagna University of Torino
DICLOSURES Medpace Kowa DSMB member MSD, Pfizer, Synageva Investigator in industry funded trials
FAMILIAL HYPERCHOLESTEROLEMIA FAITH AND CRITICISM CHOLESTEROL IMPACT ON CVD DIAGNOSTIC TOOLS THERAPEUTIC STRATEGIES
DIFFERENT STAGES OF ATHEROSCLEROTIC PLAQUE DEVELOPMENT
FIBROUS PLAQUE AT AUTOPSY The Bogalusa Heart Study Berenson GS. Am J Med Sci 2001
CHD in homozygous (n. 40) and compound heterozygous (n. 23) ADH 1 patients LDL receptor defective (RD) and LDL receptor negative (RN) mutations 100 80 60 40 RD RN 20 0 < 10 11-20 21-30 31-40 > 40 Age (years) Bertolini,Atherosclerosis 2013
Coronary angiography: complete obstruction of the left coronary artery boy, died 5yrs old LDL c=26 mmol/l M Macchiaiolo, Lancet 2012
MUSCATINE STUDY ADULT CIMT AND CHILDREN RFS Davis PH, Circulation 2001
PEDIATRIC GUIDELINES 1992 NCEP Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics 1992;89;495 501 Cholesterol in Childhood. Committee on Nutrition. Pediatrics 1998; 101;141 147 American Heart tassociation Guidelines for Pi Primary Prevention of Atherosclerotic ti Cardiovascular Disease Beginning in Childhood. Circulation 2003;107;1562 1566 Dietary Recommendations for Children and Adolescents: A Guide for Practitioners. American Heart Association. Pediatrics 2006;117;544 559 Lipid Screening and Cardiovascular Health in Childhood. Pediatrics 2008;122:198 208 Health and Risk Reduction in Children and Adolescents. AAP Pediatrics 2011;128 s5 2013 FH individuals should be treated in primary care while complex cases including children should be referred to specialized lipid or FH clinics Eur Heart Journal, 2013
DIAGNOSTIC TOOLS Which clinical phenotype Which LDL C levels Which pedigree Which age
Tendon xanthomatosis in HeFH 1769 ADH 1 heterozygous patients carrying pathogenic mutations of LDLR gene, according to age. 60 50 40 30 Males Females 20 10-0 11-20 21-30 31-40 41-50 51-60 > 60 Age (years) Bertolini,Atherosclerosis 2013
TENDON XANTHOMAS AT THE KNEES, WRISTS AND ACHILLES in HoFH 5yrs old ldboy M Macchiaiolo, Lancet 2012
FAMILIAL HYPERCHOLESTEROLEMIA PHENOTYPES Homozygote Double or Compound Heterozygote tendon and cutaneous xantomas Coronaropathy (very precocious) Aortal arch stenosis LDL C >300 mg/dl Heterozygote Very rare clinical features Hypercholesterolemia: LDL C 95 percentile
FH with homozygous or compound heterozygous mutations M/F 25/25 Age (years) 23.1 16.4 (1-57) TC (mg/dl) 723.1 174.8 (381-1246) LDL-C (mg/dl) 665.7 177.1 1 (309-1183) HDL-C (mg/dl) 31.8 9.1 (16-52) TG (mg/dl) 116.3 40.0 (62-220) Tx 92.0% Tux 67.0% Px 56.0% CAD 62.5% (21% within the second decade of life) Mean SD (range) Bertolini 2013,by courtesy
LDL cholesterol distribution in subjects <18 years belonging to 230 families genetically characterized Frequency (%) 35 30 25 20 15 10 5 0 <60 81-100 121-140 161-180 201-220 241-260 281-300 321-340 >360 61-80 101-120120 141-160 160 181-200 221-240 240 261-280 280 301-320 320 341-360 360 non FH LDL cholesterol (mg/dl) Bertolini S, by courtesy 2012 FH
DIAGNOSIS: Lipoprotein changes and age Morrison J.Metabolism 1979,28,641
DIAGNOSIS which lipoprotein levels Lipids in Subjects Aged 5 to 19 Years SR Daniels, Pediatrics 2008
COLESTEROLEMIA IN FH CHILDREN VS Laboratory data CONTROLS 16 14 Wiegman A, EAP 2010 p<0.001 ^ LDL-c cholester rol in mm mol/l 12 p<0.001 10 ^ 8 6 4 p<0.001 ^ 2 0 Data by LIPID Wiegman CLUB,ROME 2014 A N = 415 nonfh 108 FDB 1358 heterofh 10 homofh
Family History and Cardiovascular Risk in Familial Hypercholesterolemia Child with LDL C 3.5 35mmol mmol/l (135 mg/dl dl) and one parent with definite FH has 0.98 (95% CI: 0.96 0.99) 0.99) post test test probability of heterozygosity for LDL receptor mutation Wiegman A, Circ 2003
DOMINANT INHERITANCE 65 yrs pcvd,tx LDL C 220 mg/dl 35 yrs pcvd LDL C 230 mg/dl Smoker 38 yrs pcvd+ LDL C 200 mg/dl Smoker 37 yrs pcvd LDL C 210 mg/dl C.A.6 yrs LDL 160 mg/dl AA.8 yrs LDL C 480 mg/dl
FH: Autosomal inheritance ADH GENE PREVALENCE PICTURE FH1 (classical FH) LDLR 1.300 1:500 1:500 HeFH: TC 250 500500 mg/dl 19p13 1:1,000,000 xanthomas, pchd (40 60 yrs) HoFH: TC 600 1200 mg/dl Xanthomas, very precocious pchd (<10yrs) FH2 (FDB) ApoB2 p23 24 24 1:700 HeFH: TC 250 500 mg/dl xanthomas, pchd (50 60 yrs) HoFH: TC >500 mg/dl Xanthomas, pchd (<30yrs) FH3 PCSK9 1p32 VERY RARE HeFH3: TC 250 400 mg/dl Xanthomas, pchd ARH LDLR AP1 rare HoFH phenocopy Sniderman AD,JACC 2014 Sniderman Ad, et al. J Am Coll Cardiol. 2014. 20;63(19):1935 1947
DIAGNOSIS additional markers Gene analysis Mutation detection Biochemistry Endotelial wall Lp(a) Inflammatory markers Hs CRP Selectins c IMT FMD
LDLR MUTATIONS and HeFH LIPOPROTEIN PROFILE O Guardamagna et al, J Ped 2009
Overlap of clinical and mutation diagnosis of heterozygous familial hypercholesterolaemia
SIMON BROOME SCORE PROBABLE FH
P SELECTIN AND HS CRP IN DYSLIPIDEMIC CHILDREN Guardamagna O et al. Atherosclerosis 2009
Lp(a) and pcvd Rischio pcvd ridotto Rischio pcvd aumentato Lp(a) predicts pcvd (OR 2.5, 95% IC: 1.16 5.63, p=0.01) Guardamagna O, J Pediatrics 2011
lipids/361/johan gort
cimt in HeFH CHILDREN A Wiegman, Lancet 2004
FH Prevalence and diagnosis in different countries Michael Livingston, Steve E. Humphries (UK), Olivier S. Descamps (Belgium)
FH homozygotes (frequencies) NORTHERN ITALY 1: 2.814.000 CENTRAL ITALY 1: 2.500.000 SOUTHERN ITALY 1: 580.000 ITALIAN ISLANDS 1: 551.000
Estimated millions of individuals world wide with familial hypercholesterolaemia
SCREENING QUESTIONS who to screen how to screen when to screen
SCREENING Strategies from 5 EU Countries 2011 POPULATION COUNTRY SCREENING 4 yrs child of FH family Netherlands CASCADE 4 yrs child of FH family 5 yrs children Child. of dyslip+/cvd+ 10 yrs child of FH family Norway Slovenia Italy UK CASCADE UNIVERSAL SELECTIVE CASCADE Kusters DM et al, Arch dis child 2011;97(3): 272 6.
At 1 9 yrs Overlap di LDL C tra controlli ed FH a diverse età At 20 39 yrs D Wald,BMJ 2007
Cardiovascular Risk Reduction in High Risk Pediatric Patients (AHA Scientific Statement) CURRENT RECOMMENDATION : screen children adolescents with 1. positive family history of dyslipidemia or premature CVD ( 55 years of agefor men and 65years of agefor women). 2. all children at age 9 11 Daniels et al. Pediatrics 2011
THERAPEUTIC STRATEGIES FOOD SUPPLEMENTARY AND NOVEL FOODS DRUGS
FOOD Special Turku Coronary Risk Factor Intervention Project (Strip study) Dietary Intervention Study in Children (Disc Study) Randomized prospective Study, N 1062 infants> 7months 60 mesi Follow-up Randomized double blind Study N= 663 children 8-10 yrs 7.4 yrs follow-up General Popolation Recruitment : 80 <LDL-C<98 percentile Fat Content : total 30-35% Satured:PUFA=1:2 Cholesterol < 200 mg/day Primary End point : CT reduction Fat Content: Total 28%, Satured <8%,PUFA <9% Primary End point: CT reduction Rask-Nissila L et al. Circulation 2000 Obarzanek E et al. Pediatrics 2001
Results: The DISC study p<0,001 p<0,05 Perez Jimenez F, Atherosclerosis 2002
LIFESTYLE APPROACH FOOD PHYSICAL ACTIVITY 1-2 hrs A DAY Diet: CHILD I, since 2yrs, allowed Satured fats can be restricted since 12 months CHILD II: LIPIDS 25-28% DANIELS, PEDIATRICS 2011 M Mitka, JAMA 2012
DIETARY SUPPLEMENT Fiber Fitosterol RYR and Policosanol Probiotic?
LDL-C and ApoB REDUCTION IN CHILDREN AFTER PHYTOSTEROL TREATMENT (3 MONTHS) p=0,07 250 200 150 100 50 0 p=0,01 P <0,01 150 125 100 75 50 25-16,5-22.9-19.2 0 FH FCHL IPERCT -13.8-14.8-12.3 FH FCHL IPERCT BASAL APOB POST PHYTO APOB BASAL LDL C POST PHYTO PHYTO LDL C Guardamagna O, Acta diabetol 2011
Treatment goal is to reduce LDL-C under the 95 percentile (135 mg%) if possible under 90 percentile (110mg%) Guidelines AAP 2011 NUTRITION DRUG
DRUG TREATMENT THE BIG BIG MATTER To Treat or not to Treat? Selecting the patients Treatment Options Target levels When to start
American Academy of Pediatrics GUIDELINES 2011 Daniels SR et al. Pediatrics 2011 Drugs to children older than 10 yrs if: LDL-C >190 mg/dl without other risk factors LDL-C >160 mg/dl if familial CAD positive history or at least 2 risk factors (HDL-C reduction, hypertension, obesity) are present LDL-C>130 mg/dl if diabetes is present PRAVASTATIN: first choice drug LDL-C >500 mg/dl drugs can be delivered before 10 yrs of age
LDL C (%) CHANGE ON STATIN THERAPY WMD (95% CI) ATORVASTATINA 10, 20 mg SIMVASTATINA 40 mg LOVASTATINA 40 mg LOVASTATINA 40 mg PRAVASTATINA 40 mg PRAVASTATINA 20 mg PRAVASTATINA 20 mg McCrindle 2003 De Joungh 2002 Clauss 2005 Stein 1999 Wiegman 2004 Wiegman 2004 Knipscheer 1996 50% 0 H.J. Avis, ATVB 2007
PLUTO STUDY: ROSUVASTATINA IN BAMBINI FH Avis HJ et al. JACC 2010
ADVERSE EFFECT OF STATIN IN CHILDREN Avis HJ,Curr Opin Invest Drugs 2009
LDL-C burden of FH treated patients Vuorio, Atherosclerosis 2013
CONCLUSIONS FAITH AND CRITICISM TEST AS SOON AS POSSIBLE SCREENING method Pedigree Normalize LIFESTYLE Confirm 3 6 months later Exclude secondary LDLc exceeds 130 mg/dl Drug starting age LONG TERM OUTCOME
DIAGNOSIS the practice 2002 20142014 677 patients t FH 13% 4% 1% 28% 31% 23% FCHL IperCT IperLp(a) IperTG Rare
Prevalence (%) of CAD in homozygous and compound heterozygous FH and ARH patients 100 100 80 80 60 60 40 40 FH ARH 20 0 < 10 11-20 21-30 31-40 41-50 51-60 Age (years) Bertolini,by courtesy