LIPID CLUB Rome, 2014

Transcription

1 LIPID CLUB Rome, 2014 June the 6h 6th Hyperlipidaemia in FH Children Ornella Guardamagna University of Torino

2 DICLOSURES Medpace Kowa DSMB member MSD, Pfizer, Synageva Investigator in industry funded trials

3 FAMILIAL HYPERCHOLESTEROLEMIA FAITH AND CRITICISM CHOLESTEROL IMPACT ON CVD DIAGNOSTIC TOOLS THERAPEUTIC STRATEGIES

4 DIFFERENT STAGES OF ATHEROSCLEROTIC PLAQUE DEVELOPMENT

5 FIBROUS PLAQUE AT AUTOPSY The Bogalusa Heart Study Berenson GS. Am J Med Sci 2001

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8 CHD in homozygous (n. 40) and compound heterozygous (n. 23) ADH 1 patients LDL receptor defective (RD) and LDL receptor negative (RN) mutations RD RN 20 0 < > 40 Age (years) Bertolini,Atherosclerosis 2013

9 Coronary angiography: complete obstruction of the left coronary artery boy, died 5yrs old LDL c=26 mmol/l M Macchiaiolo, Lancet 2012

10 MUSCATINE STUDY ADULT CIMT AND CHILDREN RFS Davis PH, Circulation 2001

11 PEDIATRIC GUIDELINES 1992 NCEP Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics 1992;89; Cholesterol in Childhood. Committee on Nutrition. Pediatrics 1998; 101; American Heart tassociation Guidelines for Pi Primary Prevention of Atherosclerotic ti Cardiovascular Disease Beginning in Childhood. Circulation 2003;107; Dietary Recommendations for Children and Adolescents: A Guide for Practitioners. American Heart Association. Pediatrics 2006;117; Lipid Screening and Cardiovascular Health in Childhood. Pediatrics 2008;122: Health and Risk Reduction in Children and Adolescents. AAP Pediatrics 2011;128 s 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

12 DIAGNOSTIC TOOLS Which clinical phenotype Which LDL C levels Which pedigree Which age

13 Tendon xanthomatosis in HeFH 1769 ADH 1 heterozygous patients carrying pathogenic mutations of LDLR gene, according to age Males Females > 60 Age (years) Bertolini,Atherosclerosis 2013

14 TENDON XANTHOMAS AT THE KNEES, WRISTS AND ACHILLES in HoFH 5yrs old ldboy M Macchiaiolo, Lancet 2012

15 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

16 FH with homozygous or compound heterozygous mutations M/F 25/25 Age (years) (1-57) TC (mg/dl) ( ) LDL-C (mg/dl) ( ) HDL-C (mg/dl) (16-52) TG (mg/dl) (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

17 LDL cholesterol distribution in subjects <18 years belonging to 230 families genetically characterized Frequency (%) < > non FH LDL cholesterol (mg/dl) Bertolini S, by courtesy 2012 FH

18 DIAGNOSIS: Lipoprotein changes and age Morrison J.Metabolism 1979,28,641

19 DIAGNOSIS which lipoprotein levels Lipids in Subjects Aged 5 to 19 Years SR Daniels, Pediatrics 2008

20 COLESTEROLEMIA IN FH CHILDREN VS Laboratory data CONTROLS Wiegman A, EAP 2010 p<0.001 ^ LDL-c cholester rol in mm mol/l 12 p< ^ p<0.001 ^ 2 0 Data by LIPID Wiegman CLUB,ROME 2014 A N = 415 nonfh 108 FDB 1358 heterofh 10 homofh

21 Family History and Cardiovascular Risk in Familial Hypercholesterolemia Child with LDL C mmol mmol/l (135 mg/dl dl) and one parent with definite FH has 0.98 (95% CI: ) 0.99) post test test probability of heterozygosity for LDL receptor mutation Wiegman A, Circ 2003

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23 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

24 FH: Autosomal inheritance ADH GENE PREVALENCE PICTURE FH1 (classical FH) LDLR :500 1:500 HeFH: TC mg/dl 19p13 1:1,000,000 xanthomas, pchd (40 60 yrs) HoFH: TC mg/dl Xanthomas, very precocious pchd (<10yrs) FH2 (FDB) ApoB2 p :700 HeFH: TC mg/dl xanthomas, pchd (50 60 yrs) HoFH: TC >500 mg/dl Xanthomas, pchd (<30yrs) FH3 PCSK9 1p32 VERY RARE HeFH3: TC mg/dl Xanthomas, pchd ARH LDLR AP1 rare HoFH phenocopy Sniderman AD,JACC 2014 Sniderman Ad, et al. J Am Coll Cardiol ;63(19):

25 DIAGNOSIS additional markers Gene analysis Mutation detection Biochemistry Endotelial wall Lp(a) Inflammatory markers Hs CRP Selectins c IMT FMD

26 LDLR MUTATIONS and HeFH LIPOPROTEIN PROFILE O Guardamagna et al, J Ped 2009

27 Overlap of clinical and mutation diagnosis of heterozygous familial hypercholesterolaemia

28 SIMON BROOME SCORE PROBABLE FH

29 P SELECTIN AND HS CRP IN DYSLIPIDEMIC CHILDREN Guardamagna O et al. Atherosclerosis 2009

30 Lp(a) and pcvd Rischio pcvd ridotto Rischio pcvd aumentato Lp(a) predicts pcvd (OR 2.5, 95% IC: , p=0.01) Guardamagna O, J Pediatrics 2011

31 lipids/361/johan gort

32 cimt in HeFH CHILDREN A Wiegman, Lancet 2004

33 FH Prevalence and diagnosis in different countries Michael Livingston, Steve E. Humphries (UK), Olivier S. Descamps (Belgium)

34 FH homozygotes (frequencies) NORTHERN ITALY 1: CENTRAL ITALY 1: SOUTHERN ITALY 1: ITALIAN ISLANDS 1:

35 Estimated millions of individuals world wide with familial hypercholesterolaemia

36 SCREENING QUESTIONS who to screen how to screen when to screen

37 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):

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39 At 1 9 yrs Overlap di LDL C tra controlli ed FH a diverse età At yrs D Wald,BMJ 2007

40 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

41 THERAPEUTIC STRATEGIES FOOD SUPPLEMENTARY AND NOVEL FOODS DRUGS

42 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

43 Results: The DISC study p<0,001 p<0,05 Perez Jimenez F, Atherosclerosis 2002

44 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

45 DIETARY SUPPLEMENT Fiber Fitosterol RYR and Policosanol Probiotic?

46 LDL-C and ApoB REDUCTION IN CHILDREN AFTER PHYTOSTEROL TREATMENT (3 MONTHS) p=0, p=0,01 P <0, , FH FCHL IPERCT FH FCHL IPERCT BASAL APOB POST PHYTO APOB BASAL LDL C POST PHYTO PHYTO LDL C Guardamagna O, Acta diabetol 2011

47 Treatment goal is to reduce LDL-C under the 95 percentile (135 mg%) if possible under 90 percentile (110mg%) Guidelines AAP 2011 NUTRITION DRUG

48 DRUG TREATMENT THE BIG BIG MATTER To Treat or not to Treat? Selecting the patients Treatment Options Target levels When to start

49 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

50 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 % 0 H.J. Avis, ATVB 2007

51 PLUTO STUDY: ROSUVASTATINA IN BAMBINI FH Avis HJ et al. JACC 2010

52 ADVERSE EFFECT OF STATIN IN CHILDREN Avis HJ,Curr Opin Invest Drugs 2009

53 LDL-C burden of FH treated patients Vuorio, Atherosclerosis 2013

54 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

55 DIAGNOSIS the practice patients t FH 13% 4% 1% 28% 31% 23% FCHL IperCT IperLp(a) IperTG Rare

56 Prevalence (%) of CAD in homozygous and compound heterozygous FH and ARH patients FH ARH 20 0 < Age (years) Bertolini,by courtesy