Francesco Martino. Diagnosis of FH and dyslipidaemia in childhood: the why and how. The therapy?
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1 Dipartimento di Pediatria e Neuropsichiatria Infantile Policlinico Umberto I Sapienza Università di Roma Francesco Martino Diagnosis of FH and dyslipidaemia in childhood: the why and how. The therapy?
2 Atherosclerosis is a process that is already detectable in children, even at the fetal stage
3 maternal nutritional imbalances maternal hypercholesterolemia maternal obesity gestational Diabetes smoke Abuse of drugs or alcohol viral infections environmental pollutants Hereditary genetic factors Reprogramming of fetal metabolic gene targets - DNA methylation / inactive chromatin - Histone deacetylation / inactive chromatin -mirna / genes inhibition translation Early cardiovascular risk marckers in infant / child (overweight / obesity - hypertension - dyslipidemia - hyperglycemia - insulin resistance) atherosclerosis
4 Atherosclerosis from childhood to adulthood FASEB J (2002);16: (modified) The cardiovascular risk factors may act at any age dyslipidemia obesity hypertension diabetes sedentary lifestyle (Predominant in adulthood) smoke alcohol stress Family history of premature CVD in relatives of 1st and 2nd degree atheroma rupture of plaque stenosis early fatty streaks fetus fatty streaks children Martino et all. adult atherosclerotic diseases
5 Lipid risk factors for CVD Hypercholesterolemia Hypertriglyceridemia Reduction of HDL High concentrations of apob Small dense LDL Lipoprotein (a)
6 PEDIATRIC DYSLIPIDEMIAS Medication-related dyslipidemia Dyslipidemia related to lifestyle factors Dyslipidemia secondary to a medical condition Genetic dyslipidemia
7 vs. 1/200 Recently direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. J Clin Endocrinol Metab 2012;97: Endocrinol Metab Clin N Am 43 (2014)
8 In Italy only for 1% of people with heterozygous FH is made a correct diagnosis. European Heart Journal (2013) 34,
9 Pathophysiology of heterozygous FH Elevated LDL col. Only 50% funzional LDLR Mutations (~ 1700) in: LDLR (79%), apolipoprotein B (~5%) PCSK9 (<1%) unidentified genes (5 30%) Atherosclerosis CVD
10 Cardiovascular risk factors Angiotensin II, oxygen radicals, shear stress foam cells NO Oxidative stress OxLDL-C macrophages Endothelial dysfunction
11 cholesterol and Cellular activation in hypercholesterolemic children oxidative stress PLATELETS Martino F et al. scd40l J Am Coll Cardiol (2007); 49 (19): Martino F et al. J Am Coll Cardiol 2007;49: GP91phox Martino F Martino et al. F et al. Pediatrics Pediatrics 2008;122: ;122: Violi F et al. Circulation. 2009;120:
12 MONOCYTES Cellular activation in hypercholesterolemic children cholesterol and Mieloperossidasi P.Pignatelli, L.Loffredo, F. Martino et al. Atherosclerosis. 2009; 205: oxidative stress Down regulation of CD11b and CD18 Martino F. et al. NMCD; 2009;19:
13 0,6 0,5 0,4 0,3 0,2 0,1 0,0 mm IMT * NC HC *p< NC HC Martino F.et all. Pediatrics. 2008;122:e FMD *p< 0.005
14 J Pediatr 2012 Dec;161(6):
15
16 Medicine (Baltimore) Sep;93(12):e71. doi: /MD
17 Medicine (Baltimore) Sep;93(12):e71.
18 need to identify Strategies for Detection of and treat early FH in childhood children and teenagers with dyslipidemia and cascade screening of families using a other risk factors combined phenotypic and genotypic strategy for CVD universal screening selective screening based on family history
19 Survey on cholesterol in childhood Basilicata, Calabria, Lazio TOTAL COLESTEROL (mg/ dl) children (n) children (%) unknown value , ,6 > ,0 school districts in Rome unknown value ,5 npublished data ,3 > ,2
20 Calabrian Sierras Community Study (CSCS) children Blood Pressure are not related to: Blood Lipids
21 TOTAL CHOLESTEROLEMIA An epidemiological study performed on Italian students 19% Calabrian Sierras Community Study (CSCS) children 55% 12% 71% 14% 9% Fondi Study (~200 children) preliminary data 6% 14% up to 170 from 170 to 180 from 180 to 200 over 200 Cholesterolemic values in mg/dl
22 Prevalence of metabolic syndrome Age years MS N total subjects Diagnostic % criteria used for the diagnosis of MS 4,2 4,4 4,7 3,6 4,2 MS based on the percentile distributions: ( 90th for WC, triglycerides, blood M glucose, 43/870 = and 4,9% systolic or diastolic BP F 27/787 = 3,4% and 10th to HDL cholesterol) International Journal of Cardiology 177 (2014)
23 TOTAL CHOLESTEROLEMIA An epidemiological study performed on 750 Italian families PAEDITRIC LIPID CLINIC DEPARTMENT OF PEDIATRICS SAPIENZA UNIVERSITY ROME 20,2 9,9 8,2 18, ,3 50,3 18,8 4,3 PROBANDS up to 170 from 170 to 180 from 180 to 200 from 200 to 300 over 300 2,3 SIBLINGS Cholesterolemic values in mg/dl
24 .three new mutations of the LDLR gene (G266C, T368M and D451Y) have been identified.
25 Editorial Lipid concentrations in children and adolescents: it is not all about obesity
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27 LIPOPROTEIN CHANGES DURING THE HYPERTRIGLYCERIDEMIA (Pattern B) TG LDL2 lipoproteinlipase LDL3 hepatic lipase TG CETP HDL HDL2 HDL3
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30 The screening of LPL led to identify 8 exonic variants. Most of them have been previously reported, while the p.ser45asn variant is described here for the first time
31 The Mediterranean style as an elixir for CVD prevention PEOPLE HABIT AVOID THE EARLY ADIPOSITY REBOUND ADEQUATE INTAKE: ENERGY,MICRO AND MACRONUTRIENTS intervention strategies PROMOTE BREASTFEEDING WEANING from about J Phys Act Health 2012 Jul;9(5): months of age. Nutr Metab Cardiovasc Dis 2014 Jan;24(1): PUBERTY ADOLESCENCE (plan interventions and education programs for preventing CVD)
32 MEDITERRANEAN DIET RICH IN: deriving from ANTIOXIDANTS SUBSTANCES Fruit Olive oil vegetable Fish (ac.grassi ω3) FIBERS AND FOLIC ACID beans from San Nicola village "Suriaca Russa Janca" COMPLEX CARBOHYDRATES Pasta and bread
33 Poor or less Activity Twice a week LUDIC ACTIVITY ANAEROBIC ACTIVITY AEROBIC ACTIVITIES Bike Swimming Long walks Alternate days Every day ONE HOUR WALK (or more if possible) SPORTS Tennis - Basket Volleyball ecc. go up and down stairs San Nicola Village SCHEDULE of ACTIVITIES
34 breakfast dinner 5 Meals snack in the morning Treatment afternoon for snack lunch Lifestyle modification through exercise and diet remains the front-line treatment for children with abnormal lipid levels dyslipidemic for children older than 2 years children total fat 30% daily calories saturated fat 7-10% MUFA 10% PUFA 10% Protein 15-20% Carbohydrate 50-55% cholesterol limited to mg/day.
35 Fibers that reduce blood cholesterol levels Beet fiber Guar gum Karaya gum Konjac mannan Locust-bean gum Pectin Psyllium seed Soybean polysaccharide Xanthan gum dietary supplementation
36 VISCOSITY OF SOME WATER-SOLUBLE FIBERS GLUCOMANNAN XANTHAN PSYLLIUM 12,0 x 10-1 cp 6,2 x 10-1 cp 2,1 x 10-1 cp Kim E et al.: J Nutr (1996): 29:
37 Glucomannan is not absorbed by the body however it slows down the absorption of carbohydrates and inhibits the absorption of lipids
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39 Effect of glucomannan on plasma lipid and glucose concentrations, body weight, and blood pressure: systematic review and meta-analysis Nitesh Sood, Am J Clin Nutr 2008;88:
40
41
42
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44 Marjet J.A.M et all
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46 New treatment options to lower LDL cholesterol levels have been testing in randomized clinical trials.
47
48 Take home message Cohort studies show that subclinical atherosclerosis is a progressive disease that arises in childhood and continues through the adulthood. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population. In order to prevent CVD later in life, children with hypercholesterolemia should be identified and treated as early as possible. Lifestyle modification through exercise and diet remains the front-line treatment for children with abnormal lipid levels.
49 Take home message Glucomannan alone or in combination with low-dose chromium-polynicotinate or policosanol was able to significantly reduce total cholesterol and LDL-cholesterol without changing HDL-cholesterol, triglycerides and glucose. When the effects of life-style modification are not sufficient, drug terapy should be considered in boys aged 8 to 10 years or older or girls experiencing menarche
50 Dipartimento di Pediatria e Neuropsichiatria Infantile Policlinico Umberto I Sapienza Università di Roma Thanks for your attention
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