Hyperlipidemia in Pediatrics ACC CONFERENCE MAY 6, 2009 SALLY RAVANOS, MD

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1 Hyperlipidemia in Pediatrics ACC CONFERENCE MAY 6, 2009 SALLY RAVANOS, MD

2 Purpose of Screening Multiple adult diseases are now appearing in children and adolescents Type II Diabetes Mellitus Hypertension Cardiovascular disease Obesity Cardiovascular disease is the leading cause of death and morbidity in the US Most often occurs in adulthood Atherosclerosis begins in childhood

3 Known Risk Factors for Adult CVD Increased LDL Decreased HDL Elevated blood pressure Type I or II diabetes mellitus Tobacco abuse Obesity

4 Atherosclerosis

5 Causes of Atherosclerosis Genetic Some people have increased susceptibility to the effects of higher lipid levels Defects in pathways of cholesterol synthesis/breakdown Environmental Increased intake of saturated and trans fats Increased cholesterol intake Increased carbohydrate intake Obesity Metabolic syndrome Decreased physical activity

6 Where does it all begin? Multiple studies of the development of atherosclerosis starting in childhood Bogalusa Heart Study Muscatine Study Cardiovascular Risk in Young Finns Study Pathobiological Determinants of Atherosclerosis in Youth Pathobiological Determinants of Atherosclerosis in Youth (PDAY)

7 Bogalusa Heart Study Followed people from birth to 39 years in Bogalusa, LA Cross sectional surveys of approx 3500 children Seven surveys done since 1973 Five follow up surveys done in young adults since 1978 Autopsies obtained after accidental deaths in study subjects between age 2 and age 39 Findings: Extent of atherosclerosis increased with age Elevated LDL, TG, total cholesterol and decreased HDL correlated with a greater extent of atherosclerosis Increased atherosclerosis with h/o obesity, dyslipidemia, and HTN

8 Muscatine Study Subjects initially recruited in the 1970s between age 8 and 18 years Underwent serial physical exams and laboratory assessments including lipid profiles Were reexamined between age 20 and 34 years Carotid ultrasonography used to evaluate intimal medial thickness (IMT) in adults age 33 to 42 that had been part of the original Muscatine cohort 346 men/379 women Increased IMT in those with h/o increased total cholesterol and obesity/htn in childhood Obesity more predictive in women

9 Cardiovascular Risk in Young Finns Study Approx 2000 adults initially studied in childhood and followed up 21 years later Elevated childhood LDL, systolic blood pressure, increased BMI, and smoking correlated with increased carotid IMT.

10 PDAY Early 1980 s 629 men and 227 women age who died of accidental causes with favorable lipoprotein profiles HDL>35 mg/dl Non-HDL< 160 mg/dl Examined nonlipid risk factors and their effects on atherosclerosis Cardiovascular risk factors Vascular pathologic features of HTN Tobacco abuse Obesity Impaired glucose tolerance Investigators assessed the aorta and coronary arteries for atherosclerosis Increased fatty streaks and fibrous plaques on autopsy were associated with tobacco abuse, hypertension, impaired glucose tolerance and obesity despite normal lipid profiles

11 PDAY Results generated a risk score based on age, sex, non-hdl cholesterol, HDL, smoking, blood pressure, obesity, and hyperglycemia These scores calculated in 18 to 30 yo accurately predicted coronary artery calcification scores in 33 to 45 yo in the CARDIA study

12 Summary of Studies Evidence shows that increased CVD risk factors such as elevated total cholesterol/ldl, HTN, and obesity correlate with faster progression of atherosclerosis both on autopsy and by carotid ultrasonography.

13 AAP Guidelines for Hyperlipidemia Screening New guidelines released in 2008 Increased push for childhood screening because of studies showing increased progression of atherosclerosis in association with CVD risk factors and elevated cholesterol in childhood Also increase in adult illnesses in childhood d has led to increased push for screening Screening should identify children/adolescents with progressive atherosclerosis who are most at risk of CVD in adulthood

14 Lack of Evidence Very little evidence linking childhood CVD risk factors such as hyperlipidemia to adult CV events, such as stroke and MI A trial requiring random assignment of children to a healthy lifestyle and an unhealthy lifestyle for 15 or more years is not feasible and would likely cause harm in the long run

15 When should screening occur? Serum lipid/lipoprotein p p levels vary widely with age. Increase from birth to age 2 to levels similar to young adults LDL/total cholesterol decrease during puberty Screening should take place after age 2 and no later than age 10 Levels also vary with gender and ethnicity

16 Who should be screened? Children and adolescents with family history of dyslipidemia or premature CVD Age 55 or less in men Age 65 or less in women Children and adolescents with unknown family history Children and adolescents with CVD risk factors Overweight (85%<BMI<95%) Obesity (BMI>95%) Hypertension (BP>95%) Smoking Diabetes mellitus

17 What is abnormal? Category Percentile Total Cholesterol, mg/dl Acceptable <75th <170 <110 LDL, mg/dl Borderline 75 th -95th Elevated >95 th >200 >130 Adapted from 1992 NCEP guidelines for children and adolescents AHA guidelines state that TG> 150 mg/dl and HDL < 35 mg/dl should be considered abnormal.

18 Metabolic Syndrome Adult Definition Clinical Measure Waist circumference, cm Lipid levels Triglycerides, gy mg/dl 150 HDL, mg/dl Fasting glucose level, mg/dl >100 Blood pressure, mm Hg 130/85 Any 3 of the following 5 features 102 in men or 88 in women <40 in men or <50 in women There is currently no accepted definition of metabolic syndrome in children and adolescents.

19 Case #1 12 year old male Height and weight at 50 th percentile Total cholesterol 500 mg/dl LDL 300 mg/dl TG 70 mg/dl HDL 45 mg/dl Evidence of xanthomas on physical exam Father with MI at age 30 and multiple relatives with hyperlipidemia

20 Case #2 15year old female Height at 50 th percentile Weight >95 th percentile BMI> 95 th percentile Total cholesterol 250 mg/dl LDL 150 mg/dl Acanthosis nigricans evident on exam

21 Case #3 13year old male Type I diabetes mellitus diagnosed at age 8 Total cholesterol 225 mg/dl HDL 35 mg/dl HgbA1c 8.5%

22 Recommendations for Treatment Population based approach For use in all children and adolescents to prevent development of CVD risk factors Healthy lifestyle Should not be implemented before age 2 Decreased total fat (<30% of calories), saturated fat (<10% of calories), and cholesterol intake (<200mg/day) Increased physical activity Decreased juice and soda intake Decreased trans fat intake (<1%)

23 Treatment Individual approach Used for children and adolescents with risk factors Family history of CVD or hyperlipidemia Personal history of hyperlipidemia, p DM, HTN, obesity, etc Family or personal history of genetic dyslipidemias Heterozygous or homozygous familial hypercholesterolemia Initially focuses on dietary and activity changes, but can progress to pharmacologic intervention if LDL not lowered enough Dietary changes Saturated fat <7% of total calories Cholesterol <200mg/day

24 Non-pharmacologic interventions Dietary changes Increased physical activity Increases HDL Decreases triglycerides Increased soluble fiber intake Binds with cholesterol l in bile acids to remove it from enterohepatic circulation Child s age + 5g/day to max of 20g/day at age 15 Plant stanols and sterols Decrease absorption of dietary cholesterol

25 When do pediatricians use medications? Patient Characteristics Recommended Cut Points No CVD risk factors LDL persistently >190 despite diet therapy CVD risk factors present LDL persistently >160 despite diet therapy Children with diabetes mellitus LDL 130 Medications i only used if patients are 8 years old, but can be used in younger patients with extremely elevated cholesterol (e.g., LDL >500). More aggressive treatment would also be indicated in children with diabetes, renal disease, congenital heart disease, collagen vascular diseases, and childhood cancer survivors.

26 Bile-Acid Binding Resins Bind cholesterol in the intestinal lumen to prevent reuptake via enterohepatic circulation 10-20% decrease in cholesterol below baseline Side effects Gastrointestinal discomfort Bloating Cramping Constipation Dosage forms difficult for children Granular powder to be mixed with liquid Large unbreakable tablet

27 Niacin Lowers LDL and triglycerides Increased HDL Decreases hepatic production of VLDL and may lower lipoprotein i (a) Side effects are prohibitive of use in children Flushing (76%) Hepatic failure (increased transaminases in 24%) Myopathy Glucose intolerance Hyperuricemia Not recommended for routine use in pediatrics

28 3-HMG CoA Reductase Inhibitors (Statins) Inhibit the rate-limiting enzyme in endogenous cholesterol synthesis Lowers intracellular cholesterol Upregulates LDL receptors Increased clearance of LDL from circulation Side effects (sometimes more severe in kids) Increased LFT s Increased CK rhabdomyolysis Teratogenesis Several clinical trials have revealed that short-term term statin use is safe and effective One study demonstrated improvement in endothelial function with statins

29 Cholesterol-Absorption Inhibitors Ezetimibe Questionable effect in adults Side effects Gastrointestinal discomfort Small, easily tolerated tablet

30 Fibrates Inhibit the synthesis and increase the clearance of VLDL apoprotein B decrease in VLDL production decreased triglyceride levels No extensive studies in children

31 Back to the cases How would you treat these patients? Case #1 Case #2 Case #3

32 Summary of AAP Guidelines Screen with fasting lipid panel using LDL-C as the target for therapy Screen those children with family history or other CVD risk factors between 2 and 10 years of age Recheck fasting lipids every 3-5 years If over age 8 and LDL-C over 190 (160 with risk factors, 130 with DM), treat with a drug (likely a statin)

33 Problems with Recommendations Cost effectiveness of screening so many children Risk of labeling Safety of long-term drug treatment for hyperlipidemia is unknown in children Safety has only been tested in the short term in those with familial l hypercholesterolemiah l Some concerns regarding statins affecting growth and development

34 References Daniels SR, Greer FR; American Academy of Pediatrics, Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008; 122(1): Haney EM,et al. Screening and Treatment t for Lipid id Disorders in Children and Adolescents: Systematic ti Evidence Review for the US Preventive Services Task Force. Pediatrics. 2007; 120(1): Steiner MJ, Brown WD, and E Liles. An Assessment of the New Lipid Screening Guidelines. Pediatrics. 2008; 122: Raitakari OT, Juonala M, Kahonen M, et al. Cardiovascular Risk Factors in Childhood and Carotid Artery Intima-Media Thickness in Adulthood: The Cardiovascular Risk in Young Finns Study. JAMA. 2003; 290(17): Davis PH, Dawson JD, Riley WA, and Lauer RM. Carotid Intimal-Medial Thickness is Related to Cardiovascular Risk Factors Measured from Childhood Through Middle Age: The Muscatine Study. Circulation. 2001; 104; McCrindle BW, Urbina EM, Dennison BA, Jacobson MS, Steinberger J, Rocchini AP, Hayman LL, and SR Daniels. Drug Therapy of High-Risk Lipid Abnormalities in Children and Adolescents: A Scientific Statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council on Cardiovascular Disease in the Young, With the Council on Cardiovascular Nursing. Circulation. 2007; 115; Kwiterovich PO. Recognition and Management of Dyslipidemia in Children and Adolescents. J Clin Endocrinol Metab. November 2008, 93 (11): Kavey RW, et al. Cardiovascular Risk Reduction in High-Risk Pediatric i Patients: t A Scientific Statement t t from the American Heart Associatino Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: Endorsed by the American Academy of Pediatrics. Circulation. 2006; 114;

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