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Controversies in Management of Lipids in Children & Adolescents

Ramin Alemzadeh, MD

Professor of Pediatrics

Director, CHW Diabetes Center

Medical College of Wisconsin


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Objectives Adolescents

  • Cholesterol Metabolism

  • Factors affecting Cholesterol metabolism

  • Etiologies & Prevalence of Hypercholesterolemias

  • Cholesterol as a cardiovascular risk factor

  • Approaches of Cholesterol Screening

  • Discuss the use of lipid lowering therapy & recommendations for use of HMG-CoA reductase inhibitors (STATINS)

  • Conclusions


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Dietary Cholesterol Adolescents

VLDL cholesterol

via liver synthesis

Cholesterol synthesis

Acetyl CoA

viaCirculation

LDL cholesterol

HMG-CoA

HMG-CoA reductase

Uptake via LDL receptor

Mevalonate

Intracellular Fates: esterification by ACAT and storage;

steroid hormone/ vitamin D synthesis

Cellular Cholesterol

Esterification/removal by LCAT/HDL

CE in HDL

Cholesterol excretion as bile acids

Bile Acids

(lipid absorption)

A

X

Liver uptake via apo E receptor

B

X

Cholesterol in liver partly metabolized

Summary of cholesterol metabolism.

A and B represent feedback repression of these enzymes

ACAT: acyl CoA:cholesterol acyltransferase; LCAT: lecithin:cholesterol acyltransferase


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Role of Cholesterol in The Body Adolescents

  • Importance of cholesterol synthetic pathway in body

    • component in cell membranes

    • cell proliferation

    • transmembrane signaling and important cellular functions

  • Importance of cholesterol in the brain

    • Important component in myelin sheaths

    • Brain cholesterol accounts for 25% of total body store

    • Promotes Synaptogenesis & neuronal plasticity

  • Precursor for steroid hormones such as cortisol, aldosterone, estrogen and testosterone

  • Precursor for bile salts


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Etiologies of Hypercholesterolemia Adolescents

  • Primary causes (genetic defects)

    • Heterozygous familial hypercholesterolemia (heFH)-AD

    • Homozygous familial hypercholesterolemia

    • Familial combined hyperlipidemia (hyperapobetalipoproteinemia)

    • Polygenic hypercholesterolemia

  • Secondary causes

    • Obesity

    • Hypothyroidism

    • Cholestasis

    • Immunosuppressive Rx in oncology & transplant patients

    • Antiretroviral therapy in HIV-infected children

    • Use of steroids

    • Systemic lupus erythematosus


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Heterozygous Familial Adolescents Hypercholesterolemia (heFH)

  • Autosomal dominant mode of inheritance

  • Prevalence: 1 in 500 worldwide

  • Total cholesterol: 270-500 mg/dL

  • ~50% of men experience a cardiovascular event (CVE) by age 50 years

  • Only 15% of men reach 65 years without experiencing a CVE


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Homozygous Familial Hypercholesterolemia Adolescents

  • Total Cholesterol > 500 mg/dL

  • Relatively normal TG

  • Severe Defect in LDL receptor

  • Occurs in about 1 in 1 million persons

  • Tuberous or tendon xanthomas

  • Symptoms of vascular disease before puberty

  • Rarely survive beyond 2nd decade of life

  • Little or no response to drugs

  • Respond to plasmapheresis and LDL- apheresis


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Concentrations of Total and LDL Cholesterol Among Children & Adolescentsin the U.S.

  • NHANES 1999 to 2006 for participants 6 to 17 years of age.

  • The mean concentration of total cholesterol among participants 6 to 17 years of age was 163.0 mg/dL (n=9868).

  • The mean concentration for LDL-C for participants 12 to

  • 17 years of age was 90.2 mg/dL (n=2724).

  • An elevated concentration of total cholesterol (95th% for age & gender: 191-208 mg/dL) for 9.6% to 10.7%.

  • An elevated concentration of LDL-C (95th% for age & gender: 133-137 mg/dL) was noted for 5.2% to 6.6% of participants.

  • Approximately 0.8% (n=26) of adolescents 12 to 17 years of age were potentially eligible for pharmacological treatment for elevated concentrations of LDL-C.

Ford ES et al Circulation 2009


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Concentrations of Total and LDL Cholesterol Among Children & Adolescentsin the U.S.

Ford ES et al Circulation 2009


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Cholesterol is a Risk Factor AdolescentsNot a Disease

Belay, et al. Pediatrics 2007;119:370-380


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The Atherosclerotic Process in Children Adolescents

  • Atherosclerotic disease begins in childhood

    • Autopsies of young Korean and Vietnam veterans

    • Pathobiological Determinants of atherosclerosis in Youth (PDAY): victims of accidental trauma, suicide, or homicide

    • Bogalusa Heart Study: victims of accidents or suicide

  • Lipid levels show strong genetic & environmental components:

    • Monogenic dyslipidemias

    • High fat diet, polygenic disorders and environmental causes like obesity are the most common causes of hypercholesterolemia in children


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Atherosclerosis Begins in Childhood Adolescents

Berenson GS et al, N Engl J Med, 1998


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The Effects of Multiple Risk Factors on the Extent of Atherosclerosis

  • Vascular endothelial dysfunction initiates atherosclerotic process

  • Extent of atherosclerotic lesions correlated with elevations in:

    • Total cholesterol

    • LDL Cholesterol

    • Triglycerides

    • Blood Pressure

    • BMI

Berenson et al, Bogalusa Heart Study. N Engl J Med, 1998


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The function of the vascular endothelium: Progression to Atherosclerosis

  • Regulation of vascular tone

  • Controls vascular cell growth, particularly smooth muscle proliferation

  • Controls leukocyte and platelet adhesion by secretion of selectins and adhesion molecules

  • Thrombotic and fibrinolytic properties

  • Endothelial dysfunction-

    leads to Increased intima media thickening (IMT) and atherosclerotic plaque


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B-Mode Measurement of Carotid Atherosclerosis

Intima-Media Thickness (cIMT)


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Carotid artery IMT as a surrogate Atherosclerosis for coronary artery disease

  • The Muscatine study found an association between increased carotid IMT and coronary calcification in young adults. (Circulation 1999;100:838-842).

  • The Multicenter Anti-Atheroma study showed that IMT of the carotid bulb was associated with coronary stenosis in adults with coronary disease (r=0.68, p=0.01). (Stroke 1997;28:1189-1194).

  • The Rotterdam Study found that the risk of a first myocardial infarction increased when the baseline mean IMT was 0.822 mm or greater, and the risk of stroke when the mean IMT was 0.75 mm or greater. (Circulation 1997;96:1432-7).

  • Risk factor profile in 12- to 18-year-old adolescents predicts adult cIMT independently of contemporaneous risk factors (Raitakari et al JAMA 2003; 290: 2227-2283).

  • Numerous adult studies have shown statin therapy prevents the progression of carotid IMT or reduces carotid IMT.


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Carotid IMT in Young Patients with heFH Atherosclerosis

  • 28 patients (11-27 years of age;12M/16F) with FH vs 28 controls

  • cIMT (0.710.15 vs 0.490.08 mm;p<0.001)

  • cIMT correlated with:

    • Total cholesterol

    • LDL-cholesterol

    • Triglycerides

    • Systolic BP

Lavrencic et al; Heart 1996;76:321-325


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Usefulness of Childhood Lipoprotein Measures in Predicting Adult SubclinicalAtherosclerosis: The Bogalusa Heart Study

Mean levels of adult carotid IMT by quartile of childhood lipoprotein measures in the Bogalusa Heart Study cohort.

Frontini et al Pediatrics 2008; 121: 924-929


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Early Surrogate Markers of Atherosclerosis in Children & Adolescents

  • Mean carotid intima-media thickness (cIMT)1

  • Flow-mediated dilatation of the brachial artery (FMD): vascular dilatation and nitric-oxide response to ischemia2

  • Electron beam computer tomography (EBCT): coronary calcifications3

  • Multimodal magnetic resonance imaging (MRI): plaque burden & composition in common carotid artery and abdominal aorta

1. Weigman et al, JAMA 2004

2. de Jongh et al, J Am Coll of Cardiol 2002

3. Gidding et al, Circulation 1998


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Coronary Artery Plaque (CAP) Scanning Adolescents

  • Approximate amounts of lipid Rich, fibrotic, & calcified plaque:

    • Lipid Rich-33%

    • Fibrotic-46%

    • Fibrotic & calcified-20%

  • CAP can be visualized by B-mode U/S

  • Calcified plaque is detectable by electron beam computer tomography (EBCT)

  • Multi-Slice (64-slice) CT

Calcification of left coronary artery (LCA)

Mixed plaque with predominant soft tissue,

Calcification and remodelling & ? ulceration


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Usefulness of EBCT in Adolescents Adolescents& Young Adults with heFH

  • 29 youths 11 to 23 years old with FH

  • Significant coronary calcification in 7 out of 29

  • Increased BMI was associated with the presence of coronary calcium

  • No other risk factors (i.e., gender, LDL-C level, family history of CAD, tobacco use, etc) were associated with the presence of coronary calcium

Gidding et al, Circulation 1998; 98: 2580-2583


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Original National Cholesterol Education Program (NCEP)-1992 Adolescents

NCEP guidelines

ClassificationTotal cholesterolLDL

  • High > 200  130

  • Borderline 170-199 110-129

  • Acceptable < 170 < 110


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National Cholesterol Education Program (NCEP) & AHA Recommendations in Children

  • >2 years of age with parental CHD or a first degree family history of premature CVD

  • AHA* Steps I & II Diets: 6-12 months

  • Dietary supplements: fiber, antioxidants, fish oil (omega-3 fatty acids), etc

  • Physical activity

  • Statin therapy in children 10 years and older

American Heart Association (AHA)

Coronary Heart Disease (CHD)

Cardiovascular Disease (CVD)


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Original NCEP Guidelines-1992 Recommendations in Children

Lipid-lowering Drug Treatment

  • Child at least 10 years of age

  • LDL-C > 160 mg/dL c/ family hx of premature CVD or 2 risk factors*

  • LDL-C > 190 mg/dL c/out family hx or 2 risk factors*

  • Treatment goal: LDL-C<110 mg/dL

    *HDL-C<35, smoking, DM, obesity, HTN, lack of exercise


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Current NCEP Modifications* Recommendations in Children

  • Overweight & obese should trigger screening

  • Screen overweight & obese with lipid abnormality for metabolic syndrome

  • Statin is first-line Rx for children meeting the criteria for lipid-lowering drugs

  • Additional risk factors or high-risk conditions may lower cut point for LDL-C level and age (8 years) for initiation of Rx:

    • Male gender

    • HDL-C<35,  TG, &  VLDL

    • Features of metabolic syndrome

    • Diabetes, HIV infection, SLE, organ transplantation, cancer survivors

    • Hypertension

    • Current smoking and passive smoke exposure

    •  Lipoprotein(a),  homocysteine &  C-reactive protein

*McCrindle et al. AHA Scientific Statement. Circulation 2007;115:1948-19657


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*AAP: American Academy of Pediatrics Recommendations in Children

de Ferranti et al. NEJM 2008; 359:1309-1312


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Pharmacotherapy Recommendations in Children

  • Drugs of choice

    • Bile acid sequestrants (BAS)- cholestyramine, colestipol

    • proven efficacy and safety

  • Alternative therapy

    • Niacin alone or in combination with BAS

    • Fibric acid derivatives or fibrates

    • HMG-CoA reductase inhibitors (statins)


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Statins Approved for Use in Children Recommendations in Children

Belay et al., Pediatrics 2007: 119: 370-380


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Hydroxamethylglutaryl-CoA Recommendations in Children(HMG-CoA) Reductase Inhibitors

  • Recent studies have focused on statins

    • 7 Short-term and Long-term Clinical trials

  • Efficacy similar to adult patients

    •  LDL-C by 18-35%

    • pravastatin 5-20 mg/d

    • lovastatin 10-40 mg/d

    • simvastatin 10 mg/d

    • atrovastatin 10-20 mg/d


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Efficacy of 6-month Statin Therapy in Recommendations in ChildrenChildren with Familial Hypercholesterolemia


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Does Long-term Statin Therapy Affect Cardiovascular Outcomes in Pediatric FH?

  • Two-year pravastatin therapy1

    • Lowered LDL-C & TC

    • Lowered carotid IMT

    • No effect on LFTs or CPK

    • No effect on growth or other endocrine functions

    • No effect on pubertal hormones or maturation

  • Two-year pravastatin therapy:LDLR genotype (defective vs null) influenced clinical response to pravastatin2

    • Lowered LDL-C & TC

    • Lowered carotid IMT

1. Wiegman et al. JAMA 2004; 292: 331-337

2. Koeijvoets et al Circulation 2005; 112: 3168-3173


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Impact of Statins on Vascular End points in Pediatric FH?

Changes from baseline (striped bar) to 28 weeks

(while bar) in flow-mediated dilatation (FMD) in

Placebo and simvastatin groups with familial

Hypercholesterolemia; *p<0.0001vs baseline;

†p<0.05 for change in placebo vs change vs

simvastatin groups.

Mean carotid intima-media thickness (IMT) changes

From baseline for the different carotid arterial wall

segments in the pravastatin and placebo groups of

Children with familial hypercholesterolemia.

Jongh et al, J Am Coll Cardiol 2002; 40:2117-2121

Wiegman et al, JAMA 2004;292:331-337


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Potential Effects of Statin Therapy in Pediatric FH?on Steroid Synthetic Pathway

  • Inhibition of this steroid pathway by a statin may have pleiotropic effects

  • Influencing antioxidant activity

  • Intracellular processes:

    • signal transduction

    • cell proliferation

    • apoptosis

  • Structural components

  • Synthesis of Steroid hormones


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Smith-Lemli-Opitz in Pediatric FH?Syndrome

  • Autosomal recessive disorder

    • Caused from mutation in the DHCR7 gene

    • Located at 11q12-13

    • Encodes for sterol-Δ7-reductase

  • Defects in sterol-Δ7-reductase

    • Build up of 7-dehydrocholesterol

    • Deficiency of cholesterol

  • Common characteristics:

    • Multiple malformations at birth.

    • Mental retardation later.

  • Occurrence:

    • 1 in 20,000 people of central European decedents.

    • Rare in Africans and Asians.


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Statin Toxicities in Adults in Pediatric FH?

  • Hepatotoxicity:<0.1%: 2:1 female to male> 60 yrs

  • Myotoxicity: 0.5% lovastatin

    • Statin use with other CYP3A4 inhibitors also increase risk of myopathy: i.e., cyclosporin, erythromycin, azole antifungals

  • Rhabdomyolysis: ? depletion of mevalonate, farnesol, geranylgeraniol, and mitochondrial ubiquinone

  • Peripheral Neuropathy: ? small risk; exacerbated in diabetics

  • Teratogenicity: CNS and cardiac anomalies due to inhibition of cholesterol synthesis and alteration of sterol-dependent morphogens by the lipophilic statins crossing the placenta

  • Cognitive effects: ? Not conclusive

  • Cancer: ? Not conclusive


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Systematic Review & Meta-analysis of Statins for heFH in Children: Evaluationof Cholesterol Changes and Side Effects

  • The search yielded 2,174 titles.

  • Of the 63 studies retrieved and reviewed 56 were excluded.

  • 7 randomized control trials (RCTs) were included in the systematic review, and 4 were included in the meta-analysis.

  • Significant heterogeneity was detected due to methodological differences & concerns:

    • Suboptimal blinding

    • Absence of intention-to-treat in 6 trials despite stated intention

    • Suboptimal RCT quality criteria

    • Gender distribution and duration

  • The meta-analysis showed significant LDL lowering, HDL elevation, and increases in height and weight with statins.

  • The meta-analysis could not be performed for many side effects of statins, but individual trials showed no significant side effects.

Clodagh S, et al Pediatr Cardiol 2009


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Systematic Review & Meta-analysis of Statins for heFH in Children: Evaluationof Cholesterol Changes and Side Effects

Clodagh S, et al Pediatr Cardiol 2009


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Systematic Review & Meta-analysis of Statins for heFH in Children: Evaluationof Cholesterol Changes and Side Effects

  • Many authors or institutions were duplicated or acknowledged in multiple trials.

  • All 7 trials disclosed funding from pharmaceutical sources, which in each case was the manufacturer of the statin under investigation.

    • This bias may explain why no negative trials of statins for pediatric heFH have been published.

    • This also may explain the lack of intention-to-treat analysis in many trials.

    • External funding is a known cause of positive publication bias.

  • Meta-analysis showed significant LDL lowering with statin treatment.

  • Further studies, including epidemiologic and multicenter studies, are required.

Clodagh S, et al Pediatr Cardiol 2009


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Statins: Compliance & Safety in Children Children: Evaluation

  • Compliance high but therapy was brief

    • duration- 24 weeks to 2 year

    • drop-out rates low

  • Safety

    • studies have been underpowered for safety

    • elevation of liver transaminases in 1% to 5% of children

    • No myopathy has been reported

    • effects on growth & development may not be evident for years

    • Adverse events such as headache and flu-like and GI symptoms and/or sore throat were reported in about 64% and 65% of statin and placebo treated patients, respectively


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Clinical Effects of Statins in Adults: Relevance to Pediatrics

  • Distinguish primary vs secondary intervention studies in adults

  • Statin therapy is aimed at mitigating the thrombogenic potential of existing plaque in adults

  • Statins have decreased cardiac mortality without showing reduction in total mortality in adults

  • Aggressive lipid-lowering in children based on studies in adults is not justified

  • Prevention of atherosclerotic plaque development and maturation in children is the goal of statin therapy


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Conclusions Pediatrics

  • Lack of definitive long-term data on the effect of drug therapy on preventing CHD in children & adolescents

  • Long-term safety of most lipid lowering agents in children is unknown- Bile acid sequestrans are the safest option

  • Balance unknown risks of treatment against estimated risk of premature CHD

  • Statin therapy is recommended in adolescents with heFH

  • ? Primary prevention strategy in high risk asymptomatic children: independent clinical trials are needed

  • Assess the use of various biomarkers including hs-CRP cutoffs in developing therapeutic strategies in adolescents

  • Noninvasive imaging of childhood atherosclerosis can spare traditionally at-risk children with heFH from risk of unnecessary pharmacotherapy

  • ? use of statins versus life-style changes in adolescents with T2DM and MS at higher risk of CVD than those with heFH


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