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Factors affecting Cholesterol metabolism. Etiologies & Prevalence of ... Concentrations of Total and LDL Cholesterol Among Children & Adolescents ...

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controversies in management of lipids in children adolescents

Controversies in Management of Lipids in Children & Adolescents

Ramin Alemzadeh, MD

Professor of Pediatrics

Director, CHW Diabetes Center

Medical College of Wisconsin

  • 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

Dietary Cholesterol

VLDL cholesterol

via liver synthesis

Cholesterol synthesis

Acetyl CoA


LDL cholesterol


HMG-CoA reductase

Uptake via LDL receptor


Intracellular Fates: esterification by ACAT and storage;

steroid hormone/ vitamin D synthesis

Cellular Cholesterol

Esterification/removal by LCAT/HDL


Cholesterol excretion as bile acids

Bile Acids

(lipid absorption)



Liver uptake via apo E receptor



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

role of cholesterol in the body
Role of Cholesterol in The Body
  • 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
etiologies of hypercholesterolemia
Etiologies of Hypercholesterolemia
  • 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
heterozygous familial hypercholesterolemia hefh
Heterozygous Familial 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
homozygous familial hypercholesterolemia
Homozygous Familial Hypercholesterolemia
  • 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
concentrations of total and ldl cholesterol among children adolescents in the u s
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

concentrations of total and ldl cholesterol among children adolescents in the u s9
Concentrations of Total and LDL Cholesterol Among Children & Adolescentsin the U.S.

Ford ES et al Circulation 2009

cholesterol is a risk factor not a disease
Cholesterol is a Risk Factor Not a Disease

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

the atherosclerotic process in children
The Atherosclerotic Process in Children
  • 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
atherosclerosis begins in childhood
Atherosclerosis Begins in Childhood

Berenson GS et al, N Engl J Med, 1998

the effects of multiple risk factors on the extent of atherosclerosis
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

the function of the vascular endothelium progression to atherosclerosis
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


B-Mode Measurement of Carotid

Intima-Media Thickness (cIMT)

carotid artery imt as a surrogate for coronary artery disease
Carotid artery IMT as a surrogate 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.
carotid imt in young patients with hefh
Carotid IMT in Young Patients with heFH
  • 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

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

early surrogate markers of atherosclerosis in children adolescents
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

coronary artery plaque cap scanning
Coronary Artery Plaque (CAP) Scanning
  • 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

usefulness of ebct in adolescents young adults with hefh
Usefulness of EBCT in 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

original national cholesterol education program ncep 1992
Original National Cholesterol Education Program (NCEP)-1992

NCEP guidelines

ClassificationTotal cholesterolLDL

  • High > 200  130
  • Borderline 170-199 110-129
  • Acceptable < 170 < 110
national cholesterol education program ncep aha recommendations in children
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)

original ncep guidelines 1992
Original NCEP Guidelines-1992

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

current ncep modifications
Current NCEP Modifications*
  • 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


*AAP: American Academy of Pediatrics

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

  • 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)

Statins Approved for Use in Children

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

hydroxamethylglutaryl coa hmg coa reductase inhibitors
Hydroxamethylglutaryl-CoA(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
does long term statin therapy affect cardiovascular outcomes in pediatric fh
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

impact of statins on vascular end points
Impact of Statins on Vascular End points

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

potential effects of statin therapy on steroid synthetic pathway
Potential Effects of Statin Therapy 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
smith lemli opitz syndrome
Smith-Lemli-Opitz 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.
statin toxicities in adults
Statin Toxicities in Adults
  • 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
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

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

Clodagh S, et al Pediatr Cardiol 2009

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

statins compliance safety in children
Statins: Compliance & Safety in Children
  • 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
clinical effects of statins in adults relevance to pediatrics
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
  • 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