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Hyperlipidemia in Childhood


Hyperlipidemia in Childhood Radha R. Cohen, M.D., F.A.A.P Pediatric Grand Rounds April 1, 2004 Hyperlipidemia in Childhood Overview Basic lipoprotein structure and ... – PowerPoint PPT presentation

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Title: Hyperlipidemia in Childhood

Hyperlipidemia in Childhood
  • Radha R. Cohen, M.D., F.A.A.P
  • Pediatric Grand Rounds
  • April 1, 2004

Hyperlipidemia in Childhood Overview
  • Basic lipoprotein structure and metabolism
  • Role of childhood hyperlipidemia in
  • Classification of hyperlipidemias
  • Pediatric cholesterol screening guidelines
  • Management of hyperlipidemia in children

Hyperlipidemia in Childhood Definition
  • Hyperlipidemias group of metabolic disorders
    characterized by an abnormal accumulation of
    various lipids in plasma. This may be due to
    genetics, diet or other acquired factors.
  • Cholesterol and trigylceride are the primary
    lipids in plasma. Because they are insoluble in
    plasma, they are transported within the vascular
    space as lipoproteins.

Hyperlipidemia in Childhood Lipoprotein structure
Lipoprotein structure
  • hydrophobic core
  • triglyceride and/or
  • cholesterol ester
  • surface coat
  • phospholipid monolayer
  • interspersed free cholesterol and apolipoproteins

Hyperlipidemia in Childhood 4 Major Classes of
  • Lipoproteins are divided into several classes
    based on their density.
  • Each class appears to have distinct functions and
    atherogenic risk.

Hyperlipidemia in Childhood Classes of
  • Total Cholesterol measured in the blood or serum
    can be viewed as the sum of cholesterol carried
    in the different major lipoproteins
  • LDL-cholesterol
  • HDL-cholesterol
  • VLDL-cholesterol

Hyperlipidemia in Childhood LDL
  • LDL-cholesterol makes up the majority (60-70) of
    cholesterol in the blood.
  • It has B-100 as its major apolipoprotein
    lipoproteins that contain B-100 accumulate in
    arteries and within atherosclerotic plaques.
  • It is viewed as the atherogenic lipid high
    levels in adults have been correlated with
    coronary artery disease.

Hyperlipidemia in Childhood LDL
  • LDL-cholesterol receptors are present throughout
    the body and their metabolism is highly regulated
    by intracellular cholesterol levels.
  • Brown and Goldstein received the Noble prize in
    1985 for their work elucidating the control and
    metabolism of LDL-receptors.

Hyperlipidemia in Childhood HDL
  • HDL-cholesterol typically makes up 20-25 of the
    total cholesterol.
  • It is involved with transport of surplus
    cholesterol out of the tissue this reverse
    transport may be responsible for its protective
    action against atherosclerosis.
  • In populations with elevated LDL, HDL-levels are
    inversely correlated with coronary

Hyperlipidemia in Childhood VLDL and Chylomicrons
  • These are the largest of the lipoproteins and are
    major carriers of triglycerides (TG).
  • TG are the main storage form of fatty acids. Long
    chain fatty acids are absorbed in the intestine
    and combine to form triglycerides and are
    transported through the thoracic duct to enter
    the blood stream as chylomicrons.
  • Chylomicrons are cleared from the blood stream
    after fasting by lipoprotein lipase.

Hyperlipidemia in Childhood Atherosclerosis
  • Clear evidence linking abnormalities in lipid and
    lipoprotein levels to premature atherosclerosis.
  • Studies in adults show an unequivocal
    relationship of elevated levels of total
    cholesterol and LDL-C to premature

Atherosclerosis and Coronary Artery Disease
  • Atherosclerosis is a disease of large arteries
    that causes deposits of yellowish plaques
    containing lipoid material and cholesterol in the
    intima of vessel walls.
  • This is the pathogenic mechanism for coronary and
    peripheral vascular disease in adults.

Atherosclerosis and Coronary Artery Disease
  • Advanced lesion results from
  • proliferation of smooth muscle cells and
  • formation of collagen matrix by smooth muscle
  • accumulation of lipid within the cells and
    surrounding tissue

Atherosclerosis Begins in Childhood
  • In 1962, Strong and McGill reported the autopsy
    findings of gt500 subjects ages 1-69 yrs
  • Fatty streaks rare in 1st decade of life but
    almost universal by age 20 yrs

Progression of Atherosclerosis
  • In Strong McGills study, fibrous plaques were
    1st observed in the second decade but increased
    in frequency and extent during the 3rd 4th

Atherosclerosis and CAD
  • Later in life, fibrous plaques may occlude the
    vessel lumen and potentiate thrombus formation.

Hyperlipidemia in Childhood CAD Begins in
  • Clinical sequelae of atherosclerosis do not
    generally occur until later in life.
  • However, there is significant evidence that the
    pathologic changes begin years prior and are
    linked to childhood cholesterol levels.

Cholesterol Levels in Childhood and
  • Bogalusa Heart Study
  • children who had their coronary risk factors
    measured sequentially as participants in this
    study and then died accidentally were studied at
  • extent of fatty streaks was related to total and
    LDL cholesterol
  • fatty streaks in coronaries related best to VLDL
  • inverse relationship of fatty streaks to HDL

Cholesterol Levels in Adolescence Linked to
  • PDAY (Pathological Determinants of
    Atherosclerosis in Youth) Study- ongoing autopsy
    study of progression of atherosclerosis in
    subjects 15-34yrs
  • VLDL and LDL positively and HDL negatively
    associated with fatty streaks and fibrous plaques
  • Raised lesions were found in those as young as

Cholesterol Levels in Childhood and CAD in
  • Epidemiological investigations provide further
    evidence of the importance of cholesterol levels
    in pediatrics
  • Cross-population studies show children from
    countries with high incidence of CAD in adulthood
    have higher cholesterol levels than their
    counterparts in countries with low incidence of
  • Within a population, elevated levels of total and
    LDL cholesterol in children have been associated
    with CAD in adult relatives

Hyperlipidemia in Childhood Summary of Data
  • Evidence demonstrates that
  • fatty streaks occur in young people and then
    progress to atherosclerotic plaques
  • extent of arterial lesions is related to serum
    lipid (cholesterol) levels
  • manipulation of cholesterol levels can affect
    development of atherosclerosis
  • therefore...
  • Efforts to prevent the development and
    progression of atherosclerosis should begin in
    childhood and adolescence.

Hyperlipidemia in Childhood Goal of the
  • Goal of detection / treatment...
  • prevention of premature coronary artery disease
  • Foundation of this goal depends on...
  • coronary artery disease begins in childhood
  • coronary artery disease is related to blood
    cholesterol levels
  • lowering cholesterol in children will be
    effective in ? CAD

National Cholesterol Education Program (NCEP)
  • The NCEP was created by the National Heart, Lung,
    and Blood Institute of the NIH in 1985.
  • Its charge was to reduce the prevalence of
    hypercholesterolemia in the US population and
    thereby reduce the morbidity and mortality
    associated with CAD.

Hyperlipidemia in Childhood Definitions
  • Hypercholesterolemia
  • total-C or LDL-C ? 95th for age
  • Hypertriglyceridemia
  • TG ? 95th for age
  • These are working definitions of hyperlipidemia
  • Levels associated with the least risk of
    developing CAD in adulthood have not been

Hyperlipidemia in Childhood Normal Values
National Cholesterol Education Program (NCEP)
Expert Panel on Blood Cholesterol Levels in
Children and Adolescents
Hyperlipidemia in Childhood Normal Values
National Cholesterol Education Program (NCEP)
Expert Panel on Blood Cholesterol Levels in
Children and Adolescents
Hyperlipidemia in Childhood Classification
  • Primary versus Secondary
  • first consideration - whether the hyperlipidemia
    is primary (genetic dyslipidemias) or secondary
    to a metabolic disease or exogenous cause
  • common secondary causes during infancy
  • glycogen storage disease and biliary atresia
  • common secondary causes in childhood
  • hypothyroidism, diabetes, nephrotic syndrome
  • common exogenous causes
  • oral contraceptives, alcohol, steroids

Hyperlipidemias Secondary Causes
Exogenous Alcohol Contraceptives
Steroid therapy Endocrine and Metabolic
Acute intermittent prophyria Diabetes
mellitus Hypopituitarism Hypothyroidism
Lipodystrophy Pregnancy Storage disease
Cystine storage disease Gaucher disease
Glycogen storage disease Juvenile
Tay-Sachs disease Niemann-Pick disease
Tay-Sachs disease
Renal Chronic renal failure
Hemolytic-uremic syndrome Nephrotic
syndrome Hepatic Benign recuurent
intrahepatic cholestasis Congenital biliary
atresia Acute and transient Burns
Hepatitis Others Anorexia nervosa
Idiopathic hypercalcemia Klinefelter
syndrome Progeria Systemic lupus
erythematosus Werner syndrome
KwiterovichPDisorders of lipid metabolism, in
Rudolph AM (ed) Pediatrics, ed 17.
Hyperlipidemia in Childhood Frederickson
  • In Circulation 1965, Frederickson and Lees
    published a description of 5 phenotypes to
    categorize people with familial hyperlipidemia
    according to their pattern of elevation of plasma
  • As knowledge progressed, it has become apparent
    that there may be several different genetic and
    secondary causes of the same Frederickson
  • This classification system has now fallen out of

Hyperlipidemias Fredrickson Classification
Clinically Important Genetic Dyslipidemias
  • For clinical purposes, the following categories
    are more useful in determining risk of
    atherosclerosis, and planning treatment
  • Hypercholesterolemia
  • Combined hyperlipidemia
  • Hypoalphalipoproteinemia

  • Defined as total cholesterol gt170mg/dL for
    children ages 2-19 yrs
  • An isolated elevation of cholesterol is nearly
    always due to increase in LDL-C
  • 2 genetic disorders are assoc. with
  • Total-C LDL-C 2-5Xnormal
  • -familial hypercholesterolemia
  • -familial defective apoB-100

  • Familial hypercholesterolemia is caused by a
    mutation in LDL receptor gene on short arm of
    chromosome 19.
  • Familial defective apoB-100 is due to rare
    mutations of the apoB gene.
  • In both cases, LDL receptors are unable to
    interact with apo-B, the protein ligand on LDL
  • Both have autosomal dominant pattern of

Familial Hypercholesterolemia
  • Most commonly recognized form of familial
    hyperlipidemia in childhood
  • Incidence of heterozygotes is 1500 and
    homozygotes 1 1 million
  • Homozygotes present in childhood with serum
    cholesterol between 400-800mg/dL and cutaneous
    and tendon xanthomas. Angina and MI before
    adolescence are common, and most have severe CAD
    by age 30. Aortic stenosis is also seen.

Tendon Xanthomas
tendon xanthomas of the achilles and elbow
Tendon Xanthomas
tendon xanthomas of the hand
Cutaneous Xanthomas
Familial Hypercholesterolemia Findings in
left coronary artery narrowing
supravalvar lipid deposition
Eye Findings in Familial Hypercholesterolemia
Early corneal arcus
Cholesterol deposits in retinal fundus
Familial Hypercholesterolemia Heterozygous Form
  • LDL-C is gt 95 at birth.
  • Lipid levels remain markedly elevated throughout
    childhood and adulthood with total cholesterol
    300-400mg/dL and LDL-C 200-300mg/dL.
  • Clinical manifestations include tendon xanthomas
    after age 20, early corneal arcus, and CAD after
    age 30.
  • This diagnosis should strongly be suspected in
    anyone with high LDL-C and tendon xanthomas in
    the patient or 1st degree relatives.

Familial Hypercholesterolemia and CAD
  • In heterozygous males, the risk for development
    of CAD is estimated to be 20 at age 40yrs, 45
    at age 50yrs, and 75 at age 60yrs.
  • FH is thought to account for 3 of premature CAD
    in the US.

Familial Hypercholesterolemia
  • Family history and screening of family members
    should reveal 1/2 of 1st degree relatives with FH
  • Diagnosis can be confirmed by measuring LDL
    receptor activity in cultured skin fibroblasts or
    identifying the gene mutation.
  • Prenatal diagnosis is possible by assessing LDL
    receptor activity in cultured amniotic cells.
  • Genetic counseling is important, especially if
    partners cholesterol is elevated or not known.

Combined Hyperlipidemia
  • Familial combined hyperlipidemia was 1st
    described by Goldstein et al. as dominantly
    inherited hyperlipidemia and CAD.
  • Affected individuals have either TG or LDL-C gt90
    or both TG LDL-C gt90.
  • Phenotype may vary among family members or even
    from time to time in same individual.
    Presentation usually delayed until 3rd decade of
    life. No cutaneous or ocular findings.
  • Thought to affect 1 of population and account
    for 10 of premature CAD.

  • Defined as HDL-C lt 10 for age and sex associated
    with normal LDL-C and TG levels.
  • Appears to have autosomal dominant pattern of
    inheritance in that 1/2 of family members have
    low HDL-C and premature atherosclerosis.
  • No clinical manifestations other than premature
    atherosclerosis with CAD common as early as 4th

Cholesterol Screening in Children
  • The NCEP recommended selective screening of
    children and adolescents, targeting those who
    were likely to become adults with high blood
    cholesterol and who would thus be at an increased
    risk for the development of cardiovascular

Cholesterol Screening
  • Reasoning for selective screening
  • children and adolescents with elevated blood
    cholesterol (particularly LDL) frequently come
    from families in which there is a high incidence
    of CAD among adult members
  • high blood cholesterol aggregates in families as
    a result of both shared environments and genetic
  • major risk factor for hypercholesterolemia in a
    child is a family history of premature CAD or

Cholesterol Screening
  • NCEP did not recommend universal screening
  • Reasons against universal screening
  • quite a few children with high cholesterol will
    not have high enough levels as adults to require
  • leads to many young people inappropriately
    labeled as having disease
  • could lead to overuse of cholesterol-lowering
    drugs in children

Cholesterol Screening
  • Reasons for recommending universal screening
  • 50 of children with elevated cholesterol levels
    would be missed
  • universal screening may benefit young parents as
  • children are more likely to receive regular
    health care than young adults

Cholesterol Screening
  • Selective screening approach
  • based on detailed family history and assessment
    of concomitant risk factors
  • makes it possible to identify a high risk subset
    while providing a reasonable balance between the
    number to be tested and the number to be detected

Selective Cholesterol Screening
  • Who should be screened?
  • Children and adolescents with
  • -family history of premature atherosclerosis
    (parents or grandparents with MI, angina
    pectoris, peripheral vascular disease,
    cerebrovascular disease, or sudden cardiac death
    at or before age 55yrs)
  • -parent with high cholesterol (gt240mg/dL)
  • -unknown family history, especially those with
    other risk factors (hypertension, diabetes,
    obesity, smoking)

Age for Cholesterol Screening
  • When do you screen?
  • Anytime after 2 years of age
  • cholesterol levels relatively stable by this time
  • no treatment recommendations for children less
    than 2 years old
  • If levels acceptable, repeat after 5 years

Cholesterol Screening
  • What do you order?
  • Total Blood Cholesterol
  • less expensive, random/nonfasting
  • Fasting Lipid Profile
  • 12 hour fast
  • measure total cholesterol, HDL, TG
  • LDL estimated by formula from Lipid Research
  • LDL total cholesterol - (TG/5 HDL)
  • inaccurate if TG gt 400 mg/dl or if not fasting

Cholesterol Screening
  • What to measure also depends on reason for
  • parental high cholesterol ? total cholesterol
  • family history of CAD ? fasting lipid profile
  • LDL level determines risk and need for treatment

Cholesterol Screening
Cholesterol Screening
  • If LDL-C lt110 mg/dL, no further testing.
  • If LDL-C 110-129 mg/dL,educate family, prescribe
    Step One diet, and recheck in 1 year.
  • If LDL-C gt130 mg/dL, evaluate for causes (r/o
    secondary causes like hypothyroidism, diabetes
    if familial suspected, measure lipid profiles of
    family) and begin treatment.

Management of Elevated Cholesterol
  • LDL-Cgt130 mg/dL
  • Start Step One Diet
  • Recheck level in 6 wks.
  • If LDL not lt110 mg/dL, intensify Step One Diet
    and recheck in 3 months.
  • If goal still not met, prescribe Step Two diet
    for next 3 months.
  • If goal still not met after 1 yr with diet alone,
    consider pharmacotherapy.

Hyperlipidemia in Childhood Detection and
long term monitoring recheck lipoprotein
analysis 2x / year
Diet Therapy
  • Primary approach to treating children and
    adolescents with elevated cholesterol levels
  • Aim of diet therapy is to reduce elevated blood
    cholesterol levels while maintaining a
    nutritionally adequate eating pattern
  • It is prescribed in two steps that progressively
    reduce the saturated fatty acid (SFA) and
    cholesterol intake

Diet Therapy
  • Step One diet
  • lt 30 total calories from fat
  • lt 10 total calories from SFA
  • lt 300 mg/day cholesterol
  • adequate calories for growth and development
  • Requires detailed assessment of current eating
    patterns and instruction by a physician, RD, or
    other professional

Diet Therapy
  • Step Two diet
  • prescribed if careful adherence to Step One diet
    for at least 3 months fails to achieve the
    minimal goals of therapy
  • further reduction of SFAs and cholesterol
  • lt 30 calories from fat (SAME as Step One)
  • lt 7 total calories from SFA
  • lt 200 mg/day cholesterol

Diet Therapy
National Cholesterol Education Program (NCEP)
Expert Panel on Blood Cholesterol Levels in
Children and Adolescents
Mg of Cholesterol in Foods
cholesterol (? 300 mg/day)
  • bacon, 3 slices 16 mg
  • chicken (3.5 oz), lt meat, no skin75 mg
  • shrimp (3.5 oz) 195 mg
  • egg, yolk 213 mg
  • cheddar cheese (1 oz) 30 mg
  • bread, one slice 0 mg
  • butter (one TBS) 31 mg
  • margarine (one TBS) 0 mg
  • McDonalds Big Mac 100 mg
  • McDonalds Egg McMuffin 235 mg
  • Pizza Hut Pan Pizza (1 slice) 25 mg
  • potato chips (1 oz) 0 mg
  • cola, regular 0 mg
  • chocolate chip cookies(4) 18mg
  • peanuts (1 oz) 0 mg

Diet Therapy
  • General food guidelines
  • meat, poultry, and fish
  • major sources of high quality protein
  • but also major contributors of SFA, total fat,
    and cholesterol
  • use LEAN meat, remove skin from poultry
  • eggs
  • good source of high quality protein, iron, vits
  • yolks very high in cholesterol (whitesnone)
  • 2 egg whites substituted for 1 egg in recipes

Diet Therapy
  • Fats and oils
  • ?intake of saturated oils coconut, palm kernel,
  • ?intake of unsaturated oils sunflower, corn,
    canola, olive, peanut
  • margarine instead of butter (with unsaturated oil
    listed as first ingredient)

Diet Therapy
  • Plant stanol esters
  • Are available in low-fat margarine spreads
  • Also available in salad dressings and snack bars
  • Structurally stanol esters are similar to
    cholesterol and inhibit cholesterol absorption in
    the gut by competitive mechanisms

Plant Sterol Esters
  • Studies have demonstrated that consumption of
    low-fat margarine containing stanol esters can
    lower total and LDL cholesterol by 10-15 in
    hypercholesterolemic subjects
  • Have been studied in children with no adverse
    clinical effects noted
  • Does not affect HDL-C or TG levels
  • Effects on Total and LDL-C seen in 4-8 weeks with
    a daily dose of 2-3 g (3 Tbsp of the
    commercially available products)
  • Examples Benecol and Take Control

  • In addition to diet prescription, dont forget to
    recommend regular aerobic exercise
  • 30-45 minutes, at least 4-5 times a week
  • Can increase HDL-C
  • Can help with regards to other risk factors for
    CAD, such as obesity and hypertension

Drug Therapy
  • Only a small proportion of children should be
    considered for drug treatment because of the
  • potential side effects
  • relative expense of medications
  • lack of definitive, prospective data on the
    effect of such treatment on children

Drug Therapy
  • Consider drug therapy
  • following adequate trial of diet therapy
    for 6 months to 1 year if
  • LDL remains gt 190 mg/dl
  • LDL remains gt 160 mg/dl and
  • family history of premature CAD or
  • 2 other risk factors still exist (HDLlt45 mg/dl,
    obesity, diabetes, hypertension)
  • LDL gt 130 mg/dl but lt160 mg/dl, no specific
    recommendations for drug therapy

Drug Therapy
  • Only approved for children older than 10 years of
  • Diet exercise therapy must continue
  • Follow up
  • 6 weeks after starting medication
  • every 3 months thereafter until goal is met
  • then every 6 months

Drug Therapy
  • Bile-acid binding resins
  • Ezetimibe
  • HMG-CoA reductase inhibitors (statins)
  • Niacin (nicotinic acid)
  • Fibric acid derivatives

Bile Acid Sequestrants
  • Primary therapy recommended in children
  • Cholestyramine (Questran) and colestipol
  • Reduce LDL levels by 20
  • Long-term compliance limited, presumably due to
    unpalatability and GI side effects (nausea,
    bloating, constipation, flatulence)

Bile Acid Sequestrants
  • Mechanism of action
  • anion exchange resins
  • bind (-) bile acids in SI
  • resin/bile complex out via feces
  • prevents enterohepatic circulation of bile acids
  • ? bile acid concentration in hepatocytes causes
    an ? conversion of cholesterol to bile acids
  • causes ? in intracellular cholesterol
  • activates an increased uptake of LDL cholesterol
  • outcome ? plasma cholesterol

Bile Acid Sequestrants
  • Overall safe because not absorbed and lack
    systemic toxicity
  • However, they can cause malabsorption of
    fat-soluble vitamins and folic acid so a daily
    MVI containing folic acid and iron is recommended
  • Their use is limited in patients who also have
    elevated TG since they can increase TG levels
  • Check CBC and LFTs annually in patients

Bile Acid Sequestrants
  • cholestyramine and colestipol
  • both are powders that are mixed with water or
    juice before ingestion cholestyramine is also
    available as flavored bars
  • choice of one over the other depends on
    individual taste preference and side effects
  • dose is not related to body weight but to levels
    of total and LDL cholesterol
  • start on lowest dose possible, then ? one dose at
    a time until goal achieved

Bile Acid Sequestrants
  • cholestyramine and colestipol
  • dosing regimen
  • one dose 9 g packet of cholestryramine, one bar
    of cholestyramine, or 5 g colestipol
  • daily doses TC LDL
  • 1 lt245 lt195
  • 2 245-300 195-235
  • 3 301-345 236-280
  • 4 345
  • take immediately before, during, or after meals
    (largest amount of bile acids in intestine)

Ezetimibe (Zetia)
  • Relatively new agent
  • Inhibits intestinal absorption of cholesterol
  • Limited study in children 10-18 yrs
  • Lowers LDL-C by up to 15-20
  • May decrease TG and increase HDL-C
  • Given as a single 10mg dose tablet
  • No major side effects noted
  • In adults has been used in conjunction with

  • HMG-CoA reductase inhibitors work by inhibiting
    the rate-limiting step in cholesterol
  • Have been used in adults gt10-15 years with good
    success and safety
  • Can decrease Total and LDL-C by 20-60
  • Limited studies in children show efficacy and no
    significant side effects, but studies were
    underpowered for safety

  • Must monitor LFTs every 3-6 months as there is a
    potential for hepatocellular toxicity
  • Also, statins are potentially teratogenic so they
    should be used with caution in female

Hyperlipidemia in Childhood Summary
  • CAD is a major cause of significant mortality,
    morbiditity, and expense
  • It begins in childhood and progresses in severity
    as we age
  • It results from a combination of inter-related
    factors such as genetics, hypercholesterolemia,
    hypertension, obesity, diabetes, and smoking
  • Many of these risk factors are largely
    preventable and/or modifiable

Hyperlipidemia in Childhood Summary
  • Efforts to prevent the development and
    progression of atherosclerosis should begin in
    childhood and adolescence
  • Selective cholesterol screening can identify
    those children at highest risk for
  • For those children with hypercholesterolemia, a
    diet low in SFAs and cholesterol is the mainstay
    of therapy

Hyperlipidemia in Childhood
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