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808 PEDIATRIC ANNALS 35:11 | NOVEMBER 2006

CM E

Cardiovascular disease and its link

with blood cholesterol levels and

other risk factors such as smok-

ing, diabetes, hypertension, and obesity

are well documented.1 Much cardiovas-

cular disease can be prevented by good

nutrition, exercise, and avoiding risk fac-

tors such as smoking, and controlling the

medical conditions that accelerate its pro-

gression.2

The Framingham Study2 and others

identified the risk factors that increase the

incidence of coronary artery disease. These

risk factors include a family history of heart

disease, reduced level of high-density lipo-

protein (HDL) cholesterol, elevated serum

cholesterol level, hypertension, cigarette

smoking, impaired carbohydrate toler-

ance, and lack of physical activity. Male

gender also is a risk factor for premature

coronary artery disease; risk in women is

delayed by about a decade. Cardiovascular

disease remains the most common cause

of death in the United States.

Evaluation of

Dyslipidemia in Children

Frances R. Zappalla, DO


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PEDIATRIC ANNALS 35:11 | NOVEMBER 2006 809

Atherosclerosis is a chronic disease

process with origins in childhood. The

rate of disease progression is determined

by the presence of known cardiovascu-

lar risk factors (eg, dyslipidemia, hy-

pertension, diabetes mellitus, tobaccouse, physical inactivity). Atherosclero-

sis begins when there is damage to the

endothelium of the arterial wall.3 The

circulating factors in the blood includ-

ing platelets and fibrin are deposited in

the area of injury. Over time, fatty par-

ticles, in particular cholesterol, are also

deposited causing a fatty streak. This

fatty streak is the earliest precursor to

atherosclerosis. Eventually, this lesion

becomes permanent. Later, prolifera-

tion of cells in the area causes a raised

lesion to be formed. Over years, there is

additional deposition of material such

as fibrin, platelets, and cholesterol that

eventually occludes the vessel, resulting

in a myocardial infarction.

Abnormal lipid levels contribute

significantly to progression of athero-

sclerosis.4,5 Elevated low-density lipo-

protein (LDL) cholesterol, low HDL

cholesterol, and elevated triglycerides

all contribute to atherosclerosis pro-

gression. Dyslipidemia may be caused

by genetic abnormalities, diet, and, for

the high triglyceride/low HDL choles-

terol phenotype overweight and insulin

resistance.2 This article reviews dys-

lipidemias recognizable in children,

as well as dietary and pharmacologicapproaches to treatment. Recognition

and management will facilitate early

prevention of atherosclerosis.

TYPES OF LIPOPROTEINS

Circulating lipids are present in two

forms in the body: triglyceride and cho-

lesterol.6 These lipids are insoluble in

plasma, but when combined with phos-

pholipids and proteins to form lipopro-

teins, they become soluble and can be

transported in the bloodstream. The

liver and other tissues, including the

gut as part of fat absorption, assemble

lipoproteins. Lipoprotein metabolism is

dynamic, with interactions among the

various types of lipoproteins occurring

throughout the body as part of normal

metabolism.

Lipoprotein levels are genetically

regulated, and significant deviations

from normal usually have genetic

causes. There are five major classes

of lipoproteins. Chylomicrons are

formed from dietary fat in the gut and

are removed from the blood by the li-

poprotein lipase. In otherwise healthy

individuals, the chylomicrons are re-

sponsible for the transient rise in tri-

glyceride level after a meal. In individ-uals with impaired clearance, there is

a marked rise in the triglyceride level.

Very low-density lipoproteins (VLDLs)

are formed by dietary glucose and non-

esterified fatty acids in the liver and are

triglyceride rich. They are catabolized

in the blood stream, and LDL and inter-

mediate density lipoproteins are formed

from VLDL remnants. These three lat-

ter lipoproteins are rich in cholesterol

and atherogenic. The liver and small in-

testine secrete HDL. It is known as the

good cholesterol because it helps re-

move cholesterol from tissues and car-

ries it to the liver. High levels of HDL

are protective and associated with a de-

creased risk of cardiovascular disease.

Conversely, low HDL levels increase

the risk of cardiovascular disease.2

LIPID MEASUREMENTS

A lipid profile consists of individually

measured total cholesterol (TC), triglyc-

erides (TG), and HDL. Total cholesterol


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and HDL do not need to be measured

in the fasting state. LDL is a calculated

measurement based using the Friedewald

equation (LDL = TC [HDL + TG/5]).2

This equation can only be used if the tri-

glyceride level is below 400 mg/dL. Ifthe triglyceride level is above 400 mg/dL,

significant chylomicronemia is present.

An overnight fast of least 8 hours,

preferably 12 to 14 hours, is required

for an accurate triglyceride measure-

ment. Triglyceride levels are dependent

on the diet of the individual and can vary

daily; multiple fasting serum levels may

be needed to determine accurate lipid

classification.7 Severe illness can cause

transient lipid abnormalities; therefore,

lipid levels should be delayed at least 4to 6 weeks after an acute illness to get an

accurate measurement. The exception is

when hypertriglyceridemia is believed to

be the underlying cause of the disease,

such as in acute pancreatitis.

TYPES OF HYPERLIPIDEMIA

There are several types of hereditary

hyperlipidemias. A family history and

parental lipid panels are helpful to distin-

guish genetic from acquired types.6

In homozygous familial lipoprotein

lipase (LPL) deficiency, the triglyceride

levels are dramatically elevated. It is a

relatively rare disorder seen in children

and associated with pancreatitis and ab-dominal pain. The activity of LPL is di-

minished or absent causing the hydroly-

sis and removal of the chylomicrons from

the blood to be impaired. Decreased LPL

activity may also occur secondarily in

systemic lupus, pancreatitis, or immuno-

logic disorders. The risk for atheroscle-

rotic heart disease is debated. Many ge-

netic traits including heterozygosity for

this disorder can cause the high triglycer-

ide/low HDL cholesterol phenotype.

Familial hypercholesterolemia is the

lipoprotein disorder for which children

are screened. It is characterized by ele-

vated LDL and usually normal triglycer-

ides and is due to lack of functional LDL

receptors on the liver cell membrane or

abnormalities of apoplipoprotein B con-

figuration. The homozygous form can

present in the first year of life with se-

rum cholesterol levels higher than 500

mg/dL. The LDL level in the homozy-

gous form is about twice as high as the

level in a heterozygous family member.

Xanthomas can appear before age 10,

and vascular disease can present before

age 20. It is a rare disorder, occurring

once per million population. These chil-

dren may need LDL apheresis as part of

their treatment. Other disorders causing

secondary hyperlipidemia must also be

excluded to make the diagnosis. The het-

erozygote condition (1:500 population)

usually has no xanthomas, and LDL

cholesterol levels are usually above 160mg/dL.

Familial combined hyperlipidemia

presents with elevated triglycerides,

elevated serum cholesterol levels (in-

creased LDL and VLDL), or both. The

parents may have different types of fa-

milial hyperlipidemia resulting in vary-

ing levels of triglyceride or serum cho-

lesterol elevation.

Hypertriglyceridemia is associated

with lack of exercise, stress, nonfasting

blood sample, or diabetes; these must be

ruled out before a genetic dyslipidemia

is considered. High carbohydrate (sugar)

intake worsens the high triglyceride/low

HDL phenotype, whereas mono-and

polyunsaturated fats lower triglycer-

ides and raise HDL cholesterol levels.

In general, TG levels under 100 mg/dL

are normal. Levels over 200 mg/dL are

abnormal and suggest the possibility of

heterozygosity for a disorder of lipid

metabolism, especially if one of the par-

ents has a similar dyslipidemia. Levels

between 100 and 200 mg/dL are usually

secondary to overweight, insulin resis-

tance, high carbohydrate intake, lack of

fasting prior to the test, or heterozygos-

ity for a disorder of lipid metabolism.

Hypolipidemia, or low HDL level,

is also associated with increased risk of

cardiovascular disease. An HDL level

SIDEBAR.

Risk Factors for Dyslipidemia in Children

1. Discuss the rationale for choles-terol screening in children.

2. Identify children with abnormallipid profiles.

3. Implement dietary and pharma-cologic management of abnormallipid profiles.

Dr. Zappalla is attending cardiolo-

gist, Nemours Cardiac Center, Wilm-

ington, DE.

Address reprint requests to: Frances

R. Zappalla, DO, Nemours Cardiac Cen-

ter, 1600 Rockland Rd., Wilmington, DE

19899; or e-mail [email protected].

Dr. Zappalla disclosed no relevant fi-

nancial relationships.

EDUCATIONAL OBJECTIVESCM E

Parents, grandparents, or a sibling of one parent experience heart disease by age 55,including coronary angiography with evidence of coronary atherosclerosis, as well ascoronary artery bypass, balloon angioplasty, or stent placement.

Parents, grandparents, or a sibling of one parent had a documented myocardial infarct ion,angina pectoris, peripheral vascular disease, cerebrovascular disease, or sudden cardiacdeath by age 55.

Parent with elevated cholesterol level of 240 mg/dL or higher.

Parental history unknown.

Other risk factors for coronary heart disease, such as cigarette smoking, obesity witha body mass index at or above the 95th percentile for age and height, hypertension,diabetes, or physical inactivity.


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less than 40 mg/dL for men and less than

50 mg/dL in women is associated with

increasing risk. An HDL level in ex-

cess of 60 mg/dL has a protective effect

against future cardiovascular disease

and longevity is often present in familieswith HDL levels over 70 to 80 mg/dL.

HDL levels less than 25 to 30 mg/dL re-

flect a genetic abnormality and may be

associated with significant risk of accel-

eration of atherosclerosis and future car-

diovascular disease. Acute inflammation

can also lowers HDL levels.

PRIMORDIAL PREVENTION

Prevention of dyslipidemia in child-

hood is based on good nutrition and

maintenance of normal weight forheight. The American Heart Associa-

tion, with endorsement of the American

Academy of Pediatrics, released its con-

sensus statement for dietary recommen-

dations for Children and Adolescents in

September 2005.8These stated that chil-

dren should eat nutrient-dense foods and

beverages in age-appropriate amounts.

Foods that are calorie-dense with mini-

mal nutritional value (junk foods) need

to be limited and given only as discre-

tionary treats.

A healthy diet consists primarily of

fruit, vegetables, whole grains, low-fat

and nonfat dairy, lean meat and fish,

nuts, and legumes. Daily physical activ-

ity is also an integral part of this healthy

lifestyle. Foods with added sugar, salt,

and saturated and trans fats should be

limited. These foods typically are pro-

cessed foods, fast foods, snacks, and

sweetened drinks.

Not all fats are created equal and

some can be beneficial. Healthful oils

include olive, canola, and safflower. Sat-

urated fat, cholesterol, and trans fatty ac-

ids should be limited. A healthy total fat

intake is about 20% to 35% of daily cal-

ories. Saturated fat, such as that found in

whole milk, butter, cream, or fatty cuts

of meat, should be limited to less than

10% of calories. Cholesterol should be

limited to 300 mg per day, or the amount

found in one egg yolk. Trans fats or par-

tially hydrogenated oils should be kept

to a minimum because these increase

LDL (or bad cholesterol).

The Web site http://www.mypyramid.

org contains useful tools for both the prac-

titioner and the Web-savvy parent to help

achieve dietary goals. Included in the site

is a food intake calorie chart that assigns

the appropriate calorie intake based on

age, sex, and activity level beginning for

the 2-year-old. There are also downloads

available for each daily calorie require-

ment breaking down the daily require-

ment of grains, dairy, fruits, vegetables,

protein, and oils. For example, the aver-

age 2-year-old requires 1,000 to 1,400

calories a day, which should include 1

ounces of grains, 1 cup of fruits, 1 cup of

vegetables, 2 cups of milk or its equiva-

lent, and 2 ounces of protein. Using this

as a guideline, a typical breakfast for a

2-year-old could be a quarter-slice of

toast, 1 tablespoon of applesauce, cup

of milk, and of a scrambled egg. Par-

ents need to be taught appropriate portion

sizes for toddlers and young children.

Once children reach age 2, they can

be switched to low-fat (1%) milk and

nonfat dairy products. These products

are a major source of saturated fat and

cholesterol in this age group. Sweetened

drinks and foods are also a problem in

this age group. These foods should notbe forbidden but should be discretionary.

A concept that incorporates parental role

modeling is for parents to understand

they are responsible for what and where

the child eats, but the child can choose if

and how much to consume. The childs

satiety clues need to be recognized, and

children should not be forced to eat.

Dietary recommendations stress not

only the quality of the food but also the

quantity. An important aspect is learn-

ing to read food labels. After age 6 or 7,

children can be taught how to read food

labels and make good choices. Daily en-

ergy (caloric) input should be equal to

energy expenditure to maintain a healthy

weight. In order to lose weight, the scale

must be tipped so that energy expendi-

ture exceeds input.

SCREENING

The American Academy of Pediatrics

Committee on Nutrition, along with the

National Cholesterol Education Program

of the American Heart Associations

Council on Cardiovascular Disease in the

Young, has released recommendations

for acceptable lipid levels in children

and screening guidelines.9There are two

approaches to improving childrens cho-

lesterol levels. The population approach

targets all children older than 2. The em-

Not all fats are created equal

and some can be beneficial.


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phasis is on meeting nutritional goals of a

low-fat diet rich in fruits, vegetables, lean

meat, low-fat dairy, and whole grains.Education of parents, caregivers includ-

ing school and daycare staff, and primary

caregivers is essential for this approach.

The second approach is to iden-

tify high-risk children and adolescents

with elevated cholesterol levels through

screening.10Risk factors for dyslipidemia

in children are listed in the Sidebar (see

page 810). A problem with the high-risk

selective screening approach is that some

children at risk can be missed. About

25% of children need to be screened to

identify about half of those with elevated

LDL cholesterol.11High-risk parents who

are too young to demonstrate risks factors

or who have not sought medical attention

for a variety of reasons can be missed.

An acceptable total cholesterol level

is less than 170 mg/dL, with LDL of 100

mg/dL or less. A borderline measure-

ment is total cholesterol of 170 to 199

mg/dL with LDL of 100 to 129 mg/dL.

High cholesterol is a total level over 200

mg/dL with LDL 130 mg/dL or higher.

Puberty plays a factor in variability

of cholesterol levels, which rise during

prepuberty and then falling to the lowest

levels of childhood as puberty advances

(about age 12 for girls and age 14 to 16

for boys). An increase in cholesterol level

from previously established values at age

9 to 12 may not reflect worsening dyslip-

idemia but normal pubertal variability.12

Children with normal cholesterol lev-

els should be provided with education on

nutrition, healthy eating pattern recom-

mendations, and counseling on the other

risk factors that can lead to cardiovascular

disease. The fasting lipid panel should be

repeated in 5 years. Children with border-

line cholesterol levels and their families

also should be provided with advice on

reduction of risk factors and nutritional

counseling as outlined above. Studies can

be repeated in 1 year.

Children with high cholesterol levels

should be examined for secondary causes

of hyperlipidemia (eg, thyroid, liver, or

renal disorders). All family members,

including parents and siblings, should

have a fasting lipid panel. Dietary man-

agement should be initiated for the entire

family. If the child has elevated cholester-

ol, it is likely that the parents and siblings

are also affected, and they can all benefit

from a diet change. It is also easier for

the child to adhere to his diet if the whole

family is eating the same way. These chil-

dren should be re-evaluated in 3 months.

An effective cholesterol-lowering

diet requires a detailed assessment and

careful planning. Nutritional counsel-

ing by a physician, registered nurse, di-

etitian, or nutritionist is recommended

for the family to help with adherence.Emphasis is on a low-fat diet with less

than 30% of daily calories from fat, less

than 7% of calories from saturated fat,

less than 10% of calories from polyun-

saturated fat, and less than 200 mg of

dietary cholesterol. Dietary manage-

ment of elevated triglycerides, low HDL

cholesterol, or both emphasizes less the

low total fat portion of the diet and en-

courages intake of poly- and monoun-

saturates in lieu of carbohydrates.

PHARMACOLOGIC TREATMENT

The National Cholesterol Education

Program (NCEP) recommends an ad-

equate trial of dietary therapy for at least

6 months to 1 year. Drug therapy is con-

sidered in children 10 or older if LDL

remains above 190 mg/dL or if LDL

remains above 160 mg/dL and there are

two additional risk factors for cardiovas-

cular disease or diabetes.10,13Unless the

LDL cholesterol is extremely elevated

(above 250 mg/dL) or there are other

risk factors, drug therapy can be delayed

until after the adolescent growth spurt is

finished, particularly in girls.

If a child with a high triglyceride/

low HDL phenotype is overweight,

diet and exercise are the primary treat-

ment. Weight loss and dietary changes

can lower the atherogenicity of the lipid

profile effectively, even if total choles-

terol is little changed. The effect may

be less dramatic in those children who

have a familial dyslipidemia. Behavior-

al strategies are critical for the preven-

tion of the acquisition of additional risk

factors to dyslipidemia.

Historically, bile acid binding res-

ins such as cholestyramine and niacin

have been recommended in children.

These medications have low palat-

ability and often are not tolerated for

Sweetened drinks and foods are

also a problemthese foodsshould not be forbidden but

should be discretionary.


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long periods of time. The usual dose

of cholestyramine (bile acid binding

resin) is 4 to 16 g daily. It is not sys-

temically absorbed, and gastrointesti-

nal side effects are common, including

its unpleasant texture while ingesting,constipation, flatulence, and bloating.

Niacin inhibits VLDL release from

the liver and is useful in lowering tri-

glycerides and raising HDL choles-

terol. However, it too has a high rate

of gastrointestinal side effects, in ad-

dition to acute irritating symptoms,

such as flushing and warmth, immedi-

ately after taking the medicine. These

symptoms improve with time and can

be limited by gradually increasing the

dose. In adults, the dose is usually 2to 3 g daily. It is usually started at a

lower dose of 250 mg and built up as

tolerated; changes in the lipid profile

occur at doses above 1 g/day. Aspirin

usually is given with niacin in adults

and has been shown to help limit the

flushing; however, this is controver-

sial in children because of the risk of

Reyes syndrome.

Four statins have been studied in

pediatric randomized safety and effi-

cacy trials of at least 1 year: lovastatin

(Advicor), pravastatin (Pravachol),

simvastatin (Vytorin, Zocor), and ator-

vastatin (Lipitor). In addition to being

safe and effective, these studies have

shown statin treatment to improve bra-

chial artery reactivity and to slow pro-

gression of carotid artery intimal thick-

ening on ultrasound measurement.14,15

Statins reduce the livers production of

cholesterol and increase the ability of

the liver to remove LDL cholesterol

from the blood. They also moderately

reduce triglyceride levels and increase

levels of HDL cholesterol. The treat-

ment goal is LDL cholesterol below

130 mg/dL. The initial dose is 10 mg

daily, increasing to a maximum dose of

40 mg. The exception is atorvastatin,

which is twice as potent as the others

on a milligram for milligram basis.If triglycerides are consistently

above 500 mg/dL on several determi-

nations, fish oil at a dose of 2 g/day can

be initiated. If this fails, niacin can be

used. Fibrates should be reserved for

those with high risk for pancreatitis.

SUMMARY

Paying attention to cholesterol at

a young age will prevent future ath-

erosclerosis. Clinicians must teach

parents that by making the necessarynutritional and lifestyle changes, they

can prevent or lower their childs risk

for heart disease, hypertension, and di-

abetes. Recognition of the occasional

child with a genetic dyslipidemia will

allow more aggressive lipid-lowering

treatment at an age when atherosclero-

sis is first developing.

REFERENCES

1. McMahan CA, Gidding SS, Fayad ZA, et

al. Risk scores predict atherosclerotic le-sions in young people. Arch Intern Med.

2005;165(8):883-890.

2. Third Report of the National Cholesterol

Education Program (NCEP) Expert Panel

on Detection, Evaluation, and Treatment

of High Blood Cholesterol in Adults (Adult

Treatment Panel III) Final Report. Circula-

tion.2002;106(25):3143.

3. Strong JP, Malcom GT, McMahan CA, et al.

Prevalence and extent of atherosclerosis in

adolescents and young adults: implications

for prevention from the Pathobiological

Determinants of Atherosclerosis in Youth

Study.JAMA.1999;281(8):727-735.

4. Berenson GS, Srinivasan SR, Bao W, et al.

Association between Multiple Cardiovas-

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Children and Young Adults. N Engl J Med.

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5. Raitakari OT, Juonala M, Kahonen M, et

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Finns Study. JAMA. 2003;290(17):2277-

2283.

6. Scrivner C, Sly W, Childs B, et al. Chap-

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7. Benuck I, Gidding SS, Donovan M. Year-

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11. Griffin TC, Christoffel KK, Binns HJ, Mc-

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13. American Diabetes Association. Manage-

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Arterial intima-media thickness in children

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