Case #1• 14 yo white male• Referred after hypercholesterolemia detected on routine screening

because of father’s hypercholesterolemia• Total cholesterol 290 mg/dl, repeat 286 mg/dl• Triglycerides 108 mg/dl, HDL cholesterol 55 mg/dl, LDL

cholesterol 209 mg/dl• Otherwise well/No current medications• Physical exam, BP WNL, 50th percentile for Ht/Wt• No xanthelasma, cutaneous xanthomata, or Achille’s tendon

thickening

Case #1• Activity

– Soccer, swimming, biking• Diet

– Family already attempting to reduce dietary fat and cholesterol after learning of elevated cholesterol in patient and father

• Social– No tobacco/alcohol/substance abuse– Both parents come with patient to clinic, seem very supportive

Case #1• Dietary assessment

– 3-day dietary recall to determine average daily intake• Total calories: 2000 kcal/day• Composition as % of total calories

– Protein: 22%– Fat: 28%

» Saturated: 6%» Monounsaturated: 14%» Polyunsaturated: 8%

– Carbohydrate: 49%• Cholesterol content: 221 g/day• Fiber: 31 g/day

Case #153 yo

MI69 yo

breast CA

68 yodiabetes

hypertension

66 yo healthy

36 yohealthyCH 299

35 yohealthyCH 152

42 yoCH 310

44 yoCH 280

6 yohealthyCH ?

9 yohealthyCH ?

14 yohealthyCH 286

Xanthelasma Palpebrarum

Xanthomata Tuberosa

Case #2• 11 yo white male• Referred after hypercholesterolemia detected after father was found

to have hypercholestrolemia and recent myocardial infarction• Total cholesterol 254 mg/dl, repeat 250 mg/dl• Triglycerides 102 mg/dl, HDL cholesterol 53 mg/dl, LDL

cholesterol 181 mg/dl• Otherwise well/No current medications• Physical exam, BP WNL, 50th percentile for Ht/Wt• No xanthelasma, cutaneous xanthomata, or Achille’s tendon

thickening

Case #2• Activity

– Computer games, TV– Biking

• Diet– Some meals at home, but often fast food, snacks– No effort yet to alter diet

• Social– No tobacco/alcohol/substance abuse– Parents are separated, lives with mother, who works two jobs

Case #2• Dietary assessment

– 3-day dietary recall to determine average daily intake• Total calories: 2000 kcal/day• Composition as % of total calories

– Protein: 16%– Fat: 37%

» Saturated: 17%» Monounsaturated: 15%» Polyunsaturated: 5%

– Carbohydrate: 47%• Cholesterol content: 373 g/day• Fiber: 13 g/day

Case #249 yo

MI59 yo

hypertension

66 yohealthy

62 yo healthy

36 yoCH 299

MI 6 mos ago

34 yoCH 159healthy

34 yoMI

6 yohealthyCH 249

9 yohealthyCH 255

11 yohealthyCH 250

Risk Factors for Atherosclerotic Heart Disease

• Hypercholesterolemia• Smoking• Hypertension• Diabetes• Sedentary lifestyle• Male Sex• Family history of CHD• Age (male > 45 yoa, female > 55 yoa)

Evidence Relating Diet, Serum Cholesterol Level, and Coronary Heart Disease

• Animal studies• Genetic disorders, such as familial

hypercholesterolemia with elevated serum LDL cholesterol, are associated with premature atherosclerosis

• Epidemiologic studies• Clinical trials• Autopsy studies

Dietary Saturated Fat and Cholesterol Intake and Serum Total Cholesterol in Boys Aged 7-9 Years in Six Countries

Country Saturated Fat(% of energy)

Cholesterol(mg/1000 kcal)

Serum Chol(mg/dl)

Philippines 9.3 97 147

Italy 10.4 159 159

China 10.5 48 128

U. S. 13.5 151 167

Netherlands 15.1 142 174

Finland 17.7 157 190

Serum Cholesterol in Boys and Middle-Aged Men and CHD Mortality Rates in Middle-Aged

Men in Industrialized Countries

CountrySerum TotalCholesterol

(mg/dl) Boys Men

CHD MortalityPer 100,000Men aged

45-54 yearsPortugal 149 203 71Israel 155 204 119Italy 159 200 91Hungary 159 203 276*U.S. 167 217 170Netherlands 171 221 134Poland 176 192 218*Finland 190 240 264

Coronary Primary Prevention Trial (CPPT)

• Hypercholesterolemic, middle-aged men• Treated with cholestyramine• 19% reduction in fatal and/or non-fatal MI over 7

years• A 25% reduction in serum cholesterol level

resulted in a 50% reduction in CHD risk

Controlled Angiographic Trials of Cholesterol Lowering

• Several studies to date in adults• Regression of lesions in 16-47% with large

decreases in serum LDL cholesterol levels (34-48% reduction) for 2-5 years

• Main benefit may be slowing of progression of atherosclerotic lesions

Why Intervene in Children• Role of hypercholesterolemia in atherosclerosis well

established in adults• Children with elevated cholesterol are more likely to have

family members with elevated levels and come from families with premature atherosclerosis

• Tracking– Children with elevated serum cholesterol levels are likely to have

hypercholesterolemia later in life• Autopsy studies

Autopsy Studies• U.S. soldiers in Korean War (Enos et al, 1955)

– Gross coronary disease in 77% of subjects studied– Mean age 22 years– Confirmed in studies from Viet Nam War

• Holman, 1961; Strong and McGill, 1962; Stary, 1989– Aortic fatty streaks are extensive in childhood– Coronary fatty streaks appear in adolescence– Fibrous plaques appear in the second decade with progression

into the second decade• Bogalusa Study• PDAY Study

Bogalusa Study

NEJM 338:1650, 1998N=93, 2-39 yoa

Pathobiological Determinants of Atherosclerosis in Youth (PDAY)

• Multicenter post-mortem study in 1079 males, 364 females, 15-34 years of age

• Violent death• Arteries graded for atherosclerotic lesions in aorta

and right coronary artery• Serum lipoproteins measured• Serum thiocyanate measured as an index of smoking

Arterioscler Thromb Vasc Biol 17:95, 1997

PDAY Results• Extent of surface area with fatty streaks and raised lesions

increased with age in all vessels• Serum VLDL plus LDL cholesterol positively correlated

with extent of fatty streaks and raised lesions in all vessels• Serum HDL cholesterol negatively correlated with extent

of fatty streaks and raised lesions in all vessels• Smoking associated with more extensive fatty streaks and

raised lesions in aorta

Pediatric Screening Strategies

• Screen no one. Treat everyone with diet.• Screen only those children with a positive family

history of premature atherosclerotic disease or known hyperlipidemia.

• Screen all children.

National Cholesterol Education Program (NCEP) Recommendations for Pediatric Cholesterol Screening

• Screen after 2 years of age• All children with first degree relative with

symptoms or diagnosis of atherosclerotic disease, hyperlipidemia (serum cholesterol > 240 mg/dl), or sudden cardiac death before 55 years of age

Percentage of Children Aged 0-19 Years Who Would Be Screened, and Percentage of Those with LDL Cholesterol ≥130 mg/dl Who Would Be Identified, If the Presence of CV Disease or Various Levels of Elevated Total Cholesterol in at Least One

Parent Is Used to Select Children for Screening

Parental Cholesterol(mg/dl) Higher Than

Children Who Would Be Screened (%)

Sensitivity for Identification of

Children with LDL Cholesterol ≥130 mg/dl

200 63.5 86.5220 44.3 63.5240 25.1 40.5260 18.3 29.7280 15.3 28.4300 13.9 28.4

The Lipid Research Clinics Prevalence Study (N=1042)

What to Measure• Total cholesterol • Triglycerides• HDL cholesterol• Calculate LDL cholesterol

– LDL cholesterol=total cholesterol-HDL cholesterol-triglycerides/5– Not accurate if triglycerides > 400 mg/dl– Some commercial labs now measure LDL cholesterol directly

• Fasting not necessary for cholesterol measurement alone, but overnight fast is required for profile

Classification of Total and LDL Cholesterol Levels in Children and Adolescents

Total Cholesterol(mg/dl)

LDL Cholesterol(mg/dl)

Acceptable <170 <110

Borderline 170-199 110-129

High ≥200 ≥130

What to do After Screening• If total cholesterol > 95th %tile (200 mg/dl),

repeat with full profile• If confirmed, rule out secondary causes• Screen family members• Start Phase I diet and risk factor

reduction/prevention• Follow-up and consider Phase II diet to reduce

LDL cholesterol to below 95th percentile

Borderline Cases

• 70th-90th percentile (170-199 mg/dl)• Repeat, if average of two still borderline, get

complete analysis• If LDL cholesterol is borderline, start phase I diet

and risk factor reduction/prevention• Recheck in 1 year

Abnormalities not detected by a simple cholesterol measurement

• Hypertriglyceridemia• Hypoalphalipoproteinemia (low HDL)• Elevated apolipoprotein B level with normal

LDL-C (excess number of small LDL particles) • Elevated lipoprotein(a) level• Elevated homocysteine level

Secondary Causes of Hyperlipidemia

• Endocrine– Hypothyroidism– Diabetes mellitus– Glycogen storage disease

• Pregnancy• Renal Disease

– Nephrotic syndrome• Obstructive liver disease• Drugs

– Corticosteroids, isotretinoin, thiazides, anticonvulsants,-blockers, anabolic steroids, oral contraceptives

Familial Aggregation of Hyperlipidemia

• Monogenic– Heterozygous familial hypercholesterolemia

• Mutations in LDL receptor• 90% will have CHD by 65 yoa• 4% of all cases of premature CHD

– Familial Combined Hyperlipidemia• Expression variable (cholesterol and/or triglyceride elevation) and may be delayed• 11% of all cases of premature CHD

• Polygenic– Accounts for majority of cases of premature CHD– Expression of a number of genes contributing to hypercholesterolemia and

atherosclerosis combined with environmental factors

Dietary Fat in Children and Adolescents in the United States

• Age 1-19 years-14% of total calories from saturated fat

• Age 1-11 years-35% of total calories from fat• Age 12-19 years-36% of total calories from fat

Phase I Diet

• No more than 30% of total calories from fat• Less than 10% of total calories from saturated fat• Less than 300 mg of cholesterol/day• Total caloric intake appropriate for normal

growth and ideal body weight

Phase II Diet

• No more than 30% of total calories from fat• Less than 7% of total calories from saturated fat• Less than 200 mg of cholesterol/day• Total caloric intake appropriate for normal

growth and ideal body weight

Criteria for Drug TherapyIn Children and Adolescents

• 10 years of age or older• Adequate trial of dietary therapy (6 mos-1 yr)• LDL cholesterol level ≥ 190 mg/dl• LDL cholesterol level ≥ 160 mg/dl and

– Positive family history of premature CVDor

– 2 or more CVD risk factors persisting after vigorousefforts to control or eliminate these factors

Goals of Drug Therapyin Children and Adolescents

• Acceptable-LDL cholesterol level < 130 mg/dl• Ideal-LDL cholesterol level < 110 mg/dl• Monitor 6 weeks after starting therapy, then every

3 months until maximal effect, then every 6 months

• Monitor compliance, lipids, growth, and appearance of side effects

Bile Acid Sequestrants• Cholestyramine (Questran®), Colestipol (Colestid®)• Only class of drugs approved for use in children to treat

hyperlipidemia• Bind bile acids and enhance fecal elimination, up-regulate hepatic bile

acid synthesis from cholesterol, and thereby up-regulate hepatic LDL receptors

• Will often increase serum triglyceride levels in mixed hyperlipidemias• Not absorbed, side effects mainly constipation, bloating• Can lower fat-soluble vitamin and folate levels, but usually not

important clinically• Gritty, “sandy” consistency; compliance a real problem

NCEP Treatment Guidelinesfor LDL-C Levels for Adults

Definiteatherosclerotic

disease

Two ormore otherrisk factors

Initiationlevel

(mg/dl)

Goal(mg/dl)

No No > 190 < 160

No Yes > 160 < 130

Yes Yes or No > 130 <100

HMG CoA Reductase Inhibitors• “Statins”

– Cerivastatin (BaycolR)– Fluvastatin (LescolR)– Atorvastatin (LipitorR)– Lovastatin (MevacorR)– Pravastatin (PravacholR)– Simvastatin (ZocorR)

• Decrease hepatic cholesterol synthesis resulting in increased hepatic LDL receptors with increased clearance of plasma LDL particles

HMG CoA Reductase Inhibitors

• Decrease serum LDL cholesterol levels• Modest increases in serum HDL-C levels• The more potent statins, atorvastatin, cerivastatin,

and fluvastatin, also significantly decrease triglyceride levels, possibly serving as effective monotherapy in mixed hyperlipidemias

HMG CoA Reductase InhibitorsAdverse Effects

• Myalgias, myopathy, rhabdomyolysis• Risk of rhabdomyolysis and acute renal failure

especially high with combined therapy with fibric acid derivatives, niacin, cyclosporine, erythromycin, and azole antifungals

• Transaminase elevation• Fetal toxicity

Niacin• NiaspanR (extended release tablets)

– If equivalent dose of crystalline niacin is substituted, toxicity will result, and fulminant liver failure has been reported

• Decreases total cholesterol, LDL-C, and triglycerides• Increases HDL-C• Escalating dose titration to minimize side effects,

particularly flushing

NiacinAdverse Effects

• Flushing– Usually transient and improves with duration of

therapy– ASA or NSAID prior to dosing may minimize– Avoid ingestion of alcohol or hot drinks around time

of dosing– If discontinued for an extended period, must escalate

and titrate dosing again

NiacinAdverse Effects

• Transaminase elevation• Rare cases of rhabdomyolysis with concomitant HMG

CoA reductase inhibitors• Glucose intolerance• Uric acid elevation• Monitor anticoagulant therapy• Use with caution in unstable angina/recovering MI,

especially with concomitant vasoactive drugs

Fibric Acid Derivatives• Clofibrate (AtromidR), gemfibrozil (LopidR), fenofibrate

(TricorR)• Decrease triglycerides, increase HDL-C levels• Serum triglycerides > 1000 mg/dl associated with

significant risk of pancreatitis• Not to be used to treat low HDL-C as only lipid abnormality• Increased incidence of non-coronary and age-adjusted all-

cause mortality in studies (WHO)

Fibric Acid DerivativesAdverse Effects

• Myalgias, myopathy, rhabdomyolysis• Risk of rhabdomyolysis and acute renal failure especially

high with combined therapy with “statins”• Cholelithiasis • Transaminase elevation and Hgb/WBC depression• Need to reduce anticoagulant dose• Increased risk of liver and testicular malignancy• Fetal toxicity

Family Approach to Treating Hyperlipidemia and Reducing

Cardiovascular Risk • Affected family members generally have same lipid

disorder• Team Approach-Specialists from pediatrics, adult

medicine, and nutrition• Programs are designed to fit into the family routine and

alter eating habits and physical activity• Families develop an internal support structure which

improves compliance