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
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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
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
• 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
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
• 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
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