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Case #1

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

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Case #1

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  1. 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

  2. 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

  3. 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

  4. 68 yo diabetes hypertension 66 yo healthy 53 yo MI 69 yo breast CA 35 yo healthy CH 152 44 yo CH 280 42 yo CH 310 36 yo healthy CH 299 6 yo healthy CH ? 9 yo healthy CH ? 14 yo healthy CH 286 Case #1

  5. Xanthelasma Palpebrarum

  6. Xanthomata Tuberosa

  7. 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

  8. 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

  9. 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

  10. Case #2 66 yo healthy 62 yo healthy 49 yo MI 59 yo hypertension 34 yo CH 159 healthy 34 yo MI 36 yo CH 299 MI 6 mos ago 6 yo healthy CH 249 9 yo healthy CH 255 11 yo healthy CH 250

  11. 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)

  12. 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

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

  14. Serum Cholesterol in Boys and Middle-Aged Men and CHD Mortality Rates in Middle-Aged Men in Industrialized Countries

  15. 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

  16. 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

  17. 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

  18. 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

  19. Bogalusa Study N=93, 2-39 yoa NEJM 338:1650, 1998

  20. 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

  21. 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

  22. 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.

  23. 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

  24. 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 The Lipid Research Clinics Prevalence Study (N=1042)

  25. 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

  26. Classification of Total and LDL Cholesterol Levels in Children and Adolescents

  27. 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

  28. 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

  29. 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

  30. Secondary Causes of Hyperlipidemia • Endocrine • Hypothyroidism • Diabetes mellitus • Glycogen storage disease • Pregnancy • Renal Disease • Nephrotic syndrome • Obstructive liver disease • Drugs • Corticosteroids, isotretinoin, thiazides, anticonvulsants, b-blockers, anabolic steroids, oral contraceptives

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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 CVD or • 2 or more CVD risk factors persisting after vigorous efforts to control or eliminate these factors

  36. 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

  37. 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

  38. NCEP Treatment Guidelinesfor LDL-C Levels for Adults

  39. 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

  40. 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

  41. 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

  42. 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

  43. 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

  44. 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

  45. 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)

  46. 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

  47. 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

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