Case #114 yo white maleReferred after hypercholesterolemia detected on routine screening because of fathers hypercholesterolemiaTotal cholesterol 290 mg/dl, repeat 286 mg/dlTriglycerides 108 mg/dl, HDL cholesterol 55 mg/dl, LDL cholesterol 209 mg/dlOtherwise well/No current medicationsPhysical exam, BP WNL, 50th percentile for Ht/WtNo xanthelasma, cutaneous xanthomata, or Achilles tendon thickening

Case #1ActivitySoccer, swimming, bikingDietFamily already attempting to reduce dietary fat and cholesterol after learning of elevated cholesterol in patient and fatherSocialNo tobacco/alcohol/substance abuseBoth parents come with patient to clinic, seem very supportive

Case #1Dietary assessment3-day dietary recall to determine average daily intakeTotal calories: 2000 kcal/dayComposition as % of total caloriesProtein: 22%Fat: 28%Saturated: 6%Monounsaturated: 14%Polyunsaturated: 8%Carbohydrate: 49%Cholesterol content: 221 g/dayFiber: 31 g/day

Case #1

Xanthelasma Palpebrarum

Xanthomata Tuberosa

Case #211 yo white maleReferred after hypercholesterolemia detected after father was found to have hypercholestrolemia and recent myocardial infarctionTotal cholesterol 254 mg/dl, repeat 250 mg/dlTriglycerides 102 mg/dl, HDL cholesterol 53 mg/dl, LDL cholesterol 181 mg/dlOtherwise well/No current medicationsPhysical exam, BP WNL, 50th percentile for Ht/WtNo xanthelasma, cutaneous xanthomata, or Achilles tendon thickening

Case #2ActivityComputer games, TVBikingDietSome meals at home, but often fast food, snacksNo effort yet to alter dietSocialNo tobacco/alcohol/substance abuseParents are separated, lives with mother, who works two jobs

Case #2Dietary assessment3-day dietary recall to determine average daily intakeTotal calories: 2000 kcal/dayComposition as % of total caloriesProtein: 16%Fat: 37%Saturated: 17%Monounsaturated: 15%Polyunsaturated: 5%Carbohydrate: 47%Cholesterol content: 373 g/dayFiber: 13 g/day

Case #249 yoMI59 yo hypertension66 yohealthy62 yo healthy36 yoCH 299MI 6 mos ago34 yoCH 159healthy34 yoMI6 yohealthyCH 2499 yohealthyCH 25511 yohealthyCH 250

Risk Factors for Atherosclerotic Heart DiseaseHypercholesterolemiaSmokingHypertensionDiabetesSedentary lifestyleMale SexFamily history of CHDAge (male > 45 yoa, female > 55 yoa)

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

Animal studiesGenetic disorders, such as familial hypercholesterolemia with elevated serum LDL cholesterol, are associated with premature atherosclerosisEpidemiologic studiesClinical trialsAutopsy studies

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

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

Coronary Primary Prevention Trial (CPPT)Hypercholesterolemic, middle-aged menTreated with cholestyramine19% reduction in fatal and/or non-fatal MI over 7 yearsA 25% reduction in serum cholesterol level resulted in a 50% reduction in CHD risk

Controlled Angiographic Trials of Cholesterol LoweringSeveral studies to date in adultsRegression of lesions in 16-47% with large decreases in serum LDL cholesterol levels (34-48% reduction) for 2-5 yearsMain benefit may be slowing of progression of atherosclerotic lesions

Why Intervene in ChildrenRole of hypercholesterolemia in atherosclerosis well established in adultsChildren with elevated cholesterol are more likely to have family members with elevated levels and come from families with premature atherosclerosisTrackingChildren with elevated serum cholesterol levels are likely to have hypercholesterolemia later in lifeAutopsy studies

Autopsy StudiesU.S. soldiers in Korean War (Enos et al, 1955)Gross coronary disease in 77% of subjects studiedMean age 22 yearsConfirmed in studies from Viet Nam WarHolman, 1961; Strong and McGill, 1962; Stary, 1989Aortic fatty streaks are extensive in childhoodCoronary fatty streaks appear in adolescenceFibrous plaques appear in the second decade with progression into the second decadeBogalusa StudyPDAY Study

Bogalusa StudyNEJM 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 ageViolent deathArteries graded for atherosclerotic lesions in aorta and right coronary arterySerum lipoproteins measuredSerum thiocyanate measured as an index of smoking

Arterioscler Thromb Vasc Biol 17:95, 1997

PDAY ResultsExtent of surface area with fatty streaks and raised lesions increased with age in all vesselsSerum VLDL plus LDL cholesterol positively correlated with extent of fatty streaks and raised lesions in all vesselsSerum HDL cholesterol negatively correlated with extent of fatty streaks and raised lesions in all vesselsSmoking associated with more extensive fatty streaks and raised lesions in aorta

Pediatric Screening StrategiesScreen 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 ScreeningScreen after 2 years of ageAll 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 ScreeningThe Lipid Research Clinics Prevalence Study (N=1042)

What to MeasureTotal cholesterol TriglyceridesHDL cholesterolCalculate LDL cholesterolLDL cholesterol=total cholesterol-HDL cholesterol-triglycerides/5Not accurate if triglycerides > 400 mg/dlSome commercial labs now measure LDL cholesterol directlyFasting not necessary for cholesterol measurement alone, but overnight fast is required for profile

Classification of Total and LDL Cholesterol Levels in Children and Adolescents

What to do After ScreeningIf total cholesterol > 95th %tile (200 mg/dl), repeat with full profileIf confirmed, rule out secondary causesScreen family membersStart Phase I diet and risk factor reduction/preventionFollow-up and consider Phase II diet to reduce LDL cholesterol to below 95th percentile

Borderline Cases70th-90th percentile (170-199 mg/dl)Repeat, if average of two still borderline, get complete analysisIf LDL cholesterol is borderline, start phase I diet and risk factor reduction/preventionRecheck in 1 year

Abnormalities not detected by a simple cholesterol measurementHypertriglyceridemiaHypoalphalipoproteinemia (low HDL)Elevated apolipoprotein B level with normal LDL-C (excess number of small LDL particles) Elevated lipoprotein(a) levelElevated homocysteine level

Secondary Causes of HyperlipidemiaEndocrineHypothyroidismDiabetes mellitusGlycogen storage diseasePregnancyRenal DiseaseNephrotic syndromeObstructive liver diseaseDrugsCorticosteroids, isotretinoin, thiazides, anticonvulsants, b-blockers, anabolic steroids, oral contraceptives

Familial Aggregation of HyperlipidemiaMonogenicHeterozygous familial hypercholesterolemiaMutations in LDL receptor90% will have CHD by 65 yoa4% of all cases of premature CHDFamilial Combined HyperlipidemiaExpression variable (cholesterol and/or triglyceride elevation) and may be delayed11% of all cases of premature CHDPolygenicAccounts for majority of cases of premature CHDExpression of a number of genes contributing to hypercholesterolemia and atherosclerosis combined with environmental factors

Dietary Fat in Children and Adolescents in the United StatesAge 1-19 years-14% of total calories from saturated fatAge 1-11 years-35% of total calories from fatAge 12-19 years-36% of total calories from fat

Phase I DietNo more than 30% of total calories from fatLess than 10% of total calories from saturated fatLess than 300 mg of cholesterol/dayTotal caloric intake appropriate for normal growth and ideal body weight

Phase II DietNo more than 30% of total calories from fatLess than 7% of total calories from saturated fatLess than 200 mg of cholesterol/dayTotal caloric intake appropriate for normal growth and ideal body weight

Criteria for Drug TherapyIn Children and Adolescents10 years of age or olderAdequate trial of dietary therapy (6 mos-1 yr)LDL cholesterol level 190 mg/dlLDL cholesterol level 160 mg/dl andPositive family history of premature CVDor2 or more CVD risk factors persisting after vigorousefforts to control or eliminate these factors

Goals of Drug Therapyin Children and AdolescentsAcceptable-LDL cholesterol level < 130 mg/dlIdeal-LDL cholesterol level < 110 mg/dlMonitor 6 weeks after starting therapy, then every 3 months until maximal effect, then every 6 monthsMonitor compliance, lipids, growth, and appearance of side effects

Bile Acid SequestrantsCholestyramine (Questran), Colestipol (Colestid)Only class of drugs approved for use in children to treat hyperlipidemiaBind bile acids and enhance fecal elimination, up-regulate hepatic bile acid synthesis from cholesterol, and thereby up-regulate hepatic LDL receptorsWill often increase serum triglyceride levels in mixed hyperlipidemiasNot absorbed, side effects mainly constipation, bloatingCan lower fat-soluble vitamin and folate levels, but usually not important clinicallyGritty, sandy consistency; compliance a real problem

NCEP Treatment Guidelinesfor LDL-C Levels for Adults

Definite atherosclerotic disease

Two or more other risk factors

Initiation

level

(mg/dl)

Goal

(mg/dl)

No

No

> 190

< 160

No

Yes

> 160

< 130

Yes

Yes or No

> 130

HMG CoA Reductase InhibitorsStatinsCerivastatin (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 InhibitorsDecrease serum LDL cholesterol levelsModest increases in serum HDL-C levelsThe more potent statins, atorvastatin, cerivastatin, and fluvastatin, also significantly decrease triglyceride levels, possibly serving as effective monotherapy in mixed hyperlipidemias

HMG CoA Reductase InhibitorsAdverse EffectsMyalgias, myopathy, rhabdomyolysisRisk of rhabdomyolysis and acute renal failure especially high with combined therapy with fibric acid derivatives, niacin, cyclosporine, erythromycin, and azole antifungals Transaminase elevationFetal toxicity

NiacinNiaspanR (extended release tablets)If equivalent dose of crystalline niacin is substituted, toxicity will result, and fulminant liver failure has been reportedDecreases total cholesterol, LDL-C, and triglyceridesIncreases HDL-CEscalating dose titration to minimize side effects, particularly flushing

NiacinAdverse EffectsFlushingUsually transient and improves with duration of therapyASA or NSAID prior to dosing may minimizeAvoid ingestion of alcohol or hot drinks around time of dosingIf discontinued for an extended period, must escalate and titrate dosing again

NiacinAdverse EffectsTransaminase elevationRare cases of rhabdomyolysis with concomitant HMG CoA reductase inhibitorsGlucose intoleranceUric acid elevationMonitor anticoagulant therapyUse with caution in unstable angina/recovering MI, especially with concomitant vasoactive drugs

Fibric Acid DerivativesClofibrate (AtromidR), gemfibrozil (LopidR), fenofibrate (TricorR)Decrease triglycerides, increase HDL-C levelsSerum triglycerides > 1000 mg/dl associated with significant risk of pancreatitisNot to be used to treat low HDL-C as only lipid abnormalityIncreased incidence of non-coronary and age-adjusted all-cause mortality in studies (WHO)

Fibric Acid DerivativesAdverse EffectsMyalgias, myopathy, rhabdomyolysisRisk of rhabdomyolysis and acute renal failure especially high with combined therapy with statinsCholelithiasis Transaminase elevation and Hgb/WBC depressionNeed to reduce anticoagulant doseIncreased risk of liver and testicular malignancyFetal toxicity

Family Approach to Treating Hyperlipidemia and Reducing Cardiovascular Risk Affected family members generally have same lipid disorderTeam Approach-Specialists from pediatrics, adult medicine, and nutritionPrograms are designed to fit into the family routine and alter eating habits and physical activityFamilies develop an internal support structure which improves compliance

Note that this individual was referred for evaluation and treatment after hypercholesterolemia was detected on a screening test because of the fathers hypercholesterolemia. Later in this seminar, we will discuss indications for cholesterol screening in children and adolescents. Note that this patient had no physicial findings of hypercholesterolemia, such as xanthelasma, cutaneous xanthomata, or Achilles tendon thickening.Note that this family has already taken the initiative to reduce dietary fat and cholesterol in their diet after learning of the hypercholesterolemia in the patient and his father.Notice that this patient has already modified his dietary fat intake to a desirable level. Also, his cholesterol and fiber intake are in the desirable range.Examination of the patients pedigree demonstrates that the hypercholesterolemia appears to be inherited on the patients fathers side of the family. Notice that the paternal grandfather died at 53 yoa with a myocardial infarction. The patients father, although healthy, has an elevated cholesterol at 299 mg/dl. Finally, notice that the patient has two female siblings who are healthy but have not had their cholesterol measured. This pattern of inheritance would be consistent with familial hypercholesterolemia, which is due to mutations in the LDL receptor.The individual in this slide has xanthelasma palpebrarum. These are cholesterol deposits in the skin in the inner canthus of the eyes. This finding is rarely seen in children and adolescents, but is more often seen in older adults with long- standing hypercholesterolemia. This slide shows xanthomata tuberosa on the elbows. Again, such a finding would be extremely rare in children and adolescents, but is sometimes seen in older individuals with hyperlipidemia. Notice that this patient was referred after hypercholesterolemia was detected on screening after the father was found to have not only hypercholesterolemia, but had also had a recent myocardial infarction. Notice that this family has not made any effort so far to improve their dietary habits and frequently ingest fast food and other high-calorie, high-fat snacks. The fact that the parents are separated with the patient living with the mother, who works two jobs, probably contributes to the difficulty in making dietary changes.Notice that this patient ingests too high a percentage of total calories as fat with too high a proportion of saturated fat. Also, the cholesterol intake is excessive.Examination of this patients pedigree shows that the hypercholesterolemia is inherited from the fathers side of the family. Notice that the paternal grandfather died of a myocardial infarction at 49 yoa. Also note that the father has hypercholesterolemia and has had a recent myocardial infarction. This patient has two healthy younger sisters. Note that both have been screened and both have hypercholesterolemia. This pattern of inheritance would be consistent with familial hypercholesterolemia, due to mutations in the LDL receptor gene.Remember that hypercholesterolemia is only one of several risk factors for atherosclerotic cardiovascular disease. Pediatricians are in a unique position to intervene to prevent many of these risk factors later in life.Numerous animal studies have demonstrated that when animal models are made hypercholesterolemic, they readily develop atherosclerosis. Genetic disorders, such as familial hypercholesterolemia and others, are clearly associated with atherosclerosis and coronary heart disease. There have been a number of epidemiologic studies associating diet with serum cholesterol levels and coronary heart disease. We will discuss some of these. Both primary and secondary intervention clinical trials in adults with hyperlipidemia have clearly demonstrated a beneficial effect of treatment of hyperlipidemia on serum cholesterol levels and coronary heart disease. Finally, autopsy studies have demonstrated that atherosclerosis has its beginnings early in life and is clearly related to serum lipid levels and family history of early atherosclerotic disease.This slide shows that on an international scale, as dietary intake of saturated fat and cholesterol increases, so does the serum cholesterol level in children.Note that, as the serum cholesterol level in both boys and men increases, so does the CHD mortality in middle-aged men in several industrialized countries. Notice that the CHD mortality is particularly high in Hungary and Poland. This is probably due to other genetic and environmental factors impacting on the development of atherosclerosis. Dr. Gerald Berenson has conducted a large-scale population study for a number of years on a biracial cohort of children in Bogalusa, LA. His studies have yielded unique and important information on cardiovascular risk factors in children and adolescents. Autopsy studies on the enrolled subjects are an important part of his ongoing research. In this recent paper in the New England Journal of Medicine, you can see as the number of risk factors increases, the percent surface involvement with both fatty streaks, the early lesions of atherosclerosis, and mature fibrous plagues increases in both the aorta and coronary arteries of young individuals. There are three possible approaches to screening for hypercholesterolemia in children. One strategy is to screen no one and treat everyone with diet. Certainly, this is an important population-based approach that is advocated by the American Heart Association and other agencies. Another approach is to screen only those children with a positive family history of premature atherosclerotic disease or known hyperlipidemia. This approach would ensure that those individuals with a familial hyperlipidemia, who may require more intensive therapy for their disorder, would be identified. The third possible approach would be to screen all children regardless of family history. This is the approach advocated for adults. It is also an approach taken by many pediatricians for screening children. Several studies have shown that relying on family history will frequently miss individuals with hyperlipidemia. This is often due to a fragmented family structure, as well as the inability of many parents to recall or have knowledge of illness in other family members. However, we do not know the true risk of premature cardiovascular disease in individuals with hypercholesterolemia who do not have a true positive family history of premature atherosclerotic disease. The NCEP, as well as the American Heart Association and the American Academy of Pediatrics, have recommended that cholesterol screening be undertaken after two years of age and in all children with a first degree relative with symptoms or diagnosis of atherosclerotic disease, hyperlipidemia with a serum cholesterol >240 mg/dl or sudden cardiac death before 55 years of age.These data represent the rationale for screening those children who have family members with a serum cholesterol level >240 mg/dl. At this cholesterol level in the parent, only about 25% of children would be screened with a sensitivity of identification of those children with an elevated LDL cholesterol being about 40%. This cut-off represents a compromise between a higher sensitivity and the fact that to obtain a higher sensitivity, an excessive number of children would have to be screened.Note that single gene defects account for only about 15% of all cases of premature coronary heart disease. The other cases are accounted for by polygenic disorders in which expression of a number of genes contributing to hypercholesterolemia and atherosclerosis interact with environmental factors to cause hyperlipidemia and premature coronary heart disease.Th institution of a Phase I diet in children does require caution. There have been case reports of younger children presenting with failure to thrive due to overzealous dietary restriction by the parents. Any interventional diet should provide a total caloric intake appropriate for normal growth and development and maintenance of ideal body weight in children. Also, vitamin and micronutrient intake should be adequate.The Phase II diet is more restrictive than the Phase I diet, and even greater attention should be paid to ensuring adequate total caloric intake in children.The family approach to treating hyperlipidemia and reducing cardiovascular risk represents the best approach and addresses changes in, not only the diet, but the lifestyle of all family members, both hyperlipidemic and unaffected. This is the optimum approach, but does require trained personnel and resources that may not be available in many institutions. An important point in the treatment of hypercholesterolemia in children is the fact that, since drug therapy is not recommended under the age of 10, dietary therapy and increased activity and exercise represent the mainstay of treatment. It is very important not to let parents have unrealistic expectations with regard to what these interventions can achieve with the serum cholesterol level. Under the best conditions, there may be only a 10 or 15% reduction in the serum cholesterol level, even though the family is following all of your recommendations. This is particularly true in the monogenic disorders. It is important to let the family know that this is what you expect at the present time and that, when their child is older, there is the option of drug therapy which will likely lower the lipid levels to the normal range.