Case

1
Case 1

• 14 yo white male
• Referred after hypercholesterolemia detected on
  routine screening because of fathers
  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
  Achilles 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
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
  Achilles 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
36 yo CH 299 MI 6 mos ago
34 yo MI
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 gt 45 yoa, female gt 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
N93, 2-39 yoa
NEJM 3381650, 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 1795, 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 gt 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
(N1042)
25
What to Measure

• Total cholesterol
• Triglycerides
• HDL cholesterol
• Calculate LDL cholesterol
• LDL cholesteroltotal cholesterol-HDL
  cholesterol-triglycerides/5
• Not accurate if triglycerides gt 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 gt 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 lt 130 mg/dl
• Ideal-LDL cholesterol level lt 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 gt 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