clinical correlation hyperlipidemia
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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
– 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
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