Hyperlipidemia in Childhood

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Hyperlipidemia in Childhood Adolescent

• DIABESITY MEETING 22.02.05

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TOPICS

• Classification of hyperlipidemias
• Atherosclerosis in adults risk factors Rx
• Atherosclerosis in childhood.
• Management of dyslipidemia in childhood
• Management of dyslipidemia in diabetics children

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Classification of DyslipidaemiasFredrickson
(WHO) Classification
Phenotype I IIa IIb III IV V
Lipoprotein elevated Chylomicrons LDL LDL and
VLDL IDL VLDL VLDL and chylomicrons
Atherogenicity None seen
Prevalence Rare Common Common Intermediate C
ommon Rare
LDL low-density lipoprotein IDL
intermediate-density lipoprotein VLDL very
low-density lipoprotein. High-density
lipoprotein (HDL) cholesterol levels are not
considered in the Fredrickson classification.
(Adapted from Yeshurun et al., 1995)
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Type IIa (familial hypercholesterolemia FH)

• Autosomal dominant disorder due to heterozygous
  mutated LDL receptor gene
• Frequency in Europe and North America is 0.2
• Total cholesterol ranging from 230 to 500
• Xantomas -15 by second decade of life
• The risk for major coronary events 25 after age
  30, 50 by 50 years and 85 by age 60.
• Positive family history of premature
  atherosclerotic

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Type IIa (familial hypercholesterolemia FH)

• Autosomal recessive disorder due to homozygous
  mutated LDL receptor gene
• Very rare
• total cholesterol 500 to 1000mg/dl.
• Xantomas in all pts by 6y of life
• Major coronary events occur before 10y

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Type IIb (familial combined hyperlipidemia).

• The genetic defect is unknown
• Frequency in Europe and North America is 1300
• It differs from type II a in that there are no
  xanthomas noted, and triglycerides are moderately
  elevated in addition to the increase in LDL
  cholesterol.

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Type III

• Defect in the metabolism of VLDL remnants due to
  abnormal Apo E or hypothyroidism.
• Affected people may have palmar xanthomas and
  develop premature CAD.
• Both total cholesterol and triglycerides
• are elevated.

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Development of Atherosclerotic Plaques
Fatty streak
Lipid rich plaque
Normal
Fibrous cap
Foam cells
Complex plaque
Lipid core
Thrombus
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Relationship Between Cholesterol and CHD Risk
The Framingham Study
150
125
100
CHD incidence per 1000
75
50
25
0
204
205234
235264
265294
³295
Serum cholesterol (mg/100 mL)
(Adapted from Castelli WP, 1984)
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NCEP ATP IIIFocus on Multiple Risk Factors

• Uses Framingham projections of 10-year absolute
  CHD risk to identify certain patients with ³2
  risk factors for more intensive treatment.
• Raises persons with diabetes without CHD to the
  level of CHD risk equivalent.
• Identifies persons with multiple metabolic risk
  factors (metabolic syndrome) as candidates for
  intensified TLC.

TLC therapeutic lifestyle changes
(National Cholesterol Education Program, Adult
Treatment Panel III, 2001)
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Initiate therapeutic lifestyle changes (TLC) if
LDL is above goal.
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UPDATE JULY 2004
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Benefits of Cholesterol Lowering
Meta-analysis of 38 primary and secondary
intervention trials
-0.0
-0.2
-0.4
Mortality log odds ratio
-0.6
Total mortality (p0.004)
CHD mortality (p0.012)
-0.8
-1.0
0
4
8
12
16
20
24
28
32
36
40
44
48
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in cholesterol reduction
(Adapted from Gould AL, et al.,1998)
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Effects of Statins on Lipids
LDL cholesterol change
HDL cholesterol change
Triglycerides change
atorvastatin simvastatin pravastatin lovastatin fl
uvastatin
-50 -41 -34 -34 -24
6 12 12 8.6 8
-29 -18 -24 -16 -10
Daily dose of 40 mg of each drug
(Adapted from Knopp 1999)
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Effects of statins on plaque biology
Reduce lipid accumulation
Accumulation of modified lipid Endothelial cell
activation Inflammatory cell migration Inflammat
ory cell activation VSMC recruitment VSMC
proliferation and matrix synthesis Fibrous cap
formation Plaque rupture Platelet
aggregation Thrombosis
Normalize endothelial cell function
Reduce inflammatory cell infiltration into plaques
Effects on VSMC proliferation and matrix
synthesisdiffer between statins
Inhibit platelet aggregation
Reduce blood thrombogenicity
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Effect of Lipid-Modifying Therapies on Lipids
Therapy Bile acid sequestrants Nicotinic acid
Fibrates(gemfibrozil) Probucol Statins
TC Down 20 Down 25 Down 15 Down
25 Down 1530
LDL Down 1530 Down 25 Down 515 Down
1015 Down 2450
HDL Up 35 Up 1530 Up 20 Down 2030
Up 612
TG Neutral or up Down 2050 Down
2050 Neutral Down 1029
Patient tolerability Poor Poor
to reasonable Good Reasonable Good
Daily dose of 40 mg of each drug (cerivastatin
0.3 mg) TCtotal cholesterol LDLlow density
lipoprotein HDLhigh density lipoprotein TGtrigly
ceride.
(Adapted from Yeshurun 1995, Knopp 1999)
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Current Treatment Options for Dyslipidaemia

• Hypercholesterolaemia Statin Bile acid
  sequestrants
• ( LDL-C) Nicotinic acid derivatives
• Mixed dyslipidaemia Statin Fibrates
• ( LDL-C, Triglycerides)
• Hypertriglyceridaemia Fibrate Nicotinic acid
  derivatives
• ( Triglycerides)

Initial Choice
Alternative
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Cholesterol Absorption Inhibition For Broader
Lipid Control
VLDL
LDL
IDL
Statins
synthesis
BILIARY SECRETION
Absorption
Cholesterol Absorption Inhibition
INTESTINE
Excretion
DIETARY CHOLESTEROL
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DYSLIPIDEMIA IN CHILDREN SHOULD WE BE CONCERNED ?

• There are no long term studies of the
  relationship between childhood dyslpidemia and
  adulthood CHD
• However.

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Epidemiology (1)

• U.S children and adolescents have higher serum
  cholesterol levels and higher saturated fat
  intake in comparison to children from other
  countries.
• U.S adults have higher rates of CHD morbidity
  moratality

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Epidemiology (2)

• Children and adolescents with elevated serum
  cholesterol levels, particularly LDLcholesterol
  levels, often come from families in which there
  is a high incidence of coronary heart disease in
  the adult relatives
• A strong familial aggregation of total, LDL-, and
• HDLcholesterol levels exists in children and
  parents. (monogenic, polygenic, environment)
• Children and adolescents with high cholesterol
• levels are more likely than the general
  population to have high levels as adults.

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• ENOS WF, HOLMES RH, BEYER J.
• Coronary disease among United States soldiers
  killed in action in Korea preliminary report.J
  Am Med Assoc. 1953 Jul 181521090-3.

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Atherosclerosis Timeline
Foam Cells
Fatty Streak
Intermediate Lesion
Fibrous Plaque
Complicated Lesion/Rupture
Atheroma
Endothelial Dysfunction
From first decade
From third decade
From fourth decade
Thrombosis, hematoma
Smooth muscle and collagen
Growth mainly by lipid accumulation
Adapted from Stary HC et al. Circulation.
1995921355-1374.
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The Prevalence of Fibrous-Plaque Lesions in the
Aorta and Coronary Arteries in 204 Children and
Young Adults
Berenson G et al. NEJM 1998
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PDAY Prevalence of Risk Factors

HighnonHDL-C
LowHDL-C
Smoking
Hypertension
IGT
Obesity
NonHDL-CTC minus HDL-C IGTimpaired glucose
tolerance. McGill HC Jr, et al. Circulation.
2000102374-379.
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The Effect of Multiple Risk Factors on the Extent
of Atherosclerosis in Children and Young Adults.
NEJM 1998
Risk factors BMI, SBP, TG LDL-C gt 75
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J Pediatr. 2004 Oct145(4)452-7.
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Screening for hypercholesterolemia

• Progeny of parents and grandparents who at age
  younger than 55 years had angiographic-positive
  CAD, angina, or myocardial infarction peripheral
  vascular disease or sudden cardiac death.
• Progeny of parents found to have high
  cholesterol.
• For children in whom family history is unknown
  and other risk factors are present

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Screening for hypercholesterolemia
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Screening for hypercholesterolemia
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Blood cholesterol management (1)

• GOALS LDL-C lt160 mg/dL (lt130 mg/dL is even
  better, lt100 mg/dL for diabetics )
• If LDL-C is above goals, initiate additional
  therapeutic lifestyle changes (Diet)
• Consider LDL-lowering dietary options
• Emphasize weight management and increased
  physical activity

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Blood cholesterol management (2)

• Evaluate for secondary causes (thyroid-stimulating
  hormone, liver function tests, renal function
  tests,urinalysis)
• Consider pharmacological therapy for individuals
  with LDL gt190 mg/Dl with no other risk factors
  for CVD or gt160 mg/dL with other risk factors
  present
• Obesity, HT, DM, FH of premature CVD
• Bile acid-binding resins or statins are usual
  first-line agents

AHA GUIDELINES. J Ped 2003
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When Should We Treat High Triglycerides ?
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Data have shown that in children with the most
severe familial hyperlipidemias, LDL-C rarely
decreases by more than 15 with diet management
alone.
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Long-Term Safety and Efficacy of a
Cholesterol-Lowering Diet inChildren With
Elevated Low-Density Lipoprotein Cholesterol
Seven-YearResults of the Dietary Intervention
Study in Children (DISC)
Pediatrics 2001
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Diet therapy for childhood hypercholesterolemia
DISC SUDY JAMA 1995
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Cholestyramine therapy in children
Tonstad et al. J Ped 1996
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Atorvastatin in children and adolescents with
familial hypercholesterolemia
McCrindle et al. J Ped 2003
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Atorvastatin in children and adolescents with
familial hypercholesterolemia
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Atorvastatin in children and adolescents with
familial hypercholesterolemia
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Unsolved issues (1)

• Does treating elevated cholesterol level in
  patients at a younger age, rather than in
  adulthood, improve future quality of life ?
• Does pharmacologic treatment of hyperlipidemia
  during childhood or adolescence reduce
  cardiovascular morbidity and mortality in
  adulthood ?

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Unsolved issues (2)

• Is it both safe and cost-effective to treat for
  decades children with elevated cholesterol
  levels?
• Are any early indicators of atherosclerotic
  vascular disease useful for assessing the effects
  of treatment in pediatric patients long before
  clinical end points would be expected to appear ?

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Management of dyslipidemia in children/adolescents
with diabetes
Diabetes care 2003