Transcript Document

Lipid Screening AAP
Recommendations 2008
Henaro Sabino
Pediatric Cardiology
STUDIES
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 Autopsy Study of Korean War (men 18-24yo).
 Bogalusa Heart Study
• RF in children, then followed to adulthood
 Cardiovascular Health in Children
• NC: Blacks highest prevalence of Tot chol >200
 NHANES (National Health & Nutrition Examination
Surveys)
• Children & adolescents over 12yrs
• Blacks had higher HDL, lower TG
 PDAY (Pathobiological Determinants of
Atherosclerosis in Youth)
• 15-34 yo. with accidental death (autopsy)
Epidemiology of CVD:
Impact of Early Risk Factors
STUDIES
 Results:
• Pathologic process beginning with fatty streaks
as early as school-aged children.
• 13% of 4th graders & 10% of adolescents have
tot chol > 200.
• 75% of school-aged kids with high total chol have
tot chol > 200 as young adults.
• Longitudinal tracking is important to identify
these patients.
• RF for CV disease: Diabetes, obesity,
hypertension, smoking, hyperlipidemia.
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Pathobiology
•Fatty streaks  accumulation of lipid-filled macrophages
• smooth muscle proliferation  FIBROUS PLAQUE
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In Vivo STUDIES
 Risk Factors for increased intima-media thickness
of the carotid arteries (cIMT):
• increased LDL-c
• Increased apolipoprotein B
• Increased fibrinogen, homocysteine, and Creactive protein
• low HDL-c
• hypertension
• family history of early myocardial infarction
Davis et al Circulation 2001
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Lipid Metabolism
 Three sources of Cholesterol:
• Dietary: Fat ingested, absorbed & reprocessed
(bile acids & VLDL in bloodstream) by liver.
VLDL LDL to receptor sites.
• Intracellular Production: either produce
cholesterol or esterify cholesterol for recycle.
• Recycle via GI pathway.
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Classes of Plasma Lipoproteins
 Chylomicrons- origin is from dietary fat & is high in TG.
 VLDL- from de novo synthesis (liver) & is high in TG.
 LDL- from catabolism of VLDL & is major carrier of
cholesterol.
 HDL- synthesized in liver and gut, & is composed of
cholesterol & proteins.
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Mechanism of HDL?
 In Vitro: attenuate oxidation of LDL & inhibits
endotelian expression of inflammatory markers.
 Enhances reverse transport of cholesterol,
promotes efflux of cholesterol from plaque,
stabilizes plaque (less thrombogenic).
 ?Vasorelaxation and increased endothelial NO
synthase expression.
Tsujika Maki, J Lipid Research, Kuvin JT, Am Heart J 2002.
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Mechanism of HDL
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Physical Findings
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Familial Combined Hyperlipidemia
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Secondary Causes of Hyperlipidemia
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Who needs screening?
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Cholesterol Profiles
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Assessment of Lipid Levels
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Risk Factors in Lipid Management
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Management of Elevated LDL
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Management of Elevated TG
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Therapeutic Lifestyle Change Diet
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Medications for Hyperlipidemia
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Medications for Hyperlipidemia
 Cholesterol-Absorption Inhibitor: lowers LDL (as
much as 20% below baseline).
 Example: Ezetimibe
 Mechanism: Like bile acid resins, thought to act on
intestinal border to prevent absorption, but enter
into the enterohepatic system.
 Side-effects: G.I. upset (but tablet form better
tolerated).
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Medications for Hyperlipidemia
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Medications for Hyperlipidemia
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Medications for Hyperlipidemia
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Treatment in Pediatrics
 cIMT decreased in children with FH treated with
pravastatin over 2 years while it increased in the
placebo group (Weigman et. al. JAMA 2004; 292:
331)
 Flow mediated dilatation of the brachial artery
improved to normal with early simvastatin (40 mg)
treatment in 50 children with FH after 28 weeks vs.
no improvement in the placebo group (de Jongh et.
al. JACC 2002; 40: 2117)
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Safety of Statins in Pediatrics
 Docubu et. al. Lancet 1992; 339:1488.
• Simvastatin (to 40 mg/d) in 32 children
• F/U 24 mos.
• 1 pt. increased transaminases and 2 transient
elevations in CK
• Development normal
 De Jongh et. al. Circ. 2002;106:2231
• Simvastatin (to 40 mg/d) in 173 children with FH
• 3 transient increases in CK (one on
erythromycin)
• No change growth and development
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Safety of Statins in Pediatrics
 Knipscheer et. al. Ped. Research 1996; 39: 867.
• Pravastatin (20-40 mg) in 72 children with FH
• Transient increases in transaminases and CK =
in both placebo and pravastatin
 Clauss et. al. Pediatrics 2005; 116: 682.
• Lovastatin (20-40 mg) in 54 postmenarchal girls
with FH
• No diff. vs. placebo in safety, hormone levels, &
menstrual cycle length.
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Safety of Statins in Pediatrics
 McCrindle et. al. J. Pediatrics 2003; 143: 74.
• Atorvastatin (10-20 mg) in 187 children with FH
or severe hypercholesterolemia
• Excellent safety
• 6 mos. extension (10 mg) safe and no effect on
growth and development
• Routine monitoring of CK is problematic
• Psychological concerns-44% reported concerns
for disease, but 62% felt safer with medications.
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Controversy With Statins
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New York Times February 13, 2008, 11:45 am
Do Statins Make You Stupid?
By Tara Parker-Pope Cholesterol-lowering statin drugs have had a rough time of it lately.
There was the headline-making trial of the statin-combination drug Vytorin, which rattled
conventional wisdom about the value of lowering cholesterol. Business Week weighed in
with a report that asked: “Do Cholesterol Drugs Do Any Good?” And my Well column in
Science Times last month pointed out that there’s no data to show that statins prolong the
lives of many people who use them.
 Now, The Wall Street Journal has joined the fray. Health Journal columnist Melinda Beck
revisited questions about whether statin drugs have cognitive side effects that leave
users, particularly women, with muddled thinking and forgetfulness. “This drug makes
women stupid,” Dr. Orli Etingin, vice chairman of medicine at New York-Presbyterian
Hospital, declared at a recent luncheon, according to the Journal.
 Over the years, there’s been a lot of discussion about whether statins affect thinking and
memory, but drug makers point out that hundreds of studies haven’t shown a causal link
between statins and memory problems. However, anecdotal reports continue to suggest
that some patients do develop memory loss while taking the drugs.
 After I wrote about the issue several years ago, a colleague who had once memorized
poetry as a hobby told me he was unable to remember poems once he started taking
statins. Dr. Beatrice A. Golomb, assistant professor at the University of California at San
Diego, has collected thousands of stories from patients about statin side effects. She has
said common complaints from patients taking statins include being unable to remember
the name of a grandchild, walking into a room and forgetting why you are there, or
starting a sentence and being unable to finish. Some complain of personality changes or
irritability.
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Use Of Statins
 Initiation and titration
• Lowest dose qDay; baseline CK, AST, ALT
• Report all adverse effects
• Pregnancy counseling
• Drug interactions-EES, azoles
• After 4 wks.-FLP, CK, AST, ALT (concern CK > 10
ULN; trans. > 3 ULN)
• Target LDL (min 130; ideal 110) achievedrecheck 8 wk. and 3 months
• Target not met-double dose-recheck in 4 wks.
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Cost of Statins
 $4 Generic Drug Program:
• Lovastatin 10 or 20 mg (#30)
• Pravastatin 10, 20, or 40 mg (#30)
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Metabolic Syndrome
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 Atherogenic dyslipidemia
• (elevated apo B, TG ≥ 110, increased small
dense LDL particles, HDL ≤ 40)
 Raised blood pressure
 Insulin resistance +/- glucose intolerance
• Fasting glucose ≥ 110
 Proinflammatory state (TNF-alpha & IL-6 CRP)
 Prothrombotic state
• (fibrinogen, plasminogen activators, antithrombin,
von Willebrand factor, factor V Leiden, and
protein C)
 Obesity (BMI ≥ 95%ile, waist circ ≥ 90%ile)
Concerns about 2008 AAP Guidelines
 Family hx not effective screening tool:
• In population-based survey of 3,048 parents in
Canada:
 Positive history of early CV dz (i.e <55yo) had
33% sensitivity (23.7% PPV) for detection of
borderline elevated LDL, and 41% (8% PPV)
for detection of high LDL (>130). O’Loughlin j, Ped 2004
• Positive family hx AND elevated BMI increased
sensitivity for detection of abnormal lipid profile
(but no change in PPV). Eissa MA, Am J Prev Med 2009
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Concerns about 2008 AAP Guidelines
 LDL and HDL not sufficient for risk-stratification:
• Elevated ApoB and low ApoA-1 in children &
adolescents were related to increased adult IMT
and worse brachial artery flow-mediated
dilatation (FMD).
• ApoB/ApoA-1 ratio better than LDL/HDL ratio
(PPV 0.62 vs. 0.57, p=0.03) in detection of
progression to subclinical atherosclerosis.
Juonala M (Young Finn Study), J Am Coll Cardiol 2008
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Concerns about 2008 AAP Guidelines
 BMI vs. Waist Circumference
• Children with waist circumference >90%ile
compared to smaller waist controls are:
 3.6 times more likely to have low HDL
 3 times more likely to have high TG
 3.7 times more likely to have high fasting
insulin
Bassali R, Am J Prev Med Jul 2009.
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Case 1
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THANK YOU
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