Pediatric Hyperlipidemia Sarah B Clauss, MD Assistant Professor of Pediatrics Children’s National Medical Center

Lecture Outline • Learn when to screen a child for the presence of hyperlipidemia • Learn the most common patterns of hyperlipidemia in children • Learn the diet modification and medications used to manage children with hyperlipidemia

Evidence of Atherosclerosis Begins in Childhood – Pathobiological Determinants of Atherosclerosis (PDAY) • Fatty streaks and fibrous plaques is correlated with elevated cholesterol – Bogalusa Heart Study • Fatty streaks in 50% of children and 85% young adults • Extent of lesions correlate with TC, LDL, TG, BP and BMI • Extent of lesions rose exponentially with
RF Newman et al. NEJM1986, Berenson et al. NEJM 2001, McGill et al. Art Thromb Vasc Biol 1997, McGill et al Circ 2001

Cholesterol Concentration in Youth • Lipid values track into adulthood – 75% of children in Muscatine Study – 70% of children in the Bogalusa Heart Study

Cholesterol Concentrations in Youth • Cholesterol levels at birth: – TC 70 mg/dl, LDL 30 mg/dl, HDL 35 mg/dl • Cholesterol rapidly increases in the first 2 years of life • Mean TC peaks at 171 mg/dl between ages 9-11

Cholesterol Concentrations in Youth • Cholesterol levels decrease during puberty and increase thereafter • HDL levels fall permanently in young men during puberty • Ethnic differences: – AA higher HDL/lower TG than Hispanics or non-Hispanic whites

Cut Points for Cholesterol Values

Kwiterovich. J Clin Endocrinol Metab. November 2008, 93(11);4200-4209

DYSLIPIDEMIA Referral to a preventive Cardiologist • Total cholesterol (TC) >200 mg/dL (5.18 mmol/L) • LDL-C >130 mg/dL (3.36 mmol/L) • HDL-C 150 mg/dL (1.7 mmol/L) in adolescents – >130 mg/dL (1.47 mmol/L) in younger children

Who should be screened?

Case 1 • 14 year old boy was referred because of hypercholesterolemia • His father died with coronary artery disease at age of 60 –The father was diagnosed in his 40's and had multiple bypass surgeries

De Ferranti et al. NEJM 2008; 359:1309

Targeted approach to Screening • Results in 35-46% of children being screened • Studies suggest that 30-60% of children and adolescents with elevated cholesterol are likely to be missed with a targeted approach

Rifai et al. Pediatrics, 1996. Diller et al J Ped 1995. Griffin et al Pediatrics, 1989

Universal screening • Advantages – Catch all cases of hyperlipidemia • Some cases are the index and later other family members are identified

• Disadvantages – Psychological consequences – Who will counsel/treat these patients

Case 2 14 year old boy with elevated cholesterol Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL)

03/05/2009 300 226 65 40

Familial Hypercholesterolemia (FH) in children • FH is an inherited autosomal dominant disorder caused by impairment of LDLreceptor • Incidence: – 1:300 to 1:500 in North America and Europe – 1:100 in Quebec and South African Afrikaners

• High plasma concentrations of LDL-cholesterol • If untreated, the risk of coronary heart disease: – for men 80% by the age of 60 y – for women 45% by the age of 60 y Slack, Lancet 1969

1.0 0.9 0.8 0.7

Non-FH Women Non-FH Men FH Women FH Men

0.6 0.5 0.4 0.3 0.2 0.1

MED PED Registry 2001

Age

90 +

0.0 25 -3 0 30 -3 5 35 -4 0 40 -4 5 45 -5 0 50 -5 5 55 -6 0 60 -6 5 65 -7 0 70 -7 5 75 -8 0 80 -8 5 85 -9 0

Cumulative Probability of Clinical CAD

Cumulative probability of non-fatal CAD in Utah FH versus a random US population

Atherosclerosis starts early in FH • Can the progress of atherosclerosis be inhibited by cholesterol lowering therapy in children with FH??

IMT (mm)

Early treatment to inhibit atherosclerosis

0.8

T T T

0.5

10 Age (years)

40

80

Cholesterol lowering treatment in FH?

• Can the progress of atherosclerosis be inhibited by cholesterol lowering therapy in children with FH??

YES!

Counseling and Therapy • Diet Modifications

Population-based approach • In all healthy children > 2 years of age, the AHA/AAP/NCEP guidelines recommend: – low-saturated-fat – low-cholesterol diet – appropriate number of calories to support growth and development, based upon the age, sex, and activity level of the child

Population-based approach Low-saturated-fat

• Saturated fat < 10 % • Total fat < 30 % of the total calories • Dietary cholesterol < 300 mg/day

AHA strategies for children > 2 years of age • Daily moderate activity of 60 minutes • Vegetables and fruits and limit juice intake • Vegetable oils and soft margarines low in saturated fat and trans fatty acid instead of butter or most animal fats • Whole-grain not refined-grain bread and cereals • Reduce sugar-sweetened beverages and foods • Non or low-fat milk Gidding et al. Circulation 2009; 119:1161

AHA strategies for children > 2 years of age • Increase fish consumption, use lean cuts of meat and reduced-fat meat products, and remove the skin from poultry • Reduce salt intake • balanced meal, portion size, and caloric contents • Encourage eating at home • Dietary counseling Gidding et al. Circulation 2009; 119:1161

Diet Modifications • The AAP recommends that children at 12 months of age with risk factors for high cholesterol receive low fat dairy products

Niinikoski et al. Circulation 2007; 116:1032

Family Education on High Cholesterol What parts of the diet affect cholesterol levels? Dietary Fat • Monounsaturated • Polyunsaturated – Omega 3 • Saturated • Trans

Dietary Fiber • Soluble • Insoluble

What About Dairy? • Skim or 1% milk • Low fat cheeses ( < 3 grams of fat / serving) • Light, spreadable margarine instead of butter or stick margarine (Smart Balance, Olivio) • Buy low fat ice cream

Family Friendly Ways to Improve Fiber Intake • • • • •

Serve vegetables every night with dinner Eat fruit as a snack between meals Eat fresh fruit instead of drinking high sugar fruit juice Whole grain breads with > 3 g of dietary fiber/ slice Cereals > 3 g of fiber and < 12 g of sugar / serving (Cheerios, Frosted Mini-Wheats, Kix) • Low fat popcorn as a snack • Make sure you drink plenty of water as you increase your fiber intake!

Activity • Goal of 60 min of moderate to vigorous exercise activity daily • Limit screen time to < 2 hours/ day • 2008 National Capital Region Survey of Childhood Obesity – Meets 225 min/wk Middle School PE • MoCo: 45 min/wk • PG: 75 min/wk

– Semesters of PE required for HS graduation • MoCo: 2 • PG: 1

1998

2008

Case 2- Follow up 03/05/2009

09/11/2009

Total cholesterol 300 (mg/dL) LDL cholesterol 226 (mg/dL)

302

HDL cholesterol (mg/dL)

65

41

Triglycerides (mg/dL)

40

32

Normal LFTs

253

Case 2- Follow up

• Medical Therapy

When to start medical therapy • The 2007 AHA and 2008 AAP recommend statin therapy if: – Age and sex of the child • Boys should be > 10 years of age • Girls should have started their menses and have regular periods • Teratogenic effects of statin therapy  appropriate contraception

– As young as 8 years of age with severe dyslipidemia Daniels et al. Pedaitrics 2008;122:198 McCrindle et al. Circulation 2007; 115:1948

When to start medical therapy • One of the following four conditions: – LDL-C > 190 mg/dL (4.9 mmol/L) without other CVD risk factors – LDL-C > 160 mg/dL (4.1 mmol/L) but less than 190 mg/dL (4.9 mmol/L) and one of the following • Family history of premature CVD, • Two or more other CVD risk factors after vigorous attempts to control CVD risk factors (ie, overweight, hypertension, insulin resistance, or smoke exposure), • Primary disease associated with increased risk of CVD

High-risk diseases • • • • • • • •

Familial hypercholesterolemia Diabetes mellitus Chronic kidney disease Heart transplantation Kawasaki disease Chronic inflammatory disease Childhood cancer survivors Congenital heart disease

When to start medical therapy • In children less than eight years of age, pharmacological therapy should only be considered if serum LDL-C exceeds 500 mg/dL (12.9 mmol/L) • Failure of nonpharmacologic therapy After a 6 to 12 month trial of a lowsaturated fat and cholesterol diet and activity regimen

Daniels et al. Pedaitrics 2008;122:198

1998

2008

Pediatrics 2007; 119:618

Dietary supplements • Dietary supplements include –Fiber –Plant stanols, sterols

Dietary supplements Fiber • + reduce serum LDL-C • Binds with cholesterol within bile acids  removing it from the enterohepatic circulation • Supplemental fiber calculated dose of the (child's age + 5 g)/day, up to 20 g/day • Dietary sources (eg, fruit, vegetables, and whole grains) Daniels et al. Pediatrics 2008; 122:198

Dietary supplements Plant stanols and sterols • Reduce dietary cholesterol by 5 to 10 % • Margarine, orange juice, yogurt drinks, cereal bars, and dietary supplements • Decrease absorption of fat-soluble vitamins and beta carotene  multivitamin daily

Plant Sterol Foods

Lipid-altering agents • Statins • Fibric acid derivatives • Bile acid sequestrants • Cholesterol absorption inhibitors

lovastatin, simvastatin, pravastatin, atorvastatin, colesevalam: FDA approved

Statins • Most commonly used drugs in the treatment of hypercholesterolemia in adults • In children with familial hypercholesterolemia – 20 to 40 percent reduction of serum LDL-C • Inhibits HMG-CoA reductase reduce

cholesterol synthesis Upregulation of LDL receptors

McCrindle et al. J Pediatr 2003;143:74

LIPIDS-study: Longterm influence of pravastatin on intima-media thickness in children with FH

FH n=106 8-18 y

PRAVASTATIN

20-40 mg

extension

FH n=108 8-18 y

diet run in

PLACEBO IMT

IMT

IMT

baseline

52 weeks

104 weeks

Wiegman et al, JAMA 2004;292:331-377

Results • Mean age 13.0 years • 97% LDL-receptor mutation • 10 children discontinued the study – 5 in pravastatin and 5 in placebo group

• Mean LDL reduction 24%

∆ Carotid IMT (CCA+BULB+ICA)

Results IMT 0.01

* __

__ I I

0.005

I I

0 -0.005 -0.01

I __ I

-0.015 -0.02

1 Year

Wiegman et al, JAMA 2004;292:331-377

Pravastatin Placebo

I __ I 2 Year

* p = 0.02

Results safety • No serious adverse events – Tolerability was good

• ALT, AST or CPK: – One child with extreme CPK elevations (placebo group) – No differences between pravastatin and placebo group

• No changes in endocrine function • No significant clinical effect on growth and pubertal development

Conclusions Lipids-study • Pravastatin induces a significant regression of IMT in children with FH • Pravastatin seems safe and effective in children with FH

Zocor in Kids study

40 mg simvastatin

FH n=106 8-18 y

20 mg 10 mg

FH n=69 8-18 y

PLACEBO FMD

4-wk diet run in

0

FMD 8

16

24

28

48 wk

Percentage change from baseline (%)

Results: Efficacy after 48 weeks 10

Total Cholesterol

LDL-c

HDL-c

Triglycerides 4.3

3.3

0.8

0.3

0 -0.4 -10

-8.7

-20 -30

Simvastatin 40 mg Placebo

-30.9 -40 -40.7 -50

De Jongh et al, Circulation 2002;106:2231-2237

Results: Safety after 48 weeks • No serious adverse events • One discontinuation due to mononucleosis – Not drug-related

• No clinically meaningful elevations of ATL, AST or CPK • No clinically significant changes in hormones • No significant clinical effect on growth and pubertal development

Conclusions Zocor in Kids study • Simvastatin 40 mg reduced LDL-C by 41% over a period of 48 weeks • No adverse effect on growth or pubertal development • Simvastatin 40 mg is a well-tolerated and effective therapy for FH children

Side effects of statins • Gastrointestinal symptoms • Muscle cramps and myopathy • Elevation of liver transaminases

Statin Plan of care • Lowest dose, once a day, usually at bedtime • The targeted values of LDL-C – Minimal, < 130 mg/dL (3.35 mmol/L) – Optimal, < 110 mg/dL (2.85 mmol/L) – < 100 mg/dL for patients with high risks due to co-existing conditions, DM McCrindle et al. Circulation 2007; 115:1948

Statin Plan of care • Reassess four weeks after the start of therapy – Fasting lipoprotein profile, and serum creatinine kinase, alanine aminotransferase, and aspartate aminotransferase

• If effective and no SE, therapy is continued at the same dose four and eight weeks, and then every six months McCrindle et al. Circulation 2007; 115:1948

Statin Plan of care • If the targeted value is not met, – the dose is increased and reassessment in four weeks

•  If goals are not yet met, – the dose of statin may be doubled, – or another drug ezetimibe may be added until the target or the maximum dose is reached or there is evidence of toxicity McCrindle et al. Circulation 2007; 115:1948

Statin Plan of care • If there are laboratory abnormalities stop for two weeks and repeat laboratory • When the abnormalities resolve, the drug may be restarted with close monitoring

Statin Plan of care • Side effects are also more commonly seen in patients on other medications, such as cyclosporine • Caution in patients with renal insufficiency – doses should be lower

Bile acid sequestrants • Mechanism of action – Binds intestinal bile acids Interrupts the enterohepatic circulation Upregulation of LDL receptor

• Not as effective as statins • Adverse side effects that result in poor compliance (eg, constipation and bloating)

Bile acid sequestrants • Not absorbed systemically but remain in the gut and are excreted along with the bile containing cholesterol • For pre-pubertal patients with severe LDLC elevations (heterozygous familial hypercholesterolemia)

Cholesterol absorption inhibitors • Prevent intestinal absorption of cholesterol and plant sterols • Ezetimibe (10 mg per day) – Decrease in TC (28%) and LDL-C (18%) – No significant changes in TG or HDL-C – No adverse effects

Clauss et al. J Pediatr 2009; 154:869

Case 2 Follow up 03/05/2009 09/11/2009 12/18/09 Total cholesterol (mg/dL)

300

302

245

LDL cholesterol (mg/dL)

226

253

190

HDL cholesterol (mg/dL)

65

41

41

Triglyceride (mg/dL)

32

Lovastatin 10mg Q day

Case 2 follow up • Increased lovastatin to 20 mg per day • LDL  140 mg/dl • Enrolled in study demonstrating positive gene mutation for FH

Case 3 11-year-old girl referred for hyperlipidemia

Total cholesterol (mg/dL) Triglycerides (mg/dL) HDL (mg/dL) LDL (mg/dL) VLDL (mg/dL)

09/22/2009 170 615 26

Hypertriglyceridemia

Case 3 Plan of care • • • •

Diet modification and increase exercise Follow up in 3 months Amylase and Lipase Assess for fatty liver

Diet modification • Low simple carbohydrate and more complex carbohydrate • Hyperchylomicronemia, lipoprotein lipase deficiency (Frederickson's Type I), fat restriction may be necessary • Behavior modification • Whole family support and lifestyle modification Kavey et al. Circulation 2006; 114:2710

High Triglycerides •

Follow the rules on decreasing unhealthy fats and increasing fiber intake

•

Limit foods and beverages high in simple sugars (Cake, cookies, donuts, soda, etc)

•

Drinks < 10 calories / serving

•

Goal of 60 minutes of physical activity every day

•

Eat a variety of foods from all the food groups…eat fruits or vegetables with every meal

•

Work closely with nutritionist

Healthy Beverage Alternatives Instead of • Soda • Gatorade/Powerade/ Vitamin Water • Kool-Aid or Punch • Sweet Tea • Sunny Delight or Juice

Try • Diet Soda • Propel, Powerade Zero, Vitamin Water Zero • Crystal Light, Fruit2-O, Sugar Free Kool-Aid • Tea sweetened with Splenda or Equal • Sugar Free Tang

Types of carbohydrates •

SIMPLE CARBOHYDRATES:

•

COMPLEX CARBOHYDRATES:

• • • • • • • • • •

Table sugar Corn syrup Fruit juice Candy Cake Bread made with white flour Pasta made with white flour Soda pop Candy All baked goods made with white flour Most packaged cereals Honey Milk Yogurt Jam Chocolate Biscuit

• • • • • • • • • • • • • • • •

Whole Barley Buckwheat Oat bran Whole fruits Dried fruits Vegetables Oatmeal Whole grain cereal Museli Wild rice Brown rice legumes Some low fat yogurts Soybeans Skim milk Whole grain bread (wheat, buckwheat, oat, bran, multi-grain)

• • • • • • •

3 months later • Low -fat diet. • Snacks, not sure about the content of the snacks that she eats • Reduced amount of juice • Increased the amount of water • Softball practice 2 hours 3 to 4 times a week. • Plays outside with her friends

4 months later 09/22/2009 170 Total cholesterol (mg/dL) Triglycerides 615 (mg/dL) HDL (mg/dL) 26 LDL (mg/dL)

01/21/2010 201

237 41 113

Amylase 55 U/L, Lipase 89 U/L

Dietary supplements Omega-3 fatty acids • Fish oil • Lower serum TG levels; Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) • Children not eating fish – Omega-3 fatty acid supplements (1 gm) • For children with extremely elevated serum TG (600 to 1000 mg/dL) – omega-3 fatty acid supplement (dose of 2 to 4 gms per day) – + statin or fibrate therapy

Case 3 follow up

Total cholesterol (mg/dL) Triglycerides (mg/dL) HDL (mg/dL) LDL (mg/dL)

09/22/20 01/21/20 4/22/201 09 10 0 170 201 202

615

237

194

26

41 113

45 119

Fibric acid derivatives • Inhibits hepatic synthesis of VLDL • Raise HDL-C and lower TG • Indications: – severe triglyceride elevations (considered at levels >600 to 1000 mg/dL, usually prescribed for levels >1000 mg/dL) – older adolescents Pediatrics 2001;107:423

Case 4 • 15-1/2-year-old boy with elevated cholesterol. • Total cholesterol of 233 mg per dL, • LDL of 156 mg/dL • Triglycerides 44 mg/dL • HDL 68 mg/dL • VLDL 9 mg/dL

Case 4 Follow up • “I eat what ever is in the house” 07/25/2009 233

Total cholesterol (mg/dL) LDL (mg/dL) 156 HDL (mg/dL) 68 Triglycerides 44 (mg/dL)

12/8/2009 230

164 60 29

Case 4 Follow up • “Better adherence to his diet • He is still struggling with switching his milk down from 2% down to 1% milk and to using Fiber One with a fat-free diet • His mother has reduced the amount of cheese, ice cream that he is eating and she is paying more attention to the labels when she goes grocery shopping as well”

Case 4 Follow up 07/25/2009 233

Total cholesterol (mg/dL) LDL 156 (mg/dL) HDL 68 (mg/dL) Triglyceride 44 (mg/dL)

12/8/2009 230

03/11/2010 199

164

126

60

65

29

40

Current Practice

• ~ 0.8% of adolescents 12 to 17 years of age  eligible for pharmacological treatment for elevated LDL

Ford et al. Circulation 2009; 119:1108

The Clinical Picture

Summary • Atherosclerosis starts early • Screening – Targeted – Universal

• Treatment Strategies – – – –

Diet Behavior modification Medication Nutritional supplements

• Goal is prevention of cardiovascular disease

Thank you Ashraf Harahsheh, MD Michele Mietus-Snyder, MD Renata Mills, RN, CPN Erin Davis, RD Charlie Berul, MD

References • Kavey et al. Circulation 2006; 114:2710 • Klag et al. NEJM 1993 Feb 4;328(5):313-8 • De Ferranti et al. NEJM 2008; 359:1309 • Gidding et al. Pediatrics 2006; 117:544 • Gidding et al. Circulation 2009; 119:1161 • Niinikoski et al. Circulation 2007; 116:1032 • Pahkala et al. Circulation 2008; 118:2353 • Daniels et al. Pedaitrics 2008;122:198

• McCrindle et al. Circulation 2007; 115:1948 • Rodenberg et al. Circulation. 2007 Aug 7;116(6):664-8 • Pediatrics 2007; 119:618 • Daniels et al. Pediatrics 2008; 122:198 • de Ferranti et al. Up to date 18.1, January 2010 • McCrindle et al. J Pediatr 2003;143:74 • Rodenburg et al. Circulation 2007; 116:664 • Clauss et al. J Pediatr 2009; 154:869 • Ford et al. Circulation 2009; 119:1108