To Screen or Not to Screen and Other Assorted Cholesterol Questions

Transcription

1 To Screen or Not to Screen and Other Assorted Cholesterol Questions Sarah D. de Ferranti, MD MPH Department of Cardiology Children s Hospital, Boston 6/5/10 UCSF sarah.deferranti@cardio.chboston.org Topics Why we care about cholesterol in adolescence? Updates from the literature Controversies: Screening Nutritional treatment Pharmacologic treatment Atherosclerosis 1

2 Atherosclerosis and Childhood CVD is biggest killer of adults Elevated LDL causes CVD Primary prevention works in adults Low cholesterol is protective Genetically based low risk profiles associated with low lifetime risk of cardiovascular events Risk factors track High risk childhood diseases predispose to early cardiovascular disease MIs occur in children with extreme genetic hyperlipidemia Autopsy studies show atherosclerosis begins early Pathology of Atherosclerosis in Youth Age (y) Prevalence (%) RCA lesions Error bar=se AHA lesion grade PDAY: Cholesterol, BMI, blood pressure levels correlate with the presence of atherosclerosis. 1 Bogalusa: Increasing risk factor levels correlate with greater fibrous plaque area McGill HC Jr, et al. Circulation. 2000;102: NEJM 1998;338:

3 N Engl J Med 2006;354: Natural experiment re long term exposure: gene mutation in white adults leads to 15% lower LDL but 47% lower rate of CHD. Pre-clinical vascular disease Carotid IMT: greater in children with Heterozygous FH, s/p renal transplant, KD with CAA Increased in adults who had high cholesterol as children Brachial artery reactivity: abnormal in children with Type 1 DM, family history of early CAD, KD with CAA, second hand smoke exposure Interventions: Statin treatment of heterozygous FH patients positively influences Carotid IMT Brachial artery reactivity 1. Weigman De Jongh Distal common carotid artery: intimal-medial complex Increased in renal transplant, Kawasaki with aneurysms Adults who had high cholesterol as children Familial hypercholeste rolemia Urbina, E. M. et al. Hypertension 2009;54:

4 JAMA. 2004;292: According to our model, IMT will increase mm in FH patients for each year that statin therapy is postponed. 4

5 Treat your arteries like your retirement account: invest early and often John Deanfield, 2010 Multiple Risk Factors and the Extent of Atherosclerosis in Children and Young Adults Berenson, G. S. et al. N Engl J Med 1998;338: Controversies: Who to screen for lipid disorders? 5

6 Screen no one? Stigmatization for insurance coverage Risk of eating disorders Everyone should exercise and eat a heart healthy diet Case - 13 yo boy Father MI age 36, PGF MI 45. Other family members with high cholesterol, paternal uncle with MI age 40 Screen only children at risk? Personal risk factors Overweight Hypertension Non-alcoholic fatty liver High cholesterol Insulin resistance Medications (psychotropics, OCPs, steroids, immune suppression) Extreme inactivity Family History CVD including stroke Diabetes T2 Hypertension High cholesterol High risk diseases 6

7 AAP/NCEP 1992/98 Lipid Screening Guidelines Family History High Cholesterol Early CVD Fasting Profile TC Normal TC <170 mg/dl Borderline TC mg/ dl High TC 200 mg/dl Recheck in 5 years <170 mg/dl Repeat TC and average 170 mg/dl Fasting Profile AAP recommended approaches to lipid screening (2008) Screen all children with family history of early CVD <55 men, <65 in women, parents, aunts uncles, siblings, grandparents Screen all children with personal risk factors obesity, hypertension, insulin resistance, and high risk disease states High Risk Diseases Highest risk Type 1 DM Chronic kidney disease (Transplant, insufficiency) S/p heart transplant Kawasaki disease with coronary aneurysms Moderately high risk Type 2 DM Chronic inflammatory diseases (SLE, scleroderma) Increased risk Previous treatment for cancer Congenital heart disease Kawasaki disease without coronary aneurysms 7

8 Screen everyone? Because family history only catches 30-60% But False positives Cost Lack of clear evidence that pediatric screening diminishes adult cardiovascular outcomes Recommendation Screen selectively in younger ages and universally pre- and postpuberty How to screen? TC non-fasting? Fasting lipid profile? TC and HDL non-fasting? 8

9 AAP/NCEP 1992/98 Lipid Screening Guidelines Family History High Cholesterol Early CVD Fasting Profile TC Normal TC <170 mg/dl Borderline TC mg/ dl High TC 200 mg/dl Recheck in 5 years <170 mg/dl Repeat TC and average 170 mg/dl Fasting Profile AAP/NCEP 1992/98 Lipid Screening Guidelines Family History High Cholesterol Early CVD Fasting Profile TC Normal TC <170 mg/dl Borderline TC mg/ dl High TC 200 mg/dl Recheck in 5 years <170 mg/dl Repeat TC and average 170 mg/dl Fasting Profile Total Cholesterol Is Deceiving Patient 1: TC = LDL + HDL + VLDL 200 = Patient 2: TC = LDL + HDL + VLDL 200 =

10 AAP recommended approaches to lipid screening (2008) Screen all children with family history of early CVD (<55 men, <65 in women, parents, aunts uncles, siblings, grandparents) Screen all children with personal risk factors Use only a fasting lipid profile Screen every 3-5 years Start age 2 years Alternate approaches Use direct LDL as a non-fasting test However, direct LDL testing can systematically over or underestimate LDL (vs. calculated LDL) Use non-hdl cholesterol. Check TC and HDL non-fasting, followed by fasting lipid profile if abnormal Case - 13 yo boy Father MI age 36, PGF MI 45. Other family members with high cholesterol, paternal uncle with MI age 40 TC 272, HDL 32, LDL 230, TG 50 10

11 What s Abnormal? Pediatric lipid levels TC LDL TG Non-HDL HDL Abnormal* <40 Borderline** Acceptable < 170 <110 <100 <120 >45 Ideal 70 >60 *>95th %tile LRC (about 1/2 have FH of CVD or parental hyperlipidemia) ** >75th<95th%tile Lipid curves - Males A) B) Total Cholesterol (mg/dl) High 200 Borderline High LDL-Cholesterol (mg/dl) High 130 Borderline High 100 Above Normal Age (Years) Age (Years) C) D) High HDL-Cholesterol (mg/dl) Protective 40 Low Triglycerides (mg/dl) Borderline High Age (Years) Age (Years) 11

12 Lipid curves - Females A) B) 160 High Total Cholesterol (mg/dl) High Borderline High LDL-Cholesterol (mg/dl) Borderline High 100 Above Normal Age (Years) Age (Years) C) D) HDL-Cholesterol (mg/dl) Protective Low Triglycerides (mg/dl) High Borderline High Age (Years) Age (Years) The labs are abnormal: What next? Secondary Causes of Dyslipidemia EXOGENOUS: Medications (OCPs, atypical antipsychotics, steroids), alcohol ENDOCRINE: Diabetes, Hypothyroidism, Pregnancy STORAGE DISEASES: RENAL: HUS, Nephrotic Syndrome, Chronic Renal Failure HEPATIC: Cholestasis, Biliary Atresia, Hepatitis OTHERS: Obesity, acute infections, vasculitis (Kawasaki Disease), burns, TPN 12

13 Work-up Family history Assess for secondary causes Assess for other risk factors By exam and history: Meds, PMHx BP, wt/bmi, acanthosis nigricans, cutaneous cholesterol collections, fundoscopic exam, striae Labs include lipoprotein electrophoresis and/or direct LDL for pts with very high fasting TGs (>400 mg/dl), TSH, glucose, hgn A1C Case - 13 yo boy Father MI age 36, PGF MI 45. Other family members with high cholesterol TC 272, HDL 32, LDL 230, TG 50 BMI 30 th %tile Nml growth (wt & ht), no thyromegaly, nml TSH, Tanner 3 no meds, no other PMHx Primary Hyperlipidemias: Familial Hypercholesterolemia LDL receptor defects: decreased LDL clearance by liver Heterozygous 1/500 Homozygous 1/1,000,000 LDL mg/dl in heterozygotes, >400mg/dL in homozygotes Normal TG, low or normal HDL Homozygotes have clinical atherosclerotic events during childhood Heterozygotes have early clinical events: 50% of men and 25% of women by age 50 13

14 Tendinous Xanthomas Xanthelasmas Treatment: How to get started 14

15 Balance: The Plate Method Activity and Inactivity 5-30% improvement in cholesterol with activity We recommend: 60 minutes ~ 5 times per week Moderate activities count No TV in the bedroom Limit screen time to < 2 hours per day Exercise machine in front of TV Individualized Family approach Tolfrey 1998, 1999, Daniels 1999 Quick behavior modification Food Balanced plate 1/3 rd veggies, starch, protein right fat vs. no fat Portion size: size of your fist Activity Screen time 2 hrs/day 1 hr of aerobic exercise per day TV out of the bedroom High fiber diet Juice 6 oz per day Colorful eating (fruits and vegetables) Family meals Ask - Why are you eating? Exercise machine in front of TV Moderate activity counts Gradual increases in time and intensity Family activities 3 concrete goals per visit 15

16 Case - 13 yo boy Father MI age 36, PGF MI 45. Other family members with high cholesterol TC 272, HDL 32, LDL 230, TG 50 BMI 30 th %tile Nml growth (wt & ht), Tanner 4 no meds, no other PMHx Diet low in fat, vegetables and fiber 4 hours of screen time per day 1-2 hrs per day physical activity (soccer, basketball, baseball) Lipid treatment guidelines AAP 2008 Lifestyle change efforts 6 months If this fails Pharmacologic treatment in ages 8 years LDL 190 mg/dl, or LDL 160 mg/dl family history of early coronary disease OR two or more risk factors, OR Coronary disease or equivalent (stroke, peripheral artery disease) LDL <130 mg/dl - Children with diabetes Mellitus TG > 1000 mg/dl or > 600 mg/dl if lifestyle change unlikely/unsuccessful No guidelines yet for treatment of low HDL Fine Tuning Treatment: Risk factors that could modify goals Metabolic syndrome: Hypertension Obesity Insulin resistance fasting glucose >100 Hgn A1C >7% Low HDL High TG High Risk disease states Elevated lipoprotein (a) with consistent family history Gender (male) Smoke exposure 1 st or 2 nd hand HIV treatment with protease inhibitors Severe inactivity 16

17 HMG CoA Reductase Inhibitors Mechanism: inhibit cholesterol synthesis, leading to up-regulation of LDL receptors and increased LDL uptake. Actions: Reduce LDL 18 55% & Reduce TG 7 30% Increase HDL 5 15% Indications: high LDL Side effects: Rare, major: myopathy/rhabdomyolysis (renal failure) Common: increased LFTs, asymptomatic CK elevations, headache, rash, sleep disturbances,? mood disturbances, GI upset Contraindications/cautions: Pregnancy (teratogenic) Liver disease,?steatohepatitis Cyclosporine, gemfibrozil, erythromycin (risk of rhabdomyolysis) HMG CoA Reductase Inhibitors Pediatric data: 8 RCTs Length 2 months 2 years Girls and boys, primarily familial hypercholesterolemia Largest trial 214 participants Simvastatin, 1,2 lovastatin, 3,4 fluvastatin, 5 pravastatin, 6,7 atorvastatin, 8 Good compliance (90%) Minimal reported side effects No clinical effects on growth and development Some increases in DHEA and cortisol levels No long term safety data, particularly in girls Cholesterol is a precursor of steroid hormones 1. Ducobu De Jongh Stein Lambert Firth Weigman Knipsheer McCrindle 2003 Steroid Synthesis HMG-CoA is upstream from cortisol, testosterone, estradiol, vitamin D, aldosterone Excess HMG-CoA is present in hypercholesterolemia Drugs may bring precursor levels towards normal, not subnormal de Ferranti and Ludwig NEJM

18 Sattar et al. Lancet 2010; 375: Treatment of 255 (95% CI ) patients with statins for 4 years resulted in one extra case of diabetes. Sattar et al. Sattar et al. Lancet 2010; 375: Treatment of 255 (95% CI ) patients with statins for 4 years resulted in one extra case of diabetes. Sattar et al. Rough calculations translate this small risk in adults to a cumulative risk for a 10 year old of ~2.9% by age 40. Zachariah and de Ferranti Sattar et al. Lancet 2010; 375:

19 Bile Acid Sequestrants: Cholestyramine, cholestipol, colesevelam Mechanism: bind intestinal bile acids, preventing re-uptake of cholesterol, leading to up-regulation of LDL receptors and increased LDL clearance Actions: Reduces LDL 10-20% Raises HDL 2 8% May increase TG, homocysteine 1 Indications: Very high LDL < 10 years, premenarchal girls Not commonly used in post-pubertal patients 1. Tonstad et al, McCrindle et al. Case - FH Fasting TC 265, HDL 35, LDL 220, TG 50 Simvastatin 20 mg QHS started 6 wks later TC 172, LDL 120, HDL 42, TG 50 CK 275, no symptoms; LFTs normal Continue simvastatin 20 mg per day, labs every 6 months Focus on Adolescents Lifestyle factors: Irregular meal patterns Eating disorders Smoking and smoke exposure Inactivity, regardless of activity Pharmacology: OCPs, known cause of hyperlipidemia (LDL, HDL, TG) Atypical antipsychotics Alcohol, supplements and drugs of abuse Other Pregnancy 19

20 Lipid consequences of the obesity epidemic Prevalence of High BMI for Age in Boys and Girls Aged 6 Through 19 Years Ogden, C. L. et al. JAMA 2010;0: Copyright restrictions may apply." in comparison with an average-size 13-year-old boy, a boy of the same age and height weighing 11.2 kg more had a 33% higher risk of having a CHD event in adulthood [before age 60] 20

21 Case #2 17 yo boy Fam Hx: obesity, T2 DM, early MI in PGF at 50, TG high in several family members BMI >97 th %tile Exam: striae, acanthosis nigricans, normal BP Diet review: pasta, soda (32 oz/day), juice, no veg. Gym 1 x week. Metabolic Syndrome Defined as 3 of 5 abnormalities Hypertriglyceridemia Low HDL Hyperglycemia Central obesity Hypertension 23% of U.S. adults 1 4-9% of U.S. adolescents 2 ~30% of overweight kids Associated with cardiovascular disease including stroke, and diabetes type 2 in adults 3 1. Ford ES, et al. JAMA 2002;287: de Ferranti et al. Circulation Isomaa B, et al. Diabetes Care 2001;24: Case #2 cont. Elevated TC 260 Low HDL 35 Borderline LDL 110 Elevated TG

22 Case #2 cont. Elevated TC 260 Low HDL 35 Borderline LDL 110 Elevated TG 375 Fasting glucose 98 Fasting insulin 35 Hgb A1C 5.9 Dyslipidemias High Triglycerides Carbohydrate restriction, depending on Frederickson type Omega-3 fatty acids (fish oil, purified omega-3) TG > 1000 mg/dl: Fibrates Insulin resistance Rx (metformin?) Controversy about association with CVD in isolation Low HDL Increased exercise and monounsaturated fats Niacin in adults, with high Lp (a) High TG and high LDL Reduce LDL first, then TG TG and CVD risk in adults Familial hypertriglyceridemia has not been associated with CVD risk Copenhagen Male Study showed increasing risk of ischemic heart disease with increasing TG level, even when controlling for HDL, BMI and other risk factors -? Related to apob levels However others contend elevated TGs are not connected with CVD Austin et al. Circ

23 Pediatric Hypertriglyceridemia Affects 5-15% of general pediatric population Up to 32% of obese Not regularly screened for, no well-developed treatment guidelines Has not been rigorously evaluated either in terms of causes or treatment no previous pediatric RCTS of lifestyle treatment or pharmacotherapy for lowering TGs Findings: Children s Hospital Boston Preventive Cardiology TG experience Hypertriglyceridemia is a relatively common finding, occurring in ~ one quarter of our preventive cardiology clinic patients Despite the study population, most of the pediatric agedpatients did not have severe hypertriglyceridemia (consistent familial hypertriglyceridemia) Similar to adults, pediatric hypertriglyceridemia was usually associated with excess adiposity and poor lifestyle The most frequent treatment modality was not pharmacotherapy, although medications were prescribed in some cases often to treat LDL Success with treatment was moderate: TG levels declined by 23% (average: 88 mg/dl; SD 231), with lower BMI being a predictor of success Omega-3 fatty acid (EPA, DHA) Found in fatty fish (tuna, salmon, swordfish*) Lower heart disease rates in fish eaters Anti-thrombotic, anti-arrhythmic, anti-inflamatory, lower BP, improved endothelial function Actions (adults): decrease TG 25-45% (4 gm/day)? Increase LDL Effective in secondary prevention in adults (GISSI) 20 children treated with DHA had favorable lipid profile changes Dose: 1-4 gms per day depending on age/size Purity/composition issues 1. Engler

24 Fibrates (fenofibrate, gemfibrozil) Mechanism: Activate PPARα Actions: 30-50% decrease TG 10-25% decrease LDL 10-22% increase HDL Indications: high TG, risk of pancreatitis Side Effects: Elevated LFTs, CK (less common than statins) Contraindications/cautions: concurrent statins renal insufficiency Decrease in CAD in adults Small pediatric trial (n=14), minimal side effects 20.3% had at least one abnormal lipid value, based on conservative lipid cutpoints LDL-C 130 mg/dl, HDL-C 35 mg/dl, and TG levels 150 mg/dl Obesity carried a three fold risk for lipid disorders Lifestyle change for abnormal lipids would have been indicated for 22% of overweight and 43% of obese children Pharmacotherapy would have been indicated for <1% Summary Abnormal lipids are not uncommon in childhood Atherosclerotic changes can be detected For most children The degree of vascular involvement is minor The rate of progression is slow The appropriate therapeutic approach is lifestyle behavior change There are minimal long-term safety AND outcome data for pharmacotherapy during childhood We must distinguish between children with low short and medium term cardiovascular risk (the majority) and an important minority at high risk for early CVD 24

25 Recommendations Screen Selectively based on family history and personal risk factors starting age 2, every 5 years Universally age 10 and again post-puberty using non-fasting TC and HDL Exercise and diet changes are first line Pharmacotherapy can be a reasonable additional treatment in selected cases (<1%) at high risk for early CVD Base treatment on the whole picture of CVD risk, including medical history 25