Clinical correlation hyperlipidemia
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Clinical correlation hyperlipidemia
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Clinical correlation hyperlipidemia
- 1. 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
- 2. 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
- 3. 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
- 4. Case #1 53 yo MI 69 yo breast CA 68 yo diabetes hypertension 66 yo healthy 36 yo healthy CH 299 35 yo healthy CH 152 42 yo CH 310 44 yo CH 280 6 yo healthy CH ? 9 yo healthy CH ? 14 yo healthy CH 286
- 7. 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
- 8. 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
- 9. 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
- 10. Case #2 49 yo MI 59 yo hypertension 66 yo healthy 62 yo healthy 36 yo CH 299 MI 6 mos ago 34 yo CH 159 healthy 34 yo MI 6 yo healthy CH 249 9 yo healthy CH 255 11 yo healthy CH 250
- 11. 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)
- 12. 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
- 13. 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
- 14. Serum Cholesterol in Boys and Middle-Aged Men and CHD Mortality Rates in Middle-Aged Men in Industrialized Countries Country Serum Total Cholesterol (mg/dl) Boys Men CHD Mortality Per 100,000 Men aged 45-54 years Portugal 149 203 71 Israel 155 204 119 Italy 159 200 91 Hungary 159 203 276* U.S. 167 217 170 Netherlands 171 221 134 Poland 176 192 218* Finland 190 240 264
- 15. 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
- 16. 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
- 17. 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
- 18. 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
- 19. Bogalusa Study NEJM 338:1650, 1998N=93, 2-39 yoa
- 20. 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
- 21. 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
- 22. 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.
- 23. 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
- 24. 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 86.5 220 44.3 63.5 240 25.1 40.5 260 18.3 29.7 280 15.3 28.4 300 13.9 28.4 The Lipid Research Clinics Prevalence Study (N=1042)
- 25. 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
- 26. 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
- 27. 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
- 28. 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
- 29. 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
- 30. Secondary Causes of Hyperlipidemia • Endocrine – Hypothyroidism – Diabetes mellitus – Glycogen storage disease • Pregnancy • Renal Disease – Nephrotic syndrome • Obstructive liver disease • Drugs – Corticosteroids, isotretinoin, thiazides, anticonvulsants, β- blockers, anabolic steroids, oral contraceptives
- 31. 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
- 32. 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
- 33. 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
- 34. 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
- 35. Criteria for Drug Therapy In 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 CVD or – 2 or more CVD risk factors persisting after vigorous efforts to control or eliminate these factors
- 36. Goals of Drug Therapy in 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
- 37. 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
- 38. NCEP Treatment Guidelines for LDL-C Levels for Adults Definite atherosclerotic disease Two or more other risk factors Initiation level (mg/dl) Goal (mg/dl) No No > 190 < 160 No Yes > 160 < 130 Yes Yes or No > 130 <100
- 39. 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
- 40. 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
- 41. HMG CoA Reductase Inhibitors Adverse 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
- 42. 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
- 43. Niacin Adverse 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
- 44. Niacin Adverse 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
- 45. 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)
- 46. Fibric Acid Derivatives Adverse 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
- 47. 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
Notas del editor
- Note that this individual was referred for evaluation and treatment after hypercholesterolemia was detected on a screening test because of the father’s hypercholesterolemia. Later in this seminar, we will discuss indications for cholesterol screening in children and adolescents. Note that this patient had no physicial findings of hypercholesterolemia, such as xanthelasma, cutaneous xanthomata, or Achille’s tendon thickening.
- Note that this family has already taken the initiative to reduce dietary fat and cholesterol in their diet after learning of the hypercholesterolemia in the patient and his father.
- Notice that this patient has already modified his dietary fat intake to a desirable level. Also, his cholesterol and fiber intake are in the desirable range.
- Examination of the patient’s pedigree demonstrates that the hypercholesterolemia appears to be inherited on the patient’s father’s side of the family. Notice that the paternal grandfather died at 53 yoa with a myocardial infarction. The patient’s father, although healthy, has an elevated cholesterol at 299 mg/dl. Finally, notice that the patient has two female siblings who are healthy but have not had their cholesterol measured. This pattern of inheritance would be consistent with familial hypercholesterolemia, which is due to mutations in the LDL receptor.
- The individual in this slide has xanthelasma palpebrarum. These are cholesterol deposits in the skin in the inner canthus of the eyes. This finding is rarely seen in children and adolescents, but is more often seen in older adults with long- standing hypercholesterolemia.
- This slide shows xanthomata tuberosa on the elbows. Again, such a finding would be extremely rare in children and adolescents, but is sometimes seen in older individuals with hyperlipidemia.
- Notice that this patient was referred after hypercholesterolemia was detected on screening after the father was found to have not only hypercholesterolemia, but had also had a recent myocardial infarction.
- Notice that this family has not made any effort so far to improve their dietary habits and frequently ingest fast food and other high-calorie, high-fat snacks. The fact that the parents are separated with the patient living with the mother, who works two jobs, probably contributes to the difficulty in making dietary changes.
- Notice that this patient ingests too high a percentage of total calories as fat with too high a proportion of saturated fat. Also, the cholesterol intake is excessive.
- Examination of this patient’s pedigree shows that the hypercholesterolemia is inherited from the father’s side of the family. Notice that the paternal grandfather died of a myocardial infarction at 49 yoa. Also note that the father has hypercholesterolemia and has had a recent myocardial infarction. This patient has two healthy younger sisters. Note that both have been screened and both have hypercholesterolemia. This pattern of inheritance would be consistent with familial hypercholesterolemia, due to mutations in the LDL receptor gene.
- Remember that hypercholesterolemia is only one of several risk factors for atherosclerotic cardiovascular disease. Pediatricians are in a unique position to intervene to prevent many of these risk factors later in life.
- Numerous animal studies have demonstrated that when animal models are made hypercholesterolemic, they readily develop atherosclerosis. Genetic disorders, such as familial hypercholesterolemia and others, are clearly associated with atherosclerosis and coronary heart disease. There have been a number of epidemiologic studies associating diet with serum cholesterol levels and coronary heart disease. We will discuss some of these. Both primary and secondary intervention clinical trials in adults with hyperlipidemia have clearly demonstrated a beneficial effect of treatment of hyperlipidemia on serum cholesterol levels and coronary heart disease. Finally, autopsy studies have demonstrated that atherosclerosis has its beginnings early in life and is clearly related to serum lipid levels and family history of early atherosclerotic disease.
- This slide shows that on an international scale, as dietary intake of saturated fat and cholesterol increases, so does the serum cholesterol level in children.
- Note that, as the serum cholesterol level in both boys and men increases, so does the CHD mortality in middle-aged men in several industrialized countries. Notice that the CHD mortality is particularly high in Hungary and Poland. This is probably due to other genetic and environmental factors impacting on the development of atherosclerosis.
- Dr. Gerald Berenson has conducted a large-scale population study for a number of years on a biracial cohort of children in Bogalusa, LA. His studies have yielded unique and important information on cardiovascular risk factors in children and adolescents. Autopsy studies on the enrolled subjects are an important part of his ongoing research. In this recent paper in the New England Journal of Medicine, you can see as the number of risk factors increases, the percent surface involvement with both fatty streaks, the early lesions of atherosclerosis, and mature fibrous plagues increases in both the aorta and coronary arteries of young individuals.
- There are three possible approaches to screening for hypercholesterolemia in children. One strategy is to screen no one and treat everyone with diet. Certainly, this is an important population-based approach that is advocated by the American Heart Association and other agencies. Another approach is to screen only those children with a positive family history of premature atherosclerotic disease or known hyperlipidemia. This approach would ensure that those individuals with a familial hyperlipidemia, who may require more intensive therapy for their disorder, would be identified. The third possible approach would be to screen all children regardless of family history. This is the approach advocated for adults. It is also an approach taken by many pediatricians for screening children. Several studies have shown that relying on family history will frequently miss individuals with hyperlipidemia. This is often due to a fragmented family structure, as well as the inability of many parents to recall or have knowledge of illness in other family members. However, we do not know the true risk of premature cardiovascular disease in individuals with hypercholesterolemia who do not have a true positive family history of premature atherosclerotic disease.
- The NCEP, as well as the American Heart Association and the American Academy of Pediatrics, have recommended that cholesterol screening be undertaken after two years of age and in all children with a first degree relative with symptoms or diagnosis of atherosclerotic disease, hyperlipidemia with a serum cholesterol &gt;240 mg/dl or sudden cardiac death before 55 years of age.
- These data represent the rationale for screening those children who have family members with a serum cholesterol level &gt;240 mg/dl. At this cholesterol level in the parent, only about 25% of children would be screened with a sensitivity of identification of those children with an elevated LDL cholesterol being about 40%. This cut-off represents a compromise between a higher sensitivity and the fact that to obtain a higher sensitivity, an excessive number of children would have to be screened.
- Note that single gene defects account for only about 15% of all cases of premature coronary heart disease. The other cases are accounted for by polygenic disorders in which expression of a number of genes contributing to hypercholesterolemia and atherosclerosis interact with environmental factors to cause hyperlipidemia and premature coronary heart disease.
- Th institution of a Phase I diet in children does require caution. There have been case reports of younger children presenting with failure to thrive due to overzealous dietary restriction by the parents. Any interventional diet should provide a total caloric intake appropriate for normal growth and development and maintenance of ideal body weight in children. Also, vitamin and micronutrient intake should be adequate.
- The Phase II diet is more restrictive than the Phase I diet, and even greater attention should be paid to ensuring adequate total caloric intake in children.
- The family approach to treating hyperlipidemia and reducing cardiovascular risk represents the best approach and addresses changes in, not only the diet, but the lifestyle of all family members, both hyperlipidemic and unaffected. This is the optimum approach, but does require trained personnel and resources that may not be available in many institutions. An important point in the treatment of hypercholesterolemia in children is the fact that, since drug therapy is not recommended under the age of 10, dietary therapy and increased activity and exercise represent the mainstay of treatment. It is very important not to let parents have unrealistic expectations with regard to what these interventions can achieve with the serum cholesterol level. Under the best conditions, there may be only a 10 or 15% reduction in the serum cholesterol level, even though the family is following all of your recommendations. This is particularly true in the monogenic disorders. It is important to let the family know that this is what you expect at the present time and that, when their child is older, there is the option of drug therapy which will likely lower the lipid levels to the normal range.