Hyperlipidemia in Childhood

1. Hyperlipidemia in Childhood Radha R. Cohen, M.D., F.A.A.P Pediatric Grand Rounds April 1, 2004

2. Hyperlipidemia in ChildhoodOverview • Basic lipoprotein structure and metabolism • Role of childhood hyperlipidemia in atherosclerosis • Classification of hyperlipidemias • Pediatric cholesterol screening guidelines • Management of hyperlipidemia in children

3. Hyperlipidemia in ChildhoodDefinition Hyperlipidemias = group of metabolic disorders characterized by an abnormal accumulation of various lipids in plasma. This may be due to genetics, diet or other acquired factors. Cholesterol and trigylceride are the primary lipids in plasma. Because they are insoluble in plasma, they are transported within the vascular space as lipoproteins.

4. Hyperlipidemia in ChildhoodLipoprotein structure Lipoprotein structure • hydrophobic core • triglyceride and/or • cholesterol ester • surface coat • phospholipid monolayer • interspersed free cholesterol and apolipoproteins

5. Hyperlipidemia in Childhood4 Major Classes of Lipoproteins Lipoproteins are divided into several classes based on their density. Each class appears to have distinct functions and atherogenic risk.

6. Hyperlipidemia in Childhood Classes of Lipoproteins • Total Cholesterol measured in the blood or serum can be viewed as the sum of cholesterol carried in the different major lipoproteins: • LDL-cholesterol • HDL-cholesterol • VLDL-cholesterol

7. Hyperlipidemia in Childhood LDL LDL-cholesterol makes up the majority (60-70%) of cholesterol in the blood. It has B-100 as its major apolipoprotein; lipoproteins that contain B-100 accumulate in arteries and within atherosclerotic plaques. It is viewed as the atherogenic lipid; high levels in adults have been correlated with coronary artery disease.

8. Hyperlipidemia in Childhood LDL LDL-cholesterol receptors are present throughout the body and their metabolism is highly regulated by intracellular cholesterol levels. Brown and Goldstein received the Noble prize in 1985 for their work elucidating the control and metabolism of LDL-receptors.

9. Hyperlipidemia in Childhood HDL HDL-cholesterol typically makes up 20-25% of the total cholesterol. It is involved with transport of surplus cholesterol out of the tissue; this reverse transport may be responsible for its protective action against atherosclerosis. In populations with elevated LDL, HDL-levels are inversely correlated with coronary atherosclerosis.

10. Hyperlipidemia in Childhood VLDL and Chylomicrons These are the largest of the lipoproteins and are major carriers of triglycerides (TG). TG are the main storage form of fatty acids. Long chain fatty acids are absorbed in the intestine and combine to form triglycerides and are transported through the thoracic duct to enter the blood stream as chylomicrons. Chylomicrons are cleared from the blood stream after fasting by lipoprotein lipase.

11. Hyperlipidemia in ChildhoodAtherosclerosis Clear evidence linking abnormalities in lipid and lipoprotein levels to premature atherosclerosis. Studies in adults show an unequivocal relationship of elevated levels of total cholesterol and LDL-C to premature atherosclerosis.

12. Atherosclerosis and Coronary Artery Disease • Atherosclerosis is a disease of large arteries that causes deposits of yellowish plaques containing lipoid material and cholesterol in the intima of vessel walls. • This is the pathogenic mechanism for coronary and peripheral vascular disease in adults.

13. Atherosclerosis and Coronary Artery Disease • Advanced lesion results from: • proliferation of smooth muscle cells and macrophages • formation of collagen matrix by smooth muscle • accumulation of lipid within the cells and surrounding tissue • FATTY STREAK=>FIBROUS PLAQUE

14. Atherosclerosis Begins in Childhood • In 1962, Strong and McGill reported the autopsy findings of >500 subjects ages 1-69 yrs • Fatty streaks rare in 1st decade of life but almost universal by age 20 yrs

15. Progression of Atherosclerosis • In Strong & McGill’s study, fibrous plaques were 1st observed in the second decade but increased in frequency and extent during the 3rd & 4th decades.

16. Atherosclerosis and CAD • Later in life, fibrous plaques may occlude the vessel lumen and potentiate thrombus formation. • THIS IS WHAT WE WANT TO PREVENT!!!

17. Hyperlipidemia in ChildhoodCAD Begins in Childhood • Clinical sequelae of atherosclerosis do not generally occur until later in life. • However, there is significant evidence that the pathologic changes begin years prior and are linked to childhood cholesterol levels. =

18. Cholesterol Levels in Childhood and Atherosclerosis • Bogalusa Heart Study: • children who had their coronary risk factors measured sequentially as participants in this study and then died accidentally were studied at autopsy • extent of fatty streaks was related to total and LDL cholesterol • fatty streaks in coronaries related best to VLDL • inverse relationship of fatty streaks to HDL

19. Cholesterol Levels in Adolescence Linked to Atherosclerosis • PDAY (Pathological Determinants of Atherosclerosis in Youth) Study- ongoing autopsy study of progression of atherosclerosis in subjects 15-34yrs • VLDL and LDL positively and HDL negatively associated with fatty streaks and fibrous plaques • Raised lesions were found in those as young as 25yrs

20. Cholesterol Levels in Childhood and CAD in Adulthood • Epidemiological investigations provide further evidence of the importance of cholesterol levels in pediatrics • Cross-population studies show children from countries with high incidence of CAD in adulthood have higher cholesterol levels than their counterparts in countries with low incidence of CAD • Within a population, elevated levels of total and LDL cholesterol in children have been associated with CAD in adult relatives

21. Hyperlipidemia in Childhood Summary of Data • Evidence demonstrates that: • fatty streaks occur in young people and then progress to atherosclerotic plaques • extent of arterial lesions is related to serum lipid (cholesterol) levels • manipulation of cholesterol levels can affect development of atherosclerosis • therefore... • Efforts to prevent the development and progression of atherosclerosis should begin in childhood and adolescence.

22. Hyperlipidemia in ChildhoodGoal of the Pediatrician • Goal of detection / treatment... • prevention of premature coronary artery disease • Foundation of this goal depends on... • coronary artery disease begins in childhood • coronary artery disease is related to blood cholesterol levels • lowering cholesterol in children will be effective in  CAD

23. National Cholesterol Education Program (NCEP) • The NCEP was created by the National Heart, Lung, and Blood Institute of the NIH in 1985. • Its charge was to reduce the prevalence of hypercholesterolemia in the US population and thereby reduce the morbidity and mortality associated with CAD.

24. Hyperlipidemia in ChildhoodDefinitions • Hypercholesterolemia = • total-C or LDL-C  95th % for age • Hypertriglyceridemia = • TG  95th % for age • These are working definitions of hyperlipidemia • Levels associated with the least risk of developing CAD in adulthood have not been determined

25. Hyperlipidemia in ChildhoodNormal Values National Cholesterol Education Program (NCEP): Expert Panel on Blood Cholesterol Levels in Children and Adolescents

26. Hyperlipidemia in ChildhoodNormal Values National Cholesterol Education Program (NCEP): Expert Panel on Blood Cholesterol Levels in Children and Adolescents

27. Hyperlipidemia in ChildhoodClassification: • Primary versus Secondary • first consideration - whether the hyperlipidemia is primary (genetic dyslipidemias) or secondary to a metabolic disease or exogenous cause • common secondary causes during infancy • glycogen storage disease and biliary atresia • common secondary causes in childhood • hypothyroidism, diabetes, nephrotic syndrome • common exogenous causes • oral contraceptives, alcohol, steroids

28. HyperlipidemiasSecondary Causes Exogenous Alcohol Contraceptives Steroid therapy Endocrine and Metabolic Acute intermittent prophyria *Diabetes mellitus Hypopituitarism *Hypothyroidism Lipodystrophy Pregnancy Storage disease Cystine storage disease Gaucher disease *Glycogen storage disease Juvenile Tay-Sachs disease Niemann-Pick disease Tay-Sachs disease Renal Chronic renal failure Hemolytic-uremic syndrome *Nephrotic syndrome Hepatic Benign recuurent intrahepatic cholestasis *Congenital biliary atresia Acute and transient Burns Hepatitis Others Anorexia nervosa Idiopathic hypercalcemia Klinefelter syndrome Progeria Systemic lupus erythematosus Werner syndrome KwiterovichP:Disorders of lipid metabolism, in Rudolph AM (ed): Pediatrics, ed 17.

29. Hyperlipidemia in ChildhoodFrederickson Classification In Circulation 1965, Frederickson and Lees published a description of 5 phenotypes to categorize people with familial hyperlipidemia according to their pattern of elevation of plasma lipoproteins. As knowledge progressed, it has become apparent that there may be several different genetic and secondary causes of the same Frederickson phenotype. This classification system has now fallen out of use.

30. HyperlipidemiasFredrickson Classification

31. Clinically Important Genetic Dyslipidemias • For clinical purposes, the following categories are more useful in determining risk of atherosclerosis, and planning treatment: • Hypercholesterolemia • Combined hyperlipidemia • Hypoalphalipoproteinemia

32. Hypercholesterolemia • Defined as total cholesterol >170mg/dL for children ages 2-19 yrs • An isolated elevation of cholesterol is nearly always due to increase in LDL-C • 2 genetic disorders are assoc. with Total-C & LDL-C = 2-5Xnormal -familial hypercholesterolemia -familial defective apoB-100

33. Hypercholesterolemia • Familial hypercholesterolemia is caused by a mutation in LDL receptor gene on short arm of chromosome 19. • Familial defective apoB-100 is due to rare mutations of the apoB gene. • In both cases, LDL receptors are unable to interact with apo-B, the protein ligand on LDL particles. • Both have autosomal dominant pattern of inheritance.

34. Familial Hypercholesterolemia • Most commonly recognized form of familial hyperlipidemia in childhood • Incidence of heterozygotes is 1:500 and homozygotes 1: 1 million • Homozygotes present in childhood with serum cholesterol between 400-800mg/dL and cutaneous and tendon xanthomas. Angina and MI before adolescence are common, and most have severe CAD by age 30. Aortic stenosis is also seen.

35. Tendon Xanthomas tendon xanthomas of the achilles and elbow

36. Tendon Xanthomas tendon xanthomas of the hand

37. Cutaneous Xanthomas

38. Familial Hypercholesterolemia Findings in Homozygotes left coronary artery narrowing supravalvar lipid deposition

39. Eye Findings in Familial Hypercholesterolemia Early corneal arcus Cholesterol deposits in retinal fundus

40. Familial HypercholesterolemiaHeterozygous Form • LDL-C is > 95% at birth. • Lipid levels remain markedly elevated throughout childhood and adulthood with total cholesterol ~300-400mg/dL and LDL-C ~200-300mg/dL. • Clinical manifestations include tendon xanthomas after age 20, early corneal arcus, and CAD after age 30. • This diagnosis should strongly be suspected in anyone with high LDL-C and tendon xanthomas in the patient or 1st degree relatives.

41. Familial Hypercholesterolemiaand CAD • In heterozygous males, the risk for development of CAD is estimated to be 20% at age 40yrs, 45% at age 50yrs, and 75% at age 60yrs. • FH is thought to account for 3% of premature CAD in the US.

42. Familial Hypercholesterolemia • Family history and screening of family members should reveal 1/2 of 1st degree relatives with FH • Diagnosis can be confirmed by measuring LDL receptor activity in cultured skin fibroblasts or identifying the gene mutation. • Prenatal diagnosis is possible by assessing LDL receptor activity in cultured amniotic cells. • Genetic counseling is important, especially if partner’s cholesterol is elevated or not known.

43. Combined Hyperlipidemia • Familial combined hyperlipidemia was 1st described by Goldstein et al. as dominantly inherited hyperlipidemia and CAD. • Affected individuals have either TG or LDL-C >90% or both TG & LDL-C >90%. • Phenotype may vary among family members or even from time to time in same individual. Presentation usually delayed until 3rd decade of life. No cutaneous or ocular findings. • Thought to affect ~1% of population and account for 10% of premature CAD.

44. Hypoalphalipoproteinemia • Defined as HDL-C < 10% for age and sex associated with normal LDL-C and TG levels. • Appears to have autosomal dominant pattern of inheritance in that ~1/2 of family members have low HDL-C and premature atherosclerosis. • No clinical manifestations other than premature atherosclerosis with CAD common as early as 4th decade.

45. Cholesterol Screening in Children • The NCEP recommended selective screening of children and adolescents, targeting those who were likely to become adults with high blood cholesterol and who would thus be at an increased risk for the development of cardiovascular disease.

46. Cholesterol Screening • Reasoning for selective screening • children and adolescents with elevated blood cholesterol (particularly LDL) frequently come from families in which there is a high incidence of CAD among adult members • high blood cholesterol aggregates in families as a result of both shared environments and genetic factors • major risk factor for hypercholesterolemia in a child is a family history of premature CAD or hypercholesterolemia

47. Cholesterol Screening • NCEP did not recommend universal screening (controversial) • Reasons against universal screening: • quite a few children with high cholesterol will not have high enough levels as adults to require treatment • leads to many young people inappropriately labeled as having “disease” • could lead to overuse of cholesterol-lowering drugs in children

48. Cholesterol Screening • Reasons for recommending universal screening: • ~50% of children with elevated cholesterol levels would be missed • universal screening may benefit young parents as well • children are more likely to receive regular health care than young adults

49. Cholesterol Screening • Selective screening approach • based on detailed family history and assessment of concomitant risk factors • makes it possible to identify a high risk subset while providing a reasonable balance between the number to be tested and the number to be detected

50. Selective Cholesterol Screening Who should be screened? • Children and adolescents with: -family history of premature atherosclerosis (parents or grandparents with MI, angina pectoris, peripheral vascular disease, cerebrovascular disease, or sudden cardiac death at or before age 55yrs) -parent with high cholesterol (>240mg/dL) -unknown family history, especially those with other risk factors (hypertension, diabetes, obesity, smoking)