Symposium on Adult Diseases in Children - February 2009
By Vandana S. Raman, MD, and Rubina A. Heptulla, MD
Atherosclerosis begins in childhood or adolescence and progresses throughout the lifespan of an individual to cause coronary heart disease in later years. Hyperlipidemias are a relatively common but modifiable risk factor in their development. The early identification and treatment of children with hyperlipidemias is likely to retard the atherosclerotic process. Health care professionals caring for children with hyperlipidemias should be familiar with disorders of lipid homeostasis as well as clinical assessment and management strategies. Screening guidelines for children at risk as well as dietary and pharmacologic regimens are reviewed in the context of current national recommendations.
The prevalence of obesity in children and adolescents has increased dramatically in recent years. 1 Several risk factors for coronary heart disease (CHD) are associated with obesity, including diabetes, hypertension, and hyperlipidemia. 2 CHD is the leading cause of morbidity and mortality in the United States. Autopsy studies, such as the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study 3 and the Bogalusa Heart Study, 4 have indicated that the process of atherosclerotic cardiovascular disease begins early in life and is associated significantly with higher antecedent levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and lower levels of high-density lipoprotein cholesterol (HDL-C). CHD also is associated with other risk factors, such as obesity itself, cigarette smoking, and hypertension. These studies make it increasingly evident that lipid abnormalities in childhood are associated with increased risk for CHD in adulthood; therefore, lipid disorders have become a major area of concern for pediatricians. In this article, we review the specific disorders of cholesterol and triglyceride (TG) homeostasis as well as clinical assessment and management strategies for childhood hyperlipidemia.
Defects of Lipid Metabolism
Hyperlipidemias may be considered as primary, involving specific genetic abnormalities in lipid metabolism, or secondary, involving diseases that adversely affect cholesterol and TG levels. Historically, hyperlipidemias are classified according to the Fredrickson classification on the basis of the pattern of lipoproteins on electrophoresis or ultracentrifugation ( Table 1 ). 5
However, a more practical classification on the basis of whether the concentration of plasma cholesterol or triglycerides (or both) is elevated is outlined in Table 2 . 6
Disorders With Elevated Cholesterol
Familial hypercholesterolemia (FH),a common cause of hypercholesterolemia, 7 is an autosomal dominant disorder caused by mutations in the LDL receptor gene that result in LDL receptor malfunction. 8,9 This causes a defect in hepatic uptake of LDL-C particles, leading to plasma elevation of LDL-C and TC concentrations. Elevated TG and low HDL-C are sometimes seen. The frequency of heterozygous FH is about 1:500. Homozygous FH is very rare, occurring at a frequency of 1:10^6. Plasma cholesterol levels are typically increased two- to threefold above normal in heterozygotes and three- to sixfold in homozygotes. Xanthomas and symptomatic heart disease can occur in homozygous children younger than 10 years, and if untreated these individuals usually die from myocardial infarction by age 20 years. They are also at risk for valvular and supravalvular aortic stenosis. 8
Familial defective apo-B100 is caused by a mutation in apo-B100 that impairs its ability to bind to the LDL receptor. 10 Decreased affinity of the defective apo-B100 for its receptor delays the clearance of LDL-C from the plasma, leading to increased plasma LDL-C levels. There is significant overlap with FH, but the course is usually milder.
Disorders With Elevated Cholesterol and Triglyceride
Familial combined hyperlipidemia (FCH)is an autosomal dominant disorder. Its pathogenesis is not fully understood. It is associated with elevations of TC and TG levels. 11 Plasma HDL-C may be low. A high incidence of premature CHD is seen. Patients usually do not have xanthomas. Obesity, insulin resistance, and hyperuricemia are often present. Physicians also should assess patients for the metabolic syndrome. A similar phenotype can be seen in patients with diabetes mellitus, the nephrotic syndrome, and occasionally hypothyroidism.
Familial dysbetalipoproteinemia,or type III hyperlipoproteinemia, is a rare genetic disorder caused by defects in apo-E, which results in defective clearance of intermediate density lipoproteins (IDL) and chylomicrons. 12 As a result, cholesterol and TG are elevated. Patients are at risk for premature CHD. Affected individuals may have palmar or tuberous xanthomas, which are highly diagnostic.
Disorders With Elevated Triglyceride Only
Lipoprotein lipase (LPL) deficiency is a rare autosomal recessive disorder caused by a mutation in the LPL gene, which causes LPL deficiency and severe hypertriglyceridemia by blocking the clearance of TG-rich lipoproteins from the plasma. Massive accumulations of these lipoproteins in the plasma, known as the chylomicronemia syndrome, can occur, which consists of marked hypertriglyceridemia (>2000 mg/dL) and is associated with recurrent abdominal pain or pancreatitis. 13,14
Apolipoprotein CII (apo-CII) deficiency is a rare autosomal recessive disorder. It results from the lack of apo-CII, an activating cofactor for LPL, which causes a functional LPL deficiency. Plasma TG levels are usually severely elevated (>1000 mg/dL), reflecting the accumulation of chylomicrons and very low density lipoproteins (VLDL). It can cause a chylomicronemia syndrome similar to that seen in LPL deficiency. 6
Familial hypertriglyceridemia is an autosomal dominant disorder caused by overproduction of VLDL triglycerides, which cause elevations of plasma triglycerides typically in the range of 200-500 mg/dL. 15 This disorder can be associated with xanthomas or pancreatitis.
The most common secondary cause of hyperlipidemia is obesity. It is associated with elevated TG, low HDL-C, and abnormalities of LDL-C, such that it is smaller and more dense and more atherogenic. 16 Some of the other causes of secondary hyperlipidemias include liver and kidney diseases, diabetes mellitus, hypothyroidism, hypercortisolism, and use of medications such as steroids, including oral contraceptives and isotretinoin.
Evaluation of Patients With Hyperlipidemia
Determining whether dyslipidemia in the child is due to a primary or a secondary cause is important. A detailed history, including family history of premature CHD (defined as disease occurring before 55 years in men and 65 years in women), hyperlipidemias, or pancreatitis should be elicited. A thorough review of systems is important to determine the presence of any medical conditions and risk factors such as dietary and lifestyle behavior, exercise history, and exposure to smoke. A careful physical examination should be done, including the assessment of height, weight, and body mass index plotted on standardized growth charts. Tendon xanthomas, which may be present on the Achilles tendon and extensor tendons of the hands, may be seen with high cholesterol levels. Tuberous xanthomas are seen with elevated cholesterol and TG levels and occur at the site of local skin injury, such as elbows and knees. Eruptive xanthomas may be associated with hypertriglyceridemia. Additional laboratory tests aimed at ruling out secondary causes of hyperlipidemia should be performed as indicated clinically.
Screening and Management of Childhood Hyperlipidemias
In 1992, the National Cholesterol Education Program (NCEP) Expert Panel on Blood Cholesterol Levels in Children and Adolescents 17 recommended selective, not general, screening for hyperlipidemia. Screening using family history has been shown to produce high rates of false-negative results because of variable accuracy based on the definition of positive family history and lipid thresholds. 18
Considerable debate about universal screening continues. The U.S. Preventive Services Task Force (USPSTF) also has concluded that the evidence is insufficient to recommend for or against routine screening for lipid disorders in infants, children, adolescents, or young adults (up to age 20 years). 18 Selective screening includes screening of children with a family history of premature CHD or elevated blood cholesterol. USPSTF also recommends screening children with other risk factors for CHD, such as obesity, hypertension, and diabetes mellitus, or those whose family history is unknown. A new recommendation for a specific category is proposed: 19 A lipoprotein profile should be obtained if either obesity (BMI >95th percentile) or overweight (BMI from the 85th to 94th percentile) is detected, regardless of the presence of other nonlipid CHD risk factors. This recommendation is congruent with the recent guidelines from the American Academy of Pediatrics. 20
To screen for dyslipidemia, a lipoprotein profile is measured after an overnight fast. Such a profile includes TC, TG, LDL-C, and HDL-C. Levels of TC and HDL-C can be determined in the nonfasting state.
Pharmacologic therapy aimed at reducing total and LDL-C should always follow at least 6 months of dietary and lifestyle changes, except for severe cases. 17 A diet restricted in fat and cholesterol has been shown to be a safe approach in reducing cholesterol levels in children and adolescents. 21,22
The American Heart Association's (AHA's) general dietary recommendations for those aged 2 years and older stress a diet that relies primarily on fruits and vegetables, low-fat and nonfat dairy products, whole grains, lean meat, beans, fish, and so on. 23 Energy intake and physical activity should be appropriate for maintaining a normal weight for height. 24
The recommended diet for the high-risk group (i.e., children and adolescents with a family history of CHD or hypercholesterolemia or who themselves have high total cholesterol and LDL-C concentrations or other significant CHD risk factors) is similar to that recommended for the population, but restricts saturated fat to 7 percent of total calories and dietary cholesterol to 200 mg/day. 20
The goals of diet therapy are as follows: for borderline LDL-C levels, to lower the level to <110 mg/dL; for high LDL-C levels, to lower the level to <130 mg/dL as a minimal goal and <110 mg/dL as an ideal goal.
Water-soluble fibers such as psyllium 25 may also provide an additional 5 to 10 percent lowering of LDL-C. The use of foods (about 3 servings daily) supplemented with plant sterol esters 26 can reduce LDL-C up to an additional 10 percent when added to a low-fat diet.
Physical activity helps improve the lipid profile by promoting the production of HDL particles and reducing production of VLDL and LDL-C particles. 27 Increased physical activity also helps in the improvement of other risk factors such as obesity, insulin resistance, and hypertension. 28 At least 30 minutes of physical activity is recommended per day, with an increase to 60 minutes considered desirable. 29
The primary use of pharmacologic therapy in pediatrics is to lower significantly elevated LDL-C. The NCEP Expert Panel for Children and Adolescents recommends that consideration be given to pharmacologic treatment of hyperlipidemia if the child is at least 10 years old and an adequate period of dietary restriction, at least six months, has not achieved therapeutic goals. Drug therapy should be considered when:
- LDL cholesterol remains >190 mg/dL.
- LDL cholesterol remains >160 mg/dL, and a positive family history of premature CHD exists or two or more other risk factors for CHD are present after vigorous attempts at lifestyle modification.
The target LDL-C for treatment is <130 mg/dL, although therapy ideally should lower LDL-C to <110 mg/dL. 30 Newer recommendations include the consideration of pharmacologic therapy for patients 8 years and older with an LDL concentration >190 mg/dL (or >160 mg/dL with a family history of early heart disease or the presence of two or more additional risk factors or >130 mg/dL if diabetes mellitus is present). 20
Drugs in Treatment of Hyperlipidemia
The classes of drugs available for the management of dyslipidemia are outlined in Table 3.
Bile acid resins bind cholesterol-derived bile acids in the intestinal lumen and prevent their reabsorption via enterohepatic uptake. This leads to decreased intrahepatic cholesterol stores, thus causing upregulation of LDL receptors and increased clearance of LDL. Their use in children, however, is limited by frequent gastrointestinal side effects and drug interactions. They may also lead to increased TG levels. If good adherence is achieved, reduction in LDL-C of 30 percent can be achieved, although in most studies a 20-percent reduction is seen. 31
HMG-CoA reductase inhibitors, or statins, have been shown in a number of randomized controlled trials and a meta-analysis 32 to effectively reduce LDL-C and appear to be safe in the pediatric population. These agents act by inhibiting the rate-limiting step in endogenous cholesterol synthesis, decreasing intrahepatic cholesterol and upregulating LDL receptors. They may also lower TG and cause a small increase in HDL-C. Statins have been found to reduce LDL-C levels by 40 percent or more in studies. 33-35 Because of the concern for the rare but serious side effects of transaminitis and myositis, CK, AST, ALT levels should be monitored at six weeks after initiation of therapy, then at 12 weeks and every six months thereafter. 29
Niacin, infrequently used in children, lowers LDL-C and TG and raises HDL-C. Its use is limited by a high incidence of side effects, predominantly flushing, but also including glucose intolerance, hyperuricemia, myopathy, gastrointestinal symptoms, and, rarely, fulminant hepatic failure. 36
The fibrates act by increasing LPL activity on VLDL particles, lowering TG levels. Side effects include gastrointestinal complaints, liver function abnormalities, cholelithiasis, and myopathy. The risk of myopathy is substantially increased when fibrates are combined with statins. Limited experience is available in children with these drugs. 37 The use of fibrates is limited to those with severe hypertriglyceridemia at risk for pancreatitis. 38
The dietary cholesterol-absorption inhibitors represent the newest class of cholesterol-lowering agents. Ezetimibe selectively blocks cholesterol absorption in the small intestine. This causes intrahepatic cholesterol depletion and upregulation of LDL receptor. Ezetimibe appears to be beneficial when used with a statin. These medications, however, have not been extensively studied in children, particularly in combination with other medications such as statins. 20
The origins of atherosclerosis and CHD begin in childhood. With the obesity epidemic and with more aggressive screening of at-risk pediatric patients, hyperlipidemia is now a more common disorder in pediatrics. The identification of genetic dyslipidemias associated with premature cardiovascular disease is crucial during childhood to delay or prevent the atherosclerotic process. Dietary and other lifestyle interventions such as increased physical activity remain the cornerstone of therapy in most patients. Pharmacologic intervention should be considered in selected children if adequate success is not achieved via lifestyle intervention or for those children with severe dyslipidemias. Future studies are needed to determine if treatment of hyperlipidemias early in life prevents CHD in adulthood.
- Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA. 2006;295(13):1549-1555.
- Freedman DS, Mei Z, Srinivasan SR, Berenson GS, Dietz WH. Cardiovascular risk factors and excess adiposity among overweight children and adolescents: the Bogalusa Heart Study . J Pediatr. 2007;150(1):12-17.e2.
- McGill HC Jr, McMahan CA, Malcom GT, Oalmann MC, Strong JP. Effects of serum lipoproteins and smoking on atherosclerosis in young men and women. The PDAY Research Group. Pathobiological Determinants of Atherosclerosis in Youth . Arterioscler Thromb Vasc Biol. 1997;17(1):95-106.
- Berenson GS, Srinivasan SR, Bao W, Newman WP III, Tracey RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med. 1998;338(23):1650-1656.
- Kanani PM, Sperling MA. Hyperlipidemia in adolescents . Adolesc Med . 2002;13(1):37-52, v-vi.
- Kronenberg H, Melmed S, Polonsky K, Larsen PR. Williams Textbook of Endocrinology . Philadelphia, PA: Saunders; 2008:1614.
- Kwiterovich PO Jr. Identification and treatment of heterozygous familial hypercholesterolemia in children and adolescents. Am J Cardiol. 1993;72(10):30D-37D.
- Iughetti L, Predieri B, Balli F, Calandra S. Rational approach to the treatment for heterozygous familial hypercholesterolemia in childhood and adolescence: a review . J Endocrinol Invest. 2007;30(8):700-719.
- Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest. 2003;111(12):1795-1803.
- Nassar BA. Familial defective apolipoprotein B-100: a cause of hypercholesterolemia and early coronary heart disease. CMAJ. 1993;148(4):579-580.
- Cortner JA, Coates PM, Liacouras CA, Jarvik GP. Familial combined hyperlipidemia in children: clinical expression, metabolic defects, and management . J Pediatr . 1993;123(2):177-184.
- Mahley RW, Huang Y, Rall SC Jr. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): questions, quandaries, and paradoxes. J Lipid Res . 1999;40(11):1933-1949.
- Feoli-Fonseca JC, Levy E, Godard M, Lambert M. Familial lipoprotein lipase deficiency in infancy: clinical, biochemical, and molecular study . J Pediatr . 1998;133(3):417-423.
- Shankar KN, Bava HS, Shetty J, Joshi MK. Lipoprotein lipase deficiency . J Postgrad Med . 1997;43(3):81-82.
- Schaefer EJ, Genest JJ Jr, Ordovas JM, Salem DN, Wilson PW. Familial lipoprotein disorders and premature coronary artery disease. Atherosclerosis . 1994;108 suppl:S41-S54.
- Brinton EA. Lipid abnormalities in the metabolic syndrome . Curr Diab Rep . 2003;3(1):65-72.
- National Cholesterol Education Program (NCEP): highlights of the report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics . 1992;89(3):495-501.
- US Preventive Services Task Force. Screening for lipid disorders in children: US Preventive Services Task Force recommendation statement. Pediatrics . 2007;20(1):e215-e219.
- Kwiterovich PO Jr. Recognition and management of dyslipidemia in children and adolescents. J Clin Endocrinol Metab. 2008;93(11):4200-4209.
- Daniels SR, Greer FR; Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics . 2008;122(1):198-208.
- Efficacy and safety of lowering dietary intake of fat and cholesterol in children with elevated low-density lipoprotein cholesterol. The Dietary Intervention Study in Children (DISC). The Writing Group for the DISC Collaborative Research Group. JAMA . 1995;273(18):1429-1435.
- Obarzanek E, Kimm SY, Barton BA, et al; DISC Collaborative Research Group. Long-term safety and efficacy of a cholesterol-lowering diet in children with elevated low-density lipoprotein cholesterol: seven-year results of the Dietary Intervention Study in Children (DISC). Pediatrics. 2001;107(2):256-264.
- Kavey. RE, Daniels SR, Lauer RM, Atkins DL, Hayman LL, Taubert K; American Heart Association. American Heart Association guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood. Circulation. 2003;107(11):1562-1566.
- Gidding SS, Dennison BA, Birch LL, et al; American Heart Association; American Pediatric Society. Dietary recommendations for children and adolescents: a guide for practitioners: consensus statement from the American Heart Association. Circulation. 2005;112(13):2061-2075.
- Kwiterovich PO Jr. The role of fiber in the treatment of hypercholesterolemia in children and adolescents. Pediatrics . 1995;96(5 pt 2):1005-1009.
- Amundsen AL, Ose L, Nenseter MS, Ntanios FY. Plant sterol ester-enriched spread lowers plasma total and LDL cholesterol in children with familial hypercholesterolemia. Am J Clin Nutr . 2002;76(2):338-344.
- Daniels SR. Exercise and lipid abnormalities. Pediatr Cardiol. 1999;20(1):71-77; discussion 78.
- Thavendiranathan P, Jones E, Han RK, et al. Association between physical activity, adiposity, and lipid abnormalities in children with familial hyperlipidemia . Eur J Cardiovasc Prev Rehabil. 2007;14(1):59-64.
- McCrindle BW, Manlhiot C. Elevated atherogenic lipoproteins in childhood: risk, prevention and treatment. J Clin Lipid. 2008;2(3):138-146.
- McCrindle BW, Urbina EM, Dennison BA, et al; American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee; American Heart Association Council of Cardiovascular Disease in the Young; American Heart Association Council on Cardiovascular Nursing. Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing. Circulation. 2007;115(14):1948-1967.
- Tonstad S, Ose L. Colestipol tablets in adolescents with familial hypercholesterolaemia . Acta Paediatr . 1996;85(9):1080-1082.
- Avis HJ, Vissers MN, Stein EA, et al. A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2007;27(8):1803-1810.
- de Jongh S, Ose L, Szamost T, et al; Simvastin in Children Study Group. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial with simvastatin. Circulation. 2002;106(17):2231-2237.
- Stein EA, Illingworth DR, Kwiterovich PO Jr, et al. Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial. JAMA. 1999;281(2):137-144.
- Lambert M, Lupien PJ, Gagné C, et al. Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin. Canadian Lovastatin in Children Study Group . Pediatrics. 1996;97(5):619-628.
- Colletti RB, Neufeld EJ, Roff NK, McAuliffe TL, Baker AL, Newburger JW. Niacin treatment of hypercholesterolemia in children. Pediatrics . 1993;92(1):78-82.
- Wheeler KA, West RJ, Lloyd JK, Barley J. Double blind trial of bezafibrate in familial hypercholesterolaemia. Arch Dis Child. 1985;60(1):34-37.
- McCrindle BW. Hyperlipidemia in children . Thromb Res. 2006;118(1):49-58.
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Drs. Raman and Heptulla are from the Department of Pediatrics, Division of Endocrinology & Metabolism, Baylor College of Medicine and Texas Children's Hospital, Houston.
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