You are in: eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Cardiology Pediatric Lipid Disorders in Clinical PracticeArticle Last Updated: Apr 23, 2008AUTHOR AND EDITOR INFORMATIONSection 1 of 9
  Author: Henry J Rohrs III, MD, Fellow, Department of Pediatrics, Division of Pediatric Endocrinology, Shands Hospital, University of Florida Henry J Rohrs, III, is a member of the following medical societies: American Association of Clinical Endocrinologists and Lawson-Wilkins Pediatric Endocrine Society Coauthor(s): Desmond Schatz, MD, Professor, Medical Director of Diabetes Center, Department of Pediatrics, Division of Endocrinology, University of Florida; William E Winter, MD, Professor, Departments of Pathology and Laboratory Medicine and Pediatrics, University of Florida College of Medicine; Vanessa Davis, MD, Fellow, Department of Pediatrics, Division of Endocrinology, University of Florida Editors: Christopher Johnsrude, MD, Associate Professor of Pediatrics, Director of Electrophysiology, University of Louisville School of Medicine; Consulting Staff, Pediatric Cardiology Associates, PSC; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; John W Moore, MD, MPH, Professor of Clinical Pediatrics, Division of Pediatric Cardiology, Mattel Children's Hospital of University of California at Los Angeles; Gilbert Herzberg, MD, Assistant Professor, Department of Pediatrics, Section of Pediatric Cardiology, New York Medical College; Stuart Berger, MD, Professor of Pediatrics, Division of Cardiology, Medical College of Wisconsin; Chief of Pediatric Cardiology, Medical Director of Pediatric Heart Transplant Program, Medical Director of The Heart Center, Children's Hospital of Wisconsin Author and Editor Disclosure Synonyms and related keywords: atherosclerosis, pediatric lipid disorders, apoprotein, apolipoprotein, apo, cardiovascular disease, CVD, cholesterol ester, CE, coronary artery disease, CAD, coronary heart disease, CHD, familial combined hyperlipidemia, FCH, familial hypertriglyceridemia, FH, high-density lipoprotein, HDL, high-density lipoprotein cholesterol, HDL-C, hyperlipoproteinemia, HLP, intermediate-density lipoprotein, IDL, impaired fasting glucose, IFG, impaired glucose tolerance, IGT, lecithin-cholesterol acyltransferase, LCAT lipoprotein lipase, LPL, low-density lipoprotein, LDL, low-density lipoprotein cholesterol, LDL-C, low-density lipoprotein receptor, LDL-R, medium-chain triglyceride, MCT, total cholesterol, TC, triglyceride, TG, very-low-density lipoprotein, VLDL, dyslipidemia, lipid abnormalities, chylomicron syndrome, hyperchylomicronemia syndrome, hepatosplenomegaly, pancreatitis, failure to thrive, myocardial infarctions, hypertension, familial dyslipidemic hypertension, hypothyroidism, nephrosis, biliary tract disease, diabetes mellitus, remnant removal disease, remnant lipoprotein disease, or dysbetalipoproteinemia, alcoholism, renal disease, hepatic disease, insulin resistance Cushing disease, acromegaly, Tangier disease, fish-eye disease, LCAT deficiency, starvation, malabsorption, chronic anemia, Smith-Lemli-Opitz syndrome, mental retardation, ambiguous genitalia INTRODUCTIONSection 2 of 9
  Multiple studies have revealed that the early stages of atherosclerosis begin in childhood.1 If premature development of cardiovascular disease can be anticipated during childhood, the disease might be prevented.2 In adult patients, the lowering of lipid levels results in primary and secondary prevention of cardiovascular disease. The purpose of this article is to discuss the basic biology of lipoproteins, the pathophysiology of various dyslipidemias, the screening and interpretation of lipid levels in pediatric patients, and the management of pediatric lipid abnormalities. PHYSIOLOGY OF LIPIDS AND LIPOPROTEINSSection 3 of 9
Lipoprotein composition The 2 major forms of circulating lipid in the body, triglyceride (TG) and cholesterol, are insoluble in plasma. However, these lipids can be transported throughout the blood stream as lipoproteins when packaged with phospholipids and apolipoproteins (ie, apoproteins). Lipoproteins have an outer core of cholesterol, phospholipids, and apoproteins and their inner core is composed of TG and cholesterol ester (CE). Apoproteins function as (1) structural proteins, (2) proteins that make the lipoprotein particle soluble, (3) enzyme activators (eg, apoprotein C-II activates lipoprotein lipase [LPL], apoprotein A-I activates lecithin-cholesterol acyltransferase [LCAT]), and (4) ligands for receptors. Lipoproteins have been classified into 5 major classes (see Table 1). The classes of lipoprotein are not homogeneous in size or composition. For example, low-density lipoprotein cholesterol (LDL-C) can be divided into cholesterol-rich light LDL-C and cholesterol-depleted dense LDL-C. Dense LDL-C is more atherogenic than light LDL-C. Table 1. Biology of Lipoproteins
*Calculated using the Friedewald equation: LDL-C = Total cholesterol (TC) - HDL-C - TG/5. † TG/5 is the estimate of the VLDL-C. Exogenous pathway This lipoprotein pathway is termed the exogenous pathway because dietary lipids are consumed with meals. Dietary lipids (predominantly TGs) are packaged by the intestinal mucosal cells into chylomicrons. Apoprotein C-II, apoprotein B-48, and apoprotein E are the clinically important apoproteins of chylomicrons. Chylomicrons, which are TG rich, enter the lymphatic system. The thoracic duct empties into the vena cava, and chylomicrons systemically circulate. Once acted on by LPL, which is attached to the luminal side of the capillary endothelium adjacent to muscle and adipose tissue, chylomicrons release TGs as monoglycerides and free fatty acids. Chylomicrons bind to LPL via apoprotein C-II. Therefore, defects in apoprotein C-II or LPL can lead to defects in chylomicron clearance. Muscle normally burns the free fatty acids and monoglycerides for energy. Resynthesized TGs can be used for plasma and cell organelle membrane synthesis. Adipose tissue uses free fatty acids and monoglycerides to resynthesize TGs that are stored for future energy needs. As an alternative, adipocytes can use TGs in membrane synthesis, which is similar to muscle. When the chylomicrons are reduced in TG content, they become remnants that are rapidly cleared by the liver (apoprotein E binds to the LDL receptor [LDL-R]). At this time, apoprotein C-II is passed to high-density lipoprotein (HDL) particles in the circulation. In fasting normal plasma, chylomicrons and chylomicron remnants are not detected. Endogenous pathway In the endogenous pathway, the liver produces VLDL. The clinically important apoproteins in VLDL are apoprotein C-II, apoprotein B-100, and apoprotein E. Like chylomicrons, VLDL interacts with LPL via apoprotein C-II to release TG-forming intermediate-density lipoprotein (IDL) particles. With the formation of IDL, apoprotein C-II is transferred to HDL particles. IDL particles are rapidly removed by the liver via apoprotein E interaction with the LDL-R. The LDL-R is also known as the apoprotein E, apoprotein B-100 receptor. Alternatively, IDL particles are further metabolized to LDL by continued removal of TG by hepatic lipase. In the conversion from IDL to LDL, apoprotein E is shed and is picked up by HDL particles. LDL is removed by binding to the LDL-R. Approximately two thirds of circulating LDL is removed by the liver, and approximately one third is removed by extrahepatic tissues, including steroid-producing cells and cells within the subintimal space in which atheromatous plaques develop. In the subintimal (ie, subendothelial) space, the protective effect of circulating antioxidants (ie, vitamin E) is lost, and LDL is oxidized (eg, modified). Oxidized LDL is removed by the scavenger receptor, which is different from the LDL-R. Smooth muscle cells and macrophages express scavenger receptors. This uptake is not regulated, and macrophages and smooth muscle cells can take up so much LDL and cholesterol that they become foam cells. Oxidized LDL is also toxic to cells and can lead to early endothelial injury, allowing platelet adhesion and localized release of platelet-derived growth factor (PDGF). In contrast, when other cells have sufficient cholesterol, they downregulate the LDL-R to decrease cholesterol absorption into the cell. DYSLIPIDEMIASSection 4 of 9
Hyperlipidemia A review of the Frederickson phenotypes is helpful in classifying dyslipidemias. Table 2. Frederickson Classification of Dyslipidemias
The most common dyslipidemias are types IIA, IIB, and IV. Type I and type III hyperlipoproteinemia (HLP) are rare in pediatric patients, and type V is uncommon. Whether type III HLP occurs in children at all is controversial. Type I HLP Type I HLP is present when the TG elevation is predominant, with TG levels reaching or exceeding 1000-2000 mg/dL. Type I HLP is also termed chylomicron syndrome or hyperchylomicronemia syndrome for reasons noted below. In type I HLP, the plasma infranatant on standing is clear, whereas the supernate is cloudy because of elevated chylomicrons. Supernatants only form when chylomicrons are present. The presence of chylomicrons is best confirmed by obtaining plasma lipoprotein ultracentrifugation, performed by a referral laboratory that specializes in lipid analysis. Most cases of type I HLP are caused by a congenital deficiency of LPL, a congenital deficiency of apoprotein C-II, or an LPL inhibitor. In healthy children, chylomicrons are rapidly cleared from the circulation after a meal. When LPL or apoprotein C-II is deficient, chylomicrons can be detected for more than 12 hours after a meal. The normal half-life of chylomicrons in plasma is approximately 17 minutes. Because TGs are not being cleared at the tissue level (ie, TG is not released from the chylomicrons to muscle and adipose tissue), most chylomicrons are taken up by the liver and spleen, resulting in hepatosplenomegaly, macrophage uptake (foam cell formation), and rash. If prolonged hypertriglyceridemia is untreated, eruptive xanthomas (discrete 1- to 6-mm papules) may appear on the extensor surfaces of the extremities. Lipemia retinalis may also occur. The retinal vessels appear white-to-yellow because of the striking hyperchylomicronemia. When TG levels exceed 1000-2000 mg/dL, the risk of pancreatitis is increased. Infants may present with colicky abdominal pain and even failure to thrive. In older children, acute pancreatitis can cause tremendous pain, nausea, vomiting, and even death if undetected and untreated. In one study of patients with LPL deficiency, 80% presented before age 10 years, with 30% younger than 1 year. In contrast, apoprotein C-II deficiency is usually diagnosed later in life (eg, older than 13 y). Apoprotein C-II deficiency rarely presents in infancy. At least 40 molecular defects in LPL and 12 different molecular defects in apoprotein C-II have been reported. Both LPL and apoprotein C-II deficiencies are inherited as autosomal recessive traits and affect approximately 1 in 1 million persons in the general population. Because LPL and apoprotein C-II deficiencies are inherited as autosomal recessive traits, the family history is generally unrevealing, although some parents of children with LPL or apoprotein C-II deficiency were cousins. Note that lipemic serum can interfere with many laboratory determinations, including enzyme activity measurements, antigen-antibody assays, and various spectrophotometric assays. Type IIA and IIB HLP In children, type IIA HLP is defined as LDL-C concentrations of 130 mg/dL or higher. The plasma is clear. In contrast, in type IIB HLP, TG levels (VLDL levels) are elevated to 125 mg/dL or higher, and LDL-C levels are also elevated. If the TG level is typically 300-400 mg/dL or higher, the plasma appears visibly turbid (lipemic). Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevated LDL-C levels with or without a concurrent elevation in TG levels. FH affects approximately 1 in 500 persons in the general population. Besides premature cardiovascular disease, clinical findings in adults include tendon xanthomas (especially involving the Achilles tendons and the extensor tendons of the hands) and arcus senilis (involving the cornea). FH results from an inherited defect in the LDL-R. Because the LDL-R also clears IDL, and because VLDL is the precursor of IDL and LDL, patients with FH may also display elevations in IDL and VLDL. Thus, some individuals with FH display a type IIB phenotype. In FH, LDL production is increased by approximately 30% in people with one defective allele of the LDL-R gene. If an individual inherits 2 defective alleles of the LDL-R gene (eg, homozygous FH), LDL production increases by approximately 200-300%. Adults who are heterozygous for FH have 2- to 3-fold higher TC levels of 300-600 mg/dL, and LDL-C levels are commonly 250 mg/dL or higher. Patients who are homozygous for FH have TC levels of 600-1500 mg/dL (increased 5- to 6-fold). Homozygous FH is a highly hazardous condition for large blood vessels that causes extremely premature atherosclerosis. However, homozygous FH is very rare, affecting only 1 in 1 million persons. In FH, affected family members have elevated LDL-C concentration beginning early in life. Cord blood TC and LDL-C levels are already elevated. Males with FH often develop cardiovascular disease in the fourth or fifth decade of life, but the disease can manifest in teenagers. The mean age of death in males with FH is 45 years. Women with FH usually have onset of cardiovascular disease in the fifth or sixth decade of life. Of persons who have survived myocardial infarctions that occurred when they were younger than 60 years, 5% have FH. Children as young as 3 years who have homozygous FH have died from myocardial infarction from premature cardiovascular disease. Homozygous FH should be strongly suspected in deaths from myocardial infarction in individuals aged 20 years or younger. A defect in apoprotein B-100 is phenotypically similar to FH. This disorder has a frequency similar to FH. Elevated LDL-C levels result when the apoprotein B molecule is defective, even if the LDL-R molecule is normal. In FH, IDL and VLDL concentrations can be elevated because IDL is cleared via the LDL-R; however, in familial defective apoprotein B-100, because the LDL-R molecule is normal, IDL and VLDL (and TG) levels are usually normal. In contrast to FH, tendon xanthomas and arcus cornealis (arcus senilis) may be absent in patients with defective apoprotein B-100 Modest hypercholesterolemia (250-300 mg/dL) is usually present, with a TC level lower than in adults with FH (mean TC concentration in defective apoprotein B-100 is 269 mg/dL versus approximately 360 mg/dL in FH). LDL-C levels are raised by approximately 70 mg/dL. As in FH, patients with familial defective apoprotein B-100 may develop premature cardiovascular disease. Familial defective apoprotein B-100 and FH can be very difficult to clinically differentiate when patients with FH display a type IIA phenotype; however, in the absence of secondary conditions that raise TG levels, the presence of a type IIB phenotype essentially excludes familial defective apoprotein B-100. Familial combined hyperlipidemia (FCH) is inherited as an autosomal dominant trait. The etiology of FCH appears to be an overproduction of apoprotein B–containing particles (VLDL, LDL, or both). Affected individuals may exhibit type IIA, type IIB, or type IV phenotypes. In a single family with FCH, some individuals may display isolated elevations in TC/LDL (type IIA HLP) or TG (type IV HLP) levels, whereas other affected members may have a combined hyperlipidemia (increased LDL-C and TG levels [type IIB HLP]). The co-occurrence of FCH plus hypertension has been called familial dyslipidemic hypertension. Similar to FH, premature cardiovascular disease can occur in patients with FCH. Overall, FCH affects approximately 1 in 200-300 persons in the general population and occurs in approximately 15% of individuals younger than 60 years who survive a myocardial infarction. Other causes of type IIA or IIB phenotypes include hypothyroidism, nephrosis, biliary tract disease, and diabetes mellitus. In hypothyroidism, hepatic LDL-R expression is reduced, leading to elevated LDL-C levels. Lipoprotein production is typically increased in patients with nephrosis. With glycosylation of apoprotein B in patients with diabetes mellitus and increased VLDL synthesis, LDL-C levels commonly rise. Type III HLP Type III HLP (also known as remnant removal disease, remnant lipoprotein disease, or dysbetalipoproteinemia) is estimated to affect approximately 1 in 5000 persons in the general population but rarely manifests in children. It is due to increases in IDL and remnant lipoproteins and is manifested by approximately equal increases in total cholesterol and TGs. Palmar xanthomas (xanthoma striata palmaris) may occur in type III HLP and are not observed in other disorders. Genetic and environmental factors both influence the development of type III HLP. The entity should be considered when tuberous xanthomas, palmar xanthomas, or both are noted, and the patient may be obese or have underling diseases such as diabetes mellitus, hypothyroidism, alcoholism, and renal or hepatic disease. Type III HLP can be inherited as a recessive trait or, less commonly, as a dominant trait. Most adults with type III HLP are homozygous for apoprotein E-2 (one of the 3 isoforms of apoprotein E). Adults with type III HLP are at markedly increased risk for cardiovascular disease and, particularly, peripheral vascular disease. Type IV and type V HLP In type IV HLP a predominant increase in VLDL TGs is observed; however, levels are lower (eg, <1000 mg/dL) than in HLP types I or V. Type V HLP results when 2 or more causes of type IV HLP combine to produce chylomicronemia and elevated VLDL levels, which push TG levels to 1000 mg/dL or higher. Plasma samples in patients with type V HLP display a turbid infranatant and a cloudy supernate. Hypertriglyceridemia is frequently observed in children with obesity, diabetes, or both conditions. In type 1 diabetes mellitus, hypertriglyceridemia results from absolute insulin deficiency, whereas in children with obesity and type 2 diabetes mellitus, insulin resistance is the root cause combined with relative insulin deficiency. Other causes of insulin resistance, including renal disease, liver disease, ethanol abuse, pregnancy, endocrinopathies (eg, Cushing disease, hypothyroidism, acromegaly), and drugs (eg, glucocorticoids, growth hormone, androgens, thiazides, beta-blockers, estrogen), may also lead to hypertriglyceridemia. Similar to insulin, thyroid hormone regulates LPL activity. Hypothyroidism can cause elevated TG levels by lowering LPL activity. Two inherited causes of a type IV phenotype include familial hypertriglyceridemia and FCH. Familial hypertriglyceridemia is rarely expressed in childhood unless another underlying cause of hypertriglyceridemia is present. About 15% of patients with premature cardiovascular disease have hypertriglyceridemia. Other Dyslipidemic SyndromesHDL-C disorders The differential diagnosis of a depressed HDL-C includes familial disorders, genetic disorders, smoking, obesity, hypertriglyceridemia, renal failure, and drugs (eg, anabolic steroids, progestins, beta blockers, thiazides), with male sex and a sedentary lifestyle being additional risk factors. In both familial hypoalphalipoproteinemia (ie, low HDL-C) and Tangier disease depressed apoprotein A-I levels are found. Other rare genetic causes of low HDL-C levels include fish-eye disease and LCAT deficiency. In fish-eye disease, patients have TG elevations to 250-300 mg/dL, severely depressed HDL-C levels, and corneal opacities. In LCAT deficiency, cholesterol esters cannot be formed; thus, cholesterol does not move into the core of the HDL particle disc. Hypolipidemias Causes of acquired low LDL-C levels include malnutrition from starvation or malabsorption, hyperthyroidism, chronic anemia, severe hepatic dysfunction, and acute severe stress (eg, burns, trauma, myocardial infarction). Genetic forms of hypolipidemia are very rare but are potentially serious. Such conditions include abetalipoproteinemia (autosomal recessive), homozygous hypobetalipoproteinemia, heterozygous hypobetalipoproteinemia (with or without GI tract or neurologic symptoms), abetalipoproteinemia with normotriglyceridemia, and chylomicron retention disease. Low cholesterol levels secondary to deficiency of 7-dehydrocholesterol-δ-7 reductase are seen in Smith-Lemli-Opitz syndrome associated with mental retardation and ambiguous genitalia. LIPID TESTINGSection 5 of 9
Lipids can be routinely measured individually as TC, TGs, or HDL-C. Using these measurements and the Friedewald equation when TG levels are less than 400 mg/dL, LDL-C can be calculated. Direct LDL measurements allow LDL-C determination on specimens when the TG level is 400 mg/dL or higher and do not require a fasting specimen. Children should be on their regular diet for 4-6 weeks before lipid testing. Recent changes in diet that may change lipid levels are an indication to delay testing. Measurements of TC and HDL-C do not need to be performed in the fasting state. However, isolated TG measurements and lipid profile measurements (ie, when LDL-C is to be calculated) must always follow an overnight fast of least 8 hours, preferably 12-14 hours. Recent severe illness (eg, hospitalization within the last 4-6 wk) is a contraindication to lipid testing because significant stress can lead to transient decreases in lipid levels or transient lipid abnormalities (eg, hypertriglyceridemia following diabetic ketoacidosis). During acute illness, lipids should not be measured unless hypertriglyceridemia is believed to be the underlying cause of the disease (eg, pancreatitis). Lipoproteins are negative acute phase reactants and their concentrations decline within 24 hours of severe acute stress. In adults, intraindividual variation in TC over the course of one year is reported at ±8% (range 4-11%). Intraindividual variation in TG is 13-41%, whereas HDL-C varies by 4-12%. Standing TC levels are 8-12% higher than recumbent values because of a decrease in intravascular free water that leaks into the interstitial space. The use of anticoagulants in sample tubes may lower TC levels by 3% or less. National Cholesterol Education Program guidelines The National Cholesterol Education Program (NCEP) was created in 1985 by the National Heart, Lung, and Blood Institute (NHLBI). Their goal is to educate both the public and medical professionals about the benefits of lowering cholesterol levels as a way to reduce the risk for coronary heart disease. The current pediatric guidelines for cholesterol screening are based on a consensus report published in 1992 (modified in 2001) by the NCEP Expert Panel on Blood Cholesterol levels in Children and Adolescents.3, 4, 5, 6 Abnormalities in lipid levels have traditionally been defined as concentrations at or above the 95th percentile for TC, TGs, and LDL-C for age and sex, whereas low HDL-C concentrations have traditionally been defined as lower than the 5th percentile for age and sex. Many of these cutoffs have been modified by the NCEP to define healthy or desirable levels and not just levels outside of a certain concentration range defined statistically. The NCEP has not defined desirable and undesirable TG levels for children and adolescents. However, because children and adolescents are referred to clinics for elevated TG levels, an abnormal TG level must be defined. For adults, the NCEP has defined desirable levels of TGs as less than 150 mg/dL, mildly elevated levels as 150-199 mg/dL, elevated levels as 200-499 mg/dL, and levels of 500 mg/dL or higher as very high. At the Table 3. NCEP Lipid Assessments for Children
*This was not established by NCEP; these values were the adult cutpoints used at the time that the pediatric NCEP guidelines were established. The NCEP defines cardiovascular disease as premature when it manifests before age 55 years in males or before age 65 years in females. Screening should be considered in children with first- and second-degree relatives with premature cardiovascular disease and elevated cholesterol levels. In addition, a family history of dyslipidemia warrants testing. Recommendations are provided below. Furthermore, the pediatric diseases or conditions associated with cardiovascular disease and/or dyslipidemia later in life warrant testing. The NCEP identifies lifestyle, metabolic disorders, and hypertension as risk factors that may contribute to earlier onset of coronary heart disease in children. The authors have added renal disease, liver disease, untreated or undertreated hypothyroidism, Cushing syndrome, and use of certain drugs that contribute to coronary heart disease in adults. NCEP guidelines do not include male sex or renal disease as risk factors. However, male sex and renal failure and/or renal transplantation are well recognized to be associated with cardiovascular disease in adults. Pediatric conditions with an increased risk for cardiovascular disease include the following:
Indications for cholesterol testing in children include the following:
NONPHARMACOLOGICAL MANAGEMENTSection 6 of 9
If a child's TC level is less than 170 mg/dL, no further testing is required for 5 years, when the TC measurement should be repeated. Patients and families should be educated about healthy eating patterns and risk-factor reduction. If the TC level is 170-199 mg/dL, TC measurements should be repeated within the next few weeks, and the 2 results should be averaged. A fasting lipid profile should be obtained, with calculation of LDL-C in individuals in whom the TC level is initially at least 200 mg/dL or in whom the average TC level is at least 170 mg/dL. Two lipid profiles should be obtained, and the results should be averaged. If the LDL-C level is less than 110 mg/dL and the TG level is less than 125 mg/dL, no further testing is required for 5 years, when the lipid profile should be repeated. Patients and families should always be educated about healthy eating patterns and risk factor reduction. If the LDL-C level is 110-129 mg/dL, an NCEP diet is prescribed, and the child is reevaluated in one year. Previously, the recommendation was for the child to first be placed on a step-one diet, which allowed as much as 300 mg of cholesterol and as much as 10% of total fat as saturated fat in the diet. However, new guidelines now establish a single dietary recommendation to improve blood lipid levels. The fundamentals of the lipid-lowering diet include the following:5
Fat provides 9 kcal/g; however, if this figure is rounded to 10 kcal/g, 600 kcal of fat equals approximately 60 g of fat per day. By placing a numerical value on the amount of fat that the child eats per day (eg, approximately 60 g maximum) and by knowing the number of grams of fat in particular food servings, dietary fat intake can theoretically be regulated if the child adheres to a specific diet. For example, a popular double-patty fast-food cheeseburger contains approximately 34 g of fat; however, choosing a chicken breast sandwich from the same fast food menu supplies only 6 g of fat. Children should be reevaluated in 6 months to assess their progress and should be allowed one year to achieve their lipid goal. The goal of dietary intervention is to achieve an LDL-C level of 110 mg/dL or less. Management of LDL-C levels of 130 mg/dL or higher A TG level 125 mg/dL or less with an average LDL-C level of 130 mg/dL or higher defines a type IIA Frederickson phenotype. NCEP recommendations for children directly address this phenotype. Dietary measures and exercise should be instituted, and secondary causes should be sought. Ideally, the goal should be to achieve an LDL-C level lower than 110 mg/dL (at least 130 mg/dL or lower).The child should engage in regular aerobic exercise. Some patients live in areas that are considered unsafe, and parents limit their outdoor activity. Video games, computers, and television viewing have replaced many outdoor activities. Active video games such as Dance Dance Revolution, which uses flashing lights on a dance pad, are now gaining popularity. With advancement in video game consoles, this activity is now available at home or in video arcades. Other ways to increase physical activity include chores around the house, such as raking leaves, vacuuming, sweeping, and walking the dog. Ideal weight should be maintained or achieved. Although weight loss may not be feasible in a growing child, weight maintenance is not an unreasonable goal, so that the child may eventually grow into the weight. Another approach is to set a goal of lowering the rate of weight gain, which is designed to bring the child into line with an appropriate weight at some time in the future (eg, 1-5 y). Secondary causes of elevated LDL-C levels should be eliminated or minimized, such as treating hypothyroidism or improving glycemic control in diabetes. The laboratory testing should include thyroid studies (Free T4, thyroid-stimulating hormone [TSH]), glycosylated hemoglobin studies (if diabetic), liver function tests, and a renal profile. If TG and LDL-C levels are both elevated (eg, TGs >125 mg/dL and LDL-C >130 mg/dL), a type IIB phenotype is present; the nonpharmacologic treatment in patients with the type IIB phenotype is similar to treatment in those with the type IIA phenotype. Type I HLP treatment Dietary fat should be restricted to 15% of energy intake. This usually controls symptoms, reducing triglyceride levels to lower than 1000 mg/dL. Because medium-chain triglycerides (MCTs) are directly absorbed by the capillaries and because they do not contribute to chylomicron formation, MCT oil can be included in the diet. In infants, Portagen is a formula that is appropriate. Although a strict vegetarian diet may reduce the likelihood of severe hypertriglyceridemia, preventing the potential nutritional deficiencies associated with such a diet is important. Types IV HLP and type V HLP treatment With mild elevations in triglycerides (125-299 mg/dL), appropriate interventions include encouraging a healthy lifestyle; reviewing caloric intake; advising against overeating; encouraging exercise; restricting television, video games, and nonscholastic Internet use to an hour a day or less; avoiding alcohol and estrogen use; and, for all degrees of hypertriglyceridemia associated with obesity, slowing the rate of weight gain or achieving weight loss after growth is complete. Management of hypoalphalipoproteinemias (low HDL-C levels) Hypoalphalipoproteinemia is most often observed in association with FH, FCH, or acquired (insulin-resistant) hypertriglyceridemia. Therapies should therefore target the underlying disorder.
PHARMACOTHERAPY MANAGEMENT OF PEDIATRIC DYSLIPIDEMIASSection 7 of 9
When beginning medications, the assumption is that nonpharmacologic measures (as described above) did not achieve an LDL-C level of 160 mg/dL or lower after 6-12 months. Pharmacotherapy should be considered in children older than 10 years with type IIA or type IIB HLP if the following is noted:
Bile acid–binding resins The 1991 NCEP recommendations advise using bile acid–binding resins as the drugs of choice to treat type IIA HLP in children.4 However, bile acid–binding resins can lead to elevations in TG levels. Therefore, they are indicated in the treatment of type IIA HLP but are not routinely indicated for type IIB HLP. Bile acid–binding resins block bile acid reabsorption from the gut, resulting in bile acid excretion in the stool. Compensatory hepatocyte bile acid synthesis increases, which increases hepatocyte LDL-R expression. Increased LDL-R expression on the hepatocyte surface increases LDL clearance, resulting in a decrease in LDL-C concentrations. Bile acid–binding resins available in the Cholestyramine and colestipol are insoluble in at least 2-6 ounces of water and must be mixed with water or juice to avoid the development of intestinal obstruction. The resins are taken with meals (when bile acids are secreted) and are dosed in scoops or packets of 4-5 g each. Therapy begins with 1-2 packets or scoops per day, given in orange juice or water. The dose is divided between breakfast and dinner and is increased every month to achieve an LDL-C level of less than 130 mg/dL or until maximum dosage is reached (see dosing information below).
Use of bile acid–binding resins may lead to a decline in serum folate, carotinoid, and 25-hydroxyvitamin D concentrations. Fat malabsorption may occur. Children treated with bile acid–binding resins should receive supplementation with multivitamins including folate. Approximately 10% of children treated with cholestyramine have elevations in aspartate aminotransferase (AST) levels, lactate dehydrogenase (LD) levels, or both, which is surprising because these agents are not systemically absorbed. Bile acid–binding resins bind drugs in addition to bile acids and vitamins; therefore, other drugs should be taken at least one hour before or 3 hours after consumption of bile acid–binding resins. No adverse effects on growth have been noted using bile-acid binding resins. Niacin Niacin was the second-line drug recommended by the 1991 NCEP panel for treatment of elevated LDL-C concentrations.4 Niacin is also effective in patients with combined hyperlipidemia (eg, FCH or type IIB HLP) and in patients with isolated hypertriglyceridemia due to elevated VLDL levels. Niacin (ie, nicotinic acid) has been shown to be effective in adults for treating HLP types IIA, IIB, IV, and V. Niacin decreases lipoprotein production and increases lipoprotein clearance. Decrements in LDL-C levels up to 17% have been reported. Niacin has been associated with toxicities, including liver disease, GI tract upset (abdominal pain, nausea), and facial flushing. In adults, glucose intolerance and hyperuricemia have been reported. In the authors' experience, many children (or their parents) have been unable to endure the facial flushing and GI tract upset produced by niacin. These complications severely limit its use.9 Although they produce less flushing, extended-release preparations are more likely to produce liver toxicity than immediate-release preparations because higher niacin levels are sustained for longer periods of time. In children, the extended-release agents should only be used with great care and should be used only in exceptional circumstances (eg, homozygous FH). Few guidelines for niacin dosing in children are available. An effective dose must be balanced against the toxicities. Niacin should be started at a dose of 50 mg/d and very gradually increased (eg, every 4 wk or less often) until the LDL-C level is less than 160 mg/dL when treating HLP type IIA or HLP type IIB, until the TG level is less than 300 mg/dL when treating type IV HLP, or until a dose of 1500-3000 mg/m2 is reached without liver toxicity. Splitting the dose (ie, administering the dose divided twice daily or three times daily) should be attempted as soon as a dose of 100 mg/d of niacin is reached. Alanine aminotransferase (ALT) levels should be measured every 3 months. With a decline in LDL-C to less than 160 mg/dL or TG levels to less than 300 mg/dL, the dose does not need to be further increased. If the LDL-C level declines to less than 130 mg/dL (in HLP type IIA or IIB) or if the TG level decreases to less than 125 mg/dL (in type IV HLP), the niacin dose can be reduced or a trial period without the medication can be attempted. 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins) In the past, statins were considered if neither bile acid sequestrants nor niacin were effective or if the drugs were not tolerated. Statin use has markedly increased in children because these drugs are well tolerated, safe, and efficacious. Statins are now approved for use in children as young as 10 years old (pravastatin is approved for children as young as 8 y) and are more commonly being used as first-line therapy. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase catalyzes the conversion of HMG-CoA to mevalonate. This is the rate-limiting step in the synthesis of cholesterol. Inhibition of HMG-CoA reductase blocks hepatocyte synthesis of cholesterol. This stimulates the hepatocyte to produce more LDL-Rs. In turn, LDL-R expression on the surface of hepatocytes is increased, which increases LDL clearance from the circulation. Currently available statins and their doses are shown in Table 4. In children, the lowest available dosage form should be used as the starting dose. Dosage increases should be considered every 6-12 weeks until the LDL-C level is less than 160 mg/dL or until the maximum tolerable dose is reached. After the LDL-C level declines to less than 160 mg/dL, the dose does not need to be further increased. If the LDL-C level declines to less than 130 mg/dL, the statin dose can be reduced or a trial period off medication can be attempted. The LDL-C goals in children treated for hypercholesterolemia are not yet as aggressive as they are in adults. Table 4. Dosing of HMG-CoA–Reductase Inhibitors
*Renal insufficiency is indicated by a creatinine clearance of less than 30 mL/min; agents known to decrease HMG-CoA–reductase inhibitor clearance include grapefruit juice, gemfibrozil, ritonavir, cyclosporine, danazol, amiodarone, azole antifungals, macrolide antibiotics, and verapamil. Statins have been associated with hepatocellular toxicity and rhabdomyolysis. Frank rhabdomyolysis is rare. The likelihood of rhabdomyolysis increases when a statin is used with cyclosporine, gemfibrozil, erythromycin, azole antifungal agents, niacin, or antiretroviral therapies. The risk also increases with higher doses. For all statins except pravastatin and rosuvastatin, AST/ALT monitoring should be undertaken before therapy, after 6 weeks, 12 weeks, and every 6 months. For pravastatin and rosuvastatin, monitoring is recommended before therapy, after 12 weeks, and 12 weeks after dosage changes. Studies have reported decreases in LDL-C levels of as much as 40% and increases in HDL of 23%. Increases in ALT, AST, and creatine kinase levels outside the reference range are reported in most studies to occur in 1-5% of cases. US Food and Drug Administration (FDA)-approved indications for use of statins are outlined as follows:
These drugs inhibit lipoprotein production and increase lipoprotein clearance. Similar to niacin, fibric acid derivatives are useful in treating various dyslipidemias, including HLP types IIA, IIB, IV, and V. Although fibric acid derivatives are effective in adults for the treatment of type IIA phenotypes, the authors do not use fibric acid derivatives in type IIA HLPs because of the effectiveness and safety of statins. The authors reserve the use of fibric acid derivatives for persistent hypertriglyceridemia. Safety and efficacy data on fibric acid derivatives in children are limited. The table below lists doses and FDA-approved indications in adults. In adults, common toxicities include myalgias, myositis, myopathy, rhabdomyolysis, liver toxicity, gallstones, and glucose intolerance. Gemfibrozil is less likely to cause gallstones than clofibrate (discontinued from the US market). ALT levels should be monitored every 3 months in children treated with gemfibrozil. The authors have only limited experience with fenofibrate but have used gemfibrozil safely and effectively in the clinic. Table 5.
Ezetimibe has been produced as a combination pill with simvastatin (Vytorin) in adults. FDA-approved Vytorin is available in preparations that contain 10 mg of ezetimibe and 10, 20, 40 or 80 mg of simvastatin (Zocor). Because both drugs have different mechanisms of action, a synergistic effect causes a 30-60% decrease in cholesterol levels. Compliance is increased because both medicines are included in a single tablet. Limited data in children are available; therefore, widespread use is not yet established. Other medications Although aspirin is widely used in adults with atherosclerosis or for prevention of atherosclerosis, aspirin should not be used in children because of the risk of Reye syndrome. Beta-carotenes, vitamin C, and folate should be supplied in the diet in amounts to meet recommended daily allowances (RDA). However, pharmacologic doses should not be used because no current safety or efficacy data for their use in children in the treatment of dyslipidemia or prevention of cardiovascular disease are available.
In the rare patient with homozygous FH, the standard pharmacotherapy is triple therapy, which consists of a bile acid–binding resin, a statin, and a fibric acid derivative. In children aged 10 years and older, biweekly apheresis with plasma exchange for removal of LDL particles is helpful in lowering LDL-C levels. Although invasive and expensive, plasma exchange removes LDL particles, HDL particles, fibrinogen, and platelets. Liver transplantation is curative but has considerable morbidity and mortality. Suitable liver sources include cadaveric donors and living related donors who lack LDL-R mutations. Parents should not be donors because each parent is heterozygous for an LDL-R mutation. Liver transplantation could be considered when the risk of mortality from the disease exceeds the risk of dying from the liver transplant. However, the success of liver transplantation does pose important ethical controversies in transplantation for homozygous FH. Whether liver transplantation should be performed in children without clinical evidence of coronary heart disease or whether the surgeon should wait for clinical evidence of coronary heart disease to develop (eg, when the child is potentially a poor candidate for liver transplantation because of coronary heart disease) is controversial. Gene therapy for homozygous FH is in its infancy but may offer a potential cure in the future.
Pharmacotherapy to lower lipids is not indicated for type I HLP. However, in the future, high-dose vitamin antioxidant therapy may have a role in preventing pancreatic inflammation and chronic pancreatitis. In adults with type I HLP, high-dose antioxidants, including vitamin E, have been used in patients with recurrent pancreatitis. No data on the potential use of the oral lipase blocker orlistat (which may lower TG absorption and TG levels) are available.
Drugs used in adults include niacin and gemfibrozil.
Children with a strong family history of premature cardiovascular disease are not infrequently referred to the authors for evaluation and treatment; their predominant laboratory findings include low HDL-C levels and hypertriglyceridemia. When the TG level is 300 mg/dL or higher and HDL-C levels are less than 35 mg/dL with a family history of premature cardiovascular disease, pharmacotherapy (eg, niacin or fibric acid derivatives) is considered based on professional opinion. Treatment suggestions for types IV HLP and type V HLP are outlined below.
Management of Hypoalphalipoproteinemias (Low HDL-C Levels)In experimental studies, statins have been used to raise HDL-C levels in the absence of other lipid abnormalities; however, in the authors' opinion, isolated depressions in HDL-C concentrations in the pediatric population should not be treated with drugs.
Bile acid–binding resins are the initial drugs of choice for the treatment of type IIA HLP in children. Bile acid–binding resins are safe because they are not systemically absorbed and typically do not produce renal toxicity or hepatotoxicity. However, these drugs are not typically palatable; therefore, compliance is usually poor and prevents their widespread and long-term use in children with type IIA HLP. Bile acid–binding resins do not reduce LDL-C levels as effectively as statins do. Niacin is useful in various phenotypes (eg, HLP types IIA, IIB, or IV), although LDL-C levels are not lowered as effectively as through the use of statins. When treating children with type IIA HLP, the authors believe that it is prudent to discuss the advantages and disadvantages of each agent with their parents (see Media file 2). If the parent rejects bile acid–binding resins as first-line therapy for their child, the physician can offer niacin therapy. Niacin can also be offered if the child or parent accepts a trial of a bile acid–binding resin but compliance is poor or the LDL-C response is inadequate (eg, the LDL-C level remains >160 mg/dL) or the decline in LDL-C levels is only marginal (eg, the LDL-C declines <15-20%). Similar to bile acid–binding resins, a statin should be offered if compliance is poor with use of niacin, if the LDL-C response is inadequate (ie, the LDL-C level is >160 mg/dL), or if the decline in LDL-C is only marginal (eg, <15-20% decline in LDL-C level). Lovastatin, simvastatin, atorvastatin, and pravastatin appear to be equally efficacious and safe in children. In patients with type IIB HLP, niacin is the initial drug of choice. Physicians should avoid the use of bile acid–binding resins in patients with type IIB HLP because resin therapy can worsen hypertriglyceridemia. If niacin is ineffective or produces unacceptable adverse effects, either gemfibrozil or statin can be used (see Media file 3). MULTIMEDIASection 8 of 9
REFERENCESSection 9 of 9
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