Lipoproteins

Identifying Dyslipidemia in Children

         In the past decade, cardiovascular disease (CVD) risk factors have been increasingly recognized in children. More children are overweight, and obesity in the pediatric population is now considered a major U.S. health problem. Increased obesity rates are attributed to an imbalance between energy intake and energy expenditure. Children’s diets today include many foods with a high number of calories and low nutrient value, and children tend to be less physically active. Because we now know that the atherosclerotic process begins in youth and culminates with the development of vascular plaques in the third and fourth decades of life, these trends raise major concerns about the future health of overweight children.

To identify cardiovascular risk factors in children, pediatricians are increasingly using lab measurements of lipid biomarkers to identify dyslipidemia. Characterized by the elevation of total cholesterol (TC), LDL-C and/or triglycerides (TG) or low levels of HDL-C, dyslipidemia contributes to the development of atherosclerosis. Causes of dyslipidemia may be primary (genetic) or secondary.

While dyslipidemia seldom results in adverse clinical outcomes during childhood, epidemiologic studies conducted longitudinally demonstrate that cholesterol levels in children track into adulthood (1). Similarly, children whose TC was above the 90th percentile on two occasions had a positive predictive value for elevated TC (≥200 mg/dL or 5.2 mmol/L) in early adulthood of 76% for females and 81% for males (2). Such data suggest that it is possible to identify children who are likely to continue to have high TC levels as adults. Furthermore, longitudinal studies of childhood LDL-C levels also predict the thickness of the intima-media of the carotid artery, a non-invasive marker of atherosclerosis, in young adults (3,4).

But research also shows that good nutrition, a physically active lifestyle, and absence of tobacco use can lower an individual’s risk and delay or prevent the onset of CVD. Therefore, identifying children who are at risk is important to preventing health problems later in life. Here we describe the most recent recommendations for assessing lipids and lipoproteins in children.

Lipid and Lipoprotein Primer

Cholesterol and triglycerides are transported in the body in lipoprotein particles associated with apolipoproteins and phospholipids. Table 1 summarizes the four main classes of lipoproteins and their primary apolipoproteins and lipid components. LDL-C is the primary transporter of cholesterol in blood, and HDL plays an important role in reverse cholesterol transport. Particles called chylomicrons carry TG from the gut that originate from an individual’s diet, and very low-density lipoprotein (VLDL) carries TG from the liver.

Table 1 Lipoprotein Classification
Lipoprotein	Apolipoprotein	Lipid
Low density lipoprotein (LDL-C)	ApoB-100	Cholesterol
High density lipoprotein (HDL-C)	ApoA-I; ApoA-II	Cholesterol
Chylomicron	ApoB-46	ApoB-46
Very low density lipoprotein (VLDL)		Triglyceride

Dyslipidemia in Childhood

Dyslipidemias are disorders of lipoprotein metabolism resulting in abnormal excesses of TC, LDL-C, or TG, or deficiency of HDL-C. Large epidemiologic studies indicate that children’s lipid levels correlate with those of adult family members. Furthermore, children of parents with coronary heart disease (CHD) have a higher prevalence of dyslipidemia.

Genetic Dyslipidemia

Familial hypercholesterolemia (FH) is a monogenic disorder in which the LDL-receptor is defective, resulting in high LDL-C levels. The rare homozygous form results in markedly elevated LDL-C, as high as 575–965 mg/dL or 15–25 mmol/L. Physical signs include planar and tendon xanthomas and corneal arcus by 10 years of age and clinical evidence of CAD by the second decade of life (5). More common is the heterozygous form, with a population frequency of approximately 1 in 500. Children with heterozygous FH have elevated LDL-C (154–386 mg/dL or 4.0-10.0 mmol/L) and early vascular changes (6) that may regress with lipid-lowering therapy (7).

Although those with heterozygous FH are generally asymptomatic in childhood, these children may develop tendon xanthomas in the second decade of life. By 65 years of age, 50% of these females will develop CVD if the FH is left untreated; among males, this will occur 10 years sooner. Children with heterozygous FH are most easily identified if there is a family history of dyslipidemia or coronary artery disease. Recommendations for treatment of these children from an expert panel of the American Heart Association (AHA) include lowering saturated and trans-fats in the diet, increased physical activity, counseling to reduce other risk factors, and lipid-lowering therapy (Table 2) (8).

Table 2 Recommended Interventions for Children with Heterozygous Familial Hypercholesterolemia
Intervention Type	Parameter	Target
Dietary	< 30% calories from fat < 7% calories from saturated fat no trans fat	< 200 mg/dL total cholesterol
Physical Activity	Active play > 1 h/d Screen time < 2 h/d
Other CV Risk Factors	Assess and counsel: blood pressure cigarette smoking glycemic status
Pharmacotherapy	Consider statin therapy if : male patient is at least 10 years old, female patient has undergone menarche, LDL-C persists at ≥4.9 mmol/L or ≥4.2 mmol/L with other CV risk factor(s) or family history of PCAD	< 3.35 mmol/L or 130mg/dL LDL-C
Source: Reference 8.

A number of other genetic dyslipidemias are less common in children. For example, familial combined hyperlipidemia is commonly observed in adults but rarely youths. An autosomal dominant disorder with variable presentation within the same family, affected individuals have elevated LDL-C and apolipoprotein B levels and may have elevated TG levels.

Rare genetic forms of hypertriglyceridemia have also been recognized. Some monogenic disorders, such as lipoprotein lipase deficiency, result in marked TG elevation (fasting TG>5 mmol/L) and/or chylomicronemia, and they may be associated with pancreatitis in childhood.

Familial Obesity

The classic dyslipidemia associated with obesity includes elevated fasting TG levels and suppressed HDL-C levels. Therapy includes diet, lifestyle changes, and implementation of a heart-healthy lifestyle to assist the individual and the family. This type of dyslipidemia is often clustered with other CVD risk factors such as hypertension and dysglycemia. This cluster of factors, also called the metabolic syndrome, is associated with a 14-fold increased risk of clinical CVD by 50 years of age, highlighting the importance of early recognition and treatment of this disorder (9).

Secondary Causes of Dyslipidemia

In addition to obesity and the primary disorders resulting in dyslipidemia, numerous other clinical conditions are recognized causes of dyslipidemia in children. Important secondary causes include diabetes, hypothyroidism, chronic renal insufficiency or renal failure, and liver disease. Medications that adversely influence the lipid profile include retinoids used for the treatment of acne in youth, glucocorticoids, estrogen, progestins, and ß-blockers.

Lipid Measurements

Laboratory measurements of lipids should follow good quality control procedures. The National Cholesterol Education Program (NCEP) has developed criteria for the analytical performance of cholesterol assays. In addition, the CDC’s Cholesterol Reference Method Laboratory Network (CRMLN) certifies clinical diagnostic products that measure TC, HDL-C, and LDL-C. The FDA has recognized the value of the CRMLN’s certification program and encourages manufacturers to certify their products through the CRMLN. Today, TC measurements on most analyzers meet the NCEP’s 1992 criteria of 3% bias versus the reference method and imprecision. CDC’s Division of Laboratory Sciences also maintains lists of the clinical diagnostic products that have been certified by the CRMLN that can be found on the CDC Web site.

Various methods are available to determine HDL-C, but the direct method is the most widely used. This method typically involves the selective measurement of HDL-C after shielding cholesterol in the non-HDL fractions. While direct homogeneous methods for assessing LDL-C are available on many automated analyzers, most laboratories continue to calculate LDL-C by the Friedewald equation, which is based on routinely measured TC, HDL-C, and TG. The NCEP recommends that LDL-C be calculated using one of the following equations:

LDL-C (mg/dL) = TC – HDL-C – TG/5

or

LDL-C (mmol/L) = TC – HDL-C – TG/2.2

Labs can use these equations to calculate LDL-C levels except when the TGs are very high or when the sample is obtained under non-fasting conditions. At very high concentrations (400 mg/dL or 4.52 mmol/L), TG/5 or TG/2.2, which is an estimate of VLDL, will not be valid due to the presence of chylomicrons. The Friedewald equation is also not valid for patients with Type III hyperlipoproteinemia. The enzymatic measurement of TG is standardized to the methylene chloride-salicylic acid chromotropic reference method of the CDC.

Screening for Dyslipidemia in Youth

Population-wide screening for dyslipidemia in children is not currently recommended. However, the AHA recommends screening children who are most likely to have dyslipidemia or who are at increased risk of CVD (8). The two primary target groups are children with genetic dyslipidemias, often identified by a family history of hyperlipidemia and/or premature coronary artery disease (CVD onset at < 55 years of age in male relatives, < 65 years of age in female relatives), and children who are obese.

In addition, the 2006 scientific statement from AHA recommends lipid screening profiles for children with a number of pediatric disorders that increase their risk of CVD in young adulthood (8). Diabetes type 1 and 2, Kawasaki disease with coronary aneurysms, and chronic and end-stage renal disease may predispose children to very early coronary events. Hyperglycemia in type 1 diabetes is a primary mediator of atherosclerosis, while in type 2 diabetes, both hyperglycemia and insulin resistances are implicated in endothelial dysfunction. In children with chronic kidney disease, morbidity and mortality is related not only to the kidney disease but also to CVD. The recommendations and goals for intervention have been tailored to risk (2).

Table 3 Classification of CVD Risk in Children
	Total Cholesterol		LDL-Cholesterol
	mg/dL	mmol/L	mg/dL	mmol/L
Acceptable	< 170	4.40	< 110	2.85
Borderline	170–199	4.4–5.15	110–129	2.85–3.34
High	> 200	5.15	> 130	3.34
Source: References 10 and 11.

Target Values

Elevated LDL-C is the most clinically significant marker of dyslipidemia in children and is used as the basis for treatment. Table 3 (above) summarizes the NCEP (10) and American Academy of Pediatrics (AAP) (11) classification categories based on TC and LDL-C levels. A major concern among pediatric care givers has been that a single cutoff value does not reflect the changes associated with sex, growth, and maturation.

The Lipid Research Clinics (LRC) Prevalence study also defined target values for TC. This 1972–1976 study, sponsored by the National Heart, Lung, and Blood Institute, used fasting samples from a cross-sectional survey of various North American populations. More age-specific and sex-specific data from the LRC prevalence data are shown in Table 4. Levels above the 95th percentile are considered abnormal.

Table 4 Lipid Prevalence Data by Age
Total Cholesterol
Age (years)	Males				Females
	75th		95th		75th		95th
	mg/dL	mmol/L	mg/dL	mmol/L	mg/dL	mmol/L	mg/dL	mmol/L
5–9	168	4.34	189	4.89	176	4.55	197	5.09
10–14	173	4.47	202	5.22	171	4.42	205	5.30
15–19	168	4.34	191	4.94	176	4.55	207	5.35
LDL-Cholesterol
Age (years)	Males				Females
	75th		95th		75th		95th
	mg/dL	mmol/L	mg/dL	mmol/L	mg/dL	mmol/L	mg/dL	mmol/L
5–9	103	2.66	129	3.34	115	2.97	140	3.62
10–14	109	2.82	132	3.41	110	2.84	135	3.52
15–19	109	2.82	130	3.36	111	2.87	137	3.54
Source: Reference 12.

More recently, researchers developed age- and sex-specific lipoprotein threshold concentrations for adolescents 12–20 years of age based on data from the National Health and Nutrition Examination Surveys (NHANES) (13). They linked the cut points to the adult health-based thresholds for abnormal lipoproteins. Using the NHANES database for risk stratification may be problematic, however, as it does not take into account the measurement variability of lipids and lipoproteins. Until the clinical applicability of these threshold concentrations has been more thoroughly investigated, single measurements on at least two different occasions are recommended to establish an individual’s cholesterol value.

Although AAP recommends measuring HDL-C in children with hypercholesterolemia, its usefulness in managing risk is also not clear. A target value of < 5th percentile (< 40mg/dL or 1.04 mmol/L) is considered low.

Measurement of Apolipoproteins in Children

Measurement of apolipoproteins for predicting CVD risk in children is controversial. Recent studies in adults have suggested that apolipoprotein B may be superior to LDL-C in vascular disease risk prediction and that the apo-B/apo A-1 ratio may be superior to TC/HDL-C as an overall index. Apo A-1 is the major structural protein of HDL. On the other hand, apo-B is mostly associated with LDL, but it is also a component of chylomicrons, VLDL, IDL, and lipoprotein(a). In general, apo-B levels may be useful to guide therapy, but its use in managing dyslipidemia in adults is still discretionary.

Researchers have also studied apolipoprotein levels in children 4 years of age and older in a population from NHANES III (14,15). Measuring apoB levels has the advantage of not requiring the patient to fast, and in one study researchers demonstrated that it was a better screening tool than TC for identifying elevated LDL-C in youth (15). However, medical groups have not reached a consensus on using apolipoproteins to screen for dyslipidemia in children. Further investigation will be needed before any consensus can be reached.

Avoiding CVD in the Future

Based on the knowledge that atherosclerosis begins in youth and that childhood elevated cholesterol levels usually persist into adulthood, identifying dyslipidemia in children is important for prevention of the vascular changes associated with increased CVD risk later in life. Currently the management of hypercholesterolemia is aimed at reducing LDL-C, and appropriate age-related target values for intervention have been recommended. The appropriate use of HDL-C and apolipoproteins in managing risk requires further investigation.

REFERENCES

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2. Lauer RM, Clarke WR. Use of cholesterol measurements in childhood for the prediction of adult hypercholesterolemia. The Muscatine Study. JAMA 1990;264(23):3034–3038.
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