Dyslipidemia and Pediatric Obesity

Abstract

Cardiovascular disease is the leading cause of death in the United States despite a steady reduction in mortality over the last 4 decades. Much of this success is attributed to public health efforts to reduce cardiovascular risk factors, such as national dietary changes and reductions of smoking, as well as more aggressive treatment of clinical disease, including recognition and treatment of hypertension and hypercholesterolemia. The rising rates of obesity and diabetes, especially among adolescents and young adults, raise concern for impending increases in mortality due to these two factors. Some national vital statistics data have shown a leveling of CVD death rates among adults in the fifth decade of life. Major public health efforts have recently begun to address childhood obesity now as an attempt at true primary prevention. This article reviews the dyslipidemia associated with obesity in childhood and outlines a proposed approach to management.

Introduction

Cardiovascular disease (CVD) remains the leading cause of death in the United States despite a steady reduction in mortality over the last 4 decades, attributed to public health efforts to reduce cardiovascular risk factors and more aggressive treatment of clinical disease.(1) Concealed in the reduced overall mortality are increasing mortality rates due to obesity and diabetes.(1) When CVD mortality in young adults ages 35–54 yr is considered separately, there is an unsettling plateau in the net rate of CVD deaths that can be traced to the steady rise in childhood obesity and diabetes over the last 4 decades.(2) This is being interpreted as the leading edge of a new wave of cardiovascular disease (CVD) mortality.(3) Current adolescent overweight is forecast to increase future adult obesity by 5% to 15% by 2035, resulting in more than 100,000 excess prevalent cases of CVD.(4)

Concern about clinical events in middle aged and older adults has been the primary focus in cardiovascular disease but research over the past 2 decades has clearly shown that the atherosclerotic process has its beginnings in childhood.(5,6) The natural history of hypercholesterolemia in pediatrics has traditionally focused on the identification of children and adolescents with severe elevation in total (TC) and LDL cholesterol (LDL-C) levels, usually Familial Heterozygous Hypercholesterolemia (FH) (7,8). This lipid pattern occurs in 1 in 500 individuals and is inherited as an autosomal dominant. It is not associated with obesity. Children with FH have severely elevated TC and LDL-C levels from birth, and are at established high risk for premature cardiovascular disease.(7,8) The focused approach on children with severe LDL elevation in the context of FH comes from the desire to identify youth and young adults who are at greatly elevated risk for premature coronary artery disease.(7) However, the number of children with LDL elevations who meet criteria for drug treatment is small. Ford et al., reported the rate of hypercholesterolemia from a nationally representative sample of US adolescents from 1999–2006 (9) using the defined levels from the last NHLBI guidelines for management of hypercholesterolemia in childhood published in 1992 (7) (TC ≥ 200 mg/dL and LDL-C ≥ 130 mg/dL) and found 5.2% with elevated LDL-C and 10.7% with elevated TC. They next examined the proportion of US adolescents with an elevated LDL-C that would trigger pharmacological treatment based on recent AAP recommendations (9):1) LDL-C > 190 mg/dL with no other risk factors (likely genetic origin); 2) LDL-C > 160 mg/dL with ≥ 2 additional risk factors (obesity, hypertension, smoking or family history of premature CVD); and 3) LDL-C >130 mg/dL among youth with diabetes mellitus. Only 0.8% of US teens had an LDL-C value elevated enough to consider starting drug treatment, and among these, less than half had LDL-C > 190 mg/dL.(9) From these findings, the number of children who will meet criteria for drug treatment for hypercholesterolemia is small.

Trends and Prevalence in Obesity among Pediatric Populations

Unfortunately, the pediatric obesity epidemic has resulted in a second and much larger population of children with abnormal lipids, those with secondary combined dyslipidemia. Childhood obesity rates have tripled in the past 30 years with now as many as 17% of US adolescents and 16% of US children, 2–11yrs of age, defined as obese.(11) Alarmingly, prevalence rates among Black and Hispanic children and adolescents in the US are even higher.(11) Severe obesity is formally defined by the 2007 CDC/AMA/HHS Childhood Obesity Expert Committee Recommendations as a BMI > 99^th percentile for age. In a recent report from a national sample of US children and adolescents (12), almost 4%, or nearly 2.7 million of today’s youth were severely obese.. This study also examined the change in the prevalence of severe obesity from the 1980s to present, and found alarming disparities with Hispanic and African American children and adolescents, as well as those in the lowest poverty group showing the greatest increase in rates of severe obesity over the last 3 decades.

Abdominal obesity is a special concern because of its known association with insulin resistance and the metabolic syndrome. In adults, the metabolic syndrome is defined as 3 or more of the following risk factors: elevated waist circumference, triglyceride levels, BP, and/or fasting glucose, and reduced HDL-cholesterol. In the U.S., the metabolic syndrome is said to affect between 34% and 39% of adults including 7% of men and 6% of women in the 20- to 30-year old age group. As yet, there is no consensus on use of the diagnosis of the metabolic syndrome in children but the cluster of findings seen in adults often occurs with obesity in children.(13) In the first study to define the metabolic syndrome among U.S. adolescents, abdominal obesity (defined as by waist circumference above the >90^th percentile for age/gender) was found to be strongly associated with other cardiovascular risk factors defined in the metabolic syndrome, as in adults.(14) Li et al, examined changes in measures of abdominal obesity from NHANES data in 2 national cohorts of US children from 1988–1994 and from 1999–2004. (15) Waist circumference had increased at a relatively higher rate than BMI over that time period. Mean waist circumference for the population had increased from 2% to 8% depending on age and gender. Comparing these 2 cohorts, the overall relative increase in abdominal obesity for boys was 65.4% (10.5% to 17.4%) and for girls, 69.4% (10.5% to 17.8%). This is important when considering the implications of abdominal obesity for identifying overweight or obese youth who may also have increased visceral fat. Visceral fat is strongly associated with the atherogenic dyslipidemia seen in the metabolic syndrome and insulin resistance. The rate of the metabolic syndrome found among US teens has also increased along with this trend in abdominal obesity.(15)

Pathophysiology of Dyslipidemia and Pediatric Obesity

Childhood obesity appears with a powerful array of cardiovascular risk factors including combined dyslipidemia, insulin resistance and hypertension(17) and has been shown to be associated with pathologic evidence of accelerated atherosclerosis in autopsy studies in this age group.(18) The dyslipidemia pattern associated with childhood obesity consists of a combination of elevated triglycerides (TG), decreased high density lipoprotein cholesterol (HDL-C), and top normal to mildly elevated low density lipoprotein cholesterol (LDL-C).(8) Normal lipid values in childhood have been developed from major epidemiologic studies including the Bogalusa Heart Study and the Lipid Research Clinics Study and are shown in Table 1.(7,8) Normal TG levels are <100 mg/dL in children younger than age 10 years and <130 mg/dL at ages 10–18 years.(7,8) In the dyslipidemia associated with obesity, TG levels are usually between 100 and 400 mg/dL.(8) Recent NHANES data indicate this pattern is highly prevalent, present in 42.9%of children with BMI>95^th%ile.(19) Insulin resistance, another common feature in obese children and adolescents, contributes significantly to development of the combined dyslipidemia of obesity by enhancing hepatic delivery of nonesterified free fatty acids for triglyceride (TG) production and sequestration into triglyceride-rich lipoproteins. (20) High TG levels are processed into small, dense LDL and small, less stable HDL; there is both an increase in small, dense LDL and in overall LDL particle number and a reduction in total HDL-C and in large HDL particles with analysis by nuclear magnetic resonance spectroscopy (NMR). (21, 22) The combined dyslipidemia pattern seen with traditional lipid profile analysis identifies the atherogenic pattern seen with NMR analysis. (20)

Table 1.

Acceptable, Borderline High, and High Plasma Lipid and Lipoprotein Concentrations (mg/dL) for Children and Adolescents^*

Category	Acceptable	Borderline High	High†
Total Cholesterol	<170	170–199	≥200
LDL–Cholesterol	<110	110–129	≥130
Triglyceride:
0–9 years	<75	75–99	≥100
10–19 years	<90	90–129	≥130

Category	Acceptable	Borderline High	Low†
HDL–Cholesterol	>45	40–45	<40

NOTE: Values given are in mg/dL. To convert to SI units, divide the results for total cholesterol (TC), low-density lipoprotein cholesterol (LDL–C), high-density lipoprotein cholesterol (HDL–C), and non-HDL–C by 38.6; for triglycerides (TG), divide by 88.6.

^*Values for plasma lipid and lipoprotein levels are from the National Cholesterol Education Program (NCEP) Expert Panel on Cholesterol Levels in Children.(7) Non-HDL–C values are from the Bogalusa Heart Study and are equivalent to the NCEP Pediatric Panel cut points for LDL–C.

^†The cut points for high and borderline high represent approximately the 95th and 75th percentiles, respectively. Low cut points for HDL–C represent approximately the 10th percentile.

The root cause of atherogenesis remains subendothelial retention of LDL-containing lipoproteins.(23) The combined dyslipidemia of obesity is particularly atherogenic for multiple reasons: small dense LDL particles are inefficiently cleared by LDL receptors elevated total circulating LDL particles heighten the risk of entrapment in the subendothelial matrix, and decreased large HDL particles limit reverse cholesterol transport. (24,25) The atherogenicity of the combined dyslipidemia seen with childhood obesity manifests in structural and functional vascular changes assessed non-invasively as increased carotid intima-media thickness (cIMT) and increased arterial stiffness(26,27). In adults, combined dyslipidemia is the most prevalent pattern seen in individuals presenting with early clinical cardiovascular events.(21,28–30) In children, a recent report from the longitudinal Young Finns study revealed that, at 21-year follow-up, subjects with the combined dyslipidemia pattern beginning in childhood had significantly increased cIMT compared with normolipidemic controls, even after adjustment for other risk factors; cIMT was further increased when the dyslipidemia occurred in the context of the metabolic syndrome.(31) A paper from the CDC evaluated multiple CVD risk factors in US children, specifically, systolic blood pressure, fasting glucose and components of the lipid profile (32). The mean and median values of TC, LDL-C and glucose remained unchanged over multiple cohorts of US children and adolescents. However, over successive cohorts, there was a significant increase in mean and median values of TG and SBP and a decrease in HDL-C, all components of the metabolic syndrome cluster. So, whether you believe in the metabolic syndrome as a separate entity or not, pediatric lipid profiles are qualitatively worse, even if TC and LDL-C levels have not increased. Thus, the combined dyslipidemia pattern seen with obesity in childhood is increasing in prevalence and predicts vascular dysfunction in young adulthood and early clinical events in adult life.

Lifestyle Management of Combined Dyslipidemia

Treatment for combined dyslipidemia of obesity is primarily lifestyle change and this is often highly effective. Combined dyslipidemia has been shown to be very responsive to even small changes in weight status, diet composition, and activity. Most importantly, in obese children, adolescents and adults, even small amounts of weight loss are associated with significant decreases in TG levels and increases in HDL–C levels.(33–37) Even without weight loss, exercise training is associated with a significant decrease in TG levels and an increase in HDL-C, with reversion to baseline when subjects became less active.(35,38–40) A diet that limits both simple carbohydrate intake and calories addresses both combined dyslipidemia and obesity. In adults with hypertriglyceridemia, diet patterns like this significantly decreased TG by a mean of 63 percent and increased HDL–C by 8 percent.(41,42) In adolescents, a low-carbohydrate diet associated with minimal weight loss significantly reduced TG levels.(43) A 12-month follow-up study of 21-month-old children with elevated TG levels treated with a carbohydrate-restricted diet showed that a decrease in sugar and carbohydrate intake was associated with a very significant decrease in TG levels from a mean of 274.1 +/− 13.1 mg/dL before treatment to 88.8 +/− 13.3 mg/dL, within normal limits.(44) The concept of glycemic load has also been evaluated in the setting of obesity and combined dyslipidemia in adolescents and adults. The glycemic index is a measure of the blood glucose response to a 50 g portion of a selected carbohydrate; the glycemic load is the mathematic product of the glycemic index and the carbohydrate amount. In adolescents and young adults, there is evidence that low glycemic-load diets are at least as effective as low-fat diets in achieving weight loss, with decreased TG and increased HDL in subjects on the low glycemic-load diet.(45–48) For all dietary change in children and adolescents, family-based training with a registered dietitian has been shown to be the most effective way to both begin and sustain change. A straightforward approach using a diet low in simple carbohydrates and sugar with controlled calories and a regular exercise schedule is shown in Tables 2, 3 and 4 and in Figure 1; the latter was derived from forthcoming NHLBI guidelines for management of cardiovascular risk factors in childhood. (49) This is usually all that is necessary to address combined dyslipidemia in most obese children and adolescents.

Table 2.

DIET COMPOSITION: Healthy Lifestyle / Combined Dyslipidemia Diet

These diet recommendations are those recommended for all healthy children over age 2 with specific differences focused on appropriate portion size and limitation of simple carbohydrate intake. Teach portions based on estimated energy requirements for age/gender/activity level.(Table 4) Primary beverage: Fat-free unflavored milk No sugar-sweetened beverages; encourage water intake. Limit refined carbohydrates (sugars, baked goods, white rice, white bread, plain pasta), replacing with complex carbohydrates (brown rice, whole grain bread, whole grain pasta). Encourage dietary fish content* Fat content: Total fat 25–30% of daily kcal/EER Saturated fat </= 8% of daily kcal/EER Avoid trans fats as much as possible Monounsaturated and polyunsaturated fat up to 20% of daily kcal/ EER Cholesterol <300 mg/d Encourage high dietary fiber intake from naturally fiber-rich foods (fruits, vegetables, whole grains) with a goal of “age plus 5 g/d.”

^***The Food and Drug Administration (FDA) and the Environmental Protection Agency are advising women of childbearing age who may become pregnant, pregnant women, nursing mothers, and young children to avoid some types of fish and shellfish and eat fish and shellfish that are lower in mercury. For more information, call the FDA’s food information line toll free at 1–888–SAFEFOOD or visit http://www.cfsan.fda.gov/~dms/admehg3.html.

Table 3.

ACTIVITY RECOMMENDATIONS FOR OBESE CHILDREN: (56,57)

Take activity and screen time history from child and parent(s) at each visit In children over age 6 y, prescribe moderate to vigorous activity 1 h/d, with vigorous intensity physical activity** on 3/7 days Combined leisure screen time should not exceed 2 h/d Match physical activity recommendations with energy intake (Table 4) No TV in child’s bedroom

^*Examples of moderate to vigorous physical activities are walking briskly or jogging.

^**Examples of vigorous physical activities are running, playing singles tennis or soccer.

Table 4. Estimated Calorie Requirements (in Kilocalories [kcal]) for Gender and Age Groups at Three Levels of Physical Activity^a (58).

Estimates are rounded to nearest 200 calories and were determined using the Institute of Medicine (IOM) equation.

		Activity Level b,c,d
Gender	Age (years)	Sedentaryb	Moderately Activec	Actived
Child	2–3	1,000	1,000–1,400e	1,000–1,400e
Female	4–8 9–13 14–18 19–30	1,200 1,600 1,800 2,000	1,400–1,600 1,600–2,000 2,000 2,000–2,200	1,400–1,800 1,800–2,200 2,400 2,400
Male	4–8 9–13 14–18 19–30	1,400 1,800 2,200 2,400	1,400–1,600 1,800–2,200 2,400–2,800 2,600–2,800	1,600–2,000 2,000–2,600 2,800–3,200 3,000

^aThese levels are based on Estimated Energy Requirements from the IOM Dietary Reference Intakes macronutrients report (2002), calculated by gender, age, and activity level for reference-size individuals. "Reference size," as determined by the IOM, is based on median height and weight for ages up to age 18 years and median height and weight for that height to give a body mass index of 21.5 for adult females and 22.5 for adult males.

^bA sedentary activity level in childhood, as in adults, means a lifestyle that includes only the light physical activity associated with typical day-to-day life.

^cModerately active in childhood means a lifestyle that includes some physical activity, equivalent to an adult walking about 1.5 to 3 miles per day at 3 to 4 miles per hour, in addition to the light physical activity associated with typical day-to-day life.

^dActive means a lifestyle that includes more physical activity, equivalent to an adult walking more than 3 miles per day at 3 to 4 miles per hour, in addition to the light physical activity associated with typical day-to-day life.

^eThe calorie ranges shown recognize the needs of different ages within the group. For growing children and adolescents, more calories are needed at older ages.

Figure 1.

ALGORITHM FOR MANAGEMENT OF COMBINED DYSLIPIDEMIA/ HIGH TG (49)

Drug Therapy for Combined Dyslipidemia

In the rare child with combined dyslipidemia and severe hypertriglyceridemia for whom diet and exercise interventions are insufficient, there are nutriceutical and medication options that can be considered. The TG level and the timing for consideration of more advanced therapy are outlined in the algorithm (Figure 1). A recent systematic review demonstrated that omega-3 fish oil capsules are both safe and effective in adults, reducing TG by 30–45 percent, with significant associated increases in HDL–C.(50) For children, the safety of omega-3 fish oil was observed in their use in children with immunoglobulin A nephropathy and in a small series of children with dyslipidemia.(51) Because fish oil preparations are marketed directly to the public, pediatric care providers can expect to encounter children who are taking these supplements and should be prepared to offer guidance about their use. There are many generic forms of fish oil capsules that are commercially available. The University of Wisconsin maintains a preventive cardiology patient education Web site http://www.heartdecision.org. The “fish oil” section includes information about the content of various preparations. The Web site is updated every 6 months (https://www.heartdecision.org/chdrisk/v_hd/patient_edu_docs/Fish_Oil_11-2007.pdf). There is one FDA approved omega-3 fish oil preparation called Lovaza. Each capsule contains 1 gram of fish oil with a recommended dose of 4 grams/d, given either all at once or as 2 grams bid. At the recommended dosage, there are almost no reported side effects for fish oil preparations except a fishy after taste and increased burping. In some studies, there has been a 5 – 10% dose-related increase in LDL-C levels. Allergic reactions can occur in individuals who have allergies to fish. The statin medications have been studied in adults with combined dyslipidemia and have been shown to reduce total LDL particle numbers and to selectively decrease small, dense LDL.(52) One trial in children with familial hypercholesterolemia showed similar results with a significant decrease in total LDL particle number and in small, dense LDL concentration.(53) In adults, fibrates have been used to lower TG levels, and a small series in children demonstrated effective reductions in TG levels and an associated increase in HDL–C levels.(54) Finally, niacin has been used extensively in adults, but there is limited experience in children, with a single series demonstrating a high rate of side effects.(55) The use of any medication except omega-3 fish oil in youths with combined dyslipidemia should be undertaken only with the assistance of a lipid specialist.

Conclusion

The prevalence of obesity has continued to rise over the past 3 decades. The obesity epidemic is already impacting the cardiovascular health of today’s adults in their 30s and 40s. In children, obesity - especially abdominal obesity - is strongly associated with insulin resistance and with a high prevalence of the atherogenic combined dyslipidemia described here. While these cardiometabolic abnormalities have not resulted in measurable increases in total or LDL cholesterol, adult and pediatric data have revealed qualitative changes in LDL and HDL cholesterol associated with elevated measures of atherosclerosis among adolescents and with clinical disease in adults. A focused, family-based approach to management of these lipid abnormalities is critical and will require randomized trials of enhanced lifestyle approaches that will result in evidence-based treatment strategies.

Abbreviations

NHANES

National Health and Nutrition Examination Survey

CVD

cardiovascular disease

TC

Total Cholesterol

HDL-C

high density lipoprotein

LDL-C

low density lipoprotein

TG

Triglycerides