Dyslipidemia and Pediatric Obesity

Cardiovascular disease is the leading cause of death in the United States despite a reduction in mortality over the past 4 decades. Much of this success is attributed to public health efforts and more aggressive treatment of clinical disease. The rising rates of obesity and diabetes, especially among adolescents and young adults, raise concern for increases in mortality. National vital statistics have shown a leveling of cardiovascular disease death rates in the fifth decade of life. Public health efforts have begun to address childhood obesity. This article reviews the dyslipidemia associated with obesity in childhood and outlines a proposed approach to management.

Cardiovascular disease (CVD) remains the leading cause of death in the United States despite a steady reduction in mortality over the past 4 decades, attributed to public health efforts to reduce cardiovascular risk factors and more aggressive treatment of clinical disease. Concealed in the reduced overall mortality are increasing mortality rates due to obesity and diabetes. When CVD mortality middle age adults, ages 35 to 54 years 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 past 4 decades. This is interpreted as the leading edge of a new wave of CVD mortality. 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.

Concern about clinical events in middle-aged and older adults has been the primary focus in CVD but research over the past 2 decades has shown that the atherosclerotic process has its beginnings in childhood. Management of hypercholesterolemia in pediatrics has traditionally focused on the identification of children and adolescents with severe elevation in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels, usually familial hypercholesterolemia (FH). This lipid pattern occurs in 1 in 500 individuals and is inherited as 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 CVD. 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. The number of children with LDL elevations, however, who meet criteria for drug treatment is small. Ford and colleagues reported the rate of hypercholesterolemia from a nationally representative sample of US adolescents from 1999 to 2006, using the defined levels from the last National Heart, Lung, and Blood Institute (NHLBI) guidelines for management of hypercholesterolemia in childhood published in 1992 (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 pharmacologic treatment based on recent American Academy of Pediatrics recommendations : (1) LDL-C greater than 190 mg/dL with no other risk factors (likely genetic origin); (2) LDL-C greater than 160 mg/dL with greater than or equal to 2 additional risk factors (obesity, hypertension, smoking, or family history of premature CVD); and (3) LDL-C greater than 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 greater than 190 mg/dL. From these findings, the number of children who 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 as many as 17% of US adolescents and 16% of US children, 2 to 11 years of age, defined as obese. Alarmingly, prevalence rates among black and Hispanic children and adolescents in the United States are even higher. Severe obesity is formally defined by the 2007 Centers for Disease Control (CDC)/American Medical Association/Department of Health and Human Services childhood obesity expert committee recommendations as a body mass index (BMI) greater than the 99th percentile for age. In a recent report from a national sample of US children and adolescents, 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 past 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 (TG) levels, blood pressure, fasting glucose, and reduced high-density lipoprotein cholesterol (HDL-C). In the United States, the metabolic syndrome is said to affect between 34% and 39% of adults, including 7% of men and 6% of women in the 20-year-old 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. In the first study to define the metabolic syndrome among US adolescents, abdominal obesity (defined as by waist circumference above the 90th percentile for age/gender) was found to be strongly associated with other cardiovascular risk factors defined in the metabolic syndrome, as in adults. Li and colleagues examined changes in measures of abdominal obesity from National Health and Nutrition Examination Survey (NHANES) data in 2 national cohorts of US children from 1988 to 1994 and from 1999 to 2004. Waist circumference had increased at a higher rate than BMI during 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%–17.4%) and for girls 69.4% (10.5%–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.

Pathophysiology of dyslipidemia and pediatric obesity

Childhood obesity appears with a powerful array of cardiovascular risk factors, including combined dyslipidemia, insulin resistance, and hypertension, and has been shown to be associated with pathologic evidence of accelerated atherosclerosis in autopsy studies in this age group. The dyslipidemia pattern associated with pediatric obesity consists of a combination of elevated TGs, decreased HDL-C, and top normal to mildly elevated LDL-C. 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 . Normal TG levels are less than 100 mg/dL in children younger than age 10 years and less than 130 mg/dL at ages 10 to18 years. In the dyslipidemia associated with obesity, TG levels are usually between 100 and 400 mg/dL. Recent NHANES data indicate this pattern is highly prevalent, present in 42.9% of children with BMI greater than the 95th percentile. 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 TG production and sequestration into TG-rich lipoproteins. 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. The combined dyslipidemia pattern seen with traditional lipid profile analysis identifies the atherogenic pattern seen with nuclear magnetic resonance spectroscopy analysis.

Table 1
Acceptable, borderline high, and high plasma lipid and lipoprotein concentrations (mg/dL) for children and adolescents a
Category Acceptable Borderline High High b
Total cholesterol <170 170–199 ≥200
LDL–C <110 110–129 ≥130
Triglyceride
0–9 years <75 75–99 ≥100
10–19 years <90 90–129 ≥130
Category Acceptable Borderline high Low b
HDL-C >45 40–45 <40
To convert to SI units, divide the results for TC, LDL-C, HDL-C, and non–HDL-C by 38.6; for TGs, divide by 88.6.

a Values for plasma lipid and lipoprotein levels are from the National Cholesterol Education Program (NCEP) “Expert Panel on Blood Cholesterol Levels in Children and Adolescents.” Non–HDL-C values are from the Bogalusa Heart Study and are equivalent to the NCEP pediatric panel cutpoints for LDL-C.

b The cutpoints for high and borderline high represent approximately the 95th and 75th percentiles, respectively. Low cutpoints for HDL-C represent approximately the 10th percentile.

The root cause of atherogenesis remains subendothelial retention of LDL-containing lipoproteins. 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. The atherogenicity of the combined dyslipidemia seen with childhood obesity manifests in structural and functional vascular changes assessed noninvasively as increased carotid intima-media thickness (cIMT) and increased arterial stiffness. In adults, combined dyslipidemia is the most prevalent pattern seen in individuals presenting with early clinical cardiovascular events. In children, a recent report from the longitudinal Cardiovascular Risk in 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. An article from the CDC evaluated multiple CVD risk factors in US children, specifically, systolic blood pressure, fasting glucose, and components of the lipid profile. The mean and median values of TC, LDL-C, and glucose remained unchanged over multiple cohorts of US children and adolescents. Over successive cohorts, however, there was a significant increase in mean and median values of TGs and systolic blood pressure and a decrease in HDL-C, all components of the metabolic syndrome cluster. So, whether or not the metabolic syndrome is considered a separate entity, 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.

Pathophysiology of dyslipidemia and pediatric obesity

Childhood obesity appears with a powerful array of cardiovascular risk factors, including combined dyslipidemia, insulin resistance, and hypertension, and has been shown to be associated with pathologic evidence of accelerated atherosclerosis in autopsy studies in this age group. The dyslipidemia pattern associated with pediatric obesity consists of a combination of elevated TGs, decreased HDL-C, and top normal to mildly elevated LDL-C. 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 . Normal TG levels are less than 100 mg/dL in children younger than age 10 years and less than 130 mg/dL at ages 10 to18 years. In the dyslipidemia associated with obesity, TG levels are usually between 100 and 400 mg/dL. Recent NHANES data indicate this pattern is highly prevalent, present in 42.9% of children with BMI greater than the 95th percentile. 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 TG production and sequestration into TG-rich lipoproteins. 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. The combined dyslipidemia pattern seen with traditional lipid profile analysis identifies the atherogenic pattern seen with nuclear magnetic resonance spectroscopy analysis.

Table 1
Acceptable, borderline high, and high plasma lipid and lipoprotein concentrations (mg/dL) for children and adolescents a
Category Acceptable Borderline High High b
Total cholesterol <170 170–199 ≥200
LDL–C <110 110–129 ≥130
Triglyceride
0–9 years <75 75–99 ≥100
10–19 years <90 90–129 ≥130
Category Acceptable Borderline high Low b
HDL-C >45 40–45 <40
To convert to SI units, divide the results for TC, LDL-C, HDL-C, and non–HDL-C by 38.6; for TGs, divide by 88.6.

a Values for plasma lipid and lipoprotein levels are from the National Cholesterol Education Program (NCEP) “Expert Panel on Blood Cholesterol Levels in Children and Adolescents.” Non–HDL-C values are from the Bogalusa Heart Study and are equivalent to the NCEP pediatric panel cutpoints for LDL-C.

b The cutpoints for high and borderline high represent approximately the 95th and 75th percentiles, respectively. Low cutpoints for HDL-C represent approximately the 10th percentile.

The root cause of atherogenesis remains subendothelial retention of LDL-containing lipoproteins. 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. The atherogenicity of the combined dyslipidemia seen with childhood obesity manifests in structural and functional vascular changes assessed noninvasively as increased carotid intima-media thickness (cIMT) and increased arterial stiffness. In adults, combined dyslipidemia is the most prevalent pattern seen in individuals presenting with early clinical cardiovascular events. In children, a recent report from the longitudinal Cardiovascular Risk in 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. An article from the CDC evaluated multiple CVD risk factors in US children, specifically, systolic blood pressure, fasting glucose, and components of the lipid profile. The mean and median values of TC, LDL-C, and glucose remained unchanged over multiple cohorts of US children and adolescents. Over successive cohorts, however, there was a significant increase in mean and median values of TGs and systolic blood pressure and a decrease in HDL-C, all components of the metabolic syndrome cluster. So, whether or not the metabolic syndrome is considered a separate entity, 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.

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Oct 3, 2017 | Posted by in PEDIATRICS | Comments Off on Dyslipidemia and Pediatric Obesity

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