Combined dyslipidemia in childhood

Journal of Clinical Lipidology (2015) -, -–-

Review Article

Combined dyslipidemia in childhood Rae-Ellen W. Kavey, MD, MPH* Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA KEYWORDS: Dyslipidemia; Combined dyslipidemia; Mixed dyslipidemia; Atherogenic dyslipidemia; Child; Adolescent; Obesity

Abstract: Combined dyslipidemia (CD) is now the predominant dyslipidemic pattern in childhood, characterized by moderate-to-severe elevation in triglycerides and non–high-density lipoprotein cholesterol (non-HDL-C), minimal elevation in low-density lipoprotein cholesterol (LDL-C), and reduced HDL-C. Nuclear magnetic resonance spectroscopy shows that the CD pattern is represented at the lipid subpopulation level as an increase in small, dense LDL and in overall LDL particle number plus a reduction in total HDL-C and large HDL particles, a highly atherogenic pattern. In youth, CD occurs almost exclusively with obesity and is highly prevalent, seen in more than 40% of obese adolescents. CD in childhood predicts pathologic evidence of atherosclerosis and vascular dysfunction in adolescence and young adulthood, and early clinical cardiovascular events in adult life. There is a tight connection between CD, visceral adiposity, insulin resistance, nonalcoholic fatty liver disease, and the metabolic syndrome, suggesting an integrated pathophysiological response to excessive weight gain. Weight loss, changes in dietary composition, and increases in physical activity have all been shown to improve CD significantly in children and adolescents in short-term studies. Most importantly, even small amounts of weight loss are associated with significant decreases in triglyceride levels and increases in HDL-C levels with improvement in lipid subpopulations. Diet change focused on limitation of simple carbohydrate intake with specific elimination of all sugar-sweetened beverages is very effective. Evidence-based recommendations for initiating diet and activity change are provided. Rarely, drug therapy is needed, and the evidence for drug treatment of CD in childhood is reviewed. Ó 2015 National Lipid Association. All rights reserved.

Definition and prevalence The pediatric obesity epidemic has resulted in a large population of children and adolescents with secondary combined dyslipidemia (CD), the combined dyslipidemia of obesity (CDO). This is now the predominant dyslipidemic pattern in childhood, with moderate-to-severe elevation in triglycerides (TGs) and non–high-density lipoprotein cholesterol (non-HDL-C), no or mild elevation in low-density lipoprotein cholesterol (LDL-C), and reduced HDL-C.1 Analysis by nuclear magnetic resonance * Corresponding author. University of Rochester Medical Center, 1475 East Ave, Ste 1, Rochester, NY 14610, USA. E-mail address: [email protected] Submitted February 24, 2015. Accepted for publication June 5, 2015.

1933-2874/Ó 2015 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2015.06.008

(NMR) spectroscopy shows that the CD pattern on standard lipid profile is represented at the lipid subpopulation level as both an increase in small, dense LDL and in overall LDL particle number plus a reduction in total HDL-C and in large HDL particles.2–4 High LDL particle number and elevated small, dense LDL particles have each been shown to predict clinical cardiovascular disease (CVD).5–11 The atherogenicity of high LDL particle number and small, dense LDL is complex and is thought to include the high concentration of circulating LDL particles, decreased binding of small, dense LDL particles to the LDL receptor, prolonged residence time in plasma and therefore prolonged arterial wall exposure, greater binding of small, dense LDL particles to arterial wall proteoglycans and increased susceptibility to oxidation.12–18 The association of the atherogenic lipoprotein subclass profile with obesity

2 in childhood has been recognized for many years.19 The CD pattern seen with traditional lipid profile analysis identifies the atherogenic pattern seen with lipid subpopulation analysis. National Health and Nutrition Examination Survey (NHANES) data indicate this pattern is highly prevalent, present in more than 40% of adolescents with body mass index (BMI) .95th percentile.20 Obesity is also highly prevalent, affecting 16.9% of American children and adolescents, with up to 85% of overweight adolescents becoming obese adults.21,22 In the short term, 50% of obese adolescents have at least one, and 10% have 3 or more cardiovascular risk factors, including CD, hypertension, and insulin resistance.23,24 In the long term, childhood obesity predicts type II diabetes mellitus, premature CVD, and early mortality.25 From NHANES data, the mean and median values of total cholesterol (TC), LDL-C, and glucose have remained unchanged over multiple successive cohorts of US children and adolescents, but there has been a significant increase in mean and median values of TG and a decrease in HDL-C.26 A subgroup of patients often seen with CDO are children and adolescents who are being treated with second-generation antipsychotic medications. These medications are being commonly and increasingly prescribed in the pediatric age group.27 Among these drugs, several are known to be associated with sudden and severe weight gain and with significant increases in TGs and TC and reductions in HDL-C.28 Taken together, these findings suggest that CD may become even more prevalent in the future. In addition to standard lipid profile measures, elevated non–HDL-C and the TG/HDL-C ratio have emerged as useful additional lipid measures in patients being evaluated for CDO. Non–HDL-C is a measure of the cholesterol content of all the plasma atherogenic lipoproteins. TC and HDL-C can be measured accurately in plasma from nonfasting patients with non–HDL-C calculated by subtracting HDL-C from TC.1 Epidemiologic studies show that childhood non–HDL-C correlates well with adult levels. In a longitudinal cohort of more than a 1000 subjects from the Bogalusa study, evaluated both as children ages 5 to 14 years and as adults 27 years later, non–HDL-C was a strong predictor of adult lipid levels independent of baseline BMI and BMI change.29 In pathology studies in children, adolescents and young adults, non–HDL-C and HDL-C levels were the best lipid predictors of pathologic atherosclerotic lesions, each significantly associated with fatty streaks in the thoracic aorta and abdominal aorta and in the right coronary artery and with raised lesions in all 3 sites; non–HDL-C and HDL-C levels were more strongly associated with pathologic lesions than any other lipid measure.30 Non–HDL-C and LDL-C measured in childhood were also significant predictors of subclinical atherosclerosis assessed by higher carotid intima media thickness (cIMT) measurements in adulthood.31 Overall, childhood non–HDL-C was as good, or better, than other lipoprotein measures in predicting subclinical atherosclerosis assessed subsequently by cIMT in adulthood.

Journal of Clinical Lipidology, Vol -, No -, - 2015 Non–HDL-C concentrations were also associated with the metabolic syndrome in 12- to 19-year olds assessed as part of NHANES.32 In adults, non–HDL-C has been shown to be a better independent predictor of CVD events than LDL-C.33,34 The recent National Heart, Lung and Blood Institute (NHLBI) guidelines include normative values for non–HDL-C and recommend screening with non–HDL-C in childhood.1 The TG/HDL-C ratio has been shown to be a strong predictor of coronary disease extent in adults and is considered to be a surrogate index of the atherogenicity of the plasma lipid profile.35,36 In children, an elevated TG/HDL-C ratio correlates with insulin resistance and with nonalcoholic fatty liver disease (NAFLD).37–39 In a study of normal weight, overweight, and obese white children and adolescents, top tertile TG/HDL-C correlated significantly with increased cIMT in multivariate analysis.39 There are ethnic differences in lipids and insulin resistance, which manifest during adolescence: AfricanAmericans have significantly lower TGs and higher HDLC levels, and this impacts non–HDL-C levels and the TG/HDL-C ratio.40–43 In a study of obese black and white adolescents, TG/HDL-C has been shown to be a surrogate marker for elevated small dense lipoprotein particles on NMR spectroscopic analysis.44 A TG/HDL-C ratio above 3 and non–HDL-C above 120 mg/dL in white subjects and TG/HDL-C ratio above 2.5 and non–HDL-C levels above 145 mg/dL in black subjects proved to be the best predictors of LDL-C particle concentration. In this study, the combination of waist circumference with TG/HDL-C ratio explained 79% of the variance in small LDL particle and total LDL particle burden.44 The HEALTHY study characterized lipids in a diverse population of 2384 sixth grade children and found that 33% of overweight/obese children had a TG/HDL-C ratio .3.0 and 11.2% had non–HDL-C .145 mg/dL.45 NMR spectroscopy confirmed that these values on standard lipid profile identified the lipid subpopulation pattern of increased total and small, dense LDL particles.46 CDO expressed as TG/HDL ratio correlated significantly with greater BMI, waist circumference, and insulin resistance. Normal lipid values in childhood are shown in Table 1.1 Based on 95th percentile values, normal TG levels are ,100 mg/dL in children younger than age 10 years and ,130 mg/dL at ages 10 to 18 years. Normal non–HDL-C levels are ,145 mg/dL. HDL-C averages 55 mg/dL in males and females before puberty, after which mean HDL-C drops to 45 mg/dL in males. The diagnosis of CD requires that among TC, LDL-C, TG, and non– HDL-C, the average of a least 2 measurements is above the 95th percentile, plus or minus HDL-C below the 5th percentile. In children or adolescents with CD, TG levels are usually between 150 and 400 mg/dL, HDL-C is w40 mg/dL, non–HDL-C is $145 mg/dL, and TG/ HDL-C ratio exceeds 3 in whites and 2.5 in blacks. In the literature, the terminology describing CD also includes ‘‘mixed dyslipidemia’’ and ‘‘atherogenic

Kavey

Combined dyslipidemia in childhood

3

Table 1 Acceptable, borderline, and high plasma lipid, lipoprotein, and apolipoprotein concentrations (mg/dL) for children and adolescents* Category

Acceptable

Borderline

High†

TC LDL-C Non–HDL-C TG 0–9 y 10–19 y

,170 ,110 ,120

170–199 110–129 120–144

.200 .130 $145

,75 ,90

75–99 90–129

.100 .130

Category

Acceptable

Borderline

Low†

HDL-C

.45

40–45

,40

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride. Values given are in mg/dL; to convert to SI units, divide the results for TC, LDL-C, HDL-C, and non–HDL-C by 38.6; for TG, divide by 88.6. *This table is taken from the 2011 NHLBI Expert Panel Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics 2011;128(Suppl 5):S213-256. †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.

dyslipidemia.’’47,48 CD is the term used most commonly in pediatrics. This is also the lipid profile pattern seen in individuals with the metabolic syndrome and with type I and type II diabetes. In diabetics, CD is increasingly prevalent as age increases and as glycemic control decreases. There is also substantial overlap in the lipid phenotype between CDO and familial combined hyperlipidemia (FCHL).49,50 Originally considered to be a genetically discrete entity, the diagnosis of ‘‘familial CD’’ now appears to be multigenic in etiology with expression unmasked or exacerbated by lifestyle factors, especially obesity.51,52 The FCHL classification includes a heterogenous group of disorders with an apparent genetic basis: FCHL, familial dyslipidemic hypertension, hyperapolipoproteinemia B, and LDL subclass pattern B. This is the most common lipid pattern seen in patients with coronary disease. As with CDO, the mechanism of increased CVD risk in FCHL is the presence of increased numbers of apolipoprotein B–containing particles, particularly small, dense LDL particles.53,54 Recently, the diagnosis of FCHL has been redefined, requiring hypertriglyceridemia and elevation of apolipoprotein B in the patient and in more than one family member and at least one individual in the first degree pedigree with premature coronary artery disease.55–57 The family history of dyslipidemia is frequently unknown in children and adolescents with CDO and apolipoprotein B levels are not routinely measured, so some patients presenting with this phenotype likely have FCHL.

Atherosclerotic pathology of CDO An important initiating step in atherosclerosis is subendothelial retention of LDL-containing lipoproteins.58 CD is highly atherogenic because of its subpopulation

composition with increased LDL particles and small dense LDL, associated with facilitated subendothelial retention by a number of mechanisms.12–18 In the obese, insulinresistant individual, increased free fatty acid levels stimulate hepatic overproduction of TG-rich lipoprotein particles, primarily very low–density lipoprotein (VLDL), clinically manifest as high TG. Insulin resistance reduces LDL secretion and promotes lipoprotein lipase dysfunction, further elevating TGs.59 Transfer of TG to LDL and HDL particles in exchange for cholesterol leads to smaller, denser, and more atherogenic particles because the TGenriched particles are an ideal substrate for hepatic TG lipase, which is upregulated in insulin resistance.60 In childhood, CD is associated with anatomic and histologic changes at autopsy and with structural and functional vascular changes in vivo. CD in childhood is predictive of accelerated atherosclerosis and of early cardiovascular events in adult life. In both the Pathobiological Determinants of Atherosclerosis in Youth Study and the Bogalusa Heart Study, high non–HDL-C and low HDLC were strongly associated with autopsy evidence of premature atherosclerosis.61–63 High TG and low HDL-C in youth are independent predictors of increased cIMT, especially in those with full metabolic syndrome.64–67 Obese youth with elevation in TG and low HDL-C have been shown to have thicker cIMT, higher pulse wave velocity (PWV), and increased carotid artery stiffness.68–70 A strong association between higher TG/HDL-C ratio, higher non–HDL-C, and higher PWV in both lean and obese children has been demonstrated, even after adjustment for other CVD risk factors.71 A recent report from the longitudinal Young Finns study revealed that at 21-year follow-up, subjects with the CD pattern beginning in childhood had significantly increased cIMT compared with normolipidemic controls, after adjustment for other risk factors; cIMT was further increased when the dyslipidemia occurred in the context of the metabolic syndrome.72 CD identified in childhood is associated with vascular damage measured in adulthood by cIMT and PWV.67,72,73 Most importantly, in the long-term Princeton Follow-up Study, elevated TG and TG/HDL-C ratio at a mean age of 12 years predicted clinical cardiovascular events at late follow-up 3 to 4 decades later.74,75 This is the first childhood lipid parameter shown to be associated with clinical CVD. Thus, the CD pattern seen with obesity in childhood and adolescence identifies pathologic evidence of atherosclerosis and vascular dysfunction in adolescence and young adulthood, and predicts early clinical events in adult life.

Pathogenetic mechanisms There is a tight connection between CDO, visceral adiposity, insulin resistance, non NAFLD, and the metabolic syndrome. In susceptible individuals, excessive weight gain in response to caloric excess occurs disproportionately as visceral fat. An increase in visceral adipose tissue is thought to reflect inability of the subcutaneous

Journal of Clinical Lipidology, Vol -, No -, - 2015

4 Table 2

Management of combined dyslipidemia (CD)/high TG Fasting lipid profile (FLP) x 2, average results

therapy*

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride. *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 low 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/wdms/admehg3.html.

adipose tissue depot to expand its storage capacity resulting in ectopic fat deposition, primarily in the viscera but also in the liver, heart, and skeletal muscle.76,77 There are known racial, ethnic, and familial/genetic differences in the tendency to develop visceral adiposity with Hispanic, Native-American, and Asian populations at elevated risk.78 Especially in Asians, increased visceral adiposity can develop in the absence of any other measure of adiposity, and this has been associated with insulin resistance and type II diabetes.79 Unlike subcutaneous adipose tissue, visceral adipose cells produce significant amounts of proinflammatory cytokines, which have been shown to disrupt normal insulin action in fat and muscle cells and may be a major factor in causing the insulin resistance observed in patients with visceral adiposity.80 Visceral adipose tissue also contributes significantly to CDO because of increased delivery of free fatty acids to the liver via the portal vein, shown to be proportionate to visceral fat mass.81 Insulin resistance has been considered to be a primary abnormality in development of CDO and associated CVD, and obesity has been shown to correlate with hyperinsulinemia in children, adolescents, and adults.23,82,83 In

the Bogalusa Heart Study, serial cross-sectional surveys showed that higher BMI was associated with higher fasting insulin levels in childhood and adolescence and with higher fasting glucose levels in young adulthood.84 Hyperinsulinemia enhances hepatic VLDL synthesis, clinically manifest as high TGs.85 At the tissue level, insulin resistance promotes lipoprotein lipase dysfunction, further elevating TGs.86 In a study of obese, normoglycemic adolescents and lean adolescents, insulin resistance and CDO were seen only in the obese subjects, and the dyslipidemia correlated with the degree of insulin resistance.87 Insulin resistance correlates with arterial stiffness in healthy adolescents and young adults but this relationship disappears when obesity is included in the analysis.88 In a hyperinsulinemic–euglycemic clamp study, elevated TG/HDL-C ratio identified in vivo insulin resistance.37 Thus, CDO correlates closely with insulin resistance. CDO is also strongly linked with NAFLD. NAFLD is defined as hepatic fat infiltration in .5% of hepatocytes on liver biopsy with no evidence of hepatocellular injury and no history of alcohol intake. NAFLD is strongly associated with obesity, affecting at least 38% of obese adolescents in autopsy series and w50% of obese adolescents in

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Combined dyslipidemia in childhood

epidemiologic surveys.89,90 On biochemical evaluation, the most common finding is mild-to-moderate elevation in serum alanine aminotransferase.91–93 Hepatic fat deposition usually occurs in the context of generalized obesity but much more strongly reflects the presence of increased visceral adiposity. In obese children and adolescents, sequential increase in waist circumference, a proxy measure of visceral fat, is associated with progressive increase in odds ratio for prediction of ultrasound-detected hepatic steatosis.93 NAFLD is strongly associated with insulin resistance and all the components of the metabolic syndrome.93–95 In a study of adolescents with biopsy-proven NAFLD, 80% had biochemical evidence of insulin resistance.94 Fat accumulation in the liver is a significant, obesity-independent predictor of type II diabetes mellitus in multiple prospective studies. The fatty liver is resistant to the actions of insulin to inhibit production of glucose and of VLDLs. This results in mild hyperglycemia, compensatory hyperinsulinemia, and hypertriglyceridemia with secondary lowering of HDL cholesterol. The CD pattern is seen on a standard lipid profile and with NMR analysis in more than half of patients with NAFLD.95 NAFLD has been shown to be a strong, independent predictor of CVD in adults.96,97 In children and adolescents, NAFLD is also associated with atherosclerosis at autopsy and with ultrasound vascular markers associated with atherosclerosis.98 CDO, insulin resistance, and visceral adiposity are each components of the metabolic syndrome, first described by Reaven in 1988 and identified as a high-risk constellation for atherosclerotic disease.99 In adults, the metabolic syndrome is defined as 3 or more of the following components: elevated waist circumference as a measure of visceral fat, elevated TG levels, reduced HDL-cholesterol, elevated BP, and/or impaired fasting glucose.100 NAFLD has been designated as the hepatic component of the metabolic syndrome.101 In the United States, the metabolic syndrome is reported in 23% of adults, including 7% of men and 6% of women in the 20- to 30-year-old age group.102,103 There is as yet no agreed-on definition for the metabolic syndrome in childhood, but analysis of cross-sectional data from NHANES (1988–1994) showed an overall prevalence of the metabolic syndrome cluster among adolescents aged 12 to 19 years of just under 10%.104,105 The syndrome cluster was present in 28.7% of obese adolescents compared with 0.1% of those with a BMI below the 85th percentile. As age and the degree of obesity increased, the prevalence of the metabolic syndrome cluster increased, reported in 38.7% of moderately obese (mean BMI, 33.4 kg/m2) and 49.7% of severely obese (mean BMI, 40.6 kg/m2) adolescents.105 Presence of the metabolic syndrome cluster at a mean of 12 years of age was an independent predictor of adult CVD 25 years later.106 Although there is continued debate about the definition of the metabolic syndrome in children and adolescents, there is strong consensus that the combination of CDO with visceral adiposity, insulin resistance, and NAFLD is a powerful predictor of cardiometabolic risk in children and adults.107

5 Table 3 Estimated calorie requirements (kcals) for gender and age groups at 3 levels of physical activity* Calorie requirements (kcals) by activity level†,‡,x Gender

Age (y)

Sedentary†

Moderately active‡

Activex

Child Female

2–3 4–8 9–13 14–18 19–30 4–8 9–13 14–18 19–30

1000 1200 1600 1800 2000 1400 1800 2200 2400

1000–1400 1400–1600 1600–2000 2000 2000–2200 1400–1600 1800–2200 2400–2800 2600–2800

1000–1400 1400–1800 1800–2200 2400 2400 1600–2000 2000–2600 2800–3200 3000

Male

Estimates are rounded to nearest 200 calories and were determined using the Institute of Medicine (IOM) equation. *These 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. †A 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. ‡Moderately 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. xActive 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.

Diagnosis of combined dyslipidemia In children and adolescents with overweight and obesity, the NHLBI guidelines recommend lipid screening when BMI .85th percentile is first identified.1 Screening is also recommended when any other major cardiovascular risk is present, when there is a family history of early CVD or of treated dyslipidemia. Universal screening is recommended at 9 to 11 years of age and again at 17 to 19 years of age, roughly equivalent to the senior year in high school. The initial screening test can be nonfasting or fasting. In the nonfasting condition, TC and HDL-C are measured; both are stable in the nonfasting state. These measures allow calculation of non–HDL-C from TC HDL-C. On a nonfasting test, non–HDL-C .145 mg/dL should be followed by a fasting lipid profile. If those results are normal, no further lipid evaluation is needed at that time, but these children should be included in the universal screening schedule. Alternatively, a fasting lipid profile can be used for screening. Lipid evaluation should also occur if a new cardiovascular risk develops in the child or adolescent and/or if the family history changes. If the first fasting lipid

Journal of Clinical Lipidology, Vol -, No -, - 2015

6 Table 4

Diet composition: healthy lifestyle/combined dyslipidemia/TG diet

These diet recommendations are those recommended for all healthy children over age 2 y from the NHLBI Guidelines with focus on limitation of simple carbohydrate intake.  Teach portions based on EER 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, and plain pasta), replacing with complex carbohydrates (brown rice, whole grain bread, and whole grain pasta).  Encourage dietary fish content.*  Fat content: B Total fat 25%–30% of daily kcal/EER; saturated fat #8% of daily kcal/EER; cholesterol ,300 mg/d; avoid trans fats as much as possible. B Monosaturated and polyunsaturated fat up to 20% of daily kcal/EER.  Encourage high dietary fiber intake from naturally fiber-rich foods (fruits, vegetables, and whole grains) with a goal of ‘‘age plus 5 g/d.’’ EER, estimated energy requirements; TG, triglyceride. *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/wdms/admehg3.html.

profile results are abnormal, this should be repeated after 2 weeks but before 3 months, and these results should be averaged. Normative values for all the lipid components are shown in Table 1, and levels above the 95th percentile requiring further management are identified. The algorithm from the guidelines for management of CD is shown in Table 2; management of elevated LDL-C is described completely in the 2011 NHLBI guidelines and in other articles in this issue.1 For the rare child with CD and severe hypertriglyceridemia in whom TGs consistently exceed 500 mg/dL and who is at risk for pancreatitis, treatment is also described in detail in the guidelines and in accompanying articles in this issue.1 When CD is diagnosed, careful assessment to identify coexisting factors that exponentiate risk for accelerated atherosclerosis is recommended. These include evaluation for diabetes using the recommendations from the American Diabetes Association108–111 and for NAFLD using current consensus-based guidelines.93

Management of combined dyslipidemia Lifestyle change Primary treatment for CD of obesity is lifestyle change, and this is often effective in the short term. The focus is on weight control and lowering TGs with a resultant, reciprocal increase in HDL-C. CD has been shown to be responsive to 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.112–114 Exercise training alone, when associated with a decrease in body fat, has also been shown to be associated with a significant decrease in TG levels, with reversion to baseline when children

became less active.115–118 A randomized controlled trial in obese children showed that a regular exercise schedule with 20 or 40 minutes of aerobic exercise 5 days per week significantly improved fitness and demonstrated dose-response benefits for insulin resistance and visceral adiposity.119 Changes in diet composition have also been effective treatment for CDO. In adults with hypertriglyceridemia, a low-carbohydrate, high-fat diet (40 percent carbohydrate, 39 percent total fat, 8 percent saturated fat, and 15 percent monounsaturated fat) significantly decreased TG by a mean of 63 percent, with associated mean increases in LDL-C of 22 percent and HDL-C of 8 percent.120 A subsequent highcarbohydrate, low-fat diet (54 percent carbohydrate, 28 percent total fat, 7 percent saturated fat, and 10 percent monounsaturated fat) significantly increased TG back to baseline levels. In children, a follow-up study of 21-month-old children with elevated TG levels treated with a carbohydrate-restricted diet showed a decrease in sugar and carbohydrate intake associated with a decrease in TG from a mean of 274.1 6 13.1 mg/dL before treatment to 88.8 6 13.3 mg/dL after 12 months.121 In an analysis of adolescents from NHANES, the US Department of Agriculture’s Center for Nutrition Policy and Promotion’s Healthy Eating Index was used to provide an overall picture of dietary quality relative to the metabolic syndrome constellation of central obesity, elevated TG, elevated BP, reduced HDL-C level, and impaired fasting glucose level.122 There was a significant inverse association between the overall Healthy Eating Index score plus the fruit intake score and the prevalence of the metabolic syndrome components including elevated TG. There was also a trend toward lower prevalence of the metabolic syndrome components in adolescents with high activity levels, although this was not significant. Glycemic load has also been evaluated in the setting of obesity and CD in adolescents and

Kavey

Table 5

DASH-style eating plan: servings per day by food group and total energy intake 1200 Calories

1400 Calories

1600 Calories

1800 Calories

2000 Calories

2600 Calories

Grains*

4–5

5–6

6

6

6–8

Vegetables

3–4

3–4

3–4

4–5

Fruits

3–4

4

4

Fat-free or low-fat milk and milk products

2–3

2–3

2–3

Lean meats, poultry, and fish

3 or less

3–4 or less 3–4 or less

Nuts, seeds, and legumes

3 per week

3 per week

3–4 per week 4 per week

4–5 per week 1

Fats and oilsx

1

1

2

2–3

Serving sizes

Examples and notes

10–11

1 slice bread; 1 oz dry cereal; 1/2 cup cooked rice; pasta; or cereal†

4–5

5–6

1 cup raw leafy vegetable, 1/2 cup cut-up raw or cooked vegetable, 1/2 cup vegetable juice

4–5

4–5

5–6

1 medium fruit, 1/4 cup dried fruit, 1/2 cup fresh, frozen, or canned fruit, 1/2 cup fruit juice

2–3

2–3

3

1 cup milk or yogurt, 1 1/2 oz cheese

6 or less

6 or less

6 or less 1 oz cooked meats, poultry, or fish, 1 egg‡

Whole-wheat bread and rolls, whole-wheat pasta, English muffin, pita bread, bagel, cereals, grits, oatmeal, brown rice, unsalted pretzels and popcorn Broccoli, carrots, collards, green beans, green peas, kale, lima beans, potatoes, spinach, squash, sweet potatoes, tomatoes Apples, apricots, bananas, dates, grapes, oranges, grapefruit, grapefruit juice, mangoes, melons, peaches, pineapples, raisins, strawberries, tangerines Fat-free milk or buttermilk; fat-free, low-fat, or reduced-fat cheese; fat-free/low-fat regular or frozen yogurt Select only lean; trim away visible fats; broil, roast, or poach; remove skin from poultry Almonds, filberts, mixed nuts, peanuts, walnuts, sunflower seeds, peanut butter, kidney beans, lentils, split peas

2–3

3

Significance of food group to DASH eating plan Major sources of energy and fiber

Rich sources of potassium, magnesium, and fiber

Combined dyslipidemia in childhood

Food group

Important sources of potassium, magnesium, and fiber

Major sources of calcium and protein

Rich sources of protein and magnesium

Rich sources of energy, 1/3 cup or 1 1/2 oz nuts, magnesium, protein, 2 tbsp peanut butter, 2 and fiber tbsp or 1/2 oz seeds, 1/2 cup cooked legumes (dried beans, peas) 1 tsp soft margarine, 1 tsp Soft margarine, vegetable DASH study had 27% of calories as fat, oil (canola, corn, olive, vegetable oil, 1 tbsp including fat in or safflower), low-fat mayonnaise, 2 tbsp added to foods mayonnaise, light salad salad dressing dressing

7

(continued on next page)

Journal of Clinical Lipidology, Vol -, No -, - 2015

oz, ounce; tbsp, tablespoon; tsp, teaspoon. *Whole grains are recommended for most grain servings as a good source of fiber and nutrients. †Serving sizes vary between 1/2 cup and 1 1/4 cups, depending on cereal type. Check product’s Nutrition Facts label. ‡Two egg whites have the same protein content as 1 oz meat. xFat content changes serving amount for fats and oils. For example, 1 tbsp regular salad dressing 5 1 serving; 1 tbsp low-fat dressing 5 one-half serving; 1 tbsp fat-free dressing 5 zero servings.

Sweets should be low in 1 tbsp sugar, 1 tbsp jelly Fruit-flavored gelatin, fat fruit punch, hard candy, or jam, 1/2 cup sorbet, jelly, maple syrup, gelatin dessert, 1 cup sorbet and ices, sugar lemonade #2 5 or less 5 or less per week per week Sweets and 3 or less 3 or less 3 or less added sugars per week per week per week

1200 Calories Food group

Table 5

(continued )

1400 Calories

1600 Calories

1800 Calories

2000 Calories

2600 Calories

Serving sizes

Examples and notes

Significance of food group to DASH eating plan

8

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.123 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.123–126 In adolescents, a low-carbohydrate diet with or without weight loss has been shown to significantly reduce TG levels.127–129 These lifestyle change interventions have been shown to significantly reduce TG, non– HDL-C and TG/HDL-C ratio, and lead to an improvement in LDL subpopulation pattern.130,131 There are no trials of CDO evaluating clinical cardiovascular events in response to lifestyle changes initiated in childhood. However, better vascular health in adults can be related to healthy childhood risk status and behaviors, as shown in the Bogalusa Heart Study and in the Cardiovascular Risk in Young Finns study, where sustained low-risk status and healthy diet from childhood to adulthood was associated with thinner cIMT.132,133 In adults, a small number of studies have shown that lifestyle interventions improve subclinical vascular measures, specifically PWV.134,135 Interventional studies to improve vascular health in youth are limited; one small study of a 1-year weight loss intervention in prepubertal children found that those subjects who were successful in weight loss had a decrease in cIMT.136 Based on this evidence, primary recommended treatment for CDO and for related insulin resistance and NAFLD is weight loss.1 A comprehensive but straightforward weight management approach can be initiated in the pediatric, gynecologic, family practice, or subspecialty medicine setting and a suggested plan derived from the evidence-based NHLBI guidelines is described here. The process begins with calculation of appropriate energy intake for age, gender, and activity level by using Table 3.1 Then, the diet from the NHLBI guidelines recommended for children and adolescents with high TG is prescribed, matching these energy requirements (Table 4). The diet is focused on limitation of simple carbohydrate intake with specific elimination of all sugar-sweetened beverages including fruit juice. Simple carbohydrates like sugars, baked goods, white rice, white bread, and plain pasta are replaced with complex carbohydrates like brown rice, whole grain bread, and whole grain pasta. Foods high in natural fiber are encouraged with a goal of age plus 5 g of fiber per day.1 For all dietary change in children and adolescents, initial family-based training with a registered dietitian has been shown to be the most effective way to both begin and sustain change.137–140 As part of the NHLBI guidelines, the DASH diet was modified for use in childhood. This simple diet plan is rich in fruits and vegetables, low-fat or fat-free dairy products, whole grains, fish, poultry, beans, seeds, and nuts, and very low in sweets and added sugars (Table 5).1 The diet plan is

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Table 6 Activity recommendations for obese children and adolescents  Take activity and screen time history at each visit.  Prescribe moderate-to-vigorous activity* 1 h every day, with vigorous intensity physical activity† on 3/7 d.  Combined leisure screen time should not exceed 2 h/d.  Match physical activity recommendations with energy intake (Table 3).  No television in 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.

organized by servings per day by food group and by total energy intake with content matched to the guideline recommendations for management of CDO. A regular exercise schedule is prescribed, simultaneous with the diet recommendations. Based on the recommendations from the NHLBI guidelines and coincident with Physical Activity Guidelines for Americans, all children and adolescents should be involved in 60 minutes (1 hour) or more of physical activity daily (Table 6).1,141 Most of the 60 minutes should be either moderate- or vigorous-intensity aerobic physical activity, with vigorous-intensity physical activity at least 3 days a week. This level of aerobic activity is compatible with the results of the randomized controlled trial in obese children, which showed that a regular exercise schedule with 20 or 40 minutes of aerobic exercise 5 days per week significantly improved fitness and demonstrated dose-response benefits for insulin resistance and general and visceral adiposity.118 In the trial, exercise was supervised. To allow for variations in compliance in the typically unsupervised ‘‘real-world’’ setting, an hour of moderate-tovigorous activity is recommended every day of the week. Any kind of aerobic activity is useful, but weight bearing activity is most effective. To promote compliance with the activity recommendations, a discussion about the kind of exercise setting that will be easiest for each child should be undertaken and specific follow-up of activity at subsequent evaluations is necessary. A combined diet and activity approach to weight loss like this has been shown to be effective in management of CDO.112,113 Weight loss can be an emotional issue for obese children and their families so an alternative approach aimed at changing diet composition and activity without a direct approach to weight loss can be used. The same diet change and activity recommendations described previously are prescribed, but there is no calculation of caloric needs and no specific focus on weight loss. This approach has been shown to be successful in addressing all the cardiometabolic risks in case series and in randomized trials, particularly when combined with cognitive behavioral therapy.128,142–154

9 Application of these simple recommendations with infrequent monitoring has been associated with weight loss and improvement in CDO and the other cardiometabolic risk factors in obese adolescents. However, there are no data to this time evaluating the lipid subpopulation or vascular response to lifestyle change in CD in adolescents and there are no studies of long-term lifestyle change. When a 6month trial of lifestyle approach is unsuccessful, the 2011 NHLBI guidelines recommend that referral to a multidisciplinary weight loss program should be considered.1

Medication therapy for CDO Information on drug therapy for treatment of CDO in children is extremely limited. Most previous research using drug treatment to address dyslipidemia in childhood has focused on children with isolated high LDL-C, usually in the context of heterozygous familial hypercholesterolemia (FH). In adults with CDO, statin therapy has been shown to beneficially alter the standard lipid and LDL particle profiles and to improve multiple measures of vascular function and clinical cardiovascular outcomes.155–165 In children, statin treatment has been shown to effectively lower LDL-C levels and in a small number of studies, to improve LDL-C subpopulation characteristics on NMR analysis.166,167 Statins are also known to be antiinflammatory, which may be important in the proinflammatory state associated with obesity.168 A recent systematic review and meta-analysis of statin therapy in children with FH analyzed studies that included almost 800 children.169 Statin therapy decreased LDL-C by 20% to 50% but change in TGs was much less consistent, ranging from an increase of 9% to a decrease of 20%. Adverse effects from statins are rare at standard doses but include most commonly, myopathy and hepatic enzyme elevation. In the meta-analysis of statin use in children, no statistically significant differences were found between statintreated and placebo-treated children for the occurrence of any adverse events, including problems with sexual development, muscle toxicity, or liver toxicity.168 Specific guidance for initiation of statin therapy and monitoring on treatment from the NHLBI guidelines are provided in Table 7.1 There are no pediatric trials assessing clinical outcomes with statin therapy, but there have been 2 pediatric trials of statin treatment that assessed impact on vascular measures. Treatment of children with FH, who have predominantly LDL-C elevations, with simvastatin normalized endothelial function compared with normal control subjects.170 Another trial of children with FH showed regression of cIMT for those treated with pravastatin, whereas those who received placebo showed the expected age-related progression.171 There are as yet no published studies examining statin effects on vascular health (PWV or cIMT) in children or adolescents with CDO.

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10 Table 7

Recommendations for use of HMG-CoA reductase inhibitors (statins) in children and adolescents

1. Include preferences of patient and family in decision making about use of statin medications. 2. In general, do not start treatment with statins before age 10 y. Patients with high-risk family history, high-risk conditions, or multiple risk factors might be considered for medication initiation before 10 y of age. 3. Precaution/contraindication with potentially interactive medications (cyclosporine, niacin, fibric acid derivatives, erythromycin, azole antifungals, nefazodone, many human immunodeficiency virus [HIV] protease inhibitors). Check for potential interaction with all current medications at baseline. 4. Conduct baseline hepatic panel and creatine kinase (CK) before initiating treatment. Initiation and titration: 1. Choice of particular statin is a matter of preference. Clinicians are encouraged to develop familiarity and experience with one of the statins, including dosage regimen and potential drug–drug interactions. 2. Start with the lowest dose once daily, usually at bedtime. Atorvastatin and rosuvastatin can be taken in the morning or evening because of their long half-lives. 3. Review baseline CK, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). 4. Instruct the patient to report all potential adverse effects, especially muscle cramps, weakness, asthenia, and more diffuse symptoms suggestive of myopathy. 5. Advise female patients about concerns with pregnancy and the need for appropriate contraception. 6. Advise about potential future medication interactions, especially cyclosporine, niacin, fibric acid derivatives, erythromycin, azole antifungals, nefazodone, and HIV protease inhibitors. Check for potential interaction whenever any new medication is initiated. 7. Whenever potential myopathy symptoms present, stop medication and assess CK; determine relation to recent physical activity. The threshold for worrisome level of CK is 10 times above the upper limit of reported normal, considering the impact of physical activity. Monitor the patient for resolution of myopathy symptoms and any associated increase in CK. Consideration can be given to restarting the medication once symptoms and laboratory abnormalities have resolved. 8. After 4 wk, measure fasting lipid profile (FLP), ALT, and AST and compare with laboratory-specific reported normal values.  The threshold for worrisome levels of ALT or AST is $3 times the upper limit of reported normal.  Target levels for LDL-C: minimal ,130 mg/dL; ideal ,110 mg/dL. 9. If target LDL-C levels are achieved and there are no potential myopathy symptoms or laboratory abnormalities, continue therapy and recheck FLP, ALT, and AST in 8 wk and then 3 mo. 10. If laboratory abnormalities are noted or symptoms are reported, temporarily withhold the medication and repeat the blood work in 2 wk. When abnormalities resolve, the medication may be restarted with close monitoring. 11. If target LDL-C levels are not achieved, increase the dose by 1 increment (usually 10 mg) and repeat the blood work in 4 wk. If target LDL-C levels are still not achieved, dose may be further increased by one increment or another agent (bile acid sequestrant or cholesterol absorption inhibitor) may be added under the direction of a lipid specialist. Maintenance monitoring: 1. Monitor growth (height, weight, and BMI relative to normal growth charts), sexual maturation, and development. 2. Whenever potential myopathy symptoms present, stop medication and assess CK. 3. Monitor fasting lipoprotein profile, ALT, and AST every 3–4 mo in the first year, every 6 mo in the second year and beyond, and whenever clinically indicated. 4. Monitor and encourage compliance with lipid-lowering dietary and medication therapy. Serially assess and counsel for other risk factors, such as weight gain, smoking, and inactivity. 5. Counsel adolescent females about statin contraindications in pregnancy and the need for abstinence or use of appropriate contraceptive measures at every encounter. Use of oral contraceptives is not contraindicated if medically appropriate. Seek referral to an adolescent medicine or gynecologic specialist as appropriate. BMI, body mass index; LDL-C, low-density lipoprotein cholesterol.

Omega-3 fish oil therapy has been shown to be safe in adults, with some trials reporting that TG levels decreased by as much as 30% to 45%, with significant associated increases in HDL-C.172 However, more recent reports have not shown a conclusive benefit of fish oil treatment.173–175 Two recently published randomized controlled trials of omega-3 fish oil in adolescents showed a minimal decrease in TG levels but no change in LDL particle number or size, suggesting no significant benefit of fish oil treatment in children with CDO.176,177 In adults, fibrates have been used effectively and safely to lower TG levels, alone and in combination with

statins.178–181 Fibrates are peroxisome proliferatoractivated receptors agonists and act in the liver to reduce cholesterol synthesis, reduce secretion of very low–VLDLs and increase the removal of VLDLs from the blood, consequently lowering plasma TGs (by 30%–50%) and, to a lesser extent, LDL-C (reduction of 0%–30%). They increase HDL-C (by 2%–20%) by increasing apoA-I and apoA-II gene transcription. Fibrate therapy has been shown to alter LDL subclass distribution with an increase in LDL size and a decrease in LDL particles plus an increase in small HDL subclass particles.182 A meta-analysis showed fibrate therapy significantly decreased the incidence of

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nonfatal myocardial infarction but did not affect all-cause mortality.183 Meta-analyses of recent clinical trial data suggest that fibrates are effective in reducing CVD events in the subgroup of patients with atherogenic dyslipidemia or CDO.184,185 Adverse effects of fibrate therapy include a variety of gastrointestinal and dermatologic symptoms and abnormal liver function tests and cholelithiasis. There have been rare cases of myositis and rhabdomyolysis, but these have almost always occurred when fibrates are combined with statin therapy.177,179,180 In children, treatment with fibrates in a single small randomized trial (n 5 14) and 3 case series (n 5 7, n 5 17, and n 5 47) documents significant TG lowering by as much as 54% with an associated 17% increase in HDL-C.186–189 One child in a case series was thought to have myositis on clinical grounds with no reported laboratory changes.188 There were mild, transient elevations in alanine aminotransferase and aspartate aminotransferase (AST) in 2 subjects in another case series.186 No other potentially adverse effects were reported. There are no long-term trials of fibric acid derivatives in children and no studies of the vascular or clinical response to treatment. Niacin (nicotinic acid) has been used for more than 30 years to treat lipid abnormalities. The mechanism by which it alters lipid profiles is complex and includes partial inhibition of release of free fatty acids from adipose tissue and increased lipoprotein lipase activity with decreased rate of hepatic synthesis of VLDL and LDL-C. Niacin lowers total and LDL-C levels but even more impressively, decreases TGs, and raises HDL-C.190 In theory, niacin should be an effective treatment for CD. In long-term studies from the prestatin era, nicotinic acid vs placebo significantly reduced the incidence of cardiovascular events and the rate of atherosclerosis progression.191 However, recent studies in which niacin was compared with placebo in patients already treated with statin to ideal LDL-C levels, showed no efficacy for the primary end point of a composite cardiovascular event despite significantly increased HDL-C levels.192,193 There were significantly more serious adverse events in the niacin group including diagnosis of diabetes, gastrointestinal symptoms, flushing/ itching/rash, infection, and bleeding. Experience with niacin in children is limited to a single case series, which demonstrated a very high rate of side effects leading to discontinuation.194 Despite its theoretical appeal, there are no current recommendations for use of niacin to treat CD in childhood. In summary, studies have shown that in children with FH, statins improve LDL-C subpopulation characteristics on NMR analysis.165,166 The anti-inflammatory effects of statins could also be beneficial in the inflammatory state associated with obesity.167 There is substantial evidence that statins as a group are safe and well tolerated in children.168 Despite concern about hepatic side-effects with statin treatment, current evidence suggests that statins are safe in patients with NAFLD and may improve liver function tests.194 Based on this evidence, statin therapy appears

11 to be the logical first choice for treatment of CDO, which is not responsive to lifestyle change. The guidelines recommend a 6-month trial of diet and activity change before any consideration of drug therapy, as outlined in the algorithm in Table 2. If after 6 months, TGs exceed 200 mg/ dL but are less than 500 mg/dL, the guidelines suggest initiation of omega-3 fish oil therapy. However, the guidelines were published before the 2 recent randomized pediatric trials that showed no significant benefit from fish oil treatment. In patients with CD in whom the LDL-C target is achieved but non–HDL-C exceeds 145 mg/dL, drug therapy with a statin is recommended. The NHLBI guidelines provide very specific guidance for initiation and maintenance of statin therapy in children and adolescents (Table 7).1 Preliminary evidence also suggests that fibrates may potentially be effective. Use of fibrates in youth should be undertaken only with the assistance of a lipid specialist.

Conclusion In youth, CD is a prevalent and highly atherogenic lipid disorder, almost always associated with obesity. Primary therapy is lifestyle change, and this is often very effective. When drug therapy is needed, statin medications are the drug of choice, and these have an excellent safety record in children and adolescents.

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