Journal of Clinical Lipidology (2015) 9, S41S56

Combined dyslipidemia in childhood

Rae-Ellen W. Kavey, MD, MPH*

Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA

KEYWORDS: Abstract: Combined dyslipidemia (CD) is now the predominant dyslipidemic pattern in childhood,
Dyslipidemia; characterized by moderate-to-severe elevation in triglycerides and nonhigh-density lipoprotein
Combined dyslipidemia; cholesterol (non-HDL-C), minimal elevation in low-density lipoprotein cholesterol (LDL-C), and
Mixed dyslipidemia; reduced HDL-C. Nuclear magnetic resonance spectroscopy shows that the CD pattern is represented
Atherogenic dyslipidemia; at the lipid subpopulation level as an increase in small, dense LDL and in overall LDL particle number
Child; plus a reduction in total HDL-C and large HDL particles, a highly atherogenic pattern. In youth, CD
Adolescent; occurs almost exclusively with obesity and is highly prevalent, seen in more than 40% of obese ado-
Obesity lescents. 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 lim-
itation 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.
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 dyslipi-
demic pattern in childhood, with moderate-to-severe
elevation in triglycerides (TGs) and nonhigh-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: rekavey@gmail.com
Submitted February 24, 2015. Accepted for publication June 5, 2015.
(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.24 High LDL particle number
and elevated small, dense LDL particles have each been
shown to predict clinical cardiovascular disease (CVD).511
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 pro-
longed arterial wall exposure, greater binding of small,
dense LDL particles to arterial wall proteoglycans and
increased susceptibility to oxidation.1218 The association
of the atherogenic lipoprotein subclass profile with obesity

1933-2874/ 2015 National Lipid Association. All rights reserved.

http://dx.doi.org/10.1016/j.jacl.2015.06.008
S42
in childhood has been recognized for many years.19 The
CD pattern seen with traditional lipid profile analysis iden-
tifies the atherogenic pattern seen with lipid subpopulation
analysis. National Health and Nutrition Examination Sur-
vey (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, prema-
ture 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
nonHDL-C and the TG/HDL-C ratio have emerged as
useful additional lipid measures in patients being evaluated
for CDO. NonHDL-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 nonHDL-C calculated by sub-
tracting HDL-C from TC.1 Epidemiologic studies show that
childhood nonHDL-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, nonHDL-C was a
strong predictor of adult lipid levels independent of base-
line BMI and BMI change.29 In pathology studies in
children, adolescents and young adults, nonHDL-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; nonHDL-C and HDL-C levels were more
strongly associated with pathologic lesions than any other
lipid measure.30 NonHDL-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 nonHDL-C was as good, or better, than
other lipoprotein measures in predicting subclinical athero-
sclerosis assessed subsequently by cIMT in adulthood.
Journal of Clinical Lipidology, Vol 9, No 5S, October 2015
NonHDL-C concentrations were also associated with the
metabolic syndrome in 12- to 19-year olds assessed as
part of NHANES.32 In adults, nonHDL-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
nonHDL-C and recommend screening with nonHDL-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).3739 In a
study of normal weight, overweight, and obese white chil-
dren and adolescents, top tertile TG/HDL-C correlated
significantly with increased cIMT in multivariate anal-
ysis.39 There are ethnic differences in lipids and insulin
resistance, which manifest during adolescence: African-
Americans have significantly lower TGs and higher HDL-
C levels, and this impacts nonHDL-C levels and the
TG/HDL-C ratio.4043 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 nonHDL-C above 120 mg/dL in white subjects
and TG/HDL-C ratio above 2.5 and nonHDL-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
nonHDL-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 corre-
lated 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 nonHDL-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, nonHDL-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
Table 1 Acceptable, borderline, and high plasma lipid,
lipoprotein, and apolipoprotein concentrations (mg/dL) for
children and adolescents*
Category Acceptable Borderline High
TC ,170 170199 .200
LDL-C ,110 110129 .130
NonHDL-C ,120 120144 $145
TG
09 y ,75 7599 .100
1019 y ,90 90129 .130
Category Acceptable Borderline Low
HDL-C .45 4045 ,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 nonHDL-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 approxi-
mately 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 indi-
viduals 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 multi-
genic in etiology with expression unmasked or exacerbated
by lifestyle factors, especially obesity.51,52 The FCHL clas-
sification includes a heterogenous group of disorders with
an apparent genetic basis: FCHL, familial dyslipidemic hy-
pertension, hyperapolipoproteinemia B, and LDL subclass
pattern B. This is the most common lipid pattern seen in
patients with coronary disease. As with CDO, the mecha-
nism of increased CVD risk in FCHL is the presence of
increased numbers of apolipoprotein Bcontaining parti-
cles, particularly small, dense LDL particles.53,54 Recently,
the diagnosis of FCHL has been redefined, requiring hyper-
triglyceridemia 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.5557 The family history of dyslipi-
demia 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 sub-
endothelial retention of LDL-containing lipoproteins.58 CD
is highly atherogenic because of its subpopulation
S43
composition with increased LDL particles and small dense
LDL, associated with facilitated subendothelial retention
by a number of mechanisms.1218 In the obese, insulin-
resistant individual, increased free fatty acid levels stimu-
late hepatic overproduction of TG-rich lipoprotein
particles, primarily very lowdensity 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 TG-
enriched 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 Pathobio-
logical Determinants of Atherosclerosis in Youth Study and
the Bogalusa Heart Study, high nonHDL-C and low HDL-
C were strongly associated with autopsy evidence of
premature atherosclerosis.6163 High TG and low HDL-C
in youth are independent predictors of increased cIMT,
especially in those with full metabolic syndrome.6467
Obese youth with elevation in TG and low HDL-C have
been shown to have thicker cIMT, higher pulse wave veloc-
ity (PWV), and increased carotid artery stiffness.6870 A
strong association between higher TG/HDL-C ratio, higher
nonHDL-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 longitu-
dinal Young Finns study revealed that at 21-year follow-up,
subjects with the CD pattern beginning in childhood had
significantly increased cIMT compared with normolipi-
demic 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 atheroscle-
rosis 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 meta-
bolic syndrome. In susceptible individuals, excessive
weight gain in response to caloric excess occurs dispro-
portionately as visceral fat. An increase in visceral adipose
tissue is thought to reflect inability of the subcutaneous
S44 Journal of Clinical Lipidology, Vol 9, No 5S, October 2015

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 preg-
nant, 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 FDAs food information line toll free at 1888SAFEFOOD 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 ten-
dency 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 resis-
tance 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 ad-
ipose 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 hyper-
insulinemia 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 Hyperinsuline-
mia 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 disap-
pears when obesity is included in the analysis.88 In a hyper-
insulinemiceuglycemic clamp study, elevated TG/HDL-C
ratio identified in vivo insulin resistance.37 Thus, CDO cor-
relates 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
Kavey Combined dyslipidemia in childhood S45

epidemiologic surveys.89,90 On biochemical evaluation, the

Table 3 Estimated calorie requirements (kcals) for gender
most common finding is mild-to-moderate elevation in
and age groups at 3 levels of physical activity*
serum alanine aminotransferase.9193 Hepatic fat deposition
usually occurs in the context of generalized obesity but Calorie requirements (kcals) by
much more strongly reflects the presence of increased activity level,,x
visceral adiposity. In obese children and adolescents, sequen- Moderately
tial increase in waist circumference, a proxy measure of Gender Age (y) Sedentary active Activex
visceral fat, is associated with progressive increase in odds
Child 23 1000 10001400 10001400
ratio for prediction of ultrasound-detected hepatic steato- Female 48 1200 14001600 14001800
sis.93 NAFLD is strongly associated with insulin resistance 913 1600 16002000 18002200
and all the components of the metabolic syndrome.9395 In 1418 1800 2000 2400
a study of adolescents with biopsy-proven NAFLD, 80% 1930 2000 20002200 2400
had biochemical evidence of insulin resistance.94 Fat accu- Male 48 1400 14001600 16002000
mulation in the liver is a significant, obesity-independent 913 1800 18002200 20002600
predictor of type II diabetes mellitus in multiple prospective 1418 2200 24002800 28003200
studies. The fatty liver is resistant to the actions of insulin to 1930 2400 26002800 3000
inhibit production of glucose and of VLDLs. This results in Estimates are rounded to nearest 200 calories and were determined
mild hyperglycemia, compensatory hyperinsulinemia, and using the Institute of Medicine (IOM) equation.
*These levels are based on Estimated Energy Requirements from the
hypertriglyceridemia with secondary lowering of HDL
IOM Dietary Reference Intakes macronutrients report (2002), calculated
cholesterol. The CD pattern is seen on a standard lipid pro- by gender, age, and activity level for reference-size individuals. Refer-
file and with NMR analysis in more than half of patients ence size, as determined by the IOM, is based on median height and
with NAFLD.95 NAFLD has been shown to be a strong, in- weight for ages up to age 18 years and median height and weight for
dependent predictor of CVD in adults.96,97 In children and that height to give a body mass index of 21.5 for adult females and
22.5 for adult males.
adolescents, NAFLD is also associated with atherosclerosis
A sedentary activity level in childhood, as in adults, means a life-
at autopsy and with ultrasound vascular markers associated style that includes only the light physical activity associated with
with atherosclerosis.98 typical day-to-day life.
CDO, insulin resistance, and visceral adiposity are each Moderately active in childhood means a lifestyle that includes
components of the metabolic syndrome, first described by 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
Reaven in 1988 and identified as a high-risk constellation
activity associated with typical day-to-day life.
for atherosclerotic disease.99 In adults, the metabolic syn- xActive means a lifestyle that includes more physical activity,
drome is defined as 3 or more of the following components: equivalent to an adult walking more than 3 miles per day at 3 to 4
elevated waist circumference as a measure of visceral fat, miles per hour, in addition to the light physical activity associated
elevated TG levels, reduced HDL-cholesterol, elevated with typical day-to-day life.
BP, and/or impaired fasting glucose.100 NAFLD has been
designated as the hepatic component of the metabolic syn-
drome.101 In the United States, the metabolic syndrome is Diagnosis of combined dyslipidemia
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 In children and adolescents with overweight and obesity,
is as yet no agreed-on definition for the metabolic syn- the NHLBI guidelines recommend lipid screening when
drome in childhood, but analysis of cross-sectional data BMI .85th percentile is first identified.1 Screening is also
from NHANES (19881994) showed an overall prevalence recommended when any other major cardiovascular risk is
of the metabolic syndrome cluster among adolescents aged present, when there is a family history of early CVD or of
12 to 19 years of just under 10%.104,105 The syndrome clus- treated dyslipidemia. Universal screening is recommended
ter was present in 28.7% of obese adolescents compared at 9 to 11 years of age and again at 17 to 19 years of
with 0.1% of those with a BMI below the 85th percentile. age, roughly equivalent to the senior year in high school.
As age and the degree of obesity increased, the prevalence The initial screening test can be nonfasting or fasting. In
of the metabolic syndrome cluster increased, reported in the nonfasting condition, TC and HDL-C are measured;
38.7% of moderately obese (mean BMI, 33.4 kg/m2) and both are stable in the nonfasting state. These measures
49.7% of severely obese (mean BMI, 40.6 kg/m2) adoles- allow calculation of nonHDL-C from TC HDL-C. On a
cents.105 Presence of the metabolic syndrome cluster at a nonfasting test, nonHDL-C .145 mg/dL should be fol-
mean of 12 years of age was an independent predictor of lowed by a fasting lipid profile. If those results are normal,
adult CVD 25 years later.106 Although there is continued no further lipid evaluation is needed at that time, but these
debate about the definition of the metabolic syndrome in children should be included in the universal screening
children and adolescents, there is strong consensus that schedule. Alternatively, a fasting lipid profile can be used
the combination of CDO with visceral adiposity, insulin for screening. Lipid evaluation should also occur if a new
resistance, and NAFLD is a powerful predictor of cardio- cardiovascular risk develops in the child or adolescent
metabolic risk in children and adults.107 and/or if the family history changes. If the first fasting lipid
S46 Journal of Clinical Lipidology, Vol 9, No 5S, October 2015

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 preg-
nant, 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 FDAs food information line toll free at 1888SAFEFOOD 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 ar-
ticles 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 accompa-
nying 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 Association108111 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, recip-
rocal 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, adoles-
cents, and adults, even small amounts of weight loss are
associated with significant decreases in TG levels and
increases in HDL-C levels.112114 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.115118 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 high-
carbohydrate, 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 treat-
ment to 88.8 6 13.3 mg/dL after 12 months.121 In an anal-
ysis of adolescents from NHANES, the US Department of
Agricultures Center for Nutrition Policy and Promotions
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 be-
tween 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 com-
ponents in adolescents with high activity levels, although
this was not significant. Glycemic load has also been eval-
uated 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 1400 1600 1800 2000 2600 Significance of food group

Combined dyslipidemia in childhood

Food group Calories Calories Calories Calories Calories Calories Serving sizes Examples and notes to DASH eating plan
Grains* 45 56 6 6 68 1011 1 slice bread; 1 oz dry Whole-wheat bread and Major sources of energy
cereal; 1/2 cup cooked rolls, whole-wheat and fiber
rice; pasta; or cereal pasta, English muffin,
pita bread, bagel,
cereals, grits, oatmeal,
brown rice, unsalted
pretzels and popcorn
Vegetables 34 34 34 45 45 56 1 cup raw leafy vegetable, Broccoli, carrots, collards, Rich sources of potassium,
1/2 cup cut-up raw or green beans, green magnesium, and fiber
cooked vegetable, 1/2 peas, kale, lima beans,
cup vegetable juice potatoes, spinach,
squash, sweet potatoes,
tomatoes
Fruits 34 4 4 45 45 56 1 medium fruit, 1/4 cup Apples, apricots, bananas, Important sources of
dried fruit, 1/2 cup dates, grapes, oranges, potassium, magnesium,
fresh, frozen, or canned grapefruit, grapefruit and fiber
fruit, 1/2 cup fruit juice juice, mangoes,
melons, peaches,
pineapples, raisins,
strawberries, tangerines
Fat-free or 23 23 23 23 23 3 1 cup milk or yogurt, Fat-free milk or Major sources of calcium
low-fat milk 1 1/2 oz cheese buttermilk; fat-free, and protein
and milk low-fat, or reduced-fat
products cheese; fat-free/low-fat
regular or frozen yogurt
Lean meats, 3 or less 34 or less 34 or less 6 or less 6 or less 6 or less 1 oz cooked meats, Select only lean; trim Rich sources of protein
poultry, poultry, or fish, 1 egg away visible fats; broil, and magnesium
and fish roast, or poach; remove
skin from poultry
Nuts, seeds, 3 per week 3 per week 34 per week 4 per week 45 per week 1 1/3 cup or 1 1/2 oz nuts, Almonds, filberts, mixed Rich sources of energy,
and legumes 2 tbsp peanut butter, 2 nuts, peanuts, walnuts, magnesium, protein,
tbsp or 1/2 oz seeds, sunflower seeds, peanut and fiber
1/2 cup cooked butter, kidney beans,
legumes (dried beans, lentils, split peas
peas)
Fats and oilsx 1 1 2 23 23 3 1 tsp soft margarine, 1 tsp Soft margarine, vegetable DASH study had 27% of
vegetable oil, 1 tbsp oil (canola, corn, olive, calories as fat,
mayonnaise, 2 tbsp safflower), low-fat including fat in or
salad dressing mayonnaise, light salad added to foods
dressing

S47
(continued on next page)
S48 Journal of Clinical Lipidology, Vol 9, No 5S, October 2015

adults. The glycemic index is a measure of the blood

Significance of food group
glucose response to a 50-g portion of a selected carbohy-

Sweets should be low in

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.
drate; the glycemic load is the mathematic product of the
to DASH eating plan

glycemic index and the carbohydrate amount.123 In ado-

lescents and young adults, there is evidence that low
glycemic-load diets are at least as effective as low-fat di-
ets in achieving weight loss, with decreased TG and
fat

increased HDL in subjects on the low glycemic-load

diet.123126 In adolescents, a low-carbohydrate diet with
or without weight loss has been shown to significantly
fruit punch, hard candy,

sorbet and ices, sugar

reduce TG levels.127129 These lifestyle change interven-

1 tbsp sugar, 1 tbsp jelly Fruit-flavored gelatin,

jelly, maple syrup,

tions have been shown to significantly reduce TG, non

Examples and notes

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 cardio-
vascular 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
or jam, 1/2 cup sorbet,

shown in the Bogalusa Heart Study and in the Cardiovas-

gelatin dessert, 1 cup

cular 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 num-
Serving sizes

ber of studies have shown that lifestyle interventions

lemonade

Serving sizes vary between 1/2 cup and 1 1/4 cups, depending on cereal type. Check products Nutrition Facts label.

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
Calories

those subjects who were successful in weight loss had a

2600

decrease in cIMT.136
#2

*Whole grains are recommended for most grain servings as a good source of fiber and nutrients.

Based on this evidence, primary recommended treat-

ment for CDO and for related insulin resistance and
per week

NAFLD is weight loss.1 A comprehensive but straightfor-

5 or less
Calories

ward weight management approach can be initiated in the

2000

pediatric, gynecologic, family practice, or subspecialty

medicine setting and a suggested plan derived from the
per week

evidence-based NHLBI guidelines is described here. The

5 or less
Calories

process begins with calculation of appropriate energy

1800

intake for age, gender, and activity level by using

Table 3.1 Then, the diet from the NHLBI guidelines recom-
Two egg whites have the same protein content as 1 oz meat.

mended for children and adolescents with high TG is pre-

per week
3 or less

scribed, matching these energy requirements (Table 4).

Calories

The diet is focused on limitation of simple carbohydrate

1600

intake with specific elimination of all sugar-sweetened bev-

erages including fruit juice. Simple carbohydrates like
per week

oz, ounce; tbsp, tablespoon; tsp, teaspoon.

sugars, baked goods, white rice, white bread, and plain

3 or less
Calories

pasta are replaced with complex carbohydrates like brown

1400

rice, whole grain bread, and whole grain pasta. Foods

high in natural fiber are encouraged with a goal of age
per week

plus 5 g of fiber per day.1 For all dietary change in children

3 or less
Calories

and adolescents, initial family-based training with a regis-

1200
(continued )

tered dietitian has been shown to be the most effective

way to both begin and sustain change.137140 As part of
added sugars

the NHLBI guidelines, the DASH diet was modified for

Food group
Sweets and

use in childhood. This simple diet plan is rich in fruits

Table 5

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
Kavey Combined dyslipidemia in childhood
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 sin-
gles tennis, or soccer.
organized by servings per day by food group and by total
energy intake with content matched to the guideline recom-
mendations for management of CDO.
A regular exercise schedule is prescribed, simultaneous
with the diet recommendations. Based on the recommen-
dations 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 super-
vised. To allow for variations in compliance in the typically
unsupervised real-world setting, an hour of moderate-to-
vigorous 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 subse-
quent evaluations is necessary. A combined diet and activ-
ity 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 cardio-
metabolic risks in case series and in randomized trials,
particularly when combined with cognitive behavioral
therapy.128,142154
S49
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 6-
month trial of lifestyle approach is unsuccessful, the 2011
NHLBI guidelines recommend that referral to a multidisci-
plinary 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 hypercho-
lesterolemia (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.155165
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 anti-
inflammatory, which may be important in the proinflamma-
tory 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 statisti-
cally significant differences were found between statin-
treated and placebo-treated children for the occurrence of
any adverse events, including problems with sexual devel-
opment, 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 exam-
ining statin effects on vascular health (PWV or cIMT) in
children or adolescents with CDO.
S50 Journal of Clinical Lipidology, Vol 9, No 5S, October 2015

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 drugdrug 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 34 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.173175
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.178181 Fibrates are peroxisome proliferator-
activated receptors agonists and act in the liver to reduce
cholesterol synthesis, reduce secretion of very lowVLDLs
and increase the removal of VLDLs from the blood, conse-
quently lowering plasma TGs (by 30%50%) and, to a
lesser extent, LDL-C (reduction of 0%30%). They in-
crease 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
Kavey Combined dyslipidemia in childhood
nonfatal myocardial infarction but did not affect all-cause
mortality.183 Meta-analyses of recent clinical trial data sug-
gest 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 com-
bined 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 asso-
ciated 17% increase in HDL-C.186189 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 aspar-
tate aminotransferase (AST) in 2 subjects in another case
series.186 No other potentially adverse effects were re-
ported. There are no long-term trials of fibric acid deriva-
tives 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 chil-
dren.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 func-
tion tests.194 Based on this evidence, statin therapy appears
S51
to be the logical first choice for treatment of CDO, which is
not responsive to lifestyle change. The guidelines recom-
mend a 6-month trial of diet and activity change before
any consideration of drug therapy, as outlined in the algo-
rithm in Table 2. If after 6 months, TGs exceed 200 mg/
dL but are less than 500 mg/dL, the guidelines suggest initi-
ation 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 treat-
ment. In patients with CD in whom the LDL-C target is
achieved but nonHDL-C exceeds 145 mg/dL, drug therapy
with a statin is recommended. The NHLBI guidelines
provide very specific guidance for initiation and mainte-
nance 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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