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Comorbidities and complications of obesity in children and adolescents

Author: William J Klish, MD

Section Editors: Kathleen J Motil, MD, PhD, Mitchell E Geffner, MD
Deputy Editor: Alison G Hoppin, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Nov 13, 2017.

INTRODUCTION — Obesity has become one of the most important public health problems in the United States (figure 1)
[1] and many other countries [2]. As the prevalence of obesity increases so does the prevalence of the comorbidities
associated with obesity, resulting in an enormous burden of obesity-related disease worldwide [2,3]. For this reason it is
imperative that health care providers identify overweight and obese children so that counseling and treatment can be
provided.

The comorbidities of obesity in childhood and adolescence include abnormalities in the endocrine, cardiovascular,
gastrointestinal, pulmonary, orthopedic, neurologic, dermatologic, and psychosocial systems, as well as functional
limitations [4,5]. Certain comorbidities, such as type 2 diabetes mellitus and steatohepatitis, that used to be considered
"adult diseases" are now regularly seen in obese children. Moreover, obesity during adolescence increases the risk for
disease and premature death during adulthood, independent of obesity during adulthood [6-10]. As an example, in a
longitudinal study, females who had been overweight during childhood had an increased risk of death from breast cancer
and from all causes in adulthood [8]. Males who had been overweight during childhood had an increased risk of death from
ischemic heart disease.

The comorbidities of obesity in children and adolescents will be discussed here. The definition, epidemiology, etiology,
clinical evaluation of obesity in children and adolescents and the health hazards of obesity in adults are discussed
separately. (See "Definition; epidemiology; and etiology of obesity in children and adolescents" and "Clinical evaluation of
the obese child and adolescent" and "Overweight and obesity in adults: Health consequences" and "Management of
childhood obesity in the primary care setting".)

DEFINITIONS — In the discussion that follows, the term "obesity" refers to children with body mass index (BMI) ≥95th
percentile for age and sex and the term "overweight" refers to children with BMI between the 85th and 95th percentile for
age and sex, unless otherwise noted. Calculation of body mass index and definitions of obesity are discussed in detail
separately. (See "Definition; epidemiology; and etiology of obesity in children and adolescents", section on 'Definitions'.)

ENDOCRINE — Endocrine comorbidities of obesity in children and adolescents include impaired glucose tolerance,
diabetes mellitus, hyperandrogenism in females, and abnormalities in growth and puberty.

Prediabetes — Increased risk for developing type 2 diabetes mellitus (T2DM), sometimes called "prediabetes," is a
common complication of childhood and adolescent obesity [11,12]. Prediabetes is defined by moderate abnormalities in
fasting plasma glucose (FPG), glucose tolerance (as determined by an oral glucose tolerance test; OGTT), or hemoglobin
A1c (A1C, or glycated hemoglobin) (table 1). FPG and A1C are typically used for initial screening of obese children and
adolescents, but are limited by high rates of false positives and false negatives in detecting dysglycemia [13,14]. A FPG of
100 to 125 mg/dL or A1C 5.7 to 6.4 percent suggests prediabetes, and should be further evaluated with an OGTT. (See
"Epidemiology, presentation, and diagnosis of type 2 diabetes mellitus in children and adolescents", section on
'Prediabetes' and "Epidemiology, presentation, and diagnosis of type 2 diabetes mellitus in children and adolescents",
section on 'Laboratory tests'.)

The reported prevalence of prediabetes and T2DM in obese children varies considerably, presumably because of different
degrees of obesity, racial and ethnic variation, and age range of the sampled population:

● In a study of more than 6000 students in the sixth grade (average age 11.8 years), nearly 20 percent were overweight
 and 30 percent were obese [15,16]. Impaired fasting glucose (FPG ≥100 mg/dL) was present in 15.5 percent of
overweight children, 20.2 percent of obese children, and 22.5 percent of severely obese children.

● In one study of 167 children and adolescents with BMI ≥95th percentile for age and sex who were referred to an
obesity clinic, 25 percent of children and 21 percent of adolescents had evidence of impaired glucose tolerance [17].

● A population-based study from the United States used A1C >5.7 percent as an index of increased diabetes risk, and
distinguished severity of obesity as class I (BMI ≥95th percentile to <120% of the 95th percentile), class II (BMI
≥120% to <140% of the 95th percentile, or BMI ≥35), or class III (BMI ≥140% of the 95th percentile, or BMI ≥40) [18].
Among adolescents 12 to 19 years, elevated A1C was reported in 3 percent of subjects with class I obesity, 6 percent
of those with class II obesity, and 13 percent of those with class III obesity.

● In a study of 468 obese children and adolescents with elevated fasting insulin, the prevalence of impaired glucose
tolerance was 12 percent, and T2DM was 2 percent [19].

● In other populations of obese children and adolescents, the prevalence of impaired glucose tolerance ranges from 7
to 13.5 percent, and the prevalence of T2DM was less than 1 percent [20,21].

Because insulin resistance is a good predictor of impaired glucose tolerance, it would be clinically useful to quantify insulin
resistance in overweight and obese children and adolescents. However, there is no consensus on how to accurately
evaluate children for insulin resistance. In research settings the standard technique is the hyperinsulinemic euglycemic
clamp, but this technique is too invasive for clinical purposes [22].

Insulin resistance is a state in which a given concentration of insulin is associated with subnormal glucose response [23]. A
number of surrogate measures have been described, including the homeostasis model assessment of insulin resistance
(HOMA) [24], the fasting glucose-to-insulin ratio (FGIR) [25-27], and the quantitative insulin sensitivity check index
(QUICKI) (table 2) [28]. The validity of these measures as surrogates for insulin resistance in obese children and
adolescents has been assessed using various confirmatory tests (oral glucose tolerance test, frequent sampling
intravenous glucose tolerance test, and clamp testing) with variable results [22,29-33]. Other indices of insulin sensitivity,
termed an oral disposition index, are derived from data collected during a standard oral glucose tolerance test [34]. The
definition and clinical manifestations of insulin resistance are discussed separately. (See "Insulin resistance: Definition and
clinical spectrum".)

Diabetes mellitus — Type 2 diabetes mellitus (T2DM) is another comorbidity of obesity in children and adolescents [35-
37]. In the study described above, 4 percent of adolescents with BMI ≥95th percentile for age and sex had asymptomatic
T2DM [17]. Early diagnosis is imperative because aggressive treatment can slow the development of complications
including progressive neuropathy, retinopathy, nephropathy, and atherosclerotic cardiovascular disease [38]. Moreover,
individuals who present with T2DM during adolescence appear to have more rapid progression of diabetes-related
complications as compared with those who present later in life. As an example, among adolescent patients with newly
diagnosed T2DM, a large percentage had comorbidities (13.0 percent had microalbuminuria, 80.5 percent had
dyslipidemia, and 13.6 percent had hypertension) [39].

A large study of young men in Israel showed an association between BMI during adolescence and T2DM during
adulthood, as expected [40]. Of note, this association was seen even within the range of BMI that is considered normal.
Interestingly, the association disappeared after adjusting for BMI during adulthood, suggesting that T2DM is primarily
associated with obesity at or near the time of diagnosis, rather than the effects of chronic obesity since childhood.
Similarly, a large longitudinal study found that individuals who were overweight or obese during childhood but who were
not obese as adults had similar risk for T2DM as individuals who were never obese [41]. By contrast, individuals with
persistent obesity from childhood through adulthood had a significantly increased risk of T2DM in adulthood (RR 5.4; 95%
CI 3.4-8.5).

T2DM is diagnosed based on marked abnormalities of FPG, A1C, or OGTT, as outlined in the table (table 3). Screening of
overweight or obese children for T2DM is discussed separately. (See "Epidemiology, presentation, and diagnosis of type 2
diabetes mellitus in children and adolescents", section on 'Screening'.)

Metabolic syndrome — The "metabolic syndrome" is a term used to describe the clustering of metabolic risk factors for
type 2 diabetes and atherosclerotic cardiovascular disease in adults: abdominal obesity, hyperglycemia, dyslipidemia, and
hypertension. Clustering of cardiovascular risks also occurs in children and adolescents, particularly those who are
overweight or obese [42,43]. Several studies estimate that approximately 10 percent of US adolescents have metabolic
syndrome, as defined by modifications of adult criteria [44-46]. However, because puberty is associated with changes in
several of the traits that characterize metabolic syndrome, there is considerable instability to the diagnosis. In one study,
about half of the adolescents initially classified as having metabolic syndrome lost the diagnosis during a three-year
observation period, while others acquired the diagnosis [47]. The long-term implications of the metabolic syndrome in
children and adolescents are unknown. As a result, screening and treatment should be focused on the individual
cardiometabolic risk factors (obesity, dysglycemia, dyslipidemia and hypertension), while recognizing that these are often
clustered together [43].

Several different schemes have been used to define the metabolic syndrome in adolescents (table 4) [48,49]. These and
other aspects of the metabolic syndrome are discussed in detail separately. (See "The metabolic syndrome (insulin
resistance syndrome or syndrome X)", section on 'Children and adolescents'.)

Hyperandrogenism — Adolescent girls with obesity are at increased risk of hyperandrogenism and early onset polycystic
ovary syndrome (PCOS). PCOS can include a variety of clinical abnormalities, including hirsutism, menstrual irregularities,
acanthosis nigricans, acne, and seborrhea. In some patients the diagnosis may be difficult to establish during
adolescence. The clinical manifestations, diagnosis, and management of PCOS in adolescents are discussed separately.
(See "Definition, clinical features and differential diagnosis of polycystic ovary syndrome in adolescents" and "Treatment of
polycystic ovary syndrome in adolescents".)

The association of obesity with PCOS is partially responsible for the association between obesity and reduced fertility in
adult women.

Growth and puberty — Obesity in children and adolescents may be accompanied by accelerated linear growth and bone
age [50]. It is uncertain whether this accelerated growth results in stature different than that which is genetically
programmed. (See "The child with tall stature and/or abnormally rapid growth", section on 'Exogenous obesity'.)

Overweight has been associated with early onset of sexual maturation in girls [51,52]. However, this relationship is
inconsistent [53]. The relationship between obesity and pubertal onset in boys is also inconsistent [51,54]. (See "Normal
puberty", section on 'Trends in pubertal timing'.)

CARDIOVASCULAR — Obesity in children and adolescents is associated with a number of cardiovascular changes that
are linked to increased cardiovascular risk in adulthood. Two cardiovascular risk factors, hypertension and dyslipidemia,
are components of the metabolic syndrome. A minority of obese children and adolescents have no evidence of
cardiovascular risk factors (termed "metabolically healthy obesity"). These individuals also show no signs of early
atherosclerotic disease (as measured by carotid intima-media thickness), and tend to remain metabolically healthy in
adulthood [55]. (See "The metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Children and
adolescents'.)

Hypertension — The risk of hypertension (table 5) is increased in overweight and obese children and adolescents, and
increases with the severity of obesity [18,56]. Those who have body mass index (BMI) ≥95th percentile for age and sex
have approximately a three-fold higher risk of hypertension than those with BMI <95th percentile for age and sex [57].
When hypertension is assessed using ambulatory blood pressure monitoring, approximately 50 percent of obese children
have hypertension [58,59]. When casual office blood pressure measurements are used, substantially fewer cases of
hypertension are detected [60]. This discrepancy, termed "masked" hypertension, is particularly common in children with
obesity, and has clinically important consequences. (See "Ambulatory blood pressure monitoring in children", section on
'Masked hypertension'.)

The presence of hypertension during childhood predicts hypertension and metabolic syndrome during adulthood, even
after adjustment for BMI during childhood [61]. Conversely, the presence of obesity during childhood predicts hypertension
during adulthood, even after adjustment for BMI during adulthood (ie, there is a persistent effect of childhood obesity on
the risk for hypertension even if the individual loses weight by adulthood) [41]. The evaluation and management of
hypertension in children and adolescents is discussed separately. (See "Definition and diagnosis of hypertension in
children and adolescents" and "Nonemergent treatment of hypertension in children and adolescents".)

Dyslipidemia — Dyslipidemia occurs among overweight and obese children and adolescents, particularly those with a
central fat distribution [62-66] and increased adiposity (as measured by triceps skin-fold thickness ≥85th percentile) [63].
The typical pattern is one of elevated concentration of serum low-density lipoprotein (LDL)-cholesterol and triglycerides
and decreased concentration of high-density-lipoprotein (HDL)-cholesterol [56,64-66]. The risk for these abnormalities
increases with the severity of obesity [18]. (See "Dyslipidemia in children: Definition, screening, and diagnosis".)
The evaluation of hyperlipidemia in obese children and adolescents includes measurement of a fasting lipid panel (total
cholesterol, triglycerides, and HDL-cholesterol) (table 6). Treatment for dyslipidemia is discussed separately. (See "Clinical
evaluation of the obese child and adolescent", section on 'Laboratory studies' and "Dyslipidemia in children: Management"
and 'Society guideline links' below.)

Cardiac structure and function — Obesity in children is associated with alterations in cardiac structure and function that
are similar to those seen in middle-aged adults. Findings include increased left ventricular mass, which is seen in both
hypertensive and non-hypertensive children with obesity [56,67-72], increased left ventricular and left atrial diameter,
greater epicardial fat, and systolic and diastolic dysfunction [72,73].

Other cardiovascular risks — Childhood obesity is also associated with several markers for progressive atherosclerosis.
These include endothelial dysfunction, carotid intima-media thickening, the development of early aortic and coronary
arterial fatty streaks and fibrous plaques, and increased arterial stiffness [59,74-83]. These observations lend additional
support to the idea that atherosclerotic processes begin at an early age and are associated with obesity, inflammation,
hypertension, and abnormal lipid profiles [84,85]. Insulin resistance is an independent risk factor for premature carotid
atherosclerosis, after adjustment for a variety of other cardiovascular risk factors, including hypertension and dyslipidemia
[86,87].

Even modest degrees of excess adiposity contribute to cardiovascular risk. One study demonstrated that cardiovascular
risk factors are elevated in overweight youth (BMI 85th to 95th percentile), with further abnormalities in those with obesity
(BMI ≥95th percentile) [88]. This study used a twin pair design and included a several measures that have been shown to
predict cardiovascular risk, including nocturnal blood pressure, left ventricular mass index, and overnight sodium excretion.

Adult coronary heart disease — The studies outlined above describe the effects of childhood obesity on hypertension
and dyslipidemia, which are intermediate cardiovascular outcomes. However, increasing evidence demonstrates an
association between obesity during childhood and cardiovascular disease during adulthood:

● A large population study from Israel found that BMI during late adolescence was associated with cardiovascular
mortality in mid-adulthood [89]. Of note, this association was seen even within the range of BMIs considered to be
normal in adolescents, with a graded increase in risk of death as adolescent BMI rose above the 50th percentile
(figure 2). Compared with the reference group in the 5th to 24th percentiles, the obese group had a hazard ratio of 4.9
(95% CI, 3.9 to 6.1) for death from coronary heart disease. This study did not control for adult BMI. However, an
earlier study on a subgroup of this population found an association between BMI during adolescence and
angiography-proven coronary heart disease during adulthood, and that association did persist after adjusting for early-
adulthood BMI [40]. Together, these studies suggest that the processes causing coronary heart disease begin during
adolescence.

● A population-wide study from Denmark demonstrated a dramatic effect of childhood BMI on the critical outcome of
cardiovascular events [90]. Higher BMI during childhood was associated with an increased risk for fatal and nonfatal
cardiovascular events during adulthood in both males and females. The risk increased linearly with BMI at each age,
increased with increasing age of the child, and was even stronger when adjusted for birthweight. Of note, some of the
observed effects may have been mediated by the association between childhood obesity and adult obesity, because
the study did not adjust for the effect of adult BMI.

● Data from four large longitudinal studies including 6328 subjects was analyzed to determine how changes in obesity
status affect cardiovascular risk factors during adulthood [41]. Individuals who were overweight or obese during
childhood and remained obese as adults have significantly increased risks for type 2 diabetes, hypertension,
dyslipidemia, and carotid-artery atherosclerosis as adults as compared with individuals who were never obese. By
contrast, individuals who were overweight or obese during childhood but who were not obese as adults had similar
cardiovascular risks as compared with individuals who were never obese.

● A predictive model estimated that the prevalence of coronary heart disease in the United States will increase 5 to 16
percent by 2035, with more than 100,000 excess cases of coronary heart disease attributable to the increase in
childhood obesity [91].

GASTROINTESTINAL

Nonalcoholic fatty liver disease — Obesity is associated with a clinical spectrum of liver abnormalities collectively known
as nonalcoholic fatty liver disease (NAFLD) [92,93], the most common cause of liver disease in children [94,95]. The
abnormalities include steatosis (increased liver fat without inflammation) and nonalcoholic steatohepatitis (NASH,
increased liver fat with inflammation) (picture 1). The natural history of NASH in children is not well described, but in some
cases it may lead to fibrosis, cirrhosis, and ultimately liver failure [96].

The pathogenesis of NAFLD in overweight and obese individuals is not fully understood, but insulin resistance appears to
be an important component [97,98]. The pathogenesis of NAFLD is discussed in detail separately. (See "Pathogenesis of
nonalcoholic fatty liver disease" and "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in
adults", section on 'Pathogenesis'.)

There are important clinical associations between NAFLD and elements of the metabolic syndrome, including insulin
resistance, dyslipidemia, and hypertension, independent of the degree of obesity [99,100]. Therefore, children with NAFLD
should be carefully evaluated for each of these comorbidities and have global counseling about nutrition, physical activity,
and tobacco use to help prevent the development of cardiovascular disease and type 2 diabetes mellitus. (See "Clinical
evaluation of the obese child and adolescent".)

With the increased prevalence of childhood obesity, NAFLD is increasingly seen in children [101-104]. The prevalence
depends upon the population (ie, referral, community, ethnic group) and the definition of NAFLD used in the study (eg,
height of aminotransferase elevation and/or ultrasonographic findings), as illustrated by the following reports:

● In an autopsy study of 742 children and adolescents, the prevalence of fatty liver was 9.6 percent overall, and 38
percent in obese children [105]. Histologic evidence of steatohepatitis was seen in 23 percent of the subjects with fatty
liver, or 3 percent of the population overall. Of note, fatty liver was strongly associated with race, independent of
obesity: Hispanic youths had a fivefold increase in risk for fatty liver as compared with black youths, after adjustment
for BMI. White subjects had intermediate levels of risk. Because this study used histological measures of fatty liver in
an unselected population, it is the best representation of the true prevalence of fatty liver disease among US children
and adolescents.

● In the third National Health and Examination Survey (NHANES III), the prevalence of elevated ALT (>30 U/L [0.50
microkat/L]) among adolescents with BMI ≥95th percentile for age and sex was 10 percent [101]. The prevalence of
ALT >60 U/L (1.00 microkat/L, two times normal) among adolescents with BMI ≥95th percentile in this nonreferral
population was only 1 percent. Of note, the prevalence of elevated ALT (>30 U/L [0.50 microkat/L]) among
adolescents with BMI ≥95th percentile increased to 52 percent among those who reported that they ingested alcohol
at least four times per month.

● The prevalence of ultrasonic findings consistent with fatty liver was 22.5 percent in Japanese children (aged 4 to 12
years) with BMI ≥20 [106]. In a study of Chinese children that used a higher cutoff for obesity (mean BMI 30.3), the
prevalence of ultrasonic findings consistent with hepatic steatosis was 77 percent, whereas the prevalence of
ultrasonographic hepatic steatosis combined with elevated ALT was 24 percent [107].

Diagnosis — Most patients with NAFLD are asymptomatic [92]. However, they may have right upper quadrant pain,
hepatomegaly [108,109], or nonspecific symptoms such as abdominal discomfort, weakness, fatigue or malaise. They
rarely have signs of liver disease: palmar erythema, spider angiomata, muscular wasting, jaundice, or encephalopathy.
Laboratory abnormalities include elevations in liver transaminases (alanine aminotransferase [ALT], and aspartate
aminotransferase [AST]), alkaline phosphatase, and gamma glutamyl transpeptidase (GGT) [92,95,110-112]. These
abnormalities resolve with weight loss [110,113].

It is important to note that liver transaminases have only moderate sensitivity for detecting clinically significant NAFLD
[104,114]. As an example, in a large study of children and adolescents with suspected NAFLD who underwent liver biopsy,
fibrosis was seen in 12 percent of those with normal ALT and in 54 percent on those with mildly elevated ALT (defined as
ALT 26 to 50 U/L in boys and 23 to 44 U/L in girls) [115]. Advanced fibrosis (bridging fibrosis or cirrhosis) was seen in none
of the children with normal ALT, 9 percent of those with mildly elevated ALT and 15 percent of those with significantly
elevated ALT (defined as ALT ≥50 U/L in boys, and ≥44 U/L in girls). Thus, biochemical tests are only moderately helpful in
predicting the presence or severity of NAFLD. When making decisions about whether or when to proceed to liver biopsy,
the biochemical tests should be interpreted in the context of other risk factors that predict severity of NAFLD, which include
degree of obesity, clinical symptoms and signs of insulin resistance (eg, acanthosis nigricans), ethnicity (eg, Hispanic), and
obstructive sleep apnea [116]. Moreover, the upper limit of normal for ALT should be around 26 for boys, and 22 for girls,
as determined from healthy lean children in the National Health and Nutrition Examination Survey (NHANES) [117]. These
values are substantially lower than the upper limits reported in most pediatric hospital laboratories.
Imaging may confirm the presence of fatty liver, indicated by increased echogenicity on ultrasonography [110,118,119].
Advanced techniques for magnetic resonance imaging (MRI) provide a more accurate measure of steatosis [104,120].
However, the severity of hepatic steatosis does not correlate with clinical features, the degree of elevation of liver
transaminases, or inflammatory features on histology (steatohepatitis) [109,119,121,122]. Because of low sensitivity and
specificity for steatohepatitis, the clinical utility of ultrasonography or MRI for the diagnosis of fatty liver disease is
questionable [123,124]. However, we and many other providers use imaging to confirm the presence of fatty liver, and to
look for features that demand a more intensive evaluation. As examples, the presence of splenomegaly or liver nodularity
suggest more advanced liver disease, and call for a thorough evaluation, including liver biopsy. Newer imaging methods
such as elastography (which measures liver stiffness) show some promise in distinguishing patients with fibrosis from
those with simple steatosis [125,126]. However, the approach is not widely available and has not been extensively studied
in NAFLD. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults", section on
'Radiographic examinations'.)

The indications for liver biopsy for suspected NAFLD have not been established in either children or adults, and remain
controversial [95,104]. Liver biopsy is the only way to reliably distinguish between simple steatosis, steatohepatitis, and
fibrosis, and can also be helpful in excluding other causes of elevated serum aminotransferases. On the other hand,
because there is no specific treatment for NAFLD other than weight management right now, the results of a liver biopsy
are not likely to provide clinical benefit. Therefore, the benefits of performing a liver biopsy may not outweigh the costs and
risks, unless there are specific features that suggest more severe or progressive liver disease, or that raise concerns about
an alternate cause of the liver disease which requires evaluation by liver biopsy. (See "Epidemiology, clinical features, and
diagnosis of nonalcoholic fatty liver disease in adults", section on 'Role of liver biopsy'.)

In our practice, we use the following approach in patients with obesity and elevated serum aminotransferases:

● If ALT is greater than twice the upper limit of normal, we screen for viral hepatitis (anti-hepatitis C antibodies, and
hepatitis Bs antigen [HBsAg]), Wilson disease (ceruloplasmin) and alpha 1 antitrypsin deficiency (serum alpha 1
antitrypsin level, and also "pi" typing or phenotype) [95]. Autoimmune hepatitis can be screened for with autoimmune
antibodies (anti-nuclear antibodies [ANA], anti-liver-kidney-muscle antibodies [anti-LKM], and anti-mitochondrial
antibodies [AMA]), and a total immunoglobulin G (IgG) level, and by inquiring about a family history of autoimmune
disease. Of note, positive serum autoimmune antibodies are seen in about 20 percent of children and adults with
NAFLD [127]. Therefore, low-positive titers (eg, ANA 1:40) do not exclude the diagnosis of NAFLD, but patients with
high-positive titers should be further evaluated for the possibility of autoimmune hepatitis [128]. If these tests are
abnormal or equivocal, we follow up with more specific tests. We also inquire about alcohol use and investigate the
possibility of hepatotoxic drugs (eg, valproate or tetracyclines). (See "Wilson disease: Diagnostic tests" and
"Autoimmune hepatitis: Clinical manifestations and diagnosis" and "Approach to the patient with abnormal liver
biochemical and function tests".)

● We recommend and support weight loss measures, emphasizing physical activity, and counsel against alcohol use.

● If the ALT remains more than twice the upper limit of normal for six or more months (whether or not the patient has
lost weight), we recommend a liver biopsy, to establish the diagnosis and determine the severity of the fatty liver
disease, if present, especially the extent of inflammation and fibrosis. As compared to adolescents and adults,
children with NAFLD often display unique histopathological features, including portal inflammation and portal fibrosis
in the absence of ballooning; this histologic pattern has been called "type 2" NAFLD, while the pattern typically seen in
adults has been called "type 1" NAFLD [128-130].

● If the patient declines liver biopsy, we continue to counsel and support weight loss, and we check aminotransferase
levels every six months.

If the aminotransferase elevation is substantially more than twice the upper limit of normal, or if conjugated bilirubin,
neurological symptoms, splenomegaly, or any other indications of significant liver disease are present, more intensive
investigation is warranted. Patients with early onset of liver disease or other atypical features also should be evaluated for
monogenic disorders that present as fatty liver in very young children, such as inborn errors of fatty acid metabolism,
peroxisomal disorders, lysosomal storage disorders, or Wilson disease [128]. (See "Approach to the patient with abnormal
liver biochemical and function tests".)

Treatment — Weight management is the only established treatment for NAFLD; small nonrandomized studies in
children have shown improvement in liver histology or aminotransferase activity after weight loss [95,110,131-133].
Emphasis on physical activity is appropriate because of its utility in improving insulin sensitivity, which appears to be an
important pathway for the development of NAFLD. In one study, physical activity improved NAFLD (as measured by ALT
elevations), independent of weight loss [134]. Guidelines from the American Gastroenterological Association (AGA)
suggest lifestyle modification targeting weight loss as the first-line therapy for obese children with NAFLD [128]. Methods
to achieve weight loss may include bariatric surgery in selected adolescents with severe obesity. Data from adults
suggests that surgically-induced weight loss probably improves NAFLD, but the evidence base remains limited. (See
"Natural history and management of nonalcoholic fatty liver disease in adults", section on 'Weight loss' and "Surgical
management of severe obesity in adolescents".)

Pharmacologic approaches under investigation include the use of vitamin E, metformin and thiazolidinediones (eg,
pioglitazone). In small trials, none of these have shown a convincing advantage over lifestyle intervention alone [135,136].
In a placebo-controlled randomized trial that included 178 children and adolescents with biopsy-proven steatohepatitis,
there was no benefit from either vitamin E or metformin on the primary outcome of serum aminotransferase levels [137].
However, the proportion of children with histologic resolution of steatohepatitis after 96 weeks of treatment was 58 percent
(p <0.01) for those treated with vitamin E, and 41 percent (p = 0.23) for those treated with metformin, compared with 21
percent for those treated with placebo. Some of this improvement may have been due to weight loss, because all patients
were given advice on diet and exercise throughout the study, and the mean BMI z-score decreased slightly in each group.
Supported by the results of this randomized trial, the AGA guideline concludes that vitamin E (800 Int. Units daily) leads to
histological improvement in NAFLD in children, but that there is insufficient information to develop specific
recommendations for its use in clinical practice [128]. (See "Natural history and management of nonalcoholic fatty liver
disease in adults".)

Cholelithiasis — Obesity is the most common cause of gallstones in children without predisposing conditions (eg,
hemolytic anemia, history of parenteral nutrition) [138-140]. The risk for gallstones increases with BMI and is greater for
girls than boys. As an example, one study reported sevenfold greater risk for gallstones among girls with severe obesity as
compared with normal-weight girls (adjusted odds ratio 7.71) [141]. The risk was further increased for girls who used oral
contraceptives. Hispanic ethnicity is an independent risk factor for non-hemolytic gallstone disease [142]. One study
examined the prevalence of gallstones in 493 asymptomatic children and adolescents between 8 and 18 years of age, with
obesity defined as a BMI ≥2 standard deviation scores (approximately 97th percentile). Ultrasound screening detected
gallstones in 10 of the children (2 percent; eight girls and two boys), all of whom were postpubertal [143].

Signs and symptoms of gallstones in children and adolescents are nonspecific [140,144]. They include epigastric pain,
jaundice, right upper quadrant pain, nausea, vomiting, and fatty food intolerance [138,139,144]. Because early recognition
is necessary for successful management, gallbladder disease should be considered in the differential diagnosis of
persistent abdominal pain in overweight or obese adolescents [92]. Ultrasonography is the test of choice for diagnosis.

PULMONARY — Pulmonary comorbidities of obesity in children and adolescents include obstructive sleep apnea (OSA)
and the obesity hypoventilation syndrome (OHS).

Obstructive sleep apnea — Obstructive sleep apnea (OSA) describes complete obstruction of the upper airway during
sleep and cessation of air movement despite ongoing respiratory effort; partial airway obstruction is termed obstructive
hypoventilation. OSA is typically but not always associated with persistent snoring. Obesity is an important predisposing
factor; the prevalence of OSA is increased in obese children and adolescents as compared to those with healthy weights.
In a study of 64 children and adolescents with obesity, 8 percent had moderate to severe OSA [145]. The pathogenesis
and evaluation of OSA in children is discussed separately. (See "Mechanisms and predisposing factors for sleep-related
breathing disorders in children" and "Evaluation of suspected obstructive sleep apnea in children".)

The relationship between sleep and obesity is complex. There is some evidence that shortened sleep duration or sleep
fragmentation promotes obesity, and also that obstructive sleep apnea is associated with decreased insulin sensitivity in
adolescents, independent of adiposity. These associations are discussed separately. (See "Definition; epidemiology; and
etiology of obesity in children and adolescents", section on 'Sleep'.)

Obesity hypoventilation syndrome — The obesity hypoventilation syndrome is defined by extreme obesity and alveolar
hypoventilation during wakefulness. This disorder is rare but life-threatening and requires prompt diagnosis and therapy.
(See "Clinical manifestations and diagnosis of obesity hypoventilation syndrome".)

More commonly, patients with obesity also may have hypoventilation during sleep in the absence of airway obstruction,
perhaps due to the restrictive ventilatory defect caused by obesity. In the study of 64 children cited above, 17 percent had
episodes of hypoventilation, often with severe oxygen desaturation [145]. Abdominal distribution of fat mass was
associated with this finding.
Children and adolescents with obesity and sleep disordered breathing should be referred for specialty care [92,146]. They
require an aggressive weight loss program since weight loss can improve ventilation and general health. In addition, they
may require CPAP until weight loss is sufficient to restore adequate ventilation [146].

ORTHOPEDIC — Orthopedic comorbidities of obesity include slipped capital femoral epiphysis (SCFE) and tibia vara
(Blount disease). In addition, obese children have an increased prevalence of fractures, genu valgum, musculoskeletal
pain (eg, back, leg, knee, ankle, and foot), impaired mobility, and lower extremity malalignment than nonobese children
[147-150]. (See "Approach to the child with knock-knees" and "Approach to the child with bow-legs", section on 'Blount
disease'.)

Slipped capital femoral epiphysis (SCFE) — SCFE is characterized by a displacement of the capital femoral epiphysis
from the femoral neck through the physeal plate (image 1). It typically occurs in early adolescence. Obesity is a significant
risk factor. The classic presentation is that of an obese adolescent with a complaint of nonradiating, dull, aching pain in the
hip, groin, thigh, or knee, and no history of preceding trauma. Diagnosis is confirmed by radiographs. Patients with SCFE
should be referred to an orthopedic surgeon for management and an obesity specialist for an appropriate weight-loss
program to prevent occurrence of contralateral SCFE [146]. The epidemiology, presentation, evaluation, and management
of SCFE are discussed in detail separately. (See "Evaluation and management of slipped capital femoral epiphysis
(SCFE)", section on 'Clinical manifestations'.)

Tibia vara (Blount disease) — Tibia vara (Blount disease) is characterized by progressive bowed legs and tibial torsion
[151]. It results from inhibited growth of the medial proximal tibial growth plate due to excessive abnormal weight bearing
[152,153]. Tibia vara is associated with obesity [151,153-157] and is more common among Black than non-Black
individuals [152,154,156,158]. In one report, the prevalence of tibia vara among 80 Black boys (aged 13 to 19 years) who
weighed ≥210 pounds was 2.5 percent [158].

Clinical features of tibia vara include complaints of knee pain or instability and bowlegs that gradually increase in severity
[101,159]. Severe adiposity may obscure the physical findings and delay the diagnosis. Radiographs are necessary for
diagnosis (image 2). (See "Approach to the child with bow-legs", section on 'Blount disease'.)

Fractures — Obese children are more susceptible to fractures than normal weight children [149,160]. Unlike adults,
children with obesity generally have reduced bone mass when adjusted for body size [161-163]. The relative contributions
of stress from body weight during falls, vitamin D deficiency, reduced bone mass from lack of exercise, and other
biomechanical effects of obesity on bone have not been established [164,165].

NEUROLOGIC

Idiopathic intracranial hypertension — The prevalence of idiopathic intracranial hypertension (pseudotumor cerebri) is
increased in children and adolescents with obesity [166,167]. The risk increases with the severity of obesity (odds ratio
16.14 for severe obesity as compared with normal-weight children) [167]. Although as many as one-half of children who
present with idiopathic intracranial hypertension are obese, the onset of symptoms does not appear to correlate with
weight gain [168].

Children and adolescents with idiopathic intracranial hypertension typically present with headache. Associated complaints
may include nausea, vomiting, retroocular eye pain, transient visual obscurations, visual loss, and diplopia. Papilledema is
the characteristic examination finding (picture 2A-C). Idiopathic intracranial hypertension can cause severe visual
impairment or blindness. Thus, weight loss is an important component of treatment for patients with obesity and idiopathic
intracranial hypertension [62].

The evaluation and management of children and adolescents with idiopathic intracranial hypertension is discussed
separately. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis".)

DERMATOLOGIC — Dermatologic comorbidities of obesity include intertrigo, furunculosis, and hidradenitis suppurativa.
Hidradenitis suppurativa is characterized by inflammatory nodules or deep fluctuant cysts in the intertriginous skin of the
axillae and groin (picture 3). (See "Candidal intertrigo" and "Hidradenitis suppurativa: Pathogenesis, clinical features, and
diagnosis" and "Cellulitis and skin abscess: Clinical manifestations and diagnosis".)

Acanthosis nigricans (picture 4) is a common skin abnormality in individuals with obesity, and is associated with insulin
resistance. Striae distensae (stretch marks) are also common; they are caused by mechanical factors (skin distension),
possibly acting in concert with hormonal factors such as relatively high levels of adrenocorticosteroids [169].
PSYCHOSOCIAL — Psychosocial consequences of childhood obesity are widespread [62,170]. These include alienation
[171,172], distorted peer relationships, poor self-esteem [173,174], distorted body image [175], anxiety [176], and
depression [177-182]. The risk of psychosocial morbidity increases with increasing age and is greater among girls than
boys [170,173,183-185].

In community-based and referral populations, obese children and adolescents and their parents report decreased health-
related quality of life (physical, emotional, social, and school functioning) compared to healthy non-overweight children and
adolescents [181,186-189]. In the referral population, health-related quality of life among severely obese children and
adolescents was similar to that reported by children and adolescents with cancer [186].

In the early school years (age 6 to 10 years), overweight and obese children may become targets of discrimination by their
peers [62,95,190]. In one study from the 1960s of male schoolchildren from Indiana, obesity was associated with negative
characteristics (eg, laziness, lying, cheating, ugliness, dirtiness, and stupidity) [191]. In another study, schoolchildren
preferred children with a variety of handicaps to obese children as their friends [62,192]. In a more recent study from
southwest England, boys and girls who were obese at 7.5 years of age were more likely to be victims of bullying at 8.5
years of age than average weight children [193]. In addition, boys who were obese at 7.5 years were more likely to be
overt bullies at 8.5 years than average weight boys. Despite these issues, many overweight or obese young children
appear to maintain a positive self-image and self-esteem [174,194,195].

Adolescents with obesity also experience bias and bullying from their peers; many, particularly girls, develop a negative
self-image that persists into adulthood [95,175]. Data from the National Longitudinal Survey of Youth indicate that women,
but not men, who were obese in late adolescence and early adulthood completed fewer years of advanced education, and
had decreased family income, lower rates of marriage, and higher rates of poverty compared to their non-obese peers
[196]. Similar data were reported from a British cohort [197].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and
regions around the world are provided separately. (See "Society guideline links: Lipid disorders and atherosclerosis in
children" and "Society guideline links: Obesity in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond
the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition. These articles are best for patients
who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces
are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are
best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to
your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the
keyword(s) of interest.)

● Basics topic (see "Patient education: My child is overweight (The Basics)" and "Patient education: Health risks of
obesity (The Basics)")

SUMMARY

Endocrine

● The reported prevalence of impaired glucose tolerance among obese children and adolescents ranges from 7 to 25
percent, and the prevalence of type 2 diabetes ranges from 0.5 to 4 percent. (See 'Endocrine' above.)

● Fasting plasma glucose between 100 and 125 mg/dL or HbA1C between 5.7 and 6.4 percent suggests impaired
glucose tolerance, and should be further evaluated with an oral glucose tolerance test. (See 'Prediabetes' above and
"Clinical evaluation of the obese child and adolescent", section on 'Laboratory studies'.)

● The metabolic syndrome describes the clustering of abdominal obesity, hyperglycemia, dyslipidemia, and
hypertension, which are risk factors for type 2 diabetes and atherosclerotic cardiovascular disease. Several different
schemes have been used to define the metabolic syndrome in adolescents (table 4). (See 'Metabolic syndrome'
above.)

● Adolescent girls with obesity are at increased risk of hyperandrogenism and early onset polycystic ovary syndrome
 (PCOS). PCOS can include a variety of clinical abnormalities, including hirsutism, menstrual irregularities, acanthosis
nigricans, acne, and seborrhea. In some patients the diagnosis may be difficult to establish during adolescence.
Obesity during adulthood is also associated with reduced fertility. (See 'Hyperandrogenism' above.)

Cardiovascular

● Hypertension is probably the most common comorbidity associated with obesity. Children with obesity are three times
more likely to have hypertension than nonobese children. Ambulatory blood pressure monitoring detects hypertension
in about 50 percent of children and adolescents with obesity. (See 'Hypertension' above.)

● More than 50 percent of obese children have lipid abnormalities as measured by a fasting lipid profile. The typical
pattern is one of elevated concentration of serum low-density lipoprotein (LDL)-cholesterol and triglycerides and
decreased concentration of high-density-lipoprotein (HDL)-cholesterol. (See 'Dyslipidemia' above.)

● Childhood obesity also predisposes to a number of other risk factors for atherosclerosis. These include endothelial
dysfunction, carotid intima-media thickening, the development of early aortic and coronary arterial fatty streaks and
fibrous plaques, decreased arterial distensibility, and increased left atrial diameter. (See 'Other cardiovascular risks'
above.)

● Obesity during childhood and adolescence is associated with an increased risk for major cardiovascular events during
adulthood, independent of adult obesity status. (See 'Adult coronary heart disease' above.)

Gastrointestinal

● About 40 percent of obese children have fatty liver, with a prevalence that varies by ethnicity independent of obesity
status. Approximately 10 percent of obese children and adolescents have mildly elevated serum aminotransferase
concentrations, which are usually caused by nonalcoholic fatty liver disease (NAFLD). Vitamin E (800 int. units daily)
leads to histological improvement in NAFLD in children, but there is insufficient information to develop specific
recommendations for its use in clinical practice. (See 'Nonalcoholic fatty liver disease' above.)

● Asymptomatic gallstones can be detected in approximately 2 percent of obese adolescents; most of whom are
females. If symptoms develop, they tend to include epigastric pain, jaundice, right upper quadrant pain, nausea,
vomiting, and fatty food intolerance. (See 'Cholelithiasis' above.)

Pulmonary

● About 10 percent of children and adolescents with obesity have clinically significant sleep apnea, and the risk is
higher among children with severe obesity and/or consistent snoring. The diagnosis is made with polysomnography.
(See 'Obstructive sleep apnea' above and "Evaluation of suspected obstructive sleep apnea in children".)

Orthopedic

● Orthopedic comorbidities of obesity include slipped capital femoral epiphysis (SCFE) and tibia vara (Blount disease).
In addition, obese children have an increased prevalence of fractures, genu valgum, musculoskeletal pain (eg, back,
leg, knee, ankle, and foot), impaired mobility, and lower extremity malalignment than nonobese children. (See
'Orthopedic' above.)

Psychosocial

● Psychosocial consequences of childhood obesity are common, and include alienation, distorted peer relationships,
poor self-esteem, distorted body image, anxiety, and depression. The risk of psychosocial morbidity increases with
increasing age and is greater among girls than boys. (See 'Psychosocial' above.)

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REFERENCES

1. Ogden CL, Carroll MD, Lawman HG, et al. Trends in Obesity Prevalence Among Children and Adolescents in the
United States, 1988-1994 Through 2013-2014. JAMA 2016; 315:2292.
2. GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, et al. Health Effects of Overweight and Obesity in 195
 Countries over 25 Years. N Engl J Med 2017; 377:13.
3. Dietz WH, Robinson TN. Clinical practice. Overweight children and adolescents. N Engl J Med 2005; 352:2100.
4. Unger R, Kreeger L, Christoffel KK. Childhood obesity. Medical and familial correlates and age of onset. Clin Pediatr
(Phila) 1990; 29:368.
5. Lee H, Pantazis A, Cheng P, et al. The Association Between Adolescent Obesity and Disability Incidence in Young
Adulthood. J Adolesc Health 2016; 59:472.
6. van Dam RM, Willett WC, Manson JE, Hu FB. The relationship between overweight in adolescence and premature
death in women. Ann Intern Med 2006; 145:91.
7. Must A, Jacques PF, Dallal GE, et al. Long-term morbidity and mortality of overweight adolescents. A follow-up of the
Harvard Growth Study of 1922 to 1935. N Engl J Med 1992; 327:1350.
8. Must A, Phillips SM, Naumova EN. Occurrence and timing of childhood overweight and mortality: findings from the
Third Harvard Growth Study. J Pediatr 2012; 160:743.
9. Bjørge T, Engeland A, Tverdal A, Smith GD. Body mass index in adolescence in relation to cause-specific mortality:
a follow-up of 230,000 Norwegian adolescents. Am J Epidemiol 2008; 168:30.
10. Inge TH, King WC, Jenkins TM, et al. The effect of obesity in adolescence on adult health status. Pediatrics 2013;
132:1098.
11. Williams DE, Cadwell BL, Cheng YJ, et al. Prevalence of impaired fasting glucose and its relationship with
cardiovascular disease risk factors in US adolescents, 1999-2000. Pediatrics 2005; 116:1122.
12. Sabin MA, Ford AL, Holly JM, et al. Characterisation of morbidity in a UK, hospital based, obesity clinic. Arch Dis
Child 2006; 91:126.
13. Chan CL, McFann K, Newnes L, et al. Hemoglobin A1c assay variations and implications for diabetes screening in
obese youth. Pediatr Diabetes 2014; 15:557.
14. Wu EL, Kazzi NG, Lee JM. Cost-effectiveness of screening strategies for identifying pediatric diabetes mellitus and
dysglycemia. JAMA Pediatr 2013; 167:32.
15. HEALTHY Study Group, Kaufman FR, Hirst K, et al. Risk factors for type 2 diabetes in a sixth- grade multiracial
cohort: the HEALTHY study. Diabetes Care 2009; 32:953.
16. Marcus MD, Baranowski T, DeBar LL, et al. Severe obesity and selected risk factors in a sixth grade multiracial
cohort: the HEALTHY study. J Adolesc Health 2010; 47:604.
17. Sinha R, Fisch G, Teague B, et al. Prevalence of impaired glucose tolerance among children and adolescents with
marked obesity. N Engl J Med 2002; 346:802.
18. Skinner AC, Perrin EM, Moss LA, Skelton JA. Cardiometabolic Risks and Severity of Obesity in Children and Young
Adults. N Engl J Med 2015; 373:1307.
19. Shah S, Kublaoui BM, Oden JD, White PC. Screening for type 2 diabetes in obese youth. Pediatrics 2009; 124:573.
20. Shalitin S, Abrahami M, Lilos P, Phillip M. Insulin resistance and impaired glucose tolerance in obese children and
adolescents referred to a tertiary-care center in Israel. Int J Obes (Lond) 2005; 29:571.
21. Maffeis C, Pinelli L, Brambilla P, et al. Fasting plasma glucose (FPG) and the risk of impaired glucose tolerance in
obese children and adolescents. Obesity (Silver Spring) 2010; 18:1437.
22. Keskin M, Kurtoglu S, Kendirci M, et al. Homeostasis model assessment is more reliable than the fasting
glucose/insulin ratio and quantitative insulin sensitivity check index for assessing insulin resistance among obese
children and adolescents. Pediatrics 2005; 115:e500.
23. Moller DE, Flier JS. Insulin resistance--mechanisms, syndromes, and implications. N Engl J Med 1991; 325:938.
24. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell
function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28:412.
25. Silfen ME, Manibo AM, McMahon DJ, et al. Comparison of simple measures of insulin sensitivity in young girls with
premature adrenarche: the fasting glucose to insulin ratio may be a simple and useful measure. J Clin Endocrinol
Metab 2001; 86:2863.
26. Vuguin P, Saenger P, Dimartino-Nardi J. Fasting glucose insulin ratio: a useful measure of insulin resistance in girls
with premature adrenarche. J Clin Endocrinol Metab 2001; 86:4618.
27. Dimartino-Nardi J. Premature adrenarche: findings in prepubertal African-American and Caribbean-Hispanic girls.
Acta Paediatr Suppl 1999; 88:67.
28. Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: a simple, accurate method for
assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000; 85:2402.
29. Conwell LS, Trost SG, Brown WJ, Batch JA. Indexes of insulin resistance and secretion in obese children and
adolescents: a validation study. Diabetes Care 2004; 27:314.
30. Brandou F, Brun JF, Mercier J. Limited accuracy of surrogates of insulin resistance during puberty in obese and lean
children at risk for altered glucoregulation. J Clin Endocrinol Metab 2005; 90:761.
31. Uwaifo GI, Fallon EM, Chin J, et al. Indices of insulin action, disposal, and secretion derived from fasting samples
and clamps in normal glucose-tolerant black and white children. Diabetes Care 2002; 25:2081.
32. Gungor N, Saad R, Janosky J, Arslanian S. Validation of surrogate estimates of insulin sensitivity and insulin
secretion in children and adolescents. J Pediatr 2004; 144:47.
33. Muniyappa R, Lee S, Chen H, Quon MJ. Current approaches for assessing insulin sensitivity and resistance in vivo:
advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab 2008; 294:E15.
34. Sjaarda LG, Bacha F, Lee S, et al. Oral disposition index in obese youth from normal to prediabetes to diabetes:
relationship to clamp disposition index. J Pediatr 2012; 161:51.
35. Molnár D. The prevalence of the metabolic syndrome and type 2 diabetes mellitus in children and adolescents. Int J
Obes Relat Metab Disord 2004; 28 Suppl 3:S70.
36. Pinhas-Hamiel O, Dolan LM, Daniels SR, et al. Increased incidence of non-insulin-dependent diabetes mellitus
among adolescents. J Pediatr 1996; 128:608.
37. Goran MI, Davis J, Kelly L, et al. Low prevalence of pediatric type 2 diabetes: where's the epidemic? J Pediatr 2008;
152:753.
38. Hannon TS, Rao G, Arslanian SA. Childhood obesity and type 2 diabetes mellitus. Pediatrics 2005; 116:473.
39. Copeland KC, Zeitler P, Geffner M, et al. Characteristics of adolescents and youth with recent-onset type 2 diabetes:
the TODAY cohort at baseline. J Clin Endocrinol Metab 2011; 96:159.
40. Tirosh A, Shai I, Afek A, et al. Adolescent BMI trajectory and risk of diabetes versus coronary disease. N Engl J Med
2011; 364:1315.
41. Juonala M, Magnussen CG, Berenson GS, et al. Childhood adiposity, adult adiposity, and cardiovascular risk factors.
N Engl J Med 2011; 365:1876.
42. Steinberger J, Daniels SR, Eckel RH, et al. Progress and challenges in metabolic syndrome in children and
adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity
in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing;
and Council on Nutrition, Physical Activity, and Metabolism. Circulation 2009; 119:628.
43. Magge SN, Goodman E, Armstrong SC, et al. The Metabolic Syndrome in Children and Adolescents: Shifting the
Focus to Cardiometabolic Risk Factor Clustering. Pediatrics 2017.
44. Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med
2004; 350:2362.
45. Cook S, Weitzman M, Auinger P, et al. Prevalence of a metabolic syndrome phenotype in adolescents: findings from
the third National Health and Nutrition Examination Survey, 1988-1994. Arch Pediatr Adolesc Med 2003; 157:821.
46. Lambert M, Paradis G, O'Loughlin J, et al. Insulin resistance syndrome in a representative sample of children and
adolescents from Quebec, Canada. Int J Obes Relat Metab Disord 2004; 28:833.
47. Goodman E, Daniels SR, Meigs JB, Dolan LM. Instability in the diagnosis of metabolic syndrome in adolescents.
Circulation 2007; 115:2316.
48. Chi CH, Wang Y, Wilson DM, Robinson TN. Definition of metabolic syndrome in preadolescent girls. J Pediatr 2006;
148:788.
49. Zimmet P, Alberti G, Kaufman F, et al. The metabolic syndrome in children and adolescents. Lancet 2007; 369:2059.
50. Garn SM, Clark DC. Nutrition, growth, development, and maturation: findings from the ten-state nutrition survey of
1968-1970. Pediatrics 1975; 56:306.
51. Wang Y. Is obesity associated with early sexual maturation? A comparison of the association in American boys
versus girls. Pediatrics 2002; 110:903.
52. Kaplowitz PB, Slora EJ, Wasserman RC, et al. Earlier onset of puberty in girls: relation to increased body mass index
and race. Pediatrics 2001; 108:347.
53. Laron Z. Is obesity associated with early sexual maturation? Pediatrics 2004; 113:171.
54. Herman-Giddens ME, Steffes J, Harris D, et al. Secondary sexual characteristics in boys: data from the Pediatric
Research in Office Settings Network. Pediatrics 2012; 130:e1058.
55. Li S, Chen W, Srinivasan SR, et al. Relation of childhood obesity/cardiometabolic phenotypes to adult
cardiometabolic profile: the Bogalusa Heart Study. Am J Epidemiol 2012; 176 Suppl 7:S142.
56. Friedemann C, Heneghan C, Mahtani K, et al. Cardiovascular disease risk in healthy children and its association with
body mass index: systematic review and meta-analysis. BMJ 2012; 345:e4759.
57. Sorof J, Daniels S. Obesity hypertension in children: a problem of epidemic proportions. Hypertension 2002; 40:441.
58. Maggio AB, Aggoun Y, Marchand LM, et al. Associations among obesity, blood pressure, and left ventricular mass. J
Pediatr 2008; 152:489.
59. Stabouli S, Kotsis V, Papamichael C, et al. Adolescent obesity is associated with high ambulatory blood pressure and
increased carotid intimal-medial thickness. J Pediatr 2005; 147:651.
60. Aguilar A, Ostrow V, De Luca F, Suarez E. Elevated ambulatory blood pressure in a multi-ethnic population of obese
children and adolescents. J Pediatr 2010; 156:930.
61. Sun SS, Grave GD, Siervogel RM, et al. Systolic blood pressure in childhood predicts hypertension and metabolic
syndrome later in life. Pediatrics 2007; 119:237.
62. Dietz WH. Health consequences of obesity in youth: childhood predictors of adult disease. Pediatrics 1998; 101:518.
63. Williams DP, Going SB, Lohman TG, et al. Body fatness and risk for elevated blood pressure, total cholesterol, and
serum lipoprotein ratios in children and adolescents. Am J Public Health 1992; 82:358.
64. Harel Z, Riggs S, Vaz R, et al. Isolated low HDL cholesterol emerges as the most common lipid abnormality among
obese adolescents. Clin Pediatr (Phila) 2010; 49:29.
65. Morrison JA, Sprecher DL, Barton BA, et al. Overweight, fat patterning, and cardiovascular disease risk factors in
black and white girls: The National Heart, Lung, and Blood Institute Growth and Health Study. J Pediatr 1999;
135:458.
66. Caprio S, Hyman LD, McCarthy S, et al. Fat distribution and cardiovascular risk factors in obese adolescent girls:
importance of the intraabdominal fat depot. Am J Clin Nutr 1996; 64:12.
67. Hanevold C, Waller J, Daniels S, et al. The effects of obesity, gender, and ethnic group on left ventricular hypertrophy
and geometry in hypertensive children: a collaborative study of the International Pediatric Hypertension Association.
Pediatrics 2004; 113:328.
68. Urbina EM, Gidding SS, Bao W, et al. Effect of body size, ponderosity, and blood pressure on left ventricular growth
in children and young adults in the Bogalusa Heart Study. Circulation 1995; 91:2400.
69. Urbina EM, Gidding SS, Bao W, et al. Association of fasting blood sugar level, insulin level, and obesity with left
ventricular mass in healthy children and adolescents: The Bogalusa Heart Study. Am Heart J 1999; 138:122.
70. Chinali M, de Simone G, Roman MJ, et al. Impact of obesity on cardiac geometry and function in a population of
adolescents: the Strong Heart Study. J Am Coll Cardiol 2006; 47:2267.
71. Crowley DI, Khoury PR, Urbina EM, et al. Cardiovascular impact of the pediatric obesity epidemic: higher left
ventricular mass is related to higher body mass index. J Pediatr 2011; 158:709.
72. Cote AT, Harris KC, Panagiotopoulos C, et al. Childhood obesity and cardiovascular dysfunction. J Am Coll Cardiol
2013; 62:1309.
73. Sanchez AA, Levy PT, Sekarski TJ, et al. Markers of cardiovascular risk, insulin resistance, and ventricular
dysfunction and remodeling in obese adolescents. J Pediatr 2015; 166:660.
74. Freedman DS, Dietz WH, Tang R, et al. The relation of obesity throughout life to carotid intima-media thickness in
adulthood: the Bogalusa Heart Study. Int J Obes Relat Metab Disord 2004; 28:159.
75. Tounian P, Aggoun Y, Dubern B, et al. Presence of increased stiffness of the common carotid artery and endothelial
dysfunction in severely obese children: a prospective study. Lancet 2001; 358:1400.
76. Zhu W, Huang X, He J, et al. Arterial intima-media thickening and endothelial dysfunction in obese Chinese children.
Eur J Pediatr 2005; 164:337.
77. Woo KS, Chook P, Yu CW, et al. Overweight in children is associated with arterial endothelial dysfunction and intima-
media thickening. Int J Obes Relat Metab Disord 2004; 28:852.
78. Whincup PH, Gilg JA, Donald AE, et al. Arterial distensibility in adolescents: the influence of adiposity, the metabolic
syndrome, and classic risk factors. Circulation 2005; 112:1789.
79. Iannuzzi A, Licenziati MR, Acampora C, et al. Increased carotid intima-media thickness and stiffness in obese
 children. Diabetes Care 2004; 27:2506.
80. Yu JJ, Yeom HH, Chung S, et al. Left atrial diameters in overweight children with normal blood pressure. J Pediatr
2006; 148:321.
81. Meyer AA, Kundt G, Steiner M, et al. Impaired flow-mediated vasodilation, carotid artery intima-media thickening,
and elevated endothelial plasma markers in obese children: the impact of cardiovascular risk factors. Pediatrics
2006; 117:1560.
82. Groner JA, Joshi M, Bauer JA. Pediatric precursors of adult cardiovascular disease: noninvasive assessment of early
vascular changes in children and adolescents. Pediatrics 2006; 118:1683.
83. Mittelman SD, Gilsanz P, Mo AO, et al. Adiposity predicts carotid intima-media thickness in healthy children and
adolescents. J Pediatr 2010; 156:592.
84. Skinner AC, Steiner MJ, Henderson FW, Perrin EM. Multiple markers of inflammation and weight status: cross-
sectional analyses throughout childhood. Pediatrics 2010; 125:e801.
85. Osiniri I, Sitjar C, Soriano-Rodríguez P, et al. Carotid intima-media thickness at 7 years of age: relationship to C-
reactive protein rather than adiposity. J Pediatr 2012; 160:276.
86. Atabek ME, Pirgon O, Kivrak AS. Evidence for association between insulin resistance and premature carotid
atherosclerosis in childhood obesity. Pediatr Res 2007; 61:345.
87. Shah AS, Gao Z, Urbina EM, et al. Prediabetes: the effects on arterial thickness and stiffness in obese youth. J Clin
Endocrinol Metab 2014; 99:1037.
88. Zhu H, Yan W, Ge D, et al. Relationships of cardiovascular phenotypes with healthy weight, at risk of overweight, and
overweight in US youths. Pediatrics 2008; 121:115.
89. Twig G, Yaniv G, Levine H, et al. Body-Mass Index in 2.3 Million Adolescents and Cardiovascular Death in
Adulthood. N Engl J Med 2016; 374:2430.
90. Baker JL, Olsen LW, Sørensen TI. Childhood body-mass index and the risk of coronary heart disease in adulthood. N
Engl J Med 2007; 357:2329.
91. Bibbins-Domingo K, Coxson P, Pletcher MJ, et al. Adolescent overweight and future adult coronary heart disease. N
Engl J Med 2007; 357:2371.
92. Speiser PW, Rudolf MC, Anhalt H, et al. Childhood obesity. J Clin Endocrinol Metab 2005; 90:1871.
93. Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological
severity. Gastroenterology 1999; 116:1413.
94. Lavine JE, Schwimmer JB. Nonalcoholic fatty liver disease in the pediatric population. Clin Liver Dis 2004; 8:549.
95. Huang JS, Barlow SE, Quiros-Tejeira RE, et al. Childhood obesity for pediatric gastroenterologists. J Pediatr
Gastroenterol Nutr 2013; 56:99.
96. Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, et al. The natural history of non-alcoholic fatty liver
disease in children: a follow-up study for up to 20 years. Gut 2009; 58:1538.
97. Mandato C, Lucariello S, Licenziati MR, et al. Metabolic, hormonal, oxidative, and inflammatory factors in pediatric
obesity-related liver disease. J Pediatr 2005; 147:62.
98. Schwimmer JB, Deutsch R, Rauch JB, et al. Obesity, insulin resistance, and other clinicopathological correlates of
pediatric nonalcoholic fatty liver disease. J Pediatr 2003; 143:500.
99. Schwimmer JB, Pardee PE, Lavine JE, et al. Cardiovascular risk factors and the metabolic syndrome in pediatric
nonalcoholic fatty liver disease. Circulation 2008; 118:277.
100. Zhang H, Yang H, Lai C, et al. Quantitative relationship between liver fat content and metabolic syndrome in obese
children and adolescents. Clin Endocrinol (Oxf) 2015; 83:43.
101. Strauss RS, Barlow SE, Dietz WH. Prevalence of abnormal serum aminotransferase values in overweight and obese
adolescents. J Pediatr 2000; 136:727.
102. Schwimmer JB, McGreal N, Deutsch R, et al. Influence of gender, race, and ethnicity on suspected fatty liver in
obese adolescents. Pediatrics 2005; 115:e561.
103. Welsh JA, Karpen S, Vos MB. Increasing prevalence of nonalcoholic fatty liver disease among United States
adolescents, 1988-1994 to 2007-2010. J Pediatr 2013; 162:496.
104. Kohli R, Sunduram S, Mouzaki M, et al. Pediatric Nonalcoholic Fatty Liver Disease: A Report from the Expert
Committee on Nonalcoholic Fatty Liver Disease (ECON). J Pediatr 2016; 172:9.
105. Schwimmer JB, Deutsch R, Kahen T, et al. Prevalence of fatty liver in children and adolescents. Pediatrics 2006;
118:1388.
106. Tominaga K, Kurata JH, Chen YK, et al. Prevalence of fatty liver in Japanese children and relationship to obesity. An
epidemiological ultrasonographic survey. Dig Dis Sci 1995; 40:2002.
107. Chan DF, Li AM, Chu WC, et al. Hepatic steatosis in obese Chinese children. Int J Obes Relat Metab Disord 2004;
28:1257.
108. Baldridge AD, Perez-Atayde AR, Graeme-Cook F, et al. Idiopathic steatohepatitis in childhood: a multicenter
retrospective study. J Pediatr 1995; 127:700.
109. Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 2000; 30:48.
110. Franzese A, Vajro P, Argenziano A, et al. Liver involvement in obese children. Ultrasonography and liver enzyme
levels at diagnosis and during follow-up in an Italian population. Dig Dis Sci 1997; 42:1428.
111. Tazawa Y, Noguchi H, Nishinomiya F, Takada G. Serum alanine aminotransferase activity in obese children. Acta
Paediatr 1997; 86:238.
112. Kinugasa A, Tsunamoto K, Furukawa N, et al. Fatty liver and its fibrous changes found in simple obesity of children. J
Pediatr Gastroenterol Nutr 1984; 3:408.
113. Vajro P, Fontanella A, Perna C, et al. Persistent hyperaminotransferasemia resolving after weight reduction in obese
children. J Pediatr 1994; 125:239.
114. Carter-Kent C, Yerian LM, Brunt EM, et al. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological
study. Hepatology 2009; 50:1113.
115. Molleston JP, Schwimmer JB, Yates KP, et al. Histological abnormalities in children with nonalcoholic fatty liver
disease and normal or mildly elevated alanine aminotransferase levels. J Pediatr 2014; 164:707.
116. Sundaram SS, Sokol RJ, Capocelli KE, et al. Obstructive sleep apnea and hypoxemia are associated with advanced
liver histology in pediatric nonalcoholic fatty liver disease. J Pediatr 2014; 164:699.
117. Schwimmer JB, Dunn W, Norman GJ, et al. SAFETY study: alanine aminotransferase cutoff values are set too high
for reliable detection of pediatric chronic liver disease. Gastroenterology 2010; 138:1357.
118. Radetti G, Kleon W, Stuefer J, Pittschieler K. Non-alcoholic fatty liver disease in obese children evaluated by
magnetic resonance imaging. Acta Paediatr 2006; 95:833.
119. Shannon A, Alkhouri N, Carter-Kent C, et al. Ultrasonographic quantitative estimation of hepatic steatosis in children
With NAFLD. J Pediatr Gastroenterol Nutr 2011; 53:190.
120. Schwimmer JB, Middleton MS, Behling C, et al. Magnetic resonance imaging and liver histology as biomarkers of
hepatic steatosis in children with nonalcoholic fatty liver disease. Hepatology 2015; 61:1887.
121. Baker S, Barlow S, Cochran W, et al. Overweight children and adolescents: a clinical report of the North American
Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005; 40:533.
122. McNair A. Non-alcoholic steatohepatitis (NASH): why biopsy? Gut 2002; 51:898; author reply 898.
123. Bohte AE, Koot BG, van der Baan-Slootweg OH, et al. US cannot be used to predict the presence or severity of
hepatic steatosis in severely obese adolescents. Radiology 2012; 262:327.
124. Awai HI, Newton KP, Sirlin CB, et al. Evidence and recommendations for imaging liver fat in children, based on
systematic review. Clin Gastroenterol Hepatol 2014; 12:765.
125. Marginean CO, Marginean C. Elastographic assessment of liver fibrosis in children: A prospective single center
experience. Eur J Radiol 2012; 81:e870.
126. Lawlor DA, Callaway M, Macdonald-Wallis C, et al. Nonalcoholic fatty liver disease, liver fibrosis, and
cardiometabolic risk factors in adolescence: a cross-sectional study of 1874 general population adolescents. J Clin
Endocrinol Metab 2014; 99:E410.
127. Adams LA, Lindor KD, Angulo P. The prevalence of autoantibodies and autoimmune hepatitis in patients with
nonalcoholic Fatty liver disease. Am J Gastroenterol 2004; 99:1316.
128. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease:
practice guideline by the American Gastroenterological Association, American Association for the Study of Liver
Diseases, and American College of Gastroenterology. Gastroenterology 2012; 142:1592.
129. Schwimmer JB, Behling C, Newbury R, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology
2005; 42:641.
130. Suzuki A, Abdelmalek MF, Schwimmer JB, et al. Association between puberty and features of nonalcoholic fatty liver
 disease. Clin Gastroenterol Hepatol 2012; 10:786.
131. Huang MA, Greenson JK, Chao C, et al. One-year intense nutritional counseling results in histological improvement
in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol 2005; 100:1072.
132. Reinehr T, Schmidt C, Toschke AM, Andler W. Lifestyle intervention in obese children with non-alcoholic fatty liver
disease: 2-year follow-up study. Arch Dis Child 2009; 94:437.
133. Pozzato C, Verduci E, Scaglioni S, et al. Liver fat change in obese children after a 1-year nutrition-behavior
intervention. J Pediatr Gastroenterol Nutr 2010; 51:331.
134. Nobili V, Marcellini M, Devito R, et al. NAFLD in children: a prospective clinical-pathological study and effect of
lifestyle advice. Hepatology 2006; 44:458.
135. Nobili V, Manco M, Ciampalini P, et al. Metformin use in children with nonalcoholic fatty liver disease: an open-label,
24-month, observational pilot study. Clin Ther 2008; 30:1168.
136. Nobili V, Manco M, Devito R, et al. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty
liver disease: a randomized, controlled trial. Hepatology 2008; 48:119.
137. Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty
liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011; 305:1659.
138. Friesen CA, Roberts CC. Cholelithiasis. Clinical characteristics in children. Case analysis and literature review. Clin
Pediatr (Phila) 1989; 28:294.
139. Holcomb GW Jr, O'Neill JA Jr, Holcomb GW 3rd. Cholecystitis, cholelithiasis and common duct stenosis in children
and adolescents. Ann Surg 1980; 191:626.
140. Goodman DB. Cholelithiasis in persons under 25 years old. Clinicopathologic review of 96 cases. JAMA 1976;
236:1731.
141. Koebnick C, Smith N, Black MH, et al. Pediatric obesity and gallstone disease. J Pediatr Gastroenterol Nutr 2012;
55:328.
142. Mehta S, Lopez ME, Chumpitazi BP, et al. Clinical characteristics and risk factors for symptomatic pediatric
gallbladder disease. Pediatrics 2012; 129:e82.
143. Kaechele V, Wabitsch M, Thiere D, et al. Prevalence of gallbladder stone disease in obese children and adolescents:
influence of the degree of obesity, sex, and pubertal development. J Pediatr Gastroenterol Nutr 2006; 42:66.
144. Reif S, Sloven DG, Lebenthal E. Gallstones in children. Characterization by age, etiology, and outcome. Am J Dis
Child 1991; 145:105.
145. Verhulst SL, Schrauwen N, Haentjens D, et al. Sleep-disordered breathing in overweight and obese children and
adolescents: prevalence, characteristics and the role of fat distribution. Arch Dis Child 2007; 92:205.
146. Krebs NF, Himes JH, Jacobson D, et al. Assessment of child and adolescent overweight and obesity. Pediatrics
2007; 120 Suppl 4:S193.
147. Taylor ED, Theim KR, Mirch MC, et al. Orthopedic complications of overweight in children and adolescents.
Pediatrics 2006; 117:2167.
148. Stovitz SD, Pardee PE, Vazquez G, et al. Musculoskeletal pain in obese children and adolescents. Acta Paediatr
2008; 97:489.
149. Chan G, Chen CT. Musculoskeletal effects of obesity. Curr Opin Pediatr 2009; 21:65.
150. Pomerantz WJ, Timm NL, Gittelman MA. Injury patterns in obese versus nonobese children presenting to a pediatric
emergency department. Pediatrics 2010; 125:681.
151. Dietz WH Jr, Gross WL, Kirkpatrick JA Jr. Blount disease (tibia vara): another skeletal disorder associated with
childhood obesity. J Pediatr 1982; 101:735.
152. Henderson RC. Tibia vara: a complication of adolescent obesity. J Pediatr 1992; 121:482.
153. Blount WP. Tibia vara, osteochondrosis deformans tibiae. J Bone Joint Surg 1937; 19:1.
154. Thompson GH, Carter JR. Late-onset tibia vara (Blount's disease). Current concepts. Clin Orthop Relat Res 1990;
:24.
155. Davids JR, Huskamp M, Bagley AM. A dynamic biomechanical analysis of the etiology of adolescent tibia vara. J
Pediatr Orthop 1996; 16:461.
156. Loder RT, Schaffer JJ, Bardenstein MB. Late-onset tibia vara. J Pediatr Orthop 1991; 11:162.
157. Sabharwal S, Zhao C, McClemens E. Correlation of body mass index and radiographic deformities in children with
 Blount disease. J Bone Joint Surg Am 2007; 89:1275.
158. Henderson RC, Kemp GJ, Hayes PR. Prevalence of late-onset tibia vara. J Pediatr Orthop 1993; 13:255.
159. Tachdjian MO. The knee and leg. In: Clinical Pediatric Orthopedics: The Art of Diagnosis and Principles of Managem
ent, Appleton and Lange, Stamford, CT 1997. p.107.
160. Kim SJ, Ahn J, Kim HK, Kim JH. Obese children experience more extremity fractures than nonobese children and
are significantly more likely to die from traumatic injuries. Acta Paediatr 2016; 105:1152.
161. Goulding A, Jones IE, Taylor RW, et al. Bone mineral density and body composition in boys with distal forearm
fractures: a dual-energy x-ray absorptiometry study. J Pediatr 2001; 139:509.
162. Dimitri P, Wales JK, Bishop N. Fat and bone in children: differential effects of obesity on bone size and mass
according to fracture history. J Bone Miner Res 2010; 25:527.
163. Wetzsteon RJ, Petit MA, Macdonald HM, et al. Bone structure and volumetric BMD in overweight children: a
longitudinal study. J Bone Miner Res 2008; 23:1946.
164. Lenders CM, Feldman HA, Von Scheven E, et al. Relation of body fat indexes to vitamin D status and deficiency
among obese adolescents. Am J Clin Nutr 2009; 90:459.
165. Dimitri P, Jacques RM, Paggiosi M, et al. Leptin may play a role in bone microstructural alterations in obese children.
J Clin Endocrinol Metab 2015; 100:594.
166. Scott IU, Siatkowski RM, Eneyni M, et al. Idiopathic intracranial hypertension in children and adolescents. Am J
Ophthalmol 1997; 124:253.
167. Brara SM, Koebnick C, Porter AH, Langer-Gould A. Pediatric idiopathic intracranial hypertension and extreme
childhood obesity. J Pediatr 2012; 161:602.
168. Weisberg LA, Chutorian AM. Pseudotumor cerebri of childhood. Am J Dis Child 1977; 131:1243.
169. SIMKIN B, ARCE R. Steroid excretion in obese patients with colored abdominal striae. N Engl J Med 1962;
266:1031.
170. Reilly JJ, Methven E, McDowell ZC, et al. Health consequences of obesity. Arch Dis Child 2003; 88:748.
171. Strauss RS, Pollack HA. Social marginalization of overweight children. Arch Pediatr Adolesc Med 2003; 157:746.
172. Eisenberg ME, Neumark-Sztainer D, Story M. Associations of weight-based teasing and emotional well-being among
adolescents. Arch Pediatr Adolesc Med 2003; 157:733.
173. Strauss RS. Childhood obesity and self-esteem. Pediatrics 2000; 105:e15.
174. French SA, Story M, Perry CL. Self-esteem and obesity in children and adolescents: a literature review. Obes Res
1995; 3:479.
175. Stunkard A, Burt V. Obesity and the body image. II. Age at onset of disturbances in the body image. Am J Psychiatry
1967; 123:1443.
176. Becker ES, Margraf J, Türke V, et al. Obesity and mental illness in a representative sample of young women. Int J
Obes Relat Metab Disord 2001; 25 Suppl 1:S5.
177. Goodman E, Whitaker RC. A prospective study of the role of depression in the development and persistence of
adolescent obesity. Pediatrics 2002; 110:497.
178. Zametkin AJ, Zoon CK, Klein HW, Munson S. Psychiatric aspects of child and adolescent obesity: a review of the
past 10 years. J Am Acad Child Adolesc Psychiatry 2004; 43:134.
179. Pine DS, Goldstein RB, Wolk S, Weissman MM. The association between childhood depression and adulthood body
mass index. Pediatrics 2001; 107:1049.
180. Sjöberg RL, Nilsson KW, Leppert J. Obesity, shame, and depression in school-aged children: a population-based
study. Pediatrics 2005; 116:e389.
181. Zeller MH, Roehrig HR, Modi AC, et al. Health-related quality of life and depressive symptoms in adolescents with
extreme obesity presenting for bariatric surgery. Pediatrics 2006; 117:1155.
182. Frisco ML, Houle JN, Lippert AM. Weight change and depression among US young women during the transition to
adulthood. Am J Epidemiol 2013; 178:22.
183. Erickson SJ, Robinson TN, Haydel KF, Killen JD. Are overweight children unhappy?: Body mass index, depressive
symptoms, and overweight concerns in elementary school children. Arch Pediatr Adolesc Med 2000; 154:931.
184. Falkner NH, Neumark-Sztainer D, Story M, et al. Social, educational, and psychological correlates of weight status in
adolescents. Obes Res 2001; 9:32.
185. Lawlor DA, Mamun AA, O'Callaghan MJ, et al. Is being overweight associated with behavioural problems in
childhood and adolescence? Findings from the Mater-University study of pregnancy and its outcomes. Arch Dis Child
2005; 90:692.
186. Schwimmer JB, Burwinkle TM, Varni JW. Health-related quality of life of severely obese children and adolescents.
JAMA 2003; 289:1813.
187. Williams J, Wake M, Hesketh K, et al. Health-related quality of life of overweight and obese children. JAMA 2005;
293:70.
188. Fallon EM, Tanofsky-Kraff M, Norman AC, et al. Health-related quality of life in overweight and nonoverweight black
and white adolescents. J Pediatr 2005; 147:443.
189. Sawyer MG, Harchak T, Wake M, Lynch J. Four-year prospective study of BMI and mental health problems in young
children. Pediatrics 2011; 128:677.
190. Puhl RM, Peterson JL, Luedicke J. Weight-based victimization: bullying experiences of weight loss treatment-seeking
youth. Pediatrics 2013; 131:e1.
191. Staffieri JR. A study of social stereotype of body image in children. J Pers Soc Psychol 1967; 7:101.
192. Richardson SA, Goodman N, Hastorf AH, et al. Cultural uniformity in reaction to physical disabilities. Am Soc Rev
1961; 26:241.
193. Griffiths LJ, Wolke D, Page AS, et al. Obesity and bullying: different effects for boys and girls. Arch Dis Child 2006;
91:121.
194. Kaplan KM, Wadden TA. Childhood obesity and self-esteem. J Pediatr 1986; 109:367.
195. Sallade J. A comparison of the psychological adjustment of obese vs. non-obese children. J Psychosom Res 1973;
17:89.
196. Gortmaker SL, Must A, Perrin JM, et al. Social and economic consequences of overweight in adolescence and
young adulthood. N Engl J Med 1993; 329:1008.
197. Sargent JD, Blanchflower DG. Obesity and stature in adolescence and earnings in young adulthood. Analysis of a
British birth cohort. Arch Pediatr Adolesc Med 1994; 148:681.

Topic 5869 Version 53.0

GRAPHICS
Trends in obesity among children and adolescents aged 2–19 years, by age: United States,
1963–1965 through 2013–2014

Data from the United States Health and Nutrition Examination Surveys (NHANES). Obesity is defined as a body mass index
(BMI) ≥95th percentile for age and gender. This figure does not distinguish between groups with mild versus severe obesity.

Fryar CD, Carroll MD, and Ogden CL. Prevalence of Overweight and Obesity Among Children and Adolescents Aged 2–19 Years: United
States, 1963–1965 Through 2013–2014. Health E-Stats July 2016. Available at:
http://www.cdc.gov/nchs/data/hestat/obesity_child_13_14/obesity_child_13_14.htm

Graphic 62778 Version 4.0

Categories of increased risk for diabetes (prediabetes)*

FPG 100 to 125 mg/dL (5.6 to 6.9 mmol/L) (IFG)

Two-hour post-load glucose on the 75 g OGTT 140 to 199 mg/dL (7.8 to 11.0 mmol/L) (IGT)

A1C 5.7 to 6.4% (39 to 46 mmol/mol)

FPG: fasting plasma glucose; IFG: impaired fasting glucose; OGTT: oral glucose tolerance test; IGT: impaired glucose
tolerance; A1C: glycated hemoglobin.
* For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at
higher ends of the range.

Reprinted with permission from the American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care
2011; 34:S11. Copyright © 2011 American Diabetes Association. Table also published in: American Diabetes Association.
Standards of medical care in diabetes—2013. Diabetes Care 2013; 36 Suppl 1:S11. The content within this table is still current as
of the 2018 version of the Standards of Medical Care in Diabetes.

Graphic 82479 Version 13.0

Surrogate measures of insulin resistance in children and adolescents

Homeostasis model assessment (HOMA)

[Fasting insulin concentration (in microU/mL) x fasting glucose concentration (in mmol/L)] ÷ 22.5

OR

[Fasting insulin concentration (in milliunits/mL) x fasting glucose concentration (in mg/dL)] ÷ 405

The HOMA value increases with increasing insulin resistance. A threshold value to define insulin resistance in children and
adolescents has not been defined. Proposed thresholds range from >3.16 [1] to >4 [2]. Other investigators propose cutoffs
that vary with pubertal status, with a threshold of >2.5 in prepubertal children (SMR stage I), and >4.0 in pubertal-aged
children (SMR stage II and above) [3].

Fasting glucose/insulin ratio (FGIR)

Fasting glucose concentration/fasting insulin concentration

The FGIR value decreases with increasing insulin resistance. FGIR <7 suggests insulin resistance [4].

Quantitative insulin sensitivity check index (QUICKI)

1 ÷ [log fasting insulin concentration (microU/mL) + log glucose concentration (mg/dL)]

The QUICKI value decreases with increasing insulin resistance. The normal range of QUICKI in children and adolescents
has not yet been determined. In one study of obese children and adolescents, mean QUICKI was 0.313 and 0.339 in
subjects with and without insulin resistance, respectively [1].

HOMA: homeostasis model assessment; SMR: sexual maturity rating (Tanner stage); FGIR: fasting glucose/insulin ratio; QUICKI:
quantitative insulin sensitivity check index.

References: ​
1. Keskin M, Kurtoglu S, Kendirci M, et al. Homeostasis model assessment is more reliable than the fasting glucose/insulin
ratio and quantitative insulin sensitivity check index for assessing insulin resistance among obese children and adolescents.
Pediatrics 2005; 115:e500.
2. Reinehr T, Andler W. Changes in the atherogenic risk factor profile according to degree of weight loss. Arch Dis Child 2004;
89:419.
3. Valerio G, Licenziati MR, Iannuzzi A et al. Insulin resistance and impaired glucose tolerance in obese children and
adolescents from Southern Italy. Nutr Metab Cardiovasc Dis 2006; 16:279.
4. Dimartino-Nardi J. Premature adrenarche: findings in prepubertal African-American and Caribbean-Hispanic girls. Acta
Paediatr Suppl 1999; 88:67.

Graphic 71901 Version 5.0

ADA criteria for the diagnosis of diabetes

1. A1C ≥6.5%. The test should be performed in a laboratory using a method that is NGSP certified and standardized to the
DCCT assay.*
OR

2. FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least eight hours.*
OR

3. Two-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed as described by the
World Health Organization, using a glucose load containing the equivalent of 75-gram anhydrous glucose dissolved in water.*
OR

4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1
mmol/L).

ADA: American Diabetes Association; A1C: glycated hemoglobin; NGSP: National Glycohemoglobin Standardization Program;
DCCT: Diabetes Control and Complications Trial; FPG: fasting plasma glucose; OGTT: oral glucose tolerance test.
* In the absence of unequivocal hyperglycemia, criteria 1 to 3 should be confirmed by repeat testing.

Reprinted with permission from: American Diabetes Association. Standards of Medical Care in Diabetes 2011. Diabetes Care 2011;
34:S11. Copyright © 2011 American Diabetes Association. The content within this table is still current as of the 2018 version of
the Standards of Medical Care in Diabetes.

Graphic 61853 Version 13.0

Definitions of metabolic syndrome in children and adolescents

Parameters Modified ATP III IDF (10 to 16 years) NHANES III

Required

Waist circumference ≥90th percentile* ≥90th percentile

Number of abnormalities ≥3 ≥2 All

Triglyceride >95th percentile ≥150 mg/dL (1.7 mmol/L) ≥110 mg/dL (1.24 mmol/L)

HDL <5th percentile <40 mg/dL (1.03 mmol/L) ≤40 mg/dL (1.03 mmol/L)

BP Either Either ≥90th percentile

Systolic >95th percentile >130 mmHg

Diastolic >95th percentile ≥85 mmHg

Glucose Impaired glucose tolerance ≥100 mg/dL (5.6 mmol/L) Fasting ≥110 mg/dL (6.1 mmol/L)

ATP III: Adult Treatment Panel; IDF: International Diabetes Federation; NHANES: National Health and Nutrition Examination
Survey; HDL: high-density lipoprotein; BP: blood pressure.
* Ethnic-specific waist circumference (see Fernandez JR, Redden DT, Pietrobelli A, et al. Waist circumference percentiles in
nationally representative samples of African-American, European-American, and Mexican-American children and adolescents. J
Pediatr 2004; 145:439).

Graphic 66120 Version 4.0

2017 American Academy of Pediatrics updated definitions for pediatric blood pressure
categories

For children aged 1 to 13 years For children aged ≥13 years

Normal BP Systolic and diastolic BP <90 th percentile Systolic BP <120 and diastolic BP <80 mmHg

Elevated BP Systolic and diastolic BP ≥90 th percentile to Systolic BP 120 to 129 and diastolic BP <80
<95 th percentile, or 120/80 mmHg to <95 th mmHg
percentile (whichever is lower)

Stage 1 HTN Systolic and diastolic BP ≥95 th percentile to 130/80 to 139/89 mmHg
<95 th percentile + 12 mmHg, or
130/80 to 139/89 mmHg (whichever is lower)

Stage 2 HTN Systolic and diastolic BP ≥95 th percentile + 12 ≥140/90 mmHg

mmHg, or
≥140/90 mmHg (whichever is lower)

BP: blood pressure; HTN: hypertension.

Reproduced with permission from: Pediatrics, Vol. 140, doi: 10.1542/peds.2017-1904. Copyright © 2017 by the AAP.

Graphic 114574 Version 1.0

Definition of lipid levels in children from the 2011 Expert Panel Integrated Guidelines for
Cardiovascular Health and Risk reduction in Children and Adolescents*

Acceptable Borderline
Category High Δ
mg/dL (mmol/L) mg/dL (mmol/L)

TC <170 (4.4) 170 to 199 (4.4 to 5.2) ≥200 (5.2)

LDL-C <110 (2.8) 110 to 129 (2.8 to 3.3) ≥130 (3.4)

Non-HDL-C <120 (3.1) 120 to 144 (3.1 to 3.7) ≥145 (3.8)

ApoB <90 (2.3) 90 to 109 (2.3 to 2.8) ≥110 (2.8)

TG

• 0 to 9 years <75 (0.8) 75 to 99 (0.8 to 1.1) ≥100 (1.1)

• 10 to 19 years <90 (1 mmol/L) 90 to 129 (1 to 1.5) ≥130 (1.5)

Category Acceptable Borderline Low Δ

HDL-C >45 (1.2) 40 to 45 (1 to 1.2) <40 (1)

ApoA-1 >120 (3.1) 115 to 120 (3 to 3.1) <115 (3)

TC: total cholesterol; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein; ApoB: apolipoprotein B; ApoA-1:
apolipoprotein A-1; TG: triglycerides.
* Values for plasma lipid and lipoprotein levels are from the National Cholesterol Education Program (NCEP) Expert Panel on
Cholesterol Levels in Children. Non-HDL-C values from the Bogalusa Heart Study are equivalent to the NCEP Pediatric Panel cut
points for LDL-C. Values for plasma apoB and apoA-1 are from the National Health and Nutrition Examination Survey III
(NHANES III).
Δ The threshold points for high and borderline-high values represent approximately the 95th and 75th percentiles, respectively.
Low threshold points for HDL-C and apoA-1 represent approximately the 10th percentile.

Reproduced from: Daniels SR, Benuck I, Christakis DA, et al. Expert panel on integrated guidelines for cardiovascular health and
risk reduction in children and adolescents: Full report, 2011. National Heart Lung and Blood Institute. Available at:
http://www.nhlbi.nih.gov/guidelines/cvd_ped/peds_guidelines_full.pdf.

Graphic 68183 Version 3.0

BMI in adolescence predicts adult cardiovascular mortality

These data are from a large population study from Israel and show that BMI during late
adolescence was associated with cardiovascular mortality in mid-adulthood. The hazard ratio for
death is compared with the reference group with BMI between the 5th and 24th percentiles.

BMI: body mass index.

Data from: Twig G, Yaniv G, Levine H, et al. Body-mass index in 2.3 million adolescents and
cardiovascular death in adulthood. N Engl J Med 2016; 374:2430.

Graphic 107722 Version 3.0

Nonalcoholic steatohepatitis liver biopsy

Liver biopsy showing steatosis, hepatocyte balloon degeneration, mixed

acute and chronic inflammation, and pericellular fibrosis.

Courtesy of Marshall M. Kaplan, MD.

Graphic 59170 Version 1.0

Progression from minimal stable/chronic to unstable/acute
slipped capital femoral epiphysis (SCFE)

Anteroposterior view of the hip (panel A) demonstrating minimal stable/chronic

SCFE on the left. Widening, lucency, and irregularity of the physis and blurring of
the junction between the physis and the metaphysis are present in Panel A. The
child was sent home after these radiographs. Four days later, the patient returned
with an unstable/acute SCFE (panel B), highlighting the importance of urgent
management and avoidance of weight bearing until orthopedic evaluation.

Courtesy of William Phillips, MD.

Graphic 82320 Version 3.0

Blount disease radiograph

Radiograph of a patient with bilateral Blount disease showing characteristic

medial beaking and downward slope of the proximal tibia metaphysis
(arrows).

Courtesy of Scott Rosenfeld, MD.

Graphic 57787 Version 3.0

Normal optic disc Grade 0

Courtesy of Michael Wall, MD.

Graphic 54781 Version 1.0

Optic disc Frisén Grade II

Frisén Grade II showing the halo of disc edema is circumferential.

Courtesy of Michael Wall, MD.

Graphic 59423 Version 1.0

Optic disc Frisén Grade III

Frisén Grade 3 showing obscuration of a major vessel as it leaves the optic

disc (arrow).

Courtesy of Michael Wall, MD.

Graphic 72175 Version 2.0

Hidradenitis suppurativa

Comedones and bridged scars in a flexure.

Reproduced with permission from: Ridley CM, Neill SM (Eds), The Vulva, 2nd ed,
Blackwell Science, Oxford, 1999, p.141.

Graphic 77990 Version 4.0

Acanthosis nigricans

Classic hyperpigmented axillary lesion in acanthosis nigricans.

Courtesy of Jeffrey Flier, MD.

Graphic 53776 Version 3.0

Contributor Disclosures
William J Klish, MD Nothing to disclose Kathleen J Motil, MD, PhD Consultant/Advisory Boards: Mallinckrodt
Pharmaceuticals/InfaCare Pharmaceutical Corporation [Jaundice (Stannsoporfin)]. Mitchell E Geffner,
MD Grant/Research/Clinical Trial Support: Versartis [Growth (Somatropin)]. Consultant/Advisory Boards: Abbvie [Puberty
(Leuprolide)]; Daiichi-Sankyo [Type 2 diabetes (Colesevelam)]; Diurnal [Congenital adrenal hyperplasia (Hydrocortisone)];
Endo [Puberty (Histrelin)]; Ipsen [Growth (Mecasermin)]; NovoNordisk [Growth (Somatropin)]; Pfizer [Growth (Somatropin)];
Sandoz [Growth (Somatropin)]; Tolmar [DSMB; Puberty (Leuprolide)]. Other Financial Interest: McGraw-Hill [Pediatric
endocrinology (Textbook royalties)]. Alison G Hoppin, MD Nothing to disclose

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