Obese boys at increased risk for nonalcoholic liver disease: evaluation of 16 390 overweight or obese children and adolescents



Comorbidities of childhood obesity challenge health-care systems in Europe. Further, there is a lack of population-specific prevalence data and diagnostic strategies available, especially for obesity-related disturbances of liver function. Therefore, the prevalence of elevated liver enzymes and their relationship to biological parameters were studied in a large pediatric obesity cohort.


In 111 specialized pediatric obesity centers in Germany, Austria and Switzerland, 16 390 children and adolescents (age 12.4±2.6 years, 58% boys) were categorized as overweight (body mass index (BMI) >90th percentile) and obese (>97th percentile) and studied for related comorbidities, especially nonalcoholic fatty liver disease (NAFLD; as defined by aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >50 U l−1). Data were collected using a standardized software program (APV) for longitudinal multicenter documentation. Pseudonymized data were transmitted for central statistical analysis.


In this pediatric cohort, 16% of the study population was overweight, 46% obese and 35% extremely obese (>99.5th percentile extreme obesity (Xob)). NAFLD was present in 11% of the study population, but predominantly in boys (boys vs girls; 14.4:7.4%; P<0.001), in Xob (obese vs Xob; 9.5:17.0%; P<0.001) and in older age (< 12 vs 12 years; 8:12%; P<0.001; adjusted for BMI). ALT >50 U l−1 was significantly associated with fasting insulin and BMI-SDS. In multiple logistic regression models, Xob and male gender were strongly associated with NAFLD (odds ratio Xob vs normal weight=3.2; boys vs girls OR=2.3).


In a large cohort of overweight and obese European children and adolescents, markers of nonalcoholic liver disease, especially ALT, are frequent and predicted by Xob and male gender. The results underline the epidemiological dimension of this obesity-related morbidity even in childhood. Therefore, at least ALT is recommended as a screening parameter in basic care.


Obesity (OB) challenges most health-care systems worldwide.1 The increase in prevalence of childhood OB due to obesogenic environmental conditions (that is, increased consumption of processed food including fructose containing juices and sweets, physical inactivity) results in a rising prevalence of metabolic syndrome2, 3 and type 2 diabetes in populations other than minority groups.4, 5 Nonalcoholic fatty liver disease (NAFLD) is one of the consequences of the current OB epidemic and the hepatic manifestation of the metabolic syndrome. Simple steatosis can progress to nonalcoholic steatohepatitis (NASH) characterized by steatosis, inflammation and progressive fibrosis, ultimately leading to cirrhosis and end-stage liver disease. NASH was first observed in children in 1983 as a pattern of liver injury.6 NASH can even develop in obese (ob) children under 10 years of age.7 An enlarged, echogenic liver shown through ultrasonography in ob children and adolescents is highly suggestive of NAFLD or NASH. Histological confirmation of NASH is still the golden standard used to accurately assess the degree of steatosis, inflammatory lesions and fibrosis found in NASH and to distinguish NASH from simple steatosis. Liver stiffness measurement using Fibroscan may be a promising new sonographic alternative tool being used in the near future.8

In a recent study, 176 ob children and adolescents with elevated aminotransferase underwent liver biopsy and the clinical correlates of pediatric NASH were analyzed. Levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and γ-glutamyltransferase were recorded because of the correlation with fibrosis severity. However, the sensitivity and specificity of this diagnostic test were not sufficient enough to replace liver biopsy in evaluating pediatric NASH in all patients.9

There are a few population-based studies in this field, for example, data from the United States (NHANES III):10 The prevalence of elevated ALT levels (>30 U l−1) was 7.4% among white adolescents, 11.5% among Mexican American adolescents and 6.0% among black adolescents. Elevated ALT levels were present in 12.4% of male subjects compared with 3.5% of female subjects. Most prevalence studies have been conducted in cohorts of children selected for overweight (OW) or OB. By using elevated ALT as a surrogate marker of NAFLD, the prevalence varies between 10 and 25%11 in different studies. A recent critical review of ALT screening for chronic liver diseases in adults confirmed that this type of screening has high specificity, good sensitivity and is a cost-effective means to detect liver diseases including consequences of metabolic syndrome and diabetes mellitus type 2.12

Therefore, the aim of this study was to (1) estimate the prevalence of NAFLD in a very large European cohort of OW to ob children and adolescents, and (2) to analyze the association with clinical and metabolic parameters.


On the basis of the German guidelines for diagnosis and treatment of OW children and adolescents,13 a computer software program, using the visual Foxpro 9.0 compiler, was developed in 1999 to standardize prospective documentation of OW children and adolescents (APV) (http://www.a-p-v.de).14 Participation in this quality control program is the precondition for certification of OB treatment centers by the German Obesity Society (DAG) and for funding of the treatment by health insurance. Anthropometric parameters, metabolic control and treatment modalities (multiprofessional composition and intensity of lifestyle interventions) are documented longitudinally by the software. The software allows standardized patient reports, local aggregation of data and patient selection according to multiple criteria. The data that have been collected anonymously are sent to the Department of Epidemiology at the University of Ulm for central analysis. Each participating center complies with its local ethical and data management guidelines. Inconsistent data are reported back to the centers twice a year for correction. A benefit of nonindustrial grants is that this quality assessment is free of charge and results in the establishment of a large data collection:

In our study, 111 centers specialized in pediatric OB care (82 outpatient, 29 in-patient rehabilitation institutions) in Germany, Austria (3) and Switzerland (1) participated in this study. Between January 2001 and November 2009, 16 390 children (age 12.4±2.6 years, range 1–19.98 years, 58% males) were examined and evaluated at one of the participating centers for being OW or ob, and their initial measurement of liver enzymes were also recorded. The weight status was recorded as body mass index (BMI). OW was defined as a BMI above the 90th and below the 97th percentile, OB as a BMI above the 97th and below the 99.5th percentile, and extreme obesity (Xob) as a BMI above the 99.5th percentile, the latter corresponding to a BMI >40 kg m−2 in adults. German population-based reference data were used as recommended by the International Task Force of Obesity.15, 16 The degree of OW was quantified using Cole's box-cox transformation, which normalizes the BMI skewed distribution in childhood and expresses BMI as a standard deviation score (SDS-BMI).17

In this study, NAFLD was defined as the presence of elevated AST and/or ALT. The prevalence of NAFLD was estimated using a cutoff value of 50 IU l−1 for ALT and AST, corresponding to at least 1.5-fold elevated liver enzymes in all participating centers by using local reference data. According to the Diagnostic Guidelines of the German Working Group of Childhood Obesity,13 the differential diagnostic procedure for elevated ALT and/or AST-values should be performed before including the patients into the database.

Blood pressure related to height was considered elevated if above the 95th percentile of European reference data,18 according to the guidelines of the German Hypertension League (Deutsche Hochdruckliga). Abnormal lipid levels (dyslipidemia) were defined according to the American Heart Association19 using the following cutoff levels: total cholesterol >5.18 mmol l−1, low-density lipoprotein-cholesterol >3.4 mmol l−1, high-density lipoprotein-cholesterol <0.9 mmol l−1, triglycerides >1.71 mmol l−1. Oral glucose tolerance test according to WHO20 was performed following consensus guidelines in patients with Xob. An elevated measurement from the following list classified the individual as having impaired carbohydrate metabolism: impaired fasting glucose >6.1 mmol l−1, impaired glucose tolerance (glucose at 2 h in oral glucose tolerance test >7.8 mmol l−1), at risk of diabetes mellitus type 2 (impaired fasting glucose >7.0 or 2 h-oral glucose tolerance test >11.1 mmol l−1).

Statistical evaluation was performed by SAS version 9.1 (SAS Institute Inc., Cary, NC, USA). Data are presented as mean±standard deviation (±s.d.) if data were normally distributed, and median (first to third quartile) if no normal distribution could be assumed or data were nonparametric. Nominal data are shown as number (n) and percentage (%). For all parameters normal distribution was examined. Differences in means were tested using t-test, nonparametric tests (Mann–Whitney's U-test, H-test by Kruskal–Wallis and χ2-test) were used if there was no normal distribution and for binomial data. Correlations were tested by Spearman's test. As multiple tests were performed, P-values were adjusted using the Bonferroni step-down correction (Holm method21). A probability value of <0.05 was considered significant.

A multiple logistic regression analysis was used to identify the variables affecting the dependent variable NAFLD (described by odds ratio (OR) point estimates with their 95% Wald confidence limits). The independent variables included in the GLIMMIX analysis were age groups, gender and BMI categories.

ORs were calculated both with reference to normal weight and OW groups, without significant differences. Therefore, only the comparison with the OW group is shown here. In addition, least square means for NAFLD prevalence were calculated; to depict the effect of individual variables, elevated ALT and AST were adjusted for other confounders.


At the 142 treatment centers in Germany, Austria and Switzerland, a total of 44 450 children and adolescents were examined and evaluated for OB and specific interventions between January 2001 and November 2009. In 16 390 patients (36.1%; 111 centers), liver enzymes were measured during the first visit. The following results are based on this subgroup. Completeness of the data set is shown in Table 1. This subgroup did not differ significantly from the total cohort concerning age, gender or BMI (data not shown). The majority of these patients were boys (58%), at least 12 years of age (61%) and ob or extremely obese (Xob) (46 or 35%; total 81%). Blood pressure was elevated in 20% of this subgroup and increased lipids (at least one parameter) were present in 35%. With regard to carbohydrate metabolism impaired fasting glucose and/or impaired glucose, tolerance levels were diagnosed in 2.7% of this subgroup and type 2 diabetes mellitus in 0.7% of this group. Further, clinical parameters and additional cardiovascular risk factors are summarized in Table 2.

Table 1 Available data according to BMI categories
Table 2 Clinical characteristics (% or median and first+third quartile)

Prevalence of NAFLD in relation to gender, weight status and age

Clinical suspicion of NAFLD, expressed as AST and/or ALT >50 IU l−1, was detected in 11.5% out of 16 390 patients. The prevalence was significantly higher in boys than in girls (14.4 vs 7.7%; P<0.001) and also in extremely ob children and adolescents in relation to all other weight categories (normal weight (NW) 6.7%; OW 6.2%; OB 9.5% vs Xob 17%; P>0.001; Figure 1). In patients younger than 12 years of age, the percentage of elevated liver enzymes was significantly lower than in patients 12–16 years or 17–20 years of age (8.8 vs 12.2% and 20.0%; P<0.001).

Figure 1

Prevalence of NAFLD in relation to gender and weight categories (***P<0.001 significant difference in the Kruskal–Wallis test, refer to Methods section).

Without adjustment for additional confounders, only ALT but not AST correlated positively with BMI-SDS (r=0.21, P<0.001) and fasting insulin (r=0.26; P<0.001).

Simultaneous relationship between NAFLD and biological covariates was also found

In multivariable analysis (logistic regression model), relevant covariates for the presence of elevated AST and/or ALT as laboratory signs of NAFLD (>50 IU l−1) were the degree of OB, age group and sex. By using BMI category, the Xob predicted NAFLD (OR 1.72 (1.0–2.4, 95% confidence interval)), compared to OW. At 16 years of age or older, OR was 1.74 (1.3–2.2) compared to <12 years and for boys OR was 2.21 (1.75–2.63) in relation to girls (all P-values <0.001; Figure 2).

Figure 2

Effects (odds ratios (95% confidence interval)) of various biological parameters (gender, BMI category, age groups) on NAFLD in multiple logistic regression analysis (refer to Methods section).

Expressed as least square means, the risk for the presence of NAFLD is 12% (0.12±0.009) compared to 6% (0.06±0.006) for boys compared to girls; 14% (0.14±0.009) compared to 8% (0.08±0.008) and 5% (0.05±0.005) for the weight categories Xob compared to OB and OW and finally 15% (0.15±0.012), 10% (0.10±0.007) and 7% (0.07±0.005) for the age groups 17–20, 12–16 and <12 years, respectively.


In this observational study using a sample of OW and ob European children and adolescents, the main findings are the high prevalence of indicators for NAFLD and their close correlation with male gender, age and Xob. There are various challenges in determining the prevalence of NAFLD. The first challenge is making the diagnosis. This diagnosis requires liver biopsy, which is not feasible in a large clinical study and too invasive to be performed as a routine procedure. An alternative, noninvasive procedure is a liver ultrasound; however, it does not differentiate between steatosis and fibrosis. In this study, only certain centers have provided their ultrasound data. Therefore, most studies use serum aminotransferase elevations as a surrogate marker for fatty liver disease, in combination with negative markers for other types of liver disease. Recent data from the US National Health and Nutrition Examination Survey reported increased ALT level (>30 U l−1) in 8% of adolescents 12–19 years of age.10 In ob Japanese adolescents the prevalence of increased ALT (>35 U l−1) was 24%.22 Subsequent reports on relatively small clinical cohorts from Australia23 and Europe24, 25 show the global dimension of the problem.

Although liver biopsy cannot be used as a screening tool in clinical studies, autopsy series provide the opportunity to estimate the prevalence of NAFLD based on a histological diagnosis:26 In an autopsy study on 742 children and adolescents who died of unnatural causes, clinical records and histological findings were correlated. The results of this study confirm that fatty liver is the most common liver abnormality in children aged 2–19 years. Variables that were significantly associated with fatty liver in the study were increased BMI, older age, male sex, Hispanic ethnicity and Asian race. Besides the differences in ethnic proportion in Europe, these results are in line with the data from our large ob pediatric cohort: NAFLD (as defined by ALT and/or AST >50 U l−1) in 11.5% out of 16 390 patients; in boys twice as often as in girls and significantly more frequent in extremely ob adolescents.

Regarding the gender difference in the prevalence of ALT elevation, different views have been expressed: Bonito et al.27 recommended sex-related cutoff of ALT levels for ob children (ALT>30 IU l−1 for boys and >19 IU l−1 for girls). Using this definition, ALT would be elevated in 36% of the ob boys and in 55% of the ob girls in our cohort.

In contrast, as described in autopsy studies, the proportion of pathological liver histology is higher in boys than in girls (11.1 vs 7.9%).26 In the general population, liver enzymes are higher in males than in females and strongly associated with higher mortality from liver disease in males.28 Therefore the gender difference in the prevalence of elevated levels in our cohort probably represents a relevantly higher proportion of liver pathology in ob boys. In this study, a cutoff level of 50 IU l−1 was used corresponding to at least 1.5-fold elevated aminotransferase in all participating centers. Due to its relatively high cutoff value, the percentage of false-negative results could be relevant. In addition, a recent retrospective study conducted at one OB center collected data from 106 children with biopsy proven NAFLD, and it showed that the entire spectrum of histological features of NAFLD can be seen in children with normal transaminase. From this sample of 106 children, 6 out of 15 patients with normal liver enzymes had liver fibrosis.29

In the APV database, pubertal stage is clinically reported in <50% of the studied population and is therefore not usable for analysis. But the association of significantly elevated ALT with age supports the hypothesis that the pubertal increase of sex hormones may be important in the predisposition for pediatric NAFLD.30 Previous studies have suggested a protective effect from estrogen. In women with polycystic ovarian syndrome a strong relationship with NAFLD was shown, independent of insulin resistance and BMI.31, 32 With estrogen replacement therapy in postmenopausal women, the risk of NAFLD decreased significantly.33 Some of the underlying mechanisms in sex difference appeared to be due to the change of gene expression, dependent on estrogens.34 In ob adolescents, weight reduction as well as completing puberty reduces the progression of NAFLD.35, 36

The clinical relevance and indication for intervention in ob patients highly depends on the presence of inflammation and cirrhosis. NASH is the most severe histological form of inflammation and progresses to cirrhosis in 20% of ob patients.37 The most widely accepted theory is titled the ‘Two-Hit Theory’ that explains the pathogenesis of NASH resulting from fatty infiltration of the liver due to OB and insulin resistance, followed by inflammatory insults, potentially due to oxidative stress.38 NASH is significantly associated with the presence of insulin resistance and a metabolic syndrome in ob children.39, 40 The significant relation between fasting insulin, insulin resistance and NAFLD in ob children underlines the clinical dimension of these metabolic disturbances.41 In the German Guidelines, fasting insulin is not recommended during a primary care visit. Therefore the available data on insulin and insulin sensitivity in this large pediatric cohort preclude analysis in epidemiological dimensions so far. In contrast, in 2006, the determinations of ALT and/or AST were included in the diagnostic guidelines of the German Working Group of Childhood obesity.13 Subsequently, the available database concerning NAFLD increased in the APV system.

In conclusion, on the basis of this study and a representative survey completed by children and adolescents in Germany,42 70 000 ob children and adolescents are expected to be at risk for NAFLD/NASH in Germany. Therefore, this observed comorbidity in ob children and adolescents is also relevant from an epidemiological point of view. We acknowledge that our study design may be inadequate to detect all possible diagnoses of NAFLD. Other potential diagnoses may include Wilson's disease, cystic fibrosis, celiac disease or other autoimmune or metabolic diseases of the liver, including chronic alcohol misuse especially significant with adolescent boys. The primary strengths of our study are the large sample size of patients, the strong correlation of higher liver transaminases with Xob compared to OW patients, and the correlation with increasing age, male gender, fasting insulin and BMI-SDS. Besides the limitation concerning the sensitivity and specificity of aminotransferase for a histological diagnosis of NAFLD and NASH, this screening should be used until additional evidence from further studies concerning noninvasive diagnosis of NAFLD/NASH in ob children and adolescents are available.


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The APV program was supported by the German Federal Ministry of Health and by the German ‘Competence Network Adipositas,’ which is initiated by the German Federal Ministry of Education and Research (Grant Number 01 GI0839). We thank all patients, obesity centers, investigators, and staff who participated in the APV initiative. A full listing of the participating centers has recently been published elsewhere.5 SW, TR and RH received grant support from of the German ‘Competence Network Adipositas,’ which is supported by the German Federal Ministry of Education and Research (Grant Number 01 GI0839).

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Wiegand, S., Keller, KM., Röbl, M. et al. Obese boys at increased risk for nonalcoholic liver disease: evaluation of 16 390 overweight or obese children and adolescents. Int J Obes 34, 1468–1474 (2010). https://doi.org/10.1038/ijo.2010.106

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  • childhood obesity
  • nonalcoholic fatty liver disease
  • gender
  • metabolic syndrome

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