Journal of Pediatric Gastroenterology & Nutrition:
Original Articles: Hepatologyand Nutrition
Factors Associated With Hepatic Steatosis in Obese Children and Adolescents
Ruiz-Extremera, Ángeles*; Carazo, Ángel||; Salmerón, Ángela¶; León, Josefa||; Casado, Jorge||; Goicoechea, Alejandro#; Fernandez, José Manuel†; Garofano, Maximiliano‡; Ocete, Esther*; Martín, Ana Belén||; Pavón, Esther||; Salmerón, Javier§
†Endocrinology Paedriatric Unit
§Gastroenterology Unit, San Cecilio University Hospital, Granada, Spain
||Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Instituto de Salud Carlos III, Majadahonda, Spain
¶Radiology Unit, Virgen de las Nieves University Hospital. Granada, Spain
#Consejería de Salud, Junta de Andalucía, Spain.
Address correspondence and reprint requests to Ángel Carazo, San Cecilio University Hospital, Research Unit, Avda de Madrid s/n, 18012 Granada, Spain (e-mail: email@example.com).
Received 15 September, 2010
Accepted 28 February, 2011
This work was supported in part by a grant from Ciberehd (Ciberehd is funded by the Instituto de Salud Carlos III) and by grants from Consejería de Salud, Junta de Andalucía, Spain.
The authors report no conflicts of interest.
Objectives: Obesity is associated with high prevalence of hepatic steatosis. We speculate that determinant factors of susceptibility to hepatic steatosis in obesity could differ between children and adolescents.
Patients and Methods: Blood biochemical parameters, systemic oxidative stress markers, proinflammatory cytokines, and adipokine levels were determined in 157 obese children and adolescents. The subjects were divided into 2 groups: children and adolescents, identified as such in accordance with Tanner stage and the measured level of dehydroepiandrosterone sulphate. Steatosis was evaluated by ultrasonography in 127 subjects.
Results: Steatosis prevalence was 44.8%. In the “children” group, those with hepatic steatosis presented higher levels of erythrocyte oxidised glutathione (GSSG) and resistin, lower levels of high-density lipoprotein (HDL) cholesterol, and lower enzymatic activities of erythrocyte glutathione reductase (GRd) and glutathione oxidase (GPx). In the “adolescents” group, those with hepatic steatosis presented higher values for body mass index z score (BMIz), insulin, peptide C, homeostatic model assessment index (HOMA-IR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides, GSSG, and leptin. These subjects also presented lower values for soluble leptin receptor, GRd, and GPx. In the “children” group, the only independent factor of steatosis was a decrease in GRd activity (odds ratio [OR] 0.165, 95% CI 0.03–0.84, P = 0.030). Moreover, in the “adolescent” group, the independent factors were higher for GSSG (OR 6.8, 95% CI 1.6–28.7, P = 0.010) and HOMA-IR (OR 1.9, 95% CI 1.17–3.1, P = 0.009).
Conclusions: Factors associated with hepatic steatosis differ between obese children and adolescents. Oxidative stress is seen to be the main process in children, whereas in adolescents oxidative stress and insulin resistance are significant factors for steatosis.
The prevalence and magnitude of obesity among children and adolescents are increasing dramatically (1). Fourteen percent of Spanish children and adolescents are believed to be obese (2). In this period of life, obesity is associated with significant health problems, but it is also an important early risk factor for adult morbidity (3). The most important pathological consequences are nonalcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus, and cardiovascular disease (4). NAFLD is a clinical and pathological term that includes a spectrum of abnormalities ranging from simple triglyceride accumulation into the hepatocytes to hepatic steatosis with inflammation (nonalcoholic steatohepatitis). Furthermore, steatohepatitis can progress to cirrhosis. NAFLD prevalence in obese pubertal cohorts has been estimated to be around 50%, with significant male predominance (5,6); however, different results have been obtained for obese prepubertal children, ranging from 30% to 50% (7,8).
The components of metabolic syndrome are strongly associated with NAFLD; indeed, many authors regard hepatic steatosis as the liver expression of metabolic syndrome (9). The 2-hit (or multiple-hit) hypothesis is broadly accepted to explain the origin and progression of NAFLD (10). The accumulation of lipids in the cytoplasm of hepatocytes (the first hit) triggers a series of cytotoxic events (secondary hits), which culminate in steatohepatitis. In obesity, hepatic steatosis is associated with insulin and leptin resistance, high triglyceride and leptin plasma levels, low adiponectin levels, excess visceral fat, inflammation, and oxidative stress (8,11–15). Most of these conclusions are derived from studies carried out in adult or adolescent cohorts; few studies have analysed the factors associated with NAFLD in obese children. The paediatric population is not a homogeneous group, and the physiology of children and adolescents undergoes great changes between the first years of life and entry into adulthood. We speculate that the factors that determine susceptibility to NAFLD in obesity could differ between children and adolescents.
PATIENTS AND METHODS
This study was conduced at the San Cecilio University Hospital (Granada, Spain). The patient cohort comprised 157 Spanish children and adolescents ages 4 to 15 years. All of the subjects had a body mass index (BMI) above the 95th percentile for age and sex, according to Spanish BMI reference databases (16). The subjects were consecutively included in the cohort; however, patients receiving pharmacological treatment or presenting pathologies, other than obesity, that could account for a raised homeostatic model assessment index (HOMA-IR) or could propitiate hepatic steatosis were not included in the study. For example, treatment with corticoids and the presence of diabetes mellitus type 1, α-1-antitrypsin deficiency, infectious hepatitis, or Wilson disease are exclusion criteria. The participants in the study did not consume alcohol or take steatogenic medication. The ethics committee of the hospital approved the study. Patients older than 12 years and their parents provided written informed consent.
Blood samples were collected after 10 hours of fasting and divided into serum and plasma tubes. For biochemical parameter determinations, blood samples were processed and analysed by routine methods within 24 hours at the clinical analysis laboratory of the San Cecilio University Hospital. For each patient, glucose (milligram per deciliter), insulin (micro unit per milliliter), triglycerides (milligram per deciliter), total cholesterol (milligram per deciliter), low-density lipoprotein (LDL) cholesterol (milligram per deciliter), high-density lipoprotein (HDL) cholesterol (milligram per deciliter), alanine aminotransferase (ALT) (unit per liter), aspartate aminotransferase (AST) (unit per liter), and gamma glutamiltransferase (GGT) (unit per liter) were determined. The HOMA-IR was calculated to evaluate the insulin resistance.
The diagnosis of steatosis was based on liver ultrasonography scanning, which was performed on 127 subjects by a single trained, experienced radiologist using a Toshiba Powervision 6000 scanner (Toshiba Medical, Otawara, Japan) with a 3.5- to 6-MHz transducer. The radiologist was blinded to participants’ details. Hepatic steatosis was diagnosed on the basis of characteristic sonographic features, that is, evidence of diffuse hyperechogenicity of liver relative to kidneys, ultrasound beam attenuation, and poor visualisation of intrahepatic vessel borders and diaphragm (17). For quality control assessment, 10% of the subjects were reexamined and the resulting coefficient of variation was lower than 1%.
Systemic oxidative stress markers were determined in blood samples. For nitrite level determination, plasma samples were deproteinised and supernatants were used to measure the amount of nitrite via the Griess reaction at 550 nm in a microplate reader (TRIAD series, Dynex Technologies, Chantilly, VA) (18). Nitrite concentrations were calculated according to a standard curve and expressed in nanomole per milliliter. For erythrocyte glutathione peroxidase (GPx)– and glutathione reductase (GRd)–specific activities, the erythrocytes were lysed and supernatants used. The specific activities were measured following the oxidation of NADPH for 3 minutes at 340 nm in a UV-spectrophotometer (Thermo Spectronic, Biomate3, Rochester, NY) (19). The activity of both enzymes is expressed in nanomole per milligram of haemoglobin (HB). The reduced and the oxidised forms of glutathione (GSH and GSSG) were determined in blood cell lysate. Both GSH and GSSG were measured by a fluorometric method that was slightly modified (20). The samples were incubated with ophthalaldehyde and the fluorescence was measured in a plate-reader spectrofluorometer (TRIAD Series, Dynex Technologies). A standard curve of known reduced glutathione concentrations was prepared and processed with the samples. For oxidised glutathione concentration measurement, the supernatants were preincubated with N-ethylmaleimide, and then alkalinised with NaOH. The fluorescence was measured and the GSSG concentrations were calculated according to a standard curve. The levels of GSH and GSSG are expressed in nanomole per milligram of HB.
Cytokines and hormones were measured in plasma. Adiponectin (nanogram per milliliter), leptin (nanogram per milliliter), tumor necrosis factor-α (TNF-α) (picogram per milliliter), interleukin-6 (IL-6, picogram per milliliter), and monocyte chemoattractant protein-1 (MCP-1, picogram per milliliter) were measured by Luminex 100 Integrated System 2.3 software at the Bio-Plex 200 System (Bio-Rad, Austin, TX). The assays were performed according to the manufacturer's instructions. The soluble TNF-α receptor (sTNFα-R) was determined by enzyme-linked immunosorbent assay (ELISA) (Bender MedSystems, Vienna, Austria). No cross-reactivity with human TNF-α (<1 ng/mL) or TNF-β (<100 μg/mL) was detected. The soluble leptin receptor (SLR) was determined by ELISA (Enzo Life Sciences, Plymouth Meeting, PA). The dehydroepiandrosterone sulphate (DHEAS) levels were determined by ELISA (IBL-International, Hamburg, Germany).
One hundred fifty-seven obese children and adolescents were included in this study. The subjects were classified by puberty status as follows: group 1—patients with no signs of sexual maturity according to DHEAS levels (59 children); group 2—patients at different Tanner stages (21) and with high DHEAS levels (98 adolescents). To study the factors associated with liver steatosis, each patient was classified in accordance with the absence or presence of ultrasonography-detected hepatic steatosis.
Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS 15.0, SPSS Inc, Chicago, IL). The results are reported as mean ± standard deviation, unless otherwise expressed. Unvaried unadjusted analyses were performed with the independent samples t test to compare normally distributed variables, whereas the Mann-Whitney test was used for variables that were not normally distributed. The linear correlations were calculated by the Pearson correlation coefficient. Logistical regression was applied. The criterion for statistical significance was P < 0.05.
A series of variables in our cohort were studied (Tables 1 and 2), and many were found to differ between the 2 groups. The children were more obese and had more total cholesterol and higher AST levels. Insulin, glucose and HOMA-IR levels were higher among the adolescents (group 2). In the variables associated with systemic oxidative stress, only erythrocyte GPx-specific activity showed differences, being higher in group 1. In addition, leptin soluble receptor concentration, and adiponectin serum levels were higher in group 1. Nevertheless, the leptin serum level was higher in group 2. The soluble leptin receptor presented a negative correlation with the leptin level in the total group of patients (Pearson coefficient −344; P = 0.000).
The presence of hepatic steatosis was evaluated in 127 subjects (51 in group 1 and 76 in group 2), and detected in 57 subjects (20 in group 1 and 37 in group 2). Steatosis prevalence was 44.8%, and there were no significant differences in relation to age or sex. Tables 3 and 4 show the variables associated with hepatic steatosis that differed between the groups.
Table 3 represents the BMI (z score) and blood biochemical data. In group 1, HDL-C values were lower in the children with steatosis; however, in group 2, the subjects with steatosis were more obese and presented higher insulin, HOMA-IR, peptide C, ALT, AST, and triglyceride levels.
Table 4 shows the systemic oxidative stress markers and adipokine levels measured. In group 1, the children with liver steatosis presented higher values of GSSG and resistin. They also had less erythrocyte GRd- and GPx-specific activity than did the children without steatosis. In group 2, the subjects with steatosis had higher levels of GSSG, GST, GSSG/GSH index, erythrocyte GPx-specific activity, and leptin levels. Soluble leptin receptor levels were lower among the adolescents with steatosis.
We also compared the subjects with steatosis in group 1 versus those in group 2, finding the latter to be less obese and with higher insulin and peptide C levels and a higher HOMA-IR index (Table 3). Moreover, in relation to oxidative stress markers and adipokines (Table 4), the group 2 subjects with steatosis presented lower SLR and adiponectin levels.
Homa-IR and Steatosis in Relation to Age and Sex
As shown in Figure 1, the association between HOMA-IR and steatosis differed considerably in relation to age and sex. In group 1, there was no difference in HOMA-IR mean values in relation to the presence or otherwise of hepatic steatosis; however, in group 2 these values were higher for both sexes but especially among the boys with steatosis. Figure 1 also shows that the increase in HOMA-IR among the adolescent subjects (Table 1) was at the expense of boys. In relation to fasting glucose and insulin levels, we remark that all of the patients were normoglycemic (fasting glucose levels lower than 110 mg/dL). Therefore, the HOMA-IR increases were at the expense of insulin concentration. Finally, there were a correlation between age and the HOMA-IR (C of Pearson coefficient 0.511; P < 0.001) but not between the HOMA-IR and years after the onset of obesity.
Equation (Uncited)Image Tools
Multivariate analysis showed that a decrease in GRd activity was the only independent factor for hepatic steatosis in group 1 (odds ratio [OR] 0.165, 95% CI 0.03–0.84, P = 0.030); however, this analysis showed increased resistin levels to be close to statistical significance (OR 3.9, 95% CI 0.958–15.874, P = 0.064). There was no statistical significance with respect to proinflammatory markers.
Equation (Uncited)Image Tools
In group 2, the hepatic steatosis independent factors were higher for GSSG (OR 6.8, 95% CI 1.6–28.7, P = 0.010) and for the HOMA-IR (OR 1.9, 95% CI 1.17–3.1, P = 0.009). On comparing hepatic steatosis between children and adolescents, the only independent factor was found to be a higher HOMA-IR (OR 2.45, 95% CI 1.4–4.3; P = 0.002).
Equation (Uncited)Image Tools
Few studies have analysed the factors associated with fatty liver disease in obese subjects comparing the prepubertal age with the pubertal period. The aim of our study was to analyse, in a cohort of obese children and adolescents, the association of liver steatosis with a series of parameters including biochemical data, proinflammatory cytokines, adipokines, and systemic oxidative stress markers. The results obtained highlighted differences in factors associated with liver steatosis among children and adolescents.
Although the patients were consecutively included in our cohort by the presence of a BMI above the 95th percentile, the children were found to be more obese than the adolescents (Table 1). These differences in the degree of obesity, together with variations in other parameters (Tables 1 and 2), are probably a consequence of the physiological changes that take place during puberty. The presence of increased leptin levels during the pubertal period, in negative correlation with its soluble receptor, has been described previously (22,23).
The hepatic steatosis prevalence found in our cohort is in agreement with previously published results (5–8) (Table 3). In this respect, no significant differences between the sexes were observed. Although many studies have reported male predominance among obese children and adolescents presenting with liver steatosis (5,6), others have observed no such differences (24,25). These discrepancies are probably related to environmental and genetic differences among the cohorts.
The factors associated in this study with liver steatosis in obese adolescents have been described as determinant factors for adulthood obesity (9,10,12,14); they include lipid alterations, BMI, HOMA-IR, aminotransferase activity, leptin levels, and oxidative stress (Tables 3 and 4). Liver steatosis in obese children is associated only with oxidative stress and resistin levels. Moreover, although aminotransferase levels were normal in most of our subjects, increased ALT and AST in obese adolescents with steatosis (Table 3) does constitute an early manifestation of potentially serious liver disease.
The role of HOMA-IR in the development of steatosis merits special attention (Table 3, Fig. 1), because insulin resistance is believed to be a key process in the origin and progression of NAFLD during obesity (4,9,12). Nevertheless, in our study the HOMA-IR was associated only with liver steatosis in the pubertal group. It may be argued that patients without steatosis but with high HOMA-IR could present with slight hepatic steatosis, which is undetectable by ultrasonography. We also observed several subjects with steatosis but with low HOMA-IR (Fig. 1), however, and this combination is rare in adult morbidly obese patients. Another consideration is that subjects with hepatic steatosis may have developed low-grade insulin resistance in liver and adipose tissues without any repercussion in the systemic HOMA-IR. In animal models, local but not systemic insulin resistance has been reported (26). It is also possible that hepatic steatosis could have developed among the children without insulin resistance playing any significant role. Nevertheless, it is clear that the relation between insulin resistance and hepatic steatosis in obese children is not the same as in adults. A previous study (concerning an Italian cohort) has reported a correlation between hepatic steatosis and HOMA-IR among prepubertal subjects (8). This cohort presented high mean HOMA-IR values (3.16) and marked differences in relation to steatosis; these results differ from those found in the present study. In our opinion, because of the cross-sectional nature of both studies, causality cannot be unambiguously determined. The HOMA-IR mean values reported with respect to other prepubertal obese cohorts are in agreement with our results, namely 1.8 in a Spanish cohort (27) and 2.4 in an English one (28). Additionally, the latter paper reported an increase in HOMA-IR during pubertal progression, especially in boys.
In our study, aggravated oxidative stress was found to be a relevant process in liver steatosis development in both children and adolescents (Table 4). The decreased GPx- and GRd-specific activities observed in patients with steatosis could be explained as a consequence of oxidative damage in the active centre of these enzymes. In fact, previous studies have reported a decrease in erythrocyte free radical scavenging enzyme activities in situations of heightened oxidative stress (29,30). Free radical overproduction is believed to be a relevant factor associated with the origin and subsequent progression of fatty liver disease (31). The main sources of cellular oxidative stress are the endoplasmic reticulum and the mitochondrion (13,32). Mitochondrial dysfunction during obesity is closely related to hypercaloric diets (33), and a recent article suggested that this dysfunction occurs even before the onset of insulin resistance during NAFLD development (34). In accordance with these findings, antioxidants have been considered as possible options in the treatment of NAFLD, but the results to date have not been satisfactory (35,36).
Another finding in the present study that illustrates the particularity of children was the increased resistin levels recorded in patients with steatosis (Table 3). Resistin was initially characterised in rodents as an adipokine related to the development of insulin resistance (thus its name) (37); however, in humans, it is also expressed by immune cell infiltrates in adipose tissue, the liver, and other tissues (38,39). Although human resistin has been related to inflammatory and oxidative stress processes (40,41), we found no correlations with proinflammatory or oxidative stress markers. The role of resistin in human pathophysiology remains unclear; indeed, the cellular resistin receptor has not yet been cloned.
All studies are subject to some degree of bias, and care must thus be taken regarding the conclusions drawn. In our case, selection bias was controlled by the consecutive inclusion of the subjects in the cohort and by excluding patients with pharmacological treatments or pathologies, other than obesity, that could propitiate hepatic steatosis. The subjects were classified as children or adolescents using 2 methods: Tanner stages and DHEAS levels; therefore, we may assert that virtually all of those included in group 1 are prepubertal. A possible classification bias from the method used to diagnose fatty liver remains. At present, noninvasive methods, such as computed tomography, magnetic resonance imaging, or ultrasonography, are used to assess steatotic changes in the liver (42), but none of these methods can really replace the liver biopsy, which remains the criterion standard. Ethical considerations preclude the diagnosis of NAFLD by liver biopsy, especially in patients with normal transaminases. Ultrasound cannot detect steatosis if the amount of fat in the liver is less than 30% (43). Indeed, the concept of fatty liver as used in our study must be understood as “steatosis detected by ultrasound.” The nature of the method used to assess insulin resistance could also influence the conclusions drawn. HOMA-IR is a surrogate method that cannot always replace approaches based on the glucose tolerance test. Nevertheless, it has been satisfactorily correlated with the glucose tolerance test in children and adolescents with normal glycaemia (44).
In our opinion, the above limitations are not so important as to invalidate the main conclusion of our study, namely that the factors associated with NAFLD differ between obese children and adolescents. Furthermore, our findings provide new perspectives for future research, such as the precise role of resistin and the HOMA-IR in prepubertal obese subjects. Finally, the significant relevance of oxidative stress in steatosis suggests the possible involvement of hereditary factors implicated in the production and scavenging of free radicals.
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