Short- and long-term beneficial effects of a multidisciplinary therapy for the control of metabolic syndrome in obese adolescents

Visceral fat is highly correlated with metabolic syndrome in obese adolescents. The aims of this study were to determine the prevalence of metabolic syndrome and to assess the effect of a long-term (1 year) intervention with multidisciplinary therapy in predicting metabolic syndrome among obese adolescents, as well as to compare short- with long-term therapy. Eighty-three postpuberty obese adolescents were recruited, including 37 boys (body mass index [BMI], 36.19 +/- 3.85 kg/m(2)) and 46 girls (BMI, 35.73 +/- 4.42 kg/m(2)). Body composition was measured by plethysmography using the BOD POD body composition system (version 1.69, Life Measurement Instruments, Concord, CA), and visceral fat was analyzed by ultrasound. Metabolic syndrome was determined according to the World Health Organization criteria. Patients were assigned to a weight loss multidisciplinary intervention consisting of nutritional, exercise, psychological, and clinical therapy. At the beginning of therapy, we found that 27.16% of the obese adolescents presented metabolic syndrome, whereas only 8.3% did so after intervention. Indeed, in boys, BMI (36.19 +/- 3.85 to 32.06 +/- 5.85 kg/m(2)), visceral fat (4.88 +/- 1.35 to 3.63 +/- 1.71 cm), homeostasis model assessment of insulin resistance (4.77 +/- 3.41 to 3.18 +/- 2.33), and percentage of body fat (38.24% +/- 6.54% to 30.02% +/- 13.43%) presented a statistically significant reduction; and their fat-free mass percentage increased (62.14% +/- 5.78% to 69.17% +/- 12.37%). In girls, after long-term therapy, BMI (35.73 +/- 4.42 to 33.62 +/- 3.78 kg/m(2)), visceral fat (3.70 +/- 1.40 to 2.75 +/- 1.01 cm), and percentage of body fat (46.10% +/- 5.66% to 39.91% +/- 5.59%) showed a statistically significant reduction; and their fat-free mass increased (53.61% +/- 5.65% to 59.82% +/- 5.78%). In conclusion, long-term multidisciplinary therapy was effective in promoting beneficial changes in some predictors and decreasing the prevalence of metabolic syndrome in obese adolescents.     

Visceral fat: a key mediator of steatohepatitis in metabolic liver disease

Visceral obesity is intimately associated with metabolic disease and adverse health outcomes. However, a direct association between increasing amounts of visceral fat and end-organ inflammation and scarring has not been demonstrated. We examined the association between visceral fat and liver inflammation in patients with nonalcoholic fatty liver disease (NAFLD) to delineate the importance of visceral fat to progressive steatohepatitis and hence the inflammatory pathogenesis of the metabolic syndrome. We undertook a cross-sectional, proof of concept study in 38 consecutive adults with NAFLD at a tertiary liver clinic. All subjects had a complete physical examination, anthropometric assessment, and fasting blood tests on the day of liver biopsy. Abdominal fat volumes were assessed by magnetic resonance imaging within 2 weeks of liver biopsy. The extent of hepatic inflammation and fibrosis augmented incrementally with increases in visceral fat (P < 0.01). For each 1% increase in visceral fat, the odds ratio for increasing liver inflammation and fibrosis was 2.4 (confidence interval [CI]: 1.3-4.2) and 3.5 (CI: 1.7-7.1), respectively. Visceral fat remained an independent predictor of advanced steatohepatitis (odds ratio [OR] 2.1, CI: 1.1-4.2, P = 0.05) and fibrosis (OR 2.9, CI: 1.4-6.3, P = 0.006) even when controlled for insulin resistance and hepatic steatosis. Interleukin-6 (IL-6) levels, which correlated with visceral fat, also independently predicted increasing liver inflammation. Visceral fat was associated with all components of the metabolic syndrome. Conclusion: Visceral fat is directly associated with liver inflammation and fibrosis independent of insulin resistance and hepatic steatosis. Visceral fat should therefore be a central target for future interventions in nonalcoholic steatohepatitis and indeed all metabolic disease.     

Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat

BACKGROUND: Concurrent with the rise in obesity, nonalcoholic fatty liver disease is recognized as the leading cause of serum aminotransferase elevations in obese youth. Nevertheless, the complete metabolic phenotype associated with abnormalities in biomarkers of liver injury and intrahepatic fat accumulation remains to be established. METHODS: In a multiethnic cohort of 392 obese adolescents, alanine aminotransferase (ALT) levels were related with parameters of insulin sensitivity, glucose, and lipid metabolism as well as adipocytokines and biomarkers of inflammation. A subset of 72 adolescents had determination of abdominal fat partitioning and intrahepatic fat accumulation using magnetic resonance imaging. FINDINGS: Elevated ALT (> 35 U/liter) was found in 14% of adolescents, with a predominance of male gender and white/Hispanic race/ethnicity. After adjusting for potential confounders, rising ALT was associated with reduced insulin sensitivity and glucose tolerance as well as rising free fatty acids and triglycerides. Worsening of glucose and lipid metabolism was already evident as ALT levels rose into the upper half of the normal range (18-35 U/liter). When hepatic fat fraction was assessed using fast magnetic resonance imaging, 32% of subjects had an increased hepatic fat fraction, which was associated with decreased insulin sensitivity and adiponectin, and increased triglycerides, visceral fat, and deep to superficial sc fat ratio. The prevalence of the metabolic syndrome was significantly greater in those with fatty liver. INTERPRETATION: Deterioration in glucose and lipid metabolism is associated even with modest ALT elevations. Hepatic fat accumulation in childhood obesity is strongly associated with the triad of insulin resistance, increased visceral fat, and hypoadiponectinemia. Hence, hepatic steatosis may be a core feature of the metabolic syndrome.     

Association of Adolescent Obesity with Nonalcoholic Fatty Liver Disease and Related Risk Factors in Xi ’an,China

Introduction and aim. To investigate the association of adolescent obesity with nonalcoholic fatty liver disease (NAFLD) and related risk factors in Xi ’an, China.Material and methods. A total of 4141 adolescents (2,061 girls and 2,080 boys, mean age: 18.62 ± 0.66 years, age range 15-22 years) were enrolled in this investigation. Anthropometric index was measured, and liver ultrasonography and liver function biochemical test were performed in all the subjects. T test, χ² test and logistic regression analysis were used for statistical analyses. Results. The total rates of obesity was 7.9% (08/4,141). The prevalence rate of NAFLD was 8.1% (335/4141) with a declining trend from obesity, overweight to normal BMI. NAFLD prevalence rate in obese boys was significantly higher than in girls (χ² = 56.5, P < 0.01). BMI, body weight, ALT, and AST in NAFLD group were higher than in non-NAFLD group (P < 0.05). The tangent point of ALT was 36 U/L using Youden index in boys, and 33 U/L in girls.Conclusion. The prevalence of obesity and NAFLD in adolescents is higher in Xi’an than anticipated. Body weight and BMI may be the associated independent risk factors of NAFLD.     

Folgeerkrankungen und Komplikationen der Adipositas

In the industrial countries the prevalence of adipositas has risen to approximately 20% during the last decades. In addition, a further rise in adipositas-related comorbidities is to be expected. Adipositas is an important risk factor for nonalcoholic fatty liver diseases, reflux, cholelithiasis, and tumour diseases. Adipose patients have a significantly higher risk of developing colon carcinoma, gallbladder carcinoma, oesophageal adenocarcinoma, and hepatocellular carcinoma. Visceral fat measured as waist circumference or waist:hip ratio correlates more with the comorbidity risk than body mass index. Apart from insulin resistance and oxidative stress, secretion of adipokins such as leptin and proinflammatory cytokines of visceral fatty tissue play an important pathogenic role. Still not completely clarified, these pathomechanisms represent the link between visceral adipositas and many organ systems and tumourigenesis. Regarding preventive aspects, adipositas is increasingly relevant concerning the determination of risk profiles and therapy.     

Is there any link between dietary pattern and development of nonalcoholic fatty liver disease in adolescence? An expert review

Evaluation of: Oddy WH, Herbison CE, Jacoby P et al. The western dietary pattern is prospectively associated with nonalcoholic fatty liver disease in adolescence. Am. J. Gastroenterol. 108, 778–785 (2013).

The prevalence of overweight and obesity in childhood is a major public health concern. According to the obesity trend, the prevalence of pediatric nonalcoholic fatty liver disease (NAFLD) is also increasing. Nonalcoholic fatty liver disease is characterized by a spectrum of hepatic lesions (i.e., steatosis, ballooning, necroinflammation and fibrosis) that can progress to cirrhosis, hepatocellular carcinoma and liver failure with the consequent need for liver transplantation. Pediatric NAFLD is typically of primary origin and it is strongly associated with several features of the metabolic syndrome such as obesity, insulin resistance, dyslipidemia and Type 2 diabetes. The evaluated article reports the prospective relationship between dietary patterns at age 14 years and the presence of NAFLD at age 17 years. A total of 995 adolescents completed a food frequency questionnaire at 14 years and had liver ultrasound at 17 years. Prospective associations between the dietary pattern scores and the risk of NAFLD were analyzed using multiple logistic regression analyses. Nonalcoholic fatty liver disease was present in 15.2% of adolescents. A healthy dietary pattern at 14 years appeared protective against NAFLD at 17 years in centrally obese adolescents. On the contrary, a western dietary pattern at 14 years in this cohort was associated with an increased risk of NAFLD at 17 years, particularly in obese adolescents.     

The impact of visceral fat in nonalcoholic fatty liver disease: cross-sectional and longitudinal studies

Background Nonalcoholic fatty liver disease is increasing worldwide, and attention is being paid to its association with obesity and metabolic syndrome. The aim of this study was to elucidate the role of visceral fat accumulation in hepatic steatosis by cross-sectional and longitudinal studies. Methods We enrolled 125 patients in a cross-sectional study and 28 patients in a longitudinal study and examined visceral and subcutaneous fat thickness, hepatic steatosis score, and biochemical parameters. In the longitudinal study, the influence of weight change on fat distribution and hepatic steatosis was investigated. Results In the cross-sectional study, the severity of hepatic steatosis showed a significant positive correlation with body mass index, visceral fat thickness, serum albumin, alanine aminotransferase (ALT), cholinesterase, fasting insulin, and the homeostasis model assessment of insulin resistance. ALT, visceral fat thickness, and serum albumin were independent factors for hepatic steatosis. In the longitudinal study, visceral fat thickness fluctuated closely with changes in body weight, and had the strongest relationship with the change of hepatic steatosis by multivariate analysis. Conclusions Visceral fat was the most important factor for the development of hepatic steatosis. Visceral fat thickness can be measured by sonography easily, noninvasively, and repeatedly for assessment of central obesity and monitoring of the efficacy of treatment of nonalcoholic fatty liver disease.     

Association of abdominal fat distribution and cardiometabolic risk factors among obese Korean adolescents

The association between abdominal fat distribution and cardiometabolic risk factors using direct measures of abdominal fat in adolescents has not been extensively researched. This study was designed to investigate the association between visceral and subcutaneous fat and cardiometabolic risk factors, in obese Korean adolescents. The study enrolled 175 adolescents (72 boys, 103 girls), from ages nine to 19 years, who were referred to the Obesity Clinic of Asan Medical Center. Body mass index (BMI) and waist circumference (WC) were measured for each study participant. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were calculated by computed tomography. Blood pressure, fasting plasma glucose, total cholesterol, triglycerides, HDL cholesterol, insulin and homeostasis model assessment (HOMA) score were measured. Systolic blood pressure, HDL cholesterol, fasting insulin and the HOMA score were significantly correlated with BMI, WC, VAT and SAT. In addition, VAT was significantly correlated with diastolic blood pressure and triglyceride levels. On multiple regression analysis, VAT was independently correlated with blood pressure, triglycerides, HDL cholesterol, fasting insulin and the HOMA score, while SAT was independently correlated with systolic blood pressure, fasting insulin and the HOMA score. This study determined that cardiovascular risk factors are closely associated with VAT, while insulin resistance is closely associated with both VAT and SAT among obese Korean adolescents.     

Visceral fat accumulation and insulin resistance are important factors in nonalcoholic fatty liver disease

Background Nonalcoholic fatty liver diseases are often associated with obesity, insulin resistance, and excessive visceral fat accumulation. The aims of this study were (1) to evaluate the relationship between the severity of fatty liver and visceral fat accumulation in nonalcoholic fatty liver diseases, and (2) to investigate the relationships of fatty liver with biochemical data and insulin resistance. Methods One hundred twenty-nine subjects (63 women) with fatty liver diagnosed by ultrasonography were enrolled. Subjects positive for hepatitis B virus, hepatitis C virus, or autoimmune antibodies and those whose alcohol intake was over 20 g/day were excluded. The visceral fat area at the umbilical level and the liver–spleen ratio were evaluated by computed tomography. Results The severity of fatty liver evaluated by ultrasonography showed a significant positive relationship with the visceral fat area and waist circumstance (fatty liver severity: mild, 92.0 ± 30.9 cm²; moderate, 122.1 ± 32.6 cm²; severe, 161.0 ± 48.4 cm²; P < 0.0001). The visceral fat area and liver–spleen ratio were negatively correlated (r = −0.605, P < 0.0001). The severity of fatty liver showed strong positive relationships with serum aspartate aminotransferase, alanine aminotransferase, fasting plasma glucose, fasting plasma insulin, and insulin resistance. The severity of fatty liver was positively related to the visceral fat area in 49 nonobese subjects (body mass index <25). Conclusions The severity of fatty liver was positively correlated with visceral fat accumulation and insulin resistance in both obese and nonobese subjects, suggesting that hepatic fat infiltration in nonalcoholic fatty liver disease may be influenced by visceral fat accumulation regardless of body mass index.     

Association between low thigh fat and non-alcoholic fatty liver disease

Background and Aim:  Some people have a fatty liver despite having low visceral fat and a low body mass index (BMI). We investigated whether fat distribution, especially thigh subcutaneous fat and thigh intramuscular fat, is associated with non-alcoholic fatty liver disease (NAFLD).
Methods:  The patients consisted of 408 men and women. NAFLD was defined by an ultrasound scan and excluded other liver diseases. Visceral, subcutaneous abdominal, intramuscular, and subcutaneous thigh adipose tissue was measured by computed tomography.
Results:  The frequency of NAFLD decreased over a quartile of thigh fat independently of BMI in the female patients. Additional adjustments for age and visceral fat area did not change the results. This finding was not observed in the male patients. To investigate the relationship between each fat distribution and NAFLD, we performed a logistic regression analysis. Fat distribution was divided into four groups: visceral fat, abdominal subcutaneous fat, thigh subcutaneous fat, and thigh intramuscular fat. All four fat components were chosen as variables for the regression model. Age, BMI, and the homeostasis model assessment (HOMA) index were then adjusted successively. A larger subcutaneous fat area was negatively associated with NAFLD after adjustment for visceral fat and abdominal subcutaneous fat areas in women, but not in men. It did not change even after age adjustment, BMI, and the HOMA index.
Conclusion:  Low femoral subcutaneous fat amounts were shown to be independently associated with fatty liver disease in women. These results show the importance of accurate measurements of other regional body compositions as well as visceral fat amounts when investigating NAFLD.     

Fatty liver: a novel component of the metabolic syndrome

Although the epidemic of obesity has been accompanied by an increase in the prevalence of the metabolic syndrome, not all obese develop the syndrome and even lean individuals can be insulin resistant. Both lean and obese insulin resistant individuals have an excess of fat in the liver which is not attributable to alcohol or other known causes of liver disease, a condition defined as nonalcoholic fatty liver disease (NAFLD) by gastroenterologists. The fatty liver is insulin resistant. Liver fat is highly significantly and linearly correlated with all components of the metabolic syndrome independent of obesity. Overproduction of glucose, VLDL, CRP, and coagulation factors by the fatty liver could contribute to the excess risk of cardiovascular disease associated with the metabolic syndrome and NAFLD. Both of the latter conditions also increase the risk of type 2 diabetes and advanced liver disease. The reason why some deposit fat in the liver whereas others do not is poorly understood. Individuals with a fatty liver are more likely to have excess intraabdominal fat and inflammatory changes in adipose tissue. Intervention studies have shown that liver fat can be decreased by weight loss, PPARgamma agonists, and insulin therapy.     

Should visceral fat, strictly linked to hepatic steatosis, be depleted to improve survival?

Numerous epidemiologic studies have implicated abdominal obesity as a major risk factor for insulin resistance, type 2 diabetes mellitus, cardiovascular disease, stroke, metabolic syndrome and its further expression, i.e., nonalcoholic fatty liver disease and death. Using novel models of visceral obesity, several studies have demonstrated that the relationship between visceral fat and longevity is causal, while the accrual of subcutaneous fat does not appear to play an important role in the etiology of disease risk. The need of reducing the visceral fat to improve survival, mainly taking into account the strict link between nonalcoholic fatty liver disease and the coronary artery disease is discussed.     

Negative correlation between neuropeptide Y/agouti-related protein concentration and adiponectinemia in nonalcoholic fatty liver disease obese adolescents submitted to a long-term interdisciplinary therapy

The complexity pathogenesis in the nonalcoholic fatty liver disease (NAFLD) involves an interplay between adipokines and neuroendocrine regulation of energy balance, including the role of neuropeptide Y (NPY)/agouti-related protein (AgRP) system. The first aim of this study was to assess the effect of long-term interdisciplinary intervention on NAFLD in obese adolescents, and the second objective was to establish the relationship between NPY/AgRP ratio and adiponectinemia. Fifty-five postpuberty obese adolescents were submitted to interdisciplinary intervention. The group was divided between subjects with and without NAFLD (n = 19 and 36, respectively). Blood samples were collected to measure glycemia, hepatic transaminases, lipid profile, insulin resistance, and sensitivity. Adiponectin, NPY, and AgRP concentrations were measured by enzyme-linked immunosorbent assay. Food intake was measured using 3-day diet records. It was observed at baseline that important clinical parameters including body weight, body mass index, visceral fat, homeostasis model assessment of insulin resistance, quantitative insulin sensitivity check index, triglycerides, very low-density lipoprotein cholesterol, and hepatic transaminases were more altered in NAFLD patients. After the intervention, these parameters, total energy, and macronutrient intake were reduced significantly in both groups. The most important finding was the positive correlation between AgRP and visceral fat in all patients and the negative correlation between NPY/AgRP and adiponectinemia only in NAFLD obese adolescents. The NAFLD patients presented more altered clinical parameters than the non-NAFLD subjects, including the negative correlation between adiponectinemia and NPY/AgRP. These results suggested that NAFLD obese adolescents presented an inflammatory profile that can influence the neuroendocrine regulation of energy balance, suggesting an additional impairment in the weight loss therapy.     

Relationship between insulin resistance and serum alanine aminotransferase as a surrogate of NAFLD (nonalcoholic fatty liver disease) in obese Korean children

There has been increasing number of obese children who accompany obesity-related comorbidities. It has been known that nonalcoholic fatty liver disease (NAFLD) as one of obesity-related comorbidities is related with insulin resistance. So, we investigated the relation between insulin resistance and NAFLD, using serum alanine aminotransferase (ALT) as a surrogate of NAFLD among obese children in Korea. The study subjects were 909 obese children aged 9–12 years (boys 613, girls 296). Body mass index (BMI), waist circumference (WC), blood pressure, fasting blood glucose, fasting insulin, lipid profile were measured. ALT, liver enzyme was used as a surrogate of NAFLD and homeostasis model assessment of insulin resistance (HOMA-IR) was used as the index of insulin resistance. The prevalence of elevated serum ALT (≥40 mg/dl) was 33.4% in boys, and 19.6% in girls respectively. In boys, ALT was correlated with BMI, waist circumference, total cholesterol, triglyceride, HDL-cholesterol, systolic and diastolic blood pressure, HOMA-IR, fasting serum insulin. Odds ratio for HOMA-IR against the elevated ALT (≥40 mg/dl) was 1.061 (95% confidence interval, 1.020–1.103, P = 0.003). In girls, ALT was correlated with BMI, waist circumference, total cholesterol, triglyceride, glucose, systolic and diastolic blood pressure, HOMA-IR, fasting serum insulin. Odds ratio for HOMA-IR against the elevated ALT (≥40 mg/dl) was 1.042 (95% confidence interval, 0.998–1.088, P = 0.063). Among obese Korean children, insulin resistance and ALT, lipid profile, BMI, WC, blood pressure showed significant correlation. Especially, in boys, higher ALT is founded to be independently associated with insulin resistance.     

Lower birth weight and visceral fat accumulation are related to hyperinsulinemia and insulin resistance in obese Japanese children.

This study aimed to reveal the relation of birth weight (or the birth weight standard deviation score [BWSDS]) and visceral fat accumulation to hyperinsulinemia and insulin resistance. We examined obese Japanese children (650 boys and 317 girls) with a mean age of 10.3 years (range, 6-15 years). The mean percentage of overweight to the standard body weight of Japanese children was 52.1% in boys and 51.4% in girls. Abdominal fat thickness (maximum preperitoneal fat thickness; Pmax) was measured using ultrasonography. The fasting serum insulin and plasma glucose levels were measured, and the homeostasis model assessment-insulin resistance (HOMA-R) and quantitative insulin sensitivity check index (QUICKI) were calculated. We divided the subjects into four groups according to their birth weight or BWSDS, and compared anthropometric measurements, Pmax, blood pressure, serum insulin levels, HOMA-R and QUICKI among the quartiles. The relationships of both birth weight (or BWSDS) and Pmax to serum insulin levels (or HOMA-R, QUICKI) were examined with multiple regression analyses. The fasting serum insulin level and HOMA-R were highest in the quartile with the lowest birth weight or BWSDS. The birth weight and BWSDS were inversely related to the serum insulin levels and HOMA-R, positively related to QUICKI, and independent of Pmax. Our findings suggest that both lower birth weight and visceral fat accumulation may be independently related to hyperinsulinemia and insulin resistance in obese Japanese children.     

Nonalcoholic steatohepatitis and the metabolic syndrome

Relatively recently, the liver has been recognized as a major target of injury in patients with insulin resistance or the metabolic syndrome. Insulin resistance is associated with fat accumulation in the liver, a condition called nonalcoholic fatty liver disease (NAFLD). Excess fat in the liver is not a benign condition. Some patients with NAFLD develop necroinflammatory changes in the liver called nonalcoholic steatohepatitis (NASH) and a fraction of those will develop cirrhosis. About 20% all adults have NAFLD and 2% to 3% of adults have NASH. Approximately 20% of patients with NASH are at risk for developing cirrhosis and subsequently dying from end-stage liver disease. The diagnosis of NASH requires a high index of suspicion, especially in obese patients over the age of 45 years who have diabetes, because these are the patients at greatest risk for developing cirrhosis. Treatment focuses on addressing the underlying insulin resistance with increased exercise and weight reduction.     

Body composition and metabolic factors in obese children and adolescents

OBJECTIVE: Body composition is associated with metablic factors in adults; however, data are limited regarding obese children. This study was undertaken to assess body composition, regional fat distribution, and metabolic factors in obese 6-18-y-old children and adolescents. DESIGN: Cross-sectional assessment. SUBJECTS: Thirty-six obese children and adolescents, (mean+/-s.e.m.) age 11.8+/-0.5 y, BMI 34.1+/-1.2 kg/m(2). MEASUREMENTS: Body composition was assessed by dual energy X-ray absorptiometry and computerized tomography. Fasting insulin, glucose and leptin levels, and the homeostasis model assessment of insulin sensitivity (HOMA-IR) were assessed. RESULTS: The girls had significantly lower glucose levels than the boys. The ethnic group differences (African American children vs white children) in fat mass, total CT fat, subcutaneous CT fat, insulin level, leptin level, and higher HOMA-IR were not significant after adjusting for age or pubertal stage. These differences in abdominal fat and subcutaneous abdominal fat were also not independent of total body fat or BMI. No ethnic group differences in visceral abdominal fat were noted. Insulin level and HOMA IR were associated with leptin level (independent of fat mass) and fat mass. Leptin level was associated with fat mass, total CT fat, and subcutaneous CT fat; however the associations between the CT fat measures and leptin were not independent of total body fat mass. CONCLUSIONS: Neither visceral abdominal fat, subcutaneous abdominal fat, insulin levels, or insulin resistance differed by ethnic group when adjusted for age or pubertal status. This contrasts with findings in adults and non-obese children which suggest lower levels of visceral fat and higher insulin levels and insulin resistance in African American children and adolescents.     

Increased circulating zonulin in children with biopsy-proven nonalcoholic fatty liver disease

AIM:To investigate the potential association of circulating zonulin with the stage of liver disease in obese children with biopsy-confirmed nonalcoholic fatty liver disease(NAFLD).METHODS:A case-control study was performed.Cases were 40 obese children with NAFLD.The diagnosis of NAFLD was based on magnetic resonance imaging(MRI)with high hepatic fat fraction(HFF≥5%),and confirmed by liver biopsy with≥5%of hepatocytes containing macrovesicular fat.Controls were selected from obese children with normal levels of aminotransferases,and without MRI evidence of fatty liver as well as of other causes of chronic liver diseases.Controls were matched(1-to 1)with the cases on age,gender,pubertal stage and as closely as possible on body mass index-standard deviation score.All participants underwent clinical examination,laboratory testsincluding zonulin,inflammatory and metabolic parameters,and MRI for measurement of HFF and visceral adipose tissue.RESULTS:Zonulin values were significantly greater in obese subjects with NAFLD than in those without NAFLD[median(interquartile range),4.23(3.18-5.89)vs 3.31(2.05-4.63),P<0.01].In patients with NAFLD,zonulin concentrations increased significantly with the severity of steatosis and the Spearman’s coefficient revealed a positive correlation between zonulin values and steatosis(r=0.372,P<0.05);however,we did not find a significant correlation between zonulin and lobular inflammation(P=0.23),ballooning(P=0.10),fibrosis score(P=0.18),or presence of nonalcoholic steatohepatitis(P=0.17).Within the entire study population,zonulin levels were positively associated with gamma-glutamyl transferase,2-h insulin,HFF,and negatively associated with whole-body insulin sensitivity index(WBISI),after adjustment for age,gender and pubertal status.When the associations were restricted to the group of NAFLD patients,2-h insulin,hepatic fat,and WBISI retained statistical significance.CONCLUSION:Circulating zonulin is increased in children and adolescents with NAFLD and correlates with the severity of steatosis.     

Pancreatic fat and β-cell function in overweight/obese children with nonalcoholic fatty liver disease

AIM: To analyze the associations of pancreatic fat with other fat depots and β-cell function in pediatric nonalcoholic fatty liver disease (NAFLD).METHODS: We examined 158 overweight/obese children and adolescents, 80 with NAFLD [hepatic fat fraction (HFF) ≥ 5%] and 78 without fatty liver. Visceral adipose tissue (VAT), pancreatic fat fraction (PFF) and HFF were determined by magnetic resonance imaging. Estimates of insulin sensitivity were calculated using the homeostasis model assessment of insulin resistance (HOMA-IR), defined by fasting insulin and fasting glucose and whole-body insulin sensitivity index (WBISI), based on mean values of insulin and glucose obtained from oral glucose tolerance test and the corresponding fasting values. Patients were considered to have prediabetes if they had either: (1) impaired fasting glucose, defined as a fasting glucose level ≥ 100 mg/dL to < 126 mg/dL; (2) impaired glucose tolerance, defined as a 2 h glucose concentration between ≥ 140 mg/dL and < 200 mg/dL; or (3) hemoglobin A1c value of ≥ 5.7% to < 6.5%.RESULTS: PFF was significantly higher in NAFLD patients compared with subjects without liver involvement. PFF was significantly associated with HFF and VAT, as well as fasting insulin, C peptide, HOMA-IR, and WBISI. The association between PFF and HFF was no longer significant after adjusting for age, gender, Tanner stage, body mass index (BMI)-SD score, and VAT. In multiple regression analysis with WBISI or HOMA-IR as the dependent variables, against the covariates age, gender, Tanner stage, BMI-SD score, VAT, PFF, and HFF, the only variable significantly associated with WBISI (standardized coefficient B, -0.398; P = 0.001) as well as HOMA-IR (0.353; P = 0.003) was HFF. Children with prediabetes had higher PFF and HFF than those without. PFF and HFF were significantly associated with prediabetes after adjustment for clinical variables. When all fat depots where included in the same model, only HFF remained significantly associated with prediabetes (OR = 3.38; 95%CI: 1.10-10.4; P = 0.034).CONCLUSION: In overweight/obese children with NAFLD, pancreatic fat is increased compared with those without liver involvement. However, only liver fat is independently related to prediabetes.