Search Results (17)

Background/Objectives: Children and teenagers display a distinct metabolic dysfunction-associated steatohepatitis (MASH) phenotype, yet studies of childhood MASH are scarce and validated animal models lacking, limiting the development of treatments. Poor vitamin C (VitC) status may affect MASH progression and often co-occurs with high-fat diets and related metabolic imbalances. As a regulator of DNA methylation, poor VitC status may further contribute to MASH by regulating gene expression This study investigated guinea pigs—a species that, like humans, depends on vitC in the diet—as a model of pediatric MASH, examining the effects of poor VitC status on MASH hallmarks and global DNA methylation levels. Methods: Sixty-two juvenile guinea pigs were exposed to a high-fat diet for 16 weeks. Results: Juvenile guinea pigs exhibited hepatic histopathology representative of pediatric MASH, confirmed by portal inflammation and fibrosis. Consistent with pediatric MASH, juvenile guinea pigs displayed increased lobular and portal inflammation (p < 0.05 and p < 0.0001, respectively) but less steatosis (p < 0.001) compared to adults. Compared to the controls, the guinea pigs deprived in VitC showed lower body weight (p < 0.01), higher expression of hepatic inflammatory genes (p < 0.05), and a lower global hydroxymethylcytosine to methylcytosine ratio in the high-fat groups (p < 0.05). Conclusions: Our study validates guinea pigs as a model of pediatric MASH and suggests that VitC contributes to an altered gene expression signature through the regulation of DNA hydroxymethylation. We postulate that nutritional co-deficiencies in MASH, such as low VitC, may accelerate disease progression and deserve further attention. Full article

In the past thirty years, childhood obesity rates have risen significantly worldwide, affecting over 340 million children in affluent nations. This surge is intricately tied to metabolic disorders, notably insulin resistance, type 2 diabetes mellitus (T2DM), and the continually evolving spectrum of metabolic-associated (dysfunction) steatotic liver disease (MASLD). This review underscores the alarming escalation of childhood obesity and delves comprehensively into the evolving and dynamic changes of nomenclature surrounding diverse conditions of hepatic steatosis, from the initial recognition of non-alcoholic fatty liver disease (NAFLD) to the progressive evolution into MASLD. Moreover, it emphasizes the crucial role of pediatric endocrinologists in thoroughly and accurately investigating MASLD onset in children with T2DM, where each condition influences and exacerbates the progression of the other. This review critically highlights the inadequacies of current screening strategies and diagnosis, stressing the need for a paradigm shift. A proposed solution involves the integration of hepatic magnetic resonance imaging assessment into the diagnostic arsenal for children showing insufficient glycemic control and weight loss post-T2DM diagnosis, thereby complementing conventional liver enzyme testing. This holistic approach aims to significantly enhance diagnostic precision, fostering improved outcomes in this vulnerable high-risk pediatric population. Full article

Childhood obesity is a global public health problem. Worldwide, 41 million children under 5 years and 340 million children and adolescents between 5 and 19 years are overweight. In addition, the recent COVID-19 epidemic has further amplified this social phenomenon. Obesity is a condition associated with various comorbidities, such as nonalcoholic fatty liver disease (NAFLD). The pathophysiology of NAFLD in obesity is intricate and involves the interaction and dysregulation of several mechanisms, such as insulin resistance, cytokine signaling, and alteration of the gut microbiota. NAFLD is defined as the presence of hepatic steatosis in more than 5% of hepatocytes, evaluated by histological analysis. It can evolve from hepatic steatosis to steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma, and end-stage liver failure. Body weight reduction through lifestyle modification remains the first-line intervention for the management of pediatric NAFLD. Indeed, studies suggest that diets low in fat and sugar and conversely rich in dietary fibers promote the improvement of metabolic parameters. This review aims to evaluate the existing relationship between obesity and NAFLD in the pediatric population and to assess the dietary patterns and nutritional supplementations that can be recommended to prevent and manage obesity and its comorbidities. Full article

Childhood obesity increases the risk of developing metabolic syndrome later in life. Moreover, metabolic dysfunction may be inherited into the following generation through non-genomic mechanisms, with epigenetics as a plausible candidate. The pathways involved in the development of metabolic dysfunction across generations in the context of childhood obesity remain largely unexplored. We have developed a mouse model of early adiposity by reducing litter size at birth (small litter group, SL: 4 pups/dam; control group, C: 8 pups/dam). Mice raised in small litters (SL) developed obesity, insulin resistance and hepatic steatosis with aging. Strikingly, the offspring of SL males (SL-F1) also developed hepatic steatosis. Paternal transmission of an environmentally induced phenotype strongly suggests epigenetic inheritance. We analyzed the hepatic transcriptome in C-F1 and SL-F1 mice to identify pathways involved in the development of hepatic steatosis. We found that the circadian rhythm and lipid metabolic process were the ontologies with highest significance in the liver of SL-F1 mice. We explored whether DNA methylation and small non-coding RNAs might be involved in mediating intergenerational effects. Sperm DNA methylation was largely altered in SL mice. However, these changes did not correlate with the hepatic transcriptome. Next, we analyzed small non-coding RNA content in the testes of mice from the parental generation. Two miRNAs (miR-457 and miR-201) appeared differentially expressed in the testes of SL-F0 mice. They are known to be expressed in mature spermatozoa, but not in oocytes nor early embryos, and they may regulate the transcription of lipogenic genes, but not clock genes, in hepatocytes. Hence, they are strong candidates to mediate the inheritance of adult hepatic steatosis in our murine model. In conclusion, litter size reduction leads to intergenerational effects through non-genomic mechanisms. In our model, DNA methylation does not seem to play a role on the circadian rhythm nor lipid genes. However, at least two paternal miRNAs might influence the expression of a few lipid-related genes in the first-generation offspring, F1. Full article

As in adults, childhood obesity is associated with several metabolic disorders; however, there is little information regarding complex obesity-derived complications such as hepatic steatosis or endothelial dysfunction at early ages. Therefore, the objective of the present study was to analyze the effect of a nutritional and physical exercise program on obesity comorbidities in the form of subclinical atherosclerosis and non-alcoholic fatty liver in young children. A total of 148 children completed the study. For nine months (one academic year), children carried out a nutritional and physical activity program of 3 h/week. Anthropometric, clinical, liver ultrasound and carotid intima-media thickness (cIMT) parameters were evaluated. Our results showed that the program significantly improved anthropometrical parameters, especially regarding BMI and body fat (p < 0.001 and p = 0.004, respectively). The effect on metabolic parameters was limited, although a significant reduction on triglycerides was observed (p = 0.009). The education program had a great influence on the echogenic parameters, since the percentage of children with light steatosis decreased from 35% to 4% at the end of the study. In addition, cIMT also decreased significantly in both groups, although there was no statistically significant differences between groups. In conclusion, detection of early complications of obesity through sonographic parameters may allow early intervention, as in the present study, to prevent obesity co-morbidities in children. Full article

In the last decade, the survival of subjects affected by cancer in childhood has significantly improved. The increased lifespan of childhood cancer survivors (CCS) led to a greater risk for long-term, therapy-related morbidity. To identify the clinical predictors of metabolic adverse outcomes in CCS (average off-therapy period: 12 years), we recruited 126 survivors of different childhood cancers (86.5% hematological cancers) who received at least anticancer chemotherapy, consecutively approached during their annual oncohematological outpatient visit. At examination, anthropometric measures and cancer-related history were collected. Moreover, a fasting venous sample was carried out for measuring fasting plasma glucose and insulin, glycated hemoglobin, lipid panel, and transaminases. We calculated the indexes of insulin resistance (HOMA-IR, McAuley, and QUICKI) and secretion (HOMA-β), liver steatosis (Hepatic Steatosis Index) and fibrosis (FIB-4 and NAFLD fibrosis score), and visceral fat dysfunction (Visceral Adiposity Index). More than one-third of the subjects (37.3%) did not have normal weight, with 11.1% of them affected by obesity. At recruitment, obese subjects were at significantly higher risk for impaired fasting glucose, metabolic syndrome, visceral adipose dysfunction, and liver steatosis/fibrosis. Subjects who received bone marrow transplantation were prone to insulin resistance, while survivors of lymphoma presented a visceral adipose dysfunction These results suggest a carefully metabolic monitoring of CCS, particularly in subgroups at higher risk, to early detect these conditions, promptly begin therapeutic interventions, and mitigate the dysmetabolic-related health burden. Full article

Background: Early-life exposure to the Chinese famine has been related to the risk of obesity, type 2 diabetes, and nonalcoholic fatty liver disease later in life. Nevertheless, the long-term impact of famine exposure on metabolic associated fatty liver disease (MAFLD), a recently proposed term to describe liver disease associated with known metabolic dysfunction, remains unknown. The aim of our study was to explore the relationship between early famine exposure and MAFLD in adulthood. Methods: A total of 26,821 participants (10,994 men, 15,827 women) were recruited from a cohort study of Chinese adults in Shanghai. We categorized participants into four famine exposure subgroups based on the birth year as nonexposed (1963–1967), fetal-exposed (1959–1962), childhood-exposed (1949–1958), and adolescence-exposed (1941–1948). MAFLD was defined as liver steatosis detected by ultrasound plus one of the following three criteria: overweight/obesity, type 2 diabetes, or evidence of metabolic dysregulation. Multivariable logistic regression models were performed to examine the association between famine exposure and MAFLD. Results: The mean ± standard deviation age of the participants was 60.8 ± 6.8 years. The age-adjusted prevalence of MAFLD was 38.3, 40.8, 40.1, and 36.5% for the nonexposed, fetal-exposed, childhood-exposed, and adolescence-exposed subgroups, respectively. Compared with nonexposed participants, fetal-exposed participants showed an increased risk of adulthood MAFLD (OR = 1.10, 95% CI 1.00–1.21). The significant association between fetal famine exposure and MAFLD was observed in women (OR = 1.22, 95% CI 1.08–1.37), but not in men (OR = 0.88, 95% CI 0.75–1.03). In age-balanced analyses combining pre-famine and post-famine births as the reference, women exposed to famine in the fetal stage still had an increased risk of MAFLD (OR = 1.15, 95% CI 1.05–1.26). Conclusions: Prenatal exposure to famine showed a sex-specific association with the risk of MAFLD in adulthood. Full article

Background: Owing to the increasing rate of pediatric obesity, its complications such as non-alcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA) have become prevalent already in childhood. We aimed to assess the relationship between these two diseases in a cohort of children with obesity. Methods: We enrolled 153 children with obesity (mean age 10.5 ± 2.66, mean BMI 30.9 ± 5.1) showing OSA. Subjects underwent a laboratory evaluation, a cardio-respiratory polysomnography (PSG), and a liver ultrasound. Results: All subjects had a clinical diagnosis of OSA based on the AHI > 1/h (mean AHI 8.0 ± 5.9; range 2.21–19.0). Of these, 69 showed hepatic steatosis (62.3% as mild, 20.3% as moderate, and 17.4% as severe degree). A strong association between ALT and apnea/hypopnea index (AHI) was observed (p = 0.0003). This association was not confirmed after adjusting for hepatic steatosis (p = 0.53). By subdividing our population according to the presence/absence of steatosis, this association was found only in the steatosis group (p = 0.009). As the severity of steatosis increased, the significance of its association with AHI compared to the absence of steatosis became progressively stronger (all p < 0.0001). Conclusions: Hepatic steatosis seems to drive the association between OSA and ALT levels, suggesting a potential pathogenic role of OSA in NAFLD. Full article

Background: Time restricted feeding (TRF) refers to dietary interventions in which food access is limited during a specific timeframe of the day. TRFs have proven useful in improving metabolic health in adult subjects with obesity. Their beneficial effects are mediated, in part, through modulating the circadian rhythm. Nevertheless, the translation of these dietary interventions onto obese/overweight children and adolescents remains uncharacterized. The objective of this study is to explore the feasibility of temporal dietary interventions for improving metabolic health in the context of childhood obesity. Methods: We have previously developed a mouse model of early adiposity (i.e., childhood obesity) through litter size reduction. Mice raised in small litters (SL) became obese as early as by two weeks of age, and as adults, they developed several obesity-related co-morbidities, including insulin resistance, glucose intolerance and hepatic steatosis. Here, we explored whether two independent short-term chrono-nutritional interventions might improve metabolic health in 1-month-old pre-pubertal SL mice. Both TRFs comprised 8 h feeding/14 h fasting. In the first one (TRF1) Control and SL mice had access to the diet for 8 h during the dark phase. In the second intervention (TRF2) food was available during the light:dark transitions. Results: TRF1 did not alter food intake nor ameliorate adiposity in SL-TRF1. In contrast, SL-TRF2 mice showed unintentional reduction of caloric intake, which was accompanied by reduced total body weight and adiposity. Strikingly, hepatic triglyceride content was completely normalized in SL-TRF1 and SL-TRF2 mice, when compared to the ad lib-fed SL mice. These effects were partially mediated by (i) clock-dependent signals, which might modulate the expression of Pparg or Cpt1a, and (ii) clock-independent signals, such as fasting itself, which could influence Fasn expression. Conclusions: Time-restricted feeding is an effective and feasible nutritional intervention to improve metabolic health, namely hepatic steatosis, in a model of childhood obesity. These data open new avenues for future safe and efficient chrono-nutritional interventions aimed to improve metabolic health in children with overweight/obesity. Full article

(1) Background: High sugar intake is prevalent among children and is associated with non-alcoholic fatty liver disease (NAFLD). The purpose of this study is to determine if a high intake of free sugars and sugary beverages (SB) in childhood is associated with NAFLD in adulthood; (2) Methods: At 24 years, 3095 participants were assessed for severe hepatic steatosis (controlled attenuation parameter >280 dB/m) and had dietary data collected via a food frequency questionnaire at age three years. Multiple logistic regression models adjusted for total energy intake, potential confounders, and a mediator (offspring body mass index (BMI) at 24 years); (3) Results: Per quintile increase of free sugar intake association with severe hepatic steatosis at 24 years after adjusting for total energy was odds ratio (OR):1.07 (95% CL: 0.99–1.17). Comparing the lowest vs. the highest free sugar consumers, the association was OR:1.28 (95% CL: 0.88–1.85) and 1.14 (0.72, 1.82) after full adjustment. The OR for high SB consumption (>2/day) compared to <1/day was 1.23 (95% CL: 0.82–1.84) and OR: 0.98 (95% CL: 0.60–1.60) after full adjustment; (4) Conclusions: High free sugar and SB intake at three years were positively but weakly associated with severe hepatic steatosis at 24 years. These associations were completely attenuated after adjusting for confounders and 24-year BMI. Full article

The prevalence of childhood obesity has increased over the years in the United States and contributed to a rise in metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Animal studies suggested the role of histamine blockade on mesenteric lymphatics tone, contributing to weight gain and hepatic steatosis. This study aimed to investigate an association between antihistamines (AH) use in children and obesity. A single-center retrospective cohort study on children with a diagnosis of NAFLD, followed in the gastroenterology clinic, was performed between January 2018 and April 2019. The demographics, medications, and body mass index (BMI) were assessed. Participants were divided into an AH group with documented use and comparison group, antihistamine naïve. Of the 32 participants in the study, 13 used AH, and 19 did not. Antihistamine users had a mean increase in BMI percentile per year of 1.17 compared to a decrease of 0.06 in comparison group (p = 0.0008). AH usage correlated with a mean increase in BMI z-score of 0.23 per year, as opposed to a decrease by 0.012 in comparison group (p = 0.0016). No difference was found in triglycerides (TG), glucose, and liver enzymes. AH use increases BMI percentiles and z-scores over time and is associated with obesity in children. Full article

Background. Childhood obesity is becoming a major health issue and contributes to increasing the risk of cardiovascular disease in adulthood. Since dysregulated metabolism of bile acids (BAs) plays a role in progression of obesity-related disorders, including steatosis and hypertension, this study aimed to investigate BAs profiles in obese children with and without steatosis and hypertension, as well as exploring the interplay between BAs profile and vascular function. Methods. BAs concentrations were quantified with liquid chromatography-tandem mass spectrometry in 69 overweight/obese children and adolescents (mean age, 11.6 ± 2.5 years; 30 females). Liver steatosis was defined with abdomen ultrasonography, whilst hypertension was defined according to the current European guidelines. Vascular function was assessed with ultrasound technique, by measuring carotid intima media thickness (cIMT) and common carotid artery distensibility (cDC). Results. Total and individual glycine-conjugated BAs concentrations were found to be significantly higher in males compared to females, as well as in pre-pubertal compared to pubertal stage (p < 0.05 for both). No difference in BAs concentration was observed between hypertensive and normotensive subjects. Total BAs and glycine conjugated BAs were significantly higher in participants with steatosis compared to those without (p = 0.004 for both). The values of total glycine-conjugate acids were positively correlated with cDC and this association remained significant in linear regression after adjusting for sex, age, pubertal stage, body mass index and aspartate aminotransferase. Conclusion. The results suggest a possible role of BAs in the pathogenesis of liver and/or vascular damage in children and adolescent. Further studies are hence needed to validate these preliminary findings. Full article

(1) Background: Alanine aminotransferase (ALT) is used to screen for non-alcoholic fatty liver disease (NAFLD) in children; however, the optimal age to commence screening is not determined. Our objective was to describe whether ALT trends from 9–24 years were associated with hepatic steatosis at 24 years in a population-based UK cohort. (2) Methods: The sample included 1156 participants who were assessed for hepatic steatosis at 24 years and had at least two ALT measurements at 9, 15, 17, and/or 24 years. Controlled attenuation parameter scores were used to assess steatosis (low (<248 dB/m), mild/moderate (248–279 dB/m), severe (>279 dB/m)). Sex-stratified mixed-effects models were constructed to assess the liver enzyme trends by steatosis level. (3) Results: The final sample was 41.4% male and 10.4% had severe steatosis. In both sexes, ALT trends from 9 to 24 years differed in those with low vs. severe steatosis at 24 years (p < 0.001). There was no evidence of differences prior to puberty. At 17 years, the low vs. severe geometric mean ratio (GMR) was 0.69, 95% CI: 0.57–0.85 in males and (0.81, 0.65–1.01) females. At 24 years, the GMR was (0.53, 0.42–0.66) in males and (0.67, 0.54–0.84) females. (4) Conclusions: Higher ALT concentration in adolescence was associated with hepatic steatosis at 24 years. The increased screening of adolescents could strengthen NAFLD prevention and treatment efforts. Full article

Nonalcoholic Fatty Liver Disease (NAFLD) is a common cause of chronic liver disease in childhood and strongly associated with obesity. Routine biochemical non-invasive tests remain with low accuracy for diagnosis of NAFLD. We performed a cross-sectional study to examine potential associations between anthropometric and biochemical parameters, specially TGF-β, a prognosis marker for hepatic steatosis (HS). Between May and October 2019, seventy-two overweight adolescents were enrolled, of which 36 had hepatic steatosis. Hepatic, lipidic and glycemic profiles, and levels of vitamin D, ferritin and TGF-β were analyzed. Hierarchical cluster and a discriminant model using canonical correlations were employed to depict the overall expression profile of biochemical markers and the biochemical degree of perturbation. Median values of alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT), and TGF-β were higher in the adolescents with HS. Values of body mass index (BMI)/age and ALT, but not of TGF-β, were gradually increased proportionally to augmentation of steatosis severity. In a multivariate analysis, TGF-β plasma concentrations were associated with occurrence of hepatic steatosis independent of other covariates. Discriminant analysis confirmed that TGF-β concentrations can identify HS cases. Our data reveal that HS patients exhibit a distinct biosignature of biochemical parameters and imply TGF-β as an important biomarker to evaluate risk of steatosis development. Full article

Fatty liver disease is a serious complication of childhood obesity. Calorie-restricted regimen (RCR) is one of the effective therapy for this condition. Aim of the study was to evaluate the effect of lycopene-rich tomato sauce with oregano and basil extracts in obese children with fatty liver on RCR. 61 obese children with fatty liver were enrolled, 52 completed the study. A randomized cross over clinical trial was performed. Participants were assigned to RCR alone or with a supplement of lycopene-rich tomato juice for 60 days; subsequently, the groups were switched to the alternative regimen for the next 60 days. Reduction in BMI, HOMA-IR, cholesterol, triglycerides, liver size, and steatosis was more profound in tomato-supplemented group. Leptin decreased in both groups whereas adiponectin raised only after tomato supplementation. RCR is associated with the impaired engagement of T-cells glycolysis and proliferation, tomato-supplementation resulted in glycolytic metabolic activation of T-cells. Tomato juice ameliorates glucose and lipid metabolism in obese children, improve oxidative and inflammatory state and modulates the mitochondrial metabolism of T-cells contributing to a maintenance of a proper immune surveillance in children, impaired by RCR. The addition of tomato to RCR could be considered a protective and preventive support to obese child. Full article