Treatment Of Nonalcoholic Fatty Liver Disease In Children Research Articles

Shorter leukocyte telomere length protects against NAFLD progression in children

Leukocyte telomere length (LTL) gets shorter with each cell division and is also sensitive to reactive oxygen species damage and inflammatory processes. Studies in adults with non-alcoholic fatty liver disease (NAFLD) have found that increased fibrosis but not ALT levels are associated with shorter LTL. Few pediatric studies have been conducted; as such, we sought to evaluate potential associations between LTL and liver disease and liver disease progression in pediatric patients. Using data from the Treatment of NAFLD in Children (TONIC) randomized controlled trial, we assessed the potential predictive relationship between LTL and liver disease progression based on two successive liver biopsies over 96 weeks. We assessed the potential relationship between LTL and child age, sex, and race/ethnicity and features of liver disease including components of histology. We subsequently evaluated predictors for improvement in non-alcoholic steatohepatitis (NASH) at 96 weeks including LTL. We also assessed predictors of lobular inflammation improvement at 96 weeks using multivariable models. Mean LTL at baseline was 1.33 ± 0.23 T/S. Increasing lobular and portal inflammation were associated with longer LTL. In multivariable models, greater lobular inflammation at baseline was associated with longer LTL (Coeff 0.03, 95% CI 0.006–0.13; p = 0.03). Longer LTL at baseline was associated with worsening lobular inflammation at 96 weeks (Coeff 2.41, 95% CI 0.78–4.04; p < 0.01). There was no association between liver fibrosis and LTL. The association between LTL and pediatric NASH does not parallel adults with no association between fibrosis stage and NASH. Conversely, longer LTL was associated with more lobular inflammation at baseline and increased lobular inflammation over the 96-week period. Longer LTL in children may indicate greater risk for future complications from NASH.

Alanine Aminotransferase and Gamma-Glutamyl Transpeptidase Predict Histologic Improvement in Pediatric Nonalcoholic Steatohepatitis.

Predictive, noninvasive tools are needed to monitor key features of nonalcoholic fatty liver disease (NAFLD) in children that relate to improvement in liver histology. The purpose of this study was to evaluate the relationship between liver chemistries and liver histology using data from the CyNCh (Cysteamine Bitartrate Delayed-Release for the Treatment of NAFLD in Children) clinical trial. This study included 146 children. Improvement in liver histology, defined as decrease in nonalcoholic fatty liver disease (NAFLD) Activity Score ≥2 points without worsening of fibrosis, occurred in 43 participants (30%). There were 46 participants with borderline zone 1 nonalcoholic steatohepatitis (NASH) at baseline, with resolution in 28% (12 of 46). Multivariate models were constructed using baseline and change in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) at 52weeks, for improvement in (1) liver histology primary outcome, (2) borderline zone 1 NASH, and (3) fibrosis. For improvement in histology, the model (P<0.0001) retained baseline and change in GGT (area under the receiver operating characteristic [AUROC], 0.79; 95% confidence interval [CI], 0.71-0.87). For borderline zone 1 NASH, the model (P=0.0004) retained baseline and change in ALT (AUROC, 0.80; 95% CI, 0.67-0.93). For fibrosis, the model (P<0.001) retained baseline and change in ALT (AUROC, 0.80; 95% CI, 0.67-0.93). Additional clinical parameters were added to the models using Akaike's information criterion selection, and significantly boosted performance: improvement in histology with AUROC of 0.89 (95% CI, 0.82-0.95), borderline zone 1 NASH with AUROC of 0.91 (95% CI, 0.83-0.99), and fibrosis with AUROC of 0.89 (95% CI, 0.82-0.94). Models were validated using data from the TONIC (Treatment of Nonalcoholic Fatty Liver Disease in Children) trial. In children with NAFLD, dynamic changes in serum ALT and GGT are associated with change in liver histology and appear to be powerful indicators of histological response.

Vitamin D and non-alcoholic fatty liver disease in children

Objective The aim of this study was to explore the serum 25-(OH)Vitamin D and its correlation with liver function in children who have suffered from non-alcoholic fatty liver disease(NAFLD), and to explore the necessity of vitamin D treatment of NAFLD in children. Methods Forty children with NAFLD diagnosed by imaging were selected from the outpatient of pediatric digestive department of Shengjing Hospital of China Medical University, selected as observation group from July 2017 to August 2019, and 37 healthy children were selected as control group.The clinical data were collected and serum 25-(OH)Vitamin D were detected at the same time. Results There was no significant difference in 25-(OH)Vitamin D among children with NAFLD at different ages and gender(P>0.05). The level of 25-(OH)Vitamin D in children with NAFLD[(21.30±8.77)μg/L]was significantly lower than that in the control group[(28.53±10.18)μg/L](t=3.343, P<0.01). The incidence of vitamin D deficiency(<20 μg/L)and insufficiency(<30 μg/L)in children with NAFLD(35/40=87.50%)was significantly higher than that in the control group(22/37=59.46%)(χ2=10.035, P<0.05). Serum 25-(OH)Vitamin D was negatively correlated with fasting insulin(r=-0.464, P<0.01)and homeostasis model assessment of insulin resistance(r=-0.444, P<0.01), but not correlated with BMI, transaminase level(ALT, AST), uric acid and blood lipid(TG, TC, HDL-C, LDL-C, sd-LDL, Apo-A1, Apo-B). Vitamin D deficiency was the risk factor of NAFLD(OR=1.088, P<0.01). Conclusion Vitamin D deficiency is common in pediatric NAFLD, which may be a risk factor of NAFLD.The mechanism may be that vitamin D deficiency aggravates insulin resistance and further aggravates liver damage in children with NAFLD. Key words: Children; Non-alcoholic fatty liver disease; 25-(OH)Vitamin D

Therapeutic Effects of Green Tea on Nonalcoholic Fatty Liver Disease in 10-16-Year-Old Children

Introduction: Nonalcoholic Fatty Liver Disease (NAFLD) is characterised by fat accumulation in the liver. Treatment of NAFLD in children is an important issue but the options are limited. Green tea has antioxidant and anti-hyperlipidemic effects but studies; on the effect of green tea in children are limited. Aim: To investigate effect of green tea on NAFLD in children. Materials and Methods: In this study. 52 children aged 10-16 years with NAFLD were divided into two groups of 26 each: Intervention and control. For both groups, modification of diet and intensification of physical activity were prescribed for three months. Intervention group was also treated with green tea tablets. Sonography and measurements of liver enzymes {Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)}, lipid profile and Body Mass Index (BMI) were conducted before and after the intervention. The data were analysed by the Statistical Package for the Social Sciences (SPSS) version 19.0 using ANCOVA. Results: After treatment with green tea, fatty liver grade decreased significantly in the intervention group compared to control group (p<0.0001). In addition, this treatment caused significant decrease in ALT, AST, and triglyceride levels and significant increase in High-Density Lipoprotein (HDL) level (p<0.05), but Low-Density Lipoprotein (LDL) level did not decrease significantly in the intervention group compared to control. Conclusion: Oral prescription of green tea was effective in improving fatty liver grade, decreasing hepatic fat accumulation and improving liver function, weight loss and reducing ALT and AST without any side effects. These effects can be due to green tea compounds such as polyphenols especially catechin and antioxidant and anti-hyperlipidemic effects. Keywords Author Keywords:Alanine aminotransferase; Aspartate aminotransferase; Green tea extract; Nonalcoholic steatohepatitis

Hepatic Nuclear Receptor Expression Associates with Features of Histology in Pediatric Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children and adults. This study examined the relationship between hepatic nuclear receptor (NR) expression and histologic features of NAFLD. Drugs targeting a variety of NRs for nonalcoholic steatohepatitis (NASH) are in clinical trials. Liver messenger RNA was isolated from 40 children (10‐19 years) undergoing end‐of‐treatment biopsy in the Treatment of NAFLD in Children (TONIC) trial. High‐throughput quantitative polymerase chain reaction assayed NR messenger RNA. Cluster analysis was used to group 36 NRs, and NR levels were related to histologic measures of specific NAFLD features. Cluster analysis determined five groupings of NRs. Significant (P < 0.05) differential expressions of specific NRs associated with histologic measures include farnesoid X receptor alpha and retinoic acid receptor (RARβ and RARβ) for steatosis; estrogen receptor alpha (ERα) and peroxisome proliferator‐activated receptor gamma 3 (PPARγ3) for hepatocellular ballooning; ER and PPARγ2 for lobular inflammation; PPARα/δ/γ1/γ2, ERα, constitutive androstane receptor, chicken ovalbumin upstream promoter transcription factor 1, RARα, RARβ1, retinoid X receptor, pregnane X receptor, thyroid hormone receptors α and β, and nuclear receptor related‐1 for fibrosis; and ERα and RARβ/β1/α for diagnosis of NASH. Conclusion: Differential expression of specific NRs correlates with histologic severity of specific NAFLD features. These NRs are pleiotropic transactivators regulating basal metabolic functions and inflammatory responses. Derangement of activity of these receptors in NAFLD provides a rationale for exploiting their ability with receptor‐specific ligands to ameliorate NASH and its consequences.

An interpretation of the AASLD practice guideline on the diagnosis and management of nonalcoholic fatty liver disease in 2017

The American Association for the Study of Liver Diseases (AASLD) updated and published the Practice Guidance for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease (NAFLD) in July 2017, which provides recommendations for the accurate diagnosis, treatment, and effective prevention of NAFLD. Related metabolic diseases should be considered during the initial evaluation of patients suspected of NAFLD. Noninvasive diagnostic techniques including transient elastography, magnetic resonance elastography, and serum biochemical models should be used to evaluate the development and progression of liver fibrosis in patients with NAFLD. Clinical liver pathology report should clearly differentiate between nonalcoholic fatty liver (NAFL), NAFL with inflammation, and nonalcoholic steatohepatitis (NASH) and identify the presence or absence of liver fibrosis and its degree. Early medication for NAFLD can only be used in patients with pathologically confirmed NASH and liver fibrosis, and it is not recommended to use pioglitazone and vitamin E as the first-line drugs for patients with NASH which has not been proven by biopsy or non-diabetic NASH patients. Foregut bariatric surgery can be considered for obese patients with NAFLD/NASH who meet related indications. It is emphasized that the risk factors for cardiovascular disease should be eliminated for NAFLD patients. Statins can be used for the treatment of dyslipidemia in patients with NAFLD/NASH, but they cannot be used in patients with decompensated liver cirrhosis. Routine screening or hepatocellular carcinoma surveillance is not recommended for NASH patients without liver cirrhosis. Cardiovascular disease should be taken seriously during liver transplantation evaluation. There is still no adequate clinical evidence for the treatment of NAFLD in children and adolescents, and intensive lifestyle intervention is recommended as the first-line therapy for such patients.

EFFECT OF SYNBIOTICS IN CHILDREN WITH NON‐ALCOHOLIC FATTY LIVER DISEASE

Introduction:Synbiotics have beneficial effect on intestinal inflammation and permeability (1, 2, 3). We aimed to analyze the effect of long term (4 months) synbiotic treatment on non‐alcoholic fatty liver disease (NAFLD) in obese children.Patients and Methods:The study included the 28 children with NAFLD (12.2 ± 2.2 years and 64.3% male) based on the clinical and liver ultrasound (US) findings (severe fatty liver in 25%, moderate in 57% and mild in 18%) and 28 age‐and sex matched healthy children. At baseline, patients and control group underwent anthropometric measurements including body mass index (BMI) and laboratory evaluation including liver function tests, serum lipids, HOMA‐IR, cytokeratin‐18 (CK‐18), ethanol, tumor necrosis factor alpha (TNF‐α), oxidant (TOS) and anti‐oxidant (TAS) and zonulin levels and stool calprotectin level. All the patients with NAFLD were treated with synbiotics including Bifidobacterium lactis, Lactobacillus acidophilus and Lactobacillus casei (7 million CFU/day) plus inulin 100 mg (Maflor plus capsules®), 1 capsules per day for 4 months. Clinical and laboratory analysis was repeated in patients 4 months after synbiotic treatment and the results were compared with baseline and control group.Results:Apart from anthropometric measurements; liver function tests and lipid profile, serum ethanol (4.9 ± 3.9 vs. 0.6 ± 0.8 mg/dl, p = 0.001), TNF‐α (9.9 ± 7.4 vs. 6.1 ± 4.6 pg/mL, p = 0.03), and stool calprotectin level (14.1 ± 17.4 vs. 7.2 ± 0.8 ng/mL, p = 0.01) were significantly high in patients with NAFLD compared to healthy children. After treatment, improvement in anthropometric parameters was seen in all patients. Significant decrease was found in liver function tests, serum ethanol (4.9 ± 3.9 vs. 0.9 ± 1.4 mg/dl, p = 0.001) and TNF‐α (9.9 ± 7.4 vs. 8.4 ± 7.4 pg/mL, p = 0.01) levels and stool calprotectin level (14.1 ± 17.4 vs. 7.9 ± 1.5 ng/mL, p = 0.04) after treatment, whereas serum TAS levels (1.4 ± 0.3 vs. 1.8 ± 0.4 mmol trolox Eq/L, p = 0.02) were significantly increased. Liver US revealed severe fatty liver in 14.3%, moderate in 39.2%, mild in 39.2% and normal in 14.3% of the patients. Liver US findings were improved in 19 patients (67.8%) when compared to baseline US findings. It was found that ethanol (5.3 ± 4 vs. 0.9 ± 1.47 mg/dl, p = 0.001), TNF‐α (9.6 ± 7.1 vs. 5.5 ± 3 pg/mL, p = 0.026) levels, BMI (30.5 ± 6.6 vs. 28.6 ± 6.1 kg/m2, p = 0.001) were significantly decreased and TAS levels (1.4 ± 0.3 vs. 1.8 ± 0.3 mmol trolox Eq/L, p = 0.03) were significantly increased compared to baseline findings in the US improved group (n = 19), whereas significant differences were observed in only ethanol (5.8 ± 4 vs. 1.1 ± 1.3 mg/dl, p = 0.01) and TAS (1.2 ± 0.3 vs. 2.2 ± 0.4 mmol trolox Eq/L, p = 0.02) levels in patients without any US improvement (n = 9).Conclusion:Synbiotics are effective for the treatment of NAFLD in children, and it may be related with the effect of synbiotics on inflammation (decrease in TNF‐α level) and BMI.

Nonalcoholic fatty liver disease in children and adolescents - Relationship with Polycystic Ovary Syndrome.

Nonalcoholic fatty liver disease (NAFLD) is defined as the accumulation of triglycerides (TGs) within hepatocytes exceeding 5 % of liver weight. NAFLD is a spectrum of pathological processes from nonalcoholic fatty liver or simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. As NAFLD induces metabolic syndrome (MS), then, NAFLD is associated with insulin resistance (IR), type 2 diabetes mellitus (T2DM), hypertension and even Polycystic Ovary Syndrome (PCOS). Because it is well established that patients carrying gene mutations also develop NAFLD in the absence of IR, the genetic predisposition to NAFLD is also discussed. Little is known about the diagnosis and treatment of NAFLD in children and adolescents and the lack of non-invasive diagnostic tools in these populations is a major problem faced by physicians. The present review aims to discuss recent findings of NAFLD in children and adolescents and, considering the features in common with PCOS, we also discuss their relationship.

Improvement in liver histology is associated with reduction in dyslipidemia in children with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), the most common cause of liver disease among US children, may be associated with cardiovascular disease (CVD) risk. The present study sought to determine the prevalence of dyslipidemia in children with NAFLD and assess dyslipidemia by liver histology and histologic changes. Individuals in the Treatment of NAFLD in Children (TONIC) trial were included (N = 173). In the TONIC trial, children with NAFLD were randomized to vitamin E, metformin, or placebo for 96 weeks. Nonalcoholic steatohepatitis (NASH) improved in 56 children. Change in lipid levels from baseline and 96 weeks was compared between patients with and without histologic improvement and with and without NASH. Dyslipidemia was frequent, with low high-density lipoprotein (HDL) (< 40 mg/dL) in 61.8%, hypertriglyceridemia (≥ 130 mg/dL) in 50.3%, hypercholesterolemia (≥ 200 mg/dL) in 23.7%, elevated low-density lipoprotein (LDL) (≥ 130 mg/dL) in 21.5%, elevated non-HDL cholesterol (non-HDL-C) (≥ 145 mg/dL) in 35.2%, and triglycerides/HDL > 3.0 in 57.2% of patients. Histologic improvement was associated with significant decreases in cholesterol (-11.4 mg/dL vs -1.9 mg/dL, P = 0.04), LDL (-11.2 mg/dL vs -2.1 mg/dL, P = 0.04), and non-HDL-C (-8.8 mg/dL vs 0.5 mg/dL, P = 0.03) compared with those without improvement. Children with NASH resolution had significant decreases in cholesterol (-10.0 mg/dL vs -0.9 mg/dL, P = 0.02) and non-HDL-C (-7.3 mg/dL vs 1.1 mg/dL, P = 0.01) compared with those without NASH resolution. There was no improvement in triglycerides, HDL level, or triglycerides/HDL ratio in either group. Dyslipidemia is frequent in children with NAFLD. NASH resolution and histologic improvement are associated with improvements in some forms of dyslipidemia.

Non-alcoholic fatty liver disease in children: focus on nutritional interventions.

With increasing prevalence of childhood obesity, non-alcoholic fatty liver disease (NAFLD) has emerged as the most common cause of liver disease among children and adolescents in industrialized countries. It is generally recognized that both genetic and environmental risk factors contribute to the pathogenesis of NAFLD. Recently, there has been a growing body of evidence to implicate altered gut microbiota in the development of NAFLD through the gut-liver axis. The first line of prevention and treatment of NAFLD in children should be intensive lifestyle interventions such as changes in diet and physical activity. Recent advances have been focused on limitation of dietary fructose and supplementation of antioxidants, omega-3 fatty acids, and prebiotics/probiotics. Convincing evidences from both animal models and human studies have shown that reduction of dietary fructose and supplement of vitamin E, omega-3 fatty acids, and prebiotics/probiotics improve NAFLD.

Non-alcoholic Fatty liver disease in children.

In the last years, there has been extremely much information which reveals an alarming increase of obesity in children and, at the same time, an increase of the incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD implies a wide range of affections starting from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH); the latter can evolve to cirrhosis and hepatic carcinoma. All these affections were noticed in children, too. The article presents data on the epidemiology, pathogeny, clinical and paraclinical findings, and treatment of NAFLD in children.

Non-alcoholic fatty liver disease in obese children and adolescents

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in children and adolescents in industrialized countries. Recent studies have demonstrated a prevalence rate of NAFLD in overweight and obese children and adolescents in Germany of up to 30%. The spectrum of NAFLD ranges from pure fatty infiltration (simple steatosis) to inflammation (steatohepatitis, synonymous NASH) to fibrosis and cirrhosis. Age, gender, ethnicity, insulin resistance, and sex steroids are implicated in the pathogenesis of NAFLD in childhood and adolescence. Moreover, NAFLD in the pediatric age group is associated with marked cardiovascular comorbidities. This review focuses on current data regarding epidemiology, pathophysiology, comorbidities, and treatment of NAFLD in children and adolescents.

A Critical Appraisal of Advances in Pediatric Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in children; its rise has been related to the increasing prevalence of obesity. Significant advancements have been made in the investigation of the etiopathogenesis and genetic risk factors for the disease. Pediatric fatty liver disease often displays a histologic pattern distinct from that found in adults, and liver biopsy remains the gold standard for diagnosis of nonalcoholic steatohepatitis (NASH). Lifestyle modifications that result in weight loss remain the first-line treatment of NAFLD in children. Recent adult and pediatric clinical trials on the use of antioxidants combined with lifestyle intervention for NAFLD have demonstrated encouraging results, and additional trials are underway. In this review, the authors provide an overview of current concepts in epidemiology, histologic features, diagnosis, pathophysiology, genetic risk factors, and treatment of NAFLD in children.

Pediatric nonalcoholic fatty liver disease: a multidisciplinary approach

Nonalcoholic fatty liver disease (NAFLD) is a multifactorial condition, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis. NAFLD affects both adults and children who present with particular risk factors, including obesity, sedentary lifestyle and/or a predisposing genetic background. The escalation of the prevalence of NAFLD in children worldwide is a worrying phenomenon because this disease is closely associated with the development of both cirrhosis and cardiometabolic syndrome in adulthood. The etiopathogenesis of primary NAFLD in children is unknown; however, considerable knowledge about the mechanisms of liver damage that occur during disease progression has been gathered over the past 30 years. Understanding the pathogenetic mechanisms, together with the histological pattern, provide the basis to characterize potential early predictors of the disease, suitable noninvasive diagnostic tools and design novel specific treatments and possible management strategies. Despite a few clinical trials on the use of antioxidants combined with lifestyle intervention for NAFLD that showed encouraging results, to date, no treatment guidelines exist for children with NAFLD. In this Review, we provide an overview of current concepts in epidemiology, histological features, etiopathogenesis, diagnosis and treatment of NAFLD in children and adolescents.

Fatty liver disease in children: eat now pay later

With the recent epidemic in childhood obesity, nonalcoholic fatty liver disease (NAFLD) has become an emerging problem and a common cause of chronic liver disease in children. In this review, the most recent insights on the pathogenesis, diagnosis, natural history, and treatment of NAFLD in children are discussed.

The obesity epidemic and nonalcoholic fatty liver disease in children

Childhood obesity is a worldwide health problem associated with an increase in the prevalence and severity of nonalcoholic fatty liver disease (NAFLD). This review covers the progress made between 2005 and 2007 in understanding the epidemiology, histology, and treatment of pediatric NAFLD. The number of children with NAFLD presents a major public health crisis. Noninvasive diagnostic tools offer future promise, but currently are unable to grade and stage disease. Therefore, pediatric NAFLD remains a clinico-pathological diagnosis requiring direct demonstration of liver steatosis and the exclusion of other causes of fatty liver and/or hepatitis. There are currently no proven therapies for NAFLD in children; however, TONIC (Treatment of Nonalcoholic Fatty Liver Disease in Children), the first multicenter clinical trial of pediatric NAFLD, is currently in progress. Such studies are imperative to address fundamental questions regarding cause and cure.