NAFLD and Liver Fibrosis in Obese Adolescents
NAFLD and Liver Fibrosis in Obese Adolescents
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease resulting from excessive
 fat accumulation in the liver. Due to its close association with obesity, it has become the
 most common liver disease in children in the United States. NAFLD can result in progressive
 fibrosis and lead to end-stage liver disease. Best practices in management of pediatric NAFLD
 are not clearly defined.

 Our aim is to clarify the natural history of NAFLD in obese children after weight loss
 surgery compare to lifestyle intervention. Our secondary aim is to investigate the added
 value of elastography for the screening and diagnosis of NASH with fibrosis.
The study population will consist of obese adolescents, male and female, age 7-18, that will
 go through weight loss reduction surgery (WLS) in the Obesity Clinic at Tel Aviv Sourasky
 Medical Center. A control group matched for age and sex will consist of patients that will go
 through conventional treatment (see below) at the Obesity Clinic in Dana Dwek Children's
 Hospital.

 Written informed consent form will be signed by the participant before enrollment Patient
 Population Patients with a diagnosed primary liver disease (autoimmune liver disease,
 metabolic liver disease, Wilson's disease, alpha 1 antitrypsin deficiency), patients treated
 with medications known to induce steatosis (such as valproate, amiodarone or prednisone), and
 patients with hepatic virus infections or history of parenteral nutrition were excluded from
 the study.

 Study Design and measurements This clinical trial aims to asses the effect of bariatric
 surgery and dietary intervention on hepatic fibrosis in obese pediatric population with NAFLD
 (Clinical Trial Registration- MOH_2017-06-07_000470,
 https://my.health.gov.il/CliniTrials/Pages/MOH_2017-06-07_000470.aspx). At the initial visit,
 data were collected on socioeconomic parameters, lifestyle, birth details, and medical,
 family, and social histories. All patients underwent anthropometric measures (height, weight
 and BMI) and a physical examination focused on obesity-related conditions. Laboratory
 evaluation included liver enzyme profile, lipid profile, glucose, insulin, and HbA1C. Liver
 fibrosis was estimated by Shearwave elastography (Supersonic) and categorized into 4 levels,
 F0-F4, according to liver stiffness (measured by kPa), as recently demonstrated elsewhere
 [9]. Liver steatosis was calculated by a hepatorenal index (HRI) and divided into 3 levels of
 severity. All measurements were taken by a single experienced radiologist (MW), who was
 blinded to the results of other parameters of the patients. A multidisciplinary team included
 a gastroenterologist, hepatologists, a registered dietitian (RD) and a psychologist. All
 participants received nutritional recommendations (see below) and general recommendation for
 a healthy lifestyle (regular engagement in daily physical activity and reduction of screen
 time). Compliance with the dietary guideline was reviewed by a RD on a biweekly basis with a
 3-day food questionnaire (2 weekdays and 1 day of the weekend). Blood tests and elastography
 were repeated after 3 months of intervention.

 Determination of the BMI percentiles for age and gender was based on WHO growth charts.
 "Obesity" was defined as a BMI >95th percentile . Abnormal glucose metabolism included taking
 a hypoglycemic medication or having an elevated homeostatic model assessment index of insulin
 resistance, glucose, or HBA1c. Hypertriglyceridemia and hypercholesterolemia were defined as
 a serum level >95 percentile for age and sex. Hypertension was diagnosed as systolic and/or
 diastolic blood pressure ≥95 percentile for age and sex. Patients with clinical suspicion of
 obstructive sleep apnea (OSA) were diagnosed by polysomnography that was conducted by the
 hospital's sleep specialists. Socioeconomic status was defined according to parents' years of
 education.

 The dietary intervention The participants received nutritional recommendations for a low
 carbohydrate, low glycemic load, and isocaloric diet. The diet was composed of carbohydrates
 (CHO;30-40%), fats (35-50%), and proteins (20-25%), and was tailored to individual
 preferences and calorie requirements. The number of CHO, protein and fat servings was
 determined based on the recommended total energy requirements for age, calculated on the
 basis of dietary reference intake (DRI). Participants were not instructed to restrict
 calories, but to reduce carbohydrate based on their glycemic load. High glycemic index (GI)
 carbohydrate intake (refined grains, potatoes, sweet and salted snacks and sugar sweetened
 beverages) was completely restricted, low GI carbohydrates (non-starchy vegetables, legumes,
 nuts,) were allowed and some low /moderate GI carbohydrate were allowed but limited such as
 fruits and whole grain bread.

 The subjects were instructed about appropriate food choices, and each participant was
 provided a diet information booklet containing food list, sample menus and recipes

 Statistical Analyses Descriptive statistics were examined for all variables. Continuous
 variables were expressed as median with interquartile range (IQR) when they were not normally
 distributed and as mean ± standard deviation (SD) for normally distributed variables.
 Categorical variables were presented as number and percentage. Categorical variables were
 compared by the McNamer test and continuous and ordinal variables by the Wilcoxon test. The
 Fischer test was used when the McNamer test was not applicable for some variables. The
 Pearson correlation and simple linear regression analysis were performed to examine bivariate
 associations between fibrosis and metabolic and nutritional parameters. The Wilcoxon signed
 rank test was applied to compare the difference between steatosis, fibrosis, and metabolic
 parameters between the 2 time points (baseline and 3-month follow-up). A P level <0.05 was
 considered statistically significant. All statistical tests were 2-sided. The statistical
 analysis was performed with SPSS (IBM SPSS statistics, version 22, IBM Corp. Armonk, NY, USA,
 2013.).
IInclusion criteria:

 -  Age 13-18 years.

 -  No other chronic disease except the metabolic syndrome.

 -  Not taking any medication

 Exclusion criteria:

 -  Children that are known to suffer from genetic/metabolic disorders that can cause
 steatosis- Wilson disease, hypothyroidism, autoimmune hepatitis, Alpha 1 antitrypsin.

 -  Children infected with HBV or HCV, HAV.

 -  Children that use medications that can cause liver steatosis- amiodarone, MTX,
 Corticosteroids

 -  Children with significant ethanol consumption ->10 gr per day for women and >20gr per
 day for men.

 -  Pregnant women.

 -  Obesity due to syndromes or monogenic disease

 General withdraw criteria:

 • If the participant withdraws his consent.