Renal impairment is prevalent in pediatric NAFLD/MASLD and associated with disease severity.

OBJECTIVES: Renal impairment is prevalent in adults with nonalcoholic fatty liver disease (NAFLD/metabolic dysfunction associated steatotic liver disease [MASLD]) and is associated with increased mortality. Pediatric data are limited. Our objective was to determine the prevalence of hyperfiltration or chronic kidney disease (CKD) in children with NAFLD/MASLD and determine links with liver disease severity. METHODS: Data from children who had previously participated in prospective, multicenter, pediatric studies by the Nonalcoholic Steatohepatitis Clinical Research Network (NASH-CRN) were collected. Renal function was determined using the calculated glomerular filtration rate (cGFR). Hyperfiltration was defined as cGFR > 135 mL/min/1.73m2, while CKD stage 2 or higher as cGFR < 90 mL/min/1.73 m2. Renal dysfunction progression was defined as transition from normal to hyperfiltration or to CKD stage ≥ 2, or change in CKD by ≥1 stage. Multinomial logistic regression models were used to determine the prevalence of CKD and independent associations between CKD and liver disease severity. RESULTS: The study included 1164 children (age 13 ± 3 years, 72% male, 71% Hispanic). The median cGFR was 121 mL/min/1.73 m2; 12% had CKD stage 2-5, while 27% had hyperfiltration. Hyperfiltration was independently associated with significant liver fibrosis (odds ratio: 1.45). Baseline renal function was not associated with progression in liver disease over a 2-year period (n = 145). Renal dysfunction worsened in 19% independently of other clinical risk factors. Progression of renal impairment was not associated with change in liver disease severity. CONCLUSIONS: Renal impairment is prevalent in children with NAFLD/MASLD and hyperfiltration is independently associated with significant liver fibrosis. Almost 1/5 children have evidence of progression in renal dysfunction over 2 years, not associated with change in liver disease severity. Future assessments including additional renal impairment biomarkers are needed.

Development of Fibro-PeN, a clinical prediction model for moderate-to-severe fibrosis in children with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Liver fibrosis is common in children with NAFLD and is an important determinant of outcomes. High-performing noninvasive models to assess fibrosis in children are needed. The objectives of this study were to evaluate the performance of existing pediatric and adult fibrosis prediction models and to develop a clinical prediction rule for identifying moderate-to-severe fibrosis in children with NAFLD. APPROACH AND RESULTS: We enrolled children with biopsy-proven NAFLD in the Nonalcoholic Steatohepatitis Clinical Research Network within 90 days of liver biopsy. We staged liver fibrosis in consensus using the Nonalcoholic Steatohepatitis Clinical Research Network scoring system. We evaluated existing pediatric and adult models for fibrosis and developed a new pediatric model using the least absolute shrinkage and selection operator with linear and spline terms for discriminating moderate-to-severe fibrosis from none or mild fibrosis. The model was internally validated with 10-fold cross-validation. We evaluated 1055 children with NAFLD, of whom 26% had moderate-to-severe fibrosis. Existing models performed poorly in classifying fibrosis in children, with area under the receiver operator curves (AUC) ranging from 0.57 to 0.64. In contrast, our new model, fibrosis in pediatric NAFLD was derived from fourteen common clinical variables and had an AUC of 0.79 (95% CI: 0.77-0.81) with 72% sensitivity and 76% specificity for identifying moderate-to-severe fibrosis. CONCLUSION: Existing fibrosis prediction models have limited clinical utility in children with NAFLD. Fibrosis in pediatric NAFLD offers improved performance characteristics for risk stratification by identifying moderate-to-severe fibrosis in children with NAFLD.

A Multidisciplinary Approach to Infants With GERD-Like Symptoms: A New Paradigm.

OBJECTIVES: Infants with gastroesophageal reflux disease (GERD)-like symptoms have been classically defined as having a wide array of symptoms. In these instances, anti-reflux medications are ineffective and overprescribed. Rather these symptoms are more attributable to dysphagia and unsettledness/colic. To address these conditions at our center, both speech language pathologist (SLP) and/or occupational therapist (OT) have contributed to evaluation. We hypothesized that dysphagia and unsettledness/colic are highly prevalent, yet under recognized in this population. METHODS: Full-term infants with typical development and under 6 months of age (N = 174) were included. Infants with suspected dysphagia and/or evident colic/unsettledness were evaluated by SLP and OT, respectively. RESULTS: GERD-like symptoms were present in 109 infants with attributes of dysphagia in n = 46, unsettledness/colic in n = 37, and combined in n = 26. CONCLUSION: A multidisciplinary approach, including SLP and OT, is recommended for the evaluation of infants with GERD-like symptoms.

Incidence of Type 2 Diabetes in Children With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Type 2 diabetes (T2D) is a growing problem in children. Children with NAFLD are at potentially high risk for developing T2D; however, the incidence of T2D in this population is unknown. This study aimed to determine the incidence of T2D in children with NAFLD and identify associated risk factors. METHODS: Children with NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network were followed longitudinally. Incidence of T2D was determined by using clinical history and fasting laboratory values. Cumulative incidence curves were developed for time to T2D. A Cox regression multivariable model was constructed using best subsets Akaike's Information Criteria selection. RESULTS: This study included 892 children with NAFLD and with a mean age of 12.8 years (2.7) followed for 3.8 years (2.3) with a total 3234 person-years at risk. The incidence rate of T2D was 3000 new cases per 100,000 person-years at risk. At baseline, 63 children had T2D, and during follow-up, an additional 97 children developed incident T2D, resulting in a period prevalence of 16.8%. Incident T2D was significantly higher in females versus males (hazard ratio [HR], 1.8 [1.0-2.8]), associated with BMI z-score (HR, 1.8 [1.0-3.0]), and more severe liver histology including steatosis grade (HR, 1.3 [1.0-1.7]), and fibrosis stage (HR, 1.3 [1.0-1.5]). CONCLUSIONS: Children with NAFLD are at high risk for existing and incident T2D. In addition to known risk factors for T2D (female and BMI z-score), severity of liver histology at the time of NAFLD diagnosis was independently associated with T2D development. Targeted strategies to prevent T2D in children with NAFLD are needed.

Nonalcoholic fatty liver disease risk and histologic severity are associated with genetic polymorphisms in children.

BACKGROUND AND AIMS: NAFLD is the most common chronic liver disease in children. Large pediatric studies identifying single nucleotide polymorphisms (SNPs) associated with risk and histologic severity of NAFLD are limited. Study aims included investigating SNPs associated with risk for NAFLD using family trios and association of candidate alleles with histologic severity. APPROACH AND RESULTS: Children with biopsy-confirmed NAFLD were enrolled from the NASH Clinical Research Network. The Expert Pathology Committee reviewed liver histology. Genotyping was conducted with allele-specific primers for 60 candidate SNPs. Parents were enrolled for trio analysis. To assess risk for NAFLD, the transmission disequilibrium test was conducted in trios. Among cases, regression analysis assessed associations with histologic severity. A total of 822 children with NAFLD had mean age 13.2 years (SD 2.7) and mean ALT 101 U/L (SD 90). PNPLA3 (rs738409) demonstrated the strongest risk ( p = 2.24 × 10 -14 ) for NAFLD. Among children with NAFLD, stratifying by PNPLA3 s738409 genotype, the variant genotype associated with steatosis ( p = 0.005), lobular ( p = 0.03) and portal inflammation ( p = 0.002). Steatosis grade associated with TM6SF2 ( p = 0.0009), GCKR ( p = 0.0032), PNPLA3 rs738409 ( p = 0.0053), and MTTP ( p = 0.0051). Fibrosis stage associated with PARVB rs6006473 ( p = 0.0001), NR1I2 ( p = 0.0021), ADIPOR2 ( p = 0.0038), and OXTR ( p = 0.0065). PNPLA3 rs738409 ( p = 0.0002) associated with borderline zone 1 NASH. CONCLUSIONS: This study demonstrated disease-associated SNPs in children with NAFLD. In particular, rs6006473 was highly associated with severity of fibrosis. These hypothesis-generating results support future mechanistic studies of development of adverse outcomes such as fibrosis and generation of therapeutic targets for NAFLD in children.

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

BACKGROUND AND AIMS: 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. APPROACH AND RESULTS: 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 52 weeks, 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. CONCLUSIONS: 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.

Low and High Birth Weights Are Risk Factors for Nonalcoholic Fatty Liver Disease in Children.

OBJECTIVES: To examine the distribution of birth weight in children with nonalcoholic fatty liver disease (NAFLD) compared with the general US population, and to investigate the relationship between birth weight and severity of NAFLD. STUDY DESIGN: A multicenter, cross-sectional study of children with biopsy-proven NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network Database. Birth weight was categorized as low birth weight (LBW), normal birth weight (NBW), or high birth weight (HBW) and compared with the birth weight distribution in the general US population. The severity of liver histology was assessed by birth weight category. RESULTS: Children with NAFLD (n = 538) had overrepresentation of both LBW and HBW compared with the general US population (LBW, 9.3%; NBW, 75.8%; HBW, 14.9% vs LBW, 6.1%; NBW, 83.5%; HBW 10.5%; P < .0001). Children with HBW had significantly greater odds of having more severe steatosis (OR, 1.82, 95% CI. 1.15-2.88) and nonalcoholic steatohepatitis (OR, 2.03; 95% CI, 1.21-3.40) compared with children with NBW. In addition, children with NAFLD and LBW had significantly greater odds of having advanced fibrosis (OR, 2.23; 95% CI, 1.08-4.62). CONCLUSION: Birth weight involves maternal and in utero factors that may have long-lasting consequences. Children with both LBW and HBW may be at increased risk for developing NAFLD. Among children with NAFLD, those with LBW or HBW appear to be at increased risk for more severe disease.

Quantitative MRI for hepatic fat fraction and T2* measurement in pediatric patients with non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. The gold standard for diagnosis is liver biopsy. MRI is a non-invasive imaging method to provide quantitative measurement of hepatic fat content. The methodology is particularly appealing for the pediatric population because of its rapidity and radiation-free imaging techniques. OBJECTIVE: To develop a multi-point Dixon MRI method with multi-interference models (multi-fat-peak modeling and bi-exponential T2* correction) for accurate hepatic fat fraction (FF) and T2* measurements in pediatric patients with NAFLD. MATERIALS AND METHODS: A phantom study was first performed to validate the accuracy of the MRI fat fraction measurement by comparing it with the chemical fat composition of the ex-vivo pork liver-fat homogenate. The most accurate model determined from the phantom study was used for fat fraction and T2* measurements in 52 children and young adults referred from the pediatric hepatology clinic with suspected or identified NAFLD. Separate T2* values of water (T2*W) and fat (T2*F) components derived from the bi-exponential fitting were evaluated and plotted as a function of fat fraction. In ten patients undergoing liver biopsy, we compared histological analysis of liver fat fraction with MRI fat fraction. RESULTS: In the phantom study the 6-point Dixon with 5-fat-peak, bi-exponential T2* modeling demonstrated the best precision and accuracy in fat fraction measurements compared with other methods. This model was further calibrated with chemical fat fraction and applied in patients, where similar patterns were observed as in the phantom study that conventional 2-point and 3-point Dixon methods underestimated fat fraction compared to the calibrated 6-point 5-fat-peak bi-exponential model (P < 0.0001). With increasing fat fraction, T2*W (27.9 ± 3.5 ms) decreased, whereas T2*F (20.3 ± 5.5 ms) increased; and T2*W and T2*F became increasingly more similar when fat fraction was higher than 15-20%. Histological fat fraction measurements in ten patients were highly correlated with calibrated MRI fat fraction measurements (Pearson correlation coefficient r = 0.90 with P = 0.0004). CONCLUSION: Liver MRI using multi-point Dixon with multi-fat-peak and bi-exponential T2* modeling provided accurate fat quantification in children and young adults with non-alcoholic fatty liver disease and may be used to screen at-risk or affected individuals and to monitor disease progress noninvasively.

Screening for elevated risk of liver disease in preschool children (aged 2-5 years) being seen for obesity management.

OBJECTIVES: Elevated alanine aminotransferase can heighten concern for the presence of nonalcoholic fatty liver disease in obese children. Guidelines recommend alanine aminotransferase screening of obese children start at the age of 10 years. We examined alanine aminotransferase values routinely obtained for tertiary obesity care among preschool (2-5 years) and school-age children. METHODS: Medical records of children attending a tertiary obesity clinic and with alanine aminotransferase measured within 6 months of the initial visit were reviewed. Children with known genetic abnormalities were excluded. Children were grouped by age to focus attention on groups not covered by screening guidelines. Associations with elevated alanine aminotransferase (>30 IU/L) were examined. RESULTS: A total of 284 records were analyzed (73 preschool, 143 young school-age (6-9 years), 68 older school-age (10-11 years)). Children were primarily Hispanic and had body mass index ≥ 99th percentile (preschool children 92%, young school-age 73%, older school-age 59%). In all, 26% of preschool children had elevated alanine aminotransferase (young school-age 30%, older school-age 44%). Preschool children with elevated alanine aminotransferase had higher body mass index compared to preschool children with alanine aminotransferase ≤ 30 IU/L (median body mass index 27.8 kg/m(2) vs 24.0 kg/m(2); Mann-Whitney U test, p = 0.003), but there was no disparity for elevated alanine aminotransferase related to Hispanic ethnicity. For older children, Hispanic ethnicity, not body mass index, predicted elevated alanine aminotransferase. CONCLUSION: Alanine aminotransferase elevation was common in these preschool children. Screening severely obese children for elevated alanine aminotransferase should begin at the age of 2 years.

Relationship of hepatic steatosis to adipose tissue distribution in pediatric nonalcoholic fatty liver disease.

OBJECTIVE: Central adiposity, a component of insulin resistance syndrome, is a risk factor for nonalcoholic fatty liver disease (NAFLD) in adults. To determine whether a similar relationship occurs in children, hepatic fat content and adipose tissue distribution were assessed in obese children at risk for NAFLD. METHODS: We reviewed the charts of obese children undergoing evaluation for NAFLD because of hepatomegaly or elevated serum alanine aminotransferase (ALT) without obvious etiology. Hepatic fat fraction and adipose tissue distribution were obtained by rapid magnetic resonance imaging (MRI) techniques. Hepatic fat content was determined by a modification of the Dixon method that involves fast gradient echo. Body fat distribution was assessed by using heavily T1-weighted fast gradient echo technique on a single slice at the level of the umbilicus, and regions of interest were demarcated based upon pixel intensity threshold value including visceral adipose tissue (VAT) and subcutaneous adipose tissue content (SAT). RESULTS: Ten children underwent hepatic MRI only. Twenty-nine children underwent hepatic and adipose tissue distribution MRI. There was a correlation between hepatic fat fraction and VAT (r = 0.37, P < 0.05) but not body mass index or SAT. Elevated serum ALT was associated with a higher hepatic fat fraction (P < 0.001) and VAT (P = 0.06). CONCLUSION: Visceral adiposity is a risk factor for pediatric NAFLD.

The spectrum of fatty liver in obese children and the relationship of serum aminotransferases to severity of steatosis.

OBJECTIVES: Non-alcoholic fatty liver disease is an emerging diagnosis in the pediatric population. Previously, ultrasonography and serum aminotransferases have been used to estimate prevalence of the disorder. A lack of concordance has been noted between these two diagnostic tests. To better understand the spectrum of fatty liver in obese children and the relationship of serum aminotransferases to the severity of steatosis, hepatic MRI was used to quantitate fat content. METHODS: Twenty-two children, ages 6 to 18 years, with obesity (BMI > 95th percentile for age) and hepatomegaly (liver edge more than 2 cm below the right costal margin) underwent hepatic MRI for fat quantitation. Hepatic MRI was performed using a modification of the Dixon method that used a fast gradient echo sequence rather than traditional spin echo. Scan times were sufficiently brief to allow completion within a single breath hold. Serum aminotransferases were obtained within one month of MRI. RESULTS: Twenty-one of 22 subjects had an elevated hepatic fat fraction. Seven of 7 subjects with a fat fraction of < or =18% had a normal serum ALT. Twelve of 13 subjects with fat fraction of >18% had an elevated serum ALT. Hepatic fat fraction correlated with serum ALT but did not correlate with age, BMI, or serum AST. CONCLUSION: The spectrum of fatty liver is larger than detected by screening for abnormal serum aminotransferases alone. Abnormalities in serum ALT occur exclusively in more severe cases of fatty liver.