Gestational and Developmental Contributors of Pediatric MASLD.

Pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) is common and can be seen as early as in utero. A growing body of literature suggests that gestational and early life exposures modify the risk of MASLD development in children. These include maternal risk factors, such as poor cardiometabolic health (e.g., obesity, gestational diabetes, rapid weight gain during pregnancy, and MASLD), as well as periconceptional dietary exposures, degree of physical activity, intestinal microbiome, and smoking. Paternal factors, such as diet and obesity, also appear to play a role. Beyond gestation, early life dietary exposures, as well as the rate of infant weight gain, may further modify the risk of future MASLD development. The mechanisms linking parental health and environmental exposures to pediatric MASLD are complex and not entirely understood. In conclusion, investigating gestational and developmental contributors to MASLD is critical and may identify future interventional targets for disease prevention.

Food Insecurity and Pediatric Nonalcoholic Fatty Liver Disease Severity.

OBJECTIVE: To determine the association between food insecurity and pediatric nonalcoholic fatty liver disease (NAFLD). METHODS: Cross-sectional study of patients < 21 years of age with histologically confirmed NAFLD. The Household Food Security Survey Module was administered to determine food insecurity status. Skin lipidomics were performed to explore pathophysiologic mechanisms. RESULTS: Seventy-three patients with histologically confirmed NAFLD completed the Household Food Security Survey Module. Of these, the majority were male (81%) and non-Hispanic (53%), with a mean age at biopsy of 13 ± 3 years. Food insecurity was seen in 42% (n = 31). Comparison of features between food insecure and food secure subgroups revealed no differences in sex, ethnicity, BMI z-score, aminotransferases, or histologic severity. However, children experiencing food insecurity presented on average 2 years before their food secure counterparts (12.3 ± 3.0 vs 14.4 ± 3.6 years, P = .015). A subset of 31 patients provided skin samples. Skin lipidomics revealed that food insecurity was associated with down-regulated features from the lipoamino acid class of lipids, previously linked to inflammation and adipocyte differentiation. CONCLUSIONS: Food insecurity is highly prevalent in children with NAFLD and is associated with earlier presentation. Lipidomic analyses suggest a possible pathophysiologic link that warrants further exploration.

Longitudinal Links between Changes in Body Composition and Liver Disease Severity in Children and Adolescents with Metabolic Dysfunction-Associated Steatotic Liver Disease.

OBJECTIVE: To investigate the relationship between longitudinal changes in body composition and liver disease severity in children with metabolic dysfunction-associated steatotic liver disease (MASLD). STUDY DESIGN: This longitudinal, single-center, retrospective analysis included patients aged <20 years followed for MASLD who had had ≥2 bioelectrical impedance analyses (BIAs) performed. MASLD regression was defined as alanine aminotransferase (ALT) normalization or a decrease of >50% from baseline. Fat and skeletal muscle mass were adjusted for size by calculating respective indices (dividing by height2). Logistic and linear regressions were used to determine the independent relationship between changes in body composition over time and serological markers of liver disease severity. RESULTS: We included 258 patients (75% male, 50% Hispanic) with a median age of 14 years (IQR, 11-16 years) at the time of first BIA. Median body mass index (BMI) z-score at baseline was 2.33 (IQR, 2.04-2.62). Median time from first to last BIA was 12 months (IQR, 6-24 months). A decrease in fat mass index was independently associated with reductions in ALT and gamma glutamyl transferase and increased odds of MASLD regression (OR; 0.55; P < .001). Fat mass index reduction was superior to BMI z-score in predicting MASLD regression. Change in skeletal muscle mass index was not associated with change in ALT or gamma glutamyl transferase. CONCLUSIONS: Changes in fat mass, not skeletal muscle mass, are associated with serological markers of liver injury in youth with MASLD. Fat mass changes outperform BMI z-score changes in predicting MASLD regression. BIA can serve as an adjunct biomarker of liver disease progression.

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.

Nutritional deficiencies in children.

PURPOSE OF REVIEW: The purpose of this review is to summarize commonly encountered nutritional deficiencies in children and their implications. Considering data suggesting that the majority of children with the United States consume unhealthy diets, the growing interest in the consumption of limiting diets, as well as the insidious clinical presentation of nutritional deficiencies, this is a timely and highly relevant review. RECENT FINDINGS: The underlying socioeconomic and medical circumstances that predispose to nutritional deficiencies in the Western world are covered. The high index of suspicion required to recognize nutritional deficiencies and the limitations of available testing are also discussed. Finally, the need for the development of accurate nutritional biomarkers is presented as a future research priority. SUMMARY: Nutritional deficiencies are not uncommon, even in high resource countries. Clinicians should remain vigilant and include nutritional deficiencies in the differential diagnoses of patients presenting with nonspecific symptoms.

Longitudinal evaluation of pediatric and young adult metabolic dysfunction-associated steatotic liver disease defined by MR elastography.

OBJECTIVES: To inform clinical monitoring of children and young adults with metabolic dysfunction-associated steatotic liver disease (MASLD) by characterizing the real-world natural history of MASLD and identifying baseline predictors of liver disease progression. MATERIALS AND METHODS: This retrospective study included consecutive patients ages < 23 years with MASLD who underwent serial MR elastography (MRE) and/or MR fat fraction (FF) examinations between 09/2009 and 11/2022. Outcomes of MASLD were defined based on maximum ratio values. A relative change ≥ 19% in liver stiffness measures (LSM) and an absolute change ≥ 5% for liver FF were considered clinically meaningful. Random intercept models characterized the yearly rate of change in LSM (kilopascals per year) and FF (percentage per year). RESULTS: One hundred twenty-one patients (87 males, mean age at baseline: 12 ± 3 [SD] years) underwent 297 MRE examinations. The mean interval between the first and last MRE was 34 (± 24) months (range: 1-120 months). Among the 114 patients with serial LSM, 33% (38/114) showed progression, 46% (53/114) remained stable, and 21% (23/114) showed regression. Among the 88 patients with serial FF measures, 57% (50/88) showed progression, 2% (2/88) remained stable, and 41% (36/88) showed regression. LSM progression was associated with Hispanic ethnicity, baseline BMI-for-age percentile, baseline mean liver FF, and GGT changes over time. Predictors for liver FF progression included ALT, AST, GGT, and LDL. CONCLUSION: In a real-world sample of children and young adults with MASLD who underwent serial liver MRI, a minority of patients demonstrated improvements in liver stiffness or FF over time. KEY POINTS: Question In children, there is scarce data regarding the natural history of MASLD. Findings In this retrospective study, most children and young adults with MASLD had either unchanged or worsening liver stiffness (n = 91/114, 79%) and liver fat (n = 52/88, 59%). Clinical relevance Our findings emphasize the need for optimized care in pediatric MASLD. The identified risk factors for the progression of liver fat and stiffness may help to identify children who require interventions beyond changes in lifestyle.

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.

Randomized placebo-controlled trial of losartan for pediatric NAFLD.

BACKGROUND AND AIMS: To date, no pharmacotherapy exists for pediatric NAFLD. Losartan, an angiotensin II receptor blocker, has been proposed as a treatment due to its antifibrotic effects. APPROACH AND RESULTS: The Nonalcoholic Steatohepatitis Clinical Research Network conducted a multicenter, double-masked, placebo-controlled, randomized clinical trial in children with histologically confirmed NAFLD at 10 sites (September 2018 to April 2020). Inclusion criteria were age 8-17 years, histologic NAFLD activity score ≥ 3, and serum alanine aminotransferase (ALT) ≥ 50 U/l. Children received 100 mg of losartan or placebo orally once daily for 24 weeks. The primary outcome was change in ALT levels from baseline to 24 weeks, and the preset sample size was n = 110. Treatment effects were assessed using linear regression of change in treatment group adjusted for baseline value. Eighty-three participants (81% male, 80% Hispanic) were randomized to losartan (n = 43) or placebo (n = 40). During an enrollment pause, necessitated by the 2019 coronavirus pandemic, an unplanned interim analysis showed low probability (7%) of significant group difference. The Data and Safety Monitoring Board recommended early study termination. Baseline characteristics were similar between groups. The 24-week change in ALT did not differ significantly between losartan versus placebo groups (adjusted mean difference: 1.1 U/l; 95% CI = -30.6, 32.7; p = 0.95), although alkaline phosphatase decreased significantly in the losartan group (adjusted mean difference: -23.4 U/l; 95% CI = -41.5, -5.3; p = 0.01). Systolic blood pressure decreased in the losartan group but increased in placebo (adjusted mean difference: -7.5 mm Hg; 95% CI = -12.2, -2.8; p = 0.002). Compliance by pill counts and numbers and types of adverse events did not differ by group. CONCLUSIONS: Losartan did not significantly reduce ALT in children with NAFLD when compared with placebo.

Presence of Alpha 1 Antitrypsin Risk Variants is Not Associated With Histologic Severity of Pediatric NAFLD.

BACKGROUND: Among adults with nonalcoholic fatty liver disease (NAFLD), alpha-1-antitrypsin (A1AT) heterozygosity has been linked to advanced liver disease; pediatric data remain unclear. OBJECTIVE: The objective of this study is to determine whether A1AT PiZ or PiS variants are associated with liver disease severity in youth with NAFLD. METHODS: Retrospective study of youth with confirmed NAFLD. Multivariable logistic regression used to determine independent associations between A1AT risk variants and histologic severity [NAFLD activity score (NAS) ≥5 and/or significant fibrosis (stage ≥2)]. RESULTS: The cohort included 269 patients, mean age 12 [±3] years with NAFLD and A1AT phenotyping (n = 260) and/or A1AT levels (n = 261). The mean NAS of the cohort was 4.2 [±1.5]; 50% had any, and 18% had significant fibrosis. Most (86%) had the MM A1AT phenotype, while 7% had the MS and 3% the MZ phenotype (the rest had other, nonpathogenic variants). Mean A1AT level was 123 mg/dL [±20]. A1AT levels did not differ by low versus high NAS (122 ± 2 vs 126 ± 19 mg/dL, P = 0.12) or by no/mild versus significant fibrosis (123 ± 20 vs 126 ± 20 mg/dL, P = 0.23, respectively). Carriers and noncarriers of the PiS or PiZ variants had similar NAS (mean NAS 3.8 ± 1.6 vs 4.2 ± 1.4; P = 0.25, respectively). Fibrosis severity did not differ by carrier vs noncarrier group: 38% versus 52% had any fibrosis ( P = 0.17) and 14% versus 18% had significant fibrosis ( P = 0.80, respectively). Multivariable modeling showed no association between A1AT risk variants and histologic severity. CONCLUSION: While not uncommon, carriage of the A1AT PiZ or PiS risk variants was not associated with histologic severity in children with NAFLD.

Prevalence of incidental sonographic findings of hepatic steatosis in children under 4 years of age.

BACKGROUND: The age of onset of nonalcoholic fatty liver disease (NAFLD) and its prevalence in young children is incompletely understood. OBJECTIVE: We sought to evaluate the prevalence of ultrasound findings of hepatic steatosis in a cohort of children less than 4 years of age. MATERIALS AND METHODS: This is an institutional review board-approved retrospective review of ultrasounds performed on children less than 4 years of age from January 2022 to August 2022 at a single quaternary care center. Two independent blinded reviewers evaluated for qualitative and semi-quantitative findings of hepatic steatosis. Per prior literature, hepatorenal index (HRI)>1.75 was used as a threshold suggestive of hepatic steatosis. Chi-square, Mann-Whitney U test, and logistic regression analyses were performed for univariable and multivariable statistical analyses. Kappa statistics were used to assess agreement between reviewers. RESULTS: Eighty-five males and 102 females, median age of 1.1 years (interquartile range 2.1 years), were included. Qualitative findings of hepatic steatosis were seen in 26/187 (14%; 95% CI 10-20%). An HRI>1.75 was present in 15/187 (8%; 95% CI: 5-13%) of examinations, including 11 females and 4 males, and 7/123 (6%) participants <2 years old. Among participants with overweight or obesity, 8/43 (19%) had HRI>1.75 vs. 7/144 (5%) participants without overweight or obesity (P=0.004). Each percentile increase in anthropometrics percentile (weight-to-length or BMI, depending on age) was associated with 22 increased odds of HRI>1.75 (P=0.02). CONCLUSION: Prevalence of sonographic findings of hepatic steatosis in an unselected sample of preschool-age children is 8-14%, and are more common in participants with overweight/obesity.

Clinically Meaningful Body Mass Index Change Impacts Pediatric Nonalcoholic Fatty Liver Disease.

OBJECTIVE: To investigate the prevalence and characteristics of children with nonalcoholic fatty liver disease (NAFLD) who reduce their body mass index (BMI) z-score (BMIz) by >.25, a goal in obesity medicine, and to determine the BMIz decrease needed for serum aminotransferase normalization. STUDY DESIGN: This retrospective, single-center study included patients aged <18 years followed for NAFLD. Patients who had undergone weight loss surgery or had other reasons for weight loss/gain were excluded. Logistic regression was used to determine the odds of achieving a BMIz change of >-.25, as well as predictors of this outcome. RESULTS: Of the 784 children who met the study criteria (median age, 13 years; 66% male; 24% Hispanic), 541 had a lowest BMIz at >90 days following the baseline clinic visit. Of these children, 168 (31%) had a BMIz change of >-.25 from baseline over a median of 367 days (IQR, 201-678 days). Decreases in serum aminotransferase and lipid levels were seen in both groups (with and without a BMIz change of >-.25); however, these decreases were more pronounced in children who achieved a BMIz drop of >.25. Hemoglobin A1c concentration did not change in either group. Young age (OR, .861; 95% CI, .81-.92; P < .01) and non-Hispanic ethnicity (OR of non-Hispanic vs Hispanic, .61; 95% CI, .38-.97; P < .04) were predictors of a BMIz change >-.25. The BMIz decrease associated with normalization of serum alanine aminotransferase was .27. CONCLUSIONS: A BMIz reduction of >.25 is associated with significant changes in serum aminotransferase levels. These findings can further guide the clinical management of children with NAFLD.

Microbiota-Driven Activation of Intrahepatic B Cells Aggravates NASH Through Innate and Adaptive Signaling.

BACKGROUND AND AIMS: Nonalcoholic steatohepatitis is rapidly becoming the leading cause of liver failure and indication for liver transplantation. Hepatic inflammation is a key feature of NASH but the immune pathways involved in this process are poorly understood. B lymphocytes are cells of the adaptive immune system that are critical regulators of immune responses. However, the role of B cells in the pathogenesis of NASH and the potential mechanisms leading to their activation in the liver are unclear. APPROACH AND RESULTS: In this study, we report that NASH livers accumulate B cells with elevated pro-inflammatory cytokine secretion and antigen-presentation ability. Single-cell and bulk RNA sequencing of intrahepatic B cells from mice with NASH unveiled a transcriptional landscape that reflects their pro-inflammatory function. Accordingly, B-cell deficiency ameliorated NASH progression, and adoptively transferring B cells from NASH livers recapitulates the disease. Mechanistically, B-cell activation during NASH involves signaling through the innate adaptor myeloid differentiation primary response protein 88 (MyD88) as B cell-specific deletion of MyD88 reduced hepatic T cell-mediated inflammation and fibrosis, but not steatosis. In addition, activation of intrahepatic B cells implicates B cell-receptor signaling, delineating a synergy between innate and adaptive mechanisms of antigen recognition. Furthermore, fecal microbiota transplantation of human NAFLD gut microbiotas into recipient mice promoted the progression of NASH by increasing the accumulation and activation of intrahepatic B cells, suggesting that gut microbial factors drive the pathogenic function of B cells during NASH. CONCLUSION: Our findings reveal that a gut microbiota-driven activation of intrahepatic B cells leads to hepatic inflammation and fibrosis during the progression of NASH through innate and adaptive immune mechanisms.

Sarcopenia is highly prevalent in children with autoimmune liver diseases and is linked to visceral fat and parent-perceived general health.

BACKGROUND: Patients with autoimmune hepatitis (AIH) and primary or autoimmune sclerosing cholangitis are at nutritional risk; their body composition and has not been extensively studied. We aimed to describe their body composition and identify clinical links. METHODS: Using magnetic resonance imaging (MRI), two reviewers segmented total psoas muscle area (tPMSA), visceral fat area (VFA) and subcutaneous fat area (mm2 ) and measured visceral and subcutaneous thickness (mm). Clinical, laboratory and quality of life (QoL; using PedsQL) data were collected. Sarcopenia was defined as tPMSA ≤5th percentile. Analysis of variance, Wilcoxon rank test and multivariable modelling were performed. A paediatric cohort with non-alcoholic fatty liver disease (NAFLD) was used as a comparator following propensity score matching. RESULTS: Fifty-eight patients with autoimmune liver disease (AILD) (33 [57%] with AIH) were included: median age 16 years (interquartile range [IQR]: 13-18), 33 (57%) male. Median time from diagnosis to MRI was 15 months (IQR: 2-39 months). Two patients (3%) had a BMIz indicative of mild malnutrition. tPMSA was measurable in 52 subjects (90%). Of those, 25 (48%) had sarcopenia. Sarcopenic patients had a lower blood urea nitrogen compared to non-sarcopenic (median [IQR]: 9.5 [8.0, 12.0] vs 11 [10, 14] mg/dL; P = .023). There was no difference in corticosteroid use between groups. The VFA of sarcopenic patients was higher (3156 [2064, 7492]) vs 2084 [688, 3092]) mm2 ; P = .005). Patient-reported QoL negatively associated with VFA and general health negatively associated with VFA. Compared with NAFLD, the odds ratio for sarcopenia with AILD was 14.5 (95% confidence interval: 2.3-90.7). CONCLUSION: In autoimmune liver diseases, sarcopenia is highly prevalent, associated with increased visceral fat and QoL.

Non-Invasive Approaches to Estimate Liver Steatosis and Stiffness in Children With Non-Alcoholic Fatty Liver Disease.

OBJECTIVES: To develop pediatric-specific models that predict liver stiffness and hepatic steatosis in non-alcoholic fatty liver disease (NAFLD), based on clinical and laboratory data. METHODS: Children with NAFLD, who had undergone magnetic resonance imaging with proton density fat fraction (MRI-PDFF) for steatosis quantification and/or magnetic resonance elastography (MRE) for liver stiffness assessment were included. We used data from patients imaged between April 2009 to July 2018 to develop a predictive model for fat fraction and stiffness. We validated the performance of the models using data from a second cohort, imaged between 2018 and 2019. RESULTS: The first cohort (n = 344) consisted of predominantly non-Hispanic (80%), male (67%) adolescents. MRE data were available for 343 children, while PDFF data were available for 130. In multivariable regression, ethnicity, insulin levels, platelet count, and aspartate aminotransferase independently predicted liver stiffness and these variables were used to develop the predictive model. Similarly, sex, ethnicity, alanine aminotransferase, and triglycerides levels independently predicted liver PDFF and were used in the PDFF model. The AUC of the optimal cutoff for the model that predicted a stiffness of >2.71 kPa was 0.70 and for the model that predicted PDFF >5% was 0.78. The validation group (n = 110) had similar characteristics. The correlation coefficient of the model with the measured liver stiffness was 0.30 and with the measured liver PDFF was 0.26. CONCLUSIONS: Pediatric-specific models perform poorly at predicting exact liver stiffness and steatosis; however, in the absence of magnetic resonance imaging can be used to predict the presence of significant steatosis (>5%) and/or significant stiffness (>2.71). Thus, imaging remains an invaluable adjunct to laboratory investigations in determining disease severity.

Insight Into the Adolescent Patient Experience With Nonalcoholic Fatty Liver Disease.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the leading chronic liver disease in youth, yet little is known about the adolescent patient's experience with NAFLD, which is key for treatment engagement. We examined adolescents' experiences with NAFLD diagnosis, thoughts on how NAFLD affects their daily life, understanding and perceptions of diagnosis and treatment, and impressions of how to improve care. METHODS: Utilizing a mixed-method design, adolescents with NAFLD (N = 16; Mean age = 15.8 years; Mean BMI = 37 kg/m 2 ) participated in focus groups. To supplement qualitative data, adolescents and their caregiver completed measures assessing illness perceptions, adolescent quality of life, and eating/activity behaviors. RESULTS: Focus group themes suggested reactions to diagnosis varied from unconcerned to anxious. NAFLD diagnosis occurred within the context of other psychological/medical concerns and was not perceived to affect most adolescents' daily lives. Although adolescents understood general contributors to NAFLD, comprehension of their diagnosis varied. Adolescents were more likely to make lifestyle changes when families were supportive, and they preferred tailored recommendations for health behavior change from the healthcare team. Notably, 62.5% of adolescents were more concerned about their weight than NAFLD. Almost half (43.8%) identified as food insecure. CONCLUSIONS: Adolescents with NAFLD may benefit from personalized treatment. Care could be enhanced by ensuring comprehension of diagnosis, problem-solving personal, and family barriers and increasing family support. Harnessing adolescents' desire for weight loss may be a more salient driver for change in disease status. Interventions should also address systemic barriers such as food insecurity to ensure equitable care.

American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD).

OBJECTIVE: To provide evidence-based recommendations regarding the diagnosis and management of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) to endocrinologists, primary care clinicians, health care professionals, and other stakeholders. METHODS: The American Association of Clinical Endocrinology conducted literature searches for relevant articles published from January 1, 2010, to November 15, 2021. A task force of medical experts developed evidence-based guideline recommendations based on a review of clinical evidence, expertise, and informal consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RECOMMENDATION SUMMARY: This guideline includes 34 evidence-based clinical practice recommendations for the diagnosis and management of persons with NAFLD and/or NASH and contains 385 citations that inform the evidence base. CONCLUSION: NAFLD is a major public health problem that will only worsen in the future, as it is closely linked to the epidemics of obesity and type 2 diabetes mellitus. Given this link, endocrinologists and primary care physicians are in an ideal position to identify persons at risk on to prevent the development of cirrhosis and comorbidities. While no U.S. Food and Drug Administration-approved medications to treat NAFLD are currently available, management can include lifestyle changes that promote an energy deficit leading to weight loss; consideration of weight loss medications, particularly glucagon-like peptide-1 receptor agonists; and bariatric surgery, for persons who have obesity, as well as some diabetes medications, such as pioglitazone and glucagon-like peptide-1 receptor agonists, for those with type 2 diabetes mellitus and NASH. Management should also promote cardiometabolic health and reduce the increased cardiovascular risk associated with this complex disease.

Standardized Feeding Protocol Improves Delivery and Acceptance of Enteral Nutrition in Children Immediately After Liver Transplantation.

Delivery of adequate nutrition after liver transplantation (LT) surgery is an important goal of postoperative care. Existing guidelines recommend early enteral nutrition after abdominal surgery and in the child who is critically ill but data on nutritional interventions after LT in children are sparse. We evaluated the impact of a standardized postoperative feeding protocol on enteral nutrition delivery in children after LT. Data from 49 children (ages 0-18 years) who received a LT prior to feeding protocol implementation were compared with data for 32 children undergoing LT after protocol implementation. The 2 groups did not differ with respect to baseline demographic data. After protocol implementation, enteral nutrition was started earlier (2 versus 3 days after transplant; P = 0.005) and advanced faster when a feeding tube was used (4 versus 8 days; P = 0.03). Protocol implementation was also associated with reduced parenteral nutrition use rates (47% versus 75%; P = 0.01). No adverse events occurred after protocol implementation. Hospital length of stay and readmission rates were not different between the 2 groups. In conclusion, implementation of a postoperative nutrition protocol in children after LT led to optimized nutrient delivery and reduced variability of care.

Under-reporting of Hepatic Steatosis in Children: A Missed Opportunity for Early Detection.

OBJECTIVE: To determine the prevalence of underreporting of hepatic steatosis found incidentally on computed tomography (CT). STUDY DESIGN: Retrospective cross-sectional study including patients <18 years of age who had undergone unenhanced abdominal CT for evaluation of nephrolithiasis. Hepatic and splenic attenuation were measured independently by 2 reviewers. Hepatic steatosis was defined using various previously established criteria (4 original criteria designed to detect moderate/severe steatosis and 3 secondary criteria designed to identify mild steatosis). Radiology reports and clinical notes were reviewed for documentation of steatosis. Serum alanine aminotransferase levels were collected. Kappa statistics were used to assess agreement between reviewers. RESULTS: A total of 584 patients were included. Agreement between reviewers' measurements for categorical classification of presence of steatosis was excellent (kappa statistic agreement >87%). The prevalence of hepatic steatosis ranged from 3% to 35%, depending on the criterion. Using absolute liver attenuation <48 Hounsfield units (most likely reflective of the truth, given alanine aminotransferase distribution and body mass index data), the prevalence was 7% (n = 42). Steatosis was reported for only 12 of 42 (28%) of these patients and was documented in clinical notes in only 3 of those cases. CONCLUSIONS: Hepatic steatosis is underreported as an incidental finding of CT for nephrolithiasis. Given the prevalence and silent nature of nonalcoholic fatty liver disease, a high level of suspicion is needed, so as not to miss the opportunity to identify steatosis in childhood.

Glomerular Hyperfiltration Is Associated with Liver Disease Severity in Children with Nonalcoholic Fatty Liver Disease.

OBJECTIVES: To determine the prevalence of renal impairment in a large cohort of youths with histologically confirmed nonalcoholic fatty liver disease (NAFLD), and to determine its association with liver disease severity. STUDY DESIGN: Clinical, laboratory, and histology data were collected retrospectively in a pediatric cohort with biopsy-confirmed NAFLD at a tertiary care center between 2010 and 2017. Histological NAFLD severity was scored using validated criteria. Glomerular filtration rate (GFR) was calculated and categorized as low (<90 mL/min/1.73 m2), normal (90-136 mL/min/1.73 m2), or high (>136 mL/min/1.73 m2). Univariate and multivariate modeling were used to determine differences between the GFR groups and to control for confounders. RESULTS: The cohort comprised 179 patients (82% non-Hispanic; median age; 14 years; IQR, 12-16 years). One-third of the patients had abnormal renal function, including 36 (20%) with glomerular hyperfiltration and 26 (15%) with low GFR. In multivariable logistic regression, compared with normal GFR, hyperfiltration was independently associated with higher NAFLD activity score (aOR, 2.96; 95% CI, 1.49-5.87; P = .002), after adjusting for age, sex, ethnicity, obesity severity, presence of type 2 diabetes mellitus, and medications. CONCLUSIONS: In this large cohort with histologically confirmed NAFLD, renal impairment was highly prevalent and associated with liver disease severity, independent of obesity severity. Screening patients with confirmed NAFLD for renal complication is recommended.

Muscle Mass Is Linked to Liver Disease Severity in Pediatric Nonalcoholic Fatty Liver Disease.

OBJECTIVE: To investigate the association between muscle mass and liver disease severity in pediatric patients with non-alcoholic fatty liver disease (NAFLD). STUDY DESIGN: This was a retrospective study of patients aged <20 years followed from 2009 to 2018. Muscle mass was estimated in all patients by measuring magnetic resonance imaging-based total psoas muscle surface area (tPMSA) and correcting for height (tPMSA index = tPMSA/height2). Two cohorts were studied, one with histological confirmation of NAFLD (n = 100) and the other with magnetic resonance imaging (MRI) evidence of hepatic steatosis (n = 236). Histology was scored using Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) criteria. MRI-measured proton density fat fraction (PDFF) and liver stiffness were collected. Demographic, clinical, and socioeconomic status (using a validated Community Deprivation Index [CDI]) were assessed as covariates. Univariate regression analyses, followed by multivariable regression analyses, were used to determine the relationships between tPMSA index and NAS, MRI-PDFF, and liver stiffness, adjusting for clinical, demographic, and CDI variables. RESULTS: In the multivariable regression analyses, higher steatosis score was associated with a lower tPMSA index (OR, 0.73; 95% CI, 0.56-0.96) and younger age (OR, 0.84; 95% CI, 0.73-0.97). Liver PDFF was also significantly associated with the tPMSA index (P = .029), sex (P = .019), and CDI (P = .005). In contrast, liver stiffness was not associated with tPMSA in multivariable analyses. CONCLUSIONS: tPMSA index was independently associated with both imaging and histological features of hepatic steatosis severity in children. Future studies should directly explore the presence and directionality of causative links between muscle mass and steatosis, as well as whether interventions that enhance muscle mass can reduce disease severity in children with NAFLD.