Pediatric Chronic Liver Disease Research Articles

Nonalcoholic Fatty Liver Disease and Continuous Metabolic Syndrome in Adolescents with Overweight/Obesity.

Nonalcoholic fatty liver disease is the leading cause of pediatric chronic liver disease. Although nonalcoholic fatty liver disease is closely associated with obesity, its relationship with metabolic syndrome in children is not fully understood. The main aim of this study was to evaluate the association between nonalcoholic fatty liver disease and a combination of cardiometabolic risk factors in adolescents with overweight/obesity, using a pediatric metabolic syndrome score (PsiMS) to predict metabolic syndrome. A retrospective cohort study was conducted. Subjects with overweight/obesity aged 10 to 17 followed at two clinical centers in Portugal (2018 - 2021) were enrolled. The independent association of nonalcoholic fatty liver disease with PsiMS, and of other potential predictors, was tested through multiple regression analyses. Receiver operator characteristic curve analysis was performed to estimate the optimal cutoff of PsiMS to discriminate metabolic syndrome. Eighty-four subjects were included (median age at baseline 11.5 years). The prevalence rate of nonalcoholic fatty liver disease was 51% and the prevalence rate of metabolic syndrome was 7%. The mean PsiMS was 2.05 ± 0.48 at the first evaluation, and 2.11 ± 0.52 at the last evaluation (mean follow-up time was 15 months). The nonalcoholic fatty liver disease group had significantly (p < 0.05) higher weight and body mass index z-scores, higher rate of severe obesity and higher waist circumference percentile. PsiMS was highly accurate in predicting metabolic syndrome (area under the curve = 0.96), with an optimal cutoff of 2.46 (sensitivity 100%, specificity 89%). In the univariate analysis, no statistically significant association was observed between nonalcoholic fatty liver disease and PsiMS. In the multiple regression analysis, female sex had a negative association with PsiMS (first and last evaluation). Independent predictors of a higher PsiMS at first evaluation were: ≥ 2 metabolic syndrome criteria, body mass index z-score, insulin resistance and dyslipidemia. At the last evaluation, independent predictors of a higher PsiMS were: nonalcoholic fatty liver disease, baseline PsiMS and body mass index increase from baseline. The results suggest a good performance of the PsiMS to assess metabolic syndrome and that nonalcoholic fatty liver disease is associated with PsiMS at follow-up.

GOOD CORRELATION BETWEEN LIVER STIFFNESS MEASUREMENT AND APRI, FIB-4, PLATELET COUNT, IN PEDIATRIC AUTOIMMUNE HEPATITIS.

•Due to the invasive nature of the liver biopsy, there is a growing interest in the use of non-invasive markers of liver fibrosis. •There is a significant and positive correlation between APRI. FIB-4 and platelet count and liver stiffness measurement evaluated by transient elastography in pediatric autoimmune hepatitis. There is limited evidence focusing on the use of non-invasive markers to assess liver fibrosis in pediatric chronic liver diseases. The aim of the study was to evaluate the correlation between liver stiffness measurement (LSM) using transient liver elastography (TLE) and serum non-invasive markers in pediatric autoimmune hepatitis (AIH). Cross-sectional study between May 2016 and February 2020. Twenty-eight children with AIH (age range between 3 and 20 years old) who had undergone TLE and had routine serum tests were enrolled. Patients were divided into 2 groups: (1) Liver fibrosis degree ≥F2 (TLE ≥6.45 kPa) and (2) <F2 (TLE <6.45 kPa). The groups were compared using Fisher's exact test for categorical variables and the Mann-Whitney test for quantitative variables. The correlation between TLE, APRI, FIB-4 and platelet count was assessed using the Spearman coefficient (Rs). Twenty-eight AIH pediatric patients were enrolled, 21 were female and 22 had AIH type 1. Following the cut-off of 6.45 kPa in TLE, 20 patients (71%) were included in group 1, and 8 in group 2. A statistically significant difference was found between the two groups on APRI and FIB-4 results (P=0.0306 and P=0.0055, respectively). There was a significant correlation between TLE with APRI and FIB-4 (Rs=0.67 and 0.78, respectively; P<0.01) as well as with platelet count (Rs=-0.68; P<0.01). APRI, FIB-4 and Platelet Count showed a good and positive correlation with transient liver elastography in pediatric patients with AIH.

Impact of sarcopenia on clinical outcomes in pediatric chronic liver disease post-liver transplantation: prevalence and implications.

The purpose of this retrospective single-center study was to determine the frequency of sarcopenia and its association with mortality and other morbidities in children with chronic liver disease who had undergone liver transplantation. Sarcopenia, a muscle-wasting syndrome, is common in patients with advanced liver disease and is associated with increased morbidity and mortality. While sarcopenia in adults has been extensively studied, there is little information in this regard about children and adolescents with chronic liver diseases. The study included 108 children and adolescents who had undergone liver transplantation. Sarcopenia was measured using skeletal muscle index at the third lumbar vertebral level and assessed using abdominal computed tomography imaging. The frequency of sarcopenia in the studied population was found to be 45.7%. Patients with sarcopenia were more likely to be male (P<0.0001), older (P<0.0001), and had lower height-for-age z-scores (P=0.012). Genetic/metabolic diseases were the most common underlying cause of sarcopenia in children. Except for a higher rate of transplant rejection in the sarcopenia group (P=0.035), there was no significant difference in mortality rates (P=0.688) or post-LT complications between the two groups. One year after LT, computed tomography-derived body composition parameters revealed no significant differences between children who survived and those who did not. Our findings indicated a high frequency of sarcopenia in children with chronic liver disease, implying that more research is needed to better understand its impact on clinical outcomes in this population.

Sarcopenia is associated with osteopenia and impaired quality of life in children with genetic intrahepatic cholestatic liver disease.

Sarcopenia occurs in pediatric chronic liver disease, although the prevalence and contributing factors in genetic intrahepatic cholestasis are not well-described. The objective of this study was to measure muscle mass in school-aged children with genetic intrahepatic cholestasis and assess relationships between sarcopenia, clinical variables, and outcomes. Estimated skeletal muscle mass (eSMM) was calculated on dual-energy x-ray absorptiometry obtained in a Childhood Liver Disease Research Network study of children with bile acid synthesis disorders(BASD) alpha-1 antitrypsin deficiency (a1ATd), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Relationships between eSMM, liver disease, and transplant-free survival were assessed. eSMM was calculated in 127 participants (5-18y): 12 BASD, 41 a1ATd, 33 CIC, and 41 ALGS. eSMM z-score was lower in CIC (-1.6 ± 1.3) and ALGS (-2.1 ± 1.0) than BASD (-0.1 ± 1.1) and a1ATd (-0.5 ± 0.8, p < 0.001). Sarcopenia (defined as eSMM z-score ≤- 2) was present in 33.3% of CIC and 41.5% of ALGS participants. eSMM correlated with bone mineral density in the 4 disease groups (r=0.52-0.55, p < 0.001-0.07), but not serum bile acids, bilirubin, aspartate aminotransferase/platelet ratio index, or clinically evident portal hypertension. Of the 2 patients who died (1 with sarcopenia) and 18 who underwent liver transplant (LT, 4 with sarcopenia), eSMM z-score did not predict transplant-free survival. eSMM z-score correlated with the Physical Pediatric Quality of Life Inventory score (r=0.38-0.53, p = 0.007-0.04) in CIC and a1ATd. Severe sarcopenia occurs in some children with ALGS and CIC. The lack of correlation between eSMM and biochemical cholestasis suggests mechanisms beyond cholestasis contribute to sarcopenia. While sarcopenia did not predict transplant-free survival, LT and death were infrequent events. Future studies may define mechanisms of sarcopenia in genetic intrahepatic cholestasis.

Quantitative ultrasound fatty liver evaluation in a pediatric population: comparison with magnetic resonance imaging of liver proton density fat fraction

BackgroundBiopsy remains the gold standard for the diagnosis of hepatic steatosis, the leading cause of pediatric chronic liver disease; however, its costs call for less invasive methods.ObjectiveThis study examined the diagnostic accuracy and reliability of quantitative ultrasound (QUS) for the assessment of liver fat content in a pediatric population, using magnetic resonance imaging proton density fat fraction (MRI-PDFF) as the reference standard.Materials and methodsWe enrolled 36 patients. MRI-PDFF involved a 3-dimensional T2*-weighted with Dixon pulse multiple-echo sequence using iterative decomposition of water and fat with echo asymmetry and least squares estimation (IDEAL IQ). QUS imaging relied on the ultrasound system “RS85 A” (Samsung Medison, Seoul, South Korea) and the following software: Hepato-Renal Index with automated region of interest recommendation (EzHRI), Tissue Attenuation Imaging (TAI), and Tissue Scatter Distribution Imaging (TSI). For each QUS index, receiver operating characteristic (ROC) curve analysis against MRI-PDFF was used to identify the associated cut-off value and the area under the ROC curve (AUROC). Concordance between two radiologists was assessed by intraclass correlation coefficients (ICCs) and Bland–Altman analysis.ResultsA total of 61.1% of the sample (n=22) displayed a MRI-PDFF ≥ 5.6%; QUS cut-off values were TAI=0.625 (AUROC 0.90, confidence interval [CI] 0.77–1.00), TSI=91.95 (AUROC 0.99, CI 0.98–1.00) and EzHRI=1.215 (AUROC 0.98, CI 0.94–1.00). Inter-rater reliability was good-to-excellent for EzHRI (ICC 0.91, 95% C.I. 0.82–0.95) and TAI (ICC 0.94, 95% C.I. 0.88–0.97) and moderate to good for TSI (ICC 0.73; 95% C.I. 0.53–0.85).ConclusionOur results suggest that QUS can be used to reliably assess the presence and degree of pediatric hepatic steatosis.Graphical abstract

Evaluation of Vitamin D Levels in Children With Liver Transplant.

Vitamin D deficiency is common in pediatric chronic liver disease despite oral replacement. We evaluated vitamin D deficiency before and after liver transplant and the relationship between posttransplant and pretransplant vitamin D deficiency and graft rejection. Pediatric recipients with chronic liver disease (N =138) were divided into 4 groups: cholestatic liver diseases, cirrhosis, metabolic disorders, and acute liver failure. Pretransplant and posttransplant vitamin D levels, liver function tests, Pediatric End-Stage Liver Disease scores, rejection activity index scores by graft liver biopsy, and posttransplant patient survival were recorded. There were 62 (45%) female and 76 (55%) male participants (mean transplant age, 6.1 ± 5.6 years). Pretransplant mean available vitamin D of 90 patients was 25.2 ± 20.9 ng/mL, with 36 (40%) within reference range. Posttransplant level for 109 patients was 27.3 ± 18 ng/mL, with 64 (58.7%) within reference range. Pretransplant and posttransplant levels were available for 61 patients, and mean pretransplant levels were lower than posttransplant levels (23.7 ± 19.3 vs 28.3 ± 16.9 ng/mL; P = .01). Patients with cholestatic liver disease had lower pretransplant vitamin D levels (P = .04), which disappeared after transplant. Pretransplant vitamin D levels were positively correlated with serum albumin levels (r = 0.20) in all patients and negatively correlated with total/direct bilirubin (r = 0.29 and r = -0.30) in those with liver diseases and cirrhosis. No correlations were found between pretransplant vitamin D levels and Pediatric End-Stage Liver Disease scores, rejection activity index scores, and posttransplant mortality. Vitamin D deficiency is prevalent in pediatric chronic liver disease before and after transplant, especially for cholestatic liver diseases. However, no association between vitamin D levels and liver graft rejection or patient survival was noted. We recommend close monitoring and individualized vitamin D supplementation before and after liver transplant.

Screening Patterns of Nonalcoholic Fatty Liver Disease in Children with Obesity in Canadian Primary Care: A Cross-Sectional Study.

Nonalcoholic fatty liver disease (NAFLD) is the most common pediatric chronic liver disease, and children with a body mass index (BMI) ≥95th percentile are recommended to be screened for NAFLD by liver enzymes. This study aimed to determine the frequency and predictors of screening for NAFLD among children with obesity in Canada and to evaluate a sample of children with suspected NAFLD. This cross-sectional study used data from the Canadian Primary Care Sentinel Surveillance Network, a repository of electronic medical record data from Canadian primary care practices. Of n = 110,827 children aged 9-18 years, 13.9% (n = 9,888) had a BMI ≥95th percentile. Only 8.7% (n = 859) of these patients were screened for NAFLD in the last year, and 23.6% (n = 2336) were ever screened. Using logistic regression, screening in the last year was associated with demographic and clinical characteristics, including previous liver enzyme assessment, prior antidiabetic prescription, and prior anxiolytic prescription. Among children with suspected NAFLD (n = 1,046), 34.7% had a BMI ≥99th percentile and approximately 8% were at increased risk of significant liver disease. The study revealed low screening rates for NAFLD in Canadian primary care and highlighted the important role of primary care providers in identifying and managing pediatric NAFLD.

Diagnostic performance of ultrasound hepatorenal index for the diagnosis of hepatic steatosis in children.

Non-alcoholic fatty liver disease (NAFLD) is increasing in prevalence and is the most common cause of pediatric chronic liver disease. Objective US-based measures of hepatic steatosis are an unmet clinical need. To evaluate the diagnostic performance of quantitative measurement of liver echogenicity (hepatorenal index, or HRI) for hepatic steatosis in a pediatric cohort. We identified pediatric patients (≤18years old) who underwent both clinically indicated abdominal US and MRI with liver proton-density fat fraction (PDFF) within the 3-month period during the timeframe of July 2015-April 2020 (n=69). Using ImageJ, we drew small circular regions of interest (ROIs) and large freehand ROIs in the liver and right kidney on single longitudinal and transverse images to measure echogenicity (arbitrary units). We calculated four HRIs (liver-to-kidney ratio) as well as liver histogram features. Five pediatric radiologists independently reported the qualitative presence/absence of hepatic steatosis. We used Pearson correlation (r) to assess associations and receiver operating characteristic (ROC) curve analyses to evaluate diagnostic performance. Multivariable logistic regression was used to further assess relationships. Mean patient age was 11.6 (standard deviation [SD] 4.7, range 0.3-18) years; 27/69 (39.1%) were female. Mean PDFF was 12.5% (SD 13.1%, range 1-48%); 34/69 (49.3%) patients were classified as having hepatic steatosis by MRI (PDFF ≥6%). There were significant, positive correlations between all four US HRI methods and PDFF (r=0.51-0.61); longitudinal freehand ROIs exhibited the strongest correlation (r=0.61; P<0.0001). Longitudinal freehand ROI HRI had moderate diagnostic performance for the binary presence of steatosis (area under the curve [AUC]=0.80, P<0.0001), with an optimal cut-off value >1.75 (sensitivity=70.6%, specificity=77.1%). Radiologists' sensitivity for detecting hepatic steatosis ranged from 79.4% to 97.1%, and specificity ranged from 91.2% to 100%. Significant multivariable predictors of PDFF ≥6% included HRI (P=0.002; odds ratio [OR]=34.2), body mass index (BMI) percentile (P=0.005; OR=1.06), and liver gray-scale echogenicity standard deviation (P=0.02; OR=0.79) (receiver operating characteristic AUC = 0.92). Quantitative US HRI has moderate diagnostic performance for detecting liver fat in children and positively correlates with MRI PDFF. Incorporation of BMI-percentile and gray-scale echogenicity standard deviation improved diagnostic performance.

Approach to Pediatric Obesity and Nonalcoholic Fatty Liver Disease.

With the rapidly increasing numbers of children diagnosed with obesity, pediatricians are facing more and more challenges regarding the complex care of these patients. Pediatric nonalcoholic fatty liver disease (NAFLD) is now the most prevalent cause of pediatric chronic liver disease, given its association with obesity. As NAFLD increases a child's risk of developing long-term complications including cirrhosis and hepatocellular carcinoma, efficient diagnosis and effective management is paramount. This article aims to provide a brief overview of NALFD, and discuss the updated diagnosis and management approach for pediatric NAFLD, with a particular focus on the role of the pediatrician. [Pediatr Ann. 2021;50(11):e474-e477.].

Higher Mortality in Pediatric Liver Transplant Candidates With Sarcopenia.

Little is known about the impact of sarcopenia (reduced muscle mass and function) in pediatric chronic liver disease. We compared psoas muscle surface area (PMSA), measured at the 4th lumbar vertebrae, in children listed for liver transplantation (LT) to that of healthy controls and studied the impact of sarcopenia on transplant-associated outcomes. The effect of PMSA (raw value and z score) on survival was studied using multivariable proportional hazards, whereas the impact of PMSA on other transplant-associated outcomes was assessed by multivariable linear or logistic regression. The correlation of PMSA with anthropometric values and markers of disease severity was studied using Spearman's rank-order correlation. Mean PMSA was significantly lower in LT candidates (n=57, 699.4 ± 591.9 mm2 [mean±SD]) than controls (n=53, 1052.9±960.7 mm2 ; P=0.02). For LT candidates, there was an increased risk of death (either while on the waiting list or following transplantation) with lower PMSA (hazard ratio [HR], 1.6 per 100 mm2 [P=0.03]; 95% confidence interval [CI], 1.1-2.8), amounting to a 4.9 times higher risk of death for every 1 unit decrease in PMSA z score (HR, 4.9 [P=0.05], 95% CI, 1.2-34.5), adjusting for age and sex. PMSA did not correlate with posttransplant length of intubation, hospital length of stay, or perioperative complications. PMSA also did not correlate with calculated (r=0.10, P=0.60) or appealed Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease scores (r=0.10, P=0.69). Pediatric LT candidates have a significant reduction in muscle compared with controls. LT candidates with lower PMSA experience significant increases in mortality. As such, sarcopenia may provide a novel indicator of disease severity in children with chronic liver disease.

Kupffer Cell Hyaline Globules in Children With Autoimmune Hepatitis

Hyaline globules (HGs) in the cytoplasm of Kupffer cells (KCs) have been appraised for being a typical feature of autoimmune hepatitis (AIH). This study aimed to determine how useful Kupffer cell hyaline globules (KCHGs) are in diagnosing AIH vs. other causes of pediatric chronic liver diseases (PCLDs). This retrospective study recruited 124 children; 58 with AIH, 50 with chronic hepatitis C virus (HCV) infection, and 16 with Wilson's disease (WD). Two pathologists retrieved paraffin blocks of liver biopsies and prepared new cut sections for Periodic acid-Schiff-Diastase (PAS-D) stain. They independently examined liver biopsies before starting treatment. Two pediatricians reviewed medical records for demographic, clinical, laboratory, and serological findings. Females represented 48.6% of the studied children with a median age of 5.8 (4.9) years. Pathologists identified KCHGs in 67.24%, 12.5%, and 6.0% of AIH, WD, and HCV affected children respectively, P<0.001. A significantly higher proportion of seropositive than seronegative AIH patients had KCHGs (77.5% vs. 50.0%), (P<0.05). In multivariate analysis, KCHGs and prolonged prothrombin time were the only significant predictors that differentiate between AIH and the other studied PCLDs. The odds ratio of having AIH increased 68 times if KCHGs were seen. Among children with AIH, the presence of KCHGs was associated with higher median levels of direct bilirubin 2.2 (1.3) vs. 1.2 (2.2), and immunoglobulin G 3.2 (1.9) vs. 2.0 (1.7), (P<0.05), but not to histopathological findings or hepatic fibrosis and activity. KCHGs are key indicators that can differentiate between AIH and other PCLDs, and between seropositive and seronegative AIH.

Pediatric non-alcoholic fatty liver disease predicted by anthropometric values through transient elastography.

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of pediatric chronic liver disease, which is strongly associated with obesity. Transient elastography, together with anthropometric values including waist-to-height ratio (WHtR) and body mass index (BMI) z-scores are a more precise diagnostic method of NAFLD than ultrasonography. Through transient elastography, we investigate the principal anthropometric values associated with pediatric NAFLD. Healthy children between the ages of 6-18years whose BMIs were ≥85% of normal were recruited as the overweight-and-obese group, and children whose BMIs ranged between 5%-85% were recruited as the control group. Non-alcoholic fatty liver disease was evaluated via transient elastography. BMI z-score and WHtR were measured. A total of 107 (58 overweight-and-obese, 49 control) children were recruited. As evaluated by transient elastography, children in the overweight-and-obese group had significantly higher controlled attenuation parameter and liver stiffness measurement values than the control group. To detect fatty liver, WHtR with a cut-off point of 0.481 and BMI z-score with cut-off point of 1.075 had the best sensitivity and specificity. To identify liver stiffness or inflammation, WHtR with cut-off point of 0.514 and BMI z-score with cut-off point of 1.62 had the best sensitivity and specificity. Controlled attenuation parameter demonstrated a fair correlation with WHtR and BMI z-scores, even in the normal range of these parameters. Transient elastography together with anthropometric measurements demonstrate that pediatric NAFLD may develop earlier than expected. We present principal anthropometric values associated with pediatric NAFLD.

Vitamin D Effect on Ultrasonography and Laboratory Indices and Biochemical Indicators in the Blood: an Interventional Study on 12 to 18-Year-Old Children with Fatty Liver.

PurposeThe rising prevalence of childhood obesity in the past decades has caused non-alcoholic fatty liver disease (NAFLD) to become the most common cause of pediatric chronic liver disease worldwide. This study was aimed at determining the effect of vitamin D (Vit D) on ultrasonography and laboratory indices of NAFLD and some blood biochemical indicators in children.MethodsIn this interventional study liver ultrasonography was performed in 200 children with overweight and obesity. A 108 had fatty liver among which 101 were randomly divided into two groups of study (n=51) and control (n=50). The study group was treated with Vit D, 50000 U once a week whereas the control group received placebo with the same dose and package, both for 12 weeks. At the end of the intervention lab tests and ultrasound study was performed once again to evaluate the response to treatment.ResultsIt was found out that Vit D supplementation improved the fatty liver grade in the study group. The mean changes in hemoglobin (Hb), uric acid, highdensity lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), insulin, albumin and alanine aminotransferase (ALT) was significantly higher in the study group compared to controls (p<0.05). After the intervention and means adjustment, a significant difference was obtained in HDL-C, insulin, LDL-C and homeostasis model assessment of insulin resistance (HOMA-IR) between the two groups.ConclusionVit D supplementation in addition to improving the fatty liver grade in ultrasonography and increasing the blood Vit D level, increases the HDL and Hb level besides decreasing uric acid, LDL, HOMA-IR, insulin and ALT levels.

Operational Definitions for Chronic Liver Disease Manifestations and Recurring Clinical Events in Biliary Atresia.

The disease course of biliary atresia (BA) may be complicated by development of chronic liver disease (CLD) manifestations (eg, ascites) and recurring clinical events (eg, cholangitis). Most pediatric CLD-manifestations/events lack standardized operational definitions, leading to inconsistent identification in clinical research. This study aimed to develop operational research definitions of CLD-manifestations/events in BA for application in retrospective analysis. Operational definitions of CLD-manifestations/events were developed by literature review and revised by a panel of experienced pediatric hepatologists. Definitions were applied to a single-center review of infants with BA post-Kasai. Manifestations/events were captured until last clinical visit with native liver (SNL), liver transplantation (LT), or death. Native liver survival and event-free survival were estimated by Kaplan-Meier method. Cluster analysis was performed to identify similar patterns of manifestation/event development. Of 65 infants with BA post-Kasai (2006-18; median Kasai 56.8 days; 65% girls), 29 underwent LT (median 12.9 months) and 4 died without LT (median 6.9 months). Seventy-six percent of CLD-manifestations/events presented within the first year. Presence of definite clinically evident portal hypertension, thrombocytopenia, and dCE ascites were associated with poor transplant-free survival (P < 0.01). Similar pattern developments of CLD-manifestations/events identified 3 outcome groups: poor outcomes (87.8% LT/death), SNL with manifestations/events, and SNL with few/no events. Operational definitions can provide a timely description of the disease course progression in infants with BA. Research definitions may provide better consistency in future pediatric CLD studies. Furthermore, definitions may serve as endpoints in therapeutic trials or used as variables for disease pattern identification in potential multicenter studies.

Clinicohistological correlation of etiological spectrum of chronic liver disease diagnosed during noncirrhotic stages in children: Can need of liver biopsy be obviated?

Background and AimLimited data exist regarding the etiological spectrum of the subset of chronic liver diseases (CLDs) diagnosed in noncirrhotic states in children. Our primary objective was to study the clinicoetiological profile of CLDs detected in noncirrhotic stages in children younger than 12 years of age. The secondary objective was to find the hepatic histological correlation of provisional diagnosis by different ranks of doctors.MethodsThis was an observational epidemiological study, cross‐sectional in design, conducted in a tertiary‐care setting over a 2‐year period.ResultsThirty‐seven cases were enrolled, with a mean ± SD age of 8 ± 4.1 years and a male:female ratio of 1.8:1. Etiologies noted were Wilson disease (n = 8), autoimmune hepatitis (n = 4), secondary hemochromatosis (n = 4), chronic hepatitis B (n = 3), chronic hepatitis C (n = 2), non‐alcoholic steatohepatitis (n = 2), progressive familial intrahepatic cholestasis (n = 2), extrahepatic biliary atresia (n = 2), Alagille syndrome (n = 1), galactosemia (n = 1), Gaucher disease (n = 1), Niemann‐Pick disease (n = 1), and Budd–Chiari syndrome (n = 1), with an inconclusive diagnosis in five children. Relevant investigations were ordered more frequently by the specialist consultant (SC) and super specialist (SS) combined in comparison with the senior resident (SR) and junior resident (JR) together. (P = 0.0013). Irrelevance of the tests ordered was significantly higher in the junior tier (JR and SR; SR > JR) in contrast to the senior tier of doctors (SC and SS) (P < 0.01). The clinicohistological correlation of an etiological diagnosis significantly differed between the junior and senior ranks of physicians. We noted that an ideal clinical acumen could help to avoid liver biopsy for etiological diagnosis in 78.3% (29/37) of the study population.ConclusionInterpretation of clinical presentation by the senior set of doctors is preferable, which could obviate the need for liver biopsy regarding diagnosis in a proportion of pediatric CLD patients.

Prenatal Exposure to Air Pollution and Traffic and the Risk of Child Liver Injury in European Children-The HELIX Project

Nonalcoholic fatty liver disease (NAFLD) is now the most prevalent pediatric chronic liver disease, affecting an estimated 8% of the general pediatric population and 34% of children with obesity. It is expected to become the leading cause of liver pathology, liver failure and indication for liver transplantation in children in the next decade. Toxicological studies and limited epidemiologic evidence support a link between early life air pollution exposure and liver injury. Non-invasive clinical biomarkers can help assess liver injury and suspected NAFLD. This study evaluated the associations of prenatal and childhood air pollution and traffic exposure with biomarkers of child liver injury.The study population included 1103 children from the “Human Early Life Exposome (HELIX)” project. Liver injury biomarkers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and cytokeratin 18 (CK-18), were measured in serum between ages 6-10 years. Air pollutant exposures were based on land-use regression or dispersion models and included nitrogen dioxide, particulate matter &amp;le 10μm, and particulate matter &amp;le 2.5μm. Markers of traffic included traffic density on nearest road and load in 100 meters buffer, and inverse distance to nearest road. Exposure assignments were made to residential address during whole pregnancy period (prenatal) or to residential and school addresses for year preceding outcome assessment (childhood). Generalized additive models were fitted, adjusting for potential confounders selected using directed acyclic graphs.Prenatal and childhood air pollution exposures were not associated with liver injury biomarkers in childhood. Results for traffic markers were null, except for a positive association between closer proximity to road prenatally and higher AST. There was no consistent evidence of an interaction with child sex or child overweight/obese status for any exposure.This study did not find prenatal or childhood air pollution or traffic exposure to be associated with biomarkers of liver injury in children.

DeepLiverNet: a deep transfer learning model for classifying liver stiffness using clinical and T2-weighted magnetic resonance imaging data in children and young adults.

Although MR elastography allows for quantitative evaluation of liver stiffness to assess chronic liver diseases, it has associated drawbacks related to additional scanning time, patient discomfort, and added costs. To develop a machine learning model that can categorically classify the severity of liver stiffness using both anatomical T2-weighted MRI and clinical data for children and young adults with known or suspected pediatric chronic liver diseases. We included 273 subjects with known or suspected chronic liver disease. We extracted data including axial T2-weighted fast spin-echo fat-suppressed images, clinical data (e.g., demographic/anthropomorphic data, particular medical diagnoses, laboratory values) and MR elastography liver stiffness measurements. We propose DeepLiverNet (a deep transfer learning model) to classify patients into one of two groups: no/mild liver stiffening (<3kPa) or moderate/severe liver stiffening (≥3kPa). We conducted internal cross-validation using 178 subjects, and external validation using an independent cohort of 95 subjects. We assessed diagnostic performance using accuracy, sensitivity, specificity and area under the receiver operating characteristic curve (AuROC). In the internal cross-validation experiment, the combination of clinical and imaging data produced the best performance (AuROC=0.86) compared to clinical (AuROC=0.83) or imaging (AuROC=0.80) data alone. Using both clinical and imaging data, the DeepLiverNet correctly classified patients with accuracy of 88.0%, sensitivity of 74.3% and specificity of 94.6%. In our external validation experiment, this same deep learning model achieved an accuracy of 80.0%, sensitivity of 61.1%, specificity of 91.5% and AuROC of 0.79. A deep learning model that incorporates clinical data and anatomical T2-weighted MR images might provide a means of risk-stratifying liver stiffness and directing the use of MR elastography.

Elastography for Pediatric Chronic Liver Disease: A Review and Expert Opinion.

In adults with chronic liver diseases, ultrasound and magnetic resonance shear wave elastography (SWE) can replace liver biopsy in several clinical scenarios. Several guidelines on the use of ultrasound SWE for the adult population have been published. However, the number of publications in the pediatric population is limited, and available guidelines on SWE do not specifically address pediatric chronic liver diseases. In this article, we review the literature on the use of SWE for pediatric chronic liver diseases and provide expert opinion on how to use SWE, both ultrasound and magnetic resonance techniques, in the pediatric population.

Higher Waitlist Mortality in Pediatric Acute-on-chronic Liver Failure in the UNOS Database.

Acute-on-chronic liver failure (ACLF), whereas increasingly well-defined in adults, has been poorly characterized in pediatric patients other than having a poor prognosis. This study aimed to identify ACLF and evaluate prognosis in the American pediatric population. Modified ACLF definitions (p-CLIF) were applied to 11,300 children listed for liver transplantation from March 2002 through 2017 in the Organ Procurement and Transplantation Network (OPTN) database. Pediatric ACLF patients have greater mortality within 90 days from listing (46.6% by p-CLIF) than other types of failure (<30%), including acute liver failure, as well as greater mortality within the first 30 and 90 days after transplantation than all other types of liver failure, but do not have increased mortality rates relative to other groups between 90 and 365 days from transplant. Although some ACLF listings also received 1B status, ACLF mortality at 90 days was greater than the general 1B population (50 vs 29.4%). Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease scores of ACLF patients are lower than 1B listings, and do not predict waitlist or posttransplant death. Greater number of organ failures does correlate with increased mortality. Biliary atresia is the leading etiology of pediatric chronic liver disease, accounting for over 30% of chronic and 45% of ACLF listings, yet is protective against mortality (hazard ratio [HR] = 0.142 for ACLF). Receiving exception approval is independently but similarly protective in ACLF (HR = 0.145). These findings pose a challenge for allocation decisions but indicate greater attention to ACLF is needed, as scoring systems may not capture these children's risk of early death, which appears to currently be mitigated by exceptions. Multicenter, clinical, preferably prospective study of ACLF is necessary to determine how to prioritize ACLF relative to other liver failure types to address its relatively higher early mortality.

Progression of Fatty Liver Disease in Children Receiving Standard of Care Lifestyle Advice

Nonalcoholic fatty liver disease (NAFLD) is the most common pediatric chronic liver disease. Little is known about outcomes in recognized youth. We compared paired liver biopsies from 122 of 139 children with NAFLD (74% male; 64% white; 71% Hispanic; mean age, 13 ± 3 years; age range, 8-17 years) who received placebo and standard of care lifestyle advice in 2 double-blind, randomized clinical trials within the nonalcoholic steatohepatitis (NASH) clinical research network from 2005 through 2015. We analyzed histologic changes with respect to baseline and longitudinal change in clinical variables using regression analysis. At enrollment, 31% of the children had definite NASH, 34% had borderline zone 1 NASH, 13% had borderline zone 3 NASH, and 21% had fatty liver but not NASH. Over a mean period of 1.6 ± 0.4 years, borderline or definite NASH resolved in 29% of the children, whereas 18% of the children with fatty liver or borderline NASH developed definite NASH. Fibrosis improved in 34% of the children but worsened in 23%. Any progression to definite NASH and/or in fibrosis was associated with adolescent age, and higher waist circumference, levels of alanine or aspartate aminotransferase, total and low-density lipoprotein cholesterol at baseline (<0.05), and over follow-up time, with increasing level of alanine aminotransferase, hemoglobin A1C (P<.05), gamma-glutamyl transferase and development of type 2 diabetes (P<.01). Increasing level of gamma-glutamyl transferase was also associated with reduced odds of any improvement (P= .003). One-third of children with NAFLD enrolled in placebo groups of clinical trials had histologic features of progression within 2 years, in association with increasing obesity and serum levels of aminotransferases and loss of glucose homeostasis.