Liver Disease In Children Research Articles

Caroli’s Disease vs Caroli Syndrome: Clinical and Radiological Spectrum, with disease Outcome at a Teaching Hospital in Lahore

Background: Caroli disease and Caroli syndrome are part of the clinical spectrum of ductal plate (DP) malformations, also referred to, as the fibrocystic liver diseases. This article aimed to study both these conditions, in terms of clinical features and disease outcome at a teaching hospital. Objective: To describe the clinical spectrum, laboratory and imaging findings, management course and outcome of fibrocystic liver diseases in children, at the University of Child Health Sciences, Lahore, Pakistan. Study Design: Cross-sectional Study. Settings: Department of Pediatric Gastroenterology & Hepatology, University of Child Health Sciences, Lahore Pakistan. Duration: January 2014 to July 2017. Methods: The study included patients with Caroli disease and Caroli Syndrome, confirmed on the basis of characteristic findings on magnetic resonance cholangiopancreatography. SPSS v.20 was used for statistical analysis. Results: The mean age of 15 patients included in the study was 6.54 ± 4.18 years. Among them, 7/15 (46.7%) had Caroli’s disease (CD), whereas 8/15 (53.3%) had Caroli’s syndrome (CS). Male to female ratio was 4:1. CS pre-dominantly affected male children (8:0), while CD affected both genders almost equally (4:3). CD commonly presented with recurrent cholangitis (6/7, 85%), while CS as portal hypertension (7/8, 87.5%). Renal involvement was found in 5/15(33.33%) patients; mostly in CS (4/5,80%) and one (6.66%) patient progressed to end stage renal disease. One patient of CD underwent lobectomy and one died of end stage liver disease. Two patients of CS were treated with shunt surgery with partial splenectomy. Six patients are doing well after endoscopic variceal band ligation and propranolol prophylaxis. Conclusion: Caroli disease and Caroli syndrome are two sides of the same coin; it is important to differentiate the two disorders, especially from management point of view. CS is more common in our set up, leading to portal hypertension, which can be treated with sclerotherapy, endoscopic band ligation or shunt surgery. CD leads to cholangitis, which is managed with antibiotics.

Noninvasive scores are poorly predictive of histological fibrosis in paediatric fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. Roughly a quarter of paediatric patients with NAFLD develop nonalcoholic steatohepatitis and fibrosis. Here, we evaluated the diagnostic accuracy of previously published noninvasive fibrosis scores to predict liver fibrosis in a large European cohort of paediatric patients with NAFLD. The 457 patients with biopsy-proven NAFLD from 10 specialized centers were included. We assessed diagnostic accuracy for the prediction of any (F ≥ 1), moderate (F ≥ 2) or advanced (F ≥ 3) fibrosis for the AST/platelet ratio (APRI), Fibrosis 4 score (FIB-4), paediatric NAFLD fibrosis score (PNFS) and paediatric NAFLD fibrosis index (PNFI). Patients covered the full spectrum of fibrosis (F0: n = 103; F1: n = 230; F2: n = 78; F3: n = 44; F4: n = 2). None of the scores were able to accurately distinguish the presence of any fibrosis from no fibrosis. For the detection of moderate fibrosis, area under the receiver operating characteristic curve (AUROC) were: APRI: 0.697, FIB-4: 0.663, PNFI: 0.515, PNFS: 0.665, while for detection of advanced fibrosis AUROCs were: APRI: 0.759, FIB-4: 0.611, PNFI: 0.521, PNFS: 0.712. Fibrosis scores showed no diagnostic benefit over using ALT ≤ 50/ > 50 IU/L as a cut-off. Established fibrosis scores lack diagnostic accuracy to replace liver biopsy for staging of fibrosis, giving similar results as compared to using ALT alone. New diagnostic tools are needed for Noninvasive risk-stratification in paediatric NAFLD.

Accurate prediction of biliary atresia with an integrated model using MMP-7 levels and bile acids.

Biliary atresia (BA) is a rare fatal liver disease in children, and the aim of this study was to develop a method to diagnose BA early. We determined serum levels of matrix metalloproteinase-7 (MMP-7), the results of 13 liver tests, and the levels of 20 bile acids, and integrated computational models were constructed to diagnose BA. Our findings demonstrated that MMP-7 expression levels, as well as the results of four liver tests and levels of ten bile acids, were significantly different between 86 BA and 59 non-BA patients (P < 0.05). The computational prediction model revealed that MMP-7 levels alone had a higher predictive accuracy [area under the receiver operating characteristic curve (AUC) = 0.966, 95% confidence interval (CI): 0.942, 0.989] than liver test results and bile acid levels. The AUC was 0.890 (95% CI 0.837, 0.943) for liver test results and 0.825 (95% CI 0.758, 0.892) for bile acid levels. Furthermore, bile levels had a higher contribution to enhancing the predictive accuracy of MMP-7 levels (AUC = 0.976, 95% CI 0.953, 1.000) than liver test results. The AUC was 0.983 (95% CI 0.962, 1.000) for MMP-7 levels combined with liver test results and bile acid levels. In addition, we found that MMP-7 levels were highly correlated with gamma-glutamyl transferase levels and the liver fibrosis score. The innovative integrated models based on a large number of indicators provide a noninvasive and cost-effective approach for accurately diagnosing BA in children. Video Abstract (MP4 142103 KB).

Outcome of pediatric living donor liver transplant: Experience from Pakistan; a resource limited setting.

Liver transplantation (LT) has emerged as a lifesaving modality for many liver diseases in children. Pediatric LT is an established treatment in the Western world but is relatively a new procedure in resource-limited countries like Pakistan. The study aims to highlight the outcomes and survival of pediatric recipients from the first pediatric liver transplant center in Pakistan. A retrospective analysis of pediatric LT was done from 2012 to 2019. The study was conducted in the Hepatobiliary and liver transplant department of Shifa International Hospital (SIH), Islamabad. A detailed analysis for indications for pediatric LT, survival, and complications was done. Forty-five patients under 18 years of age underwent Living donor liver transplant (LDLT) in SIH. Median age was 9 years and M:F of 2:1. Cryptogenic liver disease followed by Wilson disease were the two most common indications of LT. The majority of patients had chronic liver disease 34 (75%) while 11 (24%) had acute liver failure. The right lobe graft was the most common type of graft 19 (42.2%). Thirty days, 1-year, 3-year, and 5-year survival was 77.8%, 75.6%, 73.3%, and 60.6% respectively. Mortality was highest in patients with biliary atresia 4 (33%). Causes of death included pulmonary embolism, sepsis, surgical complications, and acute kidney injury. Mean survival was 88.850 months (±7.899) (CI 73.369-104.331). Pediatric LDLT has offered disease-free survival for patients. Survival can improve further with nutritional rehabilitation and anticipation and management of post-operative complications.

Unveiling the interplay between NSAID-induced dysbiosis and autoimmune liver disease in children: insights into the hidden gateway to autism spectrum disorders. Evidence from ex vivo, in vivo, and clinical studies.

Autism spectrum disorders (ASD) represent a diverse group of neuropsychiatric conditions, and recent evidence has suggested a connection between ASD and microbial dysbiosis. Immune and gastrointestinal dysfunction are associated with dysbiosis, and there are indications that modulating the microbiota could improve ASD-related behaviors. Additionally, recent findings highlighted the significant impact of microbiota on the development of autoimmune liver diseases, and the occurrence of autoimmune liver disease in children with ASD is noteworthy. In the present study, we conducted both an in vivo study and a clinical study to explore the relationship between indomethacin-induced dysbiosis, autoimmune hepatitis (AIH), and the development of ASD. Our results revealed that indomethacin administration induced intestinal dysbiosis and bacterial translocation, confirmed by microbiological analysis showing positive bacterial translocation in blood cultures. Furthermore, indomethacin administration led to disturbed intestinal permeability, evidenced by the activation of the NLRP3 inflammasomes pathway and elevation of downstream biomarkers (TLR4, IL18, caspase 1). The histological analysis supported these findings, showing widened intestinal tight junctions, decreased mucosal thickness, inflammatory cell infiltrates, and collagen deposition. Additionally, the disturbance of intestinal permeability was associated with immune activation in liver tissue and the development of AIH, as indicated by altered liver function, elevated ASMA and ANA in serum, and histological markers of autoimmune hepatitis. These results indicate that NSAID-induced intestinal dysbiosis and AIH are robust triggers for ASD existence. These findings were further confirmed by conducting a clinical study that involved children with ASD, autoimmune hepatitis (AIH), and a history of NSAID intake. Children exposed to NSAIDs in early life and complicated by dysbiosis and AIH exhibited elevated serum levels of NLRP3, IL18, liver enzymes, ASMA, ANA, JAK1, and IL6. Further, the correlation analysis demonstrated a positive relationship between the measured parameters and the severity of ASD. Our findings suggest a potential link between NSAIDs, dysbiosis-induced AIH, and the development of ASD. The identified markers hold promise as indicators for early diagnosis and prognosis of ASD. This research highlights the importance of maintaining healthy gut microbiota and supports the necessity for further investigation into the role of dysbiosis and AIH in the etiology of ASD.

Leukocyte cell-derived chemotaxin 2 correlates with pediatric non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD), newly renamed metabolic dysfunction-associated liver disease (MASLD), is a leading cause of liver disease in children and adults. There is a paucity of data surrounding potential biomarkers and therapeutic targets, especially in pediatric NAFLD. Leukocyte cell-derived chemotaxin 2 (LECT2) is a chemokine associated with both liver disease and skeletal muscle insulin resistance. Our aim was to determine associations between LECT2 and common clinical findings of NAFLD in pediatric patients. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum LECT2 concentrations in children (aged 2-17 years) with and without NAFLD. LECT2 concentrations were then correlated to clinical parameters in NAFLD. Mean LECT2 was significantly elevated in children with NAFLD versus healthy controls (n = 63 vs. 42, 5.83 ± 1.98 vs. 4.02 ± 2.02 ng/mL, p < 0.005). Additionally, LECT2 had strong correlations with body mass index (BMI) (Pearson r = 0.301, p = 0.002). A LECT2 concentration of 3.76 mg/mL predicts NAFLD with a sensitivity of 90.5% and specificity of 54.8%. Principal component analysis and logistic regression models further confirmed associations between LECT2 and NAFLD status. This study demonstrates increased serum LECT2 concentrations in pediatric NAFLD, which correlates with BMI and shows strong predictive value within these patients. Our data indicate that LECT2 is a potential diagnostic biomarker of disease and should be further investigated in pediatric as well as adult NAFLD.

Development and validation of a nomogram to predict allograft survival after pediatric liver transplantation.

Liver transplantation is the main treatment for cholestatic liver disease and some metabolic liver diseases in children. However, no accurate prediction model to determine the survival probability of grafts prior to surgery exists. This study aimed to develop an effective prognostic model for allograft survival after pediatric liver transplantation. This retrospective cohort study included 2032 patients who underwent pediatric liver transplantation between January 1, 2006, and January 1, 2020. A nomogram was developed using Cox regression and validated based on bootstrap sampling. Predictive and discriminatory accuracies were determined using the concordance index and visualized using calibration curves; net benefits were calculated for model comparison. An online Shiny application was developed for easy access to the model. Multivariable analysis demonstrated that preoperative diagnosis, recipient age, body weight, graft type, preoperative total bilirubin, interleukin-1β, portal venous blood flow direction, spleen thickness, and the presence of heart disease and cholangitis were independent factors for survival, all of which were selected in the nomogram. Calibration of the nomogram indicated that the 1-, 3-, and 5-year predicted survival rates agreed with the actual survival rate. The concordance indices for graft survival at 1, 3, and 5 years were 0.776, 0.757, and 0.753, respectively, which were significantly higher than those of the Pediatric End-Stage Liver Disease and Child-Pugh scoring systems. The allograft dysfunction risk of a recipient could be easily predicted using the following URL: https://aspelt.shinyapps.io/ASPELT/ / CONCLUSION: The allograft survival after pediatric liver transplantation (ASPELT) score model can effectively predict the graft survival rate after liver transplantation in children, providing a simple and convenient evaluation method for clinicians and patients.

Current status and future directions of liver transplantation for metabolic liver disease in children.

Orthotopic liver transplantation (OLT) in the care of children with inborn errors of metabolism (IEM) is well established and represent the second most common indication for pediatric liver transplantation in most centers worldwide, behind biliary atresia. OLT offers cure of disease when a metabolic defect is confined to the liver, but may still be transformative on a patient's quality of life reducing the chance of metabolic crises causing neurological damage in children be with extrahepatic involvement and no "functional cure." Outcomes post-OLT for inborn errors of metabolism are generally excellent. However, this benefit must be balanced with consideration of a composite risk of morbidity, and commitment to a lifetime of post-transplant chronic disease management. An increasing number of transplant referrals for children with IEM has contributed to strain on graft access in many parts of the world. Pragmatic evaluation of IEM referrals is essential, particularly pertinent in cases where progression of extra-hepatic disease is anticipated, with long-term outcome expected to be poor. Decision to proceed with liver transplantation is highly individualized based on the child's dynamic risk-benefit profile, their family unit, and their treating multidisciplinary team. Also to be considered is the chance of future treatments, such as gene therapies, emerging in the medium term.

Risk factors and cardio-metabolic outcomes associated with metabolic-associated fatty liver disease in childhood

Non-Alcoholic Fatty Liver Disease (NAFLD) is defined as increased liver fat percentage, and is the most common chronic liver disease in children. Rather than NAFLD, Metabolic-Associated Fatty Liver Disease (MAFLD), defined as increased liver fat with presence of adverse cardio-metabolic measures, might have more clinical relevance in children. We assessed the prevalence, risk-factors and cardio-metabolic outcomes of MAFLD at school-age. This cross-sectional analysis was embedded in an ongoing population-based prospective cohort study started in 2001, in the Netherlands. In 1910 children of 10 years, we measured liver fat fraction by magnetic resonance imaging (MRI), body mass index (BMI), blood pressure, and lipids, insulin, and glucose concentrations. Childhood lifestyle factors were obtained through questionnaires. MAFLD was defined as ≥2% liver fat in addition to excess adiposity (BMI or visceral adiposity), presence of metabolic risk (blood pressure, triglycerides and HDL-concentrations) or prediabetes (glucose). Of all children, 49.6% had ≥2% liver fat, and 25.2% fulfilled the criteria of MAFLD. Only non-European descent was associated with increased odds of MAFLD at nominal significance (Odds Ratio 1.38, 95% Confidence Interval 1.04, 1.82). Compared to children with <2% liver fat, those with MAFLD had increased odds of cardio-metabolic-risk-factor clustering (Odds Ratio 7.65, 95% Confidence Interval 5.04, 11.62). In this study, no NAFLD-associated childhood risk factors were associated with increased odds of childhood MAFLD, yet the findings suggest that ethnicity could be, despite mostly explained by socio-economic factors. Use of MAFLD criteria, rather than NAFLD, may identify children at risk for impaired cardio-metabolic health. Erasmus University MC, the Netherlands Organisation for Health Research and Development, the Ministry of Health, Welfare, and Sport, and the European Research Council.

FRI591 Association Of TSH Levels And NAFLD Severity In Children And Adolescents

Abstract Disclosure: M. Untalan: None. N.A. Crimmins: None. A. Mencin: None. K. Yates: None. X. Stavra: None. V. Thaker: None. Background: Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation and is now the most common form of chronic liver disease in children and adolescents. Recent studies have indicated an association between subclinical hypothyroidism (SH) and NAFLD. An underactive thyroid gland produces insufficient T3 and T4 involved in hepatic fat metabolism that could contribute to NAFLD. While increased TSH has been documented in individuals with NAFLD, its independent role with NAFLD disease severity is yet to be clarified. Objective: To study the relationship of TSH levels and the severity of NAFLD/NASH, as well as determine whether changes in TSH levels are associated with changes in NAFLD/NASH among children. Methods: This retrospective study used data from two cohorts within the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). TSH, free and total T4, total T3, TPO antibodies and thyroglobulin (TBG) levels were assessed in samples obtained first at baseline and then at 52-96 weeks. Individuals with overt hypothyroidism, abnormal TPO antibody levels, and those receiving thyroid treatment were excluded from analysis. SH was defined as TSH &amp;gt; 4.4 mIU/L. Linear and multinomial regression models were used to identify the association between TSH, SH and NAFLD severity measured by NAFLD activity score (NAS), fibrosis stage, steatosis level, lobular and portal inflammation and ballooning while adjusting for potential confounders (sex, age, race, BMI-z, HOMA-IR and non-HDL levels). Longitudinal analysis was conducted by mixed-effects model. Analyses were performed with SAS and R statistical software. Results: 218 individuals and 421 observations were included in the cross-sectional and longitudinal analyses, respectively. Children with more severe grades of steatosis were more likely to be younger (p = 0.03) and male (p = 0.02). At baseline, TSH was not significantly associated with any NAFLD histological measures. Longitudinal analyses revealed a positive association of change in TSH and steatosis level after adjusting for covariates, and follow-up time (p = 0.03). Change in SH was associated with change in fibrosis stage (p = 0.01). Adding HOMA-IR and non-HDL levels to the models did not change this relationship. The positive relationship of total T3 and T4 with NAS was explained by TBG. Conclusion: In a large cohort of pediatric patients with biopsy-confirmed NAFLD, high TSH levels correlated with increasing steatosis grade and NAS, and SH with increased liver fibrosis. Markers of impaired thyroid function may help predict disease severity in pediatric patients with NAFLD. Presentation: Friday, June 16, 2023

548 Annual screening for liver disease in children

548 Annual screening for liver disease in children

Association of single nucleotide polymorphism in patatin like phopholipase domain containing 3 (PNPLA3) gene with paediatric non-alcoholic fatty liver disease

Background: Non-alcoholic fatty liver disease (NAFLD) is the most unabating cause of chronic liver disease in children and adolescents. This study aimed to examine the association of single nucleotide polymorphism in patatin-like phospholipase domain containing 3 (PNPLA3) gene with paediatric non-alcoholic fatty liver disease. Methods: This case-control study was conducted from June 2021 to December 2022. Fifty-one overweight children aged 6–17 years were recruited in this study and divided into NAFLD (cases) and non-NAFLD (controls) groups based on hepatic steatosis detected by liver ultrasonography. We analysed the rs738409 polymorphism by TaqMan assay and examined its association with NAFLD. Results: Thirty-one (60.8%) children were in the case group and 20 (39.2%) children were in the control group. Alanine aminotransferase (P&lt;0.001) and triglycerides (P=0.02) were found to be significantly higher in cases. However, no significant association was found between the PNPLA3 rs738409 single nucleotide polymorphism (SNP) and the presence of NAFLD in children. Conclusion: Our study didn't find any association between PNPLA3 rs 738409 single nucleotide polymorphisms and presence of NAFLD in children, but we discovered that high alanine aminotransferase and triglycerides level can be useful in screening overweight children for NAFLD. Bangabandhu Sheikh Mujib Medical University Journal 2023;16(3): 139-143

Features of the gut microbiota in children with chronic liver diseases

The value of the liver–gut axis is increasingly recognized as a major modulator of autoimmunity. There is no comparative analysis of data on the taxonomic diversity of the intestinal microbiota in chronic liver diseases in children. Purpose. To investigate the taxonomic diversity of the intestinal microbiota in children with chronic liver diseases compared with healthy patients, to identify differences in bacterial diversity in autoimmune and non-autoimmune liver diseases, as well as the impact of immunosuppressive therapy on the intestinal microbiota. Material and methods. A metagenomic analysis of the gut microbiota of 24 children with chronic liver diseases (mean age 10,3 ± 4,7 years) was carried out with the identification of the V3–V4 region of the 16S rRNA gene. The group included 18 children with autoimmune liver diseases and 6 children with non-autoimmune liver diseases. The control group consisted of fecal samples of 34 apparently healthy children. Results. When comparing fecal samples of children with autoimmune liver diseases with samples of healthy children, the taxa of Bacteroides dorei, Collinsella aerofaciens, Ruminococcus caffidurs prevailed, and for children of the control group — Neisseria flavescens. When comparing samples of patients with non-autoimmune liver diseases and the control group, it was found that the taxa Bacteroides fragilis, Klebsiella pneumoniae, Bifidobacterium longum prevailed in healthy children. When comparing fecal samples from children with autoimmune and non-autoimmune liver diseases, it was found that Veillonella dispar, Cloacibacillus porcorum, Veillonella parvula, Prevotella histicola and Bacteroides eggerthii taxa dominate in patients with non-autoimmune diseases. No dominant taxa of the gut microbiota were found in children with autoimmune liver diseases. It has been established that the taxa Veillonella dispar, Faecalibacterium prausnitzii, Roseburia inulinivorans, Bacteroides xylanisolvens and Alistipes obesi prevail in patients receiving immunosuppressive therapy, and the taxa Phascolarctobacterium succinatutens, Bacteroides ovatus, Solobacterium mooreis and Holdemanella massilien prevail in patients not receiving immunosuppressive therapy. Conclusion. A recent study of the gut microbiota in children with chronic liver disease shows differences in the imbalance of the gut microbiota compared to the results obtained in adults. The gut microbiota model is capable of distinguishing autoimmune liver diseases from non-autoimmune diseases. Immunosuppressive therapy is accompanied by the dominance of taxa that reduce the production of short-chain fatty acids.

Relationship of gut microbiota and immunological response in obesity-related non-alcoholic fatty liver disease in children.

In the development of NAFLD plays an important role the intestinal microflora. Our aim was to characterize role microbiota in children. Distinctive gut microbiota composition was observed in children, characterized and short-chain fatty acid producing bacteria. For the treatment of NAFLD it is possible by therapeutic manipulations with prebiotics and probiotics to modulate the gut microbiota and maintain the integrity of the intestinal barrier are potential agents.

Real-time ultrasound-derived fat fraction in pediatric population: feasibility validation with MR-PDFF.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. To avoid limitations of liver biopsy and MRI, quantitative ultrasound has become a research focus. Ultrasound-derived fat fraction (UDFF) is based on a combination of backscatter coefficient and attenuation parameter. The objectives of the study were to determine (1) agreement between UDFF/MRI proton density fat fraction (MR-PDFF) and (2) whether BMI and age are predictive for UDFF. This cross-sectional prospective study included a convenience sample of 46 children referred for clinically indicated abdominal MRI. MR-PDFF and five acquisitions of UDFF were collected. Intraclass correlation coefficient (ICC) and Bland-Altman analysis were used to assess agreement between MR-PDFF and UDFF. Receiver operating characteristic curves were calculated for UDFF prediction of liver steatosis (MR-PDFF ≥ 6%). Multivariable regression was performed to assess BMI and age as predictors for UDFF. Twenty-two participants were male, 24 were female, and the mean age was 14 ± 3 (range: 7-18) years. Thirty-six out of 46 participants had normal liver fat fraction <6%, and 10/46 had liver steatosis. UDFF was positively associated with MR-PDFF (ICC 0.92 (95% CI, 0.89-0.96). The mean bias between UDFF and MR-PDFF was 0.64% (95% LOA, -5.3-6.6%). AUROC of UDFF for steatosis was of 0.95 (95% CI, 0.89-0.99). UDFF cutoff of 6% had a sensitivity of 90% (95% CI, 55-99%) and a specificity of 94% (95% CI, 81-0.99%). BMI was an independent predictor of UDFF (correlation: 0.55 (95% CI, 0.35-0.95)). UDFF shows strong agreement with MR-PDFF in children. A UDFF cutoff of 6% provides good sensitivity and specificity for detection of MR-PDFF of ≥ 6%.

The relative contributions of soft tissue mass components as risk or protective factors of non-alcoholic fatty liver disease in children.

Several body components are known to be associated with non-alcoholic fatty liver disease (NAFLD) in children. However, the relative contributions of soft tissue mass components as risk or protective factors of NAFLD are largely unknown because measurements of these components are often highly correlated. Therefore, we aimed to estimate levels of association between soft tissue mass components and NAFLD. We collected the medical records of 555 Chinese children (aged 3-18 years). Five mutually exclusive and exhaustive components of soft tissue mass were measured using dual energy X-ray absorptiometry. NAFLD was diagnosed with abdominal B-ultrasound scan. We fit Dirichlet regression and multivariate linear regression models wherein age and NAFLD were used as predictors of the proportional measurements of soft tissue mass components. The proportion of android fat was significantly higher in children with NAFLD than in those without NAFLD (ratio of proportions ranged from 1.18 to 1.30), whereas proportions of trunk lean and limb lean were significantly lower (ratio of proportions ranged from 0.87 to 0.92 for trunk lean and from 0.82 to 0.91 for limb lean). The proportion of gynoid fat was slightly higher in boys with NAFLD than in those without NAFLD (ratio = 1.05), but this proportion was not significantly higher in girls. The association between the proportion of android fat and NAFLD appeared to be somewhat greater than the associations between proportions of trunk lean or limb lean components and NAFLD. Our findings suggest that lowering fat mass and increasing lean mass can both be used to combat NAFLD in children and that more studies are needed to determine the association between gynoid fat and NAFLD.

Cystic fibrosis liver disease in children - A review of our current understanding.

Cystic fibrosis is the second most common genetic disease in infancy. It is the result of a mutated channel protein, the CFTR, which secretes chloride ions, fluidifying secretions. Recent improvements in the treatment have increased life expectancy in these patients. Nevertheless, liver involvement remains the third cause of death. Unfortunately, our understating of the physiopathology is still deficient. Biliary obstruction secondary to the presence of thick secretions is considered to lead to cirrhosis. However, treatment with ursodeoxycolic acid has not changed the natural history. Furthermore, the presence of portal hypertension in the absence of cirrhosis cannot be explained. Recently, the role of CFTR as modulator of immune tolerance has been proposed, which could explain the presence of a persistent portal inflammation leading to fibrosis, and the gut-liver axis would also have a role in disease presentation and progression.

The role of adipocytokines in the development of non-alcoholic fatty liver disease in children and adolescents

Over the past 20 years, the proportion of overweight and obese children and adolescents has increased significantly in most countries. Obesity represents a major cardiometabolic risk and is closely associated with comorbidities such as hypertension, hyperlipidemia, hyperinsulinemia, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). There is a lot of uncertainty regarding the diagnosis of metabolic syndrome in children, mainly due to the various and conflicting definitions that have been proposed. The prevalence of metabolic syndrome varied significantly in children (from 6 to 39%) depending on the applied definition criteria. According to these definitions, only 2% of children met all the criteria for metabolic syndrome. Over the past decade, studies have shown that, in parallel with the increase in the prevalence of obesity in the pediatric population, NAFLD has become the most common form of liver disease in childhood. In NAFLD, inflammatory cytokines/adipokines and other factors lead to steatohepatitis and/or fibrosis. Recently, several adipocytokines and inflammatory cytokines have been identified with significant positive (leptin, chemerin, vaspin, TNF-α, IL-6 and IL-8) or negative (adiponectin) associations with metabolic risk factors. Some of them can be considered as pathophysiological factors linking obesity and its complications such as insulin resistance and NAFLD. However, data on other adipocytokines and their role in metabolism remain controversial and partially unknown, especially with regard to their role in childhood (resistin, NAMPT, FGF-21, A-FABP, RBP4, lipocalin-2, omentin-1, hsCRP). Adipocytokines are a novel and powerful tool not only for the diagnosis and stratification of NAFLD and the metabolic syndrome, but also as a potential therapeutic target. Adipocytokine therapy requires further study in all patients with metabolic syndrome and NAFLD, especially in children and adolescents.

Abnormal distribution of fat tissue and its association with intestinal failure-associated liver disease in children and adolescents with long-time parenteral nutrition support: A case-control study.

Patients with intestinal failure (IF) often present with abnormal body composition characterized by high fat mass. However, the distribution of fat and its association with the development of IF-associated liver disease (IFALD) remain unclear. This study aims to investigate the body composition and its relationship with IFALD in older children and adolescents with IF. This retrospective case-control study enrolled patients with IF receiving parenteral nutrition (PN) at Keio University Hospital who initiated PN before the age of 20 years (cases). The control group included patients with abdominal pain, with available computed tomography (CT) scan and anthropometric data. CT scan images of the third lumbar vertebra (L3) were used for body composition analysis and compared between the groups. Liver histology was compared with CT scan findings in IF patients who underwent biopsy. Nineteen IF patients and 124 control patients were included. To account for age distribution, 51 control patients were selected. The median skeletal muscle index was 33.9 (29.1-37.3) in the IF group and 42.1 (39.1-45.7) in the control group (P < 0.01). The median visceral adipose tissue index (VATI) was 9.6 (4.9-21.0) in the IF group and 4.6 (3.0-8.3) in the control group (P = 0.018). Among the 13 patients with IF who underwent liver biopsies, 11 (84.6%) had steatosis, and there was a tendency for fibrosis to correlate with VATI. Patients with IF exhibit low skeletal muscle mass and high visceral fat, which may be related to liver fibrosis. Routine monitoring of body composition is recommended.

Combined effect of PNPLA3 rs738409 and UGT1A1 rs10929303 gene polymorphisms on nonalcoholic fatty liver disease in children

Objective: To investigate the combined effects of patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 (C > G) and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) rs10929303 (C > T) on nonalcoholic fatty liver disease (NAFLD) in children and adolescents so as to provide scientific evidence for NAFLD genetic research. Methods: 1 027 children and adolescents aged 7-18 were selected as the research subjects. The general situation, past medical history, height and body weight measurements, and B- mode ultrasound test of the liver were investigated by dedicated full-time personnel. In addition, the morning fasting venous blood was collected to measure the blood biochemical indicators. DNA was extracted and genotyped for PNPLA3 rs738409 and UGT1A1 rs10929303. Logistic regression analysis was used to analyze the association and combined effect of the two gene polymorphisms and NAFLD. Statistical analysis was performed by t-test, Mann-Whitney U test, or c2 test according to different data. Results: The GG genotype of PNPLA3 rs738409 and the CC genotype of UGT1A1 rs10929303 were associated with an increased risk of developing NAFLD in children by 89% (OR = 1.89, 95% CI: 1.11-3.23, P = 0.019) and 96% (OR = 1.96, 95% CI: 1.21-3.17, P = 0.006), respectively, while the concurrent risk of NAFLD in those who carried the above two genotypes increased by 306% compared with those who did not carry both genotypes (OR = 4.06, 95% CI: 1.90 ~ 8.66, P < 0.001). Conclusion: The combined effect of PNPLA3 and UGT1A1 gene polymorphisms can significantly increase the risk of NAFLD in children, providing new evidence for elucidating the genetic susceptibility to NAFLD.