Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) and Thyroid Function in Childhood Obesity: A Vicious Circle?

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a multisystem disorder characterized by the presence of fatty liver degeneration associated with excess adiposity or prediabetes/type 2 diabetes or metabolic dysregulation. An intricate relationship between the liver and thyroid has been reported in both health and disease. Simultaneously, there is a strong correlation between obesity and both MAFLD and thyroid dysfunction. In this narrative review, we highlighted the relationship between MAFLD and thyroid function in children and adolescents with obesity in order to explore how thyroid hormones (THs) act as predisposing factors in the onset, progression, and sustainability of MAFLD. THs are integral to the intricate balance of metabolic activities, ensuring energy homeostasis, and are indispensable for growth and development. Regarding liver homeostasis, THs have been suggested to interact with liver lipid homeostasis through a series of processes, including stimulating the entry of free fatty acids into the liver for esterification into triglycerides and increasing mitochondrial ß-oxidation of fatty acids to impact hepatic lipid accumulation. The literature supports a correlation between MAFLD and obesity, THs and obesity, and MAFLD and THs; however, results in the pediatric population are very limited. Even though the underlying pathogenic mechanism involved in the relationship between MAFLD and thyroid function remains not fully elucidated, the role of THs as predisposing factors of MAFLD could be postulated. A potential vicious circle among these three conditions cannot be excluded. Identifying novel elements that may contribute to MAFLD could offer a practical approach to assessing children at risk of developing the condition.

Laparoscopic Cholecystectomy in Children: The Experience of Two Centers Focusing on Indications and Timing in the Era of "New Technologies".

BACKGROUND: In children, laparoscopic cholecystectomy (LC) is now considered the gold standard for gallbladder (GB) removal. In the past, hemolytic disorders associated with cholelithiasis represented the most frequent conditions requiring LC; this is being overtaken by cholelithiasis and biliary conditions in overweight or ex-premature children. AIMS: This study aims to describe current indications and timing for LC in pediatric patients. METHODS: Retrospective study. Data on previous medical therapy, ultrasound, pre- and intraoperative aspects, and histology were collected for patients treated in 2020-2023. RESULTS: In total, 45 patients were enrolled: 15 who underwent urgent surgery and 30 electives. Groups differed in terms of obesity rate, symptoms, ultrasound features, and intraoperative status. The most relevant risk factors for surgical complexity were age and pubertal stage, elevated cholestasis indexes, and gallbladder wall thickness > 3 mm at ultrasound. GB wall thickening ≥3 mm, US Murphy sign, fluid collections, and gallbladder distention on ultrasound correlated with high surgical scores. CONCLUSIONS: Indications for laparoscopic cholecystectomy in children seem to evolve caused by changing characteristics of the pediatric population. Patients with overweight/obesity may develop more complex GB diseases. Asymptomatic patients should be considered for surgery after observation, considering age and/or pubertal maturation when other risk factors are absent.

Fat-Soluble Vitamins Deficiency in Pediatric Cholestasis: A Scoping Review.

BACKGROUND: This review aims to identify the current indications and gaps in the management of fat-soluble vitamins in pediatric patients with cholestasis. METHODS: A comprehensive review of the literature using PubMed, Scopus, Web of Science and Embase was performed. Two authors independently identified the most relevant studies published over the past 20 years up to February 2022, including original papers, narrative reviews, observational studies, clinical trials, systematic reviews and meta-analyses. The literature was screened, and preclinical studies about pathogenetic mechanisms were also included. Keywords searched for each fat-soluble vitamin (A, D, E and K), alone or in combination, were "cholestasis", "chronic liver disease", "biliary atresia", "malnutrition" and "nutritional needs". Studies published prior to the selected time range were searched manually and, when considered relevant, included within the list of references. RESULTS: Eight hundred twenty-six articles were initially screened. From these, 48 studies were selected. A comparison of the recommended methods of supplementation for fat-soluble vitamins was then carried out. The causes of malabsorption were explained and current methods for defining deficiency and monitoring complications were summarized. CONCLUSIONS: According to the literature, children with cholestasis are at a higher risk of fat-soluble vitamin deficiency. Although there are general recommendations, the treatment for vitamin deficiency is not uniformly validated.

Non-syndromic bile duct paucity and non-IgE cow's milk allergy: a case report of challenging nutritional management and maltodextrin intolerance.

BACKGROUND: Cholestasis in extremely premature infants (EPI) constitutes a nutritional challenge and maltodextrins have been reported as a possible strategy for hypoglycaemia. We aim to describe the nutritional management of an EPI with non-syndromic bile duct paucity (NSBDP) and feeding intolerance. CASE PRESENTATION: A patient, born at 27 weeks of gestational age, presented cholestatic jaundice at 20 days of life with a clinical picture of NSBDP. Patient's growth was insufficient with formula rich in medium-chain triglyceride (MCT) and branched-chain amino acids (BCAA). Due to frequent fasting hypoglicemic episodes, maltodextrins supplements were provided. He subsequently presented severe abdominal distension and painful crises, which required hospital admission and withdrawal of maltodextrins. Hypercaloric extensively hydrolysed formula provided weight gain, glycemic control, and parallel improvement in cholestasis. CONCLUSIONS: Our case suggests caution with the use of maltodextrins in infants, especially if premature. Commercial preparations for hepatopatic patients contain higher concentrations of MCTs and BCAAs, but personalized strategies must be tailored to each patient.

Gilbert or Crigler-Najjar syndrome? Neonatal severe unconjugated hyperbilirubinemia with P364L UGT1A1 homozygosity.

BACKGROUND: Several mutations of bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1) have been reported in patients with unconjugated hyperbilirubinemia. Few reports are available about the p.Pro364Leu mutation (P364L, c.1091C > T) in homozygous newborns. We describe the clinical, laboratory and therapeutic approach in two Chinese neonates with severe jaundice, homozygous for the P364L mutation. CASE PRESENTATION: Two Chinese breastfed female infants presented prolonged unconjugated hyperbilirubinemia at the age of 1 month. Total bilirubin was higher than 15 mg/dl (D < 1). An exhaustive etiological work-up to detect possible causes of hyperbilirubinemia (notably hemolytic ones) was negative. The promoter and coding regions of UGT1A1 were amplified by polymerase chain reaction (PCR) from genomic DNA isolated from leukocytes. Both patients resulted homozygous for a variant site within the coding region of the gene in the 4 exon, c.1091C > T, p.Pro364Leu. In front of the persistently high level of unconjugated bilirubin, phototherapy was performed without persistent results. A treatment with phenobarbital was then begun and bilirubin level progressively decreased, with a complete and persistent normalization. The therapy was stopped. CONCLUSION: UGT1A1 enzyme activity associated with the P364L mutation has been described as 35.6% of the wild-type enzyme activity. Photo-therapy and phenobarbital can be useful in front of persistently high level of unconjugated bilirubin. Our cases presented high bilirubin values, overlapping between Gilbert syndrome (GS) and Crigler-Najjar syndrome type II (CNS), but the complete normalization of bilirubin makes GS more likely. Homozygous P364L variant can be associated with severe neonatal unconjugated hyperbilirubinemia in Chinese infants, but jaundice can completely resolve in a few months, contrary to what happens in Crigler-Najjar syndrome type II.

Late-Onset Pyloric Stenosis and Intussusception With Final Diagnosis of Food Proteins' Hypersensitivity in Schaaf-Yang Syndrome: A Case Report.

Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder whose clinical spectrum includes neurodevelopment delay, dysmorphic features, and gastrointestinal symptoms such as feeding difficulties, gastroesophageal reflux, and chronic constipation. Given the small number of patients diagnosed with this syndrome, our aim is to describe novel clinical features that have not yet been reported. The patient we are describing is a 14-year-old male affected by a severe form of SYS. Initial clinical presentation included respiratory distress at birth, feeding difficulties, and neurodevelopmental delay. Since the age of 8 months, he had been tube fed with a semi-elemental formula, and this was well tolerated. At 9 years of age, the pathological mutation (variant p.Val701fs in MAGEL2 gene) associated with SYS was diagnosed. At 13 years of age, he presented severe gastrointestinal symptoms associated to progressive feeding difficulties. He also suffered from recurrent pancreatitis, late-onset pyloric stenosis and intussusception. Histology showed duodenal villous atrophy with a negative serology for celiac disease. Food protein's hypersensitivity was diagnosed and symptoms resolved after starting an elemental formula.

Diagnostic approach to neonatal and infantile cholestasis: A position paper by the SIGENP liver disease working group.

Neonatal and infantile cholestasis (NIC) can represent the onset of a surgically correctable disease and of a genetic or metabolic disorder worthy of medical treatment. Timely recognition of NIC and identification of the underlying etiology are paramount to improve outcomes. Upon invitation by the Italian National Institute of Health (ISS), an expert working grouped was formed to formulate evidence-based positions on current knowledge about the diagnosis of NIC. A systematic literature search was conducted to collect evidence about epidemiology, etiology, clinical aspects and accuracy of available diagnostic tests in NIC. Evidence was scored using the GRADE system. All recommendations were approved by a panel of experts upon agreement of at least 75% of the members. The final document was approved by all the panel components. This position document summarizes the collected statements and defines the best-evidence diagnostic approach to cholestasis in the first year of life.

Liver histology in children with glycogen storage disorders type VI and IX.

BACKGROUND: Glycogen storage diseases (GSD) type VI and IX are caused by liver phosphorylase system deficiencies and the two types are clinically indistinguishable. AIM: As the role of liver biopsy is increasingly questioned, we aim to assess its current value in clinical practice. METHODS: We retrospectively reviewed children with diagnosis of GSD VI and IX at a paediatric liver centre between 2001 and 2018. Clinical features, molecular analysis and imaging were reviewed. Liver histology was reassessed by a single histopatologist. RESULTS: Twenty-two cases were identified (9 type VI, 9 IXa, 1 IXb and 3 IXc). Features at presentation were hepatomegaly (95%), deranged AST (81%), short stature (50%) and failure to thrive (4%). Liver biopsy was performed in 19 patients. Fibrosis varied in GSD IXa with METAVIR score between F1-F3 and ISHAK score of F2-F5. METAVIR score was F2-F3 in GSD VI and F3-F4 in GSD IXc. Hepatocyte glycogenation, mild steatosis, lobular inflammatory activity and periportal copper binding protein staining were also demonstrated. CONCLUSIONS: Although GSD VI and IX are considered clinically mild, chronic histological changes of varying severity could be seen in all liver biopsies. Histopathological assessment of the liver involvement is superior to biochemical parameters, but definitive classification requires a mutational analysis.

Case Report: Early Treatment With Chenodeoxycholic Acid in Cerebrotendinous Xanthomatosis Presenting as Neonatal Cholestasis.

Background: Cerebrotendinous xanthomatosis (CTX) is an inborn disorder of bile acid synthesis which causes progressive accumulation of toxic metabolites in various organs, particularly in brain and tendons. Most cases are diagnosed and treated in the second or third decade of life, when neurological involvement appears. We describe a case of CTX presenting as neonatal cholestasis. Results: The child presented cholestasis at 2 months of life. In the following months jaundice slowly disappeared, with a normalization of bilirubin and aminotransferases, respectively, at 6 and 8 months. A LC-Mass Spectrometry of the urines showed the presence of cholestanepentols glucuronide, which led to the suspicion of cerebrotendinous xanthomatosis. The diagnosis was confirmed by the dosage of cholestanol in serum and the molecular genetic analysis of the CYP27A1 gene. Therapy with chenodeoxycholic acid (CDCA) was started at 8 months and is still ongoing. The child was monitored for 13 years by dosage of serum cholestanol and urinary cholestanepentols. A strictly biochemical and neurological follow up was performed and no sign of neurological impairment was observed. Conclusions: Prompt diagnosis and treatment of CTX presenting as neonatal cholestasis may prevent further neurological impairment.

Pediatric autoimmune liver disease and extra-hepatic immune-mediated comorbidities.

BACKGROUND: Autoimmune liver disease (AILD) includes autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC). AILD is often associated with other extra-hepatic immune-mediated disorders (EDs), but there are few pediatric studies available to date. In this study we evaluated the association between AILD and EDs in our pediatric series. METHODS: In this single centre retrospective study 48 patients (39 AIH and 9 ASC children) were evaluated. Thirty-six children were primarily referred to our Centre for liver disease suspicion, while the remaining twelve had a previous diagnosis of EDs. All the patients were screened for various EDs at AILD diagnosis and yearly during the follow-up. RESULTS: Mean duration of follow-up was 9 years and 1 month. Twenty-two (46%) patients had a diagnosis of EDs. Ulcerative colitis (UC) was the most frequent EDs (9 patients), followed by autoimmune thyroid disease (5 patients) and celiac disease (5 patients). In 7 out of 9 UC patients, ASC was present. CONCLUSIONS: Our study showed a high association (46%) between AILD and EDs. In particular, in 8 out of 9 ASC patients UC was diagnosed (p-value 0.007). It is important to look for EDs in AILD children and, conversely, AILD in EDs children with abnormal liver function tests.

Epilepsy surgery in a liver-transplanted girl with temporal lobe epilepsy and hippocampal sclerosis following PRES with status epilepticus.

INTRODUCTION: Posterior reversible encephalopathy syndrome (PRES) with status epilepticus may occur after liver transplant. This may rarely lead to refractory epilepsy and hippocampal sclerosis (HS). CASE DESCRIPTION: We report the first case of epilepsy surgery in a liver-transplanted patient with refractory temporal lobe epilepsy. A 3-year-old girl underwent liver transplant for congenital biliary atresia. Four days after transplant she manifested PRES with status epilepticus, but she recovered within a couple of weeks. At the age of 5 years she started presenting complex partial seizures, that became refractory to antiepileptic drugs (AED), worsening psychosocial performances. The pre-surgical work-up identified a left HS and temporal pole alterations. A left antero-mesial temporal lobectomy was performed, leading to epilepsy remission and allowing AED withdrawal. CONCLUSION: Drug-resistant temporal lobe epilepsy and HS may occur as sequelae of PRES with status epilepticus related to liver transplant and cyclosporine use. In this setting early epilepsy surgery may reduce the time of chronic exposure to AED and severe illness due to repeated seizures. This option might have additional advantages in the subgroup of epileptic patients with liver transplant, preserving the liver from the potential damage due to multiple AED trials and their interaction with commonly used immunosuppressant drugs.