Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children, but diagnosis is challenging due to limited availability of noninvasive biomarkers. Machine learning applied to high‐resolution metabolomics and clinical phenotype data offers a novel framework for developing a NAFLD screening panel in youth. Here, untargeted metabolomics by liquid chromatography–mass spectrometry was performed on plasma samples from a combined cross‐sectional sample of children and adolescents ages 2‐25 years old with NAFLD (n = 222) and without NAFLD (n = 337), confirmed by liver biopsy or magnetic resonance imaging. Anthropometrics, blood lipids, liver enzymes, and glucose and insulin metabolism were also assessed. A machine learning approach was applied to the metabolomics and clinical phenotype data sets, which were split into training and test sets, and included dimension reduction, feature selection, and classification model development. The selected metabolite features were the amino acids serine, leucine/isoleucine, and tryptophan; three putatively annotated compounds (dihydrothymine and two phospholipids); and two unknowns. The selected clinical phenotype variables were waist circumference, whole‐body insulin sensitivity index (WBISI) based on the oral glucose tolerance test, and blood triglycerides. The highest performing classification model was random forest, which had an area under the receiver operating characteristic curve (AUROC) of 0.94, sensitivity of 73%, and specificity of 97% for detecting NAFLD cases. A second classification model was developed using the homeostasis model assessment of insulin resistance substituted for the WBISI. Similarly, the highest performing classification model was random forest, which had an AUROC of 0.92, sensitivity of 73%, and specificity of 94%. Conclusion: The identified screening panel consisting of both metabolomics and clinical features has promising potential for screening for NAFLD in youth. Further development of this panel and independent validation testing in other cohorts are warranted.

Background: The prevalence and incidence of youth‐onset nonalcoholic fatty liver disease (NAFLD) far exceeds other paediatric chronic liver diseases and represents a considerable public health issue globally.Methods: Here, we performed a narrative review of current knowledge regarding the epidemiology of paediatric NAFLD, selected concepts in pathogenesis, comorbidities, diagnosis, and management, and issues related to the transition to adulthood.Results: Paediatric NAFLD has become increasingly more prevalent, especially in certain subgroups, such as children with obesity and certain races/ethnicities. The pathophysiology of paediatric NAFLD is complex and multifactorial, driven by an interaction of environmental and genetic factors. Once developed, NAFLD in childhood is associated with type 2 diabetes, hypertension, increased cardiovascular disease risk, and end‐stage liver disease. This predicts an increased burden of morbidity and mortality in adolescents and young adults. Early screening and diagnosis are therefore crucial, and the development of noninvasive biomarkers remains an active area of investigation. Currently, treatment strategies are focused on lifestyle changes, but there is also research interest in pharmacological and surgical options. In the transition from paediatric to adult care, there are several potential challenges/barriers to treatment and research is needed to understand how best to support patients during this time.Conclusions: Our understanding of the epidemiology and pathophysiology of paediatric NAFLD has increased considerably over recent decades, but several critical knowledge gaps remain and must be addressed in order to better mitigate the short‐term and long‐term risks of youth‐onset NAFLD.

Purine nucleosides and nucleotides are released in the extracellular space following cell injury and act as paracrine mediators through a number of dedicated membrane receptors. In particular, extracellular ATP (eATP) significantly influences T-lymphocyte activation and phenotype. The purpose of this review is to discuss the role of ATP signaling in the T-cell-mediated alloimmune response. In various animal models of solid transplantation, the purinergic axis has been targeted to prevent acute rejection and to promote long-term graft tolerance. The inhibition of ATP-gated P2X receptors has been shown to halt lymphocyte activation, to downregulate both Th1 and Th17 responses and to promote T-regulatory (Treg) cell differentiation. Similarly, the inhibition of ATP signaling attenuated graft-versus-host disease in mice undergoing hematopoietic cell transplantation. Significantly, different drugs targeting the purinergic system have been recently approved for human use and may be a viable therapeutic option for transplant patients. The inhibition of eATP signaling downregulates the alloimmune response, expands Treg cells and promotes graft survival. This robust preclinical evidence and the recent advances in pharmacological research may lead to intriguing clinical applications.

Hematopoietic stem and progenitor cells (HSPCs) are multipotent stem cells that have been harnessed as a curative therapy for patients with hematological malignancies. Notably, the discovery that HSPCs are endowed with immunoregulatory properties suggests that HSPC-based therapeutic approaches may be used to treat autoimmune diseases. Indeed, infusion with HSPCs has shown promising results in the treatment of type 1 diabetes (T1D) and remains the only “experimental therapy” that has achieved a satisfactory rate of remission (nearly 60%) in T1D. Patients with newly diagnosed T1D have been successfully reverted to normoglycemia by administration of autologous HSPCs in association with a non-myeloablative immunosuppressive regimen. However, this approach is hampered by a high incidence of adverse effects linked to immunosuppression. Herein, we report that while the use of autologous HSPCs is capable of improving C-peptide production in patients with T1D, ex vivo modulation of HSPCs with prostaglandins (PGs) increases their immunoregulatory properties by upregulating expression of the immune checkpoint-signaling molecule PD-L1. Surprisingly, CXCR4 was upregulated as well, which could enhance HSPC trafficking toward the inflamed pancreatic zone. When tested in murine and human in vitro autoimmune assays, PG-modulated HSPCs were shown to abrogate the autoreactive T cell response. The use of PG-modulated HSPCs may thus provide an attractive and novel treatment of autoimmune diabetes.