Interplay between metabolic dysfunction-associated fatty liver disease and renal function: An intriguing pediatric perspective

Over recent years,the nomenclature of non-alcoholic fatty liver disease has undergone significant changes.Indeed,in 2020,an expert consensus panel proposed the term“Metabolic(dysfunction)associated fatty liver disease”(MAFLD)to underscore the close association of fatty liver with metabolic abnormalities,thereby highlighting the cardiometabolic risks(such as metabolic syndrome,type 2 diabetes,insulin resistance,and cardiovascular disease)faced by these patients since childhood.More recently,this term has been further replaced with metabolic associated steatotic liver disease.It is worth noting that emerging evidence not only supports a close and independent association of MAFLD with chronic kidney disease in adults but also indicates its interplay with metabolic impairments.However,comparable pediatric data remain limited.Given the progressive and chronic nature of both diseases and their prognostic cardiometabolic implications,this editorial aims to provide a pediatric perspective on the intriguing relationship between MAFLD and renal function in childhood.

From the liver to the heart: Cardiac dysfunction in obese children with non-alcoholic fatty liver disease

In the last decades the prevalence of non-alcoholic fatty liver disease(NAFLD) has increased as a consequence of the childhood obesity world epidemic. The liver damage occurring in NAFLD ranges from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Recent findings reported that fatty liver disease is related to early atherosclerosis and cardiac dysfunction even in the pediatric population. Moreover, some authors have shown an association between liver steatosis and cardiac abnormalities, including rise in left ventricular mass, systolic and diastolic dysfunction and epicardial adipose tissue thickness. In this editorial, we provide a brief overview of the current knowledge concerning the association between NAFLD and cardiac dysfunction.

Pediatric non-alcoholic fatty liver disease and kidney function: Effect of HSD17B13 variant

BACKGROUND Growing evidence supports a genetic link between non-alcoholic fatty liver disease(NAFLD)and chronic kidney disease(CKD).Interesting data demonstrated that both the major NAFLD risk polymorphisms such as the I148M polymorphism in the patatin like phospholipase containing domain 3(PNPLA3)and the E167K allele in the transmembrane 6 superfamily member 2 gene(TM6SF2)affect renal function.Recently the hydroxysteroid 17-beta dehydrogenase 13(HSD17B13)gene has been recognized as a novel genetic variant involved in NAFLD pathophysiology.In particular,it has been showed the protective effect of the rs72613567:TA variant of this gene against liver damage both in adults and children.AIM To investigate the impact of the rs72613567:TA variant of the HSD17B13 gene on estimated glomerular filtration rate(eGFR)in obese children.METHODS We enrolled 684 obese children(mean age 10.56±2.94 years;mean BMI-SDS 2.98±0.78)consecutively attending our Obesity Clinic.All the patients underwent a careful clinical assessment and a comprehensive biochemical evaluation.To detect hepatic steatosis,a liver ultrasound was performed.NAFLD was defined by ultrasound detected liver steatosis and/or alanine aminotransferase(ALT)levels>40 IU/L.The study population was divided on the basis of the NAFLD presence.Genotyping for the rs72613567:TA variant of the HSD17B13 gene in all the enrolled subjects was also made.RESULTS Patients carrying the HSD17B13 rare A allele showed higher eGFR levels compared with homozygous patients both among subjects with and without NAFLD.A general linear model confirmed a direct and significant association of eGFR values with HSD17B13 genotype independently of PNPLA3 and TM6SF2 polymorphisms both in patients with and without NAFLD.A comparison of regression line confirmed the influence of HSD17B13 genotype on the relationship between eGFR and age both among patients with and without NAFLD.H omozygous patients for HSD17B13 genotype with NAFLD showed a significantly higher decline of eGFR with the increase of the age compared with the patients with NAFLD carrying the HSD17B13 rare A allele(P value for intercepts=0.005;P value for slopes=0.94).The same effect was observed among patients without NAFLD(P value for intercepts=0.0012;P value for slopes=0.87).CONCLUSION Carriers of the HSD17B13 rare A allele showed higher eGFR levels than homozygous subjects both among subjects with and without NAFLD and independently of PNPLA3 I148M and TM6SF6 E167K polymorphisms.

Advances in paediatric nonalcoholic fatty liver disease:Role of lipidomics

Due its close relationship with obesity,nonalcoholic fatty liver disease(NAFLD)has become a major worldwide health issue even in childhood.The most accepted pathophysiological hypothesis is represented by the“multiple hits”theory,in which both hepatic intracellular lipid accumulation and insulin resistance mainly contribute to liver injury through several factors.Among these,lipotoxicity has gained particular attention.In this view,the pathogenic role of different lipid classes in NAFLD(e.g.,sphingolipids,fatty acids,ceramides,etc.)has been highlighted in recent lipidomics studies.Although there is some contrast between plasma and liver findings,lipidomic profile in the NAFLD context provides novel insights by expanding knowledge in the intricate field of NAFLD pathophysiology as well as by suggesting innovative therapeutic approaches in order to improve both NAFLD prevention and treatment strategies.Selective changes of distinct lipid species might be an attractive therapeutic target for treating NAFLD.Herein the most recent evidence in this attractive field has been summarized to provide a comprehensive overview of the lipidomic scenario in paediatric NAFLD.

Relationship between nonalcoholic fatty liver disease and chronic kidney disease could start in childhood

The relationship between nonalcoholic fatty liver disease(NAFLD)and chronic kidney disease(CKD)has gained considerable scientific interest in adults over the past few years.However,this association has recently emerged in children.Several published studies have suggested a role for NAFLD as a risk factor for CKD from the earliest age,with a potential influence of the major NAFLD risk polymorphisms,resulting in an increased risk of both cardiovascular and metabolic diseases.In view of the progressive course and increased cardiometabolic risk closely related to NAFLD and CKD,we focused on the link between these diseases in childhood.

Telemedicine in the COVID-19 era:Taking care of children with obesity and diabetes mellitus

Severe acute respiratory syndrome coronavirus 2 infection was declared a pandemic in January 2020.Since then,several measures to limit virus transmission have been imposed;among them,home confinement has been the most severe,with drastic changes in the daily routines of the general population.The“stay at home”rule has impaired healthcare service access,and patients with chronic conditions were the most exposed to the negative effects of this limitation.There is strong evidence of the worsening of obesity and diabetes mellitus in children during this period.To overcome these issues,healthcare providers have changed their clinical practice to ensure follow-up visits and medical consultation though the use of telemedicine.Telemedicine,including telephone calls,videocalls,data platforms of shared telemedicine data platforms mitigated the negative effect of pandemic restrictions.Published evidence has documented good metabolic control and weight management outcomes in centers that performed extensive telemedicine services last year during the pandemic.This review discusses studies that investigated the use of telemedicine tools for the management of pediatric obesity and diabetes.

COVID-19 and pediatric fatty liver disease:Is there interplay?

The rapid global spread of coronavirus disease 2019(COVID-19)infection has become a major health issue with higher morbidity and mortality rates.Besides respiratory symptoms,a growing body of evidence indicates a variety of gastrointestinal manifestations including liver involvement.In this regard,several data supported an association between COVID-19 infection and liver injury in adults,while in children there is compelling but currently limited evidence.In particular,patients with COVID-19 have shown a higher risk of liver injury(mainly expressed as increased transaminase levels or hepatic steatosis).Conversely,a greater risk of more severe forms of COVID-19 infection has been observed in subjects with pre-existing chronic liver diseases.The dramatic interplay between COVID-19 and liver damage has been related to the inflammatory pathways chronically active in patients with nonalcoholic fatty liver disease and acutely in those affected by COVID-19,but other different pathogenic mechanisms have also been supposed.Of note,patients with previous metabolic comorbidities also had a higher risk of severe COVID-19 infection.This emphasizes the pathogenic interrelation of the inflammatory pathways with a dysregulated metabolic milieu in COVID-19 patients.Taking into account the prognostic role of fatty liver in COVID-19 patients and its intrinsic relationship with metabolic abnormalities even in childhood,a strict monitoring of this condition is recommended.We aimed to summarize the most recent evidence regarding the potential interplay between pediatric fatty liver and COVID-19.

Metabolic-associated fatty liver disease from childhood to adulthood:State of art and future directions

In 2020,an international group of experts proposed to replace the term of nonalcoholic fatty liver disease with metabolic-associated fatty liver disease(MAFLD).This recent proposal reflects the close association of fatty liver with metabolic derangements,as demonstrated by previous robust data.Several factors[including genetics,inflammation,metabolic abnormalities,insulin resistance(IR),obesity,prenatal determinants,and gut–liver axis]have been found to be involved in MAFLD pathophysiology,but this tangled puzzle remains to be clearly understood.In particular,IR has been recognized as a key player in metabolic impairments development in children with fatty liver.On this ground,MAFLD definition focuses on the pathophysiological basis of the disease,by emphasizing the crucial role of metabolic impairments in this condition.Although primarily developed for adults,MAFLD diagnostic criteria have been recently updated with an age-appropriate definition for sex and age percentiles,because of the increasing attention to cardiometabolic risk in childhood.To date,accumulating evidence is available on the feasibility of MAFLD definition in clinical practice,but some data are still conflicting in highly selected populations.Considering the growing prevalence worldwide of fatty liver and its close relationship with metabolic dysfunction both in children and adults with subsequent increased cardiovascular risk,early strategies for MAFLD identification,treatment and prevention are needed.Novel therapeutic insights for MAFLD based on promising innovative biological techniques are also emerging.We aimed to summarize the most recent evidence in this intriguing research area both in children and adults.

Advances in pediatric non-alcoholic fatty liver disease: From genetics to lipidomics

As a result of the obesity epidemic,non-alcoholic fatty liver disease(NAFLD)represents a global medical concern in childhood with a closely related increased cardiometabolic risk.Knowledge on NAFLD pathophysiology has been largely expanded over the last decades.Besides the well-known key NAFLD genes(including the I148M variant of the PNPLA3 gene,the E167K allele of the TM6SF2,the GCKR gene,the MBOAT7-TMC4 rs641738 variant,and the rs72613567:TA variant in the HSD17B13 gene),an intriguing pathogenic role has also been demonstrated for the gut microbiota.More interestingly,evidence has added new factors involved in the“multiple hits”theory.In particular,omics determinants have been highlighted as potential innovative markers for NAFLD diagnosis and treatment.In fact,different branches of omics including metabolomics,lipidomics(in particular sphingolipids and ceramides),transcriptomics(including micro RNAs),epigenomics(such as DNA methylation),proteomics,and glycomics represent the most attractive pathogenic elements in NAFLD development,by providing insightful perspectives in this field.In this perspective,we aimed to provide a comprehensive overview of NAFLD pathophysiology in children,from the oldest pathogenic elements(including genetics)to the newest intriguing perspectives(such as omics branches).

Gut microbiota and COVID-19: An intriguing pediatric perspective

Gastrointestinal(GI)involvement has been reported in approximately 50%of patients with coronavirus disease 2019(COVID-19),which is due to the pathogenic role of inflammation and the intestinal function of the angiotensinconverting enzyme 2 and its receptor.Accumulating adult data has pointed out that gut dysbiosis might occur in these patients with a potential impact on the severity of the disease,however the role of gut microbiota in susceptibility and severity of COVID-19 disease in children is still poorly known.During the last decades,the crosstalk between gut and lung has been largely recognized resulting in the concept of“gut-lung axis”as a central player in modulating the development of several diseases.Both organs are involved in the common mucosal immune system(including bronchus-associated and gut-associated lymphoid tissues)and their homeostasis is crucial for human health.In this framework,it has been found that the role of GI dysbiosis is affecting the homeostasis of the gutliver axis.Of note,a gut microbiome imbalance has been linked to COVID-19 severity in adult subjects,but it remains to be clarified.Based on the increased risk of inflammatory diseases in children with COVID-19,the potential correlation between gut microbiota dysfunction and COVID-19 needs to be studied in this population.We aimed to summarize the most recent evidence on this striking aspect of COVID-19 in childhood.

Omics era in type 2 diabetes:From childhood to adulthood

Parallel to the dramatic rise of pediatric obesity, estimates reported an increasedprevalence of type 2 diabetes (T2D) already in childhood. The close relationshipbetween obesity and T2D in children is mainly sustained by insulin resistance(IR). In addition, the cardiometabolic burden of T2D including nonalcoholic fattyliver disease, cardiovascular disease and metabolic syndrome is also strictlyrelated to IR. Although T2D pathophysiology has been largely studied in anattempt to improve therapeutic options, molecular mechanisms are still not fullyelucidated. In this perspective, omics approaches (including lipidomics,metabolomics, proteomics and metagenomics) are providing the most attractivetherapeutic options for T2D. In particular, distinct both lipids and metabolites areemerging as potential therapeutic tools. Of note, among lipid classes, thepathogenic role of ceramides in T2D context has been supported by several data.Thus, selective changes of ceramides expression might represent innovativetherapeutic strategies for T2D treatment. More, distinct metabolomics pathwayshave been also found to be associated with higher T2D risk, by providing novelpotential T2D biomarkers. Taken together, omics data are responsible for theexpanding knowledge of T2D pathophysiology, by providing novel insights toimprove therapeutic strategies for this tangled disease. We aimed to summarizethe most recent evidence in the intriguing field of the omics approaches in T2Dboth in adults and children.

Rituximab-induced IgG hypogammaglobulinemia in children with nephrotic syndrome and normal pre-treatment IgG values

BACKGROUND In paediatric patients with complicated nephrotic syndrome(NS), rituximab(RTX) administration can induce persistent IgG hypogammaglobulinemia among subjects showing low basal immunoglobulin G(IgG) levels.AIM To evaluate the effect of RTX on IgG levels and infections in patients with complicated NS and normal basal IgG levels.METHODS We consecutively enrolled all patients with complicated NS and normal basal IgG levels undergoing the first RTX infusion from January 2008 to January 2016. Basal IgG levels were dosed after 6 wk of absent proteinuria and with a maximal interval of 3 mo before RTX infusion. The primary outcome was the onset of IgG hypogammaglobulinemia during the follow-up according to the IgG normal values for age [mean ± standard deviation(SD)].RESULTS We enrolled 20 patients with mean age at NS diagnosis of 4.2 ± 3.3 years. The mean age at the first RTX infusion was 10.9 ± 3.5 years. Eleven out of twenty patients(55%) developed IgG hypogammaglobulinemia. None of these patients showed severe or recurrent infections. Only one patient suffered from recurrent acute otitis media and underwent substitutive IgG infusion. Three patients undergoing only the two "starting doses" experienced normalization of IgG levels. Using Kaplan-Meier analysis, the cumulative proportion of patients free of IgG hypogammaglobulinemia was 57.8% after the first RTX dose, 51.5% after the third dose, 44.1% after the fourth dose, and 35.5% after the fifth dose.CONCLUSION RTX can induce IgG hypogammaglobulinemia in patients with pre-RTX IgG normal values. None of the treated patients showed severe infections.

Tangled relationship between insulin resistance and microalbuminuria in children with obesity

Childhood obesity represents a complex disease with a well-known cardiometabolic burden including fatty liver,type 2 diabetes,metabolic syndrome,and cardiovascular disease.From a pathogenic point of view,insulin resistance(IR)represents the key factor underlying the spectrum of these obesity consequences.As observed in adults,recent data supported the occurrence of microalbuminuria(MA)as marker of early kidney dysfunction and its potential link with cardiometabolic factors also in children with obesity.In fact,a well-documented pathophysiological hypothesis both in adults and children supported an intimate correlation with the major feature of obesity such as IR through the influence of insulin on renal hemodynamics.Based on the clinical and prognostic relevance of this relationship in daily practice(including an increased risk of chronic kidney disease development overtime),more scientific attention needs to be paid to the evaluation of early kidney damage in children with obesity.In this paper,we attempt to address three debated questions regarding the intriguing liaison between IR and MA in children with obesity:(1)What is the prevalence of pediatric MA?(2)What is the state of art of MA in children with obesity?and(3)Is there a link between IR and MA in children with obesity?

Transition process in children with chronic liver diseases:what is the challenging point?

Pediatric chronic liver diseases encompass a wide spectrum of hepatopathies with a relevant health medical and financial burden(1,2).In addition to inherited disorders(e.g.,Alagille syndrome,metabolic disorders,etc.),there are numerous chronic liver conditions including metabolic dysfunction-associated steatotic liver disease(MASLD)and autoimmune liver diseases affecting morbidity,quality of life,and life expectancy of these young patients(3,4).To complicate matters,the exact prevalence of childhood chronic liver diseases is still unknown since their asymptomatic course especially in the early stages but increasing rates are reported worldwide(1,5,6).Moreover,management of these chronic conditions represents a great challenge for clinicians as it requires a lifelong multi-disciplinary approach(1).Worthy of note,advances in the knowledge of pathophysiological mechanisms underlying liver diseases greatly improved their natural history with increased survival rates into adulthood(1,3).Given that,adult hepatologists are increasingly dealing with most of these conditions(3).