Obesity-related non-alcoholic fatty liver disease (NAFLD) represents the most common cause of pediatric liver disease due to overweight/obesity large-scale epidemics. In clinical practice, diagnosis is usually based on clinical features, blood tests, and liver imaging. Here, we underline the need to make a correct differential diagnosis for a number of genetic, metabolic, gastrointestinal, nutritional, endocrine, muscular, and systemic disorders, and for iatrogenic/viral/autoimmune hepatitis as well. This is all the more important for patients who are not in the NAFLD classical age range and for those for whom a satisfactory response of liver test abnormalities to weight loss after dietary counseling and physical activity measures cannot be obtained or verified due to poor compliance. A correct diagnosis may be life-saving, as some of these conditions which appear similar to NAFLD have a specific therapy. In this study, the characteristics of the main conditions which require consideration are summarized, and a practical diagnostic algorithm is discussed.

Pediatric obesity management strategies suffer from a high rate of dropout and persistence of weight excess, despite the use of new tools, such as automated mobile technology (MT). We aimed to compare the efficacy of two 6-month personalized MT protocols in terms of better engagement, adherence to follow-up visits and improved anthropometric and lifestyle parameters. MT contacts consisted of three personalized/not automated What’s App® self-monitoring or challenge messages per week. Messages, sent by a dedicated coach were inserted between three-monthly in-presence regular visits with (PediaFit 1.2) or without (PediaFit 1.1) monthly free-of charge short recall visits carried out by a specialized pediatric team. The sample included 103 children (mean age 10 years, range 6–14) recruited in the Pediatric Obesity Clinic between January 2017 and February 2019, randomized into Intervention group (IG) (n = 24 PediaFit 1.1; n = 30 PediaFit 1.2) and Control group (CG) (total n = 49). Controls received standard treatment only (indications for healthy nutrition and physical activity, and three months in presence regular visits). Overall, both IGs achieved significantly better results than the CGs for all considered parameters. Comparison of the two IGs at the sixth month in particular showed an IG 1.2 statistically significantly lower drop-out rate (10% vs. 62%, p = 0.00009), along with significantly improved BMI (p = 0.003), Screen Time (p = 0.04) and fruit and vegetables consumption (p = 0.02). The study suggests that the hybrid association of messaging through personalized/not automated MT plus monthly free-of charge recall visits may improve the prefixed outcomes of MT weight loss intervention programs.

The term non-alcoholic fatty liver disease (NAFLD) appears unfitting both in adults and in children. As obesity and metabolic syndrome play a relevant pathogenic role, an international group of adults’ liver disease experts has proposed to rename this condition metabolic (dysfunction)-associated fatty liver disease (MAFLD). While this new more appropriate and useful definition has mostly been met with good reactions in adults, it may present a tangled path in pediatrics. Here we further stress the recommendations of the North American and the European Societies for Pediatric Gastroenterology, Hepatology and Nutrition that a hyperechogenic liver in a child affected by obesity or overweight with chronically elevated liver enzymes should not be assumed to have NAFLD only. Especially in those patients who are not in the classic age range or who have particularly severe laboratory anomalies, other genetic, metabolic (inborn errors of metabolism, IEM), endocrine, intestinal and hepatic pediatric-onset conditions, should in fact be excluded, particularly when response to a weight loss trial is not available. The term pediatric fatty liver disease (PeFLD) with three subtypes (1. contextual diagnosis of an IEM; 2. Metabolic (dysfunction)-associated fatty liver; 3. unknown cause of fatty liver) has recently been proposed aiming to separate true MAFLD from IEM and/or the other above mentioned conditions, which may be rare when considered individually but represent a large group when considered collectively. Although the cost-effectiveness ratio of this attitude is still indeterminate, it is likely that the advantage of the early identification of a specifically treatable pediatric-onset liver disease associated to/mimicking MAFLD would be rewarding.

Odevixibat, an ileal bile acid transporter (IBAT) inhibitor, is effective for the treatment of pruritus in children diagnosed with progressive familial intrahepatic cholestasis (PFIC) type 1 and 2. There are no studies showing the efficacy of Odevixibat in children with different subtypes of PFIC. We describe the case of a 6-year-old girl with chronic cholestatic jaundice. In the last 12 months laboratory data showed high serum levels of bilirubin (total bilirubin x 2.5 ULN; direct bilirubin x 1.7 ULN) and bile acids (sBA x 70 ULN), elevated transaminases (x 3–4 ULN), and preserved synthetic liver function. Genetic testing showed homozygous mutation in ZFYVE19 gene, which is not included among the classic causative genes of PFIC and determined a new non-syndromic phenotype recently classified as PFIC9 (OMIM # 619849). Due to the persistent intensity of itching [score of 5 (very severe) at the Caregiver Global Impression of Severity (CaGIS)] and sleep disturbances not responsive to rifampicin and ursodeoxycholic acid (UDCA), Odevixibat treatment was started. After treatment with odevixibat we observed: (i) reduction in sBA from 458 to 71 μmol/L (absolute change from baseline: −387 μmol/L), (ii) reduction in CaGIS from 5 to 1, and (iii) resolution of sleep disturbances. The BMI z-score progressively increased from −0.98 to +0.56 after 3 months of treatment. No adverse drug events were recorded. Treatment with IBAT inhibitor was effective and safe in our patient suggesting that Odevixibat may be potentially considered for the treatment of cholestatic pruritus also in children with rare subtypes of PFIC. Further studies on a larger scale could lead to the increasing of patients eligible for this treatment.

Background ZFYVE19 (Zinc Finger FYVE-Type Containing 19) mutations have most recently been associated to a novel type of high gamma-glutamyl transpeptidase (GGT), non-syndromic, neonatal-onset intrahepatic chronic cholestasis possibly associated to cilia dysfunction. Herein, we report a new case with further studies of whole exome sequencing (WES) and immunofluorescence in primary cilia of her cultured fibroblasts which confirm the observation. Results A now 5-year-old girl born to clinically healthy consanguineous Moroccan parents was assessed at 59 days of life due to severe cholestatic jaundice with increased serum bile acids and GGT, and preserved hepatocellular synthetic function. Despite fibrosis/cirrhosis and biliary ducts proliferation on liver biopsy suggested an extrahepatic biliary obstacle, normal intra-operatory cholangiography excluded biliary atresia. Under choleretic treatment, she maintained a clinically stable anicteric cholestasis but developped hyperlipidemia. After exclusion of the main causes of cholestasis by multiple tests, abnormal concentrations of sterols and WES led to a diagnosis of hereditary sitosterolemia (OMIM #618666), likely unrelated to her cholestasis. Further sequencing investigation revealed a homozygous non-sense mutation (p.Arg223Ter) in ZFYVE19 leading to a 222 aa truncated protein and present in both heterozygous parents. Immunofluorescence analysis of primary cilia on cultured skin fibroblasts showed a ciliary phenotype mainly defined by fragmented cilia and centrioles abnormalities. Conclusions Our findings are consistent with and expands the recent evidence linking ZFYVE19 to a novel, likely non-syndromic, high GGT-PFIC phenotype with neonatal onset. Due to the possible role of ZFYVE19 in cilia function and the unprecedented coexistence of a coincidental hereditary sterol disorder in our case, continuous monitoring will be necessary to substantiate type of liver disease progression and/or possible emergence of a multisystemic involvement. What mentioned above confirms that the application of WES in children with undiagnosed cholestasis may lead to the identification of new causative genes, widening the knowledge on the pathophysiology.