Children with elevated liver enzymes are occasionally discovered through laboratory work-up from different clinical scenarios. Although the majority will have transient and/or benign conditions, a subgroup will have underlying liver disorders. The differential diagnosis is broad and therefore, a systematic approach is of utmost importance. In this article, we reviewed the most recent and relevant literature to provide a comprehensive overview of the main disease processes that cause hypertransaminasemia in children. Ultimately, we propose a practical stepwise approach to guide primary care physicians in the evaluation of abnormal liver enzymes in asymptomatic children. The first step is to obtain a complete history along with a thorough physical examination to exclude red flags, which should dictate urgent consultation with a paediatric gastroenterologist or hepatologist.  Conclusion: Hypertransaminasemia is a challenging scenario in the primary care setting. The aetiology can be broad, ranging from hepatic and extrahepatic to transient versus chronic liver disease. Timely referral to a specialised centre is of paramount importance for conducting targeted research and to not miss the chance of identifying a progressive, but still asymptomatic, treatable liver disease. What is Known: • Elevated liver enzyme is a challenging scenario in the primary care setting. • There are few studies guiding the evaluation of asymptomatic hypertransaminasemia in the paediatric population and a standardised approach is lacking. What is New: • We propose a practical stepwise approach to guide primary care physicians in the evaluation of abnormal liver enzymes.

Pediatric acute liver failure (PALF) is a rare, rapidly progressive clinical syndrome with significant morbidity and mortality. The phenotype of PALF manifests as abrupt onset liver dysfunction, which can be brought via disparate etiology. Management is reliant upon intensive clinical care and support, often provided by the collaborative efforts of hepatologists, critical care specialists, and liver transplant surgeons. The construction of an age-based diagnostic approach, the identification of a potential underlying cause, and the prompt implementation of appropriate therapy can be lifesaving; however, the dynamic and rapidly progressive nature of PALF also demands that diagnostic inquiries be paired with monitoring strategies for the recognition and treatment of common complications of PALF. Although liver transplantation can provide a potential life-saving therapeutic option, the ability to confidently determine the certainness that liver transplant is needed for an individual child has been hampered by a lack of adequately tested clinical decision support tools and accurate predictive models. Given the accelerated progress in understanding PALF, we will provide clinical guidance to pediatric gastroenterologists and other pediatric providers caring for children with PALF by presenting the most recent advances in diagnosis, management, pathophysiology, and associated outcomes.

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.

Neonatal cholestasis (NC) is one of the most serious diseases in newborns and infants and results from metabolic disorders, such as Niemann-Pick type C (NPC), among other causes.

We evaluated the incidence of NPC in our NC plus lysosomal storage disease (LSD) suspicious neonates and infants series.

The study included children (≤3 years old) with a history of NC together with a suspicion of LSD, referred from Spanish Hospitals during the period 2011-2020. Screening for NPC was done by plasma biomarker assay (chitotriosidase activity and 7-ketocholesterol), and Sanger sequencing for NPC1 and NPC2 genes.

We screened NPC disease in 17 patients with NC plus organomegaly and that were LSD suspicious, finding 5 NPC patients (29.4%) and 2 carriers.

Our results emphasize the need to study NPC when NC and visceral enlargement arise in a newborn or infant.

Inborn errors of metabolism (IEM), otherwise known as inherited metabolic disorders (IMD), are individually rare, but collectively common. IEM pose a challenge to diagnosis, as neonates present with nonspecific signs. A high index of suspicion is essential. Knowledge on clinical presentation may be life saving, especially for conditions that are treatable. It is important for the first-line physicians not to miss treatable disorders. Simplified classification and algorithmic approach help in the clinical setting. This article describes the classification of IEM into three groups, namely group 1 - intoxication disorders, group 2 - energy defects, and group 3 - storage disorders. Clinical presentations of IEM in the neonatal period, a quick guide to the diagnosis with the help of baseline investigations (glucose, arterial blood gas, lactate, ammonia, and ketone abbreviated as GALAK), a tabulated guide to the diagnosis with the help of tandem mass spectrometry (TMS), and gas chromatography and mass spectrometry (GCMS) are summarized in this article. Four principles of therapy that include substrate reduction, provision of deficient metabolites, disposal of toxic metabolites, and increase in enzyme activity are elaborated with particular stress to the diet management. In addition, a list of medications used in the treatment of different disorders classified according to Society for the Study of IEM (SSIEM) is presented.

Despite the recent advances involving molecular studies, the neonatal cholestasis (NC) diagnosis still relays on the expertise of medical teams. Our aim was to develop models of etiological diagnosis and unfavourable prognosis which may support a rationale diagnostic approach. We retrospectively analysed 154 patients born between January 1985 and October 2019. The cohort was divided into two main groups: (A) transient cholestasis and (B) other diagnosis (with subgroups) and also in two groups of outcomes: (I) unfavourable and (II) favourable. Multivariate logistic regression analysis identified the lower gestational age as the only variable independently associated with an increased risk of transient cholestasis and signs and/or symptoms of sepsis with infectious or metabolic diseases. Gamma-glutamyl transferase serum levels > 300 IU/L had a positive predictive value for both diagnosis of biliary atresia and for alpha-1-antitrypsin deficiency (A1ATD) and for unfavourable prognosis. A model of diagnosis for A1ATD (n = 34) showed an area under the ROC curve = 0.843 [confidence interval (CI): 0.773-0.912].Conclusion: This study identified some predictors of diagnosis and prognosis which helped to build a diagnostic decision algorithm. The unusually large subgroup of patients with A1ATD in this cohort emphasizes its predictive diagnostic model. What Is Known • The etiological diagnosis of neonatal cholestasis (NC) requires a step-by-step guided approach, and diagnostic models have been developed only for biliary atresia. • Current algorithms neither address the epidemiology changes nor the application of the new molecular diagnostic tools. What Is New • This study provides diagnostic predictive models for patients with A1ATD, metabolic/infectious diseases, and transient cholestasis, and two models of unfavourable prognosis for NC. • A diagnostic decision algorithm is proposed based on this study, authors expertise and the literature.

Acute liver failure is a condition that is defined as a sudden, complete, or nearly complete loss of liver functions without any previous liver disease, usually accompanied by encephalopathy, which can be reversible, but with a mortality rate of 55-70%. Acute liver failure newborns is an acute liver failure in the first 28 days of life. The Pediatric Acute Liver Failure Working Group identified the presence of coagulopathy as the main finding for the identification of acute liver failure in childhood following vitamin K administration. Although the incidence of acute liver failure is reported to be 17/100 000 in all ages, its incidence is not known exactly in newborn and childhood. The most common cause of acute liver failure in the newborn period is the gestational alloimmune liver disease that was previously known as neonatal hemochromatosis. This is followed by viral infections, metabolic diseases, hemophagocytic lymphohistiocytosis, and other rare causes. In the neonatal period, acute liver failure is a rare condition with a high mortality rate. For this reason, the vital signs of the patients should be closely monitored and supportive treatments should be planned according to the follow-up and the etiology of the disease should be clarified urgently. In this process, acyclovir treatment until herpes simplex virus infection is excluded and lactose-free feeding until galactosemia is excluded are recommended as life-saving treatments. In the literature, since there is a limited number of studies related to neonatal acute liver failure, prospective studies investigating the factors affecting treatment and prognosis are needed.

Metabolic disorders in a neonate can present with involvement of any organ system and can be challenging to diagnose. A newborn can present with an acute metabolic crisis such as hyperammonemia or seizures needing immediate management, with a more chronic clinical picture such as cholestatic liver disease, or with structural abnormalities such as skeletal manifestations. Early detection of treatable metabolic conditions is important to improve outcomes. Newborn screening has facilitated early detection and initiation of therapy for many metabolic disorders. However, normal testing does not rule out a metabolic disorder and a high index of suspicion should remain when caring for any critically ill neonate without a diagnosis. Whole exome sequencing (WES) or whole genome sequencing (WGS) can be powerful tools in rapid diagnosis of a potentially treatable metabolic condition in a critically ill neonate. This review presents classic clinical presentations of neonatal metabolic disorders and also highlights some uncommon neonatal manifestations of metabolic disorders to improve the recognition and diagnosis of these conditions.

Introduction: In the last two decades there have been advances in the diagnosis and management of neonatal cholestasis, which may have changed its epidemiology, diagnostic accuracy, outcomes, and survival. Our goal was to characterize these changes over time in our setting. Methods: Retrospective cohort study in a tertiary center, enrolling patients born between January 1985 and October 2019. The cohort was divided into two periods, before (A; n = 67) and after (B; n = 87) the year 2000; and in two groups, according to patient's outcome (favorable, unfavorable). Overall survival and survival with and without orthotopic liver transplant (OLT) were evaluated in the two periods (A and B) and in different subgroups of underlying entities. Results: We found that the age of cholestasis recognition decreased significantly from period A to period B [median 43 days and 22 days, respectively, (p < 0.001)]; the changes in epidemiology were relevant, with a significant decrease in alpha-1-antitrypsin deficiency (p < 0.001) and an increase in transient cholestasis (p = 0.004). A next-generation sequencing (NGS) panel available since mid-2017 was applied to 13 patients with contributory results in 7, but, so far, only in 2 patients led to conclusive diagnosis of underlying entities. The number of cases of idiopathic cholestasis did not vary significantly. Over time there was no significant change in the outcome (p = 0.116). Overall survival and survival without OLT had no significant improvement during the period of observation (in periods A and B, 86 vs. 88%, and 85 vs. 87%, respectively). However, in period B, with OLT we achieved the goal of 100% of survival rate. Conclusions: Our data suggest that transient cholestasis became a very important subset of neonatal cholestasis, requiring specific guidance. The NGS panels can provide important inputs on disease diagnosis but, if applied without strict criteria and expertise, they can open a Pandora's box due to misinterpretation. Despite all the advances in accurate diagnosis and timely management-including early recognition of cholestasis-the improvement in patient outcomes and survival were still not significant.