Vitamin D (calciferol) is a fat-soluble vitamin that has a significant role in phospho-calcium metabolism, maintaining normal calcium levels and bone health development. The most important compounds of vitamin D are cholecalciferol (vitamin D3, or VD3) and ergocalciferol (vitamin D2, or VD2). Besides its major role in maintaining an adequate level of calcium and phosphate concentrations, vitamin D is involved in cell growth and differentiation and immune function. Recently, the association between vitamin D deficiency and the progression of fibrosis in chronic liver disease (CLD) was confirmed, given the hepatic activation process and high prevalence of vitamin D deficiency in these diseases. There are reports of vitamin D deficiency in CLD regardless of the etiology (chronic viral hepatitis, alcoholic cirrhosis, non-alcoholic fatty liver disease, primary biliary cirrhosis, or autoimmune hepatitis). Vitamin D binding protein (VDBP) is synthesized by the liver and has the role of binding and transporting vitamin D and its metabolites to the target organs. VDBP also plays an important role in inflammatory response secondary to tissue damage, being involved in the degradation of actin. As intense research during the last decades revealed the possible role of vitamin D in liver diseases, a deeper understanding of the vitamin D, vitamin D receptors (VDRs), and VDBP involvement in liver inflammation and fibrogenesis could represent the basis for the development of new strategies for diagnosis, prognosis, and treatment of liver diseases. This narrative review presents an overview of the evidence of the role of vitamin D and VDBP in CLD, both at the experimental and clinical levels.

Acute pancreatitis (AP) is a significant cause of morbidity, even in children, and is frequently associated with systemic manifestations. There are many cytokines involved in the inflammatory response characteristic of this disease. Interleukin 6 (IL-6) is one of the most important cytokines involved in AP, beginning from cellular injury and continuing to the systemic inflammatory response and distant organ involvement. IL-6 is a multifunctional cytokine that regulates acute-phase response and inflammation. It is produced by various cells and exerts its biological role on many cells through its high-affinity complex receptor. IL-6 has been investigated as a predicting maker for severe forms of AP. Many studies have validated the use of IL-6 serum levels in the first 48 h as a reliable marker for severe evolution and multisystemic involvement. Still, it has not been used in daily practice until now. This review discusses the main binding mechanisms by which IL-6 triggers cellular response and the AP pathogenetic mechanisms in which IL-6 is involved. We then emphasize the promising role of IL-6 as a prognostic marker, which could be added as a routine marker at admission in children with AP.

Acute pancreatitis (AP) is an acute-onset gastrointestinal disease characterized by a significant inflammation of the pancreas. Most of the time, AP does not leave substantial changes in the pancreas after the resolution of the symptoms but the severe forms are associated with local or systemic complications. The pathogenesis of AP has long been investigated and, lately, the importance of intracellular mechanisms and the immune system has been described. The initial modifications in AP take place in the acinar cell. There are multiple mechanisms by which cellular homeostasis is impaired, one of the most important being calcium overload. Necrotic pancreatic cells initiate the inflammatory response by secreting inflammatory mediators and attracting immune cells. From this point on, the inflammation is sustained by the involvement of innate and adaptive immune systems. Multiple studies have demonstrated the importance of the first 48 h for identifying patients at risk for developing severe forms. For this reason, there is a need to find new, easy-to-use and reliable markers for accurate predictions of these forms. This review provides an overview of the main pathogenetic mechanisms involved in AP development and the most promising biomarkers for severity stratification.

Vesicoureteral reflux (VUR) is one of the most important disorders encountered in pediatric nephrology due to its frequency and potential evolution to chronic kidney disease (CKD). The aim of our study was to identify noninvasive and easy-to-determine urinary markers to facilitate the diagnosis and staging of VUR. We performed a cross-section study including 39 patients with VUR followed over three years (August 2021–September 2023) and 39 children without urinary disorder (the control group). We measured the urinary concentration of interleukin-6 (IL-6), cathelicidin (LL-37), and neutrophil gelatinase-associated lipocalin (NGAL) in VUR and healthy controls. Moreover, we analyzed the correlation between these biomarkers and the presence of renal scars (RS), reflux nephropathy (RN), and CKD. The NGAL concentrations were significantly higher in patients with VUR than in the controls (p = 0.02). Regarding the severity of the reflux, NGAL/creatinine and LL-37/creatinine were positively correlated with severe reflux (p = 0.04, respectively, p = 0.02). In patients with VUR and RS, LL-37/creatinine was significantly lower (p = 0.01). LL-37/creatinine with an AUC of 0.71 and NGAL/creatinine with an AUC of 0.72 could be acceptable diagnostic tests for severe VUR. In conclusion, urinary IL-6, NGAL, and LL-37 could serve as valuable markers for diagnosing and predicting outcomes in patients with VUR and RN.

Cholangiopathies are defined as focal or extensive damage of the bile ducts. According to the pathogenetic mechanism, it may be immune-mediated or due to genetic, infectious, toxic, vascular, and obstructive causes. Their chronic evolution is characterized by inflammation, obstruction of bile flow, cholangiocyte proliferation, and progression toward fibrosis and cirrhosis. Immune-mediated cholangiopathies comprise primary sclerosing cholangitis (PSC), autoimmune cholangitis and IgG4-associated cholangitis in adults and biliary atresia (BA), neonatal sclerosing cholangitis (NSC) in children. The main purpose of this narrative review was to highlight the similarities and differences among immune-mediated cholangiopathies, especially those frequent in children in which cholangiocyte senescence plays a key role (BA, NSC, and PSC). These three entities have many similarities in terms of clinical and histopathological manifestations, and the distinction between them can be hard to achieve. In BA, bile duct destruction occurs due to aggression of the biliary cells due to viral infections or toxins during the intrauterine period or immediately after birth. The consequence is the activation of the immune system leading to severe inflammation and fibrosis of the extrahepatic biliary tract, lumen stenosis, and impairment of the biliary flow. PSC is characterized by inflammation and fibrosis of intra- and extrahepatic bile ducts, leading to secondary biliary cirrhosis. It is a multifactorial disease that occurs because of genetic predisposition [human leukocyte antigen (HLA) and non-HLA haplotypes], autoimmunity (cellular immune response, autoantibodies, association with inflammatory bowel disease), environmental factors (infections or toxic bile), and host factors (intestinal microbiota). NSC seems to be a distinct subgroup of childhood PSC that appears due to the interaction between genetic predisposition (HLA B8 and DR3) and the disruption of the immune system, validated by elevated IgG levels or specific antibodies [antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA)]. Currently, the exact mechanism of immune cholangiopathy is not fully understood, and further data are required to identify individuals at high risk of developing these conditions. A better understanding of the immune mechanisms and pathophysiology of BA, NSC, and PSC will open new perspectives for future treatments and better methods of preventing severe evolution.

Background and aim: Multisystemic inflammatory syndrome in children (MIS-C) is a rare and severe condition associated with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) infection in children with onset approximately 4–6 weeks after infection. To date, the precise mechanism that causes MIS-C is not known and there are many questions related to the etiology, risk factors, and evolution of this syndrome. We aimed to describe the clinical manifestations, treatment methods, and disease evolution and analyze the main risk factors for MIS-C in children hospitalized in our clinic. Material and methods: We performed a retrospective study including children with MIS-C followed-up in the 2nd Pediatric Clinic of the Emergency Clinical Hospital for Children Cluj-Napoca, Romania, for 13 months (November 2020–December 2021). Results: We included in our cohort 34 children (mean age 6.8 ± 4.6 years) who met MIS-C criteria: high and prolonged fever associated with organ dysfunction (heart, lungs, kidneys, brain, skin, eyes, bone marrow or gastrointestinal organs), and autoantibodies and/or polymerase chain reaction positives for SARS-CoV-2. Nineteen patients (55.88%) had a severe form of the disease, with multiorgan failure and shock, and myocardial or respiratory failure. The number of organs affected in the severe forms was significantly higher (more than 6 in 73.70%) than in mild forms (2–3 in 60%). Cardiac dysfunction, hypoalbuminemia, hypertriglyceridemia and hyponatremia were more important in severe forms of MIS-C. These patients required respiratory support, resuscitation with fluid boluses, vasoactive drugs, or aggressive therapy. All patients with mild forms had fully recovered compared to 63.16% in severe forms. The others with severe forms developed long-term complications (dilation of the coronary arteries, premature ventricular contraction, or myocardial fibrosis). Two patients had an extremely severe evolution. One is still waiting for a heart transplant, and the other died (hemophagocytic lymphohistiocytosis syndrome with multiorgan failure). Conclusions: From mild to severe forms with multiorgan failure, shock, and many other complications, MIS-C represents a difficult challenge for pediatricians, who must be aware of the correct diagnosis and unpredictable, possibly severe evolution.