Alexandra Mititelu

Autoimmune liver diseases (AILD), including autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC), are rare but important causes of chronic liver disease in children. Although HLA-DRB1 alleles have been associated with disease susceptibility, their role in modulating the clinical phenotype and long-term outcome of pediatric AILDs remains incompletely understood. We aimed to characterize the distribution of HLA-DRB1 alleles and genotype combinations and describe the accompanying clinical features in a pediatric AILD cohort. Thirty children diagnosed with AIH-1 (n = 14), AIH-2 (n = 6), or ASC (n = 10) underwent HLA-DRB1 genotyping. Clinical presentation, fibrosis stage, treatment response, and associated autoimmune diseases were retrospectively analyzed. The most frequent alleles copies were HLA-DRB1*03 (n = 15), predominantly identified in AIH, and HLA-DRB1*13 (n = 14), identified in both AIH and ASC. Genotype combinations involving these alleles were observed across a broad spectrum of clinical presentations, fibrosis stages, treatment responses, and extrahepatic autoimmune manifestations. In this small cohort, HLA-DRB1*14-containing genotypes were observed in several patients with severe disease features, including advanced fibrosis, cirrhosis, treatment-refractory disease, and ulcerative colitis. Patients carrying HLA-DRB1*11, HLA-DRB1*15, or HLA-DRB1*16 had favorable hepatic outcomes despite severe initial presentation or associated extrahepatic autoimmune manifestations; however, the number of carriers was small. Clinical features varied among patients carrying different genotype combinations; however, the independent contribution of the accompanying allele could not be assessed. Our findings illustrate marked clinical heterogeneity among children carrying different HLA-DRB1 alleles and genotype combinations. In this exploratory cohort, selected HLA-DRB1 combinations co-occurred with distinct clinical patterns. HLA profiling may have a role in future risk stratification and individualized follow-up of children with AILD, but these observations are hypothesis-generating, they do not support genotype-based clinical management and require validation in larger, multicenter cohorts.

Background: Serum α-tocopherol depends on lipids, so absolute concentrations misclassify vitamin E status in children with chronic liver disease (CLD). The CALIPER program defined lipid-adjusted E:cholesterol (E:C) and E:triglyceride (E:TG) ratios, but their application in mixed-etiology pediatric CLD using immunoassay has not been reported. Methods: Exploratory single-center cross-sectional study of 66 children (observed age range 4 months–17.9 years) with mixed-etiology CLD. Retinol and total vitamin E were measured by ELISA, whereas the CALIPER reference intervals applied here were established for α-tocopherol measured by HPLC; the two platforms are not interchangeable, so every classification reported is an exploratory application of those cutoffs. Vitamin E status was classified by absolute concentration, E:C (n = 15), non-cholestatic (n = 45) and post-transplant (n = 6) groups were compared. Results: Vitamin A was largely preserved (5.2% below WHO). Vitamin E was low in 45.3% by absolute concentration, 62.5% by E:C and 43.8% by E:TG. Of 35 children with a normal absolute vitamin E concentration, 11 (31.4%) were reclassified as low by E:C. Low E:C differed across groups (cholestatic 78.6%, non-cholestatic 63.6%, post-transplant 16.7%; p = 0.030). E:TG was inversely correlated with 25(OH)D (rho = −0.45; p < 0.001). Conclusions: Lipid-adjusted interpretation reclassified a substantial proportion of children whose absolute vitamin E concentration appeared adequate, and the prevalence of a low E:C ratio was lower among post-transplant participants than in the other two groups. In this exploratory cohort, the E:C ratio showed greater potential than the E:TG ratio for lipid-adjusted interpretation of vitamin E status; prospective validation against HPLC-based measurements and established functional indices is required before routine clinical adoption.

Background/Objectives: Pediatric acute pancreatitis (AP) is increasingly recognized as a clinically significant disease, yet Central and Eastern European cohort data remain limited. Acute recurrent pancreatitis (ARP) affects a substantial proportion of these children and may reflect distinct underlying etiologies. This study aimed to characterize the etiological spectrum, disease severity, and hospitalization outcomes of AP and ARP in a pediatric tertiary referral population, and to identify early clinical predictors of severity. Methods: We retrospectively analyzed 63 children hospitalized between 2018 and 2025 with 77 documented episodes of AP. Diagnosis followed INSPPIRE criteria, and severity was graded using the 2017 NASPGHAN classification. Etiologies, clinical presentation, laboratory parameters, imaging findings, and hospitalization length were compared between AP and ARP groups, across severity and etiological complexity categories using appropriate non-parametric and permutation-based methods. Results: Genetic etiologies predominated in ARP (37.0%), whereas idiopathic and infectious causes were more common in first-episode AP (24.0% and 14.0%, respectively; overall p < 0.001). Severity distribution did not differ between AP and ARP, with mild disease accounting for the majority of episodes in both groups. Serum albumin was significantly lower in moderate/severe episodes (p = 0.030). Within the single-episode subgroup, etiological complexity emerged as a significant predictor of prolonged hospitalization, with complex multifactorial or systemic etiologies associated with markedly longer stays than idiopathic or single-factor disease (Welch ANOVA p = 0.007). Conclusions: In this Romanian pediatric cohort, genetic causes dominate ARP, while idiopathic and infectious etiologies characterize first-episode AP, supporting a stepwise approach in which comprehensive etiological work-up, including genetic testing, is prioritized after recurrence. The predominance of genetic causes in ARP should be interpreted with caution, as genetic testing was applied selectively, predominantly after recurrence. Recurrence status alone does not predict severity, whereas etiological complexity at first presentation and hypoalbuminemia represent practical, accessible early markers for clinically assessing more severe disease.

Background & Aims: Accurate assessment of liver fibrosis is important for the management of pediatric chronic liver disease (CLD). Transient Elastography (TE) has emerged as a validated non-invasive method for accurately assessing hepatic fibrosis, yet it remains available only in specialized centers and requires specialized equipment. We aimed to develop and internally validate a novel, simple, blood-based scoring system—the pediatric-adapted liver score (PAL score)—to predict advanced fibrosis as defined by liver stiffness, measured using TE across diverse etiologies. Methods: A retrospective study was conducted on 107 pediatric patients with CLD who underwent liver stiffness measurement through TE. Advanced fibrosis was defined as a liver stiffness measurement corresponding to the F3 METAVIR stage or above. Independent predictors of advanced fibrosis were identified using multivariable logistic regression with manual backward elimination. To facilitate bedside utility, the regression model was simplified into a ratio-based index. Performance was assessed via the area under the receiver operating characteristic curve (AUROC) and validated using bootstrap resampling (10,000 iterations). Results: Gamma-glutamyl transferase (GGT), platelets, and albumin were identified as independent predictors of fibrosis. The simplified PAL score demonstrated good discrimination with an AUROC of 0.901 (95% CI: 0.84–0.95). While statistically equivalent to the adult-derived GGT-to-platelet ratio (GPR) and S-Index, the PAL score incorporates parameters of hepatic synthesis and portal hypertension that are absent from other ratios and is easier to calculate at the patient’s bedside. At a clinically practical integer cut-off of 5.0, the score achieved a sensitivity of 95.5% and a negative likelihood ratio of 0.06, effectively ruling out advanced fibrosis. Bootstrap validation confirmed the stability of the model (bootstrap-corrected AUC 0.901). Conclusions: The PAL score is the first simple fibrosis index derived for a diverse pediatric population. Highlighting its primary strength as a highly effective screening tool, the score achieves a sensitivity of 95.5% and a negative likelihood ratio of 0.06 at a user-friendly cut-off of 5. These robust metrics allow clinicians to confidently rule out advanced fibrosis, offering an accessible triage alternative in primary care settings where transient elastography is unavailable.

Background: Vitamin D, through its role in antimicrobial peptide (AMP) expression, may influence innate immunity and inflammation in urinary tract infections (UTIs). This study evaluated its role in patients with vesicoureteral reflux (VUR) and its contribution to the pathophysiology of reflux nephropathy (RN). Methods: We conducted a cross-sectional observational study of 25 pediatric patients with VUR, representing a subgroup analysis of a larger cohort examined in a previous study. We determined patients’ vitamin D status, correlated it with recurrent UTIs and RS, and explored its relationship with urinary LL-37, NGAL, and IL-6 levels as markers of innate immune function. Results: Serum vitamin D levels ranged from 10.7 to 123.2 ng/mL (mean 39.5 ng/mL); 12% had deficiency and 20% had insufficient levels. Low vitamin D levels were detected in patients with more than five acute pyelonephritis (APNs), with a mean value classified as insufficient (27.3 ng/mL). Patients with RS had a lower mean vitamin D level compared to those without (30.51 ng/mL vs. 41.23 ng/mL), though the difference was not statistically significant (p = 0.39). No significant associations were found between vitamin D and urinary IL-6 or NGAL levels. A strong positive correlation was observed between vitamin D and urinary LL-37/creatinine (r = 0.78, r² = 0.61). Conclusions: Vitamin D appears to influence the frequency of UTIs and the development of RS, primarily by modulating LL-37 secretion, suggesting a possible role in the pathophysiology of RN.

Biliary atresia (BA) is the leading indication for pediatric liver transplantation. In the absence of surgical treatment, BA progresses rapidly toward hepatic fibrosis and cirrhosis. Although liver biopsy remains the gold standard for histological evaluation, its utility is limited by invasiveness, associated risks, and sampling variability. These limitations have spurred the development and validation of noninvasive tools to evaluate liver fibrosis in this patient population. Multiple imaging techniques have been developed to assess liver fibrosis and cirrhosis. In recent years, additional BA-related biomarkers have been identified, showing significant potential for diagnosis, assessment of fibrosis severity, and prediction of native liver survival outcomes. This article reviews the roles and potential clinical applications of the following biomarkers: matrix metalloproteinase-7 (MMP-7), fibroblast growth factor 19 (FGF-19), interleukin-33 (IL-33), clusterin, and osteopontin. Further research is needed to confirm the utility of these prognostic biomarkers in predicting and improving outcomes in BA.

Autoimmune hepatitis (AIH) is a progressive inflammatory liver disease characterized by hypergammaglobulinemia, circulating antibodies, and distinctive histological features, with a higher prevalence in females. Immune responses targeting hepatic antigens are considered the main mechanism behind AIH. Many cytokines are involved in the inflammatory response typical of this disease. Interleukin 17 (IL-17) is a powerful pro-inflammatory protein that serves as a key link between the innate and adaptive immune systems. It plays an important role in regulating the inflammatory response in various tissues, including the liver. Several studies have shown that increased IL-17 levels are associated with the severity and progression of AIH. This review explores IL-17’s role in the AIH inflammatory pathway and summarizes existing evidence linking it to liver damage. We also highlight the potential of future therapies targeting this cytokine.

Background. Autoimmune sclerosing cholangitis (ASC) is a rare clinical entity characterized by overlapping features of autoimmune hepatitis and primary sclerosing cholangitis. It predominantly affects pediatric patients. Therapeutic management is often complex, requiring a multidisciplinary and individualized approach, especially in the context of associated autoimmune diseases. Case presentation. We present the case of a female patient diagnosed at the age of 10 with ASC, for which immunosuppressive therapy with prednisone, azathioprine (AZA), and ursodeoxycholic acid (UDCA) was initiated, with an initially favorable course. One year later, following a Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection, the patient experienced reactivation of liver disease and subsequently developed ulcerative pancolitis (UC), for which 5-aminosalicylic acid (5-ASA) therapy was initiated. Due to repeated hepatic flares and/or colitis relapses, therapy was escalated successively to mycophenolate mofetil, tacrolimus, and eventually infliximab (IFX). Despite treatment, the liver disease progressed, culminating in liver cirrhosis. Our patient developed portal hypertension and esophageal varices, with two episodes of upper gastrointestinal bleeding requiring endoscopic band ligation. At the age of 14, the patient developed recurrent episodes of non-infectious ulcerative stomatitis. Biopsy of the lesions revealed non-specific chronic inflammation, unrelated to colitis activity (confirmed microscopic remission of UC). By exclusion, an adverse drug reaction was suspected, with AZA being the most likely cause. Following its discontinuation, the lesions resolved. Beyond the physiological and therapeutic aspects, the patient displays marked emotional fragility due to prolonged and repeated hospitalizations (18 out of 60 months), which have impacted treatment adherence. Conclusions. This case highlights the complexity of managing pediatric patients with multiple autoimmune diseases. The necessary combination of immunosuppressive therapies may lead to significant adverse effects and further complicate disease progression. Moreover, psychological components play a crucial role in treatment compliance and therapeutic success, emphasizing the need for an integrated approach that includes specialized psychological support.

Background: Chronic liver disease (CLD) in children requires long-term monitoring. Liver biopsy and transient elastography (TE) are resource-intensive methods that require specialized equipment and trained personnel. Simple indirect fibrosis scores based on routine laboratory parameters offer a potentially cost-effective alternative but have not been systematically evaluated in pediatric populations with diverse CLD etiologies. Objectives: This study aimed to assess the performance of several indirect fibrosis and cirrhosis scores in predicting significant (≥F2) and advanced (≥F3) fibrosis and cirrhosis (F4) in children with CLD using TE as a comparator. Methods: We retrospectively reviewed medical records of children with CLD evaluated at a tertiary center between January 2023 and June 2025. TE results and routine laboratory data were used to calculate fibrosis scores, including APRI, FIB-4, FibroIndex, FORNS, GPR, GUCI, King’s score, and Lok’s index. ROC analyses were performed to assess each score’s ability to discriminate significant fibrosis, advanced fibrosis and cirrhosis. Optimal cut-offs were established using the Youden index. Results: GPR showed the strongest concordance with TE-based fibrosis classification across both fibrosis thresholds, achieving an AUROC of 0.835 for significant fibrosis and a superior 0.917 for advanced fibrosis. FibroIndex and APRI also demonstrated good discriminatory power for advanced disease. Utilizing mathematically optimized cut-offs, GPR (0.45) and APRI (0.84) achieved good negative predictive values (100% and 95%) and sensitivities (100% and 85%) for advanced fibrosis, establishing them as potentially valuable screening tools. For cirrhosis detection (F4), Lok’s Index performed best (AUROC 0.854). Conclusions: In this diverse pediatric cohort, simple indirect scores—particularly GPR, APRI, and FibroIndex—demonstrated the highest concordance relative to TE findings, with negative predictive values up to 100% for GPR. This indicates that they can serve as reliable first-line screening tools when TE is unavailable. While their good negative predictive values allow for the confident exclusion of severe disease—potentially sparing many children from invasive testing—their low positive predictive values limit their role in definitive diagnosis. The systematic failure of adult-derived, age-dependent formulas in this cohort underscores the critical need for specialized pediatric biomarkers.

Cholestasis in children is characterized by impaired bile flow that disrupts hepatic metabolism, nutrient homeostasis, and effects trace element balance. This narrative review summarizes current evidence on the metabolism, biological functions, and clinical implications of key trace elements—zinc, selenium, copper, and manganese—in pediatric cholestatic liver disease. The liver regulates trace element absorption, intracellular trafficking, storage, and biliary excretion; cholestasis alters these processes, leading to deficiencies or toxic accumulation. Zinc and selenium deficiencies are common and contribute to impaired growth, immune dysfunction, oxidative stress, and delayed hepatic regeneration. Conversely, reduced biliary excretion promotes copper and manganese accumulation, potentially exacerbating liver injury and causing manganese-related neurotoxicity. Recent advances in understanding metal-specific hepatic transporters and trafficking pathways have provided mechanistic insight into these alterations. Management strategies emphasize individualized supplementation, monitoring during enteral and parenteral nutrition, and prevention of deficiency and toxicity. Precision-based nutritional approaches may improve outcomes in pediatric cholestatic liver disease.