Benefits of using exchangeable copper and the ratio of exchangeable copper in a real-world cohort of patients with Wilson disease.

Wilson disease (WD) is a complex disease in which diagnosis and long-term metabolic copper control remains challenging. The absence of accurate biomarkers requires the combination of different parameters to ensure copper homeostasis. Exchangeable copper and its ratio (REC) have been suggested to be useful biomarkers in this setting. We aimed at introducing these measurements and evaluate their performance and accuracy in our real-world cohort of WD patients. Exchangeable copper and REC were measured in 48 WD patients and 56 control individuals by inductively coupled plasma-mass-spectrometry. Demographic and clinical characteristics were collected. REC was shown to be significantly higher among WD patients compared to controls and useful for WD identification by using the previously established cutoffs: 71.4% of WD patients with a recent diagnosis had REC ≥18.5% and 95.1% of long-term treated WD had REC ≥14%; only four patients of the cohort presented discordant levels. Moreover, REC values were below 15% in all the control individuals. Exchangeable copper was significantly higher in WD patients compared to controls and tended to be reduced among WD patients who were compliant to medication. This real-life study confirmed that exchangeable copper and REC are useful serum biomarkers that can be used as complementary tests to ensure WD diagnosis (REC) and copper homeostasis whithin time (exchangeable copper). The desirable target levels for this last objective still needs to be validated in prospective cohorts.

A Better Understanding of Pediatric Autoimmune Pancreatitis: Over 13 Years of Experience.

OBJECTIVES: Pediatric autoimmune pancreatitis (P-AIP) is an uncommon disease whose diagnosis requires strong clinical suspicion. Late diagnosis increases morbidity. We aimed to compare the usefulness of the 2011 International Consensus Diagnostic Criteria (ICDC) for Autoimmune Pancreatitis with the 2018 INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In search for a cuRE) criteria. METHODS: We retrospectively analyzed demographics and clinical, laboratory, radiological, and histological findings at diagnosis and during long-term follow-up in children diagnosed with AIP in 2 tertiary hospitals between 2008 and 2021. RESULTS: We included 11 patients [6 girls; median age at diagnosis, 12.5 (range 2.8-15.7) years]. The most common symptom was abdominal pain. Pancreatic enzymes were elevated in 10 patients, and serum immunoglobulin G4 was elevated in 1. Magnetic resonance imaging showed enlargement of the pancreatic head in 10 patients and general pancreatic enlargement in 1. Pancreatic and papilla tissue were obtained from 9 patients. All patients received corticosteroids (prednisolone), and 4 also received azathioprine. According to the ICDC, all patients were classified as probable or non-otherwise specified AIP. According to INSPPIRE criteria, all patients were classified as AIP. Using the INSPPIRE criteria would have avoided biopsies in 6 patients who responded well to corticosteroids. CONCLUSIONS: The INSPPIRE criteria are useful. Using the ICDC in pediatric patients can delay diagnosis and result in unnecessary invasive tests.

Heterozygous mutations of ATP8B1, ABCB11 and ABCB4 cause mild forms of Progressive Familial Intrahepatic Cholestasis in a pediatric cohort.

INTRODUCTION: Heterozygous defects in genes implicated in Progressive Familial Intrahepatic Cholestasis have been described in milder forms of cholestatic diseases. Our aim is to describe clinical, laboratory and imaging characteristics as well as treatment and outcome of a cohort of pediatric patients with heterozygous mutations in ATP8B1, ABCB11 or ABCB4. PATIENTS AND METHODS: We present a retrospective descriptive study including pediatric patients with at least one heterozygosis defect in ATP8B1, ABCB11 or ABCB4 diagnosed after a cholestatic episode. Clinical, diagnostic and outcome data were collected including gene analysis (panel of PFIC NextGeneDx®). RESULTS: 7 patients showed a heterozygous mutation: 3 patients in ABCB4, 1 in ABCB11, 2 in ABCB4 and ABCB11 and 1 in ATP8B1. The median onset age was 5.5 years with a median time of follow-up of 6 years. The initial presentation was pruritus followed by asymptomatic hypertransaminasemia and persistent cholestasis. Two patients had family history of gallbladder stones and mild hepatitis. All showed elevated transaminases and bile acids, high gamma glutamyl-transferase (GGT) in 3 and conjugated bilirubin in 2 patients. Liver biopsy showed inflammatory infiltrate or mild fibrosis with normal immunohistochemistry. All patients were treated with ursodeoxycholic acid, two patients requiring the addition of resincholestyramine. During follow-up, 3 patients suffered limited relapses of pruritus. No disease progression was observed. CONCLUSION: Heterozygous mutations in genes coding proteins of the hepatocellular transport system can cause cholestatic diseases with great phenotypic variability. The presence of repeated episodes of hypertransaminasemia or cholestasis after a trigger should force us to rule out the presence of these heterozygous mutations in genes involved in CIFP.

[Intestinal intussusception as a key sign of Celiac Disease. A pediatric case report]. / Invaginación intestinal como signo guía de enfermedad celíaca. Un caso clínico pediátrico.

Intestinal intussusception is the most frequent cause of intestinal obstruction between 6 and 36 months of age, the majority being idiopathic. The association between celiac disease and intestinal intussusception in the pediatric population has been described. We present the case of a 23-month-old male admitted due to a failure to thrive. In his ultrasound study recurrent asymptomatic ileo-ileal invaginations were found.

La invaginación intestinal es la causa más frecuente de obstrucción intestinal entre los 6 y los 36 meses de edad. La mayoría son idiopáticas. Se ha descrito la asociación entre la enfermedad celíaca y la invaginación intestinal en la población pediátrica. Se presenta el caso de un varón de 23 meses ingresado por estancamiento ponderal en cuyo estudio ecográfico se observaron invaginaciones íleo-ileales asintomáticas repetidas.

Accuracy of the Simplified Criteria for Autoimmune Hepatitis in Children: Systematic Review and Decision Analysis.

BACKGROUND/OBJECTIVES: Several studies have been conducted on the accuracy of simplified criteria for autoimmune hepatitis that were presented in 2008 as an alternative to original criteria. Our purpose is to summarize the evidence available regarding their accuracy in children and to carry out a basic clinical decision analysis based on it. METHODS: Electronic and manual searches were performed with keywords related to diagnostic validity terms. Data from included studies were extracted, and summary estimates of accuracy measures were calculated. An effect model was chosen depending on heterogeneity, and the presence of publication bias was also studied. Therapeutic threshold was calculated based on the already published data. Through a Bayesian approach, simplified criteria's clinical utility was simulated, taking into account the meta-analyzed indicators and several assumptions on the prevalence of autoimmune hepatitis. RESULTS: The search yielded 166 studies, four of which were finally included, providing a total population of 437 patients. Pooled sensitivity and specificity of the simplified criteria for the diagnosis of autoimmune hepatitis in children was 77% and 95%, respectively, with a diagnostic odds ratio of 67. No evidence of publication bias was found. For prevalences ranging from 8.5 to 85.7, the predictive value of either a positive or a negative result moved beyond the therapeutic threshold (estimated at 56%). CONCLUSIONS: The simplified criteria show high specificity and moderate sensitivity for the diagnosis of autoimmune hepatitis in children. A positive result can justify starting a therapeutic assay, but a negative result does not seem sufficient to rule out this condition.

Development and validation of a new simplified diagnostic scoring system for pediatric autoimmune hepatitis.

BACKGROUND: Children with autoimmune hepatitis (AIH) often exhibit particular features. Accordingly, seven pediatric-specific criteria have been proposed. AIM: To develop a prediction model based on them, transform it into a scoring system and study its accuracy. METHODS: A cohort of children under study for liver disease was consecutively selected. AIH diagnosis was based on classical criteria. Already proposed pediatric criteria were recorded. The best possible regression model was selected, and the beta coefficient of each criterion was translated into a whole number (points). Total scores were obtained following the points system and the best cut-off was calculated. Subsequently, accuracy of the diagnostic score was studied in the validation set. RESULTS: Among 212 included patients, 100 had AIH. The score included 5 criteria: autoantibodies (0-2 points), hypergammaglobulinemia, exclusion of viral hepatitis, exclusion of Wilson's disease (1 point each) and liver histology (3 points). In addition, a normal cholangiogram is mandatory. The validation set was formed of 70 patients (24 with AIH). In this subsample, a score of ≥6 renders a sensitivity/specificity of 95.8%/100%. The area under the receiver operating characteristic curve was 97.1%. CONCLUSION: Pediatric-specific criteria for the diagnosis of AIH can be reliably used as a scoring system.

Accuracy of the 2008 Simplified Criteria for the Diagnosis of Autoimmune Hepatitis in Children.

PURPOSE: Classical criteria for diagnosis of autoimmune hepatitis (AIH) are intended as research tool and are difficult to apply at patient's bedside. We aimed to study the accuracy of simplified criteria and the concordance with the expert diagnosis based on the original criteria. METHODS: A cohort of children under study for liver disorder was selected through consecutive sampling to obtain the prevalence of AIH within the group of differential diagnoses. AIH was defined, based on classical criteria, through committee review of medical reports. Validity indicators of the simplified criteria were obtained in an intention to diagnose approach. Optimal cut-off and the area under the receiver operating characteristic (ROC) curve were calculated. RESULTS: Out of 212 cases reviewed, 47.2% were AIH. For the optimal cut-off (6 points), the simplified criteria showed a sensitivity of 72.0% and a specificity of 96.4%, with a 94.7% positive and a 79.4% negative predictive value. The area under the ROC curve was 94.3%. There was a good agreement in the pre-treatment concordance between the classical and the simplified criteria (kappa index, 0.775). CONCLUSION: Simplified criteria provide a moderate sensitivity for the diagnosis of AIH, but may help in indicating treatment in cases under suspicion with 6 or more points.

Invaginación intestinal como signo guía de enfermedad celíaca. Un caso clínico pediátrico / Intestinal intussusception as a key sign of Celiac Disease. A pediatric case report

La invaginación intestinal es la causa más frecuente de obstrucción intestinal entre los 6 y los 36 meses de edad. La mayoría son idiopáticas. Se ha descrito la asociación entre la enfermedad celíaca y la invaginación intestinal en la población pediátrica. Se presenta el caso de un varón de 23 meses ingresado por estancamiento ponderal en cuyo estudio ecográfico se observaron invaginaciones íleo-ileales asintomáticas repetidas.

Intestinal intussusception is the most frequent cause of intestinal obstruction between 6 and 36 months of age, the majority being idiopathic. The association between celiac disease and intestinal intussusception in the pediatric population has been described. We present the case of a 23-month-old male admitted due to a failure to thrive. In his ultrasound study recurrent asymptomatic ileo-ileal invaginations were found

Heterozygous mutations of ATP8B1, ABCB11 and ABCB4 cause mild forms of Progressive Familial Intrahepatic Cholestasis in a pediatric cohort / Mutaciones en heterocigosis en ATP8B1, ACB11 y ABCB4 como causa de formas leves de Colestasis Intrahepática Progresiva Familiar en una cohorte pediátrica

Introduction: Heterozygous defects in genes implicated in Progressive Familial Intrahepatic Cholestasis have been described in milder forms of cholestatic diseases. Our aim is to describe clinical, laboratory and imaging characteristics as well as treatment and outcome of a cohort of pediatric patients with heterozygous mutations in ATP8B1, ABCB11 or ABCB4. Patients and methods: We present a retrospective descriptive study including pediatric patients with at least one heterozygosis defect in ATP8B1, ABCB11 or ABCB4 diagnosed after a cholestatic episode. Clinical, diagnostic and outcome data were collected including gene analysis (panel of PFIC NextGeneDx®). Results: 7 patients showed a heterozygous mutation: 3 patients in ABCB4, 1 in ABCB11, 2 in ABCB4 and ABCB11 and 1 in ATP8B1. The median onset age was 5.5 years with a median time of follow-up of 6 years. The initial presentation was pruritus followed by asymptomatic hypertransaminasemia and persistent cholestasis. Two patients had family history of gallbladder stones and mild hepatitis. All showed elevated transaminases and bile acids, high gamma glutamyl-transferase (GGT) in 3 and conjugated bilirubin in 2 patients. Liver biopsy showed inflammatory infiltrate or mild fibrosis with normal immunohistochemistry. All patients were treated with ursodeoxycholic acid, two patients requiring the addition of resincholestyramine. During follow-up, 3 patients suffered limited relapses of pruritus. No disease progression was observed. Conclusion: Heterozygous mutations in genes coding proteins of the hepatocellular transport system can cause cholestatic diseases with great phenotypic variability. The presence of repeated episodes of hypertransaminasemia or cholestasis after a trigger should force us to rule out the presence of these heterozygous mutations in genes involved in CIFP.(AU)

Introducción: Se han descrito defectos en los genes implicados en las colestasis intrahepáticas familiares progresivas (CIFP) causantes de colestasis más leves. El objetivo es estudiar las manifestaciones clínicas, analíticas y de imagen así como la evolución y respuesta al tratamiento de los portadores en heterocigosis de mutaciones en ATP8B1, ABCB11 y ABCB4. Pacientes y métodos: Estudio descriptivo retrospectivo de pacientes con al menos una mutación en heterocigosis en los genes ATP8B1, ABCB11 o ABCB4 diagnosticados tras un episodio de colestasis. Se recogieron variables demográficas y datos clínicos, diagnósticos, incluyendo estudio genético (panel de CIFP NextGeneDx®), tratamiento y evolución. Resultados: 7 pacientes presentaron al menos una mutación en heterocigosis: 3 en ABCB4, 1 en ABCB11, 2 en ABCB4 y ABCB11 y 1 en ATP8B1. La edad media de inicio fue de 5.5 años con un tiempo medio de evolución de 6 años. La clínica inicial fue prurito seguida de hipertransaminasemia asintomática y colestasis persistente. Dos pacientes tenían antecedentes familiares de litiasis biliar y hepatitis leve. Todos mostraron transaminasas y ácidos biliares elevados, 3 gamma-glutamiltransferasa (GGT) y 2 bilirrubina directa. La biopsia hepática mostró infiltrado inflamatorio o fibrosis leve, inmunohistoquímica normal. Fueron tratados con ácido ursodeoxicólico añadiéndose colestiramina en 2. Durante el seguimiento 3 presentaron episodios autolimitados de prurito. No se observó progresión de la enfermedad. Conclusiones: Mutaciones en heterocigosis en los genes implicados en el sistema de transporte hepatocelular pueden ocasionar cuadros de colestasis con gran variabilidad fenotípica. Episodios repetidos de hipertransaminasemia o colestasis tras un desencadenante deben hacernos sospechar mutaciones en los genes implicados en las CIFP.(AU)