Pediatric Autoimmune Hepatitis.

Pediatric autoimmune hepatitis (PAIH) is a rare necro-inflammatory disease of the liver of unknown etiology thought to derive from the dysregulation of the immune response upon exposure to environmental triggers in genetically predisposed individuals [...].

Juvenile Autoimmune Hepatitis: Recent Advances in Diagnosis, Management and Long-Term Outcome.

Juvenile autoimmune hepatitis (JAIH) is severe immune-mediated necro-inflammatory disease of the liver with spontaneous progression to cirrhosis and liver failure if left untreated. The diagnosis is based on the combination of clinical, laboratory and histological findings. Prothrombin ratio is a useful prognostic factor to identify patients who will most likely require a liver transplant by adolescence or early adulthood. JAIH treatment consists of immune suppression and should be started promptly at diagnosis to halt inflammatory liver damage and ultimately prevent fibrosis and progression to end-stage liver disease. The risk of relapse is high especially in the setting of poor treatment compliance. Recent evidence however suggests that treatment discontinuation is possible after a prolonged period of normal aminotransferase activity without the need for liver biopsy prior to withdrawal.

Vaccination practices in pediatric transplantation: A survey among member centers of the European reference network TransplantChild.

BACKGROUND: There is considerable variation in vaccination practices between pediatric transplant centers. This study aims to evaluate active immunization attitudes and practices among ERN-TransplantChild centers and identify potential areas of improvement that could be addressed by shared evidence-based protocols. METHODS: A cross-sectional questionnaire of attitudes and practices toward immunization of pediatric SOT and HSCT candidates and recipients was sent to a representative member of multidisciplinary teams from 27 European centers belonging to the ERN-TransplantChild. RESULTS: A total of 28/62 SOT programs and 6/12 HSCT programs across 21 European centers participated. A quarter of centers did not have an on-site protocol for the immunizations. At the time of transplantation, pediatric candidates were fully immunized (80%-100%) in 57% and 33% of the SOT and HSCT programs. Variations in the time between vaccine administration and admission to the waiting list were reported between the centers, with 2 weeks for inactivated vaccines and variable time (2-4 weeks) for live-attenuated vaccines (LAVs). Almost all sites recommended immunization in the post-transplant period, with a time window of 4-8 months for the inactivated vaccines and 16-24 months for MMR and Varicella vaccines. Only five sites administer LAVs after transplantation, with seroconversion evaluated in 80% of cases. CONCLUSIONS: The immunization coverage of European pediatric transplant recipients is still inconsistent and far from adequate. This survey is a starting point for developing shared evidence-based immunization protocols for safe vaccination among pediatric transplant centers and generating new research studies.

Telemedicine in Patients Affected by Chronic Liver Disease: A Scoping Review of Clinical Outcomes and the Devices Evaluated.

For patients with chronic liver disease (CLD), telemedicine is emerging as a useful tool to prevent liver decompensation or hospitalization, allowing access to and the decentralization of care, even for patients with limited resources. However, research and attendant evidence are still lacking; thus, this review aims to systematically explore the topic of telemonitoring for CLD to describe the currently used tools and clinical outcomes. The review was conducted by using key terms on PubMed/EMBASE and searching for observational studies or clinical trials (according to PRISMA recommendations) that were published between 6 April 2013 and 6 April 2023 to keep the technological framework limited to the last 10 years. The studies were described and grouped according to the aim of telemonitoring, the underlying disease, and the tools adopted to achieve remote monitoring. A total of 32 articles met the inclusion criteria. Of these, 11 articles report the successful use of a telehealth program to support and improve access to care in the management of HCV-related cirrhosis, eight articles examine the efficacy of telemedicine for remote monitoring interventions to prevent or decrease the risk of decompensation in high-risk patients, and five articles examine improvements in the physical performance and quality of life of cirrhotic patients through telehealth rehabilitation programs. Four studies were completed during the recent COVID-19 pandemic. Telehealth has the potential to provide and expand treatment access and reduce barriers to care for the most disadvantaged patients and might be able to reduce the need for hospital readmission for CLD, though most practice to test feasibility is still in the pilot stage.

Treatment with an ileal bile acid transporter inhibitor in patients with TJP2 deficiency.

There are no published data on the use of odevixibat, a selective ileal bile acid transporter (IBAT) inhibitor, in children with tight junction protein 2 (TJP2) deficiency (also named as PFIC-4). We describe a case series of five children treated with odevixibat. After treatment, serum bile acids (sBA) decreased compared to baseline [mean value: 244 (±125), vs 38 (±34) µmol/L; p = 0.007]; reduction in sBA was >70% from baseline (or <70 µmol/L) in all. Improvements in pruritus were reported in all patients. The drug was well tolerated. IBAT inhibitors should be considered a valuable treatment option in patients with TJP2 deficiency.

Paediatric porto-sinusoidal vascular disease: Two different clinical phenotypes with subtle histological differences.

BACKGROUND AND AIMS: In paediatrics, porto-sinusoidal vascular disease (PSVD) is relatively unknown and probably underdiagnosed. We aimed to describe clinical phenotypes, histology and outcome of children diagnosed with PSVD. METHODS: Retrospective multicentre study of children diagnosed with PSVD. Diagnosis of PSVD was based on histopathology reports; liver specimens were re-evaluated by two expert liver pathologists. RESULTS: Sixty two children diagnosed with PSVD (M/F = 36/26, median age 6.6 years, range 3.3-10.6), from 7 centres, were included. Thirty-six presented with non-cirrhotic portal hypertension, PH, (PH-PSVD Group = 58%) while 26 had a liver biopsy because of chronic elevation of transaminases without PH (noPH-PSVD Group = 42%). On histology review, the two groups differed for the prevalence of obliterative portal venopathy (more prevalent in PH-PSVD, p = 0.005), and hypervascularised portal tracts (more common in noPH-PSVD, p = 0.039), the other histological changes were equally distributed. At multivariate analysis, platelet count ≤185 000/mm3 was the only independent determinant of PH (p < 0.001). After a median follow-up of 7 years (range 3.0-11.2), in PH-PSVD group 3/36 (8%) required TIPS placement, 5/36 (14%) developed pulmonary vascular complications of PH, and 7/36 (19%) required liver transplantation. In noPH-PSVD none progressed to PH nor had complications. CONCLUSIONS: Paediatric patients with PSVD present with two different clinical phenotypes, one characterised by PH and one by chronic elevation of transaminases without PH. PSVD should be included among the conditions causing isolated hypertransaminasaemia. On histology, the differences between the two groups are subtle. Medium-term outcome is favourable in patients without PH; progression of the disease is observed in those with PH.

Diagnostic approach to neonatal and infantile cholestasis: A position paper by the SIGENP liver disease working group.

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.

Pregnancy outcome in women with childhood onset autoimmune hepatitis and autoimmune sclerosing cholangitis on long-term immunosuppressive treatment.

INTRODUCTION: Autoimmune hepatitis and autoimmune sclerosing cholangitis may lead to maternal and fetal complications in pregnant women diagnosed during childhood and treated long-term with immunosuppressive drugs. Immunosuppressive treatment with azathioprine is usually employed during pregnancy to maintain remission but his safety is still controversial. The aim of our study is to investigate pregnancy outcomes after maternal long-term immunosuppressive treatment for autoimmune hepatitis/sclerosing cholangitis. METHODS: We conducted a retrospective cohort study including all pregnant women who received a diagnosis of autoimmune hepatitis or autoimmune sclerosing cholangitis during childhood and followed-up from 1989 to 2021. RESULTS: Fifteen pregnancies in 12 women were observed. The median follow-up from disease onset was 26.7 years. All patients had been treated with prednisone and azathioprine (AZA) as first line therapy. At the beginning of the pregnancy, 11/12 (91.6%) patients were in spontaneous or pharmacologically induced clinical and biochemical remission and one had received a liver transplant. During pregnancy, 8 patients continued azathioprine. No relapse during pregnancy occurred in any patient. One woman presented a flare five months after delivery and a second one, one year after delivery when AZA was discontinued. The 15 pregnancies resulted in 13 livebirths (86.6%) with 9 (69.2%) full-term healthy neonates. Two miscarriages (13.3%) were recorded and cesarean section was performed in 3 women (23%). No congenital malformations were observed. CONCLUSIONS: Pregnancy in women diagnosed during pediatric age with autoimmune hepatitis or autoimmune sclerosing cholangitis and treated long-term with immunosuppressants is possible with good maternal and neonatal outcomes. Azathioprine allows, in most cases, to maintain remission with a good safety profile. Careful monitoring of these patients during pregnancy is, however, mandatory.

The frequency of rare and monogenic diseases in pediatric organ transplant recipients in Italy.

BACKGROUND: Rare diseases are chronic and life-threatening disorders affecting < 1 person every 2,000. For most of them, clinical symptoms and signs can be observed at birth or childhood. Approximately 80% of all rare diseases have a genetic background and most of them are monogenic conditions. In addition, while the majority of these diseases is still incurable, early diagnosis and specific treatment can improve patients' quality of life. Transplantation is among the therapeutic options and represents the definitive treatment for end-stage organ failure, both in children and adults. The aim of this paper was to analyze, in a large cohort of Italian patients, the main rare genetic diseases that led to organ transplantation, specifically pointing the attention on the pediatric cohort. RESULTS: To the purpose of our analysis, we considered heart, lung, liver and kidney transplants included in the Transplant Registry (TR) of the Italian National Transplantation Center in the 2002-2019 timeframe. Overall, 49,404 recipients were enrolled in the cohort, 5.1% of whom in the pediatric age. For 40,909 (82.8%) transplant recipients, a disease diagnosis was available, of which 38,615 in the adult cohort, while 8,495 patients (17.2%) were undiagnosed. There were 128 disease categories, and of these, 117 were listed in the main rare disease databases. In the pediatric cohort, 2,294 (5.6%) patients had a disease diagnosis: of the 2,126 (92.7%) patients affected by a rare disease, 1,402 (61.1%) presented with a monogenic condition. As expected, the frequencies of pathologies leading to organ failure were different between the pediatric and the adult cohort. Moreover, the pediatric group was characterized, compared to the adult one, by an overall better survival of the graft at ten years after transplant, with the only exception of lung transplants. When comparing survival considering rare vs non-rare diseases or rare and monogenic vs rare non-monogenic conditions, no differences were highlighted for kidney and lung transplants, while rare diseases had a better survival in liver as opposed to heart transplants. CONCLUSIONS: This work represents the first national survey analyzing the main genetic causes and frequencies of rare and/or monogenic diseases leading to organ failure and requiring transplantation both in adults and children.

Successful Use of Heterologous CMV-Reactive T Lymphocyte to Treat Severe Refractory Cytomegalovirus (CMV) Infection in a Liver Transplanted Patient: Correlation of the Host Antiviral Immune Reconstitution with CMV Viral Load and CMV miRNome.

Cytomegalovirus (CMV) infection is the most significant viral infection in hosts with compromised immune systems as solid organ transplant patients. Despite significant progress being made in the prevention of CMV disease in these patients, further therapeutic strategies for CMV disease and for the CMV reactivation prevention are needed. Here, we describe the outcome of the infusion of in vitro expanded CMV-reactive T-cells, taken from a healthy CMV-seropositive donor, in a liver-transplanted recipient with a refractory recurrent CMV. In this particular case, adoptive transfer of allogenic CMV-reactive T-lymphocytes resulted in the clearance of CMV infection and resolution of the pathological manifestations of the patient. In the study we also investigated circulating miRNAs, both cellular and viral, as potential biomarkers during the course of CMV infection. The results indicate that the infusion of allogenic CMV-reactive T-cells can be an effective strategy to treat CMV infection recurrence when the generation of autologous virus specific T cell clones is not possible.

Giant cell hepatitis associated with autoimmune hemolytic anemia: an update.

Giant cell hepatitis associated with autoimmune hemolytic anemia (GCH-AHA) is a rare and severe disease characterized by autoimmune hemolysis associated with acute liver injury, histologically defined by widespread giant cell transformation. It occurs after the neonatal period, most commonly in the first year of life and uniquely affects pediatric patients. It is still poorly understood and likely underdiagnosed, although in recent years there have been advances in the understanding of its pathogenesis and the liver injury is now hypothesized to be secondary to a humoral immune mechanism. Although no laboratory test specific for the diagnosis currently exists, given its severity, it is fundamental to rule out GCH-AHA when evaluating a patient in the first year of life presenting with AHA and/or with acute liver disease of unknown etiology. While GCH-AHA is progressive in nature as other autoimmune liver disorders, it differs significantly from juvenile autoimmune hepatitis (JAIH) in that a cure can be achieved after several years of intensive treatment in a portion of patients. Conventional first line therapy consist of prednisone/prednisolone combined with azathioprine, however, several immunosuppressive drugs, commonly used in the treatment of JAIH have been tried as second line therapy, including cyclosporine, cyclophosphamide, mycophenolate mofetil, 6-mercaptopurine, calcineurin inhibitors, and sirolimus. Intravenous immunoglobulins have also been used in cases of severe liver dysfunction and/or severe anemia allowing for transitory remission. More recently treatment with B-cell depletion has been attempted in some patients and encouraging results have been reported in refractory cases. Although what constitutes optimal treatment has yet to be determined, the recent progress in the understanding of the pathogenetic mechanisms of GCH-AHA have made positive strides, cautiously pointing toward a hopeful prognosis for some of these patients.

Pediatric transplantation in Europe during the COVID-19 pandemic: Early impact on activity and healthcare.

The current pandemic SARS-CoV-2 has required an unusual allocation of resources that can negatively impact chronically ill patients and high-complexity procedures. Across the European Reference Network on Pediatric Transplantation (ERN TransplantChild), we conducted a survey to investigate the impact of the COVID-19 outbreak on pediatric transplant activity and healthcare practices in both solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT). The replies of 30 professionals from 18 centers in Europe were collected. Twelve of 18 centers (67%) showed a reduction in their usual transplant activity. Additionally, outpatient visits have been modified and restricted to selected ones, and the use of telemedicine tools has increased. Additionally, a total of 14 COVID-19 pediatric transplanted patients were identified at the time of the survey, including eight transplant recipients and six candidates for transplantation. Only two moderate-severe cases were reported, both in HSCT setting. These survey results demonstrate the limitations in healthcare resources for pediatric transplantation patients during early stages of this pandemic. COVID-19 disease is a major worldwide challenge for the field of pediatric transplantation, where there will be a need for systematic data collection, encouraging regular discussions to address the long-term consequences for pediatric transplantation candidates, recipients, and their families.

Novel Diagnostic and Therapeutic Strategies in Juvenile Autoimmune Hepatitis.

Juvenile autoimmune hepatitis (JAIH) is a rare, chronic, inflammatory disease of the liver characterized by a complex interaction between genetic, immunological, and environmental factors leading to loss of immunotolerance to hepatic antigens. It affects both children and adolescents, most commonly females, and its clinical manifestations are quite variable. JAIH is progressive in nature and if left untreated may lead to cirrhosis and terminal liver failure. Although JAIH was first described almost 50 years ago, there have been few significant advances in the clinical management of these patients, both in terms of available diagnostic tools and therapeutic options. Aminotransferase activity, class G immunoglobulins and autoantibodies are the biomarkers used to diagnose AIH and monitor treatment response alongside clinical and histological findings. Despite their utility and cost-effectiveness, these biomarkers are neither an accurate expression of AIH pathogenic mechanism nor a precise measure of treatment response. Current standard of care is mainly based on the administration of steroids and azathioprine. This combination of drugs has been proven effective in inducing remission of disease in the majority of patients dramatically improving their survival; however, it not only fails to restore tolerance to hepatic autoantigens, but it also does not halt disease progression in some patients, it is often needed life-long and finally, it has deleterious side-effects. The ideal therapy should be enough selective to contrast immune-mediated live damage while preserving or potentiating the ability to develop permanent tolerance vs. pathogenic autoantigens. By reviewing the state of the art literature, this article highlights novel diagnostic and therapeutic strategies for managing pediatric AIH with a special focus on new strategies of immunotherapy. These promising tools could improve the diagnostic algorithm, more accurately predict disease prognosis, and provide targeted, individualized treatment.

Long-term follow-up of children and young adults with autoimmune hepatitis treated with cyclosporine.

BACKGROUND: Cyclosporine (CSA) is an alternative treatment for autoimmune hepatitis (AIH), however, its unknown long-term safety and efficacy have limited its use. AIMS: Examine the long-term outcome of children and young adults with AIH treated with CSA for at least 4 years. METHODS: Twenty patients were included in this retrospective study: 15 with classical AIH and 5 with autoimmune hepatitis/autoimmune sclerosing cholangitis overlap syndrome (ASC). CSA was administered as first (12 patients) or second-line (8 patients) treatment, alone or in combination with azathioprine or mycophenolate mofetil and/or prednisone. RESULTS: CSA determined initial clinical and biochemical remission in all patients. At the end of follow-up (median 8.6; range 4-20.4 years), all patients are alive with their native liver; 15 in complete remission (75%), 2 with incomplete response to treatment and 3 listed for liver transplant. Side effects were mild and transitory after dose tapering or, in 1 case, after CSA withdrawal. Hypertrichosis and moderate gingival hyperplasia were the most frequent. Two patients presented mild transient glomerular filtration rate (GFR) reduction. Median GFR at the beginning and end of treatment was not statistically different for all patients. CONCLUSIONS: CSA was effective and safe in the long-term treatment of our cohort of patients with AIH, tailoring the treatment remains key-points during CSA administration.

Old and New Treatments for Pediatric Autoimmune Hepatitis.

BACKGROUND: Autoimmune hepatitis is a rare inflammatory disease of the liver that most frequently affects children and young adults. It is a multifactorial disease of unknown etiology, characteristically progressive in nature, and if left untreated, may lead to cirrhosis and terminal liver failure. It has been known for several decades now that immunosuppressive treatment convincingly alters the outcome of most patients with autoimmune hepatitis and as such it should be started as soon as diagnosis is made. Primary goals of treatment are: normalization of hepatocellular function, extinction of the hepatic necroinflammatory process, and maintenance of a stable remission, thus preventing progression to cirrhosis and its complications. This article aims to review old and new treatments for this rare chronic disorder, from the oldest and most frequently used treatment consisting of the association of prednisone and azathioprine, to alternative medical treatments, liver transplant and promising medical strategies currently under investigation. RESULT AND CONCLUSION: The review will focus on the efficacy and safety profile of each drug, as well as on the published clinical experience with them in pediatric patients with autoimmune hepatitis.