Pediatric Autoimmune Hepatitis Research Articles

Detection of polyreactive immunoglobulin G facilitates diagnosis in children with autoimmune hepatitis.

The detection of autoantibodies is essential to diagnose autoimmune hepatitis (AIH). Particularly in children, specificity of autoantibodies decreases due to lower titers being diagnostic and being present not only in AIH but also in other liver diseases. Recently, quantification of polyreactive IgG (pIgG) for detection of adult AIH showed the highest overall accuracy compared to antinuclear antibodies (ANA), anti-smooth muscle antibodies (anti-SMA), anti-liver kidney microsomal antibodies (anti-LKM) and anti-soluble liver antigen/liver pancreas antibodies (anti-SLA/LP). We aimed to evaluate the diagnostic value of pIgG for pediatric AIH. pIgG, quantified using HIP1R/BSA coated ELISA, and immunofluorescence on rodent tissue sections were performed centrally. The diagnostic fidelity to diagnose AIH was compared to conventional autoantibodies of AIH in training and validation cohorts from a retrospective, European multi-center cohort from nine centers from eight European countries composed of existing biorepositories from expert centers (n = 285). IgG from pediatric AIH patients exhibited increased polyreactivity to multiple protein and non-protein substrates compared to non-AIH liver diseases and healthy children. pIgG had an AUC of 0.900 to distinguish AIH from non-AIH liver diseases. pIgG had a 31-73% higher specificity than ANA and anti-SMA and comparable sensitivity that was 6-20 times higher than of anti-SLA/LP, anti-LC1 and anti-LKM. pIgG had a 21-34% higher accuracy than conventional autoantibodies, was positive in 43-75% of children with AIH and normal IgG and independent from treatment response. Detecting pIgG improves the diagnostic evaluation of pediatric AIH compared to conventional autoantibodies, primarily owing to higher accuracy and specificity.

Increased IgD and CD27 Double Negative (DN) B cell population in pediatric onset autoimmune hepatitis

Autoimmune hepatitis (AIH) is a chronic, inflammatory liver disease of unknown aetiology which requires lifelong immunosuppression. Most therapeutic and outcome studies of AIH have been conducted predominantly in Caucasian (European Ancestry, EA) cohorts, with the exclusion of African American (AA) patients due to inadequate sample size. It is known that AA patients have a severe phenotype of autoimmune diseases and demonstrate a poor response to conventional medical therapy. Understanding cellular and molecular pathways which determine AIH severity and progression in AA patients is likely to lead to the discovery of novel, personalised and better tolerated therapies. The aim of the study is to determine the distinct effector B cell phenotypes which contribute to disease severity and progression of AIH in AA children as compared to their EA cohorts. PBMCs were isolated from blood samples collected from patients visiting Children’s Healthcare of Atlanta (CHOA) and were grouped into AA, (n = 12), EA, (n = 11) and controls (n = 12) and were processed for flow cytometry. Markers of B cell development, maturation and activation were assessed namely CD19, CD21, IgD, CD27, CD38, CD11c, CD24, CD138. AA children with AIH demonstrated an expansion of CD19 + ve, Activated Naïve (aN), (CD19+ IgD-/CD27- Double Negative (DN2) ([CD19+/IgD-/CD27++CD38++) cells. Plasmablasts were significantly higher along with Signalling Lymphocytic activation molecule F7 (SLAMF7). Unswitched memory [CD19+] IgD+CD27+ (USM) B cells were significantly contracted in AA patients with AIH. B cell phenotyping reveals a distinct profile in AA AIH patients with a major skewing towards the expansion of effector pathways which have been previously characterised in severe SLE in AA patients. These results suggest that the quantification and therapeutic target of B cell pathway could contribute substantially to the clinical approach to AIH especially in the AA population.

Outcomes and management in paediatric autoimmune hepatitis presenting as acute liver failure: Individual patient data meta-analysis.

Autoimmune hepatitis (AIH) in children presenting in acute liver failure (ALF) can be fatal and often requires liver transplantation (LTx). This individual patient data meta-analysis (IPD) aims to examine management and outcomes of this population, given the lack of large cohort studies on paediatric AIH first presenting as ALF (AIH-ALF). A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses of IPD statement using PubMed and Excerpta Medica dataBASE, and included English studies published between 2000 and 2020. The study included patients under 21 years of age, diagnosed with type 1 or 2 AIH and presenting with ALF. Data extracted included clinical and biochemical characteristics, interventions, and outcomes. Three hundred and thirty eligible patients from 61 studies were identified, with an additional five patients from our institution. The majority were female (66.8%), with a median age of 10. Overall, 59.7% achieved native liver survival (NLS), 35% underwent LTx, and 5% died before LTx. The use of corticosteroids with non-steroid immunomodulators increased the likelihood of NLS by 2.5-fold compared to corticosteroids alone. AIH-1 was associated with 3.3-fold odds for NLS, compared to AIH-2. However, on multivariate analysis, only AIH-1 was identified as an independent predictor for NLS (OR 3.8 [95% CI 1.03-14.2], p = .04). While corticosteroids and non-steroid immunomodulators treatment may offer enhanced probability of achieving NLS, treatment regimens for AIH-ALF may need to consider patient-specific factors, especially AIH type. This highlights the potential for NLS in AIH-ALF and suggest a need to identify biomarkers which predict the need for combination immunosuppression to avoid LTx.

Evaluating Clinical Presentations and Diagnostic Procedures in Pediatric Autoimmune Hepatitis

Background: The aim of the current research was to assess the clinical manifestations and diagnostic methods used in juvenile cases of Autoimmune Hepatitis (AIH).
 Methods: This study employed a retrospective cross-sectional design to investigate pediatric patients diagnosed with AIH at Children’s Medical Center Hospital, which is affiliated to Tehran University of Medical Sciences (TUMS), Tehran, Iran. The study included patients who received routine examinations, treatments, and follow-ups during the period from 2018 to 2021.
 Results: The present investigation encompassed the evaluation of 52 pediatric patients, mostly female, with a mean age of 7.76 years. The vast majority of patients have encountered the occurrence of acute AIH. Positive findings for the Anti-Smooth Muscle Antibodies (ASMA) test were seen in 50% of the patients. The mean score for fibrosis in the observed individuals was 2.56, whereas the mean value for the Hepatitis Activity Index (HAI) in a subset of 29 patients was found to be 7.34. One patient succumbed to the condition, one case underwent transplantation, and another individual was identified as a candidate for liver transplantation.
 Conclusion: Patients with AIH saw a decrease in long-term survival. There was no observed disparity in prognosis based on gender; nevertheless, it was noted that males had a shorter lifespan, perhaps attributable to an earlier beginning of the illness. The presence of cirrhosis at the time of diagnosis constituted a significant risk factor for unfavorable prognosis, as it was associated with an elevated overall risk of mortality owing to liver dysfunction.

Report of an Iranian child with chronic abdominal pain and constipation diagnosed as glycogen storage disease type IX: a case report

BackgroundGlycogen storage disease type IX is a rare disorder that can cause a wide variety of symptoms depending on the specific deficiency of the phosphorylase kinase enzyme and the organs it affects.Case presentationA 4-and-a-half-year-old Caucasian girl was referred to our clinic with a liver biopsy report indicating a diagnosis of glycogen storage disease. Prior to being referred to our clinic, the patient had been under the care of pediatric gastroenterologists. The patient’s initial symptoms included chronic abdominal pain, constipation, and elevated liver transaminase. With the help of the pediatric gastroenterologists, cholestasis, Wilson disease, and autoimmune hepatitis were ruled out. Given that glycogen storage diseases type I and type III are the most common, we initially managed the patient with frequent feedings and a diet that included complex carbohydrates such as a corn starch supplement and a lactose restriction. Following an unfavorable growth velocity and hepatomegaly during the follow-up period, genetic analysis was conducted, which revealed a novel mutation of the phosphorylase kinase regulatory subunit beta gene— a c.C412T (P.Q138x) mutation. As the diagnosis of glycogen storage disease type IX was confirmed, the treatment regimen was altered to a high protein diet (more than 2 g/kg/day) and a low fat diet.ConclusionGiven the mild and varied clinical manifestations of glycogen storage disease type IX, it is possible for the diagnosis to be overlooked. It is important to consider glycogen storage disease type IX in children who present with unexplained hepatomegaly and elevated transaminase levels. Furthermore, due to the distinct management of glycogen storage disease type IX compared with glycogen storage disease type I and glycogen storage disease type III, genetic analysis is essential for an accurate diagnosis.

The Predictive Value of Autoantibodies in Determining Autoimmune Hepatitis (AIH) Severity

Background: The presence of autoantibodies is a prerequisite for the diagnosis of autoimmune hepatitis (AIH). However, most autoantibodies are not disease-specific, and serological overlap between AIH and other chronic liver diseases is common. Since the prognostic parameters of AIH are limited, this study aimed to investigate the relationship between histopathological findings on liver biopsy with different types of autoantibodies associated with AIH and how autoantibodies can predict the severity and extent of disease. Methods: The present study was performed on 30 patients with a definite diagnosis of AIH according to the International Autoimmune Hepatitis Group (IAIHG) criteria. Pediatric AIH patients underwent liver tissue examinations at the time of diagnosis at accession, which confirmed characteristic histological changes. AIH-related serologic major and minor autoantibodies were measured using indirect immunofluorescence assays and ELISA kit (EUROIMMUN, Germany), respectively, and were compared within all patients, and the results were recorded. Finally, the obtained data were analyzed using SPSS V25 software. Results: Out of 30 patients, 17 (56.66%) were female, and the age range of patients was 17-11 years (8.46±6.95). Anti-nuclear antibody (ANA) (73.3%), smooth muscle antibody (SMA)-anti-smooth muscle actin antibody (ASMA) (70%), perinuclear anti-neutrophilic cytoplasmic antibodies (p-ANCA) (63%), and liver kidney microsomal (LKM) (43.3%) were the most common autoantibodies found in children with AIH. There was a significant relation between the severity of histological findings and the presence of LKM antibodies (P<0.05). The highest sensitivity for predicting severe AIH based on histopathological findings was ANA autoantibody positivity and the presence of at least two primary autoantibodies (LKM and SMA-ASMA). On the other hand, positive LKM antibodies had the highest specificity and positive predictive value (PPV) in AIH severity prediction. Conclusion: The results of the present study suggested that there might be a significant correlation between the presence of primary LKM autoantibodies and biopsy results, so it can possibly act as an accurate autoantibody for predicting the severity of AIH, while other AIH-related autoantibodies did not seem to have a significant correlation with biochemical and histological findings.

Detection of Novel Biomarkers in Pediatric Autoimmune Hepatitis by Proteomic Profiling.

Autoimmune hepatitis (AIH) is characterized by immune-mediated hepatocyte injury resulting in the destruction of liver cells, causing inflammation, liver failure, and fibrosis. Pediatric (AIH) is an autoimmune inflammatory disease that usually requires immunosuppression for an extended period. Frequent relapses after treatment discontinuation demonstrate that current therapies do not control intrahepatic immune processes. This study describes targeted proteomic profiling data in patients with AIH and controls. A total of 92 inflammatory and 92 cardiometabolic plasma markers were assessed for (i) pediatric AIH versus controls, (ii) AIH type 1 versus type 2, (iii) AIH and AIH-autoimmune sclerosing cholangitis overlapping syndrome and (iv) correlations with circulating vitamin D levels in AIH. A total of 16 proteins showed a nominally significant differential abundance in pediatric patients with AIH compared to controls. No clustering of AIH subphenotypes based on all protein data was observed, and no significant correlation of vitamin D levels was observed for the identified proteins. The proteins that showed variable expression include CA1, CA3, GAS6, FCGR2A, 4E-BP1 and CCL19, which may serve as potential biomarkers for patients with AIH. CX3CL1, CXCL10, CCL23, CSF1 and CCL19 showed homology to one another and may be coexpressed in AIH. CXCL10 seems to be the central intermediary link for the listed proteins. These proteins were involved in relevant mechanistic pathways for liver diseases and immune processes in AIH pathogenesis. This is the first report on the proteomic profile of pediatric AIH. The identified markers could potentially lead to new diagnostic and therapeutic tools. Nevertheless, considering the complex pathogenesis of AIH, more extensive studies are warranted to replicate and validate the present study's findings.

The Ultrastructure of Hepatic Stellate Cell-Macrophage Intercellular Crosstalk as a New Morphological Insight into Phenomenon of Fibrogenesis in Pediatric Autoimmune Hepatitis.

Ultrastructural assessment of the HSC population and NPCs was performed in transmission electron microscopy (TEM) using pretreatment liver biopsies from 25 children (8 boys and 17 girls) aged 4-17 with clinic-pathologically diagnosed untreated AIH. Submicroscopic evaluation allowed easy identification of numerous HSCs in the form of transitory cells, i.e., T-HSCs, accompanied by signs of fibrosis. T-HSCs included cells with features of activation initiation (iHSCs) and activation perpetuation (pHSCs), indicating high HSC activation plasticity. The pHSCs were markedly elongated and mainly showed a distinct loss of lipid cytoplasmic material, expanded and dilated channels of granular endoplasmic reticulum, and linear bundles of microfilaments beneath the cell membrane. They were surrounded by usually mature collagen fibers. Frequently activated KCs/MPs adhered directly to T-HSCs. Between them, tight intercellular junctions were formed by means of point desmosomes. Our qualitative TEM observations indicate a key role of T-HSCs in liver fibrogenesis in pediatric AIH, with the essential involvement of activated KCs/MPs that directly adhere to them. Tight intercellular junctions, being the ultrastructural exponent of the specific cellular mechanisms of the crosstalk between NPCs, can play a vital role in hepatic collagen fibroplasia. A better understanding of HSC population morphology at the ultrastructural level in AIH seems important not only to improve the disease morphological diagnostics but to also provide new insights into therapeutic interventions for the phenomenon of liver fibrogenesis.

HLA Associations in pediatric autoimmune liver diseases: Current state and future research initiatives.

The strongest genetic association with autoimmunity is within chromosome 6p21, where the human leukocyte antigen (HLA) complex resides. This review will focus on the HLA associations within pediatric autoimmune hepatitis, autoimmune sclerosing cholangitis and primary sclerosing cholangitis. In general, there is considerable overlap in HLA genotypes conferring susceptibility to pediatric autoimmune liver diseases, however unique HLA associations and protective HLA genotypes exist. There are numerous areas for future research initiatives in pediatric autoimmune liver diseases and HLA associations with clinical outcomes, autoantigen discovery and novel therapeutics targeting the HLA- autoantigen- T cell pathway will be highlighted.

Everolimus is Safe as a Second-/Third-Line Therapy in Pediatric Autoimmune Hepatitis.

Pretransplant AIH patients aged 0-18 years who received everolimus therapy from 2014 to 2021 were retrospectively identified. All patients underwent regular plasma monitoring of everolimus trough levels to avoid toxicity and assess adherence. Special attention was paid to the clinical and biochemical occurrence of everolimus-related adverse events. We report six difficult-to-treat AIH patients who received everolimus therapy for 8-46 months (median 28 months). No side effects were reported when everolimus plasma trough levels were in the therapeutic range. Liver transaminases improved in 5 of 6 patients at everolimus introduction and significantly decreased at the last follow-up (FU) in our cohort (P < 0.05). None of our patients achieved complete biochemical remission at the last FU and 3 of 6 admitted to have suboptimal adherence to therapy. Our data bring preliminary safety for the use of everolimus as a second-/third-line therapy in pediatric AIH. Although liver transaminases improved in our cohort, prospective studies are needed to determine if everolimus can induce long-term remission.

Noninvasive biomarkers for the diagnosis and management of autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a rare disease of unclear etiology characterized by loss of self-tolerance that can lead to liver injury, cirrhosis, and acute liver failure. First-line treatment consists of systemic corticosteroids, or budesonide, and azathioprine, to which most patients are initially responsive, although predictors of response are lacking. Relapses are very common, correlate with histological activity despite normal serum transaminases, and increase hepatic fibrosis. Furthermore, current regimens lead to adverse effects and reduced quality of life, whereas medication titration is imprecise. Biomarkers that can predict the clinical course of disease, identify patients at elevated risk for relapse, and improve monitoring and medication dosing beyond current practice would have high clinical value. Herein, we review novel candidate biomarkers in adult and pediatric AIH based on prespecified criteria, including gene expression profiles, proteins, metabolites, and immune cell phenotypes in different stages of AIH. We also discuss biomarkers relevant to AIH from other immune diseases. We conclude with proposed future directions in which biomarker implementation into clinical practice could lead to advances in personalized therapeutic management of AIH.

Ultrastructural Profile Combined with Immunohistochemistry of a Hepatic Progenitor Cell Line in Pediatric Autoimmune Hepatitis: New Insights into the Morphological Pattern of the Disease.

Considering that the heterogenic population of a hepatic progenitor cell line (HPCL) can play a vital role in autoimmune hepatitis (AIH), we decided to conduct pioneering retrospective evaluation of these cells in pediatric AIH by means of transmission electron microscopy (TEM). The aim of the study was to assess the ultrastructure of the HPCL in children with untreated AIH. Ultrastructural analysis of the HPCL population, preceded by immunohistochemical staining for cytokeratin 7 (CK7), was performed using pretreatment liver biopsies from 23 children with clinicopathologically diagnosed AIH. Immunohistochemical assessment for CK7 allowed detection of proliferating immature epithelial cells differentiating towards periportal and intralobular intermediate hepatocytes without marked formation of ductular reactions in AIH children. Using TEM, we distinguished three morphological types of HPCs: I—the most undifferentiated progenitor cells; III—intermediate hepatocyte-like cells; II—intermediate bile duct cells. Most frequent were the cells differentiating towards hepatocytes, most rare—those differentiating towards cholangiocytes. The results indicate that an HPCL may be an important source of hepatocyte regeneration. Ultrastructural analyses of the HPCL population, combined with immunohistochemistry for CK7, might be a useful tool to evaluate liver cell regeneration, including fibrogenesis, and may help better understand the morphological pattern of the disease, in pediatric AIH. Frequent appearance of an HPCL in the vicinity of fibrotic foci, often accompanied by hyperactive Kupffer cells and transitional hepatic stellate cells, may indicate their significant involvement in liver fibrogenesis.

Update on the diagnosis of pediatric autoimmune hepatitis

Update on the diagnosis of pediatric autoimmune hepatitis

Clinical characteristics of paediatric autoimmune hepatitis at a referral hospital in Sub Saharan Africa.

Autoimmune hepatitis (AIH) is a progressive inflammatory liver disease of unknown aetiology. The number of reported AIH cases is increasing in the developed countries but the same cannot be said about sub Saharan Africa (SSA). Paediatric AIH diagnosis is usually missed and patients present with decompensated liver disease. Our study highlights the clinical profile of paediatric AIH cases at a referral hospital in Ghana. This is a retrospective review of all cases of children diagnosed with autoimmune hepatitis at the gastroenterology clinic in Korle Bu Teaching Hospital, Accra, Ghana. Data was extracted from the patients' records from April 2016 to October 2019. These children were diagnosed based on the presence of autoantibodies, elevated immunoglobulin G and histologic presence of interphase hepatitis with the exclusion of hepatitis A, B, C and E depending on their clinical presentation, Wilson's disease, HIV, Schistosomiasis and sickle cell disease. Thirteen patients aged between 5 years to 13 years with a mean age of 10 years were diagnosed with AIH. All the patients had type 1 AIH with majority 8 (61.5%) being females. Most of the children presented with advanced liver disease with complications. Three patients had other associated autoimmune diseases. The patients were treated with prednisolone with or without azathioprine depending on the severity of the liver disease. Majority of paediatric AIH presents with advanced liver disease. There is the need for early detection to change the natural history of AIH in SSA.

Multiparametric MRI as a Noninvasive Monitoring Tool for Children With Autoimmune Hepatitis.

Autoimmune hepatitis (AIH) is a progressive liver disease managed with corticosteroids and immunosuppression and monitored using a combination of liver biochemistry and histology. However, liver biopsy is invasive with risk of pain and bleeding. The aim of the present study was to investigate the utility of noninvasive imaging with multiparametric magnetic resonance imaging (MRI) (mpMRI) to provide clinically useful information on the presence and extent of hepatic inflammation, potentially guiding immunosuppression. Eighty-one participants (aged 6-18), 21 healthy and 60 AIH patients, underwent multiparametric MRI to measure fibro-inflammation with iron-corrected T1 (cT1) at the Children's Memorial Health Institute in Warsaw alongside other clinical blood tests and liver biopsy at recruitment and after an average of 16-month follow-up (range 9-22 months). Correlation analyses were used to investigate the associations between cT1 with blood serum markers and histological scores. At recruitment, patients with AIH had a higher cT1 value than healthy controls (P < 0.01). cT1 correlated significantly with key histopathological features of disease. Treatment naïve AIH patients showed evidence of inflammation and heterogeneity across the liver compared to healthy controls.At follow-up, cT1 showed utility in monitoring disease regression as most patients showed significantly reduced fibro-inflammation with treatment (P < 0.0001) over the observational period. Six patients had histological fibrosis and clear fibro-inflammation on MR despite biochemical remission (normalized aspartate aminotransferase (AST), alanine aminotransferase (ALT), and immunoglobulin G [IgG]). Multiparametric MRI can measure disease burden in pediatric AIH and can show changes over time in response to therapy. Active disease can be seen even in biochemical remission in children.

Clinical and laboratory data in pediatric autoimmune hepatitis: study from referral center in Iran

Background: Autoimmune hepatitis (AIH) is an auto-inflammatory liver disease of children and adults, affecting patients of any age, sex, race or ethnicity, with more prevalence in females. Objective: The aim of this study was to evaluate clinical manifestation, laboratory findings, and outcome of children with autoimmune hepatitis. Materials and methods: We evaluated 86 patients treated and followed with final diagnosis of AIH between years 2010 to 2018. Physical findings (including jaundice, hepatomegaly, splenomegaly and encephalopathy), liver enzymes, liver histology and autoantibodies (including ANA, Anti LKM-1 and ASMA) were extracted from medical files. Then the patients were followed for their final outcome (including response to medical treatment or successful treatment withdrawal, liver transplantation or death). Results: Among 86 patients with AIH with mean age 9.10±4.36 years old, 66.27% were females. Jaundice (75.6%) and hepatomegaly (46.5%) were the most frequent physical findings, followed by splenomegaly (32.6%) and encephalopathy (17.4%). Aminotransferases including AST and ALT were elevated at least 3 times more than upper limit of normal in most of the patients (61.6% and 55.81%, respectively). Autoantibodies were available in 53 of 86 patients, 24.5% had AIH-1, 3.8% had AIH-II and 67.9% were seronegative. Medical treatment including prednisolone and azathioprine was started for patients, 53 of 86 cases (61.6%) had remission and 11 of 86 (13.7%) tolerated medication withdrawal successfully. Among all cases, 26 (30.2%) patients needed liver transplantation. Mortality rate was 9 among dice and hepatomegaly was the most frequent clinical findings. Mortality rate was 10.5%.

Soluble PD1 levels are increased with disease activity in paediatric onset autoimmune hepatitis and inflammatory bowel disease

Introduction: Immune mediated liver diseases entail a broad category which are associated with increased morbidity and mortality amongst the paediatric population. Programmed Death 1 (PD1) is an inhibitory receptor mainly expressed by T cells, and when activated shed into plasma as soluble PD1(sPD1). The AIM of this study was to evaluate sPD1 levels in plasma of paediatric patients with Autoimmune Hepatitis (AIH), Primary Sclerosing Cholangitis (PSC), AIH and PSC overlap, Inflammatory Bowel Disease (IBD) alone, and concurrent PSC/IBD and AIH/IBD in order to identify a biomarker to response or predict relapse verses remission.Methods: Plasma samples were collected from 41 paediatric patients. AIH patients were further categorized into active, incomplete responders and responders, based on response to standard therapy. sPD1 levels were measured and compared between PSC, PSC/AIH, IBD alone, PSC/IBD and AIH/IBD patients and between active AIH, incomplete responders and responders. Flow cytometry was performed to further analyze CD45RA+, CD3CD4, CD8, CCR7, CXCR3, CD38 and PD1.Results: In the AIH group, those with active disease demonstrated a significantly higher sPD1 levels in comparison to responders (*p > .001). However, the incomplete responders didn’t show a reduction in sPD1 in comparison to active AIH and patients with IBD alone. Interestingly, patients with PSC showed significantly lower level of sPD1 compared to active AIH (*p < .002), whereas, patients with PSC in conjunction with AIH (*p < .006) or IBD (*p < .02) demonstrated a significant increase in sPD1. In addition, we have observed increased levels of circulating CD4 and CD8 bound PD1 in active AIH but not in PSC or responders suggesting T cells activation. CD4+ PD1 double positive cells demonstrated increased expression of CXCR3. Thus, suggesting the activation of PD1 + T cells is mediating through CXCR3 in Autoimmune hepatitis.Conclusions: Our study demonstrates that sPD1 levels correlate with active disease state of AIH and IBD. sPD1 levels did not correlate with PSC. However, PSC in conjunction with AIH or IBD showed higher levels of sPD1. This suggests that T cell activation plays a critical role in active AIH and IBD but not in PSC. Soluble PDI levels could be used as a clinical biomarker to assess response in patients with AIH and for prospectively monitoring PSC patients for development of IBD or AIH.

Polymorphism in Macrophage Migration Inhibitory Factor -173GC in Pediatric Patients with Autoimmune Hepatitis

PurposeAutoimmune hepatitis (AIH) is a chronic disease that may lead to cirrhosis. The immunopathogenesis of AIH is not fully understood and it mainly involves T-cell mediated mechanism. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that promotes T cell response and its polymorphism may serve as a severity marker of AIH. No previous study has considered investigating MIF polymorphism in children with AIH.MethodsForty-two children with definite diagnosis of AIH were enrolled along with 100 age and sex matched controls. All participants were tested for polymorphism at -173GC (rs755622) of MIF gene. All patients received the standard protocol of steroid plus azathioprine to achieve remission. Liver biopsy was performed at time of diagnosis for all patients and only 18 of them underwent a second biopsy after treatment.ResultsNo statistically significant differences in the frequency of the genotypes GG and GC or in allele distribution were found in both patient and control groups (p=0.590, 0.640 respectively). Initial alanine aminotransferase (ALT) levels at the time of presentation was significantly higher in the GC group than GG group (p=0.020). GC genotype significantly correlated with disease relapse (r=0.41, p=0.007). Regression of necroinflammation and the fibrosis score in the second liver biopsy was statistically significant in the GG group (p<0.0001, p=0.010 respectively).ConclusionMIF -173GC polymorphism is associated with clinically significant markers of pediatric AIH, including increased initial serum ALT levels, may help predict necroinflammatory/fibrosis regression effectively, following immunosuppressive treatment.

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

BackgroundChildren with autoimmune hepatitis (AIH) often exhibit particular features. Accordingly, seven pediatric-specific criteria have been proposed. AimTo develop a prediction model based on them, transform it into a scoring system and study its accuracy. MethodsA 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. ResultsAmong 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%. ConclusionPediatric-specific criteria for the diagnosis of AIH can be reliably used as a scoring system.

Racial disparities in presentation and outcomes of paediatric autoimmune hepatitis.

Most studies on autoimmune hepatitis (AIH) in children are in predominantly Caucasian cohorts. Paediatric AIH in African Americans (AA) is understudied, with a dearth of clinical predictors of outcome, often leading to serious complications and even mortality. The aim of the study was to define disease presentation, progression, response to therapy and outcomes in paediatric AIH in a well-defined, large, single centre, demographically diverse population. We conducted a review of patients with AIH who were followed at this tertiary liver transplant centre. Clinical and laboratory covariates were assessed with regard to disease presentation, progression and outcomes in AA vs Non-AA children. African Americans patients constituted 42% of this cohort. At 1-year follow-up, AA children were receiving significantly higher doses of steroids compared to non-AA. More AA presented with end-stage liver disease (ESLD) with high immunoglobulin G and GGT:platelet ratio. After adjusting for other risk factor variables like gender, age at presentation and ESLD, AA children were at 4.5 times higher risk for significant outcome liver transplant/death within the first 12months of presentation. Post-transplant, recurrent AIH was seen in 50% of AA vs 8% in non-AA. African American patients with AIH are more likely to present with ESLD and have an increased early risk for transplantation with high likelihood of disease recurrence post-transplantation. Studies are needed to delineate factors such as inherent biology, genetics and access to care. Early referral and tailored immunosuppressive regimens are required for AA patients with AIH.