Autoimmune Sclerosing Cholangitis Research Articles

Autoimmune hepatitis – an increasingly common cause of hypertransaminasaemia among children. Case report and literature review

Autoimmune hepatitis is a chronic inflammatory process of unknown ethology, characterised by high levels of transaminases and IgG antibodies, the presence of tissue autoantibodies, and a typical histological picture. In the population of children, the paediatric form of autoimmune hepatitis and autoimmune sclerosing cholangitis are collectively classified as juvenile autoimmune liver disease. The condition often coexists with other autoimmune disorders. This paper aims to present the clinical profile of a paediatric patient with full-blown autoimmune hepatitis and describe the available therapies. The patient, a 13-year-old boy, was referred to a specialised hospital because of increasing hypertransaminasaemia. The patient was hospitalised for the first time at a district hospital for abdominal pain, and during his stay, elevated transaminases were found with a tendency to increase in follow-up tests. The picture suggested an inflammatory process of the liver and biliary tract. Upper gastrointestinal endoscopy revealed lesions consistent with chronic gastritis and portal gastropathy. Treatment included thiazolidinedioic acid, vitamin K, ursodeoxycholic acid, rifaximin, ciprofloxacin, and proton pump inhibitors. Therapy is aimed at maintaining immunosuppression and inhibiting the inflammatory response that leads to cirrhosis, and most commonly uses steroids alongside proton pump inhibitors for added protection or, alternatively, mycophenolate mofetil, cyclosporine A, tacrolimus, and biologic therapy. Ursodeoxycholic acid also exhibits immunomodulatory properties and makes it possible to reduce steroid doses and thus decrease the likelihood of adverse effects of therapy.

Association Between MR Elastography Liver Stiffness and Histologic Liver Fibrosis in Children and Young Adults With Autoimmune Liver Disease.

Background: Liver fibrosis is an important clinical endpoint of progression of autoimmune liver disease (AILD); its monitoring would benefit from noninvasive imaging tools. Objective: To assess the relationship between MR elastography (MRE) liver stiffness measurements and histologic liver fibrosis, as well as to evaluate the performance of MRE and biochemical-based clinical markers for stratifying histologic liver fibrosis severity, in children and young adults with AILD. Methods: This retrospective study used an existing institutional registry of children and young adults diagnosed with AILD [primary sclerosing cholangitis (PSC), ASC (autoimmune sclerosing cholangitis), or AIH (autoimmune hepatitis)]. The registry was searched to identify patients who underwent both a research abdominal 1.5-T MRI that included liver MRE (performed for registry enrollment) and a clinically indicated liver biopsy within a 6-month interval. MRE used a 2D gradient-recalled echo sequence. One analyst measured mean liver shear stiffness (kPa) for each examination. Laboratory markers of liver fibrosis [aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 score (FIB-4)] were recorded. For investigational purposes, one pathologist determined histologic METAVIR liver fibrosis stage, blinded to clinical and MRI data. Spearman rank-order correlation was calculated between MRE liver stiffness and METAVIR liver fibrosis stage. ROC analysis was used to evaluate diagnostic performance for identifying advanced fibrosis (i.e., differentiating METAVIR F0-F1 from F2-F4 fibrosis), calculating sensitivity and specificity at the Youden's index. Results: The study included 46 patients (median [IQR] age, 16.6 [13.7-17.8] years; 20 female, 26 male); 12 had PSC, 10 had ASC, and 24 had AIH. Median MRE liver stiffness was 2.9 kPa (IQR: 2.2-4.0 kPa). MRE liver stiffness and METAVIR fibrosis stage showed strong positive correlation (rho=0.68). For identifying advanced liver fibrosis, MRE liver stiffness had AUC of 0.81, with sensitivity of 65.4% and specificity of 90.0%; APRI had AUC of 0.72, with sensitivity of 60.0% and specificity of 85.0%; and FIB-4 had AUC of 0.71, with sensitivity of 64.0% and 85.0%. Conclusion: MRE liver stiffness measurements were associated with histologic liver fibrosis severity. Clinical Impact: The findings support a role for MRE in noninvasive monitoring of liver stiffness, a surrogate for fibrosis, in children and young adults with AILD.

Epidemiology, clinical features and management of autoimmune hepatitis in Switzerland: a retrospective and prospective cohort study.

The Swiss Autoimmune Hepatitis Cohort Study is a nationwide registry, initiated in 2017, that collects retrospective and prospective clinical data and biological samples from patients of all ages with autoimmune hepatitis treated at Swiss hepatology centres. Here, we report the analysis of the first 5 years of registry data. A total of 291 patients with autoimmune hepatitis have been enrolled, 30 of whom were diagnosed before 18 years of age and composed the paediatric cohort. Paediatric cohort: median age at diagnosis 12.5 years (range 1-17, interquartile range (IQR) 8-15), 16 (53%) girls, 6 (32%) with type 2 autoimmune hepatitis, 8 (27%) with autoimmune sclerosing cholangitis, 1 with primary biliary cholangitis variant syndrome, 4 (15%) with inflammatory bowel disease and 10 (41%) with advanced liver fibrosis at diagnosis. Adult cohort: median age at diagnosis 54 years (range 42-64, IQR 18-81), 185 (71%) women, 51 (20%) with primary biliary cholangitis variant syndrome, 22 (8%) with primary sclerosing cholangitis variant syndrome, 9 (4%) with inflammatory bowel disease and 66 (32%) with advanced liver fibrosis at diagnosis. The median follow-up time for the entire cohort was 5.2 years (IQR 3-9.3 years). Treatment in children: 29 (97%) children were initially treated with corticosteroids, 28 of whom received combination treatment with azathioprine. Budesonide was used in four children, all in combination with azathioprine. Mycophenolate mofetil was used in five children, all of whom had previously received corticosteroids and thiopurine. Treatment in adults (data available for 228 patients): 219 (96%) were treated with corticosteroids, mostly in combination with azathioprine. Predniso(lo)ne was the corticosteroid used in three-quarters of patients; the other patients received budesonide. A total of 78 (33%) patients received mycophenolate mofetil, 62 of whom had previously been treated with azathioprine. Complete biochemical response was achieved in 13 of 19 (68%) children and 137 of 182 (75%) adults with available follow-up data. All children were alive at the last follow-up, and none had undergone liver transplantation. Five (2%) adults underwent liver transplantation, two of whom had a fulminant presentation. Four (2%) adults with autoimmune hepatitis died (two from liver-associated causes). Patients with autoimmune hepatitis in Switzerland had clinical features similar to those in other cohorts. The proportion of patients diagnosed with primary biliary cholangitis variant syndrome was higher than expected. Autoimmune hepatitis was managed according to guidelines, except for the use of budesonide in a small proportion of paediatric patients. The outcomes were excellent, but the findings must be confirmed over a longer follow-up period.

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.

Longitudinal changes in quantitative magnetic resonance imaging metrics in children and young adults with autoimmune liver disease.

To assess longitudinal changes in quantitative MRI metrics in pediatric and young adult patients with autoimmune liver disease (AILD). This prospective, IRB-approved study included 20 children and young adults (median age = 15years) with primary sclerosing cholangitis (PSC)/autoimmune sclerosing cholangitis (ASC) and 19 (median age = 17years) with autoimmune hepatitis (AIH). At a field strength of 1.5-T, T2*-corrected T1 mapping (cT1), 3D fast spin-echo MRCP, and 2D gradient recalled echo MR elastography (MRE) were performed at baseline, one year, and two years. cT1 and quantitative MRCP were processed using LiverMultiScan and MRCP + , respectively (Perspectum Ltd, Oxford, UK). Linear mixed models were used to assess longitudinal changes in quantitative MRI metrics. Spearman rank-order correlation was used to assess relationships between changes in quantitative MRI metrics. Changes in quantitative MRI metrics greater than established repeatability coefficients were measured in six (cT1) and five (MRE) patients with PSC/ASC as well as in six patients (cT1 and MRE) with AIH, although linear mixed models identified no significant changes for the subgroups as a whole. For PSC/ASC, there were positive correlations between change in liver stiffness and changes in bile duct strictures (ρ = 0.68; p = 0.005) and bile duct dilations (ρ = 0.70; p = 0.004) between baseline and Year 2. On average, there were no significant changes in quantitative MRI metrics over a two-year period in children and young adults with AILD. However, worsening cholangiopathy was associated with increasing liver stiffness by MRE in patients with PSC/ASC.

Natural history and prognosis of pediatric PSC with updates on management.

Natural history and prognosis of pediatric PSC with updates on management.

P210 Long-term outcome of very early onset inflammatory bowel disease associated with primary sclerosing cholangitis: a multicenter study from the Pediatric IBD Porto Group of ESPGHAN

Abstract Background Primary sclerosing cholangitis related to inflammatory bowel disease (PSC-IBD) diagnosed under the age of 6 years (i.e., VEO-IBD) may have unique characteristics and disease course. We aimed to analyze the characteristics and natural history of children with VEO PSC-IBD and compare them to children diagnosed with PSC-IBD at an older age. Methods This was a multicenter, retrospective, study evaluating patients diagnosed with both IBD and PSC before (VEO-PSC-IBD) or after the age of 6 years (PSC-IBD), followed at 14 centers affiliated with the Porto IBD Interest group of ESPGHAN. Demographic, clinical, laboratory, endoscopic, and imaging data were collected at baseline and every six months thereafter for a minimum follow-up of 12 months. IBD-related (clinical remission, need for systemic steroids, therapy escalation and surgery) and PSC-related outcomes (biliary and portal hypertensive complications, need for treatment escalation and liver transplantation, cholangiocarcinoma, and death) were analyzed at 1, 3, and 5 years. Results A total of 69 children with both IBD and PSC were included: 28 with VEO PSC-IBD [median age 5.2 (3.7-5.9) years, 21 UC (75%), 4 IBDU (14%) and 3 (15%) CD] and 41 with PSC-IBD [median age 15.7 (13.3-16.9) years, 34 UC (83%), 6 IBDU (1.5%) and 1 (0.2%) CD]. IBD was diagnosed prior to PSC in 28 of the 69 patients (40%), simultaneously in 30 (43%), and after PSC in 11 (16%), with no significant differences between VEO PSC-IBD and PSC-IBD. Most patients with UC presented with extensive disease at diagnosis (89% in VEO PSC-UC vs. 89% in PSC-UC, p = 0.72). Both groups presented most often with mild intestinal disease at diagnosis (mean PUCAI of VEO IBD-PSC 34±16, vs 31±19 of IBD-PSC, p=0.11; mean PCDAI 31±33 vs. 21±27, respectively, p=0.14). A higher number of VEO-IBD-PSC patients were diagnosed with autoimmune sclerosing cholangitis than older children [24 (86%) vs. 27 (66%) PSC-IBD, p=0.04], whereas no other differences were found for PSC-related variables. During follow-up, no significant differences were found in major IBD outcomes. The risk of developing biliary strictures and escalating therapy to vancomycin from ursodeoxycholic acid was lower in the VEO-PSC-IBD group (Figure 1 and 2, Log-rank p=0.02 and p=0.02), while no difference was found for portal hypertension and liver transplantation at 5-year follow-up. No cases of cholangiocarcinoma or death were reported. Conclusion IBD-PSC has similar baseline characteristics whether diagnosed as VEO-IBD or thereafter. However, a milder disease course in terms of biliary complications and the need for PSC-related therapy escalation, with an overall mild intestinal disease at presentation in all patients, characterize this specific subcohort of patients.

Association of HLA DRB1 Allele Profile with Pediatric Autoimmune Liver Disease in India

The aim of this study is to study the association of human leukocyte antigen (HLA) DRB1 alleles with treatment response in Indian children with autoimmune liver disease (AILD). HLA DRB1 alleles of 71 Indian children with pediatric AILD (pAILD) were analyzed along with 25 genetically confirmed patients with Wilson disease as controls. After 1 year of therapy, all those who failed to normalize aspartate & alanine transferase (AST/ ALT) (below 1.5 times of upper limit of normal) and/or failed to normalize IgG levels, or who had >2 relapses (AST/ALT levels >1.5 times of upper limit of normal) while on treatment, were labeled as difficult to treat (DTT). HLA DRB1∗3 was found to be significantly associated with AIH type 1 (46.2% vs. 4% in controls; P corrected=0.011). Majority of the patients [55 (77.5%)] had chronic liver disease at presentation, with 42 (59.2%) having portal hypertension and 17 (23.9%) having ascites. Out of the 71 with pAILD, 19 (26.8%) were DTT. HLA DRB1∗14 was found to be independently associated with DTT cases (36.8% vs. 9.6%, OR 5.87, 95% CI 1.07-32.09, P= 0.041). Other factors independently associated with DTT were presence of autoimmune sclerosing cholangitis (OR 8.57, P=0.008) and high-risk varices (OR 7.55, P=0.016), improving the correctness of classification of the model from 73.2% to 84.5%. HLA DRB1∗14 is independently associated with treatment response in pAILD and HLA DRB1∗3 is associated with AIH type 1. HLA DRB1 alleles may thus provide supportive information for diagnosis and prognosis of AILD.

Hepatic Dry Copper Weight in Pediatric Autoimmune Liver Disease.

Elevated hepatic dry copper weight is recognized in adults with autoimmune liver disease (AILD) and chronic cholestasis. We aim to review hepatic dry copper weight in pediatric AILD. Retrospective review of pediatric AILD managed at our institution from 1999 to 2018, and 104 patients with hepatic dry copper weight assessment were included. Median age at presentation was 13.4 years (interquartile range, IQR, 11.7-14.9), 60% female, 54% autoimmune hepatitis, 42% autoimmune sclerosing cholangitis, and 4% primary sclerosing cholangitis. Histological features of advanced liver fibrosis in 68%. Median hepatic dry copper weight was 51.1 µg/g dry weight (IQR, 28.0-103.8). Elevated hepatic dry copper weight (>50 µg/g dry weight) was present in 51%, and was not associated with AILD subtype ( P = 0.83), age at presentation ( P = 0.68), or advanced fibrosis ( P = 0.53). Liver transplantation (LT) was performed in 10%, who had higher hepatic dry copper weight (148.5 µg/g dry weight [IQR, 39.5-257.3] vs 47.5 [IQR, 27.8-91.5], P = 0.04); however this was not associated with LT on multivariate analysis (hazard ratio 1.002, 95% CI 0.999-1.005, P = 0.23). In 8 (7.7%) patients ATP7B was sequenced and potentially disease causing variants were identified in 2 patients, both who required LT. Elevations in hepatic dry copper weight are common in pediatric AILD. Unlike in adults, it is not associated with AILD subtypes with cholestasis. Higher dry copper weight was detected in patients who required LT. While further work is needed to identify the significance of copper deposition in pediatric AILD, we recommend close monitoring of patients with elevated levels for progressive liver disease.

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.

HLA, gut microbiome and hepatic autoimmunity.

Genetic susceptibility to autoimmune liver diseases is conferred mainly by polymorphisms of genes encoding for the human leukocyte antigens (HLA). The strongest predisposition to autoimmune hepatitis type 1 (AIH-1) is linked to the allele DRB1*03:01, possession of which is associated with earlier disease onset and more severe course. In populations where this allele is very rare, such as in Asia, and in DRB1*03-negative patients, risk of AIH-1 is conferred by DRB1*04, which is associated with later disease onset and milder phenotype. AIH type 2 (AIH-2) is associated with DRB1*07. The pediatric condition referred to as autoimmune sclerosing cholangitis (ASC), is associated with the DRB1*13 in populations of Northern European ancestry. DRB1*1501 is protective from AIH-1, AIH-2 and ASC in Northern European populations. Possession of the DRB1*08 allele is associated with an increased risk of primary biliary cholangitis (PBC) across different populations. DRB1*03:01 and B*08:01 confer susceptibility to primary sclerosing cholangitis (PSC), as well as DRB1*13 and DRB1*15 in Europe. The hepatic blood supply is largely derived from the splanchnic circulation, suggesting a pathophysiological role of the gut microbiome. AIH appears to be associated with dysbiosis, increased gut permeability, and translocation of intestinal microbial products into the circulation; molecular mimicry between microbial and host antigens may trigger an autoaggressive response in genetically-predisposed individuals. In PBC an altered enteric microbiome may affect intestinal motility, immunological function and bile secretion. Patients with PSC have a gut microbial profile different from health as well as from patients with inflammatory bowel disease without PSC.

Long-Term Follow-Up into Adulthood of Pediatric-Onset Primary Sclerosing Cholangitis and Autoimmune Sclerosing Cholangitis.

We reviewed records of patients followed for PSC or AIC between 1998 and 2019 at a pediatric referral center. Features at diagnosis, biochemical and liver-related outcomes (cholangitis, liver transplant, and cirrhosis) were compared. Forty patients (27 PSC, 13 AIC) were followed for 92 months on average (standard deviation 79 months) with extension into adulthood in 52.5%; 70% had associated inflammatory bowel disease (IBD). The proportion of patients with significant fibrosis and abnormal baseline liver tests (serum bilirubin and transaminase levels) were similar in both groups. One year postdiagnosis, 55% (15/27) of PSC patients had normal liver tests versus only 15% (2/13) in the AIC group (P = 0.02). During follow-up, more liver-related events occurred in the AIC group (69% versus 27%, hazard ratio [HR] = 3.7 [95% confidence interval (CI): 1.4-10] P = 0.01). Baseline elevated serum bilirubin levels (HR = 5.3 [95% CI: 1.7-16.9] P = 0.005) and elevated transaminase levels at 1 year (HR = 9.09 [95% CI: 1.18-66.7) P = 0.03) were predictive of liver-related events, while having IBD was not (HR = 0.48 (95% CI: 0.15-1.5) P = 0.22). Pediatric patients with AIC and PSC presented at a similar fibrosis stage, however, with a more severe hepatitis in AIC. In this cohort, AIC was associated with more liver-related events, primarily driven by a higher rate of cirrhosis compared with PSC; transplant rates were similar.

Clinical course of inflammatory bowel disease and impact on liver disease outcomes in patients with autoimmune sclerosing cholangitis

Background & AimsAutoimmune sclerosing cholangitis (ASC) is a childhood sclerosing cholangitis frequently associated with inflammatory bowel disease (IBD). We describe the IBD phenotype in ASC patients and associated liver disease outcomes. MethodsSingle center retrospective observational review of ASC patients, with a control population of pediatric IBD. Demographic and clinical parameters were obtained. Clinical endpoints were escalation of IBD therapy (biologic or colectomy) and transplant-free survival. ResultsIn 93 ASC patients (53.8% female) and median follow up of 172 months: 70% had IBD, 25.8% underwent liver transplant. Median age at liver transplant was 21.7 years, at 131 months from ASC diagnosis. There was no association between presence of IBD and transplant-free survival, whilst those requiring second-line immunomodulators for ASC had poorer long-term liver prognosis. During follow-up 22 (33.8%) ASC-IBD required biologic or colectomy. On multivariate analysis ASC was associated with a lower risk of escalation of IBD therapy (HR 0.14, 95% CI 0.05–0.42; P=.001), including biologic therapy (HR 0.21, 95% CI 0.08–0.55, P=.002), but not colectomy on univariate analysis (HR 1.54, 95% CI 0.43–5.44, P=.51). ConclusionsIBD is common in ASC and during longterm follow up a third of ASC-IBD required escalation of IBD therapy; however ASC-IBD was lower risk compared to IBD alone. IBD does not appear to impact on transplant-free survival in patients with ASC, however second-line immunomodulators for ASC are associated with poorer IBD and liver outcomes.

The Covert Surge: Murine Bile Acid Levels Are Associated With Pruritus in Pediatric Autoimmune Sclerosing Cholangitis.

ObjectivesThe exact etiology of pruritus in chronic cholestasis is unknown. Pruritus intensity does not correlate with common biochemical indices and there is a lack of biomarkers guiding diagnosis and treatment. We explored profiles of bile acids (BA) and muricholic acids (MCA) as well as autotaxin (ATX) antigen levels as potential circulating biomarkers of pruritus in pediatric patients.MethodsIn 27 pediatric cholestatic patients [autoimmune sclerosing cholangitis (ASC) n = 20 (with pruritus n = 6, without pruritus n = 14); progressive familial intrahepatic cholestasis (PFIC) n = 7 (with pruritus n = 5, without pruritus n = 2)] and 23 age-matched controls pruritus was assessed by a visual analog scale of pruritus (PVAS). We obtained profiles of serum human BA including MCA using a mass-spectrometry assay and ATX antigen levels with a commercial ELISA.ResultsPFIC and ASC patients exhibited significantly higher BA-, and MCA levels, than healthy controls, but only PFIC patients showed elevated ATX antigen levels higher [median: 1,650 ng/ml, interquartile rang (IQR): 776.9–3,742] compared to controls (median: 315.9 ng/ml, IQR: 251.1–417.2; PFIC p = 0.0003). ASC patients with pruritus showed only a minor increase in total BA (tBA) levels (median: 76.5 μmol/L, IQR: 54.7–205), but strikingly higher T-conjugated BA (median: 16.4 μmol/L, IQR: 8.9–41.4) and total MCA (tMCA) (median: 1.15 μmol/L, IQR: 0.77–2.44) levels compared to ASC patients without pruritus (tBA median: 24.3 μmol/L, IQR: 16.2–80.8; p < 0.0408; T-conjugated BA median: 1.3 μmol/L, IQR: 0.8–4.9; p = 0.0023; tMCA median: 0.30 μmol/L, IQR: 0.13–0.64, p = 0.0033). BA/MCA profiles distinctly differed depending on presence/absence of pruritus. Different from PFIC patients, ATX antigen levels were not significantly elevated in ASC patients with (median: 665.8 ng/ml, IQR: 357.8–1,203) and without pruritus (median: 391.0 ng/ml, IQR: 283.2–485.6). In ASC patients, tBA, tMCA, and ATX antigen levels did not correlate with pruritus severity.ConclusionDespite the same underlying disease, pediatric ASC patients with pruritus exhibit significantly altered BA profiles and MCA levels compared to ASC patients without pruritus. ATX antigen levels seem to have little diagnostic or prognostic meaning in ASC patients. An increased ATX activity alone seems not to be causal for pruritus genesis in ASC patients.Clinical Trial Registration[www.drks.de], identifier [DRKS00026913].

Cutting edge issues in juvenile sclerosing cholangitis.

Sclerosing cholangitis (SC) is a rare chronic disorder characterised by inflammation and progressive obliterative fibrosis of the intrahepatic and/or extrahepatic bile ducts. Diagnosis is based on cholangiogram showing bile duct dilatation, narrowing and obliteration of the biliary tree, and histologically, on the presence of inflammatory bile duct damage leading to periductal fibrosis. In children the most common SC is associated with strong autoimmune features, overlapping with those of autoimmune hepatitis (AIH); this form is known as autoimmune sclerosing cholangitis, ASC. Conversely, primary SC (PSC), a condition in which the term "primary" indicates that aetiology and pathogenesis are unknown, is rare in paediatrics. Secondary SC (SSC) defines a cholangiopathy associated with an identifiable aetiology such as immunodeficiencies, infections or haematological disorders. ASC and PSC are strongly associated with inflammatory bowel disease (IBD). ASC responds biochemically well to immunosuppressive drugs and ursodeoxycholic acid (UDCA). Primary forms are exclusively managed with oral UDCA, while in the secondary forms the medical treatment depends on the underlying aetiology. Despite treatment, SC often progresses to biliary cirrhosis and end-stage liver disease requiring liver transplantation. The disease can recur after transplant. Better understanding of pathogenic mechanisms and better treatment modalities are needed to improve the prognosis of this invalidating hepatic disorder.

Expression of IL-37 Correlates With Immune Cell Infiltrate and Fibrosis in Pediatric Autoimmune Liver Diseases.

The activation of innate immune mechanisms is key for chronic liver injury. Interleukin-37 (IL-37) is a profound inhibitor of innate and adaptive immune responses, and its overexpression protects mice from liver inflammation and fibrosis. Here, we characterize the hepatic inflammatory infiltrate and expression of IL-37 in children with autoimmune liver diseases. We compared the inflammatory microenvironment of the liver in a retrospective cohort of children with primary sclerosing cholangitis (PSC), autoimmune sclerosing cholangitis (ASC) and autoimmune hepatitis (AIH) by immunohistochemistry. The expression of IL-37 was quantified in liver parenchyma and portal tracts. Double immunofluorescence was used for detection of IL-37 in specific cell types and colocalization with Smad3. AIH is characterized by a dense lymphoplasmacytic infiltrate whereas ASC shows high numbers of granulocytes in portal tracts. IL-37 expression correlates positively with liver inflammation and fibrosis, the number of infiltrating immune cells and serum markers for hepatic inflammation. IL-37 is mainly expressed in hepatocytes, cholangiocytes and infiltrating immune cells. Double staining revealed IL-37 positivity in T helper and regulatory T cells (Treg), Kupffer (KC) and hepatic stellate cells (HSC). IL-37 colocalizes with intranuclear pSmad3L in areas of liver inflammation. Pediatric ASC separates from PSC and AIH by a granulocyte-rich portal infiltrate. Upregulation of IL-37 with liver injury, the expression in Treg as well as KC and HSC and the colocalization of IL-37 with pSmad3L in cholangiocytes and hepatocytes suggest a modulating role to limit hepatic inflammation and fibrosis in pediatric autoimmune liver diseases.

Treatment and outcomes of autoimmune hepatitis in children

Introduction. Autoimmune hepatitis (AIH) is one of the auto­im­mune liver disorders recognized in children, along with autoimmune sclerosing cholangitis (ASC) and de novo AIH after liver transplant. This study aimed to as­sess the treatment in children with AIH, and to identify cor­re­la­tions with disease outcomes. Materials and method. In this retrospective study, we included 30 hospitalized chil­­dren with AIH, followed-up in our clinic over six years. All patients met the International Autoimmune Hepatitis Group’s simplified diagnostic criteria (IAIHG criteria). Results. Pediatric patients with AIH were aged between 4 months old and 17 years and 8 months old, with a mean age of 6.5 years old. There were 19 girls and 11 boys. Most pa­tients had an acute onset of the disease. Three patients de­ve­loped acute liver failure. All patients had elevated tran­sa­mi­na­ses and 16 patients had cholestasis. Most pa­tients had increased IgG levels. There were 20 children with type I AIH with SMA and ANA, and 10 children with type II AIH with anti-LKM-1 and anti-LC-1. All patients re­ceived prednisone from the diagnosis. Fifteen patients re­quired the addition of azathioprine. Full clinical recovery with a normal level of transaminases was achieved in 18 pa­tients. Complete remission was achieved in 10 patients. Most children had a favorable outcome, with only five pa­tients presenting cirrhosis. Two children died due to com­pli­ca­tions of autoimmune cirrhosis. Conclusions. The out­come of chil­dren with AIH treated with immediate im­mu­no­sup­pres­sive therapy is favorable, with good long-term survival rates and with a positive effect on the quality of life.

Use of oral vancomycin in children with autoimmune liver disease: A single centre experience.

BACKGROUNDPrevious reports showed some beneficial effect of oral vancomycin treatment (OVT) in children with primary sclerosing cholangitis; conversely, the experience in patients with other autoimmune liver diseases (AILD), including autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC), is scant. AIMTo assess the response to immunosuppressive treatment (IS) and to OVT in children diagnosed with AILD.METHODSRetrospective study of children diagnosed with AIH (normal biliary tree at cholangiography) and ASC (abnormal biliary tree at cholangiography) in the last 10 years. All underwent standard immunosuppressive therapy (IS), but non-responders received also OVT. Biochemical remission [normal aspartate aminotransferase (AST)] and immunological remission (normal IgG and negative autoantibodies) rates and Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) index were assessed and compared during the follow up.RESULTS75 children were included [69% female, median age 10.5 years (5.6-13.4 years), AIH = 54, ASC= 21]. Sixty-three patients (84%, AIH = 52, ASC = 11) were treated with standard IS and 61 achieved biochemical remission, whereas 12 not responding to IS [16%, F = 75%, median age 13.5 years, (12.2-15.7), 10 with ASC] required OVT and 8 achieved biochemical remission. Overall OVT increased the biochemical remission rate of the whole group of AILD patients from 81% (61/75) to 92% (69/75). Median values of AST, alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) decreased significantly after OVT start (P < 0.05). Complete normalization of livers enzymes (AST, ALT and GGT) was observed in 6/12 patients (50%). Decrease in SCOPE index score was reported in 5/12 patients (42%). At last follow up (median of 4.4 years, range 0.6-13.8 years) all 75 patients are alive, 6 (8%, 1 with ASC) successfully discontinued medications, 1 (with ASC) required liver transplantation.CONCLUSIONChildren with AIH and ASC respond well to IS treatment. OVT may represent a valuable treatment option to achieve biochemical remission in patients not responding to standard IS. These promising preliminary results suggest that a prospective study is indicated to define the efficacy of OVT in AILD.

АУТОИММУННЫЕ ХОЛЕСТАТИЧЕСКИЕ ПОРАЖЕНИЯ ЖЕЛЧНЫХ ПРОТОКОВ

The review presents literature data and original findings of light and electron microscopy of pathomorphological changes in the bile ducts in primary sclerosing cholangitis (PSC), immunoglobulin G4 (IgG4)-associated autoimmune sclerosing cholangitis and overlap syndromes: PSC + chronic autoimmune hepatitis (AIH); PSC + primary biliary cirrhosis (PBC).

Associations between MRI T1 mapping, liver stiffness, quantitative MRCP, and laboratory biomarkers in children and young adults with autoimmune liver disease

PurposeDefine relationships between quantitative magnetic resonance imaging (MRI) metrics and clinical/laboratory data in a pediatric and young adult cohort with autoimmune liver disease (AILD).Materials and methodsThis prospective, cross-sectional study was institutional review board-approved. Patients enrolled in an institutional AILD registry were divided into groups: (1) autoimmune hepatitis (AIH) or (2) primary sclerosing cholangitis (PSC)/autoimmune sclerosing cholangitis (ASC). Participants underwent serum liver biochemistry testing and research MRI examinations, including 3D magnetic resonance cholangiopancreatography (MRCP), magnetic resonance elastography (MRE), and iron-corrected T1 mapping (cT1). MRCP + and LiverMultiScan (Perspectum Ltd., Oxford, UK) were used to post-process 3D MRCP and cT1 data. Multiple linear regression models were used to assess relationships.Results58 patients, 35 male, median age 16 years were included; 30 in the AIH group, 28 in the PSC/ASC group. After statistical adjustments for patient age, sex, presence of inflammatory bowel disease (IBD), specific diagnosis (PSC/ASC vs. AIH), and time from diagnosis to MRI examination, left hepatic bile duct maximum diameter was a statistically significant predictor of whole liver mean cT1, cT1 interquartile range (IQR), and MRE liver stiffness (p = 0.01–0.04). Seven laboratory values were significant predictors of whole liver cT1 IQR (p < 0.0001–0.04). Eight laboratory values and right hepatic bile duct median and maximum diameter were significant predictors of liver stiffness (p < 0.0001–0.03).ConclusionsBile duct diameters and multiple laboratory biomarkers of liver disease are independent predictors of liver stiffness and cT1 IQR in pediatric patients with AILD.