An overview of paediatric autoimmune and genetic cholestatic liver disease for the adult physician

Autoimmune liver disease (AILD) represents a group of complex inflammatory liver diseases, all characterized by an aberrant autoreactivity against hepatocytes and/or biliary structures. AILD may be subclassified into four major diseases: autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and autoimmune cholangitis (AIC). Recently a new entity frequently associated with autoimmune pancreatitis and defined IgG4-related cholangitis (IgG4-RC), has been added to the spectrum of AILD. The most frequent autoimmune liver diseases of the AILD spectrum occurring in children and in young adults are AIH and PSC, overlap syndrome between AIH and PSC, also defined as autoimmune sclerosing cholangitis (ASC), representing a frequent finding in pediatric patients. Here, the morphological findings that may help liver pathologists in the differential diagnosis of AILD in pediatric patients are reviewed, underlying the frequency in liver biopsy interpretation of complex cases in which a precise diagnosis may remain controversial, due to overlap of hepatocytic and bile duct cell lesions. Among the multiple morphological changes typical of AILD, the detection of an high number of plasma cell clusters in the portal and periportal regions is generally considered one of the main clue for the diagnosis of AIH. The recent report in a 13-year old boy of IgG4-associated cholangitis, induces pathologists when detecting a huge number of plasmacells, to consider the differential diagnosis between AIH and IgG4-RC. Proceedings of the 9th International Workshop on Neonatology · Cagliari (Italy) · October 23rd-26th, 2013 · Learned lessons, changing practice and cutting-edge research

First-Degree Living-Related Donor Liver Transplantation in Autoimmune Liver Diseases.

Outcome of liver disease in children is mainly determined by severity and progression of liver fibrosis. Liver biopsy is the accepted standard for evaluating fibrosis but is limited by the need for sedation in children, sampling error, and risks including bleeding. The aim of the present study was to compare tools for noninvasive assessment of liver fibrosis in a paediatric cohort. Children undergoing liver biopsy for chronic liver disease were recruited and underwent transient elastography (TE). Liver biopsies were scored by a hepatohistopathologist from F0 (no fibrosis) to F4 (cirrhosis). TE was compared with biopsy score. During the study period, 104 children (62 boys) were enrolled (median age 13.6 years). Diagnosis was autoimmune liver disease in 27; nonalcoholic fatty liver disease in 37; posttransplant in 16; hepatitis B/C in 8; Wilson disease in 5; and the remainder, miscellaneous. TE was successful in all but 7 patients and was a good discriminator of significant fibrosis (≥ F2) (P < 0.001), severe fibrosis (≥ F3) (P < 0.001), and cirrhosis (F4) (P = 0.003). The area under the receiver operating characteristic curve for the prediction of ≥ F2, ≥ F3, and F4 using TE was 0.78, 0.79, and 0.96, respectively. TE performed best in children with autoimmune liver disease and in those posttransplant. The present study demonstrates that TE is a reliable tool in distinguishing different stages of liver fibrosis in paediatric patients. Thus, TE may serve as a useful adjunct to liver biopsy for diagnostic purposes providing a reliable method of noninvasively monitoring liver disease progression in children.

Autoimmune liver disease (AILD) incorporates primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), and autoimmune sclerosing cholangitis (ASC). ASC is a condition that includes overlap of AIH and PSC. We investigate changes in practice in relation to diagnosis and phenotype over 2 time periods. Retrospective chart review was conducted from January 2000 to 2016. Data were divided into two 8-year cohorts, CI and C2. Data were collected in 75 children, 29 in 2000-2007 (C1) and 46 in 2008-2016 (C2). Presenting AILD type was AIH in 59%, ASC in 10%, and PSC in 31%. Final AILD type was AIH in 53%, ASC in 16%, and PSC in 31%. When comparing C1 to C2, those with AIH decreased (65% vs 45%) and those with ASC increased (14% vs 18%). Use of magnetic resonance cholangio-pancreatography increased from 34% in C1 to 65% in C2. Advanced liver disease on biopsy was noted in 53% of all children at presentation. Only 5 female children progressed to liver transplant (3 ASC-IBD [inflammatory bowel disease]; 1 PSC-IBD; 1 AIH). Colonoscopy performance increased from 48% in C1 to 63% in C2 with diagnosis of AILD-IBD increasing from 31% to 52%. Right-sided disease was present in 46% and macroscopic rectal sparing in 36% of those with ulcerative colitis (UC). Colectomy was required in 3 children with large duct PSC-IBD. PSC and ASC are increasing in relevance along with IBD and reflect increasing performance of magnetic resonance cholangio-pancreatography and colonoscopy. Large duct PSC and ASC with IBD are risk factors for colectomy and along with female gender, for liver transplant.

The influence of the gut microbiota on the development of various diseases is of great interest to researchers. The conducted studies showed that in patients with chronic liver diseases, the dominant taxa of the gut microbiota were Bifidobacterium longum, Bifidobacterium adolescentis, Blautia massiliensis, and in healthy children — Neisseria flavescens. There is no comparative analysis of data on the taxonomic diversity of the intestinal microbiota in autoimmune and non-autoimmune liver diseases in children. Purpose. To investigate differences in the taxonomic diversity of fecal microbiota in patients with autoimmune and non-autoimmune liver diseases, as well as to evaluate potential biomarkers of 16S rRNA gene amplicons in these diseases by comparing the taxonomic composition. Material and methods. A metagenomic analysis of the intestinal microbiota of 24 children with chronic liver diseases (mean age 10,3 ± 4,7 years) was carried out with the isolation of the 16S rRNA gene region. The group included 18 children with autoimmune liver diseases and 6 children with non-autoimmune liver diseases. Results. The conducted study revealed 684 types of microorganisms in the studied samples of patients’ feces. The analysis of the conducted studies showed that no dominant taxa were found in the fecal samples of children with autoimmune liver diseases, while Veillonella dispar, Veillonella parvula, Cloacibacillus porcorum, Prevotella histicola and Bacteroides eggerthii were the dominant taxa in patients with non-autoimmune liver diseases. Conclusion. Studies have shown differences in the composition of the gut microbiota in children with autoimmune and non-autoimmune liver diseases.

Relevance. The influence of the gut microbiota on the development of various diseases is of great interest to researchers. The conducted studies showed that in patients with chronic liver diseases, the dominant taxa of the gut microbiota were Bifidobacterium longum, Bifidobacterium adolescentis, Blautia massiliensis, and in healthy children - Neisseria flavescens. There is no comparative analysis of data on the taxonomic diversity of the intestinal microbiota in autoimmune and non-autoimmune liver diseases in children. Purpose of the study. To investigate differences in the taxonomic diversity of fecal microbiota in patients with autoimmune and non-autoimmune liver diseases, as well as to evaluate potential biomarkers of 16S rRNA gene amplicons in these diseases by comparing the taxonomic composition. Scope and methods of research. A metagenomic analysis of the intestinal microbiota of 24 children with chronic liver diseases (mean age 10.3±4.7 years) was carried out with the identification of the V3-V4 region of the 16S rRNA gene. The group included 18 children with autoimmune liver diseases and 6 children with non-autoimmune liver diseases. Research results. The conducted study revealed 684 types of microorganisms in the studied samples of patients’ faeces. The analysis of the conducted studies showed that no dominant taxa were found in the faecal samples of children with autoimmune liver diseases, while Veillonella dispar, Veillonella parvula, Cloacibacillus porcorum, Prevotella histicola and Bacteroides eggerthii were the dominant taxa in patients with non-autoimmune liver diseases. Conclusion. Studies have shown differences in the composition of the gut microbiota in children with autoimmune and non-autoimmune liver diseases.

BackgroundThe association of autoimmune liver disease (AILD) and inflammatory bowel disease (IBD) is well documented. IBD affects about 45% of children with autoimmune sclerosing cholangitis (AISC) and about 20% of...

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The value of the liver–gut axis is increasingly recognized as a major modulator of autoimmunity. There is no comparative analysis of data on the taxonomic diversity of the intestinal microbiota in chronic liver diseases in children. Purpose. To investigate the taxonomic diversity of the intestinal microbiota in children with chronic liver diseases compared with healthy patients, to identify differences in bacterial diversity in autoimmune and non-autoimmune liver diseases, as well as the impact of immunosuppressive therapy on the intestinal microbiota. Material and methods. A metagenomic analysis of the gut microbiota of 24 children with chronic liver diseases (mean age 10,3 ± 4,7 years) was carried out with the identification of the V3–V4 region of the 16S rRNA gene. The group included 18 children with autoimmune liver diseases and 6 children with non-autoimmune liver diseases. The control group consisted of fecal samples of 34 apparently healthy children. Results. When comparing fecal samples of children with autoimmune liver diseases with samples of healthy children, the taxa of Bacteroides dorei, Collinsella aerofaciens, Ruminococcus caffidurs prevailed, and for children of the control group — Neisseria flavescens. When comparing samples of patients with non-autoimmune liver diseases and the control group, it was found that the taxa Bacteroides fragilis, Klebsiella pneumoniae, Bifidobacterium longum prevailed in healthy children. When comparing fecal samples from children with autoimmune and non-autoimmune liver diseases, it was found that Veillonella dispar, Cloacibacillus porcorum, Veillonella parvula, Prevotella histicola and Bacteroides eggerthii taxa dominate in patients with non-autoimmune diseases. No dominant taxa of the gut microbiota were found in children with autoimmune liver diseases. It has been established that the taxa Veillonella dispar, Faecalibacterium prausnitzii, Roseburia inulinivorans, Bacteroides xylanisolvens and Alistipes obesi prevail in patients receiving immunosuppressive therapy, and the taxa Phascolarctobacterium succinatutens, Bacteroides ovatus, Solobacterium mooreis and Holdemanella massilien prevail in patients not receiving immunosuppressive therapy. Conclusion. A recent study of the gut microbiota in children with chronic liver disease shows differences in the imbalance of the gut microbiota compared to the results obtained in adults. The gut microbiota model is capable of distinguishing autoimmune liver diseases from non-autoimmune diseases. Immunosuppressive therapy is accompanied by the dominance of taxa that reduce the production of short-chain fatty acids.

ntroduction. Autoimmune liver disease is a chronic and progressive inflammatory pathology; it often requires organ transplantation. In pediatrics, although the incidence is low, a significant percentage of patients also present with associated extrahepatic autoimmune diseases. Diagnosis is based on elevated transaminases and immunoglobulins, the presence of autoantibodies, and specific histological findings, with the absence of other known liver pathologies. Objective. To determine the prevalence of extrahepatic autoimmune diseases in pediatric patients with autoimmune liver disease, to describe the relationship between these entities, and to evaluate possible clinical and laboratory differences at diagnosis between patients with and without associated extrahepatic autoimmune diseases. Population and methods. Retrospective study that analyzed pediatric patients diagnosed with autoimmune liver disease between 2000 and 2022 in a tertiary-level hospital. Results. A total of 139 patients were included, with 62.6% being women. The median age at diagnosis was 7.3 years. The most frequent type of autoimmune hepatitis was type 1 (74.8%). An associated extrahepatic disease was present in 41.7% of patients; ulcerative colitis was the most common (39.7%), followed by celiac disease (20.7%) and hypothyroidism (12.1%). Ulcerative colitis was present in 73.3% of patients with autoimmune sclerosing cholangitis. Patients without associated autoimmune extrahepatic disease required liver transplantation more frequently (18.5%) than those with associated extrahepatic disease (5.2%). Conclusion. The study shows a high prevalence of extrahepatic autoimmune diseases in children with autoimmune liver disease. Ulcerative colitis is the most frequent, especially in cases of autoimmune sclerosing cholangitis.

Pediatric patients with autoimmune liver disease (ALD) frequently demonstrate clinical, histopathologic, cholangiographic, and serologic overlap between primary sclerosing cholangitis and autoimmune hepatitis, termed autoimmune sclerosing cholangitis (ASC). Several large, collaborative studies have shed light on the epidemiology and natural history of ASC in the last 5 years. A detailed genetic and environmental description of the pathogenesis remains lacking however. Here, we review recent advancements in knowledge on ASC in children, and their implications on the management of this rare disease. Consensus diagnostic criteria for ASC do not exist, and we recommend labeling a patient as ASC only when clinical criteria for each of primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) are separately met. Treatment of ASC is based on the lobular component of inflammation, which behaves similar to AIH and responds to standard immunosuppression regimens. The cholangiopathy of ASC behaves like PSC and currently dictates prognosis as there is no effective therapy and no response to immunosuppression. Rates of liver transplantation for ASC are identical to those of PSC. Rather than specifically labeling patients as ASC, the most important tasks for clinicians managing ALD are to detect treatable autoimmune lobular inflammation in PSC patients and to identify cholangiopathy in AIH patients with persistent biochemical abnormalities prior to therapeutic escalation.

Little is known about autoimmune liver disease (AILD) in Asian children. We studied the clinical features and predictors of outcome in childhood AILD in an Asian population. Retrospective review of AILD [autoimmune hepatitis type 1 and 2 (AIH1, AIH2), primary sclerosing cholangitis (PSC) and autoimmune sclerosing cholangitis (ASC)] seen at two pediatric liver units in Malaysia. At presentation, 17 (56%) of the 32 children [19 females, 59%; median (range) age 7.7 (1.8-15.5) years] with AILD (AIH1 = 18, AIH2 = 5, PSC = 0, ASC = 9) had liver cirrhosis. At final review [median (range) duration of follow-up 4.8 (0.4-12) years], 24 patients (75%) survived with a native liver. Twenty-one (66%) were in remission; 19 (AIH1 = 11; AIH2 = 4, ASC = 4) were on prednisolone and/or azathioprine, one on cyclosporine and another on mycophenolate mofetil. Three (AIH1 = 3) were in partial remission. Of the two who underwent liver transplantation (LT; 6.5%; both ASC), one died of primary graft failure after LT. Six patients (19%) died without LT (acute liver failure, n = 1; end-stage liver disease, n = 5). The overall survival rate (native liver and survival post-LT) was 78%. A delay in seeking treatment adversely affected the final outcome [survival with native liver vs. LT or death (duration between onset of disease and treatment; median ± standard error) = 2.5 ± 2.9 months vs. 24.0 ± 13.3 months; p = 0.012]. Although remission was achieved in the majority of patients with prednisolone and/or azathioprine therapy, delay in seeking diagnosis and treatment adversely affects the outcome of childhood AILD in Malaysia.

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.

Juvenile (i.e. affecting children and adolescents) autoimmune liver diseases are progressive inflammatory liver disorders that include autoimmune hepatitis and autoimmune sclerosing cholangitis. Autoimmune hepatitis (AIH) is characterized serologically by high levels of transaminases and immunoglobulin G (IgG), as well as presence of autoantibodies, and histologically by interface hepatitis, in the absence of a known etiology [1]. Three fourths of patients are girls, some 20 % have associated autoimmune disorders—including thyroiditis, vitiligo, type 1 diabetes, inflammatory bowel disease, IgA nephropathy—and about 40 % have a family history of autoimmune disease [2]. In children and adolescents, AIH has a more aggressive course than in middleage and elderly patients and often presents acutely, though its mode of presentation is very variable, and the disease should be suspected and excluded in all children with symptoms and signs of liver disease not ascribable to more common pathologies. If diagnosed early, AIH responds satisfactorily to immunosuppressive treatment, which should be started as soon as possible, as if left untreated, AIH progresses rapidly to cirrhosis and liver failure. The disease course is often fluctuating, with flares and spontaneous remissions, a pattern that may unfortunately result in delayed referral and diagnosis. The majority of children, however, on physical examination have clinical signs of an underlying chronic liver disease (e.g. spider nevi, palmar erythema, leukonychia, striae), firm liver and splenomegaly. Moreover, at ultrasound imaging, the liver parenchyma is often nodular and heterogeneous. The epidemiology of childhood AIH is unknown, but AIH type 1 (AIH-1) [anti-nuclear antibody (ANA) and/or anti-smooth muscle antibody (SMA) positive] accounts for 2/3 of the cases and presents often around puberty [2], whereas AIH-2 [positive for anti-liver kidney microsomal antibody type 1 (anti-LKM1) and/or anti liver cytosol type 1 antibody (anti-LC1)] tends to present at a younger age and also during infancy. IgG is usually raised at presentation in both types, though 15 % of children with AIH-1 and 25 % of those with AIH-2 have normal levels. IgA deficiency is common in AIH-2 [2]. Severity of disease is similar in the two types, but anti-LKM1-positive children usually have higher levels of bilirubin and transaminases at presentation than those who are ANA/SMA-positive and present significantly more frequently with fulminant hepatic failure [2]. Excluding children with the fulminant presentation, a severely impaired hepatic synthetic function (prolonged prothrombin time and hypoalbuminaemia) is usually more common in AIH-1 than in AIH-2. The severity of interface hepatitis at diagnosis is similar in both types, but cirrhosis on initial biopsy is more frequent in AIH-1 than in AIH-2, suggesting a more chronic course of disease in the former. Progression to cirrhosis during treatment is more frequent in AIH-1. In pediatrics, sclerosing cholangitis is often associated with florid autoimmune features, including elevated titres of autoantibodies, in particular ANA and SMA, elevated IgG, and interface hepatitis [3]. This AIH/sclerosing cholangitis overlap syndrome, called autoimmune sclerosing cholangitis (ASC) has been reported in between 15 and 21 % [4, 5] of patients in retrospective pediatric autoimmune liver disease series, where bile duct imaging was G. Mieli-Vergani (&) Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London SE5 9RS, UK e-mail: giorgina.vergani@kcl.ac.uk

State of Research in Pediatric Gastroenterology, Hepatology, and Nutrition: 2010 and Beyond