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Neonatal and infantile cholestasis (NIC) can represent the onset of a surgically correctable disease and of a genetic or metabolic disorder worthy of medical treatment. Timely recognition of NIC and identification of the underlying etiology are paramount to improve outcomes. Upon invitation by the Italian National Institute of Health (ISS), an expert working grouped was formed to formulate evidence-based positions on current knowledge about the diagnosis of NIC. A systematic literature search was conducted to collect evidence about epidemiology, etiology, clinical aspects and accuracy of available diagnostic tests in NIC. Evidence was scored using the GRADE system. All recommendations were approved by a panel of experts upon agreement of at least 75% of the members. The final document was approved by all the panel components. This position document summarizes the collected statements and defines the best-evidence diagnostic approach to cholestasis in the first year of life.

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

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

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

As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long-term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications. Copyright © 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

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

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

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

Noonan Syndrome (NS) is characterized by short stature, typical facial dysmorphology and congenital heart defects. The incidence of NS is estimated to be between 1:1000 and 1:2500 live births. The syndrome is transmitted as an autosomal dominant trait. In approximately 50% of cases, the disease is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the non-receptor protein tyrosine phosphatase SHP-2 protein. Autoimmune Hepatitis (AIH) is a cryptogenic, chronic and progressive necroinflammatory liver disease. Common features of AIH are hypergammaglobulinemia (IgG), presence of circulating autoantibodies, histological picture of interface hepatitis and response to immunosuppressant drugs. Conventional treatment with Prednisone and Azathioprine is effective in most patients. We describe the case of a 6 years-old girl with Noonan Syndrome and Autoimmune Hepatitis type 1. Molecular analysis of PTPN11 gene showed heterozygous mutation c.923A>G (Asn308Ser) in exon 8. Though association between NS and autoimmune disorders is known, this is the second case of association between Noonan Syndrome and Autoimmune Hepatitis type 1 described in literature. In the management of NS, an accurate clinical evaluation would be recommended. When there is a clinical suspicion of autoimmune phenomena, appropriate laboratory tests should be performed with the aim of clarifying whether the immune system is involved in NS. We think that autoimmunity represents a characteristic of NS, even if the etiopathogenesis is still unknown.

The human EBV-transformed lymphoblastoid cell line (LCL), obtained by infecting peripheral blood monocular cells with Epstein-Barr Virus, has been extensively used for human genetic, pharmacogenomic, and immunologic studies. Recently, the role of exosomes has also been indicated as crucial in the crosstalk between EBV and the host microenvironment. Because the role that the LCL and LCL exosomal cargo might play in maintaining persistent infection, and since little is known regarding the non-coding RNAs of LCL, the aim of our work was the comprehensive characterization of this class of RNA, cellular and viral miRNAs, and cellular lncRNAs, in LCL compared with PBMC derived from the same donors. In this study, we have demonstrated, for the first time, that all the viral miRNAs expressed by LCL are also packaged in the exosomes, and we found that two miRNAs, ebv-miR-BART3 and ebv-miR-BHRF1-1, are more abundant in the exosomes, suggesting a microvescicular viral microRNA transfer. In addition, lncRNA profiling revealed that LCLs were enriched in lncRNA H19 and H19 antisense, and released these through exosomes, suggesting a leading role in the regulation of the tumor microenvironment.

Background A few children with acute or chronic liver disease display histological features compatible with autoimmune hepatitis, but lack specific serological markers. Aim To describe features, management and outcome of childhood seronegative autoimmune hepatitis. Methods From 1988 to 2010, 38 children were included under the following criteria: negative virological studies, no serum autoantibodies, exclusion of other causes of liver diseases, and liver histology compatible with autoimmune hepatitis. Results Four groups were identified: (1) 12 with increased serum gamma globulin concentrations; (2) 10 with normal or low serum gamma globulins and no combined blood disease; (3) 10 with combined aplastic anemia; and (4) 6 with peripheral thrombocytopenia with/without neutropenia. Immunosuppressive treatment was associated with aminotransferases normalization in all but one child who required liver transplantation. Relapses occurred in 10 children. Lymphocytopenia was found at the time of the diagnosis of hepatitis in 13 children, 12 in groups 3 or 4. All 38 children are alive after 4–17 years, 18 still under immunosuppression. Conclusions Childhood seronegative autoimmune hepatitis includes a spectrum of disorders. Early liver histology is recommended and, if compatible with autoimmune hepatitis, immunosuppressive treatment should be started. Initial lymphocytopenia may indicate future hematological complication.

Khan Z, Sciveres M, Salis P, Minervini M, Maggione G, Cintorino D, Riva S, Gridelli B, Emma F, Spada M. Combined split liver and kidney transplantation in a three-year-old child with primary hyperoxaluria type 1 and complete thrombosis of the inferior vena cava. Pediatr Transplantation 2011: 15: E64–E70. © 2009 John Wiley & Sons A/S. Abstract: PH1 is an inborn error of the metabolism in which a functional deficiency of the liver-specific peroxisomal enzyme, AGT, causes hyperoxaluria and hyperglycolic aciduria. Infantile PH1 is the most aggressive form of this disease, leading to early nephrocalcinosis, systemic oxalosis, and end-stage renal failure. Infantile PH1 is rapidly fatal in children unless timely liver-kidney transplantation is performed to correct both the hepatic enzyme defect and the renal end-organ damage. The surgical procedure can be further complicated in infants and young children, who are at higher risk for vascular anomalies, such as IVC thrombosis. Although recently a limited number of children with IVC thrombosis have underwent successful kidney transplantation, successful multi-organ transplantation in a child with complete IVC thrombosis is quite rare. We report here the interesting and technically difficult case of a three-yr-old girl with a complete thrombosis of the IVC, who was the recipient of combined split liver and kidney transplantation for infantile PH1. Although initial delayed renal graft function with mild-to-moderate acute rejection was observed, the patient rapidly regained renal function after steroid boluses, and was soon hemodialysis-independent, with good diuresis. Serum and plasma oxalate levels progressively decreased; although, to date they are still above normal. Hepatic and renal function indices were at, or approaching, normal values when the patient was discharged 15-wk post-transplant, and the patient continues to do well, with close and frequent follow-up. This is the first report of a successful double-organ transplant in a pediatric patient presenting with infantile PH1 complicated by complete IVC thrombosis.

In a review of 382 cases of congenital portosystemic shunt, we found that presentation with neonatal cholestasis strongly predicts spontaneous closure of intrahepatic shunts (OR 8.3, 95% CI 3.4-20.2). Spontaneous closure before the 24th month of age is more likely for distal or multiple shunts, but rare for patent ductus venosus.

Juvenile autoimmune hepatitis (JAIH) is a progressive inflammatory liver disease, affecting mainly young girls, from infancy to late adolescence, characterized by active liver damage, as shown by high serum activity of aminotransferases, by elevated immunoglobulin G levels, high titers of serum non organ-specific and organ-specific autoantibodies, and by interface hepatitis on liver biopsy. It is a multifactorial disease of unknown etiology in which environmental factors act as a trigger in genetically predisposed individuals. Two types of JAIH are identified according to the autoantibody panel detected at diagnosis: AIH-1, characterized by the presence of anti-smooth muscle antibody and/or antinuclear antibody and AIH-2, by anti-liver-kidney microsomal antibody type 1 and/or by the presence of anti-liver cytosol type 1 antibody. Epidemiological distribution, genetic markers, clinical presentation and pattern of serum cytokines differentiate the two types of AIH suggesting possible pathogenetic mechanisms. The most effective therapy for AIH is pharmacological suppression of the immune response. Treatment should be started as soon as the diagnosis is made to avoid severe liver damage and progression of fibrosis. The aim of this review is to outline the most significant and peculiar features of JAIH, based largely on our own personal database and on a review of current literature.

Obscure gastrointestinal (GI) bleeding is defined as bleeding from the GI tract that persists or recurs, with no obvious etiology, after esophagogastroduodenoscopy (EGD), colonoscopy, and radiologic evaluation of the small bowel. We present the case of a 17-yr-old girl who for two years had been suffering from recurrent episodes of melena and/or enterorrhagia. Fifteen yr earlier she had undergone a split-liver transplant with Roux-en-Y biliary reconstruction. A series of endoscopic and radiologic investigations had failed to find the source of the bleeding. Suspecting the presence of ectopic varices, we decided to perform single-balloon enteroscopy (SBE). We observed and aspirated a large amount of fresh red blood in the afferent loop until we found the hepaticojejunostomy. On the edge of the biliary-enteric anastomosis we observed a vascular lesion 5 mm in diameter. Judging this ectopic varix to be the source of bleeding, we placed two endoclips. The second clip placement caused varix rupture with a consequent massive hemorrhage, emergently and successfully treated with cyanoacrylate sclerotherapy. No episodes of rebleeding were observed, and no complications occurred during the entire hospital stay, and after six months of follow-up. This report highlights the importance of afferent loop examination in patients with obscure GI bleeding who have undergone liver transplant with Roux-en-Y biliary reconstruction.

OBJECTIVES Celiac disease (CD) is common in patients with autoimmune liver disease (AILD); however, the long-term response to treatment of patients with AILDs coexistent with CD has not been explored in detail. The aim of the present study was to analyze the features and the long-term response to immunosuppressive treatment in children with autoimmune hepatitis (AIH) associated with CD. METHODS Retrospective and prospective evaluation of patients followed at a single center. RESULTS Among 79 patients with AIH, 15 (19%) had CD (9 type 1, 3 type 2, 3 seronegative). In the group of patients with AIH and CD, female sex was significantly more represented than in the group of patients with AIH alone; also, in the former group, diagnosis was made significantly earlier (P < 0.05). All of the 15 patients on a gluten-free diet achieved sustained remission when treated with prednisone and azathioprine or cyclosporine. The mean period of follow-up was 73 months; discontinuation of therapy was attempted in 9 patients while in remission: 4 patients relapsed, 5 (33%) could definitively stop immunosuppressive treatment with a mean period of treatment-free sustained remission of 89 months (range 26-174). In the same period, treatment discontinuation, attempted in 24 of 64 patients with AIH without CD, was successful in 5 patients (8%; P < 0.05). CONCLUSIONS Patients with AIH coexisting with CD achieve treatment-free sustained remission in a significantly higher proportion, when compared with patients with AIH without CD, suggesting a possible long-term adjuvant effect of a gluten-free diet.

Summary Background Magnetic resonance cholangiography (MRC) has been validated as comparable to endoscopic retrograde cholangiography (ERC) for the diagnosis of sclerosing cholangitis (SC) in adult patients. In children, MRC is widely used based mainly on non-comparative studies. Patients and methods ERCs and MRCs of seven children (median age 9, range: 7–20 years) with SC and 17 controls (median age 6, range: 2 months–20 years) with other chronic liver diseases were reviewed in a blinded, random and independent way. All patients underwent both examinations within a 6-months slot. All ERCs and 17 MRCs were performed under general anesthesia. One radiologist evaluated both ERCs and MRCs and one interventional endoscopist independently reviewed only ERCs. Reviewers did not receive any clinical information. Diagnosis of SC, established on the basis of history, laboratory data, radiological examinations and clinical course, was used as gold standard to compare ERC and MRC diagnostic accuracy. Results Overall image quality was graded as very good in 57% of MRC and in 71% of ERC cases; difference was not statistically significant ( P = 0.24) although the probability for MRC to be diagnostic increased with patient's age. Depiction of first, second and fourth-order intrahepatic bile duct was better in ERC ( P = 0.004, 0.02 and 0.023, respectively); depiction of the extrahepatic bile duct was comparable ( P = 0.052). Diagnostic accuracy of MRC and ERC was very high, without statistically significant difference ( P = 0.61). Conclusion Despite an overall better depiction of the biliary tree by ERC, MRC is comparable for the diagnosis of SC in children. These data support MRC as the first imaging approach in children with suspected SC.

Wilson's disease (WD), an autosomal recessive disorder of copper transport with a broad range of genotypic and phenotypic characteristics, results from mutations in the ATP7B gene. Herein we report the results of mutation analysis of the ATP7B gene in a group of 118 Wilson disease families (236 chromosomes) prevalently of Italian origin. Using DNA sequencing we identified 83 disease-causing mutations. Eleven were novel, while twenty one already described mutations were identified in new populations in this study. In particular, mutation analysis of 13 families of Romanian origin showed a high prevalence of the p.H1069Q mutation (50%). Detection of new mutations in the ATP7B gene in new populations increases our capability of molecular analysis that is essential for early diagnosis and treatment of WD.

Autoimmune diseases of the liver and biliary tract are inflammatory diseases of unknown origin that progress spontaneously, in most cases, to severe fibrosis and cirrhosis (Maggiore et al, 2009). They are characterized by an inflammatory infiltrate in the liver tissue involving the lobule and the portal tract and, most frequently, by the presence of non-organ and liverspecific autoantibody reactivity (Mieli Vergani & Vergani, 2009). There are at least three principal disorders in humans, in which the liver damage is thought to be caused by an autoimmune mechanism: autoimmune hepatitis (AIH), where the target of the autoimmune attack is the hepatocyte, and two other conditions, autoimmune cholangitis (AIC) and primary biliary cirrhosis (PBC), where the target is the cholangiocyte. Between these three disorders exists a range of overlap of liver damage both at diagnosis and/or during the follow-up, recognized as “overlap syndrome” (Alvarez, 2006). Any autoimmune disorder may overlap with the other two. Autoimmune cholangitis may be limited, at diagnosis and during the follow-up, to the smallest intrahepatic (forth order) bile ducts in case of the socalled “small duct sclerosing cholangitis” (Chapman, 2002), or may be diffuse affecting also larger bile duct and giving the typical radiological or MRI imaging of “sclerosing cholangitis”). In children, primary biliary cirrhosis is exceptionally described, particularly before adolescence. Moreover, a rare and peculiar form of autoimmune hepatitis, typical of infancy exists, and is characterized by the unique association of Coombs positive autoimmune hemolytic anemia with the peculiar histopathological finding of diffuse giant cell transformation of the hepatocytes at a very unusual age even for infants (Maggiore et al, 2011). Immunosuppressive treatment is usually efficacious in most cases of AIH, but it is less effective in autoimmune cholangitis, particularly in case of delayed diagnosis at the stage of diffuse sclerosing cholangitis (Maggiore et al, 2009). Immunosuppressive treatment is also the only life-saving treatment recognized in “infantile giant cell hepatitis associated with autoimmune hemolytic anemia” (Maggiore et al, 2011). Liver biopsy is of paramount importance in the diagnostic work-up of autoimmune diseases of the liver and biliary tract as recognized by the major guidelines. Histological examination

The multi-detector computed tomography (MDCT) scan and magnetic resonance (MR) of the abdomen play a key role in the work-up to liver transplantation (LT) by identifying congenital anomalies or cirrhosis-related modifications, conditions that can require changes in surgical technique. Moreover, the MDCT and MR scans allow identification of cirrhotic liver hepatic masses, extrahepatic porto-systemic shunts, eventual thrombosis of portal system and radiological signs of portal hypertension associated with biliary atresia (BA). The aim of this paper is to review MDCT, MR imaging and interventional radiology procedures performed to evaluate morphological changes and degree of portal hypertension in pediatric patients with end-stage liver disease secondary to BA, who are candidates for LT. Advances in the field of MR, MDCT and in percutaneous minimally invasive techniques have increased the importance of radiology in the management of pediatric patients with BA who are candidates for LT.

Obscure gastrointestinal (GI) bleeding is defined as bleeding from the GI tract that persists or recurs, with no obvious etiology, after esophagogastroduodenoscopy (EGD), colonoscopy, and radiologic evaluation of the small bowel. We present the case of a 17-yr-old girl who for two years had been suffering from recurrent episodes of melena and/or enterorrhagia. Fifteen yr earlier she had undergone a split-liver transplant with Roux-en-Y biliary reconstruction. A series of endoscopic and radiologic investigations had failed to find the source of the bleeding. Suspecting the presence of ectopic varices, we decided to perform single-balloon enteroscopy (SBE). We observed and aspirated a large amount of fresh red blood in the afferent loop until we found the hepaticojejunostomy. On the edge of the biliary-enteric anastomosis we observed a vascular lesion 5 mm in diameter. Judging this ectopic varix to be the source of bleeding, we placed two endoclips. The second clip placement caused varix rupture with a consequent massive hemorrhage, emergently and successfully treated with cyanoacrylate sclerotherapy. No episodes of rebleeding were observed, and no complications occurred during the entire hospital stay, and after six months of follow-up. This report highlights the importance of afferent loop examination in patients with obscure GI bleeding who have undergone liver transplant with Roux-en-Y biliary reconstruction.

Background & Aims PFIC2 is caused by mutations in ABCB11 encoding BSEP. In most cases affected children need liver transplantation that is thought to be curative. We report on two patients who developed recurrent normal GGT cholestasis mimicking primary BSEP disease, after liver transplantation. Methods PFIC2 diagnosis was made in infancy in both patients on absence of canalicular BSEP immunodetection and on ABCB11 mutation identification. Liver transplantation was performed at age 9 (patient 1) and 2.8 (patient 2) years without major complications. Cholestasis with normal GGT developed 17 and 4.8years after liver transplantation, in patient 1 and patient 2, respectively, during an immunosuppression reduction period. Results Liver biopsies showed canalicular cholestasis, giant hepatocytes, and slight lobular fibrosis, without evidence of rejection or biliary complications. An increase in immunosuppression resulted in cholestasis resolution in only one patient. Both patients developed atrial fibrillation, and one melanonychia. The newborn of patient 1 developed transient neonatal normal GGT cholestasis. Immunofluorescence staining of normal human liver sections with patient's sera, collected at the time of cholestasis, and using an anti-human IgG antibody to detect serum antibodies, showed reactivity to a canalicular epitope, likely to be BSEP. Indeed, Western blot analysis showed that patient 2 serum recognized rat Bsep. Conclusions Allo-immune mediated BSEP dysfunction may occur after liver transplantation in PFIC2 patients leading to a PFIC2 like phenotype. Extrahepatic features and/or offspring transient neonatal cholestasis of possible immune mediated mechanisms, may be associated. Increasing the immunosuppressive regimen might be an effective therapy.

PH1 is an inborn error of the metabolism in which a functional deficiency of the liver-specific peroxisomal enzyme, AGT, causes hyperoxaluria and hyperglycolic aciduria. Infantile PH1 is the most aggressive form of this disease, leading to early nephrocalcinosis, systemic oxalosis, and end-stage renal failure. Infantile PH1 is rapidly fatal in children unless timely liver-kidney transplantation is performed to correct both the hepatic enzyme defect and the renal end-organ damage. The surgical procedure can be further complicated in infants and young children, who are at higher risk for vascular anomalies, such as IVC thrombosis. Although recently a limited number of children with IVC thrombosis have underwent successful kidney transplantation, successful multi-organ transplantation in a child with complete IVC thrombosis is quite rare. We report here the interesting and technically difficult case of a three-yr-old girl with a complete thrombosis of the IVC, who was the recipient of combined split liver and kidney transplantation for infantile PH1. Although initial delayed renal graft function with mild-to-moderate acute rejection was observed, the patient rapidly regained renal function after steroid boluses, and was soon hemodialysis-independent, with good diuresis. Serum and plasma oxalate levels progressively decreased; although, to date they are still above normal. Hepatic and renal function indices were at, or approaching, normal values when the patient was discharged 15-wk post-transplant, and the patient continues to do well, with close and frequent follow-up. This is the first report of a successful double-organ transplant in a pediatric patient presenting with infantile PH1 complicated by complete IVC thrombosis.

Autoimmune liver diseases in childhood includes Autoimmune Hepatitis (AIH) and Primary (Autoimmune) Sclerosing Cholangitis (P(A)SC). Both diseases are characterized by a chronic, immune-mediated liver inflammation involving mainly hepatocytes in AIH and bile ducts in PSC. Both diseases, if untreated, lead to liver cirrhosis. AIH could be classified, according to the autoantibodies pattern, into two subtypes: AIH type 1 presents at any age as a chronic liver disease with recurrent flares occasionally leading to liver cirrhosis and liver failure. Characterizing autoantibodies are anti-nuclear (ANA) and anti-smooth muscle (SMA), usually at high titer (1:100). These autoantibodies are not specific and probably do not play a pathogenic role. AIH type 2 shows a peak of incidence in younger children, however with a fluctuating course. The onset is often as an acute liver failure. Anti-liver kidney microsome autoantibodies type 1 (LKM1) and/or anti-liver cytosol autoantibody (LC1) are typically found in AIH type 2 and these autoantibodies are accounted to have a potential pathogenic role. Diagnosis of AIH is supported by the histological finding of interface hepatitis with massive portal infiltration of mononuclear cells and plasmocytes. Inflammatory bile duct lesions are not unusual and may suggest features of ''overlap'' with P(A)SC. A diagnostic scoring system has been developed mainly for scientific purposes, but his diagnostic role in pediatric age is debated. Conventional treatment with steroids and azathioprine is the milestone of therapy and it is proved effective. Treatment withdrawal however should be attempted only after several years. Cyclosporin A is the alternative drug currently used for AIH and it is effective as steroids. P(A)SC exhibit a peak of incidence in the older child, typically in pre-pubertal age with a slight predominance of male gender. Small bile ducts are always concerned and the histological picture shows either acute cholangitis (bile duct infiltration and destruction) and/or lesions suggesting chronic cholangitis as well (bile duct paucity and/or proliferation, periductal sclerosis). Small bile ducts damage may be associated, at onset or in the following years, with lesions of larger bile ducts with duct wall irregularities, strictures, dilations, and beading resulting in the characteristic ''bead-on-a-string'' appearance. The ''small duct'' (autoimmune) sclerosing cholangitis is also called autoimmune cholangitis. PSC is strictly associated to a particular form of inflammatory bowel disease (IBD) which shows features not typical of ulcerative colitis neither of Crohn's disease. Symptoms related to IBD often are present at onset (abdominal pain, weight loss, bloody stools) but the liver disease is frequently asymptomatic and it may be discovered fortuitously. Treatment of PSC is particularly challenging. In case of ''small duct'' SC or in case of evidence active inflammation on liver biopsy, immunosuppressive treatment is probably useful while in case of large bile ducts non inflammatory sclerosis, immunosuppression is probably uneffective. Ursodeoxycholic acid, however, may leads to an improvement of liver biochemistry even if there's no evidence that it may alter the course of disease. Thus, liver transplantation, is often necessary in the long term follow-up, even with a risk of disease recurrence. In adjunction to these two main disorders, many patients show an''overlap'' disease with features of both AIH and PSC. In such disorders the immune-mediated damage concerns both the hepatocyte and the cholangiocyte with a continuous clinical spectrum from AIH with minimal bile ducts lesions and PSC with portal inflammation and active inflammatory liver damage.

We report on 6 adopted asymptomatic children in whom chronic HBV infection was identified through the occurrence of an acute hepatitis B in a family member. All of the children had serum HBV-DNA >2000 pg/mL. Acute hepatitis B in a family should alert the physician regarding the possibility of existing chronic HBV infection in other members of the family, especially newly adopted children, leading to a quick evaluation of their HBV status and to an efficacious protection of susceptible family members.