Anti-liver Kidney Microsomal Type Research Articles

Hepatitis C virus-related autoimmunity before and after viral clearance: a single center, prospective, observational study.

Hepatitis C virus (HCV) chronic infection is frequently associated to autoimmune manifestations. The aim of this study was to prospectively evaluate the occurrence of clinical and/or laboratory features of autoimmunity in a cohort of 140 consecutive HCV chronically infected patients treated with direct-acting antiviral agents (DAAs) and followed-up for 96 weeks. All patients were screened for cryoglobulins, rheumatoid factor (RF), C3, C4, antinuclear antibody (ANA), anti-smooth muscle (ASMA), anti-liver kidney microsome type 1 (anti-LKM1), anti-mitochondrial antibodies (AMA), anti-neutrophil cytoplasmic antibodies (ANCA), and anti-liver cytosol type 1/soluble liver antigen (anti-LC1/SLA) autoantibodies before therapy and 12, 48 and 96 weeks after treatment. They were then grouped according to the expression of laboratory findings and related autoimmune diseases. At baseline, autoimmune manifestations were found in 70 patients: 83% of them were cryoglobulinemic, whereas ANA, AMA, perinuclear ANCA (pANCA) and LKM/LC1 autoantibodies were found in the remaining 17%. An autoimmune disease was diagnosed in 9 cases, two of them featuring an autoimmune liver disease (AILD). At the end of follow-up, despite viral clearance and regression of vasculitis, cryoglobulins persisted in 12 patients (21%), and autoantibodies disappeared or decreased in most of cases but, with the exception of the 2 patients diagnosed as AILD, associated autoimmune diseases remained stable. In one patient with relapsing cryoglobulinemia and ANA positivity, type-1 autoimmune hepatitis was defined. Conversely, autoantibodies first appeared after viral clearance in 5 patients, of whom one was diagnosed with type-1 autoimmune hepatitis and one with pANCA+ primary sclerosing cholangitis. Following DAA-induced viral clearance, cryoglobulins may persist or reappear. Autoantibodies changed dynamically in step with the disappearance of a previously diagnosed or the occurrence of a new AILD. A longer follow-up will be necessary to establish the possible diagnosis of a newly onset AILD, the reactivation of cryoglobulinemic vasculitis and even its progression to non-Hodgkin lymphoma.

Development of a New Murine Model of Type 2 Autoimmune Hepatitis Using a Human Liver Protein

Autoimmune hepatitis (AIH) is a chronic inflammatory condition of the liver characterized by parenchymal destruction, hypergammaglobulinemia, specific autoantibody production, and hepatic fibrosis and necrosis. Murine models of AIH have been described; however, little is known about the immunologic mechanisms of tissue destruction. In this study, a new murine model of type 2 AIH was developed using recombinant human cytochrome P450 (CYP) 2D6 emulsified with complete Freund's adjuvant (CFA). BALB/c mice were immunized with 2 μg/mL i.p. of CYP2D6 in CFA. The control group received CFA or phosphate-buffered saline alone. Alanine aminotransferase activity, autoantibody production, IgG concentrations, histologic damage, and specific T-cell response were evaluated. Persistent AIH, characterized by cellular infiltration, hepatic fibrosis, elevated alanine aminotransferase, and the production of anti-liver kidney microsomal antibody type 1 developed in CFA/CYP2D6-immunized mice. These mice presented high levels of IgG and its subclasses IgG1, IgG2a, and IgG2b against liver self-proteins. Interestingly, IL-2+ and interferon γ-positive Cyp2d6-specific T cells were present in greater concentrations in mice immunized with CFA/CYP2D6 compared with control. Immunization with CFA, in combination with a natural human autoantigen like CYP2D6, was demonstrated to break tolerance, resulting in a chronic form of autoimmune-related liver damage. This murine model of type 2 AIH is expected to be instrumental in understanding the immunologic mechanisms of the pathogenesis of this autoimmune liver disease.

Asymptomatic autoimmune hepatitis type 1 with normal IgG level and IgA deficiency – case report

Introduction. Autoimmune hepatitis (AIH) in children is a chronic inflammatory liver disease with a broad clinical spectrum, ranging from isolated elevated transaminases to acute liver failure. AIH is a rare condition, with an in­creased prevalence in the last years (2.4-9.9 per 100,000 chil­dren). Case report. We present the case of a young girl, 7 years old, who was admitted to our hospital for an in­crease of liver enzymes, discovered accidentally. She was asymptomatic, and no physical signs of chronic or acute liver disease were found at admission. The laboratory pa­ra­meters revealed increased transaminases without cho­les­tasis. The viral causes of hepatitis were excluded, along with alpha-1 antitrypsin deficiency and Wilson’s disease. She had a normal level of serum IgG and a low IgA level with positive antinuclear antibodies (1:80) and anti-smooth muscle antibodies (1:320), suggestive for the diagnosis of AIH type 1 and anti-liver kidney microsomal type 1 anti­bodies. The treatment with prednisone was started, and the evolution was favorable, with the normalization of la­bo­ra­tory parameters. Conclusions. This case highlights the importance of the early recognition of this pathology and the careful evaluation of any increased serum trans­ami­nases, even in asymptomatic children.

Autoimmune hepatitis in children

Autoimmune hepatitis (AIH) is a disease of unknown aetiology, in which a progressive destruction of the hepatic parenchyma occurs. This disease follows a chronic, but fluctuating course. AIH spontaneously progresses towards cirrhosis and liver failure, but often shows a relatively good response to immunosuppressive treatment1. It is characterized by a female preponderance, marked hyper-gammaglobulinaemia, circulating autoantibodies, low levels of complement factor 4 and a high prevalence of HLA B8 and DR3 and DR4 haplotypes1. Other autoimmune disorders are frequently found in patients with AIH as well as in first-degree relatives1-3. These clinical and laboratory observations led to the hypothesis that AIH is a multifactorial disease. Autoimmune associated disorders are of B and T lymphocyte origin, and other anomalies of the immune system, such as low levels of circulating IgA, are not uncommon. Two types of AIH are currently recognized according to the nature of the autoantibody detected in children at the time of diagnosis. Patients with AIH type 1 display anti-smooth muscle antibodies (SMA) and/or anti-nuclear antibodies (ANA) in their sera. AIH type 2 is characterized by anti-liver kidney microsome (LKM1) and/or anti-liver cytosol type 1 antibodies (LCl)2,3.

Should Giant Cell Hepatitis With Autoimmune Haemolythic Anaemia Be Considered a Paediatric Autoimmune Liver Disease?

Reply: We thank Dr Nastasio et al for their informative letter on giant cell hepatitis with Coombs positive haemolytic anaemia (GCH-AHA) (1). When we were commissioned by the ESPGHAN Hepatology Committee to write the Position Statement on Paediatric Autoimmune Liver Disease (2), we did consider the possibility of including GCH-AHA (3) and neonatal haemochromatosis (4), rare conditions with a possible autoimmune component to their pathogeneses. We decided not to include them for the following reasons. The major aim of the Position Statement was to formulate a diagnostic and management protocol for juvenile autoimmune liver disease on the basis of what available in the literature on conditions recapitulating classical autoimmune hepatitis, that is, sharing in common serological (positivity for anti-nuclear, anti-smooth muscle, anti-liver kidney microsomal type 1, anti-liver cytosol type 1, and/or anti soluble liver antigen) and histological (interface hepatitis, rosette formation, multilobular collapse) features. These conditions, which include autoimmune hepatitis, autoimmune sclerosing cholangitis (overlap between autoimmune hepatitis and sclerosing cholangitis) and autoimmune hepatitis after liver transplant, are not as rare as hitherto believed in the course of childhood, and, though sharing several laboratory and clinical features, differ in terms of diagnostic criteria, management, and outcome, prompting the need for a Position Statement. GCH-AHA, which most likely has an autoimmune component to its pathogenesis, is a rare disease affecting almost exclusively infants and is associated to a number of immune mediated disorders, as noted in Dr Nastasio's letter (5), raising the question as to whether the underlying problem in these children is immune dysregulation (6). The typical histological features of GCH-AHA are diffuse giant cell transformation of hepatocytes and inflammation, different from those of classical autoimmune hepatitis, rarely posing problems in regards to differential diagnosis between the 2 conditions. GCH-AHA does respond, at least partially, to immunosuppression and relapses frequently when treatment is withdrawn (5). B-cell–mediated immunity appears to be involved in both liver and systemic damage, as anti-B cell monoclonal antibodies (rituximab) are to date the most effective treatment for this condition (7), though not in all patients (8). In conclusion, we do agree that GCH-AHA has a strong immune/autoimmune component to its pathogenesis, but it differs from the more common and classical autoimmune liver diseases of childhood and adolescence. Multi-centre collaboration for a better characterisation of this serious disorder is warranted to understand its pathogenesis and devise more effective treatment.

Clinical implications of antimitochondrial antibody seropositivity in autoimmune hepatitis: a multicentre study

Antimitochondrial antibody (AMA) positivity is the serological marker of primary biliary cholangitis (PBC), but can also be sporadically detected in autoimmune hepatitis (AIH). Little is known about the clinical significance of AMA in AIH. We recruited 47 AMA-positive AIH cases from several centres and compared them with 264 well-characterized Italian AIH patients. Cases with any features of PBC were excluded. In univariate analysis, AMA-positive AIH patients were older (46 vs. 36, P=0.002) and more responsive to immunosuppression (74 vs. 59%, P=0.05), but no differences were observed between the two groups after logistic regression using AMA as a dependent variable. None of the AMA-positive AIH patients showed signs of evolving PBC features after a median follow-up of up 47 months. AMA was detected in combination with all serological AIH markers except antiliver kidney microsome type 1 and antiliver cytosol type 1. AMA was the only marker of autoimmunity in eight cases. We found no differences between AIH with and without AMA. The groups had similar clinical, biochemical and histological features. AMA-positive AIH patients did not evolve towards PBC. In some cases, AMA was the only autoantibody.

Autoimmune hepatitis: From mechanisms to therapy

Autoimmune hepatitis (AIH) is a progressive inflammatory hepatopathy and an important cause of end-stage liver disease. Its aetiology remains unknown, though both genetic and environmental factors are involved in its development. The major mechanism of autoimmune liver damage involves immune reactions against host liver antigens. Numerical and functional defects of regulatory T-cells play a permissive role enabling autoimmune liver injury to occur and persist. The most typical features of AIH are female preponderance, hypergammaglobulinaemia, seropositivity for circulating autoantibodies and a picture of interface hepatitis on histology. Two types of AIH are distinguished according to serological profile: AIH type 1 patients are positive for anti-nuclear and/or anti-smooth muscle antibodies, whereas AIH type 2 patients are defined by the positivity for anti-liver kidney microsomal type 1 antibody and/or for anti-liver cytosol type 1 antibody. Clinical manifestations are variable, and AIH onset is often ill-defined, frequently mimicking acute hepatitis; its course may be fluctuating. AIH responds to immunosuppressive treatment in the majority of cases. Steroids with or without azathioprine should be instituted promptly upon diagnosis. Remission is achieved in some 80% of patients. For the remaining 20% of patients, alternative immunosuppressive agents such as mycophenolate mofetil and calcineurin inhibitors are an option. Liver transplantation should be considered for those patients who progress to cirrhosis and develop complications of end-stage liver disease, as well as for those presenting with acute liver failure; outcomes are excellent, although the disease may recur in the allograft.

The induction of autoimmune hepatitis in the human leucocyte antigen-DR4 non-obese diabetic mice autoimmune hepatitis mouse model.

Autoimmune hepatitis (AIH) is a chronic liver disease characterized by progressive inflammation, female preponderance and seropositivity for autoantibodies such as anti-smooth muscle actin and/or anti-nuclear, anti-liver kidney microsomal type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) in more than 80% of cases. AIH is linked strongly to several major histocompatibility complex (MHC) alleles, including human leucocyte antigen (HLA)-DR3, -DR7 and -DR13. HLA-DR4 has the second strongest association with adult AIH, after HLA-DR3. We investigated the role of HLA-DR4 in the development of AIH by immunization of HLA-DR4 (DR4) transgenic non-obese diabetic (NOD) mice with DNA coding for human CYP2D6/FTCD fusion autoantigen. Immunization of DR4 mice leads to sustained mild liver injury, as assessed biochemically by elevated alanine aminotransferase, histologically by interface hepatitis, plasma cell infiltration and mild fibrosis and immunologically by the development of anti-LKM1/anti-LC1 antibodies. In addition, livers from DR4 mice had fewer regulatory T cells (Tregs ), which had decreased programmed death (PD)-1 expression. Splenic Tregs from these mice also showed impaired inhibitory capacity. Furthermore, DR4 expression enhanced the activation status of CD8+ T cells, macrophages and dendritic cells in naive DR4 mice compared to naive wild-type (WT) NOD mice. Our results demonstrate that HLA-DR4 is a susceptibility factor for the development of AIH. Impaired suppressive function of Tregs and reduced PD-1 expression may result in spontaneous activation of key immune cell subsets, such as antigen-presenting cells and CD8+ T effectors, facilitating the induction of AIH and persistent liver damage.

Autoimmune hepatitis: From mechanisms to therapy

Autoimmune hepatitis (AIH) is a progressive inflammatory hepatopathy and an important cause of end-stage liver disease. Its aetiology remains unknown, though both genetic and environmental factors are involved in its development. The major mechanism of autoimmune liver damage involves immune reactions against host liver antigens. Numerical and functional defects of regulatory T-cells play a permissive role enabling autoimmune liver injury to occur and persist. The most typical features of AIH are female preponderance, hypergammaglobulinaemia, seropositivity for circulating autoantibodies and a picture of interface hepatitis on histology. Two types of AIH are distinguished according to serological profile: AIH type 1 patients are positive for anti-nuclear and/or anti-smooth muscle antibodies, whereas AIH type 2 patients are defined by the positivity for anti-liver kidney microsomal type 1 antibody and/or for anti-liver cytosol type 1 antibody. Clinical manifestations are variable, and AIH onset is often ill-defined, frequently mimicking acute hepatitis; its course may be fluctuating. AIH responds to immunosuppressive treatment in the majority of cases. Steroids with or without azathioprine should be instituted promptly upon diagnosis. Remission is achieved in some 80% of patients. For the remaining 20% of patients, alternative immunosuppressive agents such as mycophenolate mofetil and calcineurin inhibitors are an option. Liver transplantation should be considered for those patients who progress to cirrhosis and develop complications of end-stage liver disease, as well as for those presenting with acute liver failure; outcomes are excellent, although the disease may recur in the allograft.

A novel "humanized mouse" model for autoimmune hepatitis and the association of gut microbiota with liver inflammation.

Autoimmune hepatitis (AIH) in humans is a severe inflammatory liver disease characterized by interface hepatitis, the presence of circulating autoantibodies, and hyper-gammaglobulinemia. There are two types of AIH, type 1 (AIH-1) and type 2 (AIH-2), characterized by distinct autoimmune serology. Patients with AIH-1 are positive for anti-smooth muscle and/or antinuclear autoantibodies, whereas patients with AIH-2 have anti-liver kidney microsomal type 1 and/or anti-liver cytosol type 1 autoantibodies. Cytochrome P4502D6 is the antigenic target of anti-liver kidney microsomal type 1, and formiminotransferase cyclodeaminase is the antigenic target of anti-liver cytosol type 1. It is known that AIH, both types 1 and 2, is strongly linked to the human leukocyte antigen (HLA) alleles -DR3, -DR4, and -DR7. However, direct evidence of the association of HLA with AIH is lacking. We developed a novel mouse model of AIH using the HLA-DR3 transgenic mouse on the nonobese-diabetic background by immunization of HLA-DR3- and HLA-DR3+ nonobese-diabetic mice with a DNA plasmid, coding for human cytochrome P4502D6/formiminotransferase cyclodeaminase fusion protein. Immunization with cytochrome P4502D6/formiminotransferase cyclodeaminase leads to a sustained elevation of alanine aminotransferase, development of antinuclear autoantibodies and anti-liver kidney microsomal type 1/anti-liver cytosol type 1 autoantibodies, chronic immune cell infiltration, and parenchymal fibrosis on liver histology in HLA-DR3+ mice. Immunized mice also showed an enhanced T helper 1 immune response and paucity of the frequency of regulatory T cells in the liver. Moreover, HLA-DR3+ mice with exacerbated AIH showed reduced diversity and total load of gut bacteria. Our humanized animal model has provided a novel experimental tool to further elucidate the pathogenesis of AIH and to evaluate the efficacy and safety of immunoregulatory therapeutic interventions in vivo.

Autoimmune Hepatitis

Autoimmune hepatitis (AIH) is defined by elevated serum transaminases along with the presence of one or more characteristic serum autoantibodies, including antinuclear antibody (ANA), anti–smooth muscle antibody (ASMA), and anti–liver-kidney microsomal type 1 antibody (anti-LKM-1); elevated levels of serum immunoglobulin G (IgG); interface hepatitis on histology; and responsiveness to immunosuppressive therapy. AIH has been classified into two disease subtypes based on serologic markers: type 1, which is characterized by the presence of either ANA or ASMA, and type 2, which is characterized by the presence of either anti-LKM-1 or anti–liver-cytosol antibody type 1 (anti-LC-1). This review addresses the epidemiology, natural history, pathogenesis, and management of AIH, as well as ongoing challenges. Several recent advances are highlighted, including the creation of a simplified diagnostic scoring system and the use of budesonide for AIH treatment. Figures show the pathology of AIH, treatment approach of moderate to severe AIH with combination therapy, azathioprine metabolism, and management of treatment outcomes. Tables list a comparison of type 1 and type 2 AIH, antibodies in AIH, the revised diagnostic scoring system (including a simplified version), indications for treatment in AIH, recommended treatment regimens for AIH by the American Association for the Study of Liver Diseases, and adverse effects associated with therapy for AIH. This review contains 4 highly rendered figures, 7 tables, and 146 references.

Autoimmune Hepatitis: A Classic Autoimmune Liver Disease

AIH is characterized by chronic inflammation of the liver, interface hepatitis, hypergammaglobulinemia, and production of autoantibodies. Based on the nature of the serum autoantibodies, two types of AIH are recognized: type 1 (AIH-1), positive for ANA and/or anti-smooth muscle antibody, and type 2 (AIH-2), defined by the positivity for anti-liver kidney microsomal type 1 antibody or for anti-liver cytosol type 1 antibody. AIH demonstrates a female preponderance with the female-to-male ratio of 4:1 in AIH-1 and 10:1 in AIH-2. Several genes confer susceptibility to AIH and influence clinical manifestation, response to treatment, and overall prognosis. Most are located within the human leukocyte antigen (HLA) region, which is involved in the presentation of antigenic peptides to T cells and thus in the initiation of adaptive immune responses. The strongest associations are found within the HLA-DRB1 locus. In patients with increased genetic susceptibility to AIH, immune responses to liver autoantigens could be triggered by molecular mimicry. Because of molecular mimicry, different environmental agents, drugs, and viruses might produce AIH. In AIH, T cells are numerically and functionally impaired, permitting the perpetuation of effector immune responses with ensuing persistent liver destruction. AIH is rare but highly treatable inflammatory condition of the liver. Subclinical and asymptomatic disease is common. AIH therefore needs to be considered in the differential diagnosis of all patients with elevated liver enzymes. Clinical response to immunosuppressive therapy is characteristic and supports the diagnosis.

Autoimmune hepatitis in children: Progression of 20 cases in northern Mexico

BackgroundAutoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver with nonspecific clinical manifestations that causes greater liver damage in children than in adults. AimsTo analyze the clinical progression, biochemical profiles, histopathologic changes, and treatment response in 20 children with AIH. Material and methodsA retrospective study was carried out on the variables associated with clinical progression, diagnosis, and treatment response in children seen at the the Unidad Médica de Alta Especialidad (UMAE) No. 71 IMSS in Torreón, Coahuila, Mexico, from 1992 to 2012. ResultsTwenty patients were analyzed, 75% with type 1 AIH (AIH-1) and 25% with type 2 AIH (AIH-2). Girls predominated with a 3:1 ratio of girls to boys. The mean age was 10.07 ± 6.53 years for the AIH-1 cases and 6.75 ± 3.77 years for the AIH-2 cases. There was an association with immunologic diseases in 40% of the patients.The patients in the AIH-2 group had greater biochemical profile alterations and IgA deficiency. Anti-nuclear antibody and anti-smooth muscle antibody were positive in 100% of the patients with AIH-1, and anti-liver kidney microsomal type 1 antibody was positive in 100% of the AIH-2 patients. Liver biopsy revealed interface hepatitis in both groups. The AIH-2 group responded more quickly to treatment, but had a higher recurrence rate. ConclusionsAutoimmune hepatitis in the pediatric patient should be suspected in order to make an early diagnosis and thereby establish opportune treatment. Determining the type of AIH is necessary for making adequate diagnosis and for achieving a better outcome in relation to recurrence and complication rates.

Autoimmune hepatitis in children: progression of 20 cases in northern Mexico.

Autoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver with nonspecific clinical manifestations that causes greater liver damage in children than in adults. To analyze the clinical progression, biochemical profiles, histopathologic changes, and treatment response in 20 children with AIH. A retrospective study was carried out on the variables associated with clinical progression, diagnosis, and treatment response in children seen at the the Unidad Médica de Alta Especialidad (UMAE) No. 71 IMSS in Torreón, Coahuila, Mexico, from 1992 to 2012. Twenty patients were analyzed, 75% with type 1 AIH (AIH-1) and 25% with type 2 AIH (AIH-2). Girls predominated with a 3:1 ratio of girls to boys. The mean age was 10.07 ± 6.53 years for the AIH-1 cases and 6.75 ± 3.77 years for the AIH-2 cases. There was an association with immunologic diseases in 40% of the patients. The patients in the AIH-2 group had greater biochemical profile alterations and IgA deficiency. Anti-nuclear antibody and anti-smooth muscle antibody were positive in 100% of the patients with AIH-1, and anti-liver kidney microsomal type 1 antibody was positive in 100% of the AIH-2 patients. Liver biopsy revealed interface hepatitis in both groups. The AIH-2 group responded more quickly to treatment, but had a higher recurrence rate. Autoimmune hepatitis in the pediatric patient should be suspected in order to make an early diagnosis and thereby establish opportune treatment. Determining the type of AIH is necessary for making adequate diagnosis and for achieving a better outcome in relation to recurrence and complication rates.

Detection of Anti-Lactoferrin Antibodies and Anti-Myeloperoxidase Antibodies in Autoimmune Hepatitis: A Retrospective Study

Anti-lactoferrin antibodies (ALA) and anti-myeloperoxidase antibodies (AMPA) are specific serological markers for autoimmune hepatitis (AIH). The project aimed to detect ALA and AMPA and explore their clinical significances in AIH patients. 59 AIH patients, 217 non AIH patients, and 50 healthy controls were enrolled in this study. ALA and AMPA were detected by ELISA. Antineutropil cytoplasmic antibodies (ANCA) and anti-smooth muscle antibodies (ASMA) were examined by indirect immunofluorescence. Antimitochondrial antibody M2 subtype (AMA-M2), anti-liver kidney microsomal antibody Type 1 (LKM1), anti-liver cytosol antibody Type 1 (LC1), and anti-soluble liver antigen/liver-pancreas antibodies (SLA/LP) were tested by immunoblot. The positivity for ALA was 18.6% in AIH group, only one patient in non-AIH group was positive for ALA; the positivity for AMPA was 59.3% in AIH group, with significant differences (P < 0.01) compared with other groups. The specificities for ALA and AMPA were 99.63% and 97.75%; the sensitivities were 18.64% and 59.32%; and the accuracy rates were 84.97% and 90.80%, respectively. A certain correlation was observed between ALA and SLA/LP, AMPA and ANCA, ASMA in AIH group. ALA and AMPA were associated with AIH, and had high clinical diagnostic value. Co-detection with other relative autoantibodies could play an important role in differential diagnosis of AIH.

Autoantibody and Human Leukocyte Antigen Profiles in Children With Autoimmune Liver Disease and Their First‐Degree Relatives

Familial clustering of juvenile autoimmune liver disease (AILD), including autoimmune hepatitis and autoimmune sclerosing cholangitis (ASC), is rare, despite a high prevalence of autoimmune disorders in AILD families. To investigate this discrepancy, we measured autoantibodies diagnostic for AILD, anti-nuclear, anti-smooth muscle, anti-liver kidney microsomal type 1, anti-liver cytosol type 1, and anti-soluble liver antigen antibodies, and human leukocyte antigen profiles in 31 patients and 65 of their first-degree relatives (FDR). The autoantibody profile was compared with that of 42 healthy subjects (HS). Autoantibodies were detected in 71% (22/31) patients. Anti-nuclear antibody or anti-smooth muscle antibody were present in 4/65 FDR (6.2%). HS were negative for all autoantibodies. The frequencies of homozygous HLA DRB1*0301 (DR3) genes and haplotype A1-B8-DR3 were higher in the patients (25% and 43%) than in FDR (9% and 27%) and HS (0% and 16%). The frequencies of disease-protective genes DR4 and/or DR15 were lower in the patients (25%) than in FDR (42%) and HS (42%). Only 1 family contained 2 patients with AILD, 1 with ASC and 1 with primary sclerosing cholangitis. Both patients possessed A1-B8-DR3 genes, the ASC being homozygous and the primary sclerosing cholangitis heterozygous. Six FDR had nonhepatic autoimmune disorders, none being autoantibody positive. Homozygosity for DR3 plays a major role in the predisposition to juvenile AILD. Diagnostic autoantibodies for AILD are rare among patients' FDR and not linked to clinical manifestation of AILD.

Antismooth muscle and antiactin antibodies are indirect markers of histological and biochemical activity of autoimmune hepatitis

Reactivity and titers of autoantibodies vary during the course of autoimmune hepatitis (AIH), and some autoantibodies have been associated with disease activity and adverse outcomes after treatment. The aim of this study was to assess the autoantibody behavior in AIH and its significance as predictors of biochemical and histological remission. A total of 117 patients with AIH (mean age 18.6 [4-69] years) were evaluated and tested for autoantibodies at disease onset and successively (mean 3.2 [2-6] times) after a mean follow-up evaluation of 70 [20-185] months. Antismooth muscle (ASMA), antiliver kidney microsome type 1 (anti-LKM1), antiliver cytosol type 1 (anti-LC1), antimitochondrial, antinuclear (ANA), and antiactin antibodies (AAA) were determined at disease onset and 379 other times during the follow-up evaluation through indirect immunofluorescence in rodent tissues, HEp-2 cells, and human fibroblasts. Anti-SLA/LP were assessed 45 times in the follow-up evaluation of 19 patients using enzyme-linked immunosorbent assay (ELISA). Upon admission, AIH types 1 and 2 were observed in 95 and 17 patients, respectively. Five subjects had AIH with anti-SLA/LP as the sole markers. Patients initially negative for AAA did not develop these antibodies thereafter. ANA were detected de novo in six and three subjects with AIH types 1 and 2, respectively. After treatment, only ASMA (>1:80) and AAA (>1:40) were significantly associated with biochemical (76.9% and 79.8%) and histological features (100% and 100%) of disease activity (P < 0.001). With the exception of ANA, the autoantibody profile does not markedly vary in the course of AIH. The persistence of high titers of ASMA and/or AAA in patients with AIH is associated with disease activity.

Management of Autoimmune Hepatitis in Children

See “Autoimmune Hepatitis in Children in Eastern Denmark” by Vitfell-Pedersen et al on page 376. Autoimmune hepatitis (AIH) may be particularly aggressive in children and induce severe liver damage, if untreated. On the contrary, immunosuppressive therapy, with prednisolone alone or in combination with azathioprine, leads to remission in 80% of cases resulting in a normal life expectancy, good quality of life (1), and a transplant-free survival rate of 90% (2). In this issue of JPGN, Vitfell-Pedersen et al report the features and long-term outcome of children with AIH enrolled in a paediatric population-based survey from the eastern part of Denmark (3). This retrospective study, if compared with previous European series, shows some unusual findings such as male preponderance, extremely low rate of anti-liver kidney microsomal type 1 antibody–positive patients, and absence of fulminant cases (4,5). Despite these peculiarities, which could be due to bias of the study, it is noteworthy that liver cirrhosis, present in 69.6% of patients at diagnosis, did not affect either the overall survival or the survival free of liver transplantation. This favourable outcome could suggest the possibility, reported in the literature, but still a matter of debate among experts, of reversibility of liver fibrosis in some chronic liver diseases (6,7). Obviously, this is a simple hypothesis because histological evaluation of the liver was not performed in Danish patients with sustained biochemical remission. Another relevant finding of the Danish study is that 84% of patients achieved remission in a median of 5.4 months from the start of treatment (60.6% on treatment with prednisolone and azathioprine and 24% on prednisolone alone). Consequently, treatment with prednisolone and azathioprine seemed to be more effective than prednisolone alone in inducing remission. Unfortunately, the authors did not clarify why a single treatment schedule was not used and azathioprine added only to some patients (poor control of transaminases, steroid adverse effects?) or why so many patients were not controlled by treatment. At the end of follow-up, 15% of the patients were in stable remission and off therapy. Even for this issue, no information about the putative predictors of such a good outcome was provided. Actually, despite the availability of many studies and guidelines for AIH (8), many aspects concerning children with AIH remain unclear. In this context, it would have been useful to have more details about clinical features of patients treated with steroid alone versus those treated with steroid and azathioprine, doses of immunosuppressant drugs during the different phases of the treatment, duration of each phase, and minimum required doses to maintain remission to draw conclusions about the best mode of treatment for AIH in children. Other limitations of the study are represented by the scarce use of the available autoantibody repertoire for the diagnosis of AIH (8,9) absence of indication of the autoantibodies’ serum levels considered positive for children (8), and limited use of cholangiography, which was not performed in all children with AIH to exclude biliary involvement according to American Association for the Study of Liver Diseases guidelines (8). Even with these limitations, we think that Vitfell-Pedersen study is valuable because it draws attention to many unclarified points of AIH in childhood. To date, because of the relative rarity of this condition, in common clinical practice the management of children with AIH often reflects the preferences of individual centres (8). It is probably time to initiate large multicentre prospective studies to reach common agreement on the management of children with AIH.

Autoimmune hepatitis type 2 associated with an unexpected and transient presence of primary biliary cirrhosis-specific antimitochondrial antibodies: a case study and review of the literature

BackgroundUnlike other autoimmune liver diseases, primary biliary cirrhosis (PBC) has never been reported in early childhood, while type 2 autoimmune hepatitis (AIH) is eminently a paediatric disease.Case presentationWe describe a case of type 2 AIH with serological positivity for PBC-specific anti-mitochondrial antibodies (AMA) in a 3-year old girl. We found this observation intriguing as AMA and indeed an overlap with PBC are virtually absent in Type 2 AIH, a pediatric form of AIH which is distinct precisely because it is characterized by pathognomonic anti-liver kidney microsomal type 1 (LKM-1) showing a remarkable antigen-specificity directed against cytochrome P4502D6. We also review the literature in relation to AMA positivity in paediatric age and adolescence. In our case, the presence of AIH-2-specific anti-LKM-1 and PBC-specific AMA was confirmed by indirect immunofluorescence (IIF), and immunoblotting and ELISA based on recombinant mitochondrial antigens. The clinical, laboratory and histological features of the child are given in detail. Interestingly the mother was AMA positive without other features of PBC. The child was successfully treated with immunosuppression and five years after the original diagnosis is on a low dose of prednisolone and azathioprine, with no signs of relapse. Anti-LKM-1 antibodies are still present in low titres. AMA were detectable for the first 4 years after the diagnosis and disappeared later.ConclusionThis is the first case report in the literature of AIH type 2 with an unexpected PBC-specific AMA positivity in a young child. Response to immunosuppressive treatment was satisfactory and similar to that described in AIH. A review of published reports on AMA positivity in paediatric age shows that the antibody may arise in the context of immunodeficiency and is variably associated with liver damage.

Diagnosis and Therapy of Autoimmune Hepatitis

Autoimmune hepatitis (AIH) is a chronic progressive hepatitis, characterized by interface hepatitis with lymphoplasmacellular infiltrates on liver biopsy, high serum globulin level and circulating autoantibodies. It is classified into two types, according to autoantibody profile: type 1 is characterized by anti-nuclear (ANA) and/or anti-smooth muscle (SMA) antibodies; type 2 by anti-liver kidney microsomal type 1 (anti-LKM-1) antibodies. AIH affects all ages, may be asymptomatic, frequently has an acute onset, and can present as fulminant hepatitis. The diagnosis of AIH is based on a scoring system codified by an international consensus. Corticosteroids alone or in conjunction with azathioprine is the treatment of choice in patients with AIH and results in remission induction in over 80% of patients. Alternative proposed strategies in patients who have failed to achieve remission on standard therapy or patients with drug toxicity include the use of cyclosporine, tacrolimus, budesonide or mycophenolate mofetil. Liver transplantation is the treatment of choice in managing decompensated disease, however AIH can recur or develop de novo after liver transplantation.