Autoimmune Hepatitis Type Research Articles

The influence of genetic predisposition and autoimmune hepatitis inducing antigens in disease development

Autoimmune hepatitis (AIH) is defined as a chronic liver inflammation with loss of tolerance against hepatocytes. The etiology and pathophysiology of AIH are still poorly understood because reliable animal models are limited. Therefore, we recently introduced a model of experimental murine AIH by a self-limited adenoviral infection with the AIH type 2 antigen formiminotransferase cyclodeaminase (FTCD).We could demonstrate that break of humoral tolerance towards liver specific autoantigens like FTCD and cytochrome P450 2D6 (CYP2D6) is not dependent on the genetic background. However, the development of AIH in autoantibody positive animals is determined by genetic background genes. We could also show that the break of humoral tolerance is necessary but not sufficient for the development of AIH. In contrast the break of tolerance against the ubiquitously expressed nuclear antigens (ANAs) is strictly dependent on genetic predisposition. Priming with the UGA suppressor tRNA-associated protein (soluble liver antigen; SLA) is a strong inducer of ANA reactivity, but not sufficient to cause AIH development thereby questioning the importance of anti-SLA immune response as an important driver in AIH. Monogenetic mutations such as Aire-deficiency can cause AIH in otherwise genetically resistant strains. ConclusionThe results have important implications for our understanding of the pathophysiology of AIH development and for the interpretation of humoral antibody responses in AIH.

Double Trouble Bubble: Autoimmune Overlap Syndrome Causing Portal Gastropathy, with Review of Current Literature

A 57 year old female with a past medical history of cirrhosis and high elevation of SM-Ab titer, elevated actin IGG, and anti-mitochondrial antibody significantly increased presented to the emergency department with hematemasis and bright red blood per rectum. After admission to the ICU she received 2 units packed red blood cells and was started on intravenous antibiotics, protonix, and octreotide. An esophagogastroduodenoscopy revealed esophageal and gastric varices extending into the stomach with gastropathy, not amenable to banding. A Trans-Jugular Intrahepatic Portosystemic Shunt (TIPS) was performed after resolution of bleeding. The patient was discharged with follow up for transplant evaluation while being treated with ursodiol, rifaximin, lactulose, pantoprazole, and diuretics. Autoimmune hepatitis (AIH) is a liver disease characterized by inflammatory liver histology, elevated transaminase levels, circulating autoantibodies, and increased levels of immunoglobulin G in the absence of a known etiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or antinuclear antibody (AIH type 1) and antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 (AIH type 2). There is mounting evidence that genetic susceptibility, molecular mimicry, and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4 T-cells. The histological findings of lymphocytes, plasma cells, and macrophages is non-specific but consistent with the diagnosis of AIH. A massive recruitment of activated inflammatory cells is likely to cause damage and eventually leads to portal hypertension; this prolonged elevated portal pressures then can lead to progressive congestion and eventually gastropathy. Due to large heterogeneity of the disease AIH may be unrecognized, and the clinical manifestation of AIH can range from mild or severe symptoms to fulminant hepatic failure. Growing insights into the clinical presentation of AIH highlights the importance of evaluation of the current diagnostic criteria and development of new treatment strategies to identify patients who would benefit from more efficient therapy. We present a patient in which liver transplant would be the only viable option for long term therapeutic benefit due to the untreated progression of her disease.

Uncovering the Mask: A Rare Presentation of Autoimmune Hepatitis Type 2 in a 54 Year-Old Man

Autoimmune Hepatitis (AIH) is a chronic liver disorder that is found in both adult and pediatric patients characterized by abnormal aminotranferase levels, detectable autoantibodies and elevated immunoglobulin G (IgG) with significant inflammation on liver histology with presence of plasma cells. There are two types of AIH are identified by specific serological markers. Type 1 is associated with detectable ANA and/or smooth muscle antibody (ASMA) and can be found in both adults and children. Type 2 is associated with anti-liver-kidney-microsome (anti-LKM) type 1 and/or liver cytosol type 1 and is primarily a pediatric or young adult illness. We describe an unusual case of AIH type 2 in a 54-year-old African American male, previously in good health, who presented with cyclical fevers (max of 1020) and diffuse joint pains. He worked in a rural hospital in Ghana four months prior, but had no known exposures, and had been taking malarone for prophylaxis. He regularly used whey protein powder, but denied other meds. Within one week, his AST level was 639 U/L, ALT was 972 U/L with alkaline phosphatase level of 362 U/L. Comprehensive work up for infectious causes including malaria, Babesia, EBV, Ehrlichia, CMV, and viral hepatitides were negative. His IgG level rose to 2227 mg/dl, while ANA and ASMA were undetectable. Liver biopsy was remarkable for interface hepatitis with extensive inflammation extending into the lobules and portal tracts with marked lymphocytes, plasma cells and eosinophilia. Anti-LKM was requested, but results were not available. All of these features together were consistent with a rare presentation of type 2 AIH. He was started on prednisone 30mg daily for 2 weeks then 20mg daily for 2 weeks with azathioprine 50mg daily which reduced his aminotransferases almost immediately. He was transitioned to 10mg of prednisone and 50mg azathioprine daily for maintenance after liver associated enzyme labs normalized. Despite the clinical presentation of this patient being concerning for an infectious or a drug-induced cause, it was the liver biopsy that sealed the diagnosis of AIH. Liver biopsy in AIH classically shows portal and periportal lymphocyte and plasma cell infiltrates that disrupt the parenchymal limiting plate, causing interface hepatitis. Our patient emphasizes the role of liver biopsy in patients with elevated liver enzymes for whom no identifiable etiology has been found.

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.

Transient Expression of Transgenic IL-12 in Mouse Liver Triggers Unremitting Inflammation Mimicking Human Autoimmune Hepatitis.

The etiopathogenesis of autoimmune hepatitis (AIH) remains poorly understood. In this study, we sought to develop an animal model of human AIH to gain insight into the immunological mechanisms driving this condition. C57BL/6 mice were i.v. injected with adeno-associated viral vectors encoding murine IL-12 or luciferase under the control of a liver-specific promoter. Organ histology, response to immunosuppressive therapy, and biochemical and immunological parameters, including Ag-specific humoral and cellular response, were analyzed. Mechanistic studies were carried out using genetically modified mice and depletion of lymphocyte subpopulations. Adeno-associated virus IL-12-treated mice developed histological, biochemical, and immunological changes resembling type 1 AIH, including marked and persistent liver mononuclear cell infiltration, hepatic fibrosis, hypergammaglobulinemia, anti-nuclear and anti-smooth muscle actin Abs, and disease remission with immunosuppressive drugs. Interestingly, transgenic IL-12 was short-lived, but endogenous IL-12 expression was induced, and both IL-12 and IFN-γ remained elevated during the entire study period. IFN-γ was identified as an essential mediator of liver damage, and CD4 and CD8 T cells but not NK, NKT, or B cells were essential executors of hepatic injury. Furthermore, both MHC class I and MHC class II expression was upregulated at the hepatocellular membrane, and induction of autoreactive liver-specific T cells was detected. Remarkably, although immunoregulatory mechanisms were activated, they only partially mitigated liver damage. Thus, low and transient expression of transgenic IL-12 in hepatocytes causes loss of tolerance to hepatocellular Ags, leading to chronic hepatitis resembling human AIH type 1. This model provides a practical tool to explore AIH pathogenesis and novel therapies.

Autoantibody presentation in drug-induced liver injury and idiopathic autoimmune hepatitis: the influence of human leucocyte antigen alleles.

Positive autoantibody (AAB) titres are commonly encountered in autoimmune hepatitis (AIH) and in a proportion of drug-induced liver injury (DILI) patients. The underlying mechanism for selective AAB occurrence in DILI is unknown, but could be associated with variations in immune-associated genes. Hence, we aimed to analyse human leucocyte antigen (HLA) allele compositions in DILI with positive (+) and negative (-) AAB titres and in AIH patients. High-resolution genotyping of HLA class I (A, B, C) and II (DRB1, DQB1) loci was performed on 207 DILI and 50 idiopathic AIH patients and compared with 885 healthy Spanish controls. Compared with controls, HLA-B*08:01 [44 vs. 9.7%, P=3.7E-13/corrected P-value (Pc)=1.0E-11], C*07:01 (46 vs. 24%, P=6.4E-04/Pc=0.012), DRB1*03:01 (58 vs. 21.5%, P=5.0E-09/Pc=1.0E-07) and DQB1*02:01 (56 vs. 22%, P=6.8E-08/Pc=9.0E-07) were significantly more frequent in AIH patients. The HLA-A*01:01 frequency was increased in the same population, but did not reach significance after Bonferroni's correction (34 vs. 19%, P=0.02/Pc=0.37). Fifty-eight of 207 DILI patients presented positive titres for at least one AAB (predominantly antinuclear antibody 76% and antismooth muscle antibody 28%). There was a tendency towards higher representation of DRB1*14:01 and DQB1*05:03 in DILI AAB+ compared with DILI AAB- (13.8 vs. 4.0%, P=0.02/Pc=0.5; 13.8 vs. 4.7%, P=0.04/Pc=0.5). The presence of HLA alleles B*08:01, C*07:01, DRB1*03:01, DQB1*02:01 and possibly A*01:01 enhances the risk of AIH (type 1) in Spanish patients. These alleles form part of the ancestral haplotype 8.1. HLA-DRB1*14:01 and DQB1*05:03 could potentially increase the risk of positive AAB (particularly antinuclear antibody) in Spanish DILI patients.

Autoimmune hepatitis and long-term disease course in children in Turkey, a single-center experience

The aim of this study is to determine clinic and laboratory features, treatment protocols, treatment responses, and long term follow-up of children with autoimmune hepatitis (AIH) in a region of Turkey followed at Ege University. The records of 47 children with AIH between 1998 and 2012 were retrospectively analyzed for clinical profiles, treatment response, relapse rate, and long-term side effects. The median age of the children was 10±4.1 years (55.3% females). A total of 29 patients presented with chronic hepatitis (61.7%). According to the autoantibody profiles, 40 (85.1%) and seven (14.9%) cases were classified as type 1 and type 2, respectively. Presentation with acute hepatitis and chronic hepatitis was significantly higher in type 1 disease. Laboratory findings at presentation was found similar among races as well as AIH types (P>0.05). The prednisolone was used for remission induction in 37 patients; 86.4% (n: 32) achieved a complete response, 2.7% (n: 1) achieved a partial response, and four patients (10.8%) showed no response. Maintenance was attained by low-dose steroid plus thiopurine and relapse in steroid responders (n: 32) was 9.4% (n: 3) at 8, 12, and 48 months. A total of 36% (n: 24) had neither acute nor chronic treatment side effects. Bone marrow suppression was observed in five patients and hyperglycemia was observed in one patient (10.6 and 2.1%), respectively. AIH type 1 prevails in children in a region of Turkey during the second decade of life. Low-dose corticosteroids combined with azathioprine are found.

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.

Lack of association between the CARD10 rs6000782 polymorphism and type 1 autoimmune hepatitis in a Japanese population

BackgroundPrevious genome-wide association studies have evaluated the impact of common genetic variants and identified several non-HLA risk loci associated with autoimmune liver diseases. More recent genome-wide association studies and replication analyses reported an association between variants of the CARD10 polymorphism rs6000782 and risk of type 1 autoimmune hepatitis (AIH). In this case–control study, we genotyped 326 Japanese AIH patients and 214 control subjects.ResultsGenomic DNA from 540 individuals of Japanese origin, including 326 patients with type-1 AIH and 214 healthy controls, was analyzed for two single nucleotide polymorphisms (SNPs) in the CARD10 gene. We selected CARD10 rs6000782 SNPs and genotyped these using PCR–RFLP method and direct sequencing. The Chi square test revealed that the rs6000782 variant alle (c) was not associated with the susceptibility for AIH in a Japanese population [p = 0.376, odds ratio (OR) 1.271, 95 % confidence interval (CI) 0.747–2.161] in an allele model. Our data also showed that CARD10 rs6000782 variants were not associated with AIH or with the clinical parameters of AIH.ConclusionsIn this study we examined an association between rs6000782 SNPs in the CARD10 gene and type-1 AIH. Results showed no significant association of rs62000782 with type-1 AIH in a Japanese population. This study demonstrated no association between CARD10 rs6000782 variants and AIH in a Japanese population.

Clinical analysis of liver transplantation for autoimmune hepatitis

To describe the outcomes and recurrence of autoimmune hepatitis (AIH) after liver transplantation. Clinical data of 16 patients with AIH who underwent liver transplantation were analyzed retrospectively. The postoperative cumulative survival rate of the patients was calculated. The postoperative rejections and AIH recurrence were analyzed. The Kaplan-Meier method was used for statistical analysis of survival. All patients were female, with an average age of 52.6 years (range: 41-66 years), and an average MELD score of 21.4. According serological analysis, 15 patients were AIH type 1 and 1 patient was AIH type 2. Three patients died, including 2 of pulmonary infection and 1 of graft dysfunction.The 1-, 2-and 5-year cumulative survival rates were 93.8%, 87.1% and 79.1%, respectively. Five cases (31.3%) of recurrent AIH were diagnosed based on histological evidence. Acute rejection occurred in 6 (37.5%) patients, and de novo HBV infection occurred in 1 (6.3%) patient. Liver transplantation is an effective treatment for end-stage AIH. Recurrence and rejection were commonly associated with AIH, but did not negatively impact patient survival.

Silent but Deadly Cytomegalovirus Triggering Autoimmune Hepatitis

A 54 year-old female presented with new onset jaundice associated with abdominal distension, lower extremity edema, and a 10 pound weight gain. She denied intravenous drug use, blood transfusions, any new sexual partners or a family history of liver disease. The physical examination was remarkable for spider angiomata, icteric sclera, ascites, and edema. The lab results revealed an ALP of 162 U/L, a GGT of 65 U/L, an AST 154 U/L, and an ALT of 72 U/L. Additional laboratory tests revealed an elevated ANA titer of 1:640, an anti-smooth muscle ab titer 1:40 and a significant increase in immunoglobulins specifically IgG 4100mg/dL. Interestingly, a CMV Ab IgM was positive at 36.6 u/mL as well as a CMV Ab IgG, which was positive at >10.00 u/mL. Tests for Hepatitis A, B, C, HIV, HSV, Epstein Barr virus (EBV), alpha1 antitrypsin, ceruloplasmin, iron level, ferritin and the Anti-Mitochondrial Ab were negative. A liver biopsy showed a heavy infiltration with lymphoplasmacytic inflammatory cells, interface hepatitis, with bridging necrosis, and fibrosis. These pathologic and laboratory findings led to a definitive diagnosis of autoimmune hepatitis (AIH) Type 1. In the setting of positive CMV IgG and IgM ab titers, we suggest that the trigger for AIH in this case was a preceding CMV infection. The patient responded well to corticosteroid and azathioprine therapy. Autoimmune hepatitis is of unknown etiology and causes a chronic hepatocellular inflammation with necrosis. The most supported pathogenesis of AIH postulates that a combination of environmental triggers, failure of immune system tolerance, and a genetic predisposition may induce a T cell-mediated immune attack against the liver. Case studies in the literature report AIH triggered by both virus and drugs. Furthermore, there is evidence of cross-reactivity between anti-LKM1 and antibodies against homologous regions of the cytomegalovirus (exon CMV130-135). This association could help explain the link between cytomegalovirus infection and autoimmune hepatitis seen in this case. The diagnosis of autoimmune hepatitis is often difficult as its presentation may be acute or chronic, severe or asymptomatic. Diagnosis requires multiple findings and exclusions of similar diseases. We suggest including markers for CMV as part of the differential of AIH as CMV may be an important trigger of AIH. If indeed a trigger is required to set off a sequence of events leading to autoimmune hepatitis in predisposed individuals, viruses are among the most likely candidates.Figure 1Figure 2

Autoantibodies in autoimmune liver diseases.

Autoimmune hepatitis is a chronic hepatitis of unknown etiology characterized by clinical, histological, and immunological features, generally including circulating autoantibodies and a high total serum and/or gamma globulin. Liver-related autoantibodies are very significant for the correct diagnosis and classification of autoimmune liver diseases (AILD), namely autoimmune hepatitis types 1 and 2 (AIH-1 and 2), primary biliary cirrhosis (PBC), and the sclerosing cholangitis types in adults and children. This article intends to review recent studies that investigate autoantibodies in autoimmune liver diseases from a microbiological perspective.

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.

Autoantibodies to asialoglycoprotein receptor (ASGPR) in patients with autoimmune liver diseases

BackgroundThe liver asialoglycoprotein receptor (ASGPR) is the only organ-specific autoantigenic target in autoimmune hepatitis (AIH) patients and corresponding autoantibodies (Abs) have been suggested aiding in the serology of autoimmune liver diseases (ALD). MethodsA novel enzyme-linked immunosorbent assay (ELISA) employing purified rabbit ASGPR was used to detect ASGPR Abs in patients with ALD and controls. ASGPR Ab was determined in sera from 172 patients with AIH type 1, AIH type 2 (n=42), primary biliary cirrhosis (PBC) (n=113), cryptogenic liver disease (n=30), toxic liver disease (n=11), primary sclerosing cholangitis (PSC) (n=27), HCV infection (n=25), non-alcoholic steatohepatitis (n=43) and 100 blood donors. ASGPR Ab positivity was compared with AIH-related Abs (ANA, ASMA, Abs to LKM-1, LC-1, and SLA/LP) in patients with AIH. ResultsPatients with AIH-1 and AIH-2 demonstrated an ASGPR Ab prevalence of 29.1% and 16.7%, respectively. ASGPR Ab positivity in patients with AIH-1 and AIH-2 was not significantly different to those in patients with PSC and HCV (p>0.05, respectively). ASGPR Ab levels in all study cohorts were significantly different with the highest medians in patients with AIH, PSC, and HCV infection (p<0.0001). ASGPR Ab can be found as only AIH-specific Ab determined by LIA and ELISA in 24.4% of AIH patients (48/197). ConclusionsThe novel ASGPR Ab ELISA is a specific diagnostic tool for ASGPR Ab detection in AIH. In addition to AIH, patients with PSC can demonstrate elevated ASGPR Ab amongst those with ALD suggesting a tolerance break to ASGPR in PSC.

Childhood Autoimmune Hepatitis in Bahrain: a Tertiary Center Experience.

Autoimmune hepatitis (AIH) in childhood has variable modes of presentation, and the disease should be suspected and excluded in all children presenting with symptoms and signs of prolonged or severe acute liver disease. In AIH, the liver biopsy histopathology shows inflammation in addition to presence of serum autoimmune antibodies and increased levels of immunoglobulin G (IgG). To investigate the situation of childhood autoimmune hepatitis in Bahrain and to compare it with other studies worldwide. A retrospective study describing the AIH pediatric cases diagnosed during the period of Jan 2005 to Dec 2009. We report the clinical, biochemical, histopathological, and immunological findings, mainly autoimmune profile, in addition to response to treatment, of Bahraini children with autoimmune hepatitis. Five Bahraini children, three females and two males were diagnosed as autoimmune hepatitis during the study period. Their ages at presentation ranged from 9 to 15 (median 10.6) years. One of our patients had a fulminating type. Two had other autoimmune related conditions, namely autoimmune sclerosing cholangitis and ulcerative colitis. All were AIH type 1. Variable response to conventional immunosuppressive therapy was found, from an excellent response with good prognosis, to cirrhosis, hepatic failure and liver transplantation. Childhood AIH is a rare medical problem in Bahrain, with both sexes affected and a variable response to immunosuppressive therapy.

Hyaline droplets in Kupffer cells: a novel diagnostic clue for autoimmune hepatitis.

Pediatric autoimmune hepatitis (AIH) is relatively common and has a characteristic but relatively nonspecific histopathology with a usually prominent lymphoplasmacytic infiltrate. Herein, we describe for the first time the presence of characteristic hyaline droplets in the cytoplasm of Kupffer cells on routine hematoxylin and eosin (H&E) sections in AIH. The medical records and pathologic material over a 20-year period (1992 to 2012) were reviewed from children with AIH (n=30), hepatitis B virus (n=30), and hepatitis C virus (n=30) from the pathology files at Boston Children's Hospital. All children had percutaneous needle liver biopsies. We reviewed sections stained with H&E, PAS, and PAS with diastase for the presence of hyaline droplets in all 90 biopsies. We also performed immunohistochemical analysis for IgG, IgA, and IgD in 6 biopsies with AIH. Hyaline droplets were identified in Kupffer cells throughout the lobules in 15 of 30 biopsies (easily found in 13 and rare in 2); conversely, no droplets were identified in 15. Droplets were identified in 10 AIH type 1 biopsies, 1 in AIH type 2, 3 in overlap syndrome, and 1 in unclassified. Serum IgG levels, when available, were correlated with biopsy findings. Seventeen patients had serum IgG levels available for review. The average IgG level in patients without droplets in their biopsies was 1364 mg/dL, in contrast to 3424 mg/dL in patients with droplets (P=0.021). Immunohistochemical analysis performed in 6 biopsies revealed that droplets were nearly always positive for IgG, occasionally for IgA, and rarely for IgD. None of the biopsies in patients with hepatitis C contained hyaline droplets. One biopsy of a patient with hepatitis B revealed hyaline droplets; this biopsy had an unusually prominent plasmacytic infiltrate, and the patient was found to have an elevated IgG serum level and antibodies to smooth muscle actin. As far as we are aware, hyaline droplets in Kupffer cells on routine H&E sections have never been described. They should be distinguished from the nonspecific granular lysosomal structures frequently found in Kupffer cells in a variety of chronic liver diseases and from erythrophagocytosis. Hyaline droplets may occur in AIH regardless of the type and correlate with a >2-fold increase in serum level of IgG as compared with patients without droplets in their biopsies. Identification of hyaline droplets in Kupffer cells provides a useful diagnostic clue to distinguish AIH from other forms of chronic hepatitis.

Transitioning from Idiopathic to Explainable Autoimmune Hepatitis.

Autoimmune hepatitis lacks an identifiable cause, and its diagnosis requires the exclusion of etiologically defined diseases that resemble it. Insights into its pathogenesis are moving autoimmune hepatitis from an idiopathic to explainable disease, and the goal of this review is to describe the insights that are hastening this transition. Two types of autoimmune hepatitis are justified by serological markers, but they also have distinctive genetic associations (DRB1 and DQB1 genes) and autoantigens. DRB1 alleles are the principal susceptibility factors in white adults, and a six amino acid sequence encoded in the antigen-binding groove of class II molecules of the major histocompatibility complex can influence the selection of autoantigens. Polymorphisms, including variants of SH2B3 and CARD10 genes, may affect immune reactivity and disease severity. The cytochrome mono-oxygenase, CYP2D6, is the autoantigen associated with type 2 autoimmune hepatitis, and it shares homologies with multiple viruses that might promote self-intolerance by molecular mimicry. Chemokines, especially CXCL9 and CXCL10, orchestrate the migration of effector cells to sites of injury and are associated with disease severity. Cells of the innate and adaptive immune responses promote tissue damage, and possible deficiencies in the number and function of regulatory T cells may facilitate the injurious process. Receptor-mediated apoptosis is the principal mechanism of hepatocyte loss, and cell-mediated and antibody-dependent mechanisms of cytotoxicity also contribute. Insights that explain autoimmune hepatitis will allow triggering exogenous antigens to be characterized, risk management to be improved, prognostic indices to be refined, and site-specific therapeutic interventions to emerge.

Impact of SNP rs2187668 in HLA-DQA1 on clinical presentation and treatment response in patients with type-1 autoimmune hepatitis

Background/aim: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease with limited etiopathogenetic understanding. Recently, a genome-wide association study (GWAS) identified a single nucleotide polymorphism (SNP, rs2187668) in the HLA-DQA1 gene, which is strongly associated with AIH type-1. We therefore evaluated the impact of this SNP on clinical presentation and treatment response in patients with AIH.

P1205 : Comprehensive analyses of autoimmune hepatitis type 1 associated mRNA, lncRNA, and miRNA in CD4+ T cells targeted by prednisolone treatment

P1205 : Comprehensive analyses of autoimmune hepatitis type 1 associated mRNA, lncRNA, and miRNA in CD4+ T cells targeted by prednisolone treatment

Update on Autoimmune Hepatitis.

Autoimmune hepatitis (AIH), a liver disorder affecting both children and adults, is characterized by inflammatory liver histology, elevated transaminase levels, circulating nonorganspecific autoantibodies, and increased levels of immunoglobulin G, in the absence of a known etiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or antinuclear antibody define AIH type 1 and antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2. AIH type 1 affects both adults and children, while AIH type 2 is mainly a paediatric disease, though it does occasionally affects young adults. AIH should be considered during the diagnostic workup of any patient with increased liver enzyme levels. AIH is exquisitely responsive to immunosuppressive treatment with prednisolone with or without azathioprine, with symptom free long-term survival for the majority of patients. For those who do not respond to standard treatment, or who are difficult-to-treat, mycophenolate mofetil and, in the absence of a response, calcineurin inhibitors should be tried in addition to steroids. The pathogenesis of AIH is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4 T-cells, although recent studies support the involvement of diverse populations, including Th17 cells. A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigenspecific regulatory T-cells, which ultimately aim at restoring tolerance to liver-derived antigens.