IgG4-associated Autoimmune Hepatitis Research Articles

Classical autoimmune hepatitis and the IgG4-associated autoimmune hepatitis in paediatric patients.

The IgG4-associated autoimmune hepatitis (IgG4-AIH) is a newly proposed disease entity characterised by the accumulation of the IgG4-expressing plasma cells in the liver. Its pathophysiology and clinical significance remain unclear and have poor evidence in the paediatric population. Thus, our study aims at comparing the group of paediatric patients with classical AIH and the IgG4-AIH. We carried out a retrospective analysis of 23 children (median age 8.5 years) diagnosed with AIH, who were compared according to the presence of IgG4-positive plasma cells in the liver biopsy. IgG4-AIH was defined if 10 or more IgG4 positive plasma cells/high-power field were found in the biopsy. The presence of the IgG4 component seems to be clinically insignificant. That is why, the conventional immunosuppressive protocol should be considered the standard treatment in the case of the IgG4-associated AIH.

Clinicopathological Features of Autoimmune Hepatitis with IgG4-Positive Plasma Cell Infiltration

Background: We aimed to elucidate the characteristics and prognosis of autoimmune hepatitis (AIH) patients with immunoglobulin (Ig) G4-positive plasma cell infiltration. Methods: We enrolled 84 AIH patients. The number of IgG- and IgG4-positive plasma cells was immunohistochemically counted per high-power field in the portal area. Patients with 3 or more IgG4-positive plasma cells on average and a ratio of IgG4 to IgG-positive plasma cells ≥5% were defined as IgG4-associated AIH (IgG4-AIH), and their clinicopathological characteristics and prognosis were compared to those of the remaining classical-AIH patients. Results: Ten (11.9%) and 74 patients (88.1%) were categorized as IgG4-AIH and classical-AIH patients, respectively. The median age of the IgG4-AIH patients was 67 years, the majority was female (80.0%), and the distribution was similar to that of the classical-AIH patients. The IgG4-AIH patients exhibited significantly more severe phenotypes in portal inflammation, interface hepatitis, fibrosis, and rosette formation. All clinical laboratory data were similar except for serum IgG4 levels, which were higher in IgG4-AIH patients (168.5 vs. 22.9 mg/dL, p = 0.014). During a median follow-up period of 139 months, the relapse rate was significantly lower in the IgG4-AIH group than in the classical-AIH group (11.1 vs. 49.2%; p = 0.048). Twelve (16.2%) and 6 (8.1%) classical-AIH patients underwent liver-related events and liver-related deaths, respectively. In contrast, none of the IgG4-AIH patients progressed to severe liver disease. Conclusions: The IgG4-AIH patients had more severe inflammation and advanced fibrosis in the liver. However, their prognosis was not poor compared to that of classical-AIH patients. IgG4-AIH may have a phenotype distinct from classical-AIH.

Autoimmune hepatitis and IgG4-related disease.

IgG4-related disease (IgG4-RD) is a chronic-fibroinflammatory disorder affecting a wide range of organs. Elevation of serum IgG4 concentrations and abundant infiltration of IgG4-expressing plasma cells are key diagnostic features of this autoimmune disease. Although common organ involvement of IgG4-RD includes the salivary glands, pancreas, and bile duct, hepatic involvement is less well established. Recently, five studies identified a subtype of autoimmune hepatitis (AIH), called IgG4-associated AIH (IgG4-AIH). IgG4-AIH is diagnosed based on significant accumulation of IgG4-expressing plasmacytes in the liver in patients who met the diagnostic criteria for classical AIH. Although four of the five reports regarded IgG4-AIH based on hepatic accumulation of IgG4-positive cells alone, one report diagnosed IgG4-AIH based on both hepatic accumulation of IgG4-positive cells and elevated serum concentrations of IgG4. IgG4-AIH diagnosed based on the latter criteria may be a hepatic manifestation of IgG4-RD whereas IgG4-AIH diagnosed based on the former criteria may be a subtype of AIH. In this review article, we summarize and discuss clinicopathological features of IgG4-AIH.

Clinical and histopathological features of immunoglobulin G4-associated autoimmune hepatitis in children.

We aimed to examine the frequency and the characteristics of immunoglobulin G4 (IgG4)-associated autoimmune hepatitis among pediatric patients with autoimmune hepatitis. Immunostaining for IgG and IgG4 was performed in liver biopsies of 40 pediatric patients with autoimmune hepatitis. The patients with more than 10 IgG4-positive plasma cells/high-power field were defined as IgG4-associated autoimmune hepatitis. Clinic, laboratory, and histopathological results were compared between groups. Among the 40 pediatric patients, 34 patients were type 1 and 6 patients were type 2 autoimmune hepatitis. Six patients (15%), four of the type 1 and two of the type 2 autoimmune hepatitis patients, were diagnosed with IgG4-associated autoimmune hepatitis. Clinical, laboratory, and histopathological data were initially similar in both forms. There was a positive correlation between IgG4-positive plasma cell count and degree of portal (r: 0.406, P: 0.009) and lobular inflammation (r: 0.37, P: 0.019), grade of interface hepatitis (r: 0.33, P: 0.03), and fibrosis (r: 0.318, P: 0.046). Time required for normalization of liver transaminases and serum IgG level was significantly shorter in IgG4-associated autoimmune hepatitis (3.3±0.5 vs 6.6±3.5 for alanine aminotransferase, 3.7±0.8 vs 6.7±1.2 for aspartate aminotransferase, 4.3±1.2 vs 7.1±2.7 for gamma-glutamyl transpeptidase, and 7.2±3.1 vs 12.8±4.5 for IgG). Immunoglobulin G4-associated autoimmune hepatitis can be found in pediatric age group and also in type 2 autoimmune hepatitis patients. As steroid response may be better in IgG4-associated autoimmune hepatitis, biopsy specimens should be evaluated for this entity at diagnosis.

Research advances in diagnosis and treatment of IgG4-associated autoimmune hepatitis

Research advances in diagnosis and treatment of IgG4-associated autoimmune hepatitis

Clinical characteristics of patients with IgG4-associated type I autoimmune hepatitis

Objective To investigate the expression of IgG4 in liver tissues of patients with type Ⅰ autoimmune hepatitis (AIH) and to analyze the clinical manifestation,biochemical indexes,immunological genetic features,pathological characteristics and the effects of immunosuppressive therapy.Methods From March 2012 to July 2013,45 patients diagnosed as type Ⅰ AIH were enrolled.Immunostaining of CD38,IgG and IgG4 in liver tissue slices was performed,inflammation grade G and fibrosis stage S were determined.At the same time,serological indexes (alanine aminotransferase (ALT),aspartate transaminase (AST),alkaline phosphatase (ALP),IgG,antinuclear antibody (ANA) titer,antibodies to asialoglycoprotein receptor (ASGPRAb)) of the patients were collected,serum IgG4 was tested and the response to immunosuppressive therapy was observed.Wilcoxon rank sum test and t test were performed for quantitative data comparison.Spearman correlation coefficient was used for correlation analysis.Results Among 45 patients with type Ⅰ AIH,five patients (11.1％) were IgG4 associated AIH (IgG4-AIH group).There were no significant differences in age,gender,biochemical indexes (serum levels of ALT,AST,ALP),immunity indexes (serum levels of IgG,ANA titer,ASGPRAb) and degree of liver fibrosis between patients with IgG4-associated AIH and classical AIH (40 cases) (all P＞ 0.05).Compared with classical AIH group (18.3(6.7) mg/L).The serum level of IgG4 of IgG4 AIH group was 25.8(9.2) mg/L,which significantly increased (Z=-2.041,P＜0.05).However,there was no significant difference in serum level of IgG4 between the two groups (P＞0.05).There was no correlation between the number of infiltrated IgG4 positive plasma cells and the serum level of IgG4 (r=0.311,P=0.279).The inflammation in the liver tissues of IgG4-AIH group was more significant compared with that of classic AIH group (H=4.120,P＜0.05).The number of CD38' or IgG+ plasma cells was larger compared with that of classical AIH (CD38(39.3(13.5)/high power field (HPF) vs (21.3(8.8))/HPF,IgG(39.3 (14.0))/HPFvs (18.5(8.9))/HPF;Z ＝-3.561 and-3.584,both P＜0.01).The number of IgG4+ plasma cells in liver tissues was positively correlated with the number of CD38+ or IgG+ plasma cells (r=0.884 and 0.791,both P＜0.01).Conclusions Among patients with type Ⅰ AIH,the incidence of IgG4-associated AIH was not high.The serum level of IgG4 did not significantly increase in these patients.However,the histological inflammation activity was significant along with many CD38+ or IgG+ plasma cells infiltration. Key words: Hepatitis, autoimmune; IgG4; IgG4-related disease; Pathology, clinical

Recent advances in the research of IgG4-associated autoimmune hepatitis

自身免疫性肝炎(autoimmune hepatitis,AIH)是以肝脏的慢性炎症和免疫学异常为主要病变的一种器官特异性的自身免疫性疾病,其临床特征是女性易患,常伴发肝外自身免疫性疾病,以及血清氨基转移酶升高、高球蛋白血症、血清多种自身抗体、界面性肝炎和汇管区浆细胞浸润,对免疫抑制治疗应答[1-2].近年提出的IgG4相关性自身免疫性肝炎(IgG4-associated autoimmune hepatitis,IgG4-AIH),作为AIH的一个新亚型,由于其独特的临床和病理学特征,因而受到越来越多的关注.IgG4 AIH具有AIH的基本特征,同时又具有新的特点:血清IgG4水平升高,组织学IgG4阳性浆细胞浸润,对激素的治疗反应好且复发率低[3-4].然而IgG4 AIH的发病率和临床特征尚不十分清楚.目前,国内关于IgG4-AIH的病例报道和研究极少,迫切需要对其进行系统的了解和深入的研究,以探讨其流行病学、临床特征和发病机制,更好地指导临床实践. 关键词：肝炎,自身免疫性;IgG4

Autoimmune hepatitis

The understanding of autoimmune hepatitis (AIH) has evolved in the past two decades since diagnostic criteria were developed. Now with long-term experience with well characterized cohorts, strides have been gained in understanding the true epidemiology and natural history of the disease. Therapeutic trials have also added new tools to the armamentarium in managing this challenging disease. AIH has been demonstrated to be a disease of middle-aged women, with a disease course that frequently progresses to cirrhosis, transplant or death. Despite its rare prevalence, AIH is one of the most common indications for transplantation. Diagnosis remains challenging, and the most recently adopted criteria prove very specific but lack sensitivity in the diagnosis of AIH, particularly when presenting atypically. Recently, drug-induced AIH and IgG4-associated AIH have been proposed as distinct clinicopathological entities. Clinical trials for alternate therapeutics have long been needed, and recently two agents, budesonide and mycophenolate mofeteil, show promise in treating AIH. Increasing evidence has mounted to suggest that AIH is a disease that often requires long-term treatment, and frequently progresses to end-stage liver disease. Further research identifying predictors of poor outcome, optimal therapeutic regimens and duration of treatment is much needed.

Clinical significance of immunoglobulin G4-associated autoimmune hepatitis

Immunoglobulin (Ig) G4-associated autoimmune hepatitis (AIH) is a recently identified and possibly new disease entity. However, the epidemiology and clinical features of IgG4-associated AIH remain uncertain. The aim of this study was to determine the prevalence and the clinical, serological, and histological characteristics of IgG4-associated AIH. We examined the clinical features, serum IgG4 concentration, liver biopsy histology, and IgG4-bearing plasma cell infiltration of 60 patients with type 1 AIH and 22 patients with autoimmune pancreatitis. High serum IgG4 concentration (≥ 135 mg/dL) and IgG4-bearing plasma cell infiltration in the liver (≥ 10/high-power fields [HPFs]) were found in 2 of the 60 (3.3%) patients with type 1 AIH. These patients had high serum levels of IgE, giant cell change, and rosette formation in the liver. Although corticosteroid therapy reduced the serum IgG4 concentration and normalized liver enzymes and histology, one patient developed IgG4-related sclerosing cholangitis after 5 years of follow-up. Because IgG4-associated AIH was found in over 3% of Japanese patients with type 1 AIH in our cohort, further studies are needed on this possible new disease entity and its impact on the diagnostic guidelines of AIH.

Discrimination of autoimmune hepatitis: autoantibody typing and beyond

For over 20 years autoimmune hepatitis has been classified into types 1 and 2, an autoantibody-based classification that has stood the test of time. In type 1 autoimmune hepatitis, the main circulating autoantibodies, although not specific for the disease, are antinuclear antibodies, smooth-muscle antibodies, and anti F-actin antibodies. Soluble liver antigen antibodies have been found in approximately 10-30% of adult patients with type 1 disease, and are more common in children with type 1 and type 2 autoimmune hepatitis. Atypical p-antineutrophil cytoplasmic autoantibodies frequently occur in type 1 autoimmune hepatitis but are non-specific. Antimitochondrial antibodies, although more specific and sensitive for primary biliary cirrhosis, are seen in type 1 autoimmune hepatitis, generally in conjunction with antinuclear and/or smooth-muscle antibodies. In type 2 autoimmune hepatitis, a disease which occurs predominantly in girls and young women, anti-liver-kidney microsomal-1 antibodies and anti-cytosol-1 antibodies are the major circulating autoantibodies. There also are patients with variant forms of autoimmune hepatitis who have clinical and serologic findings of autoimmune hepatitis in addition to features of primary biliary cirrhosis or primary sclerosing cholangitis. The taxonomy and definitions of these variants, often referred to as overlap syndromes, are controversial. IgG4-associated cholangitis is recognized as an entity distinct from autoimmune hepatitis. Whether or not IgG4-associated autoimmune hepatitis is a distinct entity awaits a more extensive description of clinical and immuno-histological features.

Identification and characterization of IgG4-associated autoimmune hepatitis

Autoimmune hepatitis (AIH) and autoimmune pancreatitis (AIP) share clinical and pathological features such as high serum levels of immunoglobulin (Ig) G and autoantibodies, and lymphoplasmacytic infiltration, suggesting the presence of common immunological abnormalities. However, little is known about the possible involvement of IgG4, a hallmark of AIP, in AIH. In this study, we examined whether the IgG4 response contributes to the histopathological and clinical findings in AIH. Liver sections from 26 patients with AIH, 10 patients with primary biliary cirrhosis (PBC), three patients with primary sclerosing cholangitis (PSC) and 20 chronic hepatitis patients with hepatitis C virus (HCV) infection were immunostained for IgG4. We investigated the relationship among the histopathology, the responses to steroid therapy and the IgG4 staining. Nine of the 26 liver specimens from patients with AIH showed positive staining for IgG4 whereas none of the 10 samples from patients with PBC, the three samples from patients with PSC or the 20 samples from patients with HCV hepatitis were positive. Patients with IgG4-positive AIH also showed increased serum levels of IgG. The numbers of T cells, B cells and plasma cells were significantly increased in the livers of patients with IgG4-positive AIH as compared with those patients with IgG4-negative AIH. Patients with IgG4-positive AIH also showed a marked response to prednisolone therapy. AIH may be classified into either an IgG4-associated type or an IgG4 non-associated type with the former showing a marked response to prednisolone treatment.