Autoimmune Hepatitis and Immunoglobulin G4-Associated Autoimmune Hepatitis

The serological features of autoimmune hepatitis (AIH) are the presence of antinuclear antibody (ANA), anti-smooth muscle antibody (SMA) and anti-type 1 liver-kidney microsomal antibody (anti-LKM-1), and elevated levels of serum immunoglobulin G (IgG) and hepatic enzymes. Characteristic findings in the liver include interface hepatitis, infiltration of lymphocytes and plasma cells, and rosette formation. AIH is treated with steroids and immunosuppressive drugs.

Autoimmune pancreatitis (AIP), a pancreatic disease caused by an autoimmune mechanism, is associated with elevated levels of serum IgG4 and the infiltration of IgG4-positive cells into the pancreatic parenchyma, and it is occasionally accompanied by nonpancreatic features. AIP is known to be accompanied by multiple organ failure, and systemic inflammatory diseases characterized by the infiltration of IgG4-positive plasma cells and elevated serum IgG4 levels were recently classified as IgG4-related diseases.

Recent studies have reported AIH cases with infiltrated IgG4-positive plasma cells in the liver, suggesting the involvement of IgG4 in the pathogenesis of AIH. Here, we review the characteristic features of IgG4-related disease and its association with AIH.

The term ‘autoimmune hepatitis' was introduced in 1965 [1]. Upon the discovery of hepatitis C virus in 1989, chronic hepatitis C infection was separated from non-A, non-B hepatitis. Subsequently, AIH was classified as an independent disease category, and AIH diagnostic criteria were established at the meeting of the International Autoimmune Hepatitis Group (IAIHG) in 1993 [2].

There is often a history of other autoimmune disorders in the patient or first-degree relatives. The disease predominates among women, the archetypal patient being a young female with endocrine abnormalities, but it also affects males and it can present at almost any age. Distribution of age at onset was thought to be bimodal, with peaks around puberty and between the fourth and sixth decades of life, but it has been suggested that this impression probably relates to patterns of patient referral to specialist centers [3] (fig. 1), (fig. 2).

In Japan, AIH predominantly affects women, occurring 6 times more frequently than in men, although the prevalence in men has been gradually increasing in recent years. AIH presentation is characterized by a monomodal peak after the age of 60 years, and AIH is frequently accompanied by other autoimmune diseases, including chronic thyroiditis, Sjögren's syndrome and rheumatoid arthritis. In Japan, the most frequently observed initial symptom is general malaise (60%), followed by jaundice (35%) and appetite loss (27%). Other primary symptoms include joint pain and fever (15% each), both of which are rare in chronic viral hepatitis.

Serological findings are the predominant elevation of liver enzymes over biliary enzymes, elevated serum IgG levels, and the presence of antibodies such as ANA, SMA and anti-LKM-1. Characteristic findings in the liver include interface hepatitis, infiltration of lymphocytes and plasma cells, and rosette formation. AIH is treated with steroids and immunosuppressive agents.

In Japan, AIH diagnostic criteria were established in 1996 by the Intractable Liver Disease Research Project Team of the Ministry of Health, Labor and Welfare (table 1) [4], which recommended the use of the IAIHG diagnostic criteria. The IAIHG diagnostic criteria were first established in 1993, revised in 1999, and are currently used as the international criteria (table 2) [3]. Characteristic AIH findings, including sex, clinical and serological features, liver histology and treatment response, are assessed using the scoring system, and definitive and probable diagnoses are compared before and after treatment. The criteria are complex and purely meant for scientific purposes. In 2008, the IAIHG introduced the simplified version of the AIH diagnostic criteria (table 3) [5] for routine clinical practice. This has made diagnosis easier and early therapeutic intervention possible. However, the diagnosis of AIH can be difficult because of its various clinical presentations, the presence of atypical and acute cases, and the involvement of other autoimmune diseases.

Steroids and immunosuppressive drugs such as azathioprine are effective treatments for AIH, and ursodeoxycholic acid has shown good efficacy in many studies.

AIP is known to be accompanied by multiple organ failure, including sclerosing cholangitis, liver failure, inflammation of the lacrimal and salivary glands, thyroiditis, interstitial pneumonia and interstitial nephritis. Systemic inflammatory diseases characterized by the infiltration of IgG4-positive plasma cells and elevated serum IgG4 levels were recently classified as IgG4-related disease. In 2011, the Ministry of Health, Labor and Welfare established the 2011 comprehensive diagnostic criteria for IgG4-related disease (table 4) [6].

Liver injury is observed in 60-70% of AIP cases; however, with the exception of obstructive jaundice, the cause of liver injury in AIH is not always clear. Umemura et al. [7] showed that AIP is accompanied by hepatocellular damage, such as the infiltration of IgG4-positive plasma cells near the portal vein, patterns of portal inflammation, large biliary duct damage, portal sclerosis, lobular hepatitis and cholestasis, and improvement in histological findings after steroid therapy. They called the disease IgG4 hepatopathy.

Recently, some AIH cases fulfilling the criteria of IgG4-related disease have been designated as IgG4-associated AIH [8,9]. Chung et al. [9] reported that a group of AIH patients with infiltration of IgG4-positive plasma cells were successfully treated with prednisolone (PSL) therapy. Based on the IgG4 immunoreactivity of liver biopsy samples (≥5 IgG4-positive plasma cells/high-power field, HPF), they divided 26 patients with a definitive diagnosis of AIH into IgG4-positive (9 patients, 35%) and IgG4-negative (17 patients, 65%) groups (table 1). No pancreaticobiliary lesions were observed in the AIH patients. No IgG4-positive plasma cells were observed in 10 cases of primary biliary cirrhosis or 20 cases of chronic hepatitis C. The IgG4-positive group had a significantly higher level of serum IgG than the IgG4-negative group (p < 0.01), but no significant differences in IgG4 levels were observed between these two groups. In addition, there were no significant differences in alanine aminotransferase (ALT), alkaline phosphatase, γ-glutamyl transpeptidase or ANA. On the other hand, the severity of plasma cell infiltration and lobular hepatitis were significantly high in the IgG4-positive group. Although portal inflammation and interface hepatitis were similar in both groups, the severity of portal inflammation was significantly higher in the IgG4-positive group. The infiltration of B cells, T cells and plasma cells was also significantly higher in the IgG4-positive group than in the IgG4-negative group (p < 0.05). Furthermore, ALT levels at 4, 48, 72 and 96 weeks after the initiation of PSL therapy were significantly lower in the IgG4-positive group than in the IgG4-negative group (table 2). During the administration of PSL, hepatitis relapse was observed in 6 IgG4-negative patients (35%) but not in any IgG4-positive patients. Even with the definition of IgG4 positive as the infiltration of ≥10 IgG4-positive plasma cells/HPF, the response to PSL therapy and the serum levels of IgG were significantly different between the groups.

Umemura et al. [8] also reported the pathology of IgG4-related AIH. In a study of 60 AIH patients, they defined IgG4-related AIH as the infiltration of IgG4-positive plasma cells (≥10 cells/HPF), IgG4-positive serum (≥135 mg/dl) and the ratio of IgG4 to IgG as 0.073. However, because only 2 cases fulfilled this definition, they concluded that the prevalence of IgG4-positive AIH is extremely low (2/60 cases, 3.3%).

The main difference between the studies by Chung et al. [9] and Umemura et al. [8] is that, in the latter study, the definition included the ratio of IgG4 to IgG in addition to high serum IgG4 concentration (≥135 mg/dl) and the infiltration of IgG4-positive plasma cells in liver tissue. Furthermore, while Chung et al. [9] examined cases that matched the definite diagnosis of AIH, the 60 AIH cases investigated by Umemura et al. [8] included 12 which were probable AIH. Moreover, the infiltration of IgG4-positive cells in the gallbladder and common bile duct was observed in 1 of the IgG4-associated AIH cases, indicating a case of IgG4-related sclerosing cholangitis rather than IgG4-associated AIH. Regardless of the differences, the two studies revealed that IgG4-related pathologies are associated with at least some AIH cases and that steroid treatment is effective in such IgG4-associated AIH, as in other IgG4-related diseases.

Some patients with AIH present symptoms of IgG4-related disease and respond effectively to steroid treatment. Although no unified diagnostic criteria are currently available, it is important to keep this disease in mind for definitive diagnosis and appropriate treatment. Further studies are needed to define the epidemiological features or diagnostic criteria.

The authors have no conflicts of interest to declare.