Autoimmune Hepatitis 

Autoimmune hepatitis is a chronic disease of unknown cause, characterized by continuing hepatocellular inflammation and necrosis and tending to progress to cirrhosis. Immune serum markers frequently are present, autoantibodies against liver-specific and non–liver-specific antigens and increased immunoglobulin G (IgG) levels. The disease often is associated with other autoimmune diseases. Autoimmune hepatitis cannot be explained on the basis of chronic viral infection, alcohol consumption, or exposure to hepatotoxic medications or chemicals.

Clinicians must consider the diagnosis of autoimmune hepatitis in any patient who has acute hepatitis or acute liver failure (defined by the new onset of coagulopathy). The workup of such patients should include testing for serum autoantibodies, serum protein electrophoresis, and quantitative immunoglobulins. Urgent liver biopsy, transjugular if appropriate, may help to confirm the clinical suspicion of acute autoimmune hepatitis. (See Workup.)

Rapid institution of treatment with high-dose corticosteroids may rescue patients whose autoimmune hepatitis ultimately would have progressed to either fulminant hepatic failure or cirrhosis (see Treatment). Other patients continue to deteriorate in spite of immunosuppressant therapy. Accordingly, a low threshold should exist for transferring patients with acute liver failure to tertiary care hospitals that are capable of performing emergent liver transplantation.

For patient education information, see the Hepatitis Center and Liver, Gallbladder, and Pancreas Center, as well as Hepatitis A, Hepatitis B, Hepatitis C, and Cirrhosis.

Historical background

In 1950, Waldenstrom first described a form of chronic hepatitis in young women.^[1] This condition was characterized by cirrhosis, plasma cell infiltration of the liver, and marked hypergammaglobulinemia. Kunkel, in 1950, and Bearn, in 1956, described other features of the disease, including hepatosplenomegaly, jaundice, acne, hirsutism, cushingoid facies, pigmented abdominal striae, obesity, arthritis, and amenorrhea.^{[2, 3]}

In 1955, Joske first reported the association of the lupus erythematosus (LE) cell phenomenon in active chronic viral hepatitis.^[4] This association led to the introduction of the term lupoid hepatitis by Mackay and associates in 1956.^[5] Researchers currently know that no direct link exists between systemic lupus erythematosus (SLE) syndrome and autoimmune hepatitis; thus, lupoid hepatitis is not associated with SLE.

The development of viral serologic tests represented another important step forward. These permitted hepatologists to differentiate chronic viral hepatitis from other types of chronic liver disease, including autoimmune hepatitis.

Autoimmune hepatitis now is recognized as a multisystem disorder that can occur in males and females of all ages. This condition can coexist with other liver diseases (eg, chronic viral hepatitis) and also may be triggered by certain viral infections (eg, hepatitis A) and chemicals (eg, minocycline).

The histopathologic description of autoimmune hepatitis has undergone several revisions over the years. In 1992, an international panel codified the diagnostic criteria.^[6] The term autoimmune hepatitis was selected to replace terms such as autoimmune liver disease and autoimmune chronic active hepatitis.

The panel waived the requirement of 6 months of disease activity to establish chronicity, expanded the histologic spectrum to include lobular hepatitis, and reaffirmed the nonviral nature of the disease. The panel also designated incompatible histologic features, such as cholestatic histology, the presence of bile duct injury, and ductopenia.

The proposed pathogenesis of autoimmune hepatitis involves the combination of genetic predisposition and environmental triggers. The genetic predisposition may relate to several defects in immunologic control of autoreactivity. An environmental agent triggers the autoimmune response against liver antigens, causing necroinflammatory liver damage, fibrosis, and, eventually, cirrhosis, if left untreated.

Genetic predisposition

Genetic susceptibility to developing autoimmune hepatitis has been associated with the HLA haplotypes B8, B14, DR3, DR4, and Dw3. C4A gene deletions are associated with the development of autoimmune hepatitis in younger patients.^[7] HLA-DR3–positive patients are more likely than other patients to have aggressive disease, which is less responsive to medical therapy and more often results in liver transplantation; in addition, these patients are younger than other patients at the time of their initial presentation. HLA-DR4–positive patients are more likely to develop extrahepatic manifestations of their disease.^[8]

Patients with autoimmune hepatitis have low levels of T lymphocytes that express the CD8 marker and a specific defect in a subpopulation of T cells that controls the immune response to specific liver cell membrane antigens.

Autoimmune hepatitis has also been associated with the complement allele C4AQO, resulting in a partial deficiency of complement component C4. C4 has a well-known role in virus neutralization; failure to eliminate viruses may lead to immune reaction against antigen on infected cells.

Environmental triggers

Among the several viruses implicated as triggering agents are rubella, Epstein-Barr, and hepatitis A, B, and C. Some authors have shown a high amino acid sequence homology between hepatitis C virus (HCV) polyprotein and CYP2D6, the molecular target of liver-kidney microsomal type 1 (LKM-1) antibody, which suggests that molecular mimicry may trigger production of LKM-1 antibody in HCV infection.

Drugs may also trigger autoimmune hepatitis; however, no specific drug has been identified as an etiologic agent for autoimmune hepatitis. Drug-metabolizing enzymes of phase 1 and phase 2 (ie, cytochrome P-450, uridine diphosphate glucuronosyltransferase proteins) are targets of virus-induced and drug-induced autoimmunity, as well as autoimmune hepatitis.

Pathogenesis

Current evidence suggests that liver injury in a patient with autoimmune hepatitis is the result of a cell-mediated immunologic attack. Aberrant display of human leukocyte antigen (HLA) class II on the surface of hepatocytes facilitates the exposure of normal liver cell membrane constituents to antigen-presenting cells (APCs).

APCs present hepatic antigens to uncommitted helper T lymphocytes (T_H 0). APCs and helper T lymphocytes interact at the ligand-ligand level, which, in turn, activates T_H 0. This activation is followed by functional differentiation into helper T cell 1 (T_H 1) or helper T cell 2 (T_H 2), according to the cytokines prevailing in the tissue and the nature of the antigen. T_H 1 primarily secretes interleukin 2 (IL-2) and interferon gamma, which activate macrophages and enhance expression of HLA classes I and II, thus perpetuating the immune recognition cycle.

T_H 2 cells primarily produce interleukins 4, 5, and 10, which stimulate autoantibody production by B lymphocytes.^[9]

The reasons for the aberrant HLA display are unclear. It may be initiated or triggered by genetic factors, viral infections (eg, acute hepatitis A or B, Epstein-Barr virus infection),^[10] and chemical agents (eg, interferon, melatonin, alpha methyldopa, oxyphenisatin, nitrofurantoin, tienilic acid). The asialoglycoprotein receptor and the cytochrome mono-oxygenase P-450 IID6 are proposed as the triggering autoantigens.

Physiologically, T_H 1 and T_H 2 cells antagonize each other. Regulatory mechanisms strictly control the autoantigen recognition process; their failure perpetuates an autoimmune attack. Liver cell injury can be caused by the action of cytotoxic lymphocytes that are stimulated by IL-2, complement activation, engagement of natural killer lymphocytes by the autoantibody bound to the hepatocyte surface, or reaction of autoantibodies with liver-specific antigens expressed on hepatocyte surfaces.

Autoantibody-coated hepatocytes from patients with autoimmune hepatitis are killed when incubated with autologous allogenic lymphocytes. The effector cell was shown to be an Fc receptor-positive mononuclear cell. Wen and others have shown that T-cell clones from liver biopsy specimens in children with autoimmune hepatitis who express the γ/δ T-cell receptor are preferentially cytotoxic to liver-derived cells.^[11]

Evidence for an autoimmune pathogenesis includes the following:

• Hepatic histopathologic lesions composed predominantly of cytotoxic T cells and plasma cells
• Circulating autoantibodies (ie, nuclear, smooth muscle, thyroid, liver-kidney microsomal, soluble liver antigen, hepatic lectin)
• Association with hypergammaglobulinemia and the presence of a rheumatoid factor
• Association with other autoimmune diseases
• Response to steroid and/or immunosuppressive therapy

The autoantibodies described in these patients include the following:

• Antinuclear antibody (ANA), primarily in a homogeneous pattern
• Anti–smooth muscle antibody (ASMA) directed at actin
• Anti–liver-kidney microsomal antibody (anti–LKM-1)
• Antibodies against soluble liver antigen (anti-SLA) directed at cytokeratins types 8 and 18
• Antibodies to liver-specific asialoglycoprotein receptor or hepatic lectin
• Antimitochondrial antibody (AMA) - AMA is the sine qua non of primary biliary cirrhosis (PBC) but may be observed in the so-called overlap syndrome with autoimmune hepatitis.
• Antiphospholipid antibodies^[12]

Classification

Based on autoantibody markers, autoimmune hepatitis is recognized as a heterogeneous disorder and has been subclassified into 3 types. The distinguishing features of these types are noted below in Table 1.

Table 1. Clinical Characteristics of Autoimmune Hepatitis^[13] (Open Table in a new window)

The etiology of autoimmune hepatitis is unknown. Several factors (eg, viral infection, drugs, environmental agents) may trigger an autoimmune response and autoimmune disease.

In a few patients with autoimmune hepatitis, illness onset follows acute hepatitis A, hepatitis B, or Epstein-Barr virus infections. Autoantibodies are common in patients with chronic hepatitis C virus (HCV) infection. Some patients with chronic HCV infection exhibit liver-kidney microsomal type 1 (LKM-1) antibody.

Some cases of drug-induced liver disease have an immune-mediated basis. A number of drugs (eg, methyldopa, nitrofurantoin, minocycline,^[14] adalimumab,^[15] infliximab,^[16] ) can produce an illness with the clinical features of autoimmune hepatitis. Although most cases improve when the drug is stopped, chronic cases of autoimmune hepatitis may be seen, even after drug withdrawal.^[17]

Casswall et al found Helicobacter species DNA in 50% of liver biopsies from patients with autoimmune hepatitis and ulcerative colitis.^[18]

United States statistics

Epidemiologic data are limited. Among white adults, the prevalence is estimated to be 0.1-1.2 cases per 100,000 individuals. The frequency of autoimmune hepatitis among patients with chronic liver disease ranges from 11-23%. The disease accounts for about 6% of liver transplantations in the United States. Autoimmune hepatitis type 2 (AIH-2) and AIH-3 are observed infrequently in the United States, although AIH-2 is well characterized in Europe.

International statistics

The prevalence of autoimmune hepatitis is estimated to be 0.1-1.2 cases per 100,000 individuals in Western Europe. The reported prevalence of autoimmune hepatitis in Europe ranges from 11.6-16.9 cases per 100,000 persons. The reported prevelance is higher than the estimated prevalance. This is approximately the same prevalence as primary biliary cirrhosis and twice as high as the prevalence of primary sclerosing cholangitis. Autoimmune hepatitis accounts for about 3% of liver transplantations in Europe. The reported prevalence in Japan is only 0.08-0.015 cases per 100,000 persons in Japan.

The ratio of incidence of AIH-1 to AIH-2 is 1.5-2:1 in Europe and Canada and 6-7:1 in North America, South America, and Japan. AIH-2 is more commonly described in southern Europe than in northern Europe, the United States, or Japan.

In an analysis of data from 33,379 patients with liver cirrhosis, Michitaka et al concluded that autoimmune hepatitis is the etiologic agent in 1.9% of such cases in Japan.^[19] (Hepatitis C virus was the most prevalent etiologic agent, being associated with approximately 61% of cases of liver cirrhosis.)

Racial, sexual, and age-related differences in incidence

The disease is most common in whites of northern European ancestry with a high frequency of HLA-DR3 and HLA-DR4 markers. The Japanese population has a low frequency of HLA-DR3 markers. In Japan, autoimmune hepatitis is associated with HLA-DR4.^{[20, 21, 22]}

Women are affected more often than men (70-80% of patients are women).^[23]

Autoimmune hepatitis has a bimodal age distribution, with a first peak of incidence at age 10-20 years and a second at age 45-70 years. Approximately one half of affected individuals are younger than 20 years; incidence peaks in premenstrual girls. Patients with AIH-2 tend to be younger; 80% of patients with AIH-2 are children.

However, autoimmune hepatitis may occur in people of any age, including infants and older adults.^{[22, 24, 25]} The diagnosis should not be overlooked in individuals older than 70 years.^[26] Men may be affected more commonly than women in older age groups.

The prognosis of autoimmune hepatitis depends primarily on the severity of liver inflammation. Patients with a severe initial presentation tend to have a worse long-term outlook than patients whose initial disease is mild. Similarly, the inability to enter remission or the development of multiple relapses, either during therapy or after treatment withdrawal, implies a worse long-term prognosis.

Without treatment, nearly 50% of patients with severe autoimmune hepatitis will die in approximately 5 years, and most patients will die within 10 years of disease onset.^[27] Treatment with corticosteroids has been shown to improve the chances for survival significantly. The 10-year life expectancies for treated patients with and without cirrhosis at presentation are 89% and 90%, respectively. Indeed, the life expectancy of patients in clinical remission is similar to that of the general population.

Ferreira et al concluded that immunosuppressive treatment improved the fibrosis scores, with an arrest in progression and no development into cirrhosis.^[28] Despite an apparent initial response to immunosuppressive therapy, however, histologic progress may be gradual and require several years.

Greene and Whitington found that treatment fails in about 10% of patients, then requiring alternative therapy and/or liver transplantation as liver disease progresses. Less than 10% of patients with autoimmune hepatitis die during 10 years of follow-up.^[29]

In children with autoimmune hepatitis, 70% require treatment until adulthood. Many patients already have cirrhosis at the time of diagnosis. Almost 20-25% of children with autoimmune hepatitis die or require liver transplantation as a result of the disease. Guidelines published in 2011 by the British Society of Gastroenterology (BSG) state that young patients with autoimmune hepatitis should receive immunosuppressive treatment to prevent or delay cirrhosis, even if they do not meet other treatment criteria.^[30]

HLA status affects treatment outcome. As an example, HLA DR3-positive patients are more likely to have active disease and are less responsive to therapy than patients with other HLA types. These patients also are more likely to require liver transplantation at some point.

Spontaneous resolution of disease is observed in 13-20% of patients, regardless of the inflammatory activity. This is an unpredictable event.

In a series reported by Gregorio et al in 1997, 70% of children with AIH-1 and 40% of children with AIH-2 developed cirrhosis.^[31] Of the 52 children, 17% had multiacinar or panacinar collapse with acute liver failure. The patients with the worst prognosis in this study, resulting either in death or liver transplantation, were those who were young at presentation and who had AIH-2, coagulopathy, high bilirubin counts, and severe initial histologic activity.

Hepatocellular carcinoma (HCC) is less common in patients with autoimmune hepatitis–induced cirrhosis than in those with cirrhosis caused by other factors. Nevertheless, HCC is not a rare event in autoimmune hepatitis.

In general, the following factors are associated with a worse prognosis:

• Young age at presentation
• AIH-2
• Coagulopathy
• Severe initial histologic activity