Autoimmune Hepatitis

Practice Essentials

Autoimmune hepatitis is a chronic disease of unknown cause, characterized by continuing hepatocellular inflammation and necrosis and has a tendency to progress to cirrhosis.

Signs and symptoms

Autoimmune hepatitis may present as acute or chronic hepatitis or as well-established cirrhosis, although in rare cases it presents as fulminant hepatic failure.

Approximately one third of patients present with symptoms of acute hepatitis marked by fever, hepatic tenderness, and jaundice. Some patients go on to develop signs and symptoms of chronic liver disease, while others rapidly progress to acute liver failure, as marked by coagulopathy and jaundice.

Symptoms and physical examination findings may stem from extrahepatic diseases associated with autoimmune hepatitis. Common symptoms include the following:

• Fatigue
• Upper abdominal discomfort
• Mild pruritus
• Anorexia
• Myalgia
• Diarrhea
• Cushingoid features
• Arthralgias
• Skin rashes (including acne)
• Edema
• Hirsutism
• Amenorrhea
• Chest pain from pleuritis
• Weight loss and intense pruritus (unusual)

Common findings on physical examination are as follows:

• Hepatomegaly (83%)
• Jaundice (69%)
• Splenomegaly (32%)
• Spider angiomata (58%)
• Ascites (20%)
• Encephalopathy (14%)

Pediatric patients

A study of children with autoimmune hepatitis recorded the following clinical findings and their prevalence^[1] :

• Jaundice (58%)
• Nonspecific weakness (57%)
• Anorexia (47%)
• Abdominal pain (38%)
• Pallor (26%)

See Presentation for more detail.

Diagnosis

Laboratory studies

Laboratory findings in autoimmune hepatitis include the following:

• Elevated serum aminotransferase levels (1.5-50 times reference values)
• Elevated serum immunoglobulin levels, primarily immunoglobulin G (IgG)
• Mild to moderately elevated serum bilirubin and alkaline phosphatase – In 80-90% of patients; a sharp increase in the alkaline phosphatase values during the course of autoimmune disease may reflect the development of primary sclerosing cholangitis (PSC) or the onset of hepatocellular carcinoma as a complication of cirrhosis
• Seropositive results for antinuclear antibodies (ANAs), smooth-muscle antibodies (SMAs), or liver-kidney microsomal type 1 (LKM-1) or anti–liver cytosol 1 (anti-LC1) antibodies
• Hypoalbuminemia and prolongation of prothrombin time – Markers of severe hepatic synthetic dysfunction, which may be observed in active disease or decompensated cirrhosis

Other hematologic abnormalities may include the following:

• Mild leukopenia
• Normochromic anemia
• Coombs-positive hemolytic anemia
• Thrombocytopenia
• Elevated erythrocyte sedimentation rate
• Eosinophilia (uncommon)

Biopsy

Urgent liver biopsy, transjugular if appropriate, may help to confirm the clinical suspicion of acute autoimmune hepatitis.

See Workup for more detail.

Management

For more than 3 decades, corticosteroids, either alone or in combination with azathioprine, have been the mainstays of drug therapy for patients with autoimmune hepatitis.^[2] The American Association for the Study of Liver Diseases (AASLD) and the British Society of Gastroenterology (BSG) recommend combination therapy, using the corticosteroid prednisone with azathioprine.

Relapse

Relapse occurs in 50% of patients within 6 months of treatment withdrawal and in 80% of patients within 3 years of treatment. Reinstitution of the original treatment regimen usually induces another remission; however, relapse commonly recurs after a second attempt at terminating therapy. Patients who relapse twice require indefinite therapy with either prednisone or azathioprine.

Liver transplantation

This procedure is effective for patients in whom medical therapy has failed or for those with decompensated cirrhosis caused by autoimmune hepatitis. Liver transplantation also may be used to rescue patients who present with fulminant hepatic failure secondary to autoimmune hepatitis.

See Treatment and Medication for more detail.

• References

Background

Autoimmune hepatitis is a chronic disease of unknown cause, characterized by continuing hepatocellular inflammation and necrosis and tending to progress to cirrhosis. Frequently, immune serum markers are present; they include 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 Infections Center and Digestive Disorders Center, as well as Hepatitis A, Hepatitis B, Hepatitis C, and Cirrhosis of the Liver.

In August 2012, the Centers for Disease Control and Prevention (CDC) expanded their existing, risk-based testing guidelines to recommend a 1-time blood test for hepatitis C virus (HCV) infection in baby boomers—the generation born between 1945 and 1965, who account for approximately three fourths of all chronic HCV infections in the United States—without prior ascertainment of HCV risk (see Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965).^[3] One-time HCV testing in this population could identify nearly 808,600 additional people with chronic infection. All individuals identified with HCV should be screened and/or managed for alcohol abuse, followed by referral to preventative and/or treatment services, as appropriate.

Historical background

In 1950, Waldenstrom first described a form of chronic hepatitis in young women.^[4] 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.^{[5, 6]}

In 1955, Joske first reported the association of the lupus erythematosus (LE) cell phenomenon in active chronic viral hepatitis.^[7] This association led to the introduction of the term lupoid hepatitis by Mackay and associates in 1956.^[8] 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 and this term is no longer used.

The development of viral serologic tests represented another important step forward. These tests 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.^[9] 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.

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Pathophysiology

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 may trigger 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.^[10] 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.^[11]

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 the 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 the 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.^[12]

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),^[13] 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.^[14]

Evidence for an autoimmune pathogenesis includes the following^{[15, 16, 17]} :

• 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^[18]

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^[19]

View Table

See Table

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Etiology

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,^[20] adalimumab,^[21] infliximab^[22] ) 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.^[23]

Casswall et al found Helicobacter species DNA in 50% of liver biopsies from patients with autoimmune hepatitis and ulcerative colitis.^[24]

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Epidemiology

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 prevalence is higher than the estimated prevalence. 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 the 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.^[25] (Hepatitis C virus was the most prevalent etiologic factor, being associated with approximately 61% of cases of liver cirrhosis.)

Race-, sex-, 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.^{[26, 27, 28]}

Women are affected more often than men (70%-80% of patients are women).^{[29, 16]}

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 the 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.^{[28, 30, 31]} The diagnosis should not be overlooked in individuals older than 70 years.^[32] Men may be affected more commonly than women in older age groups.

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Prognosis

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.^[33] Treatment with corticosteroids has been shown to improve the chances of 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 disease progression and no development of cirrhosis.^[34] Despite an apparent initial response to immunosuppressive therapy, however, histologic progression may be gradual and require several years.

Greene and Whitington found that treatment fails in about 10% of patients, prompting alternative therapy and/or liver transplantation as the liver disease progresses. Less than 10% of patients with autoimmune hepatitis die during 10 years of follow-up.^[35]

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.^[36]

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 the 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.^[37] 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

• References

History

Clinical features of autoimmune hepatitis widely vary. Most cases have an insidious onset. Patients may be asymptomatic or have nonspecific symptoms (eg, fatigue, anorexia, weight loss, behavioral changes, amenorrhea). Systemic or cutaneous abnormalities occur in 25% of patients. Epistaxis, bleeding gums, and bruises with minimal trauma are frequent complaints.

Autoimmune hepatitis may present as acute hepatitis, chronic hepatitis, or well-established cirrhosis. Autoimmune hepatitis rarely presents as fulminant hepatic failure.

Approximately one third of patients present with symptoms of acute hepatitis marked by fever, hepatic tenderness, and jaundice. In some patients, the acute illness may appear to resolve spontaneously; however, patients invariably develop signs and symptoms of chronic liver disease. Other patients experience rapid progression of the disease to acute liver failure, as marked by coagulopathy and jaundice. Ascites and hepatic encephalopathy also may ensue.

The chronic hepatitis associated with autoimmune hepatitis may range in severity from a subclinical illness without symptoms and with abnormal results on liver chemistries to a disabling chronic liver disease. Symptoms and physical examination findings may stem from the various extrahepatic diseases associated with autoimmune hepatitis. Common symptoms include the following:

• Fatigue
• Upper abdominal discomfort
• Mild pruritus
• Anorexia
• Myalgia
• Diarrhea
• Cushingoid features
• Arthralgias
• Skin rashes (including acne)
• Edema
• Hirsutism
• Amenorrhea
• Chest pain from pleuritis
• Weight loss and intense pruritus (unusual)

Many patients have histologic evidence of cirrhosis at the onset of symptoms. This is true both for patients with an initial presentation of acute hepatitis and for patients with chronic hepatitis. Thus, subclinical disease often precedes the onset of symptoms.

As many as 20% of patients present initially with signs of decompensated cirrhosis. In other patients, chronic hepatitis progresses to cirrhosis after several years of unsuccessful immunosuppressant therapy marked by multiple disease relapses. This occurs in 20%-40% of patients. Patients with cirrhosis may experience classic symptoms of portal hypertension, namely variceal bleeding, ascites, and hepatic encephalopathy. Patients with complications of cirrhosis should be referred for consideration of liver transplantation.

Associated disease

Autoimmune hepatitis, especially type 2, is associated with a wide variety of other disorders. Involvement of other systems may present at disease onset or may develop during the course of the active liver disease. Most of these conditions are immunologic in origin.

Patients may present with manifestations of the following hematologic disorders:

• Hypersplenism
• Autoimmune hemolytic anemia
• Coombs-positive hemolytic anemia
• Pernicious anemia
• Idiopathic thrombocytopenic purpura
• Eosinophilia

Gastrointestinal disease associated with autoimmune hepatitis includes inflammatory bowel disease, which is seen in 6% of cases. The presence of ulcerative colitis in patients with autoimmune hepatitis should prompt performance of cholangiography to exclude primary sclerosing cholangitis (PSC). A study of 140 pediatric patients with autoimmune hepatitis, autoimmune cholangitis, and overlap syndrome identified 23 patients with celiac disease.^[38]

Associated endocrinologic conditions include Graves disease (6%) and autoimmune thyroiditis (12%). Associated rheumatologic complications include the following:

• Rheumatoid arthritis and Felty syndrome
• Sjögren syndrome
• Systemic sclerosis
• Mixed connective-tissue disease
• Erythema nodosum
• Leukocytoclastic vasculitis (patients may present with leg ulcers)

Other associated conditions are as follows:

• Proliferative glomerulonephritis
• Fibrosing alveolitis
• Pericarditis and myocarditis
• Febrile panniculitis
• Lichen planus
• Uveitis

Pediatric presentation

In 1997, Gregorio et al published a series of 52 cases of autoimmune hepatitis in children (32 children with autoimmune hepatitis type 1 [AIH-1] and 20 children with autoimmune hepatitis type 2 [AIH-2]).^[37] The following summary of clinical features of AIH was based on 20 years of treating these children at King's College Hospital.

The median patient ages were 10 years for AIH-1 and 7.4 years for AIH-2. Other autoimmune disorders occurred in 20% of patients and 40% of their relatives; these included autoimmune thyroiditis, celiac disease, inflammatory bowel disease, diabetes mellitus, and other disorders. AIH-2 can be part of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), an autosomal recessive genetic disorder in which liver disease is reportedly present in about 20% of cases.^[39]

In 50% of the children, an acute presentation mimicked acute viral hepatitis (ie, abdominal discomfort, vomiting, nausea, jaundice). Fulminant hepatic failure occurred in 11% of the children and was more common in patients with AIH-2. Insidious presentation was characterized by intermittent jaundice or nonspecific symptoms. Routine blood analysis revealed incidental findings of abnormal liver enzymes. Patients with autoimmune hepatitis developed cirrhosis and portal hypertension.

In 2005, Oettinger et al published a series of 142 children with autoimmune hepatitis.^[1] Clinical findings included the following:

• Jaundice (58%)
• Nonspecific weakness (57%)
• Anorexia (47%)
• Abdominal pain (38%)
• Pallor (26%)

AIH-1 was found in 73% of the children, AIH-2 was found in 25% of the children, and 4 children could not be classified. Liver biopsy showed active hepatitis (52%), cirrhosis (38%), and mild inflammatory activity (10%).

Additional autoimmune disorders often occur in children with autoimmune hepatitis. In children with AIH-1, associated autoimmune disorders include the following:

• Ulcerative colitis
• Sclerosing cholangitis
• Arthritis
• Vasculitis
• Glomerulonephritis
• Diabetes mellitus

In children with AIH-2, associated autoimmune disorders include the following:

• Polyendocrinopathy
• Alopecia areata
• Diabetes mellitus
• Thyroiditis

Acute liver failure occurs primarily between the ages of 13 months and 4 years in children with AIH-2. It typically occurs after puberty in patients with AIH-1.

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Physical Examination

Common findings on physical examination are as follows:

• Hepatomegaly (83%)
• Jaundice (69%)
• Splenomegaly (32%)
• Spider angiomata (58%)
• Ascites (20%)
• Encephalopathy (14%)

All of these findings may be observed in patients with disease that has progressed to cirrhosis with ensuing portal hypertension. However, hepatomegaly, jaundice, splenomegaly, and spider angiomata also may be observed in patients who do not have cirrhosis.

Complications may include the following:

• Cirrhosis and complications of cirrhosis (eg, ascites, coagulopathy, hepatic coma)
• Portal hypertension
• Esophageal varices
• Malnutrition (with poor growth in children)

GI tract bleeding as a complication of portal hypertension is uncommon.

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Approach Considerations

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). In addition to aminotransferase levels and other liver function studies, the workup of such patients should include the following assays:

• Serum antinuclear antibody (ANA)
• Anti–smooth muscle antibody (ASMA)
• Liver-kidney microsomal type 1 (LKM-1) antibody
• Serum protein electrophoresis (SPEP)
• Quantitative immunoglobulins

Urgent liver biopsy, transjugular if appropriate, may help to confirm the clinical suspicion of autoimmune hepatitis.

Laboratory findings in autoimmune hepatitis include the following:

• Elevated serum aminotransferase levels (1.5-50 times reference values)
• Elevated serum immunoglobulin levels, primarily immunoglobulin G (IgG)
• Seropositive results for ANAs, SMAs, or LKM-1 or anti–liver cytosol 1 (anti-LC1) antibodies

In 50% of patients, abnormal results on liver function tests include decreased albumin levels and prolonged prothrombin time.

In August 2012, the Centers for Disease Control and Prevention (CDC) expanded their existing, risk-based testing guidelines to recommend a 1-time blood test for hepatitis C virus (HCV) infection in baby boomers—the generation born between 1945 and 1965, who account for approximately three fourths of all chronic HCV infections in the United States—without prior ascertainment of HCV risk (see Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965).^[3] One-time HCV testing in this population could identify nearly 808,600 additional people with chronic infection. All individuals identified with HCV should be screened and/or managed for alcohol abuse, followed by referral to preventative and/or treatment services, as appropriate.

• References

Autoantibody Assays

Autoimmune hepatitis is characterized by positive findings on autoantibody tests, as follows:

• AIH-1 - ASMA and ANA
• AIH-2 - Anti–LKM-1 antibody
• AIH-3 - Antibodies to soluble liver antigen (anti-SLA)

SMAs are present in 90%-100% of patients with autoimmune hepatitis type 1 (AIH-1). ANAs are present in 10% of patients with AIH-1 and in association with SMAs in 40%-60% of patients with AIH-1. Titers range from 1:100-500,000. SMAs occur in low titers in healthy children and patients with viral hepatitis and other diseases that do not affect the liver.

LKM-1 antibodies are present in 40%-45% of patients with AIH-2 and are associated with anti-LC1 antibodies in 50% of patients. Anti-LC1 antibodies occur alone in 30% of patients with AIH-2; these antibodies recognize formiminotransferase cyclodeaminase, a liver-specific 58kD metabolic enzyme. Anti-asialoglycoprotein receptor antibodies occur more often in patients with AIH-1 and may serve as a marker of inflammatory activity.

Other autoantibodies may be evident. Atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) are frequently present. Czaja et al have shown that patients with autoimmune hepatitis who have positive test results for actin antibody are younger, more commonly test positive for human leukocyte antigen (HLA)–DR3, and required transplantation more frequently than patients with ANAs who test negative for actin antibody.^[42]

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Serum Proteins and Immunoglobulins

An IgG-predominant polyclonal hypergammaglobulinemia is a common finding in patients with untreated autoimmune hepatitis. Gamma globulin values typically range from 3-4 g/dL and frequently are as high as 5-6 g/dL. Cases of hyperviscosity syndrome secondary to high IgG levels are reported. Autoimmune hepatitis is an unlikely diagnosis in patients who have acute hepatitis without hypergammaglobulinemia.

The gamma globulin or the IgG level may be followed on a regular basis as a marker of disease responsiveness to therapy.

Patients with AIH-2 commonly have partial immunoglobulin A (IgA) deficiency.^[39]

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Aminotransferases

Serum aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) are elevated in 100% of patients at initial presentation, with average values of 200-300 U/L. Aminotransferase values correlate poorly with the degree of hepatic necrosis; however, values in the thousands may indicate acute hepatitis or a severe flare of preexisting disease.

Continued elevation of the aminotransferases in the face of continuing therapy is a reliable marker for ongoing inflammatory activity in the liver. Normalization of the aminotransferase levels during therapy is an encouraging sign, but active liver inflammation is present in more than 50% of patients with normalized liver chemistries. Indeed, biochemical remission may precede true histologic remission by 3-6 months.

Typically, patients are treated for at least 1 year after documentation of normal liver chemistries. Liver biopsy is recommended by some experts to confirm that the patient is in histologic remission. Drug withdrawal may be attempted at this time (see Treatment).

Worsening of aminotransferase levels in a patient undergoing treatment or in a patient who is in remission may signal a resurgence of disease activity.

Other liver chemistries

Serum bilirubin and alkaline phosphatase values are mildly to moderately increased in 80%-90% of patients. A sharp increase in the alkaline phosphatase values during the course of autoimmune disease might reflect the development of PSC or the onset of hepatocellular carcinoma as a complication of cirrhosis.

Hypoalbuminemia and prolongation of the prothrombin time are markers of severe hepatic synthetic dysfunction, which may be observed in active disease or decompensated cirrhosis.

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Complete Blood Count and Other Blood Studies

Other hematologic abnormalities may include the following:

• Mild leukopenia
• Normochromic anemia
• Coombs-positive hemolytic anemia
• Thrombocytopenia
• Elevated erythrocyte sedimentation rate

Eosinophilia is uncommon, but counts ranging from 9% to 48% are described. Autoimmune hepatitis has even been described as the sole presenting feature of idiopathic hypereosinophilic syndrome.

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Hepatic Imaging Studies

Imaging studies, in general, are not helpful in reaching a definitive diagnosis of autoimmune hepatitis; however, the presence of heterogeneous hepatic echotexture on abdominal ultrasound or abnormal contrast enhancement on abdominal CT imaging may suggest the presence of active inflammation or necrosis.

The appearance of an irregular nodular liver may confirm the presence of cirrhosis. Furthermore, these imaging studies may be used to rule out the presence of hepatocellular carcinoma, a potential complication of autoimmune hepatitis–induced cirrhosis.

When alkaline phosphatase levels are 7-8 times reference values or gamma glutamyl transferase levels are 2-3 times reference values, a patient with autoimmune hepatitis and ulcerative colitis may require endoscopic retrograde cholangiopancreatography (ERCP) to rule out coexisting primary sclerosing cholangitis (PSC).

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Liver Biopsy

Liver biopsy is the most important diagnostic procedure in patients with autoimmune hepatitis. This procedure can be performed percutaneously, with or without ultrasound guidance, or by the transjugular route. The latter is preferred if the patient has coagulopathy or severe thrombocytopenia. A transjugular liver biopsy also may be preferable if ascites is present or if the liver is small, shrunken, and difficult to reach percutaneously.

Liver biopsy routinely is performed in the outpatient setting to investigate abnormal liver chemistries. Liver biopsy should be performed as early as possible in patients with acute hepatitis who are thought to have autoimmune hepatitis. Confirmation of the diagnosis enables initiation of treatment at an early stage in the disease process.

The role of biopsy in patients presenting with well-established cirrhosis secondary to autoimmune hepatitis is less clear. As an example, the initiation of treatment in a patient with cirrhosis, normal aminotransferase levels, and a minimally elevated gamma globulin level is not expected to influence the disease outcome.

• References

Histologic Findings

Histopathologic findings on liver biopsy specimens are crucial to determining the diagnosis of autoimmune hepatitis and the disease's severity. Liver biopsy findings can help to differentiate autoimmune hepatitis from chronic hepatitis C virus (HCV) infection, alcohol-induced hepatitis, drug-induced liver disease, primary biliary cirrhosis, and PSC.^[43]

Autoimmune hepatitis is characterized by a portal mononuclear cell infiltrate that invades the limiting plate surrounding the portal triad and permeates the surrounding lobule (ie, periportal infiltrate) and beyond. A plasma cell infiltrate sometimes occurs, which, in the past, led to the use of the term plasma cell hepatitis.

Biopsies may show evidence for interface hepatitis (ie, piecemeal necrosis), bridging necrosis, and fibrosis. Interface hepatitis essentially spares the biliary tree but may involve most of the lobule. Lobular collapse, best identified by reticulin staining, is a common finding.

Interface hepatitis does not predict a progressive disease course. By contrast, a strong likelihood exists that cirrhosis will develop when bridging necrosis is present. The presence or absence of cirrhosis on liver biopsy is an important determinant of the patient's prognosis.

Fibrosis is present in most patients with autoimmune hepatitis. Without effective therapy, fibrosis starts to connect the portal and central areas, which ultimately leads to cirrhosis.

In 1999, the International Autoimmune Hepatitis Group established a scoring system that is particularly helpful in establishing the diagnosis of autoimmune hepatitis in problematic cases.^{[44, 45]}

Histopathologic findings in patients with autoimmune hepatitis are characteristic but nonspecific; autoimmune hepatitis has findings in common with chronic viral hepatitis, drug-associated chronic hepatitis, and several other chronic liver disorders. Multinucleated giant hepatocytes are found in 10%-20% of biopsy specimens; their occurrence after the neonatal period may suggest a diagnosis of autoimmune hepatitis.

Tucker et al indicate that the presence of characteristic hyaline droplets in the cytoplasm of Kupffer cells on routine hematoxylin and eosin (H&E) from biopsy specimens in pediatric patients with autoimmune hepatitis may provide a useful diagnostic clue to distinguish this disease from other forms of chronic hepatitis.^[46]

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Approach Considerations

For more than 3 decades, corticosteroids, either alone or in combination with azathioprine, have been the mainstays of drug therapy for patients with autoimmune hepatitis.^{[2, 17]} Treatment must be individualized for patients with autoimmune hepatitis,^[16] as considerable variation in practice style exists when answering the following common clinical questions:

• How high a dose of prednisone should be used when initiating therapy?
• When should azathioprine be added to the patient's treatment regimen?
• When should a reduction in steroid dosing be considered?
• How long should treatment continue beyond biochemical remission?
• Should liver biopsy be performed in order to document histologic remission, prior to attempting withdrawal of immunosuppression?
• Should patients receive life-long low-dose maintenance therapy with azathioprine?

Azathioprine is metabolized to 6-mercaptopurine. One of the enzymes responsible for this is thiopurine methyltransferase (TPMT). About 0.3% of the population possesses mutations of the genes coding for TPMT. These individuals, with low or no TPMT activity, may develop excess levels of the metabolite 6-thioguanine. High 6-thioguanine levels, in turn, may predispose the patient to bone marrow suppression. Some authors recommend that patients undergo TPMT genotyping prior to the initiation of azathioprine therapy.^[47]

Italian investigators indicate that patients with autoimmune hepatitis who are asymptomatic should undergo the same treatment strategy as symptomatic patients because both groups experience a similar course of disease progression and clinical response to immunosuppressive medication.^[48] In addition, subclinical disease appears to be more common in those with thyroid or dermatologic conditions and routine evaluation is advised in the setting of these disorders.

• References

Initial Therapy for Adults

Approximately 65% of patients respond to initial therapy and enter histological remission; however, 80% of these patients relapse after drug withdrawal. The practice guideline of the American Association for the Study of Liver Diseases (AASLD) provides recommendations for therapy.^[49] See Table 2, below.

Table 2. Indications for Treatment of Autoimmune Hepatitis in Adults

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Treatment might not be indicated in patients with inactive cirrhosis, preexistent comorbid conditions, or drug intolerances. On the other hand, patients with a histologic diagnosis of cirrhosis may respond well to therapy and should be offered treatment in an attempt to slow disease progression.

Treatment might not be appropriate in patients with decompensated liver disease. Such individuals might be better served by liver transplantation.

The AASLD guidelines suggest 2 potential initial treatment regimens for adults (see Table 3, below). Recently, the British Society of Gastroenterology (BSG) has put forth their recommendations on treatment of autoimmune hepatitis. Essentially, the recommendations of both AASLD and BSG are the same and the differences are only in the wording. While BSG "strongly recommends" combination therapy with prednisone and azathioprine, AASLD recommends this option as "preferred."

Table 3. Treatment Regimens for Adults

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BSG guidelines strongly recommend the combination of prednisolone and azathioprine as initial therapy, whereas the AASLD notes that combination therapy is preferred to prednisone alone.^{[36, 49]}

Patients whose liver chemistries normalize after initial therapy require maintenance therapy. In the authors' opinion, prednisone dosing can be further reduced after achieving normalization of liver chemistries. The authors commonly use azathioprine alone as a maintenance drug. Azathioprine therapy is withdrawn approximately 1 year after the patient's liver chemistries have normalized.

• References

Initial Therapy for Children

The AASLD guidelines also propose an initial treatment regimen for children (see Table 4, below).

Table 4. Treatment Regimens for Children

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See Table

Prednisolone rather than prednisone may be used, at a dosage of 2 mg/kg/d (not to exceed 60 mg/d). The BSG guidelines assume use of prednisolone.^[36] Taper over 4-8 weeks, if testing of transaminase levels demonstrates gradual improvement, then administer the minimum maintenance dose required to sustain reference levels of liver enzymes.

Frequently check liver enzyme levels during the initial period of treatment (ie, first 6-8 wk). Liver enzyme levels are usually checked weekly to fine-tune the treatment and to avoid the adverse effects from the steroids.

Liver enzyme levels may require several months to return to the reference range values. In patients with autoimmune hepatitis type 1 (AIH-1), transaminase levels took a median of 0.5 years (range, 0.2-7 y) to return to the reference values; in patients with autoimmune hepatitis type 2 (AIH-2), transaminase levels took a median of 0.8 years (range, 0.02-3.2y) to return to the reference values.

If liver enzyme levels do not return to the reference values during the first 4-8 weeks of treatment or if improvement requires high doses of steroids, initiate azathioprine administration at 0.5 mg/kg/d and gradually increase to 2 mg/kg/d until transaminase levels return to the reference values. Some authors recommend starting azathioprine with prednisone at the disease onset.

• References

Alternative Agents

Budesonide may offer an alternative to prednisone. In a prospective, double-blind randomized trial by Manns et al, 60% of budesonide-treated patients had normalized liver chemistries 6 months after initiating treatment, compared with 39% of prednisone-treated patients.^[50] Furthermore, steroid-specific side effects were seen in only 28% of the budesonide-treated patients but in 53% of the prednisone-treated patients.

Budesonide was given in a dosage of 3 mg three times daily or twice daily. The initial prednisone dose was 40 mg daily, tapered to 10 mg daily. Patients also received azathioprine 1-2 mg/kg/d.^[50] Longer-term follow-up is needed to better assess the efficacy and safety of budesonide.

Based on moderate-quality evidence, the 2011 BSG guidelines strongly recommend use of budesonide for prednisolone-intolerant patients.^[36]

Cyclosporine has been used successfully to avoid high steroid doses in both adult and pediatric patients. In a study in children by Alvarez et al, cyclosporine induced biochemical remission of the hepatic inflammatory process in children with autoimmune hepatitis while causing few and well-tolerated adverse effects.^[51] In this study, cyclosporine was administered for 6 months alone, followed by combined low doses of prednisone and azathioprine for 1 month, then cyclosporine was discontinued.

A study in children and adolescents by Sciveres et al found that cyclosporine may be considered as a safe treatment for all autoimmune liver diseases and as an effective alternative for front-line therapy.^[52] This study included patients with autoimmune hepatitis, autoimmune cholangitis, and giant cell hepatitis.

• References

Treatment Endpoints

Patients may achieve 1 of 4 treatment endpoints^[49] :

• Remission
• Treatment failure
• Incomplete response
• Drug toxicity

Remission

Remission is indicated by the absence of symptoms, normalization of aminotransferases, and histologic improvement to normal or minimal inflammatory activity on liver biopsy. Patients achieving remission may be able to taper off prednisone over a 6-week period. Azathioprine can be discontinued after the withdrawal of prednisone.

Patients in acute liver failure whose liver chemistries improve rapidly after starting prednisone have an excellent short-term prognosis. Many such patients ultimately achieve clinical remission on immunosuppressant therapy.

There are no firm guidelines regarding the duration of therapy in either adults or children. However, most patients need relatively long courses of immunosuppressant therapy. It is common for treatment to continue for 1.5-2 years or longer before an attempt is made to withdraw the medications. Indeed, adults infrequently achieve clinical, laboratory, and histologic remission in less than 12 months. Immunosuppressant therapy can achieve remission in 65% of patients within 18 months and in 80% of patients by 3 years.

Histologic remission tends to lag behind clinical and laboratory remission by 3-6 months. Many clinicians—and the current practice guidelines of the AASLD^[49] —recommend that a follow-up liver biopsy be performed. This is done in an effort to avoid medication withdrawal in a patient who is not yet in histologic remission.

Treatment failure

Treatment failure is defined as deterioration in a patient's clinical condition, laboratory tests, or histologic features during therapy. This is seen in approximately 9% of patients.^[49] Some patients will have a positive response to the reinstitution of treatment with high-dose prednisone, with or without azathioprine.

Patients with severe disease (eg, acute liver failure due to autoimmune hepatitis) have a high short-term mortality rate if they fail to show normalization of at least 1 laboratory parameter after starting prednisone-based therapy or if pretreatment hyperbilirubinemia fails to improve during a 2-week treatment trial. Early liver transplantation should be considered in such individuals.

High-dose prednisone (60 mg/d) alone or prednisone (30 mg/d) plus azathioprine (150 mg/d) are alternative approaches when standard therapy fails. Patients whose condition is resistant to steroids can be treated with cyclosporine or tacrolimus.^[17] The use of these medications is supported by a number of small case series.^{[53, 54, 55]} However, the potential toxicity of these calcineurin inhibitors must be assessed carefully before initiating treatment.

In a more recent study that evaluated the clinical, biochemical, immunologic profiles, treatment response, and side effects of tacrolimus therapy in 17 patients with treatment-refractory type 1 autoimmune hepatitis who were followed for over a median of 60 months, Than et al reported that tacrolimus treatment was safe and effective, with improvements seen in liver biochemistry as well as in the levels of immunglobulin G and aspartate transaminase.^[56] Their results support the use of tacrolimus as an option for compliant patients with difficult-to-treat autoimmune hepatitis in experienced centers. However, the investigators note that the lack of an immunomodulatory effect remains.^[56]

Similarly, a few studies have supported the use of mycophenolate mofetil in patients whose disease was refractory to standard therapy.^{[17, 57, 58, 59, 60]} In these studies, a dose of 1 g orally twice per day was employed initially.

The authors have seen a number of patients who experienced treatment failure with prednisone plus azathioprine but achieved treatment success with low-dose prednisone plus mycophenolate mofetil. However, mycophenolate mofetil has not been subjected to a randomized trial in patients with autoimmune hepatitis.

Aw et al concluded that mycophenolate mofetil is an effective rescue therapy for children with autoimmune hepatitis, but not for those with autoimmune sclerosing cholangitis (ASC).^[61] Inclusion criteria for this study involved failure to achieve/maintain remission with prednisolone/azathioprine or significant treatment side effects. Of the 26 children recruited, 16 had AIH type 1, 2 had AIH type 2, and 8 had ASC. Of the 26 children, 18 responded to mycophenolate mofetil and 8 (6 with ASC) did not respond.

There are no clear guidelines as to how mycophenolate mofetil should be tapered if a therapeutic response has been achieved. The authors have used doses as low as 500 mg twice per day to maintain patients in a drug-induced remission.

Budesonide has been has been used with variable success in patients who had treatment failures.^{[62, 63]} Limited data are available regarding the use of tacrolimus, methotrexate, and other agents.

Incomplete response

Incomplete response is defined as an improvement that is insufficient to satisfy remission criteria. It is estimated to occur in 13% of patients.^[49] Many such patients will require indefinite treatment with as low an immunosuppressant dose as is needed to prevent clinical deterioration.

A prednisone schedule similar to that used after relapse (10 mg/d) is reasonable. The goal of therapy is to control disease activity at the lowest dose of medication possible. Azathioprine may help to serve as a steroid-sparing agent.

Patients should be referred for consideration of liver transplantation if they manifest signs of hepatic decompensation (eg, new onset of hypoalbuminemia, coagulopathy, variceal bleeding, ascites, hepatic encephalopathy).

Drug toxicity

Drug toxicity may occur. Patients must be tapered off from the culprit medication. Some patients successfully achieve treatment goals on alternative medications.

Cushingoid features, acne, and hirsutism develop in 80% of patients after 2 years of prednisone-based therapy. Osteoporosis with vertebral compression, diabetes, cataracts, severe emotional lability, and hypertension may develop in patients who are treated with prolonged courses of high-dose prednisone. Premature treatment withdrawal is justified in patients who develop intolerable obesity, cosmetic changes, or osteoporosis.

Azathioprine can function as a steroid-sparing agent. The authors have had great success and minimal drug-related adverse effects using a regimen of prednisone 10 mg/d plus azathioprine 50 mg/d.

Patients should be co-treated with calcium and vitamin D in order to prevent the development of steroid-induced osteoporosis. Regular exercise should be encouraged. Bone densitometry performed every 1-2 years should be used to monitor patients. Signs of early osteoporosis may warrant the institution of treatment with alendronate.

Azathioprine therapy can be complicated by cholestatic hepatotoxicity, nausea, vomiting, rash, cytopenia, and pancreatitis. These complications occur in fewer than 10% of patients treated with azathioprine at 50 mg/d.

To date, most studies of azathioprine efficacy in autoimmune hepatitis have used a dose of 50 mg/d. In contrast, many authors in the field of inflammatory bowel disease (IBD) suggest individualizing the dose so that patients achieve a 6-thioguanine level of 230-400 pmol/8x10⁸ erythrocytes.^[64] This level has been associated with optimal clinical outcomes for patients with IBD. It remains to be determined whether such an approach should be applied to azathioprine dosing in patients with autoimmune hepatitis.

Cytopenias, particularly leukopenia, may occur at any time after the initiation of azathioprine therapy. All patients undergoing treatment with azathioprine should undergo routine interval testing of the complete blood count.

Teratogenicity has been ascribed to treatment with azathioprine; however, the gastroenterology literature is replete with references that describe the safe use of azathioprine and 6-mercaptopurine in pregnant women with inflammatory bowel disease. Whether this observation can be extended to pregnant women with autoimmune hepatitis and whether azathioprine can be employed safely in these patients is unclear.

The 2011 BSG guidelines include a weak recommendation to maintain combination treatment with as little change as possible during pregnancy, whereas the AASLD guideline suggests discontinuing azathioprine in pregnant patients. Both guidelines warn of postpartum exacerbation and recommend a prompt return to standard therapy; the BSG recommends this return immediately after delivery, whereas the AASLD recommends a return 2 weeks prior to the expected delivery date.^{[36, 49]}

Hematologic malignancy has been reported in patients undergoing treatment with azathioprine; however, the risk of malignancy is thought to be low in patients with autoimmune hepatitis who are treated with low doses of the drug.

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Relapse

Relapse occurs in 50% of patients within 6 months of treatment withdrawal and in 80% of patients within 3 years of treatment. Reinstitution of the original treatment regimen usually induces another remission; however, relapse commonly recurs after a second attempt at terminating therapy. The major consequence of relapse and re-treatment is the development of drug-related complications, which occurs in 70% of patients.

Patients who relapse twice require indefinite therapy with either prednisone or azathioprine. The dose is titrated down to as low as possible in order to prevent symptoms and to maintain an AST level 5-fold below the reference range. The median dose of prednisone required to achieve this is 7.5 mg/d.

Some authors advocate indefinite treatment with azathioprine only. In one study, 60 of 72 patients (83%) receiving long-term therapy with azathioprine at a dose of 2 mg/kg/d remained in remission, with a median follow-up period of 67 months (range, 12-128 mo).^[65]

Patients should be cautioned against premature withdrawal of drug therapy. Abrupt discontinuation of medical therapy is not infrequently complicated by an acute flare of disease activity. Such flares may be severe and potentially life-threatening.

• References

Liver Transplantation

Liver transplantation is an effective form of therapy for patients in whom medical therapy has failed, or those with decompensated cirrhosis caused by autoimmune hepatitis.^[66] Liver transplantation also may be used to rescue patients who present with fulminant hepatic failure secondary to autoimmune hepatitis. A low threshold should exist for transferring patients with acute liver failure to tertiary care hospitals that are capable of performing emergent liver transplantation. Approximately 10%-20% of patients require liver transplantation.

The long-term outlook after liver transplantation is excellent, with 10-year survival rates reported as greater than 70%.^[67] Positive autoantibodies and hypergammaglobulinemia tend to disappear within 2 years of transplantation.^[68]

Recurrence of autoimmune hepatitis is described after liver transplantation.^[66] It has been reported primarily in inadequately immunosuppressed patients. It may occur more often in HLA DR3–positive recipients of livers from HLA-DR3–negative donors.

Recurrent disease is seen in 10%-35% of patients undergoing transplantation for autoimmune hepatitis. Although such recurrences are often mild, one study described the need for retransplantation in half of patients experiencing recurrent disease.^{[67, 69, 70]}

Montano-Loza et al concluded that the risk factors associated with recurrence include concomitant autoimmune disease and high levels of aspartate aminotransferase, alanine aminotransferase, and IgG prior to the transplant.^[70] The presence of moderate to severe inflammatory activity or plasma cell infiltration in the liver explant also was said to increase the recurrence risk. According to the authors, their findings suggest that incomplete suppression of disease activity before liver transplantation promotes autoimmune hepatitis recurrence.

• References

Treatment of Overlap Syndrome

Treatment combining ursodiol and immunosuppressants may be advisable in patients with the autoimmune hepatitis–primary biliary cirrhosis (PBC) overlap syndrome. In one study, of noncirrhotic patients, fibrosis progression was seen in 4 of 8 patients treated with ursodiol monotherapy, versus 0 of 6 patients treated with combination therapy.^[71] The mean duration of follow-up was 7.5 years.

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Diet and Activity

Patients with acute autoimmune hepatitis and symptoms of nausea and vomiting may require intravenous fluids and even total parenteral nutrition; however, most patients can tolerate a regular diet. A high caloric intake is desirable.

Patients with cirrhosis secondary to autoimmune hepatitis may develop ascites. A low-salt diet (generally < 2000 mg of sodium daily) is mandatory in these individuals. Patients should continue to consume protein (ie, >1.3 g protein per kg body weight), given the catabolic nature of the disease and the high risk for developing muscle wasting.

Most patients do not need hospitalization, although this may be required for clinically severe illness. Forced and prolonged bed rest is unnecessary, but patients may feel better with restricted physical activity.

• References

Long-Term Monitoring

Perform liver function tests in patients with autoimmune hepatitis (AIH) weekly during the first 6-8 weeks of treatment and then every 2-3 months, based on the results. Schedule regular follow-up visits to assess disease activity and to search for signs and symptoms of chronic liver disease.

Surveillance abdominal imaging studies (eg, ultrasound, CT, MRI) and alpha-fetoprotein testing are typically performed every 6 months in patients with most types of cirrhosis. The optimal interval for surveillance and the best type of abdominal imaging study have not yet been determined for patients with autoimmune hepatitis–induced cirrhosis. Detection of a small hepatocellular carcinoma on imaging studies should prompt immediate referral for consideration of liver transplantation.

• References

Guidelines on Autoimmune Hepatitis by the Hellenic Association for the Study of the Liver

Guidelines on autoimmune hepatitis issued by the Hellenic Association for the Study of the Liver are summarized below.^[74]

Clinical characteristics

Autoimmune hepatitis (AIH) should be considered a possibility in any individual with acute or chronic hepatitis, particularly in those with high immunoglobulin G (IgG) levels.

Untreated AIH carries high morbidity and mortality rates, so early and accurate diagnosis is mandatory.

Screening for concomitant autoimmune diseases can be considered in patients with AIH (particularly autoimmune thyroiditis), as AIH is associated with various other autoimmune-mediated conditions.

Cirrhosis should be suspected upon AIH diagnosis, since nearly one-third of adults and half of children with AIH are at the stage of cirrhosis at AIH diagnosis.

The presentation of acute AIH can take one of two clinical forms, as follows:

• Acute worsening of previously undiagnosed or misdiagnosed AIH
• Original acute-onset AIH without chronic lesions on liver histology

AIH can be classified as either (1) AIH-1, antinuclear (ANA), smooth muscle (SMA), and/or soluble liver antigens/liver pancreas antibody (anti-SLA/LP)–positive or (2) AIH-2, anti-liver/kidney microsomal antibody type-1 (anti-LKM1), anti-liver/kidney microsomal antibody type-3 (anti-LKM3), and/or liver cytosol type-1 antigen (anti-LC1)–positive.

Complications

Patients with AIH-related cirrhosis should undergo ultrasonography every 6 months to monitor for hepatocellular carcinoma (HCC).

Workup

All children with AIH should undergo magnetic resonance cholangiopancreatography (MRCP) at minimum to rule out autoimmune sclerosing cholangitis.

Patients who have AIH with cholestatic features should undergo testing for primary biliary cholangitis (PBC).

Interface hepatitis, hepatocyte rosetting, and emperipolesis strongly support but do not confirm AIH.

In daily clinical practice, the 2008 simplified score should be used for AIH diagnosis.

The 1999 revised score can help diagnose difficult AIH cases, since it incorporates treatment response as an important parameter.

Diagnosis of AIH-PBC and AIH–primary sclerosing cholangitis (PSC) variants should not be based on diagnostic scores, but they may be used cautiously in the diagnosis of childhood AIH and acute or fulminant disease.

Treatment

The goal of AIH therapy is to achieve complete biochemical and histological remission to prevent disease progression.

All patients with active disease, including those with advanced fibrosis or cirrhosis, should undergo treatment.

Induction treatment

Induction treatment for AIH should be tailored to the patient and be guided by treatment response.

First-line therapy for AIH should be prednisolone 0.5-1 mg/kg/day PO given in one dose in the morning plus azathioprine at an initial morning dose of 50 mg/dL, usually after 2 weeks, if bilirubin levels are < 6 mg/dL.

Afterward, azathioprine should be increased up to 1-2 mg/kg/day (maintenance dose).

In patients with noncirrhotic AIH who are not candidates for conventional corticosteroid therapy (eg, serious comorbidities), budesonide 9 mg/day plus azathioprine may be used as induction treatment.

Maintenance treatment

Corticosteroid-free azathioprine monotherapy (mycophenolate mofetil [MMF] is an alternative) is the optimal maintenance treatment.

In patients with mild AIH and azathioprine intolerance who have a complete response after induction therapy, low-dose long-term prednisolone monotherapy may be used to maintain remission.

Maintenance dosing should be adjusted so that persistent biochemical response (normalization of aspartate aminotransferase [AST], alanine aminotransferase [ALT], and IgG) is maintained.

Immunosuppression should be administered for at least 3 years and for at least 2 years after a complete biochemical response is achieved.

Maintenance therapy should not be discontinued without a complete biochemical or histological response (hepatitis activity index [HAI] score >3).

Monitoring

Close long-term monitoring should be maintained after treatment is discontinued, since relapses are most common during the first 6-12 months posttreatment but may occur many years afterward.

Transaminase levels usually increase after IgG levels increase in patients with AIH relapse, but liver biopsy is not suggested.

Relapses should be treated in a manner similar to that of the initial treatment schedule; this schedule is also effective in re-inducing full remission.

Long-term (probably life-long) maintenance treatment is suggested in patients whose AIH relapses during drug-withdrawal or maintenance treatment despite adequate treatment (≥4 years of immunosuppression).

Liver biopsy is recommended before treatment discontinuation in patents with AIH who have been in complete biochemical remission for at least the last 2 years of immunosuppression.

The decision to withdraw treatment should depend on direct collaboration between the patient and doctors.

Bone density should be measured upon treatment initiation and vitamin D supplementation and adequate calcium intake recommended in all patients receiving corticosteroid treatment.

If primary complete biochemical remission does not occur despite adequate treatment, misdiagnosis or therapy noncompliance should be suspected.

Patients with non-intense disease who do not respond to therapy may receive prednisolone and azathioprine at maximum doses (1 mg/kg/day and 2 mg/kg/day, respectively) as a trial; management at an expert center is recommended if there is no response.

Thioguanine nucleotides (TGN) testing could help guide redesign of the treatment strategy, since undetectable TGN may indicate altered azathioprine metabolism or noncompliance, while high TGN levels may suggest toxicity.

Treatment adherence is vital for optimal outcomes, especially in children, adolescents, and young adults.

In patients with azathioprine intolerance, MMF be considered an alternative.

Treatment in pregnancy

Pregnancy and breastfeeding are not contraindicated in females with AIH in remission.

Maintenance treatment with prednisolone, with or without azathioprine, should be continued in previously diagnosed females under therapy.

Mild flares can be observed during the first trimester and more frequently, especially in the postpartum period, requiring increased immunosuppression.

MMF should be discontinued at least 3 months prior to conception (in females or males undergoing treatment), since MMF is absolutely contraindicated in pregnancy.

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Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Treatment with corticosteroids and azathioprine is the cornerstone of achieving remission. Initiating azathioprine with prednisone at the beginning of treatment enables a faster decrease in the prednisone dose. Cyclosporine has steroid-sparing effects when administered for several months before corticosteroids and azathioprine.

• References

Prednisone

• Dosing, Interactions, etc.

Clinical Context:  Prednisone is an immunosuppressant for the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity. It stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.

• References

Prednisolone

• Dosing, Interactions, etc.

Clinical Context:  Prednisolone decreases autoimmune reactions, possibly by suppressing key components of the immune system. It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

• References

Class Summary

Rapid institution of treatment with high-dose corticosteroids may rescue patients whose disease ultimately would have progressed to either fulminant hepatic failure or cirrhosis. Treatment with corticosteroids has been shown to improve the chances for survival significantly.

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

• References

Azathioprine (Imuran, Azasan)

• Dosing, Interactions, etc.

Clinical Context:  Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease proliferation of immune cells, which results in lower autoimmune activity.

• References

Cyclosporine (Gengraf, Sandimmune, Neoral)

• Dosing, Interactions, etc.

Clinical Context:  Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, graft versus host disease) for a variety of organs. The dose is based on the ideal body weight.

• References

Class Summary

These agents inhibit immune reactions resulting from diverse stimuli. Initiating azathioprine with prednisone at the beginning of treatment enables a faster decrease in the prednisone dose. Cyclosporine has steroid-sparing effects when administered for several months before corticosteroids and azathioprine.

• References