AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Autoimmune hepatitis (AIH) is a chronic necroinflammatory hepatitis of unknown etiology, characterized histologically by a dense mononuclear infiltrate in the portal tracts and serologically by autoantibodies against liver-specific and non–liver-specific antigens and increased immunoglobulin G (IgG) levels.

To date, 2 types of AIH have been described based on differences in autoantibody patterns. AIH type 1 (AIH-1) is characterized by the presence of circulating anti–smooth muscle antibodies (ASMAs) and/or antinuclear antibodies (ANAs). AIH type 2 (AIH-2) is characterized by circulating liver-kidney microsomal type 1 (LKM-1) antibody or anti–liver cytosol 1 (anti-LC1) antibody. A more recently described third type of AIH (AIH type 3) may be distinguished by autoantibodies to soluble liver proteins or liver-pancreas antigen. The target antigen for ANA is heterogeneous, the target antigen for LKM-1 antibody is CYP2D6, and the target antigen for smooth muscle antibody (SMA) is F-actin.

Czaja et al have shown that patients with AIH 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.

Pathophysiology

The proposed pathogenesis framework involves genetic predisposition, which 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.

The HLA-DR3 and HLA-DR4 genes of the major histocompatibility complex have been implicated as genetic predisposing factors. Some evidence exists that HLA-DR3 predisposes patients to AIH at an earlier age and results more often in liver transplantation. The major genetic determinant for children with AIH-1 is HLA-DRB1, while AIH-2 is associated with the HLA-DQB1 gene. Strong evidence suggests that defects in immunologic control of autoreactivity play a role in AIH pathogenesis.

Patients with AIH 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. A genetically determined partial C4 deficiency has been reported. C4 has a well-known role in virus neutralization; failure to eliminate viruses may lead to immune reaction against antigen on infected cells. 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 LKM-1 antibody, which suggests that molecular mimicry may trigger production of LKM-1 antibody in HCV infection.

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

Current belief is that the mechanism of autoimmune liver injury is mediated by the interaction of CD4⁺ T lymphocytes and a self-antigenic peptide; this peptide must be embraced by an HLA class II molecule and must be presented to uncommitted helper T lymphocytes (T_H0) by antigen-presenting cells (APCs). APCs and helper T lymphocytes interact at the ligand-ligand level, which, in turn, activates T_H0. This activation is followed by functional differentiation into helper T cell 1 (T_H1) or helper T cell 2 (T_H2), according to the cytokines prevailing in the tissue and the nature of the antigen. T_H1 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_H2 cells primarily produce interleukins 4, 5, and 10, which stimulate autoantibody production by B lymphocytes.

Physiologically, T_H1 and T_H2 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 AIH 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 AIH who express the g/d T-cell receptor are preferentially cytotoxic to liver-derived cells.

Frequency

United States

Epidemiologic data are limited. Among white adults, AIH prevalence is estimated to be 0.1-1.2 cases per 100,000 individuals.

International

Prevalence is estimated to be 0.1-1.2 cases per 100,000 individuals in Western Europe but only 0.08-0.015 cases per 100,000 persons in Japan, making AIH of either type a rare disease. 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.

Mortality/Morbidity

• In children with AIH, 70% require treatment until adulthood.
• Many patients already have cirrhosis at the time of diagnosis.
• Almost 20-25% of children with AIH die or require liver transplantation as a result of the disease.

Sex

Females comprise 75% of patients with AIH.

Age

AIH occurs in adults and children, with two peaks of incidence at age 10-20 years and again at age 45-70 years.

• Approximately one half of affected individuals are younger than 20 years; incidence peaks in premenstrual girls.
• AIH has been reported in infants.
• Patients with AIH-2 tend to be younger; 80% of patients with AIH-2 are children.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Regardless of the mode of presentation (ie, acute vs chronic), autoimmune hepatitis (AIH) always becomes chronic, making it unnecessary to wait 6 months to prove the chronic nature of the disease.

• Clinical features of AIH are extremely variable. Modes of presentation include the following:
• • Most patients 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.
  • Some patients present with severe acute hepatitis similar to acute viral hepatitis.
  • AIH rarely presents as fulminant hepatic failure.
  • Extrahepatic manifestations sometimes are the initial symptoms that lead to the diagnosis of AIH.
• In 1997, Gregorio et al published a series of 52 cases of AIH in children (32 children with AIH-1 and 20 children with AIH-2). The following summary of clinical features of AIH was based on 20 years of treating these children at King's College Hospital:
• • 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.
  • Types of presentation
    • In 50% of the children, 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 AIH developed cirrhosis and portal hypertension.
• In 2005, Oettinger et al published a series of 142 children with AIH. Their findings were as follows:
• • Clinical findings were jaundice (58%), nonspecific weakness(57%), anorexia (47%), abdominal pain (38%), and paleness(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%).

Physical

Physical findings range from mild jaundice to hepatomegaly, splenomegaly, ascites, cutaneous manifestations of chronic liver disease, and hepatic coma.

• Most patients have firm hepatomegaly, a condition occurring in more than 90% of patients with chronic presentation of the disease. More than half of affected patients either have jaundice or a history of jaundice when diagnosed with AIH.
• Splenomegaly occurs in 50-60% of cases.
• Approximately 30% of patients may have signs of chronic liver disorder (eg, spider nevi, palmar erythema, ascites).
• Many patients progress to cirrhosis before presentation, and 10-20% may have decompensated cirrhosis.
• GI tract bleeding as a complication of portal hypertension usually is rare.
• Acute liver failure occurs primarily between the ages of 13 months and 4 years in children with AIH-2 but typically after puberty in patients with AIH-1.
• Additional autoimmune disorders often occur in children with AIH as follows:
• • In with children with AIH-1 - Ulcerative colitis, sclerosing cholangitis, arthritis, vasculitis, glomerulonephritis, and diabetes
  • In children with AIH-2 - Polyendocrinopathy, alopecia areata, diabetes, and thyroiditis

Causes

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 HCV infection. Some patients with chronic HCV infection exhibit LKM-1 antibody.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Differential diagnoses for autoimmune hepatitis (AIH) should include many causes of chronic liver disease, including a₁-antitrypsin deficiency, Wilson disease, viral hepatitis, hepatotoxic drugs, and excessive alcohol consumption.

AIH also must be differentiated from autoimmune polyendocrine syndrome type I (APS-1), autoimmunity in HCV infection, immune-mediated drug-induced hepatitis, cryptogenic hepatitis, and overlap syndrome.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Elevated serum aminotransferase levels (1.5-50 times reference values)
• Elevated serum immunoglobulin levels, primarily immunoglobulin G (IgG)
• Seropositive results for ANA, SMA, or LKM-1 or anti-LC1 antibodies
• • SMAs are present in 90-100% of patients with autoimmune hepatitis type 1 (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.
  • ANAs are present in 10% of patients with AIH-1 and in association with SMAs in 40-60% of patients with AIH-1. Other autoantibodies are sometimes helpful in the diagnosis AIH-1. SLA/LP antibodies are the most specific antibody identified in AIH-1, but are only found in 10-30% of cases. Atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) are frequently present.
  • 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 and recognize formiminotransferase cyclodeaminase, a liver-specific 58kD metabolic enzyme.
• Antiasialoglycoprotein receptor antibodies occur more often in patients with AIH-1 and may serve as a marker of inflammatory activity.
• In 50% of patients, abnormal results on hepatic synthetic function tests include decreased albumin levels and prolonged prothrombin time.

Imaging Studies

• When alkaline phosphatase levels are 7-8 times reference values or gammaglutamyl transferase levels are 2-3 times reference values, consider cholangiography to exclude a diagnosis of sclerosing cholangitis.

Histologic Findings

Histopathologic findings on liver biopsy specimens are crucial to determining the diagnosis of AIH and the disease's severity. AIH 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 use of the term plasma cell hepatitis.

The periportal lesion: Interface hepatitis (also termed piecemeal necrosis) essentially spares the biliary tree but may involve most of the lobule.

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

Histopathologic findings in patients with AIH are characteristic but nonspecific; AIH 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 AIH.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Patients with autoimmune hepatitis (AIH) usually respond to immunosuppressive therapy.

• The treatment of choice is corticosteroid administration, either alone or in combination with azathioprine.
• • Initiate prednisolone at 2 mg/kg/d (not to exceed 60 mg/d). 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 avoid adverse effects from the steroids.
  • Liver enzymes levels may require several months to return to reference range values. In patients with AIH type 1, transaminase levels took a median of 0.5 years (range, 0.2-7 y) to return to reference values; in patients with AIH type 2, transaminase levels took a median of 0.8 years (range, 0.02-3.2 y) to return to reference values. If liver enzyme levels do not return to 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 reference values. Some authors recommend starting azathioprine with prednisone at disease onset.
• A few recent reports in the adult and pediatric literature have mentioned successful cyclosporine use to avoid high steroid doses. Cyclosporine was administered for 6 months alone, followed by combined low doses of prednisone and azathioprine for 1 month, then cyclosporine was discontinued. According to a 1999 report by Alvarez et al, cyclosporine administration induced biochemical remission of the hepatic inflammatory process in children with AIH, while causing few and well-tolerated adverse effects. In 2004, Sciveres et al reported that cyclosporine may be considered as a safe treatment for all autoimmune liver diseases and as an effective alternative for front-line therapy.
• Limited data are available regarding the use of tacrolimus, methotrexate, mycophenolate mofetil, and others.

Surgical Care

Approximately 10-20% of patients require liver transplantation. Indications for liver transplantation include the following:

• Fulminant hepatic failure
• Complications of cirrhosis
• Failure of medical therapy

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Treatment with corticosteroids and azathioprine is the cornerstone for achieving remission.

Drug Category: Glucocorticoids

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

Drug Category: Immunosuppressive agents

Recent data suggest initiating azathioprine with prednisone at the beginning of treatment. This enables a faster decrease of the prednisone dose. Other studies have shown that cyclosporine has steroid-sparing effects when administered for several months before corticosteroids and azathioprine.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

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

Complications

• Cirrhosis and complications of cirrhosis (eg, ascites, coagulopathy, hepatic coma)
• Portal hypertension
• Esophageal varices
• Poor growth and malnutrition

Prognosis

• Despite an apparent initial response to immunosuppressive therapy, histologic progress may be gradual and require several years.
• In the King's College Hospital series reported by Gregorio et al in 1997, 70% of children with autoimmune hepatitis type 1 (AIH-1) and 40% of children with AIH-2 developed cirrhosis. Of the 52 children, 17% had multiacinar or panacinar collapse with acute liver failure. Patients with the worst prognosis in this study, resulting either in death or liver transplantation, were children who were young at presentation and who had AIH-2, coagulopathy, high bilirubin counts, and severe initial histologic activity.
• In general, the following factors are associated with a worse prognosis:
• • Young age at presentation
  • Diagnosis of AIH-2
  • Coagulopathy
  • Severe initial histologic activity

Patient Education

• For excellent patient education resources, visit eMedicine's Hepatitis Center and Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient education articles, Hepatitis A, Hepatitis B, Hepatitis C, and Cirrhosis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to explain to the family the seriousness of the disease and the importance of follow-up visits
• Failure to diagnose the disease in its early stage, especially when evaluating a patient with jaundice and negative results to hepatitis screening tests

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: May 31, 2006