eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Autoimmune Chronic Active Hepatitis

Author: Husam H Sukerek, MD, Consulting Staff, Department of Gastroenterology, Sabine Medical Center
Coauthor(s): Mohammad F El-Baba, MD, Assistant Professor of Pediatrics, Division of Pediatric Gastroenterology, Wayne State University School of Medicine; Divison Chief of Pediatric Gastroenterology, Children's Hospital of Michigan
Contributor Information and Disclosures

Updated: Dec 1, 2008

Introduction

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 autoimmune hepatitis 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 autoimmune hepatitis (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 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.¹

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 autoimmune hepatitis at an earlier age and results more often in liver transplantation. The major genetic determinant for children with AIH-1 is HLA-DRB1, whereas AIH-2 is associated with the HLA-DQB1 gene. Strong evidence suggests that defects in immunologic control of autoreactivity play a role in autoimmune hepatitis pathogenesis.

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. 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 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.

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_H 0) by antigen-presenting cells (APCs). 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.

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 g/d T-cell receptor are preferentially cytotoxic to liver-derived cells.²

Frequency

United States

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

International

The 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 autoimmune hepatitis 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 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.

Sex

Females comprise 75% of patients with AIH.

Age

Autoimmune hepatitis 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. Autoimmune hepatitis has been reported in infants. Patients with AIH-2 tend to be younger; 80% of patients with AIH-2 are children.

Clinical

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 autoimmune hepatitis widely vary. 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.
  • Autoimmune hepatitis rarely presents as fulminant hepatic failure.
  • Extrahepatic manifestations sometimes are the initial symptoms that lead to the diagnosis of autoimmune hepatitis.
• 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]).³ 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.
  • 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.⁴
  • Types of presentation include the following:
    • 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 autoimmune hepatitis developed cirrhosis and portal hypertension.
• In 2005, Oettinger et al published a series of 142 children with autoimmune hepatitis. Their findings were as follows:⁵
  • Clinical findings included 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 patients either have jaundice or a history of jaundice when diagnosed with autoimmune hepatitis.
• 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 is usually 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 autoimmune hepatitis 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 hepatitis C virus (HCV) infection. Some patients with chronic HCV infection exhibit liver-kidney microsomal type 1 (LKM-1) antibody.

• Search for CME/CE on This Topic »

• Hepatitis Center
• Liver, Gallbladder, and Pancreas Center
• Hepatitis A Treatment
• Hepatitis B Overview
• Cirrhosis Overview
• Hepatitis A Symptoms
• Hepatitis C Overview
• Hepatitis A Overview
• Hepatitis A Causes

• Autoimmune Hepatitis and Liver Transplantation
• Current and Future Treatments of Autoimmune Hepatitis
• Treatment of Autoimmune Hepatitis