eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Autoimmune Chronic Active Hepatitis

Husam H Sukerek, MD, Consulting Staff, Department of Gastroenterology, Sabine Medical Center
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

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.

Differential Diagnoses

Other Problems to Be Considered

Differential diagnoses for autoimmune hepatitis (AIH) should include many causes of chronic liver disease, including a ₁ -antitrypsin deficiency, Wilson disease, viral hepatitis, hepatotoxic drugs, and excessive alcohol consumption.

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

Workup

Laboratory Studies

Laboratory findings in autoimmune hepatitis (AIH) include the following:

• Elevated serum aminotransferase levels (1.5-50 times reference values)
• Elevated serum immunoglobulin levels, primarily immunoglobulin G (IgG)
• 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
  • 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 autoimmune hepatitis type 2 (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.
  • Patients with AIH-2 commonly have partial immunoglobulin A (IgA) deficiency.⁴
• 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 gamma glutamyl 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 autoimmune hepatitis and the disease's severity. 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 use of the term plasma cell hepatitis.
• 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 autoimmune hepatitis. Without effective therapy, fibrosis starts to connect the portal and central areas, which ultimately leads to cirrhosis.
• 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.

Treatment

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 autoimmune hepatitis type 1 (AIH-1), transaminase levels took a median of 0.5 years (range, 0.2-7 y) to return to reference values; in patients with autoimmune hepatitis type 2 (AIH-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 reports in the adult and pediatric literature have mentioned the successful use of cyclosporine 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.⁶ 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.⁷
• 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

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

Glucocorticoids

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

Prednisone (Deltasone, Meticorten, Orasone)

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Dosing

Adult

5-60 mg/d PO

Pediatric

2 mg/kg/d PO for 4-8 wk until liver enzyme levels return to reference values; not to exceed 60 mg/d; taper to lowest possible dose required to maintain remission

Interactions

Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, carbamazepine, or rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue, fungal, or tubercular skin infections; GI tract disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur

Prednisolone (Pediapred, Delta-Cortef)

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Dosing

Adult

5-60 mg/d PO/IV/IM

Pediatric

2 mg/kg/d PO for 4-8 wk until liver enzyme levels return to reference values; not to exceed 60 mg/d; taper to lowest possible dose required to maintain remission

Interactions

Decreases effects of salicylates and toxoids (for immunizations); phenytoin, carbamazepine, barbiturates, and rifampin decrease effects

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin lesions

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in hyperthyroidism, osteoporosis, cirrhosis, nonspecific ulcerative colitis, peptic ulcer disease, diabetes, and myasthenia gravis

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.

Azathioprine (Imuran)

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

Dosing

Adult

1 mg/kg/d PO for 6-8 wk; increase by 0.5 mg/kg q4wk until response or dose reaches 2.5 mg/kg/d

Pediatric

1.5-2 mg/kg/d PO

Interactions

Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

Contraindications

Documented hypersensitivity; low levels of serum thiopurine methyltransferase

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; check thiopurine S-methyltransferase level before therapy, low levels may accumulate thioguanine nucleotides in bone marrow and develop hematopoietic toxicity; monitor liver, renal, and hematologic function; pancreatitis rarely associated

Cyclosporine (Sandimmune, Neoral)

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. Dose is based on ideal body weight.

Dosing

Adult

4-6 mg/kg/d PO divided bid

Pediatric

4 mg/kg/d PO divided tid

Interactions

Substrate of CYP3A4, therefore, caution with coadministration of inducers or inhibitors of the isoenzyme; carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease cyclosporine concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase cyclosporine toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin

Contraindications

Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UV-B radiation in psoriasis because administration may increase risk of cancer

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Evaluate renal and liver functions often by measuring BUN and serum creatinine, serum bilirubin, and liver enzyme levels; may increase risk of infection and lymphoma; reserve IV use only for patients who cannot take oral medications; monitor cyclosporine levels to adjust dose and avoid nephrotoxicity, maintain level at approximately 250 ng/mL in the first 3 mo and 200 ng/mL for the following 3 mo

Follow-up

Further Outpatient Care

• 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 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.
• Ferreira et al concluded that immunosuppressive treatment improved the fibrosis scores, with an arrest in progression and no development into cirrhosis.⁸
• In a series reported by Gregorio et al in 1997, 70% of children with autoimmune hepatitis type 1 (AIH-1) and 40% of children with autoimmune hepatitis type 2 (AIH-2) developed cirrhosis.³ 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 the 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

Medicolegal Pitfalls

• Failure to explain to the family the seriousness of autoimmune hepatitis (AIH) 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

1. Czaja AJ, Cassani F, Cataleta M, et al. Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis. Hepatology. Nov 1996;24(5):1068-73. [Medline].

2. Wen L, Peakman M, Lobo-Yeo A, et al. T-cell-directed hepatocyte damage in autoimmune chronic active hepatitis. Lancet. Dec 22-29 1990;336(8730):1527-30. [Medline].

3. Gregorio GV, Portmann B, Reid F, et al. Autoimmune hepatitis in childhood: a 20-year experience. Hepatology. Mar 1997;25(3):541-7. [Medline].

4. Mieli-Vergani G, Vergani D. Autoimmune paediatric liver disease. World J Gastroenterol. Jun 7 2008;14(21):3360-7. [Medline].

5. Oettinger R, Brunnberg A, Gerner P, et al. Clinical features and biochemical data of Caucasian children at diagnosis ofautoimmune hepatitis. J Autoimmun. Feb 2005;24(1):79-84. [Medline].

6. Alvarez F, Ciocca M, Canero-Velasco C, et al. Short-term cyclosporine induces a remission of autoimmune hepatitis in children. J Hepatol. Feb 1999;30(2):222-7. [Medline].

7. Sciveres M, Caprai S, Palla G, et al. Effectiveness and safety of ciclosporin as therapy for autoimmune diseasesof the liver in children and adolescents. Aliment Pharmacol Ther. Jan 15 2004;19(2):209-17. [Medline].

8. Ferreira AR, Roquete ML, Toppa NH, de Castro LP, Fagundes ED, Penna FJ. Effect of treatment of hepatic histopathology in children and adolescents with autoimmune hepatitis. J Pediatr Gastroenterol Nutr. Jan 2008;46(1):65-70. [Medline].

9. Bellary S, Schiano T, Hartman G, Black M. Chronic hepatitis with combined features of autoimmune chronic hepatitis and chronic hepatitis C: favorable response to prednisone and azathioprine. Ann Intern Med. Jul 1 1995;123(1):32-4. [Medline].

10. Czaja AJ. Drug therapy in the management of type 1 autoimmune hepatitis. Drugs. Jan 1999;57(1):49-68. [Medline].

11. Debray D, Maggiore G, Girardet JP, et al. Efficacy of cyclosporin A in children with type 2 autoimmune hepatitis. J Pediatr. Jul 1999;135(1):111-4. [Medline].

12. Desmorat H, Combis JM, Pradat P. [Assessment of quality of life in chronic hepatitis C: effect of treatment]. Gastroenterol Clin Biol. Dec 2003;27(12):1084-90. [Medline].

13. Djilali-Saiah I, Renous R, Caillat-Zucman S, et al. Linkage disequilibrium between HLA class II region and autoimmune hepatitisin pediatric patients. J Hepatol. Jun 2004;40(6):904-9. [Medline].

14. Evans JS. Acute and chronic hepatitis. In: Wyllie R, Hyams JS, Fletcher J, eds. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. 2^nd ed. WB Saunders Co; 1999:600-23.

15. Fernandes NF, Redeker AG, Vierling JM, et al. Cyclosporine therapy in patients with steroid resistant autoimmune hepatitis. Am J Gastroenterol. Jan 1999;94(1):241-8. [Medline].

16. Garcia-Buey L, Garcia-Monzon C, Rodriguez S, et al. Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis C. Gastroenterology. Jun 1995;108(6):1770-7. [Medline].

17. Jackson LD, Song E. Cyclosporin in the treatment of corticosteroid resistant autoimmune chronic active hepatitis. Gut. Mar 1995;36(3):459-61. [Medline].

18. Klein C, Philipp T, Greiner P, et al. Asymptomatic autoimmune hepatitis associated with anti-LC-1 autoantibodies. J Pediatr Gastroenterol Nutr. Nov 1996;23(4):461-5. [Medline].

19. Krawitt EL. Autoimmune hepatitis. N Engl J Med. Apr 4 1996;334(14):897-903. [Medline].

20. Krawitt EL. Autoimmune hepatitis. N Engl J Med. Jan 5 2006;354(1):54-66. [Medline].

21. Manns M, Gerken G, Kyriatsoulis A, et al. Characterisation of a new subgroup of autoimmune chronic active hepatitis by autoantibodies against a soluble liver antigen. Lancet. Feb 7 1987;1(8528):292-4. [Medline].

22. Manns MP. Autoimmune hepatitis. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff's Diseases of the Liver. 8^th ed. Philadelphia, PA: Lippincott-Raven; 1999:919-35.

23. Manns MP, Kruger M. Immunogenetics of chronic liver diseases. Gastroenterology. Jun 1994;106(6):1676-97. [Medline].

24. Manns MP, Obermayer-Straub P. Cytochromes P450 and uridine triphosphate-glucuronosyltransferases: model autoantigens to study drug-induced, virus-induced, and autoimmune liver disease. Hepatology. Oct 1997;26(4):1054-66. [Medline].

25. McCaughan GW, George J. Fibrosis progression in chronic hepatitis C virus infection. Gut. Mar 2004;53(3):318-21. [Medline]. [Full Text].

26. McFarlane IG. Pathogenesis of autoimmune hepatitis. Biomed Pharmacother. Jun 1999;53(5-6):255-63. [Medline].

27. Mieli-Vergani G, Vergani D. Immunological liver diseases in children. Semin Liver Dis. 1998;18(3):271-9. [Medline].

28. Obermayer-Straub P, Strassburg CP, Manns MP. Autoimmune hepatitis. J Hepatol. 2000;32(1 Suppl):181-97. [Medline].

29. Paradis K, Alvarez F, Seidman E, et al. Pitfalls in the diagnosis of autoimmune hepatitis associated with liver and kidney microsomal proteins. J Pediatr Gastroenterol Nutr. Nov 1994;19(4):453-9. [Medline].

30. Roberts SK, Therneau TM, Czaja AJ. Prognosis of histological cirrhosis in type 1 autoimmune hepatitis. Gastroenterology. Mar 1996;110(3):848-57. [Medline].

31. Robertson DA, Zhang SL, Guy EC, Wright R. Persistent measles virus genome in autoimmune chronic active hepatitis. Lancet. Jul 4 1987;2(8549):9-11. [Medline].

32. Treichel U, Poralla T, Hess G, et al. Autoantibodies to human asialoglycoprotein receptor in autoimmune-type chronic hepatitis. Hepatology. Apr 1990;11(4):606-12. [Medline].

33. Vento S, Guella L, Mirandola F, et al. Epstein-Barr virus as a trigger for autoimmune hepatitis in susceptible individuals. Lancet. Sep 2 1995;346(8975):608-9. [Medline].

34. Vergani D, Mieli-Vergani G. Autoimmune liver disease. In: Walker WA, Durie PR, et al, eds. Pediatric Gastrointestinal Disease. 3^rd ed. Ontario, Canada: BC Decker Inc; 2000:1007-14.

35. Villalta D, Girolami D, Bidoli E, et al. High prevalence of celiac disease in autoimmune hepatitis detected by anti-tissue tranglutaminase autoantibodies. J Clin Lab Anal. 2005;19(1):6-10. [Medline].

Keywords

autoimmune chronic active hepatitis, lupoid hepatitis, plasma cell hepatitis, autoimmune hepatitis, pediatric hepatitis, liver disease in children, AIH, AIH-1, AIH-2, necroinflammatory hepatitis, autoimmune disease, juvenile cirrhosis, acute hepatitis, rubella, Epstein-Barr, hepatitis A, hepatitis B, hepatitis C, hepatitis C virus, HCV, fulminant hepatic failure, autoimmune thyroiditis, celiac disease, inflammatory bowel disease, diabetes mellitus, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, APECED,  hepatomegaly, splenomegaly, ascites, ulcerative colitis, sclerosing cholangitis, arthritis, vasculitis, glomerulonephritis

Contributor Information and Disclosures

Author

Husam H Sukerek, MD, Consulting Staff, Department of Gastroenterology, Sabine Medical Center
Husam H Sukerek, MD is a member of the following medical societies: American Academy of Pediatrics and American Medical Association
Disclosure: Nothing to disclose.

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
Mohammad F El-Baba, MD is a member of the following medical societies: American Gastroenterological Association and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

Medical Editor

Robert Baldassano, MD, Director, Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology and Nutrition, Associate Professor, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania
Robert Baldassano, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

CME Editor

Steven M Schwarz, MD, FAAP, FACN, AGAF, Professor of Pediatrics, State University of New York, Downstate Medical Center College of Medicine; Distinguished Lecturer, New York Medical College, School of Public Health
Steven M Schwarz, MD, FAAP, FACN, AGAF is a member of the following medical societies: American Academy of Pediatrics, American College of Nutrition, American College of Physician Executives, American Gastroenterological Association, American Pediatric Society, Gastroenterology Research Group, New York Academy of Medicine, North American Society for Pediatric Gastroenterology and Nutrition, and Society for Pediatric Research
Disclosure: TAP Pharmaceuticals Honoraria Speaking and teaching; Curemark, LLC Consulting fee Board membership

Chief Editor

Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine
Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)