Fernando Alvarez, Hopital St Justine, Montréal, Quebec, Canada




Autoimmune hepatitis (AIH) is a disease of unknown etiology, that follows a chronic but fluctuating course during which a progressive destruction of the hepatic parenchyma occurs. AIH often shows a good response to immunosuppressive treatment. Two types of AIH are currently recognized according to the nature of the autoantibody detected in children’ sera at the time of diagnosis. Type 1 AIH is characterized by the presence of anti-Smooth Muscle Antibodies (SMA) and/or Anti-Nuclear Antibodies (ANA), type 2 AIH by anti-Liver-Kidney Microsome (LKM) and/or anti-Liver Cytosol (LC1) antibodies.




Most patients have firm hepatomegaly at diagnosis and splenomegaly due to portal hypertension is seen in 50% of them. In more than 50% of children a jaundice is recorded. One third of the patients show signs of chronic liver disease, such as spider naevi, palmar erythema, clubbing or ascitis.





Type 1


Type 2

Age at onset (mean)

10 y

6.5 y

Onset at < 20 y of age (%)



Female preponderance (F/M)



Modes of presentation (%) :



  • Acute hepatitis




  • Chronic hepatitis




  • Hepatomegaly/Increased ALT




  • Others



Extrahepatic autoimmune diseases :

  • Ulcerative colitis
  • Crohn disease
  • Sclerosing cholangitis
  • Vasculitis
  • Arthritis
  • Thrombocytopenia
  • Enteropathy
  • Fibrosing alveolitis
  • Polyendocrinopathy
  • Vitiligo
  • Alopecia
  • Lymphoproliferative syndrome

Hemolytic anemia






Some patients present an acute liver failure at onset. Therefore, AIH must be considered in the differential diagnosis of fulminant and subfulminant hepatic failure.

Twenty to 40% of patients and/or first degree relatives show extrahepatic autoimmune diseases (see Table).




Plasma transaminase (ALT/AST) levels vary between 1.5 to 50 times the normal values at the time of diagnosis. In general, Gammaglutamyl transferase (GGT) and alkaline phosphatase (AP) are slightly increased. If plasma levels of GGT are over 7-8 time the normal values, bile duct injury should be suspected and a cholangiography considered.

Hypergammaglobulinemia, due to an hyper-Immunoglobulin G, ranging between 13 and 73 g/l is frequently observed. Determination of autoantibodies is of diagnostic value, as well as helpful for follow-up. Titres of autoantibodies when tested by indirect immunofluorescence vary between 1:100 and 1:500,000. LKM1 and LC1 can now be searched by ELISA technique or Western blot, because specific antigens have been identified and can be synthetized in vitro.

Half of the patients show low levels of albumin and coagulation factors, indicating the presence of variable degrees of liver failure at onset.




The incidence of cirrhosis varies widely from 38% to 89% of reported series of cases. The degree of portal and peri-portal inflammation at the onset, as ALT/AST levels and autoantibodies titres, is variable following the fluctuating course of the disease. The cellular infiltrate is rich in plasmocytes. In 10% to 40% of these liver biopsies inflammation is mild or even absent. Multinucleated giant hepatocytes are observed in liver biopsies of one fifth of children with AIH.



Figure 1. Interface hepatitis. Inflammatory infiltration with extension into the parenchyma.



Figure 2. Giant multinucleated hepatocytes. Inflammatory infiltration in the lobule.



Figure 3. Parenchyma transformation into liver-cell rosettes.

Recently, a particular histological picture has been described, characterized by centrilobular necrosis and inflammation, sparing the portal tracts.




From the onset of the disease the combination of prednisone at 2mg /kg/day (not exceeding 60mg) and azathioprine at 1.5 to 2mg/kg/day is the treatment of choice. Azathioprine as part of the initial treatment allows for a faster decrease of the prednisone dose. More than 80% of children with AIH show a satisfactory initial response, with normalisation of ALT/AST levels in 2 to 3 months from the begining of the treatment. The high doses of prednisone necessary to obtain the remission of the inflammatory process could be responsible for some serious complications, such as reduced growth velocity, glucose intolerance, Cushingoid facies and weight gain, generalized osteoporosis, striae, psychiatric disorders, hypertension, and cataracts.

Recently, cyclosporine has been shown to induce the biochemical remission of type 1 and type 2 AIH. The initial blood levels requiered were between 250 and 300 ng/ml until normalisation of ALT/AST and of 150ng/ml later on. After some months of normal transaminase levels, cyclosporine can be replaced by low doses of prednisone (0.3 to 0.5 mg/kg/day) and azathioprine at 1.5 mg/kg/day. This immunosuppressive treatment avoids the above described side effects of corticosteroids. In addition, cyclosporine has been useful in patients resistant to the prednisone-azathioprine treatment. The use of cyclosporine should be restricted to centres with experience in the use of this drug.

Long-term follow-up show that very few children can stop treatment without relapse. Azathioprine as monotherapy has been used for long-term maintenance with very good results. In cases of serious side effects of this drug, as hepatitis and pancreatitis, mycophenolate mofetil could be used. Bone marrow depression secondary to azathioprine could be improved decreasing the dose of the medication.

Transplantation could be necessary in patients not responding to the initial immunosuppressive treatment (10%), and in most of those with fulminant hepatic failure. In some patients a liver failure develops after several years of treatment, despite normal transaminase activity levels during follow-up. Children transplanted for AIH have more frequent episodes of rejection than those transplanted for non-immunological related liver diseases.




  1. Johnson PJ, McFarlane IG. Meeting report : International Autoimmune Hepatitis Group. Hepatology. 1993;18:998-1005.


  3. Maggiore G, Verber F, Bernard O et al. Autoimmune hepatitis associated with anti-actin antibodies in children and adolescents. J Pediatr Gastroenterol Nutr. 1993;17:376-81.


  5. Gregorio GV, Portmann B, Reid F et al. Autoimmune hepatitis in childhood : a 20-year experience. Hepatology. 1997;25:541-7.


  7. Homberg JC, Abuaf N, Bernard O et al. Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1 : a second type of "autoimmune" hepatitis. Hepatology. 1987;7:1333-9.


  9. Alvarez F, Ciocca M, Cañero-Velasco C et al. Short-term cycolsporine induces a remission of autoimmune hepatitis in children. J Hepatol. 1999;30:222-7.


  11. Maggiore G, Porta G, Bernard O et al. Autoimmune hepatitis with inital presentation as acute hepatic failure in young children. J Pediatr. 1990;116:280-2.


  13. Porta G, Gayotto LC, Alvarez F. Anti-liver kidney microsome antibody-positive autoimmune hepatitis presenting as fulminant liver failure. J Pediatr Gastroenterol Nutr. 1990;11:138-40.


  15. Herzog D, Rasquin-Weber AM, Debray D, Avarez F. Subfulminant hepatic failure in autoimmune hepatitis type 1: an unusual form of presentation. Hepatol. 1997;27:578-82.


  17. Martini E, Abuaf N, Cavalli F, Durand V, Johanet C, Homberg JC. Antibody to liver cytosol (anti-LC1) in patients with autoimmune chronic active hepatitis type 2. Hepatology. 1988;8:1662-6.


  19. Lapierre P, Hajoui O, Homberg JC, Alvarez F. Forminotransferase cyclodeaminase is an organ specific autoantigen recognized by sera of patients with autoimmune hepatitis. Gastroenterology. 1999;116:1-6.


  21. Vajro P, Hadchouel P, Hadchouel M, Bernard O, Alagille D. Incidence of cirrhosis in children with chronic hepatitis. J Pediatr. 1990;117:392-6.


  23. Pratt DS, Fawaz KA, Rabson A, Dellelis R, Kaplan MM. A novel histological lesion in gluco-corticoid-responsive chronic hepatitis. Gastroenterology. 1997;113:664-8.


  25. Te HS, Koukoulis G, Ganger DR. Autoimmune hepatitis: a histological variant associated with prominent centrilobular necrosis. Gut. 1997;41:269-71.


  27. Van Buuren HR, Van Hoogstraten HJE, Terkivatan T, Schalm SW, Vleggaar FP. High prevalence of autoimmune hepatitis among patients with primary sclerosing cholangitis. J Hepatol. 2000;33:543-8.


  29. Richardson PD, James PD, Ryder SD. Mycophenolate mofetil for maintenance of remission in autoimmune hepatitis in patients resistant to or intolerant of azathioprine. J Hepatol. 2000;33:371-5.