A 10-Year-Old Boy With a 6-Month History of Gingival Bleeding and Epistaxis

Tracie Wong, MD; Pierre Russo, MD; Petar Mamula, MD Series Editors: David A. Piccoli, MD; Petar Mamula, MD


April 17, 2007

Clinical Course and Discussion

The patient began a course of intravenous corticosteroids, followed by transition to an oral tapering course; he was simultaneously started on azathioprine. His liver enzyme levels decreased steadily over the following several months. Repeat liver biopsy revealed persistent mild inflammation; he continues on prednisone 5 mg per day and azathioprine 50 mg per day.

Autoimmune hepatitis is a process of inflammation and progressive destruction of the liver parenchyma. It is characterized on biopsy by interface hepatitis and plasma cell infiltrate in the portal areas. Laboratory markers include circulating autoantibodies and hypergammaglobulinemia. Although there is no clear etiology, hypotheses for the pathogenesis of autoimmune hepatitis propose a multifactorial model, involving environmental factors interacting with a genetically predisposed population. Exposure to triggers, such as medications and infectious agents, results in an immunoregulatory response and the generation of autoantibodies. No specific drugs or viruses have been consistently associated with the development of autoimmune hepatitis, although hepatitis A, B, and C, as well as EBV and measles, have been implicated.

Autoimmune hepatitis can be classified into 2 types on the basis of antibody profile. Type 1 autoimmune hepatitis is typified by anti-SMA, a positive ANA titer, and the presence of anti F-actin antibody. It can also be associated with positive perinuclear antineutrophil cytoplasmic antibody (pANCA), anti-DNA antibody, and serum anti-asialoglycoprotein receptor (ASGPR) antibodies. Extrahepatic autoimmune diseases that occur frequently with autoimmune hepatitis type 1 include ulcerative colitis (with or without primary sclerosing cholangitis), arthritis, vasculitis, and autoimmune thrombocytopenia. Type 2 autoimmune hepatitis -- typified by anti-liver-kidney microsome antibody and frequently associated with anti-LC-1 (liver cytosol 1) -- and anti-ASGPR antibody can be accompanied by polyendocrinopathy, vitiligo, diabetes, and thyroiditis. Type 1 disease is strongly associated with human leukocyte antigens HLA-A1 DR3 and DR4, whereas as Type 2 is associated with HLA-B14 and DRB1*07.

The pathophysiology underlying injury to the liver is thought to occur by cell-mediated and antibody-dependent cell-mediated cytotoxicity. Through the activation of CD8 and CD4 T cells, there is release of proinflammatory cytokines that induce hepatocellular damage. B-cell dysregulation also occurs with generation of IgG, which binds to normal liver membrane components and results in the formation of antibody-antigen complexes. The complexes engage natural killer cells, further contributing to liver injury.

Autoimmune hepatitis affects all ethnic groups but has a female predominance and a peak incidence in prepubertal age. The most common presentation is that of acute hepatitis with nonspecific symptoms. Anorexia, nausea and vomiting, intermittent fatigue, weight loss, pruritus, and arthralgias of the small joints are typical. Less often, patients present with gastrointestinal bleeding from portal hypertension which developed after progression to liver cirrhosis. Rarely, fulminant hepatic failure with coma or encephalopathy occurs. The incidental finding of elevated aminotransferases on routine bloodwork in an asymptomatic patient can also lead to the diagnosis.

Most patients have firm hepatomegaly and more than 50% of patients present with jaundice or have had a history of jaundice. Up to 60% also have splenomegaly and 30% also have stigmata of chronic liver disease, such as ascites, palmar erythema, and spider nevi.

Diagnosis of autoimmune hepatitis rests on the exclusion of hereditary diseases (Wilson's disease, alpha-1 antitrypsin deficiency, hemochromatosis), infectious hepatitis, toxic or alcoholic injury, and on the autoimmune marker findings on liver histology. A scoring system developed by the International Autoimmune Hepatitis Group has been used to facilitate the diagnosis of autoimmune hepatitis. Children may also need to be investigated for primary sclerosing cholangitis, which can also have positive ANA and SMA titers. Comorbid autoimmune hepatitis and hepatitis C has also been described, with high ANA/SMA titers, presence of liver-kidney microsomal antibodies type 1, and hepatitis C viremia.

Treatment of autoimmune hepatitis centers largely on immunosuppression. Corticosteroids and azathioprine have been used as first-line therapies. Corticosteroid therapy is commonly initiated at 2 mg/kg/day, with or without concurrent azathioprine, to allow faster reduction of the corticosteroid dose. Seventy-five percent to 90% of patients achieve normalized serum aminotransferases within 6-9 months. If successful, the corticosteroids may be tapered and discontinued with close monitoring. Alternative treatment options, especially for patients who do not respond to first-line therapy, include cyclosporine, tacrolimus, and mycophenolate mofetil. Transplantation is indicated in decompensated patients who have failed to respond to standard and alternative treatments or who are in fulminant hepatic failure. Sixteen percent to 55% of children with autoimmune hepatitis progress to transplantation over a 5- to 10-year period. Autoimmune hepatitis has also been reported to recur in 33% of transplanted children.

In summary, this case typifies the insidious onset of autoimmune hepatitis, and stresses the importance of its differentiation from other etiologies by a combination of serology and biopsy results. In addition, although nonspecific symptoms are the most commonly seen complaints, this subacute coagulopathic picture emphasizes the spectrum of autoimmune hepatitis presentations.


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