Should we treat asymptomatic autoimmune hepatitis?

April 30, 2009

120px-gray1086-liverBani Chander MD

Faculty Peer Reviewed

Autoimmune hepatitis (AIH) is a progressive, inflammatory disease of the liver of unknown etiology and may progress to cirrhosis. While it is does have a predilection for women, this disease entity crosses genders and ethnic groups, and may occur in both adults and children. AIH is characterized by a fluctuating course and is often associated with autoimmune features including hypergammaglobulinemia, circulating serum autoantibodies, and hepatitis with lymphoplasmacytic infiltration on liver biopsy . Autoimmune hepatitis is a heterogeneous disease with a broad spectrum of clinical manifestations ranging from mild, non-specific symptoms to fulminant hepatic failure. The physical findings range from a normal examination to the presence of hepatomegaly, jaundice and all other stigmata of cirrhosis. It is important to be aware that long periods of subclinical disease may occur for years before or even after the time of diagnosis.

Autoimmune hepatitis is most likely the result of a cell-mediated immunologic attack against hepatocytes that have an aberrant display of human leukocyte antigen (HLA) class II on the surface. These activated liver cells stimulate the clonal expansion of sensitized cytotoxic T cells. Cytotoxic T cells, in turn, invade liver tissue where they release cytokines, and destroy the liver cells. Although the etiology for aberrant HLA display in AIH remains uncertain, environmental agents are postulated to play a role; evidence points to, among other things, a viral trigger. Viruses that have been postulated to elicit disease include hepatitis viruses, EBV, measles, and CMV and disease induction may occur many years before clinical symptoms manifest. Most recently, two medications have also been implicated in inducing AIH; Minocycline and statins, both of which have been known to induce other autoimmune syndromes, have now been identified as possible triggers of AIH. Although the majority of cases of medication-associated AIH have been shown to improve with discontinuation of offending drugs, a smaller number of cases will progress into chronic AIH.

Type 1, the most common and also considered to be the classic form of autoimmune hepatitis, is characterized by circulating serum antibodies to nuclei (ANA) and/or smooth muscle (ASMA) and/or antiactin antibodies (AAA). Other autoantibodies may also occur less commonly in this type. Type 2 AIH is instead characterized by the presence of antibodies to liver/kidney microsomes (ALKM-1), which are directed towards an epitope of CYP2D6 (cytochrome P450IID6), and/or antibodies to a liver cytosol antigen (ALC-1 or LC1). Type 1 may affect people of all ages while type 2 typically affects young women.

Much is known about the disease history of symptomatic AIH, including its prognosis as well as treatment. In fact, large clinical trials have demonstrated a mortality benefit in treating those with moderate to severe disease with immunosuppressive therapy including glucocorticoids with and without azathioprine (AZA) or 6-mercaptopurine (6-MP). AZA and 6-MP may be administered as steroid-sparing agents to avoid long-term use of steroids, with their attendant long-term complications. Unfortunately, the natural history and treatment options for asymptomatic AIH remains poorly understood. While there is data to suggest that asymptomatic patients clearly have the potential to progress to cirrhosis, for the most part, the prognosis remains unclear. Given that corticosteroids have numerous toxicities, it would be helpful to know if there is a clear mortality benefit with immunosupression in those patients who remain asymptomatic.

Feld et al , in a recent retrospective study of autoimmune hepatitis, compared survival in symptomatic patients with AIH to those who were asymptomatic. The authors reviewed the charts of all patients given a clinical diagnosis of type 1 AIH at a single medical center between the years of 1970 to 2002. They found that asymptomatic patients (who made up 25% of the total cohort) tended to have overall lower serum aminotransferases, bilirubin, and immunoglobulin levels at baseline. The asymptomatic patient group was primarily composed of patients with an inflammation-induced transaminitis, but without cirrhosis on liver biopsy and with patients with inactive “burned out” cirrhosis with near normal liver enzymes and no signs of portal hypertension or hepatic decompensation.
Ten-year survival was similar in both groups (80% vs 84%) although only half of the asymptomatic group received immunosuppressive therapy.

Survival was significantly worse in patients who had cirrhosis at the time of diagnosis in this study, regardless of presence of symptoms or receipt of therapy, although prior studies have shown that elderly patients with cirrhosis actually have a better response to treatment . The authors ultimately concluded that the prognosis is good in patients with AIH who are asymptomatic at presentation and that these patients may not require any immunosuppressive therapy. However, 25% of the study group that was asymptomatic ultimately did ultimately have progression of disease and became symptomatic during follow up.

In 2002, the American Association for the Study of Liver Diseases (AASLD) published clinical guidelines for the treatment of autoimmune hepatitis. These guidelines were based on a review of the 914 previous published global studies and recommended treatment in all patients with serum aminotransferase levels greater than 10 fold the upper limit of normal or with serum aminotransferases that are five fold the upper limit of normal in conjunction with a serum gamma globulin level at least two times the upper limit of normal. However, in patients with mild to moderate AIH, these guidelines suggested that treatment “must be individualized….and should be based on clinical judgment.” While Field et al sought to clarify these guidelines, the question of treatment in an asymptomatic patient so far remains unanswered. It is clear that further studies are needed to determine which asymptomatic patients are at highest risk of progressing to cirrhosis and which may benefit from early steroid therapy.

 Bani Chander is a third year resident in internal medicine at NYU Medical Center.

Faculty Peer Reviewed by Michael Poles MD, Associate Editor of Clinical Correlations and Assistant Professor of Medicine, NYU Division of Gastroenterology

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