Clinical Insights Into Autoimmune Hepatitis: An Expert Interview With Steven L. Flamm, MD

Steven L. Flamm, MD


November 16, 2007

Editor's Note:

Autoimmune hepatitis is a nonresolving inflammation of the liver of unknown etiology, characterized by the presence of interface hepatitis on histologic examination, hypergammaglobulinemia, and autoantibodies. Its diverse features can delay diagnosis and the timely initiation of therapy. Indeed, autoimmune hepatitis should be considered in all patients who present with acute or chronic hepatitis of undetermined cause. Medscape spoke with Steven L. Flamm, MD, Associate Professor of Hepatology at Feinberg School of Medicine, Northwestern University; and Medical Director of Liver Transplantation, Northwestern Memorial Hospital, Chicago, Illinois, to explore some of the topical issues related to this disorder, as viewed within the context of new data presented at the 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD; The Liver Meeting 2007).

Medscape: What can you tell us about the patterns of clinical presentation of autoimmune hepatitis, and what are the implications for diagnosis?

Dr. Flamm: The clinical presentation of autoimmune hepatitis is variable. Many patients are asymptomatic and present for evaluation because elevated liver enzymes are discovered after routine blood testing. Other patients have nonspecific symptoms, including fatigue, right upper quadrant discomfort, amenorrhea, arthralgias, or pruritus. Finally, patients may present with signs and symptoms of advanced liver disease, including ascites, hepatic encephalopathy, or variceal bleeding. Autoimmune hepatitis classically presents as a manifestation of a chronic inflammatory process; however, it has become clear in recent years that an acute presentation characterized by the sudden onset of fatigue and jaundice in the setting of highly elevated liver enzymes may be observed.[1,2]

The diagnosis of autoimmune hepatitis must be considered so that appropriate work-up is initiated. One of the clues to the diagnosis of autoimmune hepatitis is the presence of other autoimmune diseases. In clinical practice, the diagnosis is often made by identification of a characteristic biochemical profile, antinuclear antibody (ANA) and/or smooth muscle antibody (SMA) positivity, hypergammaglobulinemia, hepatic histology consistent with autoimmune hepatitis, and response to therapy.[1]

In patients with an unclear diagnostic picture or for patients enrolled in clinical trials, a descriptive set of criteria developed by the International Autoimmune Hepatitis Study Group to standardize the diagnosis of autoimmune hepatitis may be used.[3] Classification into probable or definite autoimmune hepatitis is made based on the score as determined by demographic, biochemical, serologic, and histologic factors as well as response to therapy.

The diagnosis of autoimmune hepatitis must not be missed because untreated disease may progress to cirrhosis and death. Treatment favorably affects the natural history of disease and allows complete remission (normalization of symptoms, liver enzymes, and hepatic histology) in about 80% of patients.

Medscape: Hepatocellular carcinoma (HCC) has been reported as a rare complication of autoimmune hepatitis. In this context, a study presented during AASLD 2007 sought to determine predictive factors for the development of HCC in patients with type 1 autoimmune hepatitis.[4] What can you tell us about this study and what are the clinical implications?

Dr. Flamm: HCC is a hepatic neoplasm that occurs in the setting of cirrhosis. Different etiologies of cirrhosis are associated with different rates of HCC development. Once HCC becomes symptomatic, it is often incurable. Early HCC, on the other hand, can be successfully treated with surgical resection or liver transplantation. The AASLD has published literature-based screening guidelines for HCC with the intent to discover HCC at an early stage; these guidelines recommend liver imaging every 6 months in patients with cirrhosis secondary to many etiologies.[5]

HCC is uncommon in the setting of autoimmune hepatitis, and there is little literature to determine predictive factors for HCC in this population. In fact, it is recommended that patients with autoimmune hepatitis should be screened for HCC in the AASLD screening guidelines, although it is noted that there are insufficient data from cohort studies to accurately assess HCC incidence. This large study by Montano-Loza and colleagues[4] sought to determine factors predictive of HCC in 227 patients with autoimmune hepatitis. Subjects underwent hepatic ultrasonography and serum alpha fetoprotein measurements every 6-12 months, and were followed for a mean of 114 months.

Nine patients developed HCC, and all had cirrhosis for a minimum of 73 months (mean, 132 months) prior to the development of cancer. Factors associated with the development of HCC included presence of cirrhosis for at least 10 years, presence of portal hypertension, male sex, treatment failure, and immunosuppressive therapy for more than 3 years.

This study confirms that HCC occurs in patients with autoimmune hepatitis and long-standing cirrhosis. Patients with cirrhosis (men in particular) should be screened for HCC with hepatic imaging every 6 months until additional information is available.

Medscape: Appropriate management of autoimmune hepatitis can enhance quality of life, improve survival, and delay the need for liver transplantation. The current standard of care for autoimmune hepatitis involves the use of corticosteroids alone or in combination with azathioprine. However, about 10% of patients experience treatment failure with standard therapy. Thus, alternative therapeutic options are warranted. During this year's meeting, Sharzehi and colleagues[6] presented the results of a study assessing the utility of mycophenolate mofetil, a potent inhibitor of guanosine nucleotide synthesis, for the treatment of autoimmune hepatitis. Can you briefly discuss the key findings of this study, with a view toward the implications for clinical practice?

Dr. Flamm: The objective of medical therapy for autoimmune hepatitis is complete remission, defined by amelioration of symptoms, normalization (or near normalization) of liver enzyme levels, and resolution of hepatic inflammation. Treatment with corticosteroids and azathioprine results in complete remission in about 80% of patients. Unfortunately, about 10% of patients do not respond to therapy and about 10% of patients are intolerant of either prednisone or azathioprine. In such cases, salvage regimens are implemented.[7,8]

Mycophenolate mofetil is an immunosuppressive medication that inhibits purine biosynthesis by inhibition of inosine monophosphate dehydrogenase (IMPDH). Small case series in patients with autoimmune hepatitis intolerant or refractory to standard therapy using mycophenolate mofetil have been reported and have demonstrated improvement in liver enzyme levels and hepatic histology, as well as the ability to diminish dosages of prednisone.[9,10,11]

This retrospective study by Sharzehi and colleagues[6] sought to assess the outcome of therapy with mycophenolate mofetil in patients with autoimmune hepatitis intolerant or refractory to standard therapy. Twenty-one patients were switched to mycophenolate mofetil either because of nonresponse (n = 12) or medication intolerance (n = 9); 17 were followed for at least 6 months including 8 nonresponders and all 9 patients who suffered from medication intolerance. None of the 8 patients with treatment-refractory disease achieved biochemical improvement, whereas 8 of 9 patients with medication intolerance achieved biochemical remission. Steroid dosages diminished significantly overall.

This study suggests that the addition of mycophenolate mofetil is ineffective in achieving remission in autoimmune hepatitis patients with treatment-refractory disease; however, the addition of mycophenolate mofetil allowed for the use of lower dosages of corticosteroids. Mycophenolate mofetil was helpful in achieving remission in autoimmune hepatitis patients with azathioprine intolerance. Although there has been much enthusiasm about the potential utility of mycophenolate mofetil, data are sparse. This agent may be considered as a salvage option (0.5-2 g/day), but should not be administered on a routine basis until additional confirmatory studies have been performed.

Medscape: Let's talk a little about natural history. While significant diversity in disease severity has been reported for autoimmune disorders among different ethnic groups, there is a paucity of data regarding the impact of ethnicity on the natural history of autoimmune hepatitis. In a study presented at AASLD 2007, Verma and colleagues[12] examined the natural history of autoimmune hepatitis in blacks vs nonblacks. What were the key findings of this study?

Dr. Flamm: Autoimmune hepatitis occurs worldwide. However, data regarding its incidence, prevalence, and natural history are mainly derived from studies in Western Europe and Japan. The wide variability in incidence from different regions suggests that significant racial and ethnic differences in autoimmune hepatitis may exist. In fact, racial differences have been supported by clinical observations from the United States that show that blacks with autoimmune hepatitis present with more advanced and aggressive disease than whites.[13]

Verma and colleagues,[12] within the context of a retrospective analysis, sought to assess differences in the natural history of autoimmune hepatitis among blacks vs nonblacks. A total of 101 patients were included in the assessment. Black patients with autoimmune hepatitis were more likely than nonblacks to have cirrhosis, have liver failure at initial presentation, and be referred for liver transplantation. Additionally, overall mortality was significantly higher among black patients compared with nonblacks. Black males were most likely to have a poor outcome.

This study confirms previous observations that black patients with autoimmune hepatitis have more advanced liver disease at presentation and more aggressive disease than others (ie, nonblacks). This illustrates that for unclear reasons, racial differences in the natural history of autoimmune hepatitis do exist. Large multicenter prospective trials are needed to confirm these findings and determine what operative factors are present that might be responsible for this discrepancy. Furthermore, treatment trials in different racial and ethnic groups are necessary to determine the optimal approach for these patients who are at increased risk for poor outcomes.

Supported by independent educational grants from Bristol-Myers Squibb


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