Treatment of autoimmune hepatitis
Potential conflict of interest: Nothing to report.
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Autoimmune hepatitis (AIH) is an organ-specific autoimmune disease characterized by a break of humoral and cellular immunotolerance that mainly affects the liver, although extrahepatic manifestations are also observed in approximately 25% of patients. The disease was first described in 1951 in young women and was later termed lupoid hepatitis because of its association with anti-nuclear antibodies. The same group first described a beneficial effect of corticosteroids in these patients and thereby laid the groundwork for the first chronic liver disease that was found to be curable by drug therapy, at least in some patients. AIH usually runs a chronic course, but the disease may manifest as acute and even fulminant hepatitis.
Therefore, AIH must be considered in the differential diagnosis of acute liver failure. Like many other autoimmune diseases, AIH has, for reasons that are poorly understood, a considerable female preponderance. It can manifest in all age groups and races. Furthermore, associations with extrahepatic autoimmune diseases such as rheumatoid arthritis, autoimmune thyroiditis, ulcerative colitis, and diabetes mellitus and with a family history of autoimmune or allergic disorders have been reported.
Clinical Presentation and Diagnosis
The clinical presentation of patients with AIH is similar to the presentation of patients with other causes of hepatitis. Autoantibodies are one of the distinguishing features of AIH. The discovery of autoantibodies directed against different cellular targets, including endoplasmatic reticulum, membrane proteins, nuclear antigens, and cytosolic antigens, has led to a suggested subclassification of AIH based on specific autoantibody profiles. However, this serological heterogeneity does not influence the decision about who should be treated or when they should be treated. Because AIH can manifest itself at any age and in all ethnic groups, it should be considered a possible diagnosis in all cases of elevated aminotransferases as long as other causes of hepatitis cannot be excluded.
Seminal trials published in the early 1970s demonstrated a marked responsiveness of active chronic hepatitis to immunosuppressive therapy in most patients. Treatment with predniso(lo)ne alone or in combination with azathioprine was superior to azathioprine alone at improving symptoms and laboratory and histological manifestations of liver inflammation and at reducing the progression of liver fibrosis. In comparison with the progressive natural course, which led to decompensated end-stage liver disease in control patients, both short- and long-term survival dramatically improved for patients receiving corticosteroid-based immunosuppression (e.g., 63% versus 27% at 10 years).[3, 4] Combinations of predniso(lo)ne with azathioprine and azathioprine alone demonstrated comparable short- and long-term rates for the maintenance of remission with fewer corticosteroid-related side effects in comparison with long-term predniso(lo)ne monotherapy. Finally, budesonide was introduced as an alternative corticosteroid with at least comparable short-term remission rates and fewer steroid-specific side effects in comparison with prednisolone when both steroid regimens were combined with azathioprine. Budesonide should not be administered to patients with cirrhosis because the beneficial first-pass effect is no longer evident and thromboembolic events have been described.
The current therapeutic regimens differentiate between the induction of remission, for which higher steroid dosages are used, and the maintenance of remission, which should be sustained with the lowest necessary dose of immunosuppression (particularly for steroids) in order to minimize side effects (Table 1).
Table 1. Standard Therapy for AIH
|Weeks 3 to 4||30||15||6||50||1-2|
|Reasons for preference||Cytopenia||Postmenopausal state|
|Thiopurine methyltransferase deficiency Pregnancy Malignancy Expected therapy < 6 months||Osteoporosis Uncontrolled diabetes, hypertension, obesity Acne Emotional lability|
Predniso(lo)ne dosages of 30 to 60 mg/day or up to 1 mg/kg/day as monotherapy and a dosage of 30 mg/day combined with 50 mg of azathioprine (or 1-2 mg/kg/day) are recommended for induction therapy.[7, 8] The initially higher predniso(lo)ne doses are more likely to cause corticosteroid-related side effects, but they seem to normalize aminotransferases more rapidly. In either regimen, corticosteroids are rapidly tapered over a period of 3 months (as long as transaminase and immunoglobulin G levels continue to fall) to achieve an individual maintenance dose less than 20 mg/day. In most cases, 5 to 10 mg/day is an achievable goal. In contrast to the prompt effect of corticosteroids, it takes approximately 6 to 8 weeks for a beneficial effect of azathioprine to be seen. Therefore, the initial combination of steroids and azathioprine appears reasonable, and it is also recommended because of fewer steroid side effects with the combined regimen.[7, 8] Azathioprine can also be introduced at a later stage so that a treatment response to steroid monotherapy can be evaluated as part of the diagnosis of AIH. After at least 2 years of remission, some patients can be weaned off immunosuppression. Biopsy is recommended before efforts to withdraw immunosuppression are begun. If histological inflammatory activity is discovered, relapse seems universal; therefore, immunosuppression should be continued in such cases for the long term.
Up to 80% of patients suffer from predniso(lo)ne-specific side effects even when it is used in combination with azathioprine. The most notable adverse effects include osteoporosis, diabetes, hypertension, weight gain, cataract formation, and psychosis.[7, 8] Therefore, the topical steroid budesonide (starting at 3 × 3 mg and tapering down to 1 × 3 mg per day) in combination with azathioprine (1-2 mg/kg of body weight) should be considered as an alternative to predniso(lo)ne in such patients without cirrhosis. Patients with comorbidities that could deteriorate under systemic corticosteroids (e.g., diabetes, osteoporosis, and hypertension) also are expected to benefit the most from the budesonide regimen. Budesonide in combination with azathioprine is also effective in pediatric patients; in particular, weight gain can be reversed when prednisone is switched to budesonide. Budesonide should not be given to patients with cirrhosis because the 90% first-pass effect of this topical steroid is no longer evident and thromboembolic events have been described. The most frequent side effect of azathioprine is cytopenia (up to 46%) due to myelosuppression. Other side effects, including rash, nausea, pancreatitis, and cholestatic hepatitis, are less common (approximately 25%) but are more frequent in patients with cirrhosis.[7, 8] An assessment of blood thiopurine methyltransferase activity has been recommended for patients with cytopenia before or during azathioprine therapy, but it does not predict this complication.
Remission is defined as complete normalization of aminotransferases and immunoglobulin G as well as the disappearance of symptoms and histological signs of hepatitis. The latter usually lags behind biochemical remission by 3 to 8 months. Former treatment goals (i.e., aminotransferase levels remain elevated but less than 2 times the upper limit of normal) have been abandoned because of higher relapse rates and more frequent histological disease progression. Once biochemical remission is achieved, maintenance therapy should be continued for at least 2 years because rates of histological remission increase with the duration of therapy from approximately 25% after 12 months to approximately 80% after 36 months. After this interval of successful therapy, liver biopsy should be performed to assess the histological disease activity.
Alternative Therapies to Corticosteroids and Azathioprine
Alternative therapies to corticosteroids with or without azathioprine must be considered in cases of treatment failure or drug intolerance. Calcineurin inhibitors may be used in such cases. Cyclosporin A should be given at doses of 2 to 5 mg/kg/day to achieve 100 to 300 ng/mg of blood levels, and tacrolimus should be given at doses of 3 to 5 mg/kg twice daily. Mycophenolate mofetil is another choice as second-line therapy and is given at doses of 1.5 to 2.0 g/day. Mycophenolate mofetil seems to be beneficial for azathioprine-intolerant patients rather than patients for whom treatment has failed. Recently, anti–tumor necrosis factor antibodies such as infliximab and anti-CD20 antibodies such as rituximab were given to patients for whom standard immunosuppressive therapy failed. Cyclophosphamide, methotrexate, and 6-mercaptopurine were given to single cases with AIH. However, prospective studies of such alternative therapies in treatment-failure or intolerant patients are missing, and the numbers of patients are rather limited. Because of the significant toxicity profile of these alternative drugs, a careful benefit-risk evaluation for the individual patient seems mandatory (Table 2).
Table 2. Alternative Therapies to Corticosteroids and Azathioprine
|Cyclosporine A||3-5 mg/kg once daily||Hypertension, renal insufficiency|
|Tacrolimus||3-5 mg twice daily||Hypertension, renal insufficiency, diabetes, polyneuropathy|
|Mycophenolate mofetil||750-1000 mg twice daily||Gastrointestinal symptoms, diarrhea, leukopenia|
|Anti-tumor necrosis factor (infliximab)||5 mg/kg of body weight every 2-8 weeks||Infections, induction of AIH|
|Anti-CD20 (rituximab)||Two 1000-mg infusions on days 1 and 15||Reactivation of infections (e.g., hepatitis B)|
The authors thank Dr. Svenja Hardtke for her competent editorial assistance.