Autoimmune Hepatitis Edward L. Krawitt, M.D. N Engl J Med 2006; 354:54-66January 5, 2006 Autoimmune hepatitis is a generally progressive, chronic hepatitis of unknown cause that occurs in children and adults of all ages. Occasionally, it has a fluctuating course, with periods of increased or decreased activity. The diagnosis is based on histologic abnormalities, characteristic clinical and biochemical findings, and abnormal levels of serum globulins, including autoantibodies. Since the first descriptions of this disorder more than 50 years ago, many labels have been applied, but "autoimmune hepatitis" has been accepted as the most appropriate and least redundant term. Variant, overlapping, or mixed forms of autoimmune hepatitis that share features with other putative autoimmune liver diseases, primary biliary cirrhosis, and primary sclerosing cholangitis occur as well. The distinctions among these disorders at present are necessarily descriptive.It remains important to distinguish autoimmune hepatitis from other forms of chronic hepatitis, because a high percentage of cases respond to antiinflammatory or immunosuppressive therapy, or both. Although appropriate management can prolong survival, improve the quality of life, and avoid the need for liver transplantation, considerable therapeutic challenges remain in the treatment of this disorder.
Hepatotoxicity of Chemotherapy The Oncologist April 2001 vol. 6 no. 2162-176 Paul D. Kinga and Michael C. Perryb After assessment of tumor histology, the next important factor to consider in the selection of a chemotherapy regime is organ function. Patients who are to receive chemotherapy require careful assessment of liver function prior to treatment to determine which drugs may not be appropriate, and which drug doses should be modified. Following therapy abnormalities of liver function tests may be due to the therapy rather than to progressive disease, and this distinction is of critical importance. Furthermore, not all abnormalities in liver function are due to the tumor or its treatment, and other processes, such as hepatitis, must be kept in mind. This article reviews the hepatic toxicity of chemotherapeutic agents, and suggests dose modifications based upon liver function abnormalities. Emphasis is placed on agents known to be hepatotoxic, and those agents with hepatic metabolism.
Biologic Response Modifiers
Recombinant α-interferon is used in the treatment of hairy cell leukemia, multiple myeloma, non-Hodgkin's lymphomas, AIDS-related Kaposi's sarcoma, and myeloproliferative disorders. Its use is often accompanied by an increase in aminotransferases, which clears with discontinuation of therapy [121-124]. At high doses (>10 million units daily), hepatotoxicity may be dose-limiting [125, 126]. At lower doses, the drug is used to treat chronic viral hepatitis. The only evident hepatotoxicity in this population is the exacerbation of unrecognized autoimmune hepatitis [124, 127]. Interleukin 2 (IL-2) is used in the therapy of renal cell carcinoma and melanoma. Many patients undergoing therapy with IL-2 experience elevations of serum bilirubin in the 2 to 7 mg/dl range due to intrahepatic cholestasis [128]. Elevations of AST, ALT, and alkaline phosphatase and hypoalbuminemia and prolonged prothrombin times are also frequent. IL-2 activates Kupffer cells and induces leukocyte and platelet adhesion to hepatic sinusoidal endothelium, with subsequent impaired sinusoidal perfusion and hypoxic damage [129]. Reversal usually occurs within several days after the cessation of therapy.
124. Kirkwood JM, Ernstoff MS. Interferons in the treatment of human cancer. J Clin Oncol 1986;4:336-352.
125. Quesada JR, Talpaz M, Rios A et al. Clinical toxicity of interferons in cancer patients. J Clin Oncol 1986;4:234-243.
126. Figlin RA, DeKernion JB, Maldazys J et al. Clinical and phase I-II studies: treatment of renal cell carcinoma with alpha (human leucocyte) interferon and vinblastine in combination. Cancer Treat Rep 1985;69:263-267.
127. Garcia-Buey L, Garcia-Monzon C, Rodriguez S et al. Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis C. Gastroenterology 1995;108:1770-1777.
129. Nakagawa K, Miller FN, Simds DE et al. Mechanisms of interleukin-2 induced hepatic toxicity. Cancer Res 1996;56:507-510.
Guidelines for Therapy of Autoimmune Liver Disease Hiromi Ishibashi, M.D., 1 Atsumasa Komori, M.D., 1 Shinji Shimoda, M.D., 2 M. Eric Gershwin, M.D.3 Disclosures Semin Liver Dis. 2007;27(2):214-226. Autoimmune hepatitis (AIH) sometimes arises as an acute but more usually as a chronic hepatitis characterized by autoimmunologic features, generally including a high serum γ-globulin/immunoglobulin G (IgG) concentration and the presence of disease-specific circulating autoantibodies.[1,2] AIH is characteristically responsive to corticosteroid therapy, and the prognosis is good as long as appropriate management is performed.[1,2] The majority of AIH patients show an amelioration of symptoms with anti-inflammatory or immunosuppressive therapy, which is associated with an improvement in serum aminotransferases, bilirubin, and γ-globulin/IgG levels and histological findings. The life expectancy of correctly treated patients can approach that of age- and gender-matched controls.[3] The treatment should be applied according to the clinical stage of the disease ( Table 1 ). The treatment of AIH has three components: (1) specific therapy, namely anti-inflammatory/immunosuppressive therapy; (2) prevention and treatment of corticosteroid side effects; and (3) prevention and treatment of cirrhosis-related complications ( Table 2 ). We discuss therapy in the context of the guidelines promulgated by the American Association for the Study of Liver Diseases (AASLD) for the treatment of AIH.[4] The guidelines are accompanied by a rating, I to IV, based on the weight of the supporting evidence.
Treatment should be instituted in patients with serum aminotransferase levels greater than 10-fold the upper limit of normal (Rating, I*). Patients with serum aminotransferase levels that are fivefold the upper limit of normal in conjunction with a serum γ-globulin level at least twice the upper limit of normal should be treated (Rating, I). Histologic features of bridging necrosis or multiacinar necrosis compel therapy (Rating, I). Patients not satisfying the criteria in recommendations in the foregoing three items must be individualized and treatment should be based on clinical judgment. The presence of interface hepatitis without bridging necrosis or multiacinar necrosis on histologic examination does not compel treatment (Rating, III). Symptomatic AIH should always be treated. However, the choice of drug and dosage should be individualized based on the severity and activity of the disease as judged by symptoms, degree of elevation of serum aminotransferases and γ-globulin/IgG, histological findings, and potential side effects of the drug(s) considered for use. Prednisone, in combination with azathioprine, is the preferred initial treatment because of a lower frequency of side effects (Rating, II). Corticosteroids are the key drugs used in the anti-inflammatory/immunosuppressive therapy for AIH as shown in the 1960s.[5] Despite the AASLD recommendation, a sufficient dose (0.5 to 1.0 mg/kg body weight) of prednisone (or prednisolone) alone may be sufficient and result in clinical, laboratory, and histological improvement and thus remission of AIH. Azathioprine is usually used in combination with predniso(lo)ne, as specified in the AASLD recommendation, and is expected to confer a steroid-sparing effect. Although combination therapy of azathioprine with corticosteroid has not been directly compared with corticosteroid alone in large controlled trials with long-term follow-up, there are data that suggest that the combination regimen and corticosteroid-alone regimen have similar efficacy.[5,6,7] However, considering therapy over the long term, which is virtually lifelong in some patients, supplemental treatment with azathioprine seems wise.[8]
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