Reactivation of autoimmune hepatitis during budesonide monotherapy, and response to standard treatment
Authors: Ansgar W. Lohse, Hannah Gil
Journal: Journal of Hepatology (2010)

The large European trial of budesonide therapy suggests that budesonide might be better than prednisone in the treatment of newly diagnosed autoimmune hepatitis [[1]Manns M.P. Woynarowski M. Kreisel W. Lurie Y. Rust C. Zuckerman E. et al.European AIH-BUC-Study Group.Budesonide induces remission more effectively than prednisone in a controlled trialog patients with autoimmune hepatitis. Gastroenterology. 2010; 139: 1198-1206Google Scholar]. These results were based on the sensible combination of azathioprine and steroid, but already physicians have started using budesonide monotherapy, or combinations of budesonide and prednisone or prednisolone. We wish to report a case of autoimmune hepatitis (AIH), who experienced reactivation of disease activity during treatment with 3 × 3 mg budesonide per day and tapering doses of prednisolone, and at the same time suffered from significant steroid side-effects. Institution of standard therapy with prednisolone tapering and azathioprine leads to rapid remission and disappearance of side-effects. The 22-year-old female patient first presented in May 2009 to her general practitioner for a check-up due to non-specific mild symptoms, at which time point markedly elevated transaminases (aspartate aminotransferase (AST) 841 U/L, alananine aminotransferase (ALT) 1357 U/L and gamma-glutamyl-transferase (γ-GT) 155 U/L) were noted (Table 1). Further laboratory findings showed a slightly elevated level of total bilirubin (1.3 mg/dl) and IgG was found to be at the upper limit of normal (15.06 g/L). Autoantibody testing did only show positivity for antibodies to smooth muscle antigen (SMA) – titre 1:320 – (antinuclear antibodies (ANAs), anti-mitochrondrial antibodies (AMAs), liver-kidney microsomes (LKM), and soluble liver antigen/liver pancreas (SLA/LP) were all negative). Metabolic liver disease such as Wilson's Disease and Hemochromatosis were excluded (coeruloplasmin levels, urine copper, serum iron, and serum transferrin saturation were within normal range and eye-examination was inconspicuous). Viral markers for Hepatitis A Virus, Hepatitis B Virus, and Hepatitis C Virus were negative. The patient did not show any history of alcohol abuse nor did she recently use any known hepatotoxic drugs. Liver biopsy was not performed at this time point, because the treating physicians considered the diagnosis of autoimmune hepatitis as sufficiently confirmed.Table 1Laboratory findings at presentation and at four time points of treatment. Open table in a new tab Treatment was started with prednisolone at a starting dose of 60 mg/d (corresponding to 1.3 mg/kg body weight), with a dose reduction every four days (Fig. 1). Vitamin D and Calcium supplementation were prescribed. Due to steroid specific side effects, the patient started feeling agitated and suffered from sleep disorder. Prednisolone was gradually reduced to a level of 20 mg/d. As after an initial fall, transaminases increased again somewhat after 7 weeks of prednisolone induction therapy, and in view of the steroid side-effects, the patient was put on additional budesonide at a dose of 3 mg three times daily, while prednisolone was slowly tapered down to 2.5 mg/d. The patient tolerated budesonide well and transaminases decreased slightly, however, without reaching normal levels. Steroid-specific side-effects continued, but changed their character, as she now gained weight (5 kg in 8 weeks) and developed facial-rounding and hirsutism. In November 2009, when prednisolone dose had been tapered to 2.5 mg for 6 weeks, and during continued therapy with 3 × 3 mg budesonide/d, the patient experienced reactivation of her AIH with transaminase levels up to 217 U/L ALT. At this stage, a liver biopsy was performed to confirm reactivation of AIH and exclude other liver disease including steroid-induced non-alcoholic staetohepatitis (NASH). Histology showed moderately severe interface hepatitis (HAI-score 8/18) with dense infiltrates predominantly of plasma cells and lymphocytes. Periportal lymphocytic piecemeal necrosis with moderate fibrosis without biliary lesions was identified. Histology thus demonstrated the picture of moderately active AIH, despite six months of adequately dosed budesonide. The patient was advised by her treating gastroenterologist to discontinue the intake of desogestrel as oral contraceptive. Probably, as a consequence of that, considerable hair loss was triggered as additional unpleasant side-effect. The treating physicians considered the patient to be treatment refractory, and prednisolone dose was again raised to 20 mg/d, and then slowly decreased down to a maintenance dose of 10 mg/d. At this stage, in February 2010, the patient first presented to our department. At this time point disease was considered only mildly active with transaminases at the upper limit of normal, IgG within the normal range, SMA titre of 1:160, and mild symptoms of fatigue. Subjective well-being was quite impaired due to steroid side-effects under the combination therapy with 10 mg prednisolone daily and 3 × 3 mg budesonide daily, and in view of the hair loss. We decided to stop budesonide and start treatment with azathioprine with an initial dose of 50 mg/d (1 mg/kg) and an increase after two weeks to 75 mg/d. Prednisolone was then reduced first to 7.5 mg/d and after 12 weeks to 5 mg/d. Azathioprine was well tolerated and the patient responded quickly to the new combination regimen. Liver enzymes decreased continuously and normalized for the first time. At the same time, steroid side-effects disappeared. At the moment the patient is feeling well under azathioprine and low-dose prednisolone treatment. It is planned to phase out the steroids completely within the next few months. She is no longer suffering from any treatment-related side effects. She reintroduced the administration of an oral contraceptive and the hair loss is no longer apparent. This case demonstrates that in some patients 3 × 3 mg budesonide is insufficient to induce and/or maintain remission in autoimmune hepatitis, and in this case appeared less effective than prednisolone. In addition, steroid side-effects were considerable, and these did only change their character when budesonide was introduced into the treatment. Our group has reported in the past, that remission can be induced in more than 90% of AIH within six months by using a starting dose of 1 mg/kg prednisolone and introducing azathioprine early at a dose of 1–1.5 mg/kg body weight [[2]Kanzler S. Galle P.R. Meyer zum Büschenfelde K.H. Lohse A.W. Long term management and prognosis of autoimmune hepatitis (AIH): a single centre experience.Z. Gastroenterol. 2001; 39: 339-348Crossref PubMed Scopus (112) Google Scholar]. These data were recently confirmed in a second large patient cohort [[3]Schramm C. Weiler-Normann C. Wiegard C. Hellweg S. Müller S. Lohse A.W. Treatment response in patients with autoimmune hepatitis.Hepatology. 2010; 52: 2247-2248Crossref PubMed Scopus (42) Google Scholar]. These data and the present case should caution us in the use of budesonide in the treatment of autoimmune hepatitis, and further critical evaluation of clinical data will be needed to define its exact place in the management of patients with autoimmune liver disease [[4]Czaja A.J. Manns M.P. Advances in the diagnosis, pathogenesis, and management of autoimmune hepatitis.Gastroenterology. 2010; 139: 58-72Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar]. Diagnosis should be confirmed by biopsy, and azathioprine should be standard treatment in all confirmed cases of AIH who can tolerate the drug. The authors who have taken part in this study declared a relationship with the manufacturers of the drugs involved. AWL took part in the trial of budesonide in AIH (Manns et al; Gastroenterology 2010) sponsored by Falk Pharma, and gives lectures paid for by Falk foundation.