Elsevier

Journal of Hepatology

Volume 40, Issue 4, April 2004, Pages 646-652
Journal of Hepatology

Decreased fibrosis during corticosteroid therapy of autoimmune hepatitis

https://doi.org/10.1016/j.jhep.2004.01.009Get rights and content

Abstract

Background/Aims

Reduction in hepatic fibrosis and reversibility of cirrhosis has been described in chronic liver disease. Our goal was to determine changes in fibrosis and the frequency of histological cirrhosis in corticosteroid-treated autoimmune hepatitis (AIH).

Methods

Three hundred twenty-five liver specimens from 87 treated patients were reviewed in batch under code by one pathologist and graded by the Ishak method.

Results

Fibrosis scores improved (3.4±0.2 versus 2.6±0.2, P=0.0002) during 63±6 months, and histological activity indices decreased concurrently (6.8±0.5 versus 2.1±0.2, P<0.0001). Fibrosis scores improved in 46 patients (53%) during 57±7 months and did not progress in 23 patients during 62±12 months. The fibrosis score improved more commonly in patients who had improvement in the histological activity indices than in others (61 versus 32%, P=0.02), and the frequency of histological cirrhosis decreased from 16% (14 patients) to 11% (10 patients).

Conclusions

Fibrosis commonly improves or does not progress during corticosteroid therapy of AIH, and histological cirrhosis may disappear. Improvements in fibrosis are associated with suppression of inflammatory activity. Improvement or prevention of fibrosis may be a common but unheralded advantage of corticosteroid therapy.

Introduction

Hepatic fibrosis can be reduced in various chronic liver diseases by eliminating the etiologic agent or pathogenic basis for the liver injury [1], [2], [3]. Regression of fibrosis has followed phlebotomy for hemochromatosis [4], relief of chronic biliary obstruction [5], bone marrow transplantation for thalessemia [6], treatment of primary biliary cirrhosis with ursodeoxycholic acid and methotrexate [7], reversal of jejuno-ileal bypass surgery [8], penicillamine therapy of Wilson disease [9], and antiviral treatment of chronic hepatitis B and C [10], [11], [12], [13]. These observations in humans have been supported by murine models of hepatic injury in which biliary fibrosis has decreased after biliary decompression [14], and rabbit models in which liver fibrosis has regressed after treatment of schistosomiasis [15].

Previous reports of the disappearance of cirrhosis in corticosteroid-treated autoimmune hepatitis (AIH) have been limited by the small study populations [16], [17], [18] and concerns about sampling and interpretative errors [19], [20], [21]. Under these circumstances, estimates of the frequency and degree that fibrosis improves during corticosteroid therapy have not been possible, and the anti-fibrogenic actions of corticosteroid therapy have not been promulgated. Fibrosis can now be assessed more accurately by applying a standardized scoring system, interpreting all specimens in batch under code by a single pathologist, and focusing on changes in fibrosis rather than the complex histological requirements for cirrhosis [3], [22], [23], [24].

In this retrospective review of tissue samples prospectively acquired to assess treatment response, we evaluate changes in fibrosis and inflammatory activity in corticosteroid-treated AIH. We determine the association between fibrosis and inflammatory activity, and assess the role of corticosteroids in preventing and/or reducing fibrosis. Our primary goal is to determine if corticosteroids have an anti-fibrogenic action that can be exploited in the treatment of AIH.

Section snippets

Study population

Eighty-seven patients who satisfied international criteria for AIH [25] were selected for study because each had been enrolled in our treatment program, treated with conventional corticosteroid regimens, and monitored by liver biopsy examination. These patients constituted 64% of the 136 patients in our program who had been treated and followed similarly. Their clinical features at presentation are shown in Table 1. Our investigation had been approved by the Institutional Review Board of the

Fibrosis scores and HAI in successive tissue specimens

The fibrosis scores improved significantly during 63±6 months of treatment and follow-up (range, 6–225 months) (Fig. 1A–C). The HAI also improved significantly during this interval (Table 2). Fourteen patients (16%) had histological cirrhosis at accession, but only 10 patients (11%) had histological cirrhosis at the end of treatment.

Sixteen of 79 patients (20%) with initial fibrosis scores of 1–6 (mean score, 3.3±0.3 points) had histological resolution of fibrosis during 54±10 months of

Discussion

Our study indicates that hepatic fibrosis scores improve or do not progress in most patients with AIH who are treated with corticosteroids. Improvement in the fibrosis score typically concurs with reduction in the HAI, and liver biopsy samples obtained during active inflammation have higher HAI and fibrosis scores than biopsies obtained during quiescent phases of the disease. These findings suggest that hepatic fibrosis in AIH can frequently improve with corticosteroid therapy and that

References (50)

  • A.J Czaja et al.

    Laboratory assessment of severe chronic active liver disease (CALD): correlation of serum transaminase and gamma globulin levels with histologic features

    Gastroenterology

    (1981)
  • A.J Czaja et al.

    Sustained remission after corticosteroid therapy for type 1 autoimmune hepatitis: a retrospective analysis

    Hepatology

    (2002)
  • K Ishak et al.

    Histological grading and staging of chronic hepatitis

    J Hepatol

    (1995)
  • S.L Friedman

    Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury

    J Biol Chem

    (2000)
  • F.R Murphy et al.

    Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implcations for reversibility of liver fibrosis

    J Biol Chem

    (2002)
  • J.M Parrelli et al.

    Identification of a glucocorticoid response element in the human transforming growth factor beta 1 gene promoter

    Int J Biochem Cell Biol

    (1998)
  • J Cai et al.

    Glucocorticoids induce Kaposi's sarcoma cell proliferation through the regulation of transforming growth factor-beta

    Blood

    (1997)
  • G.L Davis et al.

    Development and prognosis of histologic cirrhosis in corticosteroid-treated HBsAg-negative chronic active hepatitis

    Gastroenterology

    (1984)
  • S.K Roberts et al.

    Prognosis of histological cirrhosis in type 1 autoimmune hepatitis

    Gastroenterology

    (1996)
  • S.L Friedman

    The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies

    N Engl J Med

    (1993)
  • P.A.L Bonis et al.

    Is liver fibrosis reversible (editorial)?

    N Engl J Med

    (2001)
  • L.W Powell et al.

    Reversal of cirrhosis in idiopathic haemochromatosis following long-term intensive venesection therapy

    Australas Ann Med

    (1970)
  • P Hammel et al.

    Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct

    N Engl J Med

    (2001)
  • P Muretto et al.

    Reversibility of cirrhosis in patients cured of thalessemia by bone marrow transplantation

    Ann Intern Med

    (2002)
  • M.M Kaplan et al.

    Sustained biochemical and histologic remission of primary biliary cirrhosis in response to medical treatment

    Ann Intern Med

    (1997)
  • Cited by (0)

    Presented in part at the meeting of the American Association for the Study of Liver Diseases, October 26, 2003, Boston, Massachusetts.

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