Acute and fulminant forms of autoimmune hepatitis were recognized by the International Autoimmune Hepatitis Group in 1992 when it codified diagnostic criteria and waived the requirement for 6 months of disease activity to establish the diagnosis.1 Numerous clinical descriptions of severe acute and fulminant autoimmune hepatitis have emerged from small retrospective analyses within single institutions before2–7 and after8–18 that decision. These limited experiences have attested mainly to the rarity of a fulminant presentation and the difficulty in developing a confident management algorithm for this manifestation.
Autoimmune hepatitis does not have a pathognomonic feature, and its laboratory, serological, and histological manifestations are found in acute and chronic liver disease of diverse causes.19, 20 Consequently, the diagnosis of autoimmune hepatitis requires confident exclusion of other causative factors, and difficulties in distinguishing toxic, drug-related, virus-induced, and autoimmune bases for severe acute liver injury can result in misclassification.2 Long-standing but indolent autoimmune hepatitis may have a spontaneous exacerbation that can be mistaken for de novo severe acute or fulminant disease.8, 9 In these patients, the chronic nature of the illness may be overlooked, and the failure to institute corticosteroid therapy may jeopardize survival.21–23
Ichai et al.24 have been diligent in supporting the diagnosis of autoimmune hepatitis in their 16 patients with severe acute and fulminant liver disease, and none had cirrhosis at transplantation. The modified international scoring system25 was not applied before or after corticosteroid treatment, and it is not possible to quantify the strength of their diagnosis. The absence of autoantibodies in 4 patients; the lack of pretreatment liver tissue examinations in 9 patients; the uncertain ratios of serum alkaline phosphatase to aminotransferase increases in all patients; and the failure to uniformly assess or report HLA risk factors, concurrent immune disorders, and immunoglobulin concentrations weaken their designation. Failure to respond to corticosteroid therapy actually downgrades the pretreatment diagnosis of autoimmune hepatitis by international scoring criteria and suggests another disease.25
Treatment failure in autoimmune hepatitis does occur,19, 23, 26 and it tends to develop in patients with early age onset,27 HLA DRB1*03,27–29 or variant syndromes, especially those in whom the features of autoimmune hepatitis are intermixed with features of primary sclerosing cholangitis.30, 31 Among children, the high concurrence of “autoimmune sclerosing cholangitis” with otherwise typical features of autoimmune hepatitis has justified the recommendation of routine cholangiography at presentation.32 Among adults with autoimmune hepatitis and inflammatory bowel disease, cholangiographic evidence of primary sclerosing cholangitis has been described in 44% and associated with treatment failure.33 There is no basis to suspect an alternative diagnosis in the patients of Ichai et al.,24 but this possibility cannot be excluded because their findings counter conventional expectations.
Corticosteroids have been advocated in the treatment of severe acute and fulminant autoimmune hepatitis because the immune-mediated mechanisms of the disease can be targeted by this treatment and anecdotal clinical experiences have supported its use.19, 26 The CD4 helper T lymphocyte is the principal effector of the disease, and it can facilitate differentiation of liver-infiltrating, cytotoxic T lymphocytes along a type 1 cytokine pathway or of antibody-producing plasma cells along a type 2 cytokine pathway.34–36 The resultant cell-mediated and antibody-dependent forms of cytotoxicity have each been implicated in the pathogenesis of autoimmune hepatitis, and corticosteroids can modulate these reactivities.
The repertoire of triggering antigens that can stimulate T and B cell activity in autoimmune hepatitis is small,37 but other defects in the immune regulatory network can amplify or perpetuate the cytotoxicity of sensitized immunocytes.34–36 The apoptotic pathway responsible for immunocyte depletion may be impaired, and the survival of autoreactive cells may be prolonged.38 Regulatory CD4+CD25+ T cells (T-reg cells) can be reduced in number and function, and their direct suppressive effect on the production of interferon gamma and their stimulatory effect on the production of interleukin (IL)-4, IL-10, and transforming growth factor beta may be diminished.39 This disturbance in the cytokine network favors the proliferation of liver-infiltrating cytotoxic CD8 T cells and perpetuation of the liver injury.
Corticosteroids limit T cell activation by inhibiting cytokine production and the expression of adhesion molecules.40–42 The drug complexes with the glucocorticoid receptor within the cytosol, and the complex then translocates to the nucleus where it interacts with glucocorticoid responsive elements in the 5′-untranslated promoter region of glucocorticoid-responsive genes. Cytokine gene expression is inhibited, and the production of IL-2, IL-4, IL-5, IL-6, IL-8, IL-12, interferon-γ, and tumor necrosis factor-α is suppressed. Nuclear factor-κB activity is also reduced by corticosteroids, and the inhibition of this transcription factor reduces RNA polymerase activity and further impairs cytokine production. Posttranscriptional effects include shortening of the half-life of cytokine mRNA and attenuation of cytokine effects on the target cells. Corticosteroids also reconstitute the number and function of the regulatory T cells, and they can restore their suppressive actions on the cell-mediated cytotoxic response.39
The diverse immunosuppressive and anti-inflammatory effects of corticosteroids on the type 1 and type 2 cytokine pathways may explain the beneficial effects of the drug that have been realized in the clinical arena. Ichai et al.24 rightly indicate that the role of corticosteroids in the treatment of severe acute and fulminant autoimmune hepatitis has not been established. This observation does not mean that treatment has failed in all cases. Indeed, as the authors indicate, several studies of similar size and retrospective nature have suggested that the prompt institution of corticosteroid therapy can be beneficial in from 36 to 100% of such patients.4, 6–8, 10–12, 16 What then determines the effectiveness of corticosteroid treatment and who should be treated or transplanted?
Disease severity is the time-honored and principal justification for corticosteroid therapy in autoimmune hepatitis, and the only predictor of outcome has been the treatment response.43 Mortality has uniformly occurred in those individuals with histological features of multilobular collapse and inability to improve laboratory indices within 2 weeks of corticosteroid treatment. A hyperbilirubinemia that does not improve or that worsens during this interval has been highly predictive of early mortality (100%) and the need for urgent transplantation.43 The patients of Ichai et al.24 had Model for End-Stage Liver Disease scores that ranged 24-47 (median score, 37); 12 of 16 patients had been treated for more than 3 months without improvement; and their deterioration was heralded by marked cholestasis. Correctly, these patients were referred for liver transplantation, but their fate could have been predicted earlier.
The study of Ichai et al.24 is an important reminder that there is a point beyond which autoimmune hepatitis cannot be salvaged by drug therapy. At present, this point can be defined only by assessing the immediate response to conventional corticosteroid treatment.43 The assessment can be made over a 2-week interval, and it is sufficiently short to avoid the infectious complications associated with protracted immunosuppressive therapy and liver failure. The experience of Ichai et al.24 should not be used to condemn corticosteroid treatment in severe acute or fulminant autoimmune hepatitis but rather to underscore the importance of defining end points when such therapy must be abandoned.
Therapeutic brinksmanship involves an assessment of risk, and the treatment decision for and against corticosteroid therapy in severe acute and fulminant autoimmune hepatitis is not quantifiable. Is the greater error to avoid treatment in patients who might respond but otherwise die or to introduce therapy to patients who will not improve and may worsen? Until there are more reliable indices of prognosis than are currently available, the former error appears greater. Accordingly, corticosteroid therapy remains appropriate for severe, immediately life-threatening and fulminant autoimmune hepatitis, but the dictum must limit the treatment to 2 weeks or less, and the implications of the Model for End-Stage Liver Disease score must be heeded.