Long-term Treatment Outcomes for Autoimmune Hepatitis in Korea

Autoimmune hepatitis is a chronic inflammatory disease of the liver characterized by increased transaminase levels, hypergammaglobulinemia, presence of circulating autoantibodies and interface hepatitis on liver biopsy (1, 2). The pathogenesis of autoimmune hepatitis is postulated to be an aberrant autoreactivity to liver cells in genetically predisposed individuals (2). In untreated autoimmune hepatitis, the mortality rates have been reported to be as high as 80% (3). Prednisolone alone or in combination with azathioprine is the standard treatment for autoimmune hepatitis, and this treatment improves clinical, biochemical and histological features and prolongs survival (4). Autoimmune hepatitis is a relatively common disease in Western countries and its clinical features and prognosis are mostly described in Caucasians. Ethnicity may affect disease severity and presentation (5, 6), but the result of immunosuppressive treatment in Asian countries is not well known and has not been reported in Korea. Although relapse after withdrawal of immunosuppressive therapy is a common and challenging problem (7), there have been no reports describing the clinical course of autoimmune hepatitis after cessation of therapy in Korea.

We examined the clinical manifestations of 86 patients treated with immunosuppressive therapy. Here, we describe the long-term clinical outcome and prognosis of autoimmune hepatitis in Koreans.

Autoimmune hepatitis is a common disease in Western countries, with a prevalence of 8 to 19 per 100,000 and an incidence of 0.6 to 1.9 per 100,000 (9). The prevalence of autoimmune hepatitis shows geographical variation with higher prevalence in Caucasian populations: Australia 62%, Germany 34%, USA 11-23%, Brazil 5-10% and Hong Kong 1% of all cases of chronic active hepatitis (9, 10). Autoimmune hepatitis is a relatively uncommon disease in Asian countries such as Japan, Hong Kong and Korea (9, 10). Hence, the clinical features of autoimmune hepatitis including response to therapy and prognosis after treatment are well studied in Caucasians. In Korea, the frequency is estimated to be less than 1% of chronic hepatitis cases and below 5% in non-B and non-C hepatitis cases (11). This is the first study to assess the clinical features, response to therapy and long-term prognosis in a large series of Korean patients with autoimmune hepatitis.

We were able to identify several differences in clinical features between our data and the Caucasian data reported in the literature. In our series, the mean age was 51 yr, the age distribution showed a peak incidence at middle age and there were only a few young patients. These findings are similar to those from a Japanese series and are different from those from a Caucasian series where the peak age was in the 4th decade. The observed differences between Caucasian and Asian data may be explained by the lower frequency of HLA-DR3 in Asian patients, which is reported to affect the early onset of disease (6, 12). Cirrhosis was present at accession in only 13% of our patients, which is less frequent than in previous Western studies that reported cirrhosis in 85% of African American patients and 38% in Caucasian American patients (13). These differences in clinical features may be explained in part by genetic differences between Asian and Caucasian populations. In Caucasians, type 1 autoimmune hepatitis is associated with human leukocyte antigen (HLA) serotype B1, B8, DR3 and DR4 (5, 6, 12). In contrast, a recent Korean study reported that type 1 autoimmune hepatitis is associated with HLA DRB1*0405, which is very similar to findings in previous Japanese reports (14, 15). We were not able to include the HLA data in this present study since HLA typing is not routinely performed in our clinics. Other clinical parameters such as the male to female ratio, degree of liver function test abnormality, detection rate of autoantibody and rate of concurrent autoimmune disease were similar to those reported in Western studies and those reported in another small series in Korea (11, 16).

Previous studies have reported that prednisolone alone or in combination with azathioprine can induce a clinical, biochemical and histological remission in 65 to 85% of cases, depending on the definition of response (3, 4, 17). It has been reported that 90% of adults show improvements in serum aminotransferase, bilirubin and g-globulin levels within 2 weeks and rarely achieve remission in less than 12 months, with the probability of remission during therapy diminishing after 2 yr (4, 18). In our study, 73 (83.7%) patients achieved remission within 4 months (median 3.5 month, range 1 to 44 months), which is comparable to findings from recent Caucasian studies. Although a substantial percentage of patients achieved successful induction of remission, relapse after withdrawal of therapy remains a common problem (7, 19-21). The frequency of relapse was 50% at 6 months and 70% at 3 yr after cessation of the immunosuppressive treatment. Only 21% achieved sustained remission after drug withdrawal in a previous study (7). In our series, more than half of the patients (54%) relapsed within a median of 4 months (range 1-96 months) and the 1-yr and 2-yr relapse rates were 41.7% and 45.8%, respectively, after the withdrawal of immunosuppressive therapy, which is comparable to previous Western data. The sustained remission rate (45.8%) may seem to be slightly higher than that reported in previous studies due to a difference in the observation period after treatment withdrawal. Since the duration of follow-up in our patients with sustained remission was 28 months (range, 7 to 64 months), which is shorter than that of previous studies, there is a possibility that the sustained remission rate in this study may have been overestimated.

There have been several reports on factors that can predict the relapse of autoimmune hepatitis after withdrawal of immunosuppressive therapy. Patients who were treated to normal serum AST, γ-globulin or immunoglobulin G levels were reported to have a lower frequency of relapse following drug cessation than patients treated to near-normal levels, in spite of the disappearance of interface hepatitis after liver biopsy (22). The duration of treatment is a predicting factor of relapse: sustained remission after drug cessation is reported to be significantly more likely (67% probability) in patients who received a total duration of therapy of 4 yr (23). In our study, although we were not able to disclose any significant pretreatment clinical factor at presentation that could predict relapse after treatment withdrawal, higher levels of serum aminotransferases (ALT and AST) at the end of treatment was a predictor of relapse. However, this finding could not be clarified since the serum levels of AST and ALT were within the normal range in both groups, and because it is critical not to withdraw treatment until biochemical remission achieves complete normalization (20, 24, 25). Similar to previous studies, those patients who relapsed had a tendency to have higher (but not statistically significant) levels of γ-globulin and immunoglobulin G. Follow-up biopsies were obtained for 11 patients after medication withdrawal. Patients with sustained remission had a lower HAI score than those who relapsed. Five of six patients who showed complete resolution of interface hepatitis at follow-up biopsy maintained sustained remission. Ideally, immunosuppressive therapy should not be withdrawn without histological resolution, but treatment withdrawal was attempted in five patients without histological remission because they had received treatment for long periods (mean 74 months, range 38 to 113 months) with clinical and biochemical remission. As a result, all patients with residual interface hepatitis at follow-up biopsy relapsed. Overall, relapse (13 patients, 54.2%) appeared within a median of 4 months in our study in spite of biochemical remission. These findings suggest that histological remission, especially normalization of the necroinflammatory score, as well as clinical and biochemical remission, should be achieved before cessation of treatment.

Our results from follow-up biopsies demonstrate that histological improvement in both the necroinflammatory score and fibrosis grade were achieved after long-term immunosuppressive therapy. Two patients who had liver cirrhosis at initial biopsy experienced complete resolution of fibrosis to grade 0 after immunosuppressive therapy. This result is in concordance with previous studies which reported significant regression of fibrosis with steroid therapy (16, 23, 26). Also, none of our patients experienced histological progression after immunosuppressive therapy.

Of the six patients who experienced disease progression in our study, one patient developed HCC during the follow-up period. Although it has been known for a long time that HCC is rare in autoimmune hepatitis, several reports describing the association between HCC and autoimmune hepatitis have recently been published (27, 28). The prognosis of autoimmune hepatitis has been reported to be excellent in previous studies, with a 10-yr life expectancy among treated patients being greater than 90%, even in patients with cirrhosis at the accession of therapy (26, 29). The prognosis of autoimmune hepatitis in our study was comparable to those in previous studies with an estimated 10-yr survival of 96.2% and a 10-yr progression-free survival of over 85%, which suggests that autoimmune hepatitis can be well managed with immunosuppressive therapy without disease progression.

In conclusion, immunosuppressive therapy for autoimmune hepatitis results in a favorable rate of remission and excellent progression-free survival, but the relapse rate after treatment withdrawal was high in our study. This suggests that long-term immunosuppressive therapy may be particularly important for treatment of patients from Korean populations.