Long-term treatment outcomes for autoimmune hepatitis in Korea.

Abstract

Immunosuppressive therapy can improve clinical, biochemical and histological features and considerably prolong survival in patients with autoimmune hepatitis. Although ethnicity may affect disease severity and presentation, the long-term outcome of immunosuppression in Korean populations is unknown. This study was aimed to assess the efficacy of immunosuppressive therapy and determine the prognosis of autoimmune hepatitis in Korean populations. We reviewed the medical records of 86 patients diagnosed as having autoimmune hepatitis at the Samsung Medical Center between 1994 and 2008. Seventy-two (83.7%) patients reached remission after a median treatment duration of 3.5 months (range 1 to 44 months). Attempts to withdraw medications were made in 24 cases after the median treatment duration of 36 months (median 6 to 125 months). Thirteen of 24 (54.1%) patients relapsed after treatment withdrawal. Of the 86 patients, 6 (7.2%) experienced disease progression and the overall 5-and 10-yr progression-free survival rates were 91.2% and 85.5%, respectively. 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 is high. This suggests that long-term immunosuppressive therapy may be particularly important for treatment of Korean patients.

Full text

Page 1

INTRODUCTION
Autoimmune hepatitis is a chronic inflammatory disease
of the liver characterized by increased transaminase levels,
hypergammaglobulinemia, presence of circulating autoanti-
bodies and interface hepatitis on liver biopsy (1, 2). The patho-
genesis of autoimmune hepatitis is postulated to be an aber-
rant autoreactivity to liver cells in genetically predisposed
individuals (2). In untreated autoimmune hepatitis, the mor-
tality rates have been reported to be as high as 80% (3). Pred-
nisolone alone or in combination with azathioprine is the
standard treatment for autoimmune hepatitis, and this treat-
ment improves clinical, biochemical and histological features
and prolongs survival (4). Autoimmune hepatitis is a rela-
tively 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 coun-
tries 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.
MATERIALS AND METHODS
Patients
We retrospectively reviewed the medical records of 86 con-
secutive patients with autoimmune hepatitis who were treated
with immunosuppressive therapy between August 1994 and
January 2008 at the Samsung Medical Center, Seoul, Korea.
All patients were seronegative for hepatitis B surface antigen
and anti-hepatitis C virus (HCV). Patients who had excessive
alcohol consumption or exposure to a hepatotoxic drug or
herbal medication were excluded from the study. Based on
pretreatment features, all patients satisfied ‘‘probable’’ or ‘‘defi-
54
Jae Sook Kil, Joon Hyoek Lee,
A-Reum Han, Ja Young Kang,
Hye Jin Won, Han Young Jung,
Hyun Min Lim, Geum-Youn Gwak,
Moon Seok Choi, Kwang Cheol Koh,
Seung Woon Paik, and Byung Chul Yoo
Department of Medicine, Sungkyunkwan University
School of Medicine, Samsung Medical Center, Seoul,
Korea
Address for Correspondence
Joon Hyoek Lee, M.D.
Department of Medicine, Sungkyunkwan University
School of Medicine, Samsung Medical Center, 81
Irwon-ro, Gangnam-gu, Seoul 135-710, Korea
Tel : +82.2-3410-3409, Fax : +82.2-3410-6983
E-mail : liverjhlee@skku.edu
J Korean Med Sci 2010; 25: 54-60ISSN 1011-8934
DOI: 10.3346/jkms.2010.25.1.54
Long-term Treatment Outcomes for Autoimmune Hepatitis in Korea
Immunosuppressive therapy can improve clinical, biochemical and histological
features and considerably prolong survival in patients with autoimmune hepatitis.
Although ethnicity may affect disease severity and presentation, the long-term out-
come of immunosuppression in Korean populations is unknown. This study was
aimed to assess the efficacy of immunosuppressive therapy and determine the
prognosis of autoimmune hepatitis in Korean populations. We reviewed the medi-
cal records of 86 patients diagnosed as having autoimmune hepatitis at the Sam-
sung Medical Center between 1994 and 2008. Seventy-two (83.7%) patients reached
remission after a median treatment duration of 3.5 months (range 1 to 44 months).
Attempts to withdraw medications were made in 24 cases after the median treat-
ment duration of 36 months (median 6 to 125 months). Thirteen of 24 (54.1%) pati-
ents relapsed after treatment withdrawal. Of the 86 patients, 6 (7.2%) experienced
disease progression and the overall 5-and 10-yr progression-free survival rates were
91.2% and 85.5%, respectively. In conclusion, immunosuppressive therapy for auto-
immune hepatitis results in a favorable rate of remission and excellent progression-
free survival, but the relapse rate after treatment withdrawal is high. This suggests
that long-term immunosuppressive therapy may be particularly important for treat-
ment of Korean patients.
Key Words : Hepatitis, Autoimmune; Immunosuppression; Recurrence; Survival
ⓒ2010 The Korean Academy of Medical Sciences.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial
License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Received : 6 June 2009
Accepted : 8 October 2009

Page 2

Treatment Outcomes for Autoimmune Hepatitis 55
nite’’ criteria proposed by the International Autoimmune
Hepatitis Group (8). This study was examined the institu-
tional review board (IRB) of Samsung Medical Center and
was granted an exemption from IRB because it was retro-
spective study (IRB number 2009-09-121).
Definition
Remission was defined as follows: 1) disappearance of symp-
toms; 2) normal serum bilirubin and globulin levels; and 3)
decrease in serum aminotransferase levels to less than twice
normal. Treatment failure was defined as clinical or labora-
torydeterioration despite compliance with conventional ther-
apy, including the development of jaundice, ascites or hepatic
encephalopathy. Incomplete response was defined as some
or no improvement in clinical or laboratory findings during
therapy, but with no worsening in the condition. Failure to
achieve remission after 3 yr of treatment was included in this
definition. A relapse was indicated by an increase in the serum
aminotransferase level to more than three-fold the upper limit
of normal. The absence of symptoms and serum aspartate
transaminase (AST) levels less than three fold normal at least
6 months after drug withdrawal during the entire period of
observation constituted a sustained remission. Patients with
acute-onset liver dysfunction (serum aminotransferase levels
higher than ten-fold the upper normal limit and/or serum
bilirubin levels higher than five-fold the upper normal limit)
were diagnosed with acute presentation. Disease progression
was defined as the occurrence of any of the following: 1) pro-
gression to cirrhosis among chronic active hepatitis patients
or an increase of at least 2 points in the Child-Pugh score;
2) occurrence of esophageal and/or gastric variceal bleeding,
spontaneous bacterial peritonitis or hepatic encephalopathy;
3) death related to liver disease; or 4) occurrence of hepato-
cellular carcinoma (HCC).
Treatment
As an initial medical treatment, all patients received pred-
nisolone monotherapy (20-60 mg/day) or a combination ther-
apy of prednisolone (20-40 mg/day) and azathioprine (50 mg/
day). Most patients received combination treatment but those
patients with leukopenia and/or thrombocytopenia due to
liver cirrhosis and women in child-bearing age who wanted
pregnancy in a near future were treated with prednisolone
alone as the initial treatment. After the initial induction, the
dose of prednisolone was gradually tapered and then reduced
to the lowest dose necessary to maintain remission. Treatment
withdrawal was attempted in 24 patients (for 11 of 24 pati-
ents, withdrawal attempts occurred after follow-up liver biop-
sy) after a 2-yr remission period. The decision to withdraw
therapy was made by the attending physician on an individ-
ual basis based on either histological (disappearance of inter-
face hepatitis) or biochemical criteria. Liver function tests
were obtained every 1-3 months during induction of remis-
sion, at 3-6 month intervals during maintenance and every
1-3 months after discontinuation of treatment.
Histological examinations
Percutaneous needle biopsy of the liver was performed in 61
(70.9%) patients immediately before initial treatment. Fol-
low-up liver biopsies were performed in 21 patients to plan
the withdrawal of treatment, which was not essential. His-
tologicalscores were assessed in accordance with the Knodell
histology activity index (HAI).
Statistical analysis
All analysis was performed using the SPSS statistical pro-
gram (release 13.0, SPSS, Inc., Chicago, IL, USA). The Mann-
Whitney U test was used to compare the differences in con-
tinuous variables, and the chi-square test was used to com-
pare the dichotomous variables. A P value <0.05 was consid-
ered statistically significant. The progression free survival and
relapse rates were calculated and plotted using the Kaplan-
Meier method.
RESULTS
Patient characteristics
The clinical and laboratory findings of the 86 patients are
summarized in Table 1.
At presentation, the median age of the patients was 51 yr
(range 17 to 79 yr) and the peak incidence was between 40
and 50 yr. Seventy-two (83.7%) patients were women. The
median duration of follow-up was 43 months (range 1 to 152
months). All the patients met pretreatment criteria for the
diagnosis of definite (18 patients) or probable (68 patients)
autoimmune hepatitis. Eighty-three (96.5%) patients had
circulating antinuclear (ANA) and/or anti-smooth muscle
(SMA) autoantibodies. Three patients (3.4%) had both ANA
and anti-mitochondrial antibodies (AMA). The most com-
mon symptoms were jaundice (45.3%) and fatigue (16.2%),
but 32 patients (37.2%) were asymptomatic and had only an
abnormal liver function test. Twenty (23.2%) patients had
symptomatic concurrent autoimmune disease; the most fre-
quent disease being rheumatoid arthritis in 7 (8.1%) patients,
followed by thyroid disease in 6 (7.0%) patients.
Response to therapy
Twelve (14.0%) patients were treated with prednisolone
monotherapy (20-60 mg/day) and 74 (86.0%) were treated
with a combination of prednisolone (20-40 mg/day) and aza-
thioprine(50 mg/day). Seventy-two (83.7%) patients reached

Page 3

56J.S. Kil, J.H. Lee, A.-R. Han, et al.
remission after a median treatment duration of 3.5 months
(range 1 to 44 months). Eleven (12.8%) patients achieved
an incomplete response. Maintenance therapy with low dose
prednisolone and azathioprine was continued in all incom-
plete responders to reduce and stabilize disease activity. Of
these patients, 2 patients stopped medication during follow-
up and after aggravation of laboratory findings, treatment
had to be re-started. One patient died of sepsis during the
low dose immunosuppressive therapy. Three (3.5%) patients
met the criteria for treatment failure. Two of three patients
died of liver decompensation within 2 month despite of com-
pliance with therapy and one patient discharged the hospi-
tal hopelessly due to liver failure.
Outcomes after treatment withdrawal
In 24 (27.9%) of the 86 patients, immunosuppressive ther-
apy was discontinued after long-term remission (median 33
months, range 24 to 90 months). Eleven (45.8%) of these
patients maintained remission for a median of 28 months
(range 7 to 64 months). Thirteen patients (54.2%) experi-
enced a relapse within a median of 4 months (range 1.2 to 96
months) following termination of treatment (Fig. 1). The re-
lapse rates in the first and second year were 41.7% and 45.8%,
respectively (Fig. 2). Previous regimens were re-administered
Table 1. Baseline clinical characteristics of patients
Data are expressed as median (range) without specific notation.
IAHG, International Autoimmune Hepatitis Group; AST, aspartate transaminase; ALT, alanine aminotransferase; PT, prothrombin time; INR, international
normalized ration; ANA, antinuclear antibodies; SMA, smooth muscle antibodies; AMA, anti-mitochondrial antibodies.
Fig. 1. Induction of remission in autoimmune hepatitis patients after
immunosuppressive treatment (A) and after withdrawal of immuno-
suppressive treatment (B). The median duration of treatment was
36 months (6-125 months) and the median time to remission was
3.5 months (1-44 months). Treatment withdrawal was attempted
in 24 of 86 patients.
Relapse
13 (54.2%)
Remission
72 (83.7%)
Incomplete response
11 (12.8%)
Treatment
failure
3 (3.5%)
Sustained
remission
11 (45.8%)
A
B
Fig. 2. The Kaplan-Meier plot of relapse rate in patients with auto-
immune hepatitis. Thirteen patients (54.2%) experienced a relapse
within a median of 4 months (range 1.2 to 96 months) following
termination of treatment. The relapse rates in the first and second
year are 41.7% and 45.8%, respectively.
Relapse rate (%)
100
80
60
40
20
0
06
Follow-up (months) of 13 patients
1218 24 3036
● Time to relapse: 4 months (median, range 1.2-96 months)
● 1-yr relapse rate: 41.7%
2-yr relapse rate: 45.8%
Age (yr)
11-20, n
21-30, n
31-40, n
41-50, n
51-60, n
61-70, n
>70, n
Female/Male, n (%)
Duration follow up (months)
Pretreatment IAHG score
Definite/Probable, n (%)
Acute presentation, n (%)
AST (IU/L)
ALT (IU/L)
Total bilirubin (mg/dL)
Globulin (g/dL)
Immunoglobulin G (mg/dL)
51 (17-79)
2
5
7
25
23
17
7
72 (83.7)/14 (16.3)
43 (1-152)
13 (10-19)
18 (20.9)/68 (79.1)
31 (36.0)
243 (42-1,580)
182 (31-1,251)
2.3 (0.3-39)
4.2 (2.4-6.9)
2,380 (1,330-4,640)
PT (INR)
Cirrhosis at accession, n (%)
Autoantibodies, n (%)
ANA positive
SMA positive
AMA positive
Concurrent immune disease, n (%)
Symptom and sign, n (%)
Fatigue
Jaundice
Anorexia
Pruritus
Ascites
Others
Asymptomatic
Medication, n (%)
Prednisolone+azathioprine
Prednisolone only
1.17 (0.92-2.2)
11 (12.8)
83 (96.5)
70 (81.4)
38 (44.2)
3 (3.4)
20 (23.3)
14 (16.3)
39 (45.3)
3 (3.5)
2 (2.3)
4 (4.7)
5 (5.8)
32 (37.2)
74 (86.0)
12 (14.0)

Page 4

Treatment Outcomes for Autoimmune Hepatitis57
for the relapsers and all patients showed response to the sec-
ond therapy.
Factors associated with relapse
The clinical and laboratory features of patients with sus-
tained remission were compared to those of patients who
relapsed (Table 2, 3). The pretreatment clinical and labora-
tory findings revealed no statistical differences between the
two groups. Prior to drug termination, the duration of treat-
ment (median 28 months, range 21 to 90 months vs. median
34 months, range 10 to 65 months) and the time to remis-
sion (median 1 month, range 0.5 to 3 months vs. median 3
months, range 0.5 to 44 months) were statistically insignif-
icant between the two groups. Patients who relapsed after
treatment withdrawal had higher levels of AST and alanine
aminotransferase (ALT) at the end of treatment than those
who had sustained remission (P<0.05). Globulin and immu-
noglobulin G levels at the time of drug withdrawal were simi-
lar between the two groups. The Knodell HAI score after
follow-up biopsy was higher in the relapsed group (median
5, range 4 to 8 vs. median 1, range 0-3; P=0.004), and in
particular, the necroinflammatory score (median 3, range 2
to 7 vs. median 1, range 0-2; P=0.004) was higher in the
relapsed patients than in patients with sustained remission.
Of the 11 patients who discontinued treatment after follow-
up liver biopsy, interface hepatitis disappeared in six patients.
Of these patients, five maintained a sustained remission and
only one patient experienced a relapse after treatment with-
drawal. All five patients who had residual interface hepatitis
relapsed after discontinuation of therapy. Among the 13 pati-
ents who withdrew treatment without follow-up liver biop-
sy, six patients maintained sustained remission and seven
patients relapsed.
Histological findings
At presentation, the median HAI score according to the
Knodell scoring system was 13 (range 4 to 15), with a medi-
an necroinflammatory HAI score of 10 (range 3 to 12) and a
median fibrosis score of 3 (range 1 to 4). A diagnosis of liver
cirrhosis was confirmed in 11 (12.8%) patients. Follow-up
liver biopsy was obtained after a median of 26 months (range
24 to 126 months) of follow-up in 21 patients. At the follow-
up biopsy, the majority of patients showed histological im-
provement in terms of the necroinflammatory score (median
3, range 1 to 10) and fibrosis score (median 1, range 1 to 3)
(Table 4, Fig. 3).
Progression free survival
During the follow-up period (median 43 months, range
Data are expressed as median (range) without specific notation.
ALT, alanine aminotransferase; AST, aspartate transaminase; PT, pro-
thrombin time; INR, international normalized ration.
Factors
Sustained
remission (n=11)
Relapse
(n=13)
P value
Age (yr)
Globulin (g/dL)
ALT (IU/L)
AST (IU/L)
Total bilirubin (mg/dL)
PT (INR)
Immunoglobulin G
(mg/dL)
Duration of treatment
(months)
Time to remission
Pretreatment Knodell score 13 (10-17)
51 (23-75)
3.8 (2.4-5.3)
413 (94-928)
458 (88-1,267)
3.4 (0.6-28)
1.2 (0.69-1.75)
2,010
(1,330-2,830)
28 (21-90)
55 (23-67)
4.5 (3.1-6.1)
281 (33-802)
363 (50-1,580)
4.3 (0.5-26)
1.1 (0.94-1.57)
2,560
(1,860-3,660)
34 (10-65)
0.733
0.119
0.072
0.186
0.087
0.459
0.174
0.733
1 (0.5-3)3 (0.5-44)
14 (10-19)
0.207
0.459
Table 2. Comparison of features upon admission of patients who
maintained remission and patients who relapsed after treatment
withdrawal
Data are expressed as median (range) without specific notation.
ALT, alanine aminotransferase; AST, aspartate transaminase; PT, pro-
thrombin time; INR, international normalized ration.
Factors
Sustained
remission (n=11)
Relapse
(n=13)
P value
Table 3. Comparison of features at the end of therapy of patients
who sustained remission and patients who relapsed after treat-
ment withdrawal
Biopsy before
treatment
Follow-up
biopsy
Table 4. Liver histology before treatment and at follow-up biopsy
Data are expressed as median (range) without specific notation.
Histological findings
Globulin (g/dL)
ALT (IU/L)
AST (IU/L)
Total bilirubin (mg/dL)
PT (INR)
Immunoglobulin G (mg/dL)
2.8 (2.5-3.6)
13 (10-58)
21 (13-54)
0.6 (0.3-1.3)
1.03 (0.7-1.1)
1,250
(1,176-1,508)
2 (18.2)
5 (45.5)
1 (0-3)
1 (0-2)
0 (0-1)
3.05 (2.5-3.5)
25 (11-63)
33 (17-90)
0.8 (0.3-1.5)
1.03 (0.91-1.9) 0.494
1,380
(1,080-1,790)
3 (23.1)
6 (46.2)
5.5 (4-8)
3 (2-7)
1 (0-3)
0.379
0.013
0.015
0.207
0.648
Autoantibody positive, n (%)
Follow-up biopsy, n (%)
Knodell score
Necroinflammatory score
Fibrosis score
0.199
0.004
0.004
0.052
No. (%) of liver biopsy
Knodell score
Necroinflammation
Periportal inflammation
Interface hepatitis
Intralobular necrosis
Total score
Fibrosis
Cirrhosis (F4), n (%)
61 (70.9)
13 (4-15)
21 (24.4)
4 (0-11)
3 (1-4)
3 (1-4)
3 (0-4)
10 (3-12)
3 (1-4)
11 (12.8)
1 (0-4)
1 (0-3)
1 (0-3)
3 (0-10)
1 (1-3)
0 (0)

Page 5

58J.S. Kil, J.H. Lee, A.-R. Han, et al.
1-152 months), disease progression was noted in six patients.
The causes of disease progression included decompensated
liver cirrhosis (two patients), hepatocelluar carcinoma (one
patient) and liver-related death (three patients). The five-year
and 10-yr progression-free survivals were 91.2% and 85.5%,
respectively (Fig. 4). The overall 10-yr survival for the 86
patients was 96.2%.
DISCUSSION
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 prog-
nosis in a large series of Korean patients with autoimmune
hepatitis.
We were able to identify several differences in clinical fea-
tures between our data and the Caucasian data reported in the
literature. In our series, the mean age was 51 yr, the age dis-
tribution 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 West-
ern studies that reported cirrhosis in 85% of African Ameri-
can 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 popula-
tions. In Caucasians, type 1 autoimmune hepatitis is associ-
ated 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 pre-
vious 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 con-
current 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, bio-
chemical and histological remission in 65 to 85% of cases,
depending on the definition of response (3, 4, 17). It has been
Fig. 3. Changes in necroinflammatory (A) and fibrosis score (B) at follow-up biopsy. Follow-up liver biopsy was obtained after a median of
26 months (range 24 to 126 months) of follow-up in 21 patients. The necroinflammatory score improve from a median of 10 (range 3 to 12)
to 3 (range 1 to 10) and the fibrosis scores improve from 3 (median 1, range 1 to 3) to 1 (range 1 to 3).
HAI, histological activity score (according to knodell’s scoring system).
A
B
Initial biopsyFollow-up biopsy
HAI score
14
12
10
8
6
4
2
0
Initial biopsy Follow-up biopsy
HAI score
5
4
3
2
1
0
Fig. 4. The Kaplan-Meier plots of progression-free survival (PFS)
for patients with autoimmune hepatitis. The five-year and 10-yr pro-
gression-free survivals are 91.2% and 85.5%, respectively.
Survival rate (%)
100
80
60
40
20
0
06 12
Years (86 patients)
1824 30 36
5 yr PFS: 91.2%
10 yr PFS: 85.5%