Initiation of interferon therapy was followed hy a prompt and marked decrease in serum aminotransferase activity in five patients with chronic active hepatitis and five patients with acu
Trang 1THt AMiiRiCAN JOURNAL OP GASTROENTEROLOGY
Copyright © 1989 by Am Coll of Gastroenterology
Vol 84, No 6 1989 Printed in U.S.A.
Original contributions
Treatment of Posttransfusion Non-A, Non-B Acute and
Chronic Hepatitis with Human Fihrohlast i^-Interferon:
A Preliminary Report
Kunihiko Ohnishi, M.D., Fumio Nomura, M.D., and Shinji lida, M.D.
First Department of Medicine, Chiba University School of Medicine Chiha, Japan
We treated five patients with posttransfusion non-A,
non-B chronic active hepatitis and six patients with
posttransfusion non-A, non-B acute hepatitis with 3
million units of human Tihroblast ^-interferon three
times weekly for 4 wk Initiation of interferon therapy
was followed hy a prompt and marked decrease in serum
aminotransferase activity in five patients with chronic
active hepatitis and five patients with acute hepatitis;
the exception was one patient with acute hepatitis in
whom serum aminotransferase levels fluctuated during
treatment Biopsy specimens ohtained immediately
after therapy showed improvement in hepatic histology
in two of four patients with chronic active hepatitis and
three of four patients with acute hepatitis Cessation of
interferon therapy was followed hy a prompt increase
in serum aminotransferase levels in five patients with
chronic active hepatitis and in one patient with acute
hepatitis, although re-elevated serum aminotransferase
levels returned gradually to the normal range in the
patient with acute hepatitis, hut did not do so in five
patients with chronic active hepatitis In another patient
with acute hepatitis whose serum aminotransferase
lev-els fluctuated during interferon therapy, serum
amino-transferase levels reached normal range after
discontin-uation of therapy At 6 months and 12 months after
discontinuation of interferon therapy, all five patients
with chronic active hepatitis showed elevated serum
aminotransferase levels, and all six patients with acute
hepatitis showed normal serum aminotransferase levels.
These results suggest that short-term and low doses of
/3-interferon therapy has an only temporal effect on
controlling the disease activity in patients with
post-transfusion non-A, non-B chronic active hepatitis, and
it might hecome an effective therapy for posttransfusion
non-A, non-B acute hepatitis.
Received Nov IS, 1988; revised Jan 31 1989; accepted Feb 3.
1989.
INTRODUCTION Non-A, non-B hepatitis accounts for most cases of posttransfusion hepatitis, and it accounts for one-third
of sporadic hepatitis (1-5) Non-A, non-B hepatitis has
a marked propensity lo progress to chronic liver disease (2-4) Some non-A non-B hepatitis cases progress to liver cirrhosis (1, 6-8) and hepatocellular carcinoma (9-12) There had been no effective therapy for non-A, non-B acute and chronic hepatitis (13) Recently
Hoof-nagle et al (14) and Thompson et al (15) treated
chronic non-A non-B hepatitis with recombinant hu-man ft-interferon and huhu-man lymphoblastoid «-inter-feron which have been reported to have beneficial
effects on chronic hepatitis B and h hepatitis (16-20),
and they demonstrated that interferon therapy is effec-tive in lowering elevated serum aminotransferase levels
to normal or nearly normal range in some patients with non-A non-B chronic hepatitis Therefore, in the present study, we treated six patients with posttransfu-sion non-A non-B acute hepatitis and five patients with posttransfusion non-A non-B chronic hepatitis with human fibroblast /3-interferon, which has been reported (21 22) to inhibit replication of hepatitis B virus, to determine whether interferon therapy can control the disease activity or the elevated serum aminotransferase levels
PATIENTS AND METHODS
Patients
Six patients with posttransfusion non-A, non-B acute hepatitis (age: 19-54 yr, two males, four females) and five patients with posttransfusion non-A non-B chronic hepatitis (age: 42 to 60 yr, four males, one female) were included in this study after informed consent was ob-tained from each patient All 11 patients had a history
of development of hepatic dysfunction following blood
596
Trang 2June 1989 ,3-INTERFERON AND NON-A, NON-B HEPATITIS 597 transfusion related surgery The incubation period from
blood transfusion to development of hepatic
dysfunc-tion ranged from 15 days to 92 days in patients with
acute hepatitis and 30 days to 90 days in patients with
chronic hepatitis None suffered from alcoholism or
other obvious disorders that could have caused liver
disease Patients with chronic hepatitis had shown
ele-vations in serum alanine and asparate aminotransferase
levels for more than 12 months (range: 12-30 months)
Furthermore, their serum aminotransferase levels had
been consistently higher than twice the upper limit of
the normal range throughout the previous 6 months
(Fig 1) Serum samples of all 11 patients were negative
for IgM hepatitis A antibody, hepatitis B surface
anti-gen, and for antinuclear, mitochondrial, and smooth
muscle antibodies, and for rheumatoid factor One
patient had stable levels of antibodies to hepatitis B
surface and core antigens, and the other two patients
had a stable and low level of antibody to hepatitis B
core antigen Liver biopsies performed just prior to
treatment showed aeute viral hepatitis in six patients,
chronic active hepatitis without bridging necrosis in
four patients, and chronic active hepatitis with bridging
necrosis in one patient
Jnterferon therapy
Treatment consisted of drip infusion of 500 ml of
saline containing 3 million units of human fibroblast
)3-interferon (Daiichi Pharmaceutical Co., Tokyo,
Ja-pan) three times weekly for 4 wk during hospitalization
and then it was stopped Liver biopsy was performed
again immediately after 4 wk of treatment in four
patients with acute hepatitis, in three patients with
chronic active hepatitis without bridging necrosis, and
in one patient with chronic active hepatitis with
bridg-ing necrosis In one patient with acute hepatitis, liver
biopsy was performed again 1 yr after the 4-wk
treat-ment Histology of the liver was evaluated by the
pa-thologist (Dr Wada K, Department of Pathology
Chiba University), who was blinded as to which
speci 6 speci S speci 4 speci 3 speci J speci I 0 I 2 3 < J 3 4 S 6 7 B 9 10 11 12
FTG I Serial determinations of alanine aminotransferase
levels in five patients with posttransfusion non-A, non-B chronic
active hepatitis treated with 3 million units of human fibroblast
&-interferon three times weekly for 4 wk.
mens were pretreatment and which were posttreatment, for infiammatory cell infiltration and necrosis in the parenchyma, infiltrate in the portal tract, and fibrosis These features were graded on a 0-2 scale Results were given mean ± SD Comparisons were made by the Student's paired / test
RESULTS
Ejfect of interferon therapy on serum aminotransferase levels
Serum aminotransferase levels began to decrease within I wk of the start of interferon therapy in all five patients with posttransfusion non-A, non-B chronic active hepatitis, and they dropped to the normal range
in three patients However, serum aminotransferase levels returned to the pretreatment values within I month after discontinuation of therapy and remained elevated during the subsequent 12 months (Fig I)
As in patients with chronic active hepatitis, interferon therapy was associated with a marked and sustained decrease in serum aminotransferase levels in five of six patients with posttransfusion non-A, non-B acute hep-atitis In these five patients, serum aminotransferase levels dropped to the normal range, and in four of these five patients they remained within the normal range
during the subsequent 12 months (Fig 2, A-D) In one
of these five patients, serum aminotransferase levels re-elevated within 3 wk after discontinuation of therapy, returned again to the normal range 4 months later without any treatment, and remained within the
nor-mal range during the subsequent 7 months (Fig IE).
In the remaining patient with posttransfusion non-A, non-B acute hepatitis, serum aminotransferase levels dropped to the normal range immediately after discon-tinuation of therapy and remained within the normal
range during the subsequent 12 months (Fig 2F).
Effect of interferon therapy on hepatic histology
Liver biopsy specimens just after interferon therapy revealed improvement in the degree of intralobular and portal infiammation and disappearance of parenchymal hepatocytic necrosis in three of four patients with post-transfusion non-A, non-B acute hepatitis and two of four patients with posttransfusion non-A, non-B
chronic active hepatitis (Fig 3, A and B, and Fig 4, A and B) However, the degree of hepatic fibrosis did not
change in patients with chronic active hepatitis even after interferon therapy (Table I) Liver biopsy speci-men 1 yr after interferon therapy revealed normal histology in a patient with posttransfusion A,
non-B acute hepatitis
DISCUSSION Non-A, non-B hepatitis has marked propensity to progress to chronic liver disease In more than 50% of
Trang 3598 OHNISHI et al Vol 84 No 6 1989
M,S 1V5 Mat.
FlCi, 2 A-F, Serial determination of alanine aminotransferase {.iLT) and asparate aminotransferase {AST) levels in six patients with
posttransfusion non-A, non-B acute hepatitis treated with 3 million units of human fibroblast /:J-interferon three times weekly for 4 wk.
cases of posttransfusion non-A, non-B acute hepatitis,
patients continue to show elevations in serum
amino-transferase levels for more than a year (2-4) Some
non-A, non-B hepatitis cases progress to chronic hepatitis
or liver cirrhosis and eventually may develop
hepato-cellular carcinoma (1 6-12), and there has been no
effective therapy for non-A non-B hepatitis (13)
Re-cently, two groups (14, 15) demonstrated that
recom-binant human «-interferon and human lymphoblastoid
a-interferon are effective in lowering elevated serum
aminotransferase levels to the normal or nearly normal
range in some patients with non-A, non-B chronic
hepatitis Hoofnagle et al (14) treated 10 patients with
well-documented non-A, non-B chronic hepatitis using
recombinant a-interferon daily at an initial dose of 5
million units, which has already been shown to inhibit
replication of several human hepatitis viruses, including
hepatitis A virus (in cell cultures) (26), hepatitis B vims
(16-19), and the hepatitis delta agent (20) In eight of
the 10 patients, elevated serum aminotransferase levels
decreased rapidly during therapy and eventually
dropped to the normal or nearly normal range
Thomp-son et al (15) treated three hypogammaglobulinemic
patients with non-A, non-B chronic hepatitis, who
ac-quired their disease from plasma or intravenous
im-munoglobulin therapy, using human lymphoblastoid
«-interferon three times weekly, and all showed a
strik-ing improvement in serum aminotransferases after the
start of each course of treatment These two reports
encouraged us to conduct a pilot study of short-term and low doses of/3-interferon for posttransfusion
non-A, non-B acute hepatitis, as well as for posttransfusion non-A, non-B chronic hepatitis Dose of /3-interferon (3 million units) and term (three times weekly for 4 wk) were based on /U-interferon treatment method, which has t>een reported to be efTective in suppression of B hepatitis viral replication (21, 22), considering the cost and beneftt of /^-interferon therapy In the present study, initiation of interferon treatment was followed
by a prompt and marked decrease in serum aminotrans-ferase activity in all five patients with posttransfusion
non-A, non-B chronic active hepatitis treated with P-interferon, which matches the reports by Hoofnagle et
al (14) and by Thompson et al (15) and provided
evidence that interferon had an effect on the disease Biopsy specimens obtained immediately after 4 wk of interferon therapy sbowed improvement in hepatic his-tology in two of four patients with chronic active hep-atitis examined, which provided further evidence that ,3-interferon has an effect on the disease However, stopping the /3-interferon therapy after 4 wk of treat-ment was followed by a prompt increase in seruni aminotransferase levels to the pretreatment values in all five patients with chronic active hepatitis treated These findings suggest that short-term and low doses of /^-interferon therapy have only a temporal effect on controlling the disease activity in patients with post-transfusion non-A non-B chronic active hepatitis
Trang 4fimc 19H9 /3-INTERFERON AND NON-A NON-B HFPATITIS 599
A
FIG 3 Liver biopsy specimens before (.4) and just after 4 wk of
(S-interfcron therapy (B) in a patient with chronic active hepatitis
(T.N.) Inflammatory' cell infiltration of the portal tract (P) was
marked before therapy (-•I), and it became less after therapy (B).
Serum aminotransferase levels before and after therapy are shown in
Figure I.
FK; 4 Liver biopsy specimens before (.•)) and immediately after
4 wk of ^-interferon therapy (S) in a patient with posttransfusion
non-A non-B acute hepatitis (S.N.) A there is moderate inflamma-tory-cell infiltration of the portal tract (P) and of the intralobuiar area B there is only slight inflammatory-cell infiltration ofthe portal trad (P) and of the intralobular area.
The present results obtained in patients with
post-transfusion non-A, non-B acute hepatitis were
encour-aging Initiation of ,3-interferon treatment was followed
by a prompt and marked decrease in serum
aminotrans-ferase activity in five of six patients with posttransfusion
non-A, non-B acute hepatitis treated with /3-interferon
as in patients with posttransfusion non-A non-B
chronic active hepatitis Differing from patients with
posttransfusion non-A, non-B chronic active hepatitis,
re-elevation of serum aminotransferase levels was not
seen after discontinuation of therapy, and serum
ami-notransferase levels remained within the normal range
during the subsequent 12 months in four of these five
patients with posttransfusion non-A, non-B acute
hep-atitis Even in a patient in whom serum
aminotrans-ferase levels re-elevated after discontinuation of
ther-apy, elevated serum aminotransferase level returned
gradually to the normal range and remained within the
normal range during the subsequent 7 months In
an-other patient in whom serum aminotransferase levels
fluctuated during interferon therapy, serum
amino-transferase levels reached the normal range after
dis-TABLE 1
Effect of ^-lnterferon Therapy on Hepatic Histology in Posttransfusion Non-A Non-B Acute and Chronic Hepatitis Patients
Group
Parenchymal Inflammation and Necrosis
Portal Inflammation
Hepatic Fibrosis Acule hepatitis (n = 4)
Before therapy After therapy Chronic hepatitis (n = 4) Before therapy After therapy
1
0
1 1
.9 ± 0.9 8 ± 0.9 6 ± 0.5 1 ±0.3
1.8 ± 1.0 0.9 ± 0.3 2.3 + 0.5 1.8 ±0.5
1.5 1.5
0 0
±
±
0.6 0.6
Values are mean ± SD There was tendency to improve in hepatic histology after therapy among patients with acute hepatitis and those with chronic hepatitis, although differences between each pair were not statistically significant probably because of a few number in each group.
continuation of therapy and remained within the nor-mal range during the subsequent 12 months Biopsy specimens obtained immediately after 4 wk of inter-feron therapy showed improvement in hepatic histology
in three of four patients with posttransfusion non-A,
Trang 5600 OHNISHI et al Vol.84, No 6, 1989
non-B acute hepatitis Biopsy specimens 1 yr after
discontinuation of 4 wk of interferon therapy showed
normal hepatic histology in one patient with
posttrans-fusion non-A, non-B acute hepatitis These results seem
to suggest that short-term and low doses of/?-interferon
therapy can become a promising and effective therapy
for posttransfusion non-A, non-B acute hepatitis A
controlled trial is in order to analyze whether the
pre-sent therapy prevents progression to chronicity
Reprint requests: Kunihiko Ohnishi, M.D., First Department of
Medicine, Chiba University School of Medicine 1-8-1 Inohana.
Chiba 280, Japan.
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