0002-9270/89/8406-0596
THt

Vol. 84, No. 6. 1989
Printed in U.S.A.

AMiiRiCAN JOURNAL OP GASTROENTEROLOGY

Copyright © 1989 by Am. Coll. of Gastroenterology

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

INTRODUCTION

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 levels fluctuated during interferon therapy, serum aminotransferase levels reached normal range after discontinuation 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 posttransfusion non-A, non-B chronic active hepatitis, and
it might hecome an effective therapy for posttransfusion
non-A, non-B acute hepatitis.

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 Hoofnagle et al. (14) and Thompson et al. (15) treated
chronic non-A. non-B hepatitis with recombinant human ft-interferon and human lymphoblastoid «-interferon. which have been reported to have beneficial
effects on chronic hepatitis B and h hepatitis (16-20),

and they demonstrated that interferon therapy is effective 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 posttransfusion 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

Received Nov. IS, 1988; revised Jan. 31. 1989; accepted Feb. 3.
1989.

596

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 obtained from each patient. All 11 patients had a history
of development of hepatic dysfunction following blood


,3-INTERFERON AND NON-A, NON-B HEPATITIS

June 1989


transfusion related surgery. The incubation period from
blood transfusion to development of hepatic dysfunction 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 elevations 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 antigen, 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, Japan) 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 bridging necrosis. In one patient with acute hepatitis, liver

biopsy was performed again 1 yr after the 4-wk treatment. Histology of the liver was evaluated by the pathologist (Dr. Wada K, Department of Pathology.
Chiba University), who was blinded as to which speci-

-6 - S - 4 - 3 - J - 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.

597

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 hepatitis. 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 reelevated within 3 wk after discontinuation of therapy,
returned again to the normal range 4 months later
without any treatment, and remained within the normal 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 discontinuation 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 posttransfusion 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 specimen 1 yr after interferon therapy revealed normal
histology in a patient with posttransfusion non-A, nonB acute hepatitis.
DISCUSSION
Non-A, non-B hepatitis has marked propensity to
progress to chronic liver disease. In more than 50% of


598

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 aminotransferase levels for more than a year (2-4). Some nonA, non-B hepatitis cases progress to chronic hepatitis
or liver cirrhosis and eventually may develop hepatocellular carcinoma (1. 6-12), and there has been no
effective therapy for non-A. non-B hepatitis (13). Recently, two groups (14, 15) demonstrated that recombinant 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. Thompson et al. (15) treated three hypogammaglobulinemic
patients with non-A, non-B chronic hepatitis, who acquired their disease from plasma or intravenous immunoglobulin therapy, using human lymphoblastoid
«-interferon three times weekly, and all showed a striking 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 nonA, 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 aminotransferase activity in all five patients with posttransfusion
non-A, non-B chronic active hepatitis treated with Pinterferon, 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 histology in two of four patients with chronic active hepatitis examined, which provided further evidence that
,3-interferon has an effect on the disease. However,
stopping the /3-interferon therapy after 4 wk of treatment 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 posttransfusion non-A. non-B chronic active hepatitis.


fimc 19H9

/3-INTERFERON AND NON-A. NON-B HFPATITIS

599

A


B

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.

The present results obtained in patients with posttransfusion non-A, non-B acute hepatitis were encouraging. Initiation of ,3-interferon treatment was followed
by a prompt and marked decrease in serum aminotransferase 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 aminotransferase levels remained within the normal range
during the subsequent 12 months in four of these five
patients with posttransfusion non-A, non-B acute hepatitis. Even in a patient in whom serum aminotransferase levels re-elevated after discontinuation of therapy, elevated serum aminotransferase level returned
gradually to the normal range and remained within the
normal range during the subsequent 7 months. In another patient in whom serum aminotransferase levels
fluctuated during interferon therapy, serum aminotransferase levels reached the normal range after dis-

B

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 inflammatory-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.

TABLE 1

Effect of ^-lnterferon Therapy on Hepatic Histology in
Posttransfusion Non-A. Non-B Acute and Chronic Hepatitis Patients
Group
Acule hepatitis (n = 4)
Before therapy
After therapy
Chronic hepatitis (n = 4)
Before therapy
After therapy

Parenchymal
Portal
Hepatic
Inflammation
Inflammation Fibrosis
and Necrosis
1.9 ± 0.9
0.8 ± 0.9

1.8 ± 1.0
0.9 ± 0.3

1.6 ± 0.5
1.1 ±0.3

2.3 + 0.5
1.8 ±0.5


0
0
1.5
1.5

± 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 normal range during the subsequent 12 months. Biopsy
specimens obtained immediately after 4 wk of interferon therapy showed improvement in hepatic histology
in three of four patients with posttransfusion non-A,


600

Vol.84, No. 6, 1989

OHNISHI et al.

non-B acute hepatitis. Biopsy specimens 1 yr after
discontinuation of 4 wk of interferon therapy showed
normal hepatic histology in one patient with posttransfusion 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 present 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.

REFERENCES
1. Alter HJ. Hoofnagle JH. Non-A. non-B: Observations on the first
decade. In: Vyas GN. Dienstag JL, Hoofnagle JH. eds. Viral
hepatitis and liver disease. Orlando. FL: Grune & Stratton.
1984:345-54.
2. Aach RD. Szmuness W. Mosley JM, et al. Serum alanine aminotransferase of donors In relation to the risk of non-A, non-B
hepatitis in recipients: The transfusion-transmitted viruses study.
N EnglJ Med 1981:304:989-94.
3. Alter HJ, Purcell RH. Holland PV, et al. Donor transaminase
and recipient hepatitis: Impact on blood transfusion services.
JAMA 198l;246:630-4.
4. Seeff LB. Wright EC, Zimmerman HJ, et al. Post-transfusion
hepatitis 1973-1975: A Veterans Administration cooperative
study. In: Vyas GN, Cohen SN, Schmid R, eds. Viral hepatitis:
A contemporary assessment of etiology, epidemiology, pathogenesis, and prevention. Philadelphia: Franklin Institute Press.
1978:371-81.
5. Alter MJ, Gerety RJ. Smallwood LA, et al. Sporadic non-A. nonB hepatitis: Frequency and epidemiology in an urban U.S. population. J Infect Dis 1982;145:886-93.
6. Bemian M. Alter HJ, Ishak KG. et al. The chronic sequelae of
non-A. non-B hepatitis. Ann Intern Med 1979;91:l-6.
7. Koretz RL, Stone O. Gitnick GL. The long-term course of nonA. non-B post-transfusion hepatitis. Gastroenterology 1980;
79:893-8.
8. Realdi G. AJberti A, Rugge M. et al. Long-term follow-up of
acute and chronic non-A, non-B post-transfusion hepatitis: Evidence of progression to liver cirrhosis. Gut 1982.23:270-5.
9. Resnick RH. Stone K. Antonioli D. Primary hepatocellular

carcinoma following non-A, non-B post-transfusion hepatitis.
Dig Dis Sci 1983;28:908-l 1.
10. Kiyosawa K, Akahane Y, Nagata A, et al. Hepatocellular carci-

11.

12.
13.

14.
15.
16.

17.
18.

19.
20.
21.
22.
23.
24.
25.
26.

noma after non-A. non-B posttransfusion hepatitis. Am J Gastroenterol 1984:79:777-81.
Iwama S, Ohnishi K. Nakajima Y. et al. A clinical study of
hepatocellular carcinoma (HCC) in relation to hepatitis B seromarkers: Implications of non-A. non-B hepatitis (NANB).
Hepatology t982-.2:l 17 (abstract).
Gilliam J, Geisinger KR. Richter JE. Primary hepatocellular

carcinoma after non-A. non-B posttransfusion hepatitis. Ann
Intern Med 1984;IOi:794-5.
Shih JW, Esterban Mur JI. Alter HJ. Non-A, non-B hepatitis:
Advances and unfulfilled expectations of the first decade. In:
Popper H, Schaffner F. eds. Progress in liver diseases, vol. 8.
Orlando, FL: Grune & Stratton. 1986:433-52.
Hoofnagle JH, Mullen KD. Jones DB. etal. Treatment of chronic
non-A, non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med 1986:315:1575-8.
Thomson BJ, Doran M. Lever AML, et al. Alpha-interferon
therapy for non-A. non-B hepatitis transmitted by gammaglobulin replacement therapy. Lancet 1987:1:539-41.
Scullard GH. Pollard RB. Smith JL. et al. Antiviral treatment of
chronic hepatitis B virus infection, 1. Changes in viral markers
with interferon combined with adenine arabinoside. J Infect Dis
1981; 143:772-83.
Dusheiko G. Dibisceglie A. Bowyer S, et al. Recombinant leukocyte interferon treatment of chronic hepatitis B. Hepatology
1985:5:556-60.
Peters M. Davis GL, Dooley JS, et al. The interferon system in
acute and chronic hepatitis. In: Popper H. Schaffner F, eds.
Progress in liver disease, vol. 8. Orlando, FL: Grune & Stratton,
1986:453-67.
Sherlock S, Thomas HC. Treatment of chronic hepatitis due to
hepatitisB virus. Lancet 1985:2:1343-6.
Hoofnagle JH, Smedile A, Mullen KD, et al. Treatment of
chronic delta hepatitis with recombinant human alpha interferon.
Gastroenterology !985;88:I665 (abstract).
lchida B. Kawaguchi H. Saito S. et al. Effects of human lymphoblastoid alpha interferon on chronic hepatitis B. Kan-Tan-Sui
1987.14:655-68 (in Japanese).
Suzuki H, lchida B, Fujisawa R, et al. Human fibroblast beta
interferon treatment of chronic hepatitis B with HBe antigen.
Kan-Tan-Sui 1984:9:611-31 (in Japanese).

Hoofnagle JH, Feinstone SM. Serologic tests for non-A, non-B
hepatitis controversy. Liver 1981:1:177-82.
Dienstag JL. Non-A. non-B hepatitis. I. Recognition, epidemiology, and chnical features. Gastroenterology 1983:85:439-62.
Dienstag JL. Non-A, non-B hepatitis, ll. Experimental transmission, putative virus agents and markers, and prevention. Gastroenterology 1983;85:743-68.
Vallbracht A, Flehmig B. Elimination of a persistent hepatitis A
infection in cell cultures by infection. In: Kircbner H. Schellekens
H. eds. The biology of the interferon system 1984. New York:
Elsevier. 1985:339-45.