Journalof Hepatology

Primedin Denmark

Munksgaani

1996; 25: 283-291
All rights

reserved

Copenhagen

Copyright 0 European Association
for the Studv of the Liver 1996.

Journalof Hepatology

ISSN 0168-8278

Side effects of high-dose interferon therapy forchronic hepatitis C
Takeshi Okanoue’, Shinichi Sakamoto’, Yoshito Itoh’, Masahito Minami’, Koichiro Yasui’,Masafumi Sakamoto’, Kenichi Nishioji’, Tatsuo Katagishi’, Yoshihiro Nakagawa2, Hisashi Tada’,
Yoshihiko Sawa3, Masayuki Mizuno4, Keizo Kagawa’ and Kei Kashima’‘Third Department of Internal Medicine, Kyoto Prefectural University of Medicine, Kyoto; ‘Depamnent of Medicine, Hoshigaoka-Kohseinenkin
Osaka; ‘Aiseikai-Yamashima Hospital, Kyoto and 4Yodogawa Christian Hospital, Osaka, Japan

Background/Aims: Various side effects have beenreported in patients treated with alpha interferon,but their incidence and prognosis remain
unknown.
Methods: Nine hundred and eighty-seven patientswith chronic active hepatitis C received 6 to 10 MU
of alpha interferon per day for 2 weeks and 3 times
per week for 22 weeks. Autoantibodies, thyroid
function tests, and fasting plasma glucose concentrations were evaluated prior to alpha interferon
therapy.
Results: Of the 987 patients, 310 were required reduction in the dose of alpha interferon to 3 MU/dayor cessation of alpha interferon therapy because ofadverse reactions such as flu-like symptoms, leukopenia, and thrombocytopenia. Of the remaining
677, five developed diabetes mellitus, 12 had
hyperthyroidism, and six acquired hypothyroidism. Of the 18 with thyroid disorders, fivedemonstrated antimicrosomal antibodies before
therapy. Forty-four patients revealed high or low

A effective in non-A, non-B hepatitis (l-3). The
LPHA INTEFWJZRONS(a1FN.s) have been shown to be

Japanese Ministry of Healthcare has approved the useof IFNs for patients with chronic active hepatitis C(CAH-C) since January 1992. Since then, more than
160000 patients with CAH-C have received IF!N

Received 8 August: revised 7 November: accepted 15 November 1995

Correspondence: Takeshi Okanoue M.D., Third Department of Internal Medicine, Kyoto Prefectural University of
Medicine,
Kawaramachi-Hirokoji
Kamigyo-ku,
Kyoto602, Japan. Tel. +75-251-5519. Fax. +75-251-0710.

Hospital,concentrations of thyroid stimulating hormone at
the end of alpha interferon therapy. Three patientsdeveloped interstitial pneumonia, one acquired
systemic lupus erythematosus-like syndrome, two
had autoimmune hepatitis, two developed rheumatoid arthritis, and one developed autoimmune
thrombocytopenic purpura. No patients had a history of an autoimmune disorder. One patient experienced sudden hearing impairment and one had
retinal detachment. Melena was seen in three patients; two of these cases were compatible withischemic colitis. Symptoms of depression were seenin 23 patients, and one patient manifested memory
loss.
Conclusion: High-dose alpha interferon therapy
induces various adverse effects. Most of the side effects cannot be predicted, but are reversible.
Key words: Chronic hepatitis C; Hearing impairment; Ischemic colitis; Retinal detachment; Side
effects of alpha interferon.

therapy for the past 3 years in Japan and many side
effects have been reported.
IFNs have a diverse biologic functions and act on
many cells and organs. Although the severity ofsymptoms is directly related to the dose and frequency of administration, remarkable individual variation has been observed. Flu-like symptoms such as
general malaise, fever, arthralgias and headaches, andthe laboratory findings of leukopenia and thrombocytopenia are early adverse effects of high-dose aIFN
administration. These adverse effects of IFN therapy
could be defined as side actions of IFN, as opposed toside effects. The most popular IFN therapy protocol
283

T. Okanoue et al.

for CAH-C in Japan consists of 6 to 10 MU/day for 2
weeks, followed by 6 to 10 MU/day 3 times/week for
22 weeks. Because the average height and weight ofpatients in Japan are lower than Western patients,
these doses of IFN for Japanese patients with chronic
hepatitis C are higher than those used in Westerncountries.
High-dose or long-term IFN administration ultimately results in the appearance of various kinds ofside effects (4-lo), such as psychological disturbances, interstitial pneumonia, thyroid disorders, diabetes mellitus, retinopathy, autoimmune diseases,
skin rash and loss of hair. It is important to evaluate
the incidence of side effects of aIFN therapy for
CAH-C.
In our 3-year experience of administering aIFN to987 patients CAH-C, we observed various kinds ofside effects, including melena and retinal detachment.
In this paper, we describe the incidence and thenature of side effects induced by high-dose aIFN
therapy.
Patients and Methods
From January 1992 to February 1995, 987 patientswith CAH-C were treated with alpha interferon at theThird Department of Internal Medicine in the Kyoto
Prefectural University of Medicine, the Departmentof Medicine in the Hoshigaoka-Kohseinenkin Hospital, the Department of Medicine in the AiseikaiYamashina Hospital and the Department of Medicine
in the Yodogawa Christian Hospital. Three hundred
and ten of the 987 patients with CAH-C required IFN
dose reduction to 3 MU/day or interruption of IFN
therapy because of adverse reactions such as flu-like
symptoms, leukopenia and thrombocytopenia during
therapy. Except for these 310 cases, 677 patientswere analyzed in this study.
Of the 677 patients, 343 patients were treated withlymphoblastoid IFN (nIFN, Sumiferon; Sumitomo
Pharmaceutical Company, Osaka, Japan, and OIF;
Otsuka Pharmaceutical
Company, Tokushima,
Japan), 224 patients were treated with recombinanthuman IFN a 2b (rIFN a 2b, Inn-on A; Schering
Plough Corporation, Kenilworth, NJ, USA) and 110
patients were treated with recombinant human IFN a
2a (rIFN a 2a, Roferon; Nippon Roche K. K., Tokyo,
Japan). Four hundred and five patients were men and272 were women. Their ages ranged from 19 to 70
years. The average ages were 45.1 years for men and46.9 years for women. These patients first received
IFN daily for 2 weeks while hospitalized and thenapproximately two-thirds of the patients were treatedby their primary physicians. All patients, except for a284

few, were followed-up monthly as outpatients in thefour participating hospitals.
All 677 patients demonstrated the presence of theanti-HCV antibody and the absence of HBsAg. Theirliver biopsy histologic findings were all compatible
with CAH. Prior to IFN therapy, all cases were tested
for the presence of antinuclear antibody (ANA; negative, ~1: 40 titer), anti-DNA antibody (negative<1:40 titer), thyroid-stimulating hormone (TSH; normal, 0.34-3.5 III/ml), thyroxine (T4; normal, 4.5-13.0
pg/dl), tri-iodothyronine (T3; normal, 0.8 1.8 @ml),
antithyroglobulin antibody (negative, < 1:100 titer),antimicrosomal antibody (negative, x1:100 titer), andfasting plasma glucose (FPG). FPG, T3, T4 and TSH
were checked after 2 and 4 months of therapy, and at
the end of the treatment. Serum samples wereobtained prior to the start of the therapy, after 2
weeks, 2 months and 4 months of therapy, and at thecompletion of IFN therapy.
The daily dose of nIFN a was 6 or 10 MU, Thedaily dose of rIFN a 2b and rIFN a 2a consisted of 6
to 10 MU and 6 to 9 MU, respectively. The protocolof this study called for a daily injection of IFN for 2
weeks and then 3 times weekly for 22 weeks.
All the patients in this study gave written informed
consent to participate in these trials and all aspects ofthese studies were approved by the Ethical Committees of the four participating hospitals.
Results
Of the 677 patients, 92 patients (13.6%) tested positive for ANA, 105 (15.5%) tested positive for antiDNA antibody, 8 (1.2%) tested positive for antithy-

TABLE 1
Change in the titer of autoantibodies during interferon therapy
Titer before

Titer after

Autoantibody

FN therapy

IFN therapy

ANA

1: 40 (84)*

1: 40
(53)
1: 80 (29)
1: 160 (2)1: 80 (5)

I: 80
1: 160
1: 320
1: 640

I:160 (3)

1: 160 (1)1: 640 (1)1: 1280 (1)1:40 (104)

1: 40
(76)
1: 80 (27)
1: 160 (1)1: 80 (1)

1: 160 (1)Anti-DNA* No. of patients

(2)
(1)
(1)
(1)

Side e@kts of high-dose interferon
TABLE 2
Side effects of high-dose interferon therapy in 677 patients withchronic active hepatitis C
Side effectNo. of cases

Onset

Hy~~hyroidism

12 (1.8%)*

Hypothyroidism

6 (0.9%)Diabetus mellitus

5 (0.7%)

Interstitial pneumonia
Autoimmune disorders

3 (0.4%)6 (0.9%)Intestinal bleeding
Psychological disorders
Cardiovascular disorders
Eruption with itching
Alopecia
Retinopathy***

3 (0.4%)24 (3.5%)5 (0.7%)86 (12.7%)
205 (30.3%)
2O-50%?

12-24 weeks(16.8 weeks) **12-24 weeks(17.7 weeks)
6-24 weeks(14.3 weeks)
4,5,23 weeks
5-20 weeks(14.7 weeks)
12,2O, 24 weeks
5 days-24 weeks
l-20 weeks
3 days-l 2 weeks
10-22 weeks* : Frequency of the side effect.
** : Average weeks of the onset.
***: The frequency reported by other Japanese doctors.

were men and 39 (39/272; 14.3%) were women, Of
the 105 patients who tested positive for anti-DNA
antibody, 63 (63/405; 15.6%) were men and 42 (42/272; 15.4%) were women. At the conclusion of IFN
therapy, 36 (36192; 39.1%) of the 92 patients showed
an elevation of the titer of ANA. Twenty-ninepatients (291105; 27.6%) showed an elevation of thetiter of anti-DNA antibody (Table 1). Of the eightpatients with antithyroglobulin antibody, six showed
an elevation of their titer upon completion of IFN
therapy. Of the 24 patients who tested positive for
antimicrosomal antibody, 22 patients developed anelevation of the titer of the antibody during or at conclusion of IFN therapy. Eleven patients had a FPG
greater than 110 mg/dl, and among them six patients
revealed a FPG over 140 mgldl before therapy. The
frequency of the side effects of IFN therapy observedin this study is shown in Table 2.
E~ducrinol~gicalroglobulin antibody and 24 (3.5%) tested positive for
antimicrosomal antibody before IFN therapy. Of the
92 patients positive for ANA, 53 (53/405; 13.1%)

disorders

Of the 671 patients with an FPG of less than 140 mgl
dl of FPG before entry into the study, five patientsdeveloped overt diabetes mellitus during IFN therapy.
Of the five patients, one patient had been followed up

TABLE 3Clinical features of 12 patients who developed hyperthyroidism during alpha interferon therapy
Patient
no.

Age

Sex

1

33

F

2

35

F

3

37

M

4

38

F

5

41

F

6

42

M

7

44

M

8

45

F

9

46

M

10

52

F

11

61

F

12

64

F

IFN dose(MU/day)rIFN a 2b
6MU
niFNa
6MU
rIFN a 2b
1OMU
nIFN a6MU
rIFN a 2a
9MU
nIFN a
6MU

nIFNa
6MU
rIFNa2b
10 MU
nIFN a6MU
nIFN a6MU
nIFN a6MU
rIFN a 2a
9MU

Duration of therapy Thyroid autoantibody
ATG
AMS(weeks)
r:

18

19
16
12
16
12
12
16
24
13
20
24

* : Data at the start of interferon therapy.
**: Data at the onset of hy~~h~oidism.
ATG: Antithyro~lobulin antibody. AMS: Anti-mic~somal

negative(negative)
negative(negative)
negative(negative)
negativef 1:400)
negative(negative)
negative(negative)
negative(nega~ve)
negative(negative)
negative(negative)
negative(negative)
negative(negative)
negative(negative)

negative*(1:1600)**
negative(negative)
negative(negative)
I :400(1:25600)
negative(negative)
negative(negative)
negative(nega~ve)
negative(negative)
negative(negative)
negative(I :6400)
negative(negative)
negative(negative)

T3(ng/ml)T4(pg/dl)TSH(N/ml)

1.3
(3.4)
1.2
(3.5)
1.4
(3.1)
1.3
(10.5)
1.3
(2.7)
1.1
(3.3)
1.7
(4.6)
1.4
(3.9)
1.6
(1.8)
1.5
(6.5)
1.1
(4.1)
1.6
(2.4)

9.5
(16.9)
9.2(17.6)
11.0(19.8)
3.5
(4.4)
9.7
(19.9)
6.9(18.0)
10.9(19.9)
9.8(17.2)
10.7(14.7)
8.9(25.0)
7.3(11.1)
12.9(18.2)

1.7”(0.03)**
2.1(0.02)
2.0(0.03)
1.3(0.02)
1.9(0.04)
1.9(0.01)
0.09(0.01)
0.97(0.03)
2.5(0.02)
2.3(0.01)
1.9(0.07)
1.6(0.10)

antibody.

285

T. Okmaue et at.
TABLE 4
Clinical features of six patients who developed hypothyroidism during alpha interferon therapy
Patient no. Age

Sex

i

46

F

2

49

M

3

56

F

4

56

F

5

62

F

6

67

M

IFN dose(MU/day)

Duration of
tberapy (weeks)Thyroid autoantibody
ATG
AMS

nIF% a6MU
nIFN a6MU
rIFN a2b
6MU
nIFN a6MU
nIFN a
6MU
nIFWa
6MU

24

negative(negative)
negative(negative)
negative(negative)
negative(negative)
negative(negative)
negative(negative)

12
2.
12
14

24

T3
(@ml)

*

~~~)**
negative(negative)
1:800(1:102400)
negative(negative)
1:1600(1:6400)
1:SOO
cl:204 800)

1.0
(0.2)
0.9
(O-5)
1.6
(3.3)
$)
1.4
(10)

T4
(mgfdl)TSH(IUltXil

7.9
(3.7)
4.1
(1.8)
9.2
(1.4)
8.1
(0.8)
1.0
(1.9)
9.2
(2.4)

2.1%
(14&o)**
2.9(78.0)

1.8(63.7)
3.5(19.4)
1.7(82.0)
3.5(87.4)* : Data at the start of interferon therapy.
**: Data at the onset of h~~~oi~srn.
ATG: Antithyroglobulin antibody.
AMS: Antimicrosomal antibody.

by her primary physici~ after she was ~sch~ed.
She developed mental status changes after 20 weeks
of IFN therapy. Her plasma glucose level was 719
mg/dl on hospitalization and nonketotic hyperosmolar coma was diagnosed. Currently, her FPG has been
well Connolly by diet therapy only. Of these fivepatients, three continued to receive IFN therapy until
the end of the protocol.
All five patients showed impaired glucose tolerance after their FPG levels recovered to pretreatment
levels.
Thyroid disorders
Hyperthyroidism developed in 12 patients, as shownin Table 3. Eight patients were women and 4 patientswere men. The onset of hyperthyroidism occurred
after 12 to 24 weeks of therapy. Of the 12 patients,
only one (Patient 4) had manifested antimicrosomal
antibody titers (1:400) prior to IFN therapy; this rose
to 1:25600 at 12 weeks of IFN therapy. Threepatients began to manifest antimicrosomal antibody
titers (1:1600, 1:400, 15400) at 18 and 13 weeks of
IFN therapy, respectively. Seven patients discontinued IFN therapy when they were diagnosed withhyperthyroidism. Of the seven patients, five received
propylthiouracil for 1 to 12 months and became
euthyroid after treatment.
Hy~~~oi~srn
developed in six patients (Table4). Four of the six patients tested positive for antimicrosomal antibody before therapy. The titer of antimicrosomal antibody in the four patients significantly
increased when they developed hypothyroidism. Of
the six patients, four ~scontinu~ IFN therapy and all286

six patients were treated with thyroxine for 4 to 18
months. Their thyroid function return& to normal.
Of the 18 patients who developed thyroid disorders,
12 received nIFN a, four were treated with rIFN a 2b
and two underwent rIFN a 2a therapy. No significant
differences in the development of thyroid disorders
among the patients who received these three kinds of
IFN therapy were observed.
Except for the 18 patients who developed thyroid
disorders, 32 patients showed low levels of TSH and12 patients showed high levels of TSH at the end of
IFN therapy, respectively. However, these 44 patientswere asymptomatic.
Interstitial pneurrwnia
Three patients developed clinical and radiographic
evidence of interstitial pne~onia during IFN therapy. All three patients were men and their ages were46, 57 and 59 years. Of the three patients, one wastreated with nIFN a and Chinese herbal medicine@ho-Sai-Koto*), which has been frequently used forchronic hepatitis patients in Japan, However, theremaining two patients received IFN alone. The findings on chest roentgenogram, computed tomographyof the chest and blood gas analysis were compatible
with interstitial pneumonia. Interstitial pneumonia inthese three patients resolved within 2 months of discontinuation of IFN.
Autoimmune disorders
One patient (a %-year-old woman) received rIFN a
2b and 13 weeks later she developed a high fever, askin rash and a dry cough. LE cell fo~ation andSide effects of high-dose intederon

rheumatoid factor (RA test) became positive, suggesting a systemic lupus erythematosus(SLE)-like
syndrome. The abnormal laboratory data returned topretreatment levels approximately 6 months later.
Two patients (a 47-year-old woman and a 54-yearold man) developed autoimmune hepatitis with nIFN
a therapy. In one patient, the ANA titer and y-globulin increased from 1: 80 to 1: 640 and from 1.5 g/d1 to
2.1 g/dl, respectively. Results of the patient’s liver
tests became significantly worse 20 weeks after thestart of IFN therapy. After discontinuationof IFN
therapy, the ANA titer, y-globulin and alanine aminotransferase levels returned to pretreatment levels.
The other patient developed autoimmune hepatitis 18
weeks after therapy and her clinical course wasalmost identical to the former patient.
Two patients (a 48-year-old woman and a 56-yearold man) developed symptoms and signs of rheumatoid arthritis at 12 weeks and 20 weeks after the onsetof IFN therapy, respectively.
The former patient
received nIFN a for 2 weeks and three times weeklyfor 10 weeks, while the other patient was treated withrIFN a 2b for 2 weeks and thrice weekly for 18
weeks before the development of a rheumatoid arthritis-like condition.
One patient (a 54-year-old woman) receiving rIFN
a 2a developed autoimmune thrombocytopenic
purpura 5 weeks after starting IFN therapy. She reported
subcutaneous and vaginal bleeding and her laboratory data on admission were as follows: WBC, 58001~1; RBC, 397x104/p1; Hgb, 11.6 g/dl; Hct, 35.6%;
Platelet count, 5OOO/pl; ESR, 115 mm/h; Prothrombin time, 100%; APTT, 33.4 s; ANA 1:40;
Bleeding time, 12 min; Coagulation time, 10 min;
PAIgG, 98.9 ng/lO’ cells; positivity for anti-platelet
antibodies, and 19.6x104/pl nucleated cells and 180/
pl megakaryocytes on examination of the bone marrow. IFN therapy was terminated and platelet transfusion and prednisolone therapy were instituted. She
subsequently completely recovered.
Intestinal bleeding
Melena was observed in three patients during IFN
therapy. Patient 1 (a 47-year-old woman) started IFN
therapy with nIFN a and 1 month later she noticed
melena without abdominal pain. Colonoscopy was
performed on the same day and demonstrated hemorrhagic erosions from the rectum to the descending
colon. She had been treated with indomethacin suppositories for prophylaxis of high fever and headache
induced by IFN administration. No skin rash waspresent and her eosinophil count was 2.5% at the startof therapy. The blastoid transformation test (11) for

indomethacin and nIFN a was negative. One week
later, nIFN a and indomethacin were administeredagain, but no melena was noted. Patient 2 (a 55-yearold-woman) and patient 3 (a 65-year-old-man) developed the sudden onset of abdominal pain and melena
after 23 weeks and 5 weeks of IFN therapy, respectively.
Colonoscopy
demonstrated
edematous
mucosa, erosions, scattered linear ulcers from therectum to the descending colon in both patients.
Biopsy specimens showed interstitial edema andhemorrhage associated with the infiltration of lymphocytes, plasma cells and eosinophils. All threepatients stopped IFN therapy and their lesions were
strikingly improved at the follow-up colonoscopy.
Their platelet counts were 173000/@ 87OOO/l_tland
67000/@ on presentation with melena. Eosinophilia
was not present in Patients 2 and 3.
Psychological disorders
Depression was diagnosed by psychologists in six
patients during IFN therapy and another 17 patients
showed symptoms of depression with IFN treatment.
Four of the six patients were men and two were
women. Their ages ranged from 35 to 64 years with amean age of 54.4 years. All six patients discontinued
IFN therapy. The onset of these symptoms and signs
ranged from 5 days to 21 weeks after the initiation of
IFN therapy. Two patients attempted suicide. However, all six patients recovered from their psychological disorders. One patient (a 58-year-old man) complained of memory loss after 20 weeks of IFN therapy and IFN therapy was discontinued. One month
later he showed complete recovery.
Retinopathy
Patients with pre-existing hypertension, diabetes mellitus and ophthalmologic symptoms underwent ophthalmoscopy after 10 to 12 weeks of IFN therapy.
Before IFN therapy, patients over 50 years old andthe patients with diabetes mellitus or hypertension
were examined by an ophthalmologist. Thus, we did
not analyze the incidence of the development of
retinopathy in 677 patients on IFN therapy.
A 40-year-old man, who received daily injectionsof nIFN’ a for 2 weeks and then 3 times weekly for 7
weeks, complained of visual disturbances. Ophthalmoscopy demonstrated leopard spots on the fundus,
resulting in the diagnosis of retinal detachment
induced by uveal effusion. He received methylprednisolone therapy without IFN administration, and 2
months later the uveal effusion resolved completely.
Ophthalmoscopy
before IFN therapy demonstrated
no abnormalities of his retina.
287

T. Okanoue et al.

Other side effects
A case of severe sensorineural hearing loss was noted
in a 55-year-old woman who received daily injectionsof nIFN a for 2 weeks and then three times weeklyfor 14 weeks. Little improvement was seen in her
audiogram 6 months later.
Skin rash with pruritus was noted in 86 patients(12.9%) and another 69 patients (10.3%) complainedof pruritus without skin rash. Of the 86 patients, 12
received n IFYNa, 46 were treated with rIFN a 2b,and 28 were on rIFN a 2a. rIFN a therapy was a significant Q~O.001) risk factor for the development ofskin rash for the patients compared with nIFN a.
Although moderate proteinuria (less than 3 g/day)
was frequently seen, nephrotic syndrome or renal
failure did not develop in these patients.
Transient sinus tachycardia and ventricular premature beats were noted in five patients. IFN therapy
was discontinued in one patient with ventricular premature beats.
Two hundred and five patients reported loss ofhair. Most of the cases of alopecia were minimal or
mild. No significant difference was noted in thedevelopment of hair loss among the three kinds of
IFN therapy.

Discussion
We have described the incidence of side effects ofaIFN in 677 Japanese patients with CAH-C who
received 6 to 10 MU of aIFN daily for 2 weeks andthen three times a week for 22 weeks. Thyroid disease
was noted in 12 patients who developed hyperthyroidism and six with hypothyroidism. Only one of the
12 patients with hyperthyroidism had a positive test
for thyroid autoantibody before therapy and none hada history of autoimmune disease. The onset of thyroid
disease ranged from 12 to 24 weeks of therapy. However, thyroid dysfunction may have developed earlier
as described by others (9). IFN administration leads toan increase in MHC class I antigen expression andmay activate a clone of autoantibody-producing
Blymphocytes. However, the mechanism of the development of thyroid disease with IFN is unclear. Some
reports (4,7,12-l 5) have described a high incidence of
the appearance of thyroid autoantibody and thyroid
disease in patients treated with IFN. The prevalence of
thyroid autoantibodies in hepatitis C patients and of
the development of thyroid dysfunction in hepatitis C
patients receiving IFN are variable (16). In the present
study, except for the 18 patients with thyroid diseaseinduced by IFN therapy, 32 patients had a low level of
TSH and 12 had a high level of TSH at the end of IFN
therapy. Schultz et al. (17) have reported the develop288

ment of thyroid disease in two of 20 patients withchronic hepatitis C treated with CXIFN.Gisslinger et al.
(18) have reported that elevated TSH levels, without achange in T4 levels, have occasionally been noted in
the patients treated with a.IFN. We cannot exclude theprogression to thyroid disease in the 44 patients withabnormal levels of TSH.
Of the 677 patients, five patients developed diabetes mellitus during IFN therapy. These five patients
continued to have impaired glucose tolerance after
their fasting plasma glucose recovered to baseline
levels. Koivisto et al. (19) have reported that IFN
stimulated counterregulatory
hormone secretion andimpaired glucose tolerance, insulin sensitivity andinsulin clearance. They have speculated that insulin
resistance induced by IFN could be due either todirect effects of IFN or indirectly to other immunomodulators or factors that were stimulated by IFN.
However, of the four cases with pre-existing diabetes
mellitus, the diabetes mellitus worsened with IFN
treatment only in two patients. Fabris et al. (20) havereported a case of type 1 diabetes mellitus whichdeveloped during aIFN therapy for chronic hepatitis
C. In our study, islet-cell antibodies were not examined and the exact mechanism underlying the development of diabetes mellitus induced by the administration of IFN remains unclear.
Interstitial pneumonia has been developed in 0.1 to
0.3% of patients with chronic hepatitis C receiving
IFN in Japan. However, approximately two-thirds ofthese cases are associated with the use of Chinese
herbal medicine, Sho-Sai-Koto,
with IFN. IFN or
Sho-Sai-Koto alone also induces interstitial pneumonia. However, combination therapy with IFN and
Sho-Sai-Koto demonstrated an increase in the development of interstitial pneumonia (21). Sho-Sai-Kotocontains seven kinds of extracted granules, including
scutellariae radix, which has been implicated in thedevelopmentof interstitial pneumonia (22). This
combination therapy has subsequently been prohibited in Japan, resulting in a decrease in the development of interstitial pneumonia. However, the mechanism of the development of interstitial pneumonia is
still unclear.
There have been reports of the exacerbation anddevelopment of autoimmune diseases (23-27) with
IFN therapy. Other reports have shown a high frequency of autoantibody formation in the absence ofclinically significant disease (18). Since IFN can act
as an immunomodulator,
IFN administration might
induce autoimmune disorders such as systemic lupus
erythematosus(28,29), rheumatoid
arthritis (30),autoimmune thrombocytopenia(3 1,32) and autoim-

Side effects of high-dose interferon

mune hemolytic anemia (33,34). We observed one
patient with an SLE-like syndrome, two with autoimmune hepatitis, two with rheumatoid arthritis and one
with thrombocytopenic
purpura. Most of thesepatients did not have pre-existing autoimmune disease and the time of onset was variable.
aIFN exerts profound effects, such as inhibition of
suppressor T cell function, augmentation of cytotoxic
T-cell and natural killer cell function, activation ofmacrophage and monocyte secretion of cytokines,
enhanced expressionof major histocompatibility(MHC) class I and II antigens and others. Thus, theimmunological actions could result in dysregulation
between self-tolerance and activation of cells recognizing autologous antigens. However, it is very difficult to determine which mechanism is responsible foreach side effect in individual cases.
Intestinal bleeding was noted in three patients, twoof whom had thrombocytopenia.
Colonoscopy demonstrated findings compatible with ischemic colitis in
two patients and hemorrhagic erosions in one. The
lesions were localized from the rectum to thedescending colon. Drug allergy was not present in all
three patients. Pecorai et al. (35) have reported a caseof ulcerative colitis in a patient with leukemia receiving IFN therapy. However, ischemic colitis has notbeen previously reported as a complication of IFN.
Sparano et al. (36) have documented the role of interlet&in-Z and aIFN in the development of colonicischemia. Therefore the developmentof ischemic
colitis in IFN therapy must be considered,
Guyer et al. (37) and Seki et al. (38) have reported
interferon-associatedretinopathy. Seki et al. (38) andothers demonstrated that interferon-associatedretinopathy was seen in 20 to 50% of the Japanese patientswith chronic hepatitis C receiving IFN. Retinopathy
was noted approximately 8-10 weeks after the initiation of IFN therapy and spontaneously resolved during IFN therapy. However, careful observation is necessary for patients with diabetes mellitus and hypertension. Retinal detachment as a side effect of IFN
had not yet been reported. The patient with retinal
detachment associated with uveal effusion did nothave evidence of hemorrhage from retinal blood vessels. The mechanism of the uveal effusion is unclear.
Depression, mania, hallucination,
dementia anddelirium are all serious side effects of IFN (39,40).
These side effects have been observed more frequently in older patients (41) and the degree of nervous system toxicity was dose-related. In our study, six
patients were diagnosed with depression, with twopatients attempting suicide. The incidence of depression increased with the duration of treatment (39).

This finding emphasizes the importance of carefulmonitoring of this side effect in IFN therapy forpatients with chronic hepatitis C.
IFN frequently induced reversible sensorineural
hearing loss (42). The present study also documented
the development of severe hearing loss and the lackof significant improvement in the patient’s audiograms 6 months after the cessation of IFN therapy.
Although it is unclear whether this hearing loss was
induced by IFN, careful monitoring for ototoxicity in
IFN therapy is necessary.
We found a few patients with cardiovascular complications. However, effects were moderate and transient. Most of the patients who developed hypothyroidism and autoimmune disorders had pre-existing
autoantibodies. However, the patients showing otherside effects did not have correlation with a pre-existing autoantibody profile.
Recently it has been reported that 12 months ofaIFN therapy can suppress the incidence of relapse
after cessation of therapy in patients with chronic
hepatitis C (43). The incidence of most adverse
effects of IFN is usually dose- and duration-dependent. Careful attention should be paid to these patients
when they receive long-term and high-dose IFN therapy. Many patients in this study required an adjustment in the daily amount of IFN because of side reactions or side effects during the 24-week protocol.
Thus, it was very difficult to evaluate the relationshipbetween the incidence of side effects of IFN and thedose of IFN administered.
In summary, high-dose and long-term IFN treatment for chronic hepatitis C patients induces various
adverse effects involving many organs. Most of theseeffects are reversible when detected early. Therefore,
careful observation is necessary for chronic hepatitis
C patients during IFN therapy.

References
Davis GL, Balart LA, Schiff ER, Lindsay K, Bodenheimer
HC Jr, Petri110 RP, Carey W, Tamburro C, Lefkowitch J, Albrecht J, Mesievitz C, Ortego TJ, Gibas A, The International
Hepatitis Therapy Group. Treatment of chronic hepatitis Cwith recombinant interferon alfa: a multicenter randomized,
controlled trial. New Engl J Med 1989; 321: 1501-6.
Di Bisceglie AM, Martin P, Kassianides C, Lisker-Melman
M, Murray L, Waggoner J, Goodman Z, Banks SM, Hoofnagle JH. A randomized, double-blind, placebo-controlled trial.
New Engl J Med 1989; 321: 1506-10.
Marcellin P, Boyer N, Giotra E, Degotte C, Courouce AM,
Degos F, Coppere H, Cales P, Couzigou P, Benhamou J-P
Recombinant human a-interferonin patients with non-A,
non-B hepatitis: a multicenter randomized controlled trialfrom France. Hepatology 1991; 13: 393-7.
Burman P, Totterman TH, Oberg K, Karlsson FA. Thyroid289

T. Okanoue et al.
autoimmunity in patients on long-term therapy with leukocyte-derived interferon. J Clin Endocrinol Metaboll986;
63:
1086-90.
5. Renault PF, Hoofnagle JH, Park Y, Mullen KD, Peters M,
Jones B, Rustgi V, Jones A. Psychiatric complications oflong-term interferon alpha therapy. Arch Intern Med 1987;
147: 1577-80.
6. Hoofnagle JH, Peters MG, Mullen KD, Jones DB, Rustgi V,
Di Bisceglie A, Hallahan C, Park Y, Meschievitz C, Jones
EA. Randomized controlled trial of a four-month course ofrecombinant human alfa interferon in chronic type B hepatitis. Gastroenterology 1988; 95: 1318-25.
7. Mayet W-J, Hess G, Gerken G, Ross01 S, Voth R, Manns M,
Meyer zum Buschenfelde K-H. Treatment of chronic type B
hepatitis with recombinant alpha-interferon induces autoantibodies not specific for autoimmune chronic hepatitis.
Hepatology 1989; 10: 24-8.
8. Renault PF, Hoofnagle JH, Side effects of alpha interferon.
Semin Liver Dis 1989; 9: 273-7.
9. Lisker-Melman M, Di Bisceglie AM, Usala SJ, Weintraubs
B, Murray LM, Hoofnagle JH. Development of thyroid disease during therapy of chronic viral hepatitis with interferon
alfa. Gastroenterology 1992; 102: 2155-60.
10. Vial T, Descotes J. Clinical toxicity of the interferons. Drug
Safety 1994; 10: 115-50.
11. Mizoguchi Y. Diagnosis of drug-induced hepatitis. In: Mizoguchi Y, ed. Disease of Drug-Induced Hepatitis. Tokyo:
Shinko-Igaku Schutsupan, 1989: 51-74.
12. Ronnblom LE, Alm GV. Oberz KE. Autoimmunity after alpha-interferon therapy for malignant carcinoid tumor. Ann
Intern Med 1991; 115: 178-83.
13. Chung YH, Shong YK. Development of thyroid autoimmunity after administration of recombinant human interferon-a2b for chronic viral hepatitis. Am J Gastroenterol 1993; 88:244-7.
14. Pateron D, Hartmann DJ, Duclos Vallee JC, Jouanolle H,
Beaugrand H. Latent autoimmune thyroid disease in patientswith chronic HCV hepatitis. J Hepatol 1992; 16: 244-5.
15. Tran A, Quaranta JF, Benzaken S, Thiers V, Chau I-IT, Hastier P, Regnier D, Dreyfus G, Pradier P, Sadoul J-L, Hebuteme X, Rampal P. High prevalence of thyroid autoantibodies in a prospective series of patients with chronic hepatitis C before interferon therapy. Hepatology 1993; 18: 253-7.
16. Marcellin P, Pouteau M, Benhamou J-P. Review. Hepatitis C
virus infection, alpha interferon therapy and thyroid dysfunction. J Hepatol 1995; 22: 364-9.
17. Schultz M, Muller R, Von zur Muhlen A, Braband G. Induction of hyperthyroidism
by interferon-a-2b(letter). Lancet
1989; i: 1453.
18. Gisslinger H, Gilly B, Woloszczuk W, Mayr WR, Havelec L,
Linkesch W, Weissel M. Thyroid autoimmunity and hypothyroidism during long-term treatment with recombinantinterferon-alpha. Clin Exp Immunol 1992; 90: 363-7.
19. Koivisto VA, Pelkonen R, Cantell K. Effect of interferon on
glucose tolerance and insulin sensitivity. Diabetes 1989; 38:
641-9.
20. Fabris P, Beterlle C, Floreani A, Greggio NA, de Lazzari F,
Naccarato R, Chiaramonte M. Development of type 1 diabetes mellitus during interferon alfa therapy for chronic HCV
hepatitis (letter). Lancet 1992; 340: 548.
21. Kamitsukasa H, Ohtake M, Kawashima H, Yagura M,
Harada H, Katayama T. Two cases of interstitial pneumonia

290

induced by interferon therapy for chronic aggressive hepatitis type C. Acta Hepatol Jpn 1993; 39: 478-83.
22. Tsukiyama K, Tasaka Y, Nakajima M, Hino J, Nakahara C,
Okimoto N, Yagi S, Soejima R. A case of pneumonitis due to
Sho-Sai-Koto. Jpn J Thorac Dis 1989; 27: 1556-61.
23. Schattner A. Interferons and autoimmunity. Am J Med Sci
1988; 295: 5324.
24. Conlon KC, Urba WJ, Smith JW, Steis RG, Long0 DL, Clark
JW. Exacerbation of symptoms of autoimmune disease in patients receiving alpha-interferon therapy. Cancer 1990; 65:2237-42.
25. Silva MO, Reddy R, Jeffers LJ, Hill M, Schiff ER. Interferon-induced
chronic active hepatitis. Gastroenterology
1991; 101: 840-2.
26. Papo T, Marcellin P, Bemuau J, Durand F, Poynard T, Benhamou J-P Autoimmune chronic hepatitis exacerbated by alpha-interferon. Ann Intern Med 1992; 116: 5 l-3.
27. Itoh Y, Okanoue T, Enjyo F, Morimoto M, Takeuchi T, Kagawa K, Kashima K. Elevated interleukin-6 and y-globulin
during interferon therapy of chronic hepatitis B. Am J Gastroenterol1992; 87: 1485-7.
28. Mehta ND, Hooberman AL, Vokes EE, Neeley S, Cotler S.
35-year-old patient with chronic myelogenous leukemia developing systemic lupus erythematosus after alpha-interferon
therapy. Am J Hematol 1992; 41: 141.
29. Schilling PJ, Kurzrock R, Kantarjian H, Gutterman JU, Talpaz M. Development of systemic lupus erythematosus after
interferon therapy for chronic myelogenous leukemia. Cancer 1991; 68: 1536-7.
30. Nadir F, Fagiuoli S, Wright HI, Nadir A, Hopp E, Gavaler J,
Van Thiel DH. Rheumatoid arthritis: a complication of interferon therapy. J Okla State Med Assoc 1994; 87: 228-30.
31. McLaughlin P, Talpaz M, Quesada JR, Saleem A, Barlogie
B. Immune thrombocytopenia
following alpha-interferon
therapy in patients with cancer. J Am Med Assoc 1985; 253:
13534.
32. Lopez Morante AJ, Saez-Royuela F, Casanova Valero F,
Yequero de1 Moral L, Martin Lorente JL, Gimenez CO. Immune thrombocytopenia
after alpha-interferon therapy in apatient with chronic hepatitis C. Am J Gastroenterol 1992;
87: 809-10.
33. Akard LP, Hoffman R, Elias L, Saiers JH. Alpha-interferon
and immune hemolytic anemia. AM Intern Med 1986; 105:306.
34. Quesada JR, Talpaz M, Rios A, Kurzrock R, Gutterman JU.
Clinical toxicity of interferons in cancer patients: a review. J
Clin Oncol 1986; 4: 234-43.
35. Pecorai P Colite ulcerosa in torso di leucemia a cellule
capellute. Descrizione di un case. Ret Prog Med 1991; 82:269-71.
36. Sparano JA, Dutcher JP, Kaleya R, Caliendo G, Fiorito J,
Mitsudo S, Shechner R, Boley S, Gucalp R, Ciobanu N,
Grima K, Wiemik PH, Brandt LJ. Colonic ischemia complicating immunotherapy with interleukin-2 and interferon-alpha. Cancer 1991; 68: 1538-44.
37. Guyer DR, Tiederman J, Yannuzzi LA, Slakter JS, Parke D,
Kelley J, Tang RA. Marmor M, Abrams G, Miller JW, Gragoudas ES. Interferon-associatedretinopathy. Arch Gphthalmol 1993; 111: 350-6.
38. Seki K, Itoh Y, Nishi Y, Isaka Y. Interferon therapy for type C
chronic active hepatitis and retinal hemorrhage. Acta Hepatol
Jpn 1993; 17: 385-91.

Side effects of high-dose interferon
39. Renault PF, Hoofnagle JH, Park Y, Mullen KD, Peters M,
Jones DB, Rustgi V, Jones EA. Psychiatric complications oflong-term interferon alpha therapy. Arch Intern Med 1989;
147: 1577-80.
40. Prasad S, Waters B, Hill PB, Portera FD, Riely CA. Psychiatric side effects of interferon alpha2b in patients treated forhepatitis C. Abstract. Clin Res 1992; 40: 840A.
4 1. Merimsky 0, Reider-Groswasser
I, Inbar M, Chaitchik S. Interferon-related
mentaldeterioration
and behaviouralchanges in patients with renal cell carcinoma. Eur J Cancer
1990; 26: 595600.

42. Kanda Y, Shigeo K, Kinoshita N, Nakano K, Yano M, Matsuo H. Sudden hearing loss associated with interferon. Lancet 1994,343: 1134-5
43. Kasahara A, Hayashi N, Hiramatsu N, Oshita M, Hagiwara
H, Katayama K, Kato M, Masuzawa M, Yoshihara H, Kishida Y, Shimizu Y, Inoue A, Fusamato H, Kamada T. Abilityof prolonged interferon treatment to suppress relapse after
cessation of therapy in patients with chronic hepatitis C: amulticenter randomized controlled trial. Hepatology 1995;
21: 291-7.

291