Efficacy of pegylated interferon plus ribavirin in combination with corticosteroid for two cases of combined hepatitis C and autoimmune hepatitis.
ABSTRACT The treatment strategy for cases of combined autoimmune hepatitis (AIH) and chronic hepatitis C (CHC) has not yet been established. A 47-year-old woman and a 53-year-old-woman were hospitalized for treatment of CHC. Ultrasonography and histological findings revealed that their liver was not cirrhotic but did have chronic damage. The histological findings of both patients were suggestive of AIH. The patients were systematically treated with pegylated interferon-alpha 2b plus ribavirin which was preceded by and combined with corticosteroid (CS), and showed sustained virological responses and normal liver function. Although these two patients with combined AIH and CHC were successfully treated with this regimen, careful attention to exacerbation of hepatic inflammation is needed because hepatitis C viral load was increased due to immunosuppression during CS treatment.
- SourceAvailable from: Seyed Moayed Alavian[show abstract] [hide abstract]
ABSTRACT: Autoimmunity and viral infections are closely associated fields, and viruses have been proposed as a likely aetiological, contributory or triggering factors of systemic autoimmune diseases. Hepatitis C virus seems to be the virus usually associated with the appearance of autoimmune diseases, and the relationship between chronic hepatitis C virus infection and some autoimmune disease has been studied. For some of these disorders their association with hepatitis C virus infection is well recognized while for others it remains probable or weak. Examples of autoimmune phenomena observed in chronic hepatitis C virus infection include rheumatoid arthritis, thyroid disease, cryoglobulinaemia, immune thrombocytopenic purpura, systemic lupus erythematosus and sjogren syndrome. To date, the etiological role and the pathogenetic involvement of the hepatitis C infection remains unknown.The aim of this study is to assess the presence of different autoimmune manifestations of hepatitis C virus infection reported in literature.Iranian journal of allergy, asthma, and immunology 12/2010; 9(4):191-206. · 0.65 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: A nationwide survey of autoimmune hepatitis (AIH) was carried out in Japan. Four hundred and ninety-six patients were enrolled by questionnaires sent to 101 hospitals with hepatology specialists. The clinical features of Japanese AIH were as follows: most patients were middle-aged women; serum autoantibodies, especially antinuclear antibody, were frequently positive, serum IgG level was high, and HLA-DR4 was the major HLA allotype. Liver-kidney microsomal type 1 antibody was positive in nine of 79 patients tested. Eight of these antibody positive patients were also positive for antinuclear antibody and five for anti-smooth muscle antibody. Ninety-two percent of the patients showed piecemeal necrosis and 60% bridging necrosis; plasma cell infiltration in the portal areas was observed in 50% of the patients. Only 12.3% were diagnosed as having liver cirrhosis. A favorable effect of corticosteroid, normalization of serum transaminases, was observed in 89% of 317 patients, who were treated with an initial dose of over 30 mg/day. Sixty-two patients were positive for hepatitis C virus (HCV) markers. In these patients, however, only one patient was liver-kidney microsomal type 1 antibody positive. Corticosteroid was effective in 30 (81%) of 37 HCV-marker-positive patients treated with this agent. Thus the efficacy of corticosteroid did not differ from that in AIH patients without HCV infection (90%). Similarly, interferon treatment was used in 20 patients, all of whom were positive for HCV-RNA, and resulted in 50% efficacy as determined by normalization of the serum transaminase level 6 months after treatment. The International Diagnostic Scoring System for the diagnosis of AIH worked well in these patients, except for HCV-infected individuals, that is, approximately 10% of the total of AIH patients.Journal of Hepatology 07/1997; 26(6):1207-12. · 9.86 Impact Factor
- The Quarterly journal of medicine 05/1971; 40(158):159-85.
Efficacy of pegylated interferon plus ribavirin in combination
with corticosteroid for two cases of combined hepatitis C
and autoimmune hepatitis
Satoshi Oeda•Toshihiko Mizuta•Hiroshi Isoda•Takuya Kuwashiro•
Noriko Oza•Shinji Iwane•Hirokazu Takahashi•Yasunori Kawaguchi•
Yuichiro Eguchi•Shuji Toda•Iwata Ozaki•Keizo Anzai•Kazuma Fujimoto
Received: 23 January 2012/Accepted: 6 March 2012/Published online: 28 March 2012
? The Author(s) 2012. This article is published with open access at Springerlink.com
autoimmune hepatitis (AIH) and chronic hepatitis C (CHC)
has not yet been established. A 47-year-old woman and a
53-year-old-woman were hospitalized for treatment of
CHC. Ultrasonography and histological findings revealed
that their liver was not cirrhotic but did have chronic
damage. The histological findings of both patients were
suggestive of AIH. The patients were systematically treated
with pegylated interferon-alpha 2b plus ribavirin which
was preceded by and combined with corticosteroid (CS),
and showed sustained virological responses and normal
liver function. Although these two patients with combined
AIH and CHC were successfully treated with this regimen,
careful attention to exacerbation of hepatic inflammation is
needed because hepatitis C viral load was increased due to
immunosuppression during CS treatment.
The treatment strategy for cases of combined
Interferon ? Ribavirin ? Corticosteroid
Autoimmune hepatitis ? Chronic hepatitis C ?
Hepatitis C virus (HCV) infection is known to be associ-
atedwith variousautoimmunediseases,such as
autoimmune hepatitis (AIH), Sjo ¨gren’s syndrome, rheu-
matoid arthritis and autoimmune thyroid disorders .
Among AIH patients, it has been reported that at least
10 % were infected with HCV in Japan . Although
corticosteroid (CS) therapy has been established as effec-
tive for AIH [3–5], there is concern about the possible
increase in HCV caused by the immunosuppressive effect
of CS in HCV-infected AIH patients. In contrast, interferon
(IFN) administration, which is effective for chronic hepa-
titis C (CHC), has been reported to initiate acute exacer-
bation of AIH , and sometimes fulminant hepatic failure
[7, 8]. Owing to these discordant treatment options for AIH
and CHC, the treatment decision for patients with both of
these hepatic diseases represents a dilemma.
Here we report two patients with combined AIH and
CHC who showed favorable outcomes with pegylated IFN
(PEG-IFN) plus ribavirin (RBV) therapy which was pre-
ceded by and combined with CS administration.
A 47-year-old woman (height 153.3 cm, weight 64.5 kg)
was referred to our hospital for treatment of CHC in
August 2006. Although she had received IFN therapy
5 years previously, eradication of HCV had not been
achieved, and her serum levels of transaminases during the
therapy had been higher than baseline.
She was not a habitual drinker, and there was no history
of blood transfusion, drug abuse or tattoos. There were no
abnormal findings in her physical examination. Blood tests
showed that the alanine aminotransferase (ALT) level
was 97 IU/L, immunoglobulin (Ig) G concentration was
S. Oeda ? T. Mizuta (&) ? H. Isoda ? T. Kuwashiro ? N. Oza ?
S. Iwane ? H. Takahashi ? Y. Kawaguchi ? Y. Eguchi ? I. Ozaki ?
K. Anzai ? K. Fujimoto
Department of Internal Medicine, Saga Medical School,
5-1-1 Nabeshima, Saga 849-8501, Japan
Department of Pathology, Saga Medical School,
5-1-1 Nabeshima, Saga 849-8501, Japan
Clin J Gastroenterol (2012) 5:141–145
3457 mg/dL, anti-nuclear antibody (ANA) titer was 1:40,
liver–kidney microsomal antibody-1 (LKM-1) was nega-
tive, HCV genotype was 2a and viral load was 2700 KIU/
mL (Table 1). HLA typing showed DR4. To distinguish
between AIH and CHC, a liver biopsy was carried out
under laparoscopy. Although characteristic laparoscopic
findings for AIH of multilobular and ecchymotic red
macula, extensive recess, furrowed recess and rough and
large tuber were not seen; microscopic findings showed
considerable infiltration of plasma cells in portal areas and
severe interface hepatitis, which are uncommon in CHC
(Fig. 1). Therefore, we determined that the main cause of
her hepatic disorder was AIH, although the diagnostic
score according to the International Autoimmune Hepatitis
Group (IAIHG) in 1999  was 12 points, defined as
‘probable’ for AIH.
We started 30 mg/day prednisolone (PSL) administration
in October 2006. Although the IgG level gradually decreased
after initiation of PSL, the ALT level remained unchanged.
Serum HCV load increased to 4800 KIU/mL during PSL
administration. After 6 weeks of PSL (ALT 101 IU/L, IgG
2008 mg/dL), a weekly subcutaneous injection of 100 lg
PEG-IFN-alpha-2b and daily oral administration of 800 mg
RBV were started in combination with 20 mg/day PSL. The
ALT level decreased gradually after starting PEG-IFN plus
RBV therapy, and HCV RNA disappeared from her serum
at week 8 of PEG-IFN plus RBV therapy. Subsequently, a
sustained virological response (SVR) was achieved by
PEG-IFN plus RBV therapy for 24 weeks. PSL was con-
tinued for 4 months after cessation of PEG-IFN plus RBV,
and then withdrawn because ALT and IgG levels remained
continuously normal (ALT 13 IU/L, IgG 1472 mg/dL at the
end of PSL administration). From the end of the treatment to
the present time, her serum ALT and IgG levels have been
within the normal ranges for 3 years without any medication
Case 2 was a 53-year-old woman (height 159 cm, weight
56.6 kg). She was diagnosed with CHC at 39 years of age,
but had not taken any medication because of low serum
Table 1 Laboratory data on
admission (Case 1)
ANA anti-nuclear antibody,
ASMA anti-smooth muscle
antibody, LKM-1 Ab liver-
kidney microsomal antibodies
type 1, AMA antimitochondrial
434 9 104/lL
Total protein8.2 g/dLIgG 3457 mg/dL
3.8 g/dL IgA299 mg/dL
Hb31.9 % IgM47 mg/dL
14.7 9 104/lL
82 IU/LANA40 times
LDH226 IU/L LKM-1 Ab(-)
48 IU/LHBs Ag(-)
0.7 mg/dL HBc Ab(-)
Cholinesterase266 IU/L HCV-RNA2700 KIU/mL
HLA-DR 4, 9
Fig. 1 Histological findings of Case 1 show considerable infiltration of plasma cells in portal areas and severe interface hepatitis. a H&E 940,
b H&E 9400
142Clin J Gastroenterol (2012) 5:141–145
ALT levels. Symptoms of dry eye and mouth appeared in
January 2008, and she was diagnosed with Sjo ¨gren’s syn-
drome and mixed connective tissue disease based on the
symptoms and serological tests, by a specialist in collagen
diseases. Her hepatic function worsened after oral admin-
istration of pilocarpine hydrochloride, therefore, she was
referred to our department.
She had a history of transfusion of blood coagulation
factors during childbirth. Laboratory tests showed that the-
ALT level was 128 IU/L, IgG level was 1933 mg/dL, ANA
titer was 1:1280, LKM-1 was negative, HLA typing showed
DR9 and DR15, HCV genotype was 1b and viral load was
3.3 log IU/mL (Table 2). Histological findings of a liver
biopsy specimen showed moderate infiltration of lympho-
cytes and plasma cells in portal areas, interface hepatitis and
rosette formation, which are typical AIH characteristics
(Fig. 3). Although the score according to the simplified
criteria of AIH (IAIHG 2008)  was 6 points, which
means ‘probable’ for AIH, we judged that her hepatic dis-
order was mainly caused by AIH, similar to Case 1.
After starting oral administration of 40 mg PSL
(0.7 mg/kg) in February 2009, her ALT and IgG levels
immediately decreased and became normalized. Serum
HCV load increased to 5.6 log IU/mL during PSL admin-
istration. After PSL administration for 13 weeks, with a
gradual decrease in dose, a weekly subcutaneous injection
of 80 lg PEG-IFN-alpha-2b and daily oral 600 mg RBV
were started in combination with 20 mg/day PSL. HCV
RNA disappeared from her serum at week 8 of PEG-IFN
plus RBV therapy, and an SVR was achieved by continuing
the treatment for 48 weeks. After the end of the PEG-IFN
plus RBV therapy, PSL dose was gradually decreased and
Peg-IFNα α2b 100µg/week
after 6 M
Clinical course of
Table 2 Laboratory data on
admission (Case 2)
ANA anti-nuclear antibody,
ASMA anti-smooth muscle
antibody, LKM-1 Ab liver-
kidney microsomal antibodies
type 1, AMA antimitochondrial
463 9 104/lL
TP 7.3 g/dLIgG1933 mg/dL
3.9 g/dLIgA322 mg/dL
Hb25.5 % IgM156 mg/dL
15.1 9 104/lL
108 IU/L ANA1280 times
LDH269 IU/LLKM-1 Ab(-)
169 IU/L AMA(-)
85 IU/L HBs Ag(-)
1.3 mg/dLHBc Ab(?)
Cholinesterase 290 IU/LHBV-DNA(-)
HCV-RNA3.3 log IU/mL
HLA-DR 9, 15
Clin J Gastroenterol (2012) 5:141–145 143
daily administration of 5 mg has continued to date. Con-
sequently, her ALT and IgG levels have remained within
the normal range (Fig. 4).
We have reported two patients with features of AIH
together with HCV infection, who were successfully trea-
ted with PEG-IFN plus RBV therapy preceded by and
combined with steroid administration. This therapeutic
challenge may represent one approach for hepatitis in
patients with combined AIH and CHC.
The most important issue in this approach is how to
judge whether the autoimmunity is associated with hepatic
inflammation in patients with HCV infection.
CHC patients sometimes become positive for autoanti-
bodies such as ANA, therefore, it is difficult to distinguish
serologically between simple CHC and CHC combined
with AIH. A variety of type 2 AIH, which is characterized
by anti-LKM-1 antibodies in the serum, has been reported
with HCV-associated AIH . However, the positivity
rate of anti-LKM-1 antibodies in Japanese CHC patients is
low , and our two cases were actually both negative.
There are some reports indicating the importance of
histological manifestations such as severe piecemeal
Fig. 3 Histological findings of Case 2 show moderate infiltration of lymphocytes and plasma cells in portal areas, interface hepatitis and rosette
formation. a H&E 940, b H&E 9400
Peg-IFN/Ribavirin 0W 4W 8W
5.6 2.4 negative
after 6 M
Clinical course of Case
144Clin J Gastroenterol (2012) 5:141–145
necrosis, lobular hepatitis, multinucleated giant cells, and
moderate or severe infiltration of plasma cells, which are
microscopic characteristics of AIH, to distinguish CHC
accompanied with AIH from simple CHC .
in the level of ALT during previous IFN treatment and his-
tological findings in Case 1, and on other accompanying
autoimmune diseases and histological findings in Case 2.
However, the treatment strategy for combined AIH/HCV
has not yet been established. It is known that IFN often
induces acute exacerbation of AIH, and occasionally ful-
minant hepatic failure [6–8], therefore, many reports have
recommended CS therapy for these patients [14, 15]. In
contrast, there are some reports showing that IFN therapy is
more effective than CS, even in combined AIH/CHC .
Petersen-Benz et al.  reported successful treatment of a
case with AIH/CHC overlap syndrome. First, they treated
RBV therapy for CHC, and achieved HCV eradication.
However, readministration of CS was required to inhibit
hepatic inflammation in this case. Therefore, we planned
pretreatmentwith CSandsubsequentIFNplus RBVtherapy
combined with continued CS for our two cases. PEG-IFN
plus RBV therapy was started at 6 weeks of CS treatment in
Case 1 versus at 13 weeks in Case 2 because the ALT level
did not decrease steadily with CS administration in Case 1.
Asaresult,favorableviral eradication wasachieved without
aggravation of hepatic inflammation in both cases.
Careful attention to viral breakthrough caused by the
immunosuppressive effect of CS is required. Indeed, HCV
load increased during CS administration in both of our
cases. Therefore, when this therapeutic regimen is admin-
istered, it is necessary to monitor the ALT level closely
until start of antiviral therapy, so as not to miss any
exacerbation of hepatic inflammation.
Judging from the changes in IgG and ALT levels during
CS treatment, it is speculated that the hepatic inflammation
in Case 1 was caused by both HCV and autoimmunity,
whereas that in Case 2 was mainly caused by AIH.
Therefore, after termination of IFN plus RBV therapy, we
attempted to stop CS treatment in Case 1, but continued a
low dose PSL in Case 2.
In conclusion, although antiviral therapy combined with
CS needs to be carefully applied, it may represent a
worthwhile treatment for CHC patients with clinical and
histological characteristics of AIH.
Conflict of interest
The authors declare that they have no conflict
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
This article is distributed under the terms of the
1. Jadali Z, Alavian SM. Autoimmune diseases co-existing with
hepatitis C virus infection. Iran J Allergy Asthma Immunol. 2010;
M, et al. Present status of autoimmune hepatitis in Japan—corre-
high rate of HCV infection. Japanese National Study Group of
Autoimmune Hepatitis. J Hepatol. 1997;26:1207–12.
3. Cook GC, Mulligan R, Sherlock S. Controlled prospective trial of
corticosteroid therapy in active chronic hepatitis. QJ Med. 1971;
4. Soloway RD, Summerskill WH, Baggenstoss AH, Geall MG,
Gitnic ´k GL, Elveback IR, et al. Clinical, biochemical, and his-
tological remission of severe chronic active liver disease: a
controlled study of treatments and early prognosis. Gastroenter-
5. Murray-Lyon IM, Stern RB, Williams R. Controlled trial of
prednisone and azathioprine in active chronic hepatitis. Lancet.
6. Shindo M, Di Bisceglie AM, Hoofnagle JH. Acute exacerbation
of liver disease during interferon alfa therapy for chronic hepatitis
C. Gastroenterology. 1992;102:1406–8.
7. Kogure T, Ueno Y, Fukushima K, Nagasaki F, Inoue J, Kakazu E,
et al. Fulminant hepatic failure in a case of autoimmune hepatitis
in hepatitis C during peg-interferon-alpha 2b plus ribavirin
treatment. World J Gastroenterol. 2007;13:4394–7.
8. Coriat R, Podevin P. Fulminant autoimmune hepatitis after suc-
cessful interferon treatment in an HIV-HCV co-infected patient.
Int J STD AIDS. 2008;19:208–10.
9. Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK,
Cancado EL, et al. International Autoimmune Hepatitis Group
Report: review of criteria for diagnosis of autoimmune hepatitis.
J Hepatol. 1999;31:929–38.
10. Hennes EM, Zeniya M, Czaja AJ, Pare ´s A, Dalekos GN, Krawitt
EL, et al. International Autoimmune Hepatitis Group. Simplified
criteria for the diagnosis of autoimmune hepatitis. Hepatology.
11. Bai L, Lu HY, Feng ZR, Yu M, Li WG, Gong WB, et al.
Detection and the production mechanism of antinuclear anti-
bodies (ANA) and anti-liver/kidney microsomal type 1 antibodies
(anti-LKM1) in patients with chronic hepatitis C. Zhonghua Shi
Yan He Lin Chuang Bing Du Xue Za Zhi. 2009;23:278–81.
12. Nishioka M, Morshed SA, Kono K, Himoto T, Parveen S, Arima
K, et al. Frequency and significance of antibodies to P450IID6
protein in Japanese patients with chronic hepatitis C. J Hepatol.
13. Carpenter HA, Czaja AJ. The role of histologic evaluation in the
diagnosis and management of autoimmune hepatitis and its
variants. Clin Liver Dis. 2002;6:685–705.
14. Schiano TD, Te HS, Thomas RM, Hussain H, Bond K, Black M.
Results of steroid-based therapy for the hepatitis C-autoimmune
hepatitis overlap syndrome. Am J Gastroenterol. 2001;96:2984–91.
15. Ballary S, Schiano T, Hartman G, Black M. Chronic hepatitis
with combined features on autoimmune chronic hepatitis and
chronic hepatitis C: favorable response to predonisone and aza-
thioprine. Ann Intern Med. 1995;123:32–4.
16. Magrin S, Craxi A, Fabiano C, Fiorentino G, Almasio P, Palazzo
U, et al. Hepatitis C virus replication in ‘autoimmune’ chronic
hepatitis. J Hepatol. 1991;13:364–7.
17. Petersen-Benz C, Kasper HU, Dries V, Goeser T. Differential
efficacy of corticosteroids and interferon in a patient with chronic
hepatitis C-autoimmune hepatitis overlap syndrome. Clin Gas-
troenterol Hepatol. 2004;2:440–3.
Clin J Gastroenterol (2012) 5:141–145 145