CASE REPORT

Hepatitis C Virus-Autoimmune
Hepatitis Overlap Syndrome in
an Adolescent

Danya Rosen, yJaime Chu, zRaffaella Morotti,

Daniela Levanon, ySamantha Rose, jjSamantha Lee,
and yRonen Arnon

epatitis C virus-autoimmune hepatitis (HCV-AIH) overlap

syndrome is characterized by clinical, immunological, and
histological features of both diseases, and not simply by the
presence of autoantibodies, as often seen with HCV infection alone
(1). Defining diagnostic criteria and determining the therapeutic
approach for HCV-AIH are challenging because of the contradictory approaches to each disease. Administration of interferon
(IFN) to the patients with HCV infection can lead to exacerbation of
the underlying AIH (2), whereas corticosteroids have been shown to
increase HCV viremia and can lead to fulminant hepatic failure
(3,4). Most of the literature in adult patients with HCV-AIH
advocates for first treating the AIH. Here, we report the first
case of HCV-AIH overlap syndrome in a pediatric patient treated
initially for HCV with pegylated interferon and ribavirin followed
by treatment for AIH with steroids, who successfully achieved
sustained viral response (SVR) of HCV and remission of AIH.
An 11-year-old girl was referred to our pediatric hepatology
clinic for elevated liver enzymes, positive autoimmune markers, and
suspected vertical transmission of HCV. She was asymptomatic, and
BMI was normal at 23.4 kg/m2. Laboratory reports were significant
for Hg 13.9 g/dL, white blood cell count 6600/mL, platelet count
270,000/mL, gamma-glutamyl transpeptidase 25 U/L, aspartate aminotransferase (AST)141 U/L, alanine aminotransferase (ALT)
262 U/L, total protein 7.5 g/dL, albumin 4.5 g/dL, and direct bilirubin
0.1 mg/dL. The international normalized ratio was 1.0. Anti-nuclear
antibody was negative, anti-smooth muscle antibody was positive
(1:320), and anti-liver kidney microsomal antibody was also positive
(exact titer unknown). Quantitative immunoglobulin G (IgG) was
1.7 g/dL (1.9 g/dL is the upper limit of normal). Hepatitis C antibody
was positive, HCV RNA was 12,800 IU/mL, and the HCV was
genotype 1b. The workup for other causes of liver disease including
hepatitis B, HIV, Wilson disease, and a-1-antitrypsin phenotype was
negative, and there was no history of drug or alcohol use. An
abdominal ultrasound showed normal liver size and echogenicity.
Percutaneous liver biopsy was consistent with that of chronic
hepatitis C with features of autoimmune hepatitis (Fig. 1).

Received July 10, 2013; accepted November 18, 2013.

From the
Department of Pediatric Gastroenterology, the yDepartment of
Pediatric Hepatology, Recanati/Miller Transplant Institute, Mount Sinai
Medical Center, New York, NY, the zDepartment of Pathology, Yale
University School of Medicine, New Haven, CT, the Department of
Pediatric Gastroenterology, Jacobi Medical Center, Bronx, NY, and the
jjDivision of Hospital Medicine, Connecticut Childrens Medical Center,
Hartford, CT.
Address correspondence and reprint requests to Danya Rosen, MD, One
Gustave L. Levy Place, Box 1656, New York, NY 10029 (e-mail:
danya.rosen@mssm.edu).
The authors report no conflicts of interest.
Copyright # 2015 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0000000000000257

JPGN

Volume 61, Number 2, August 2015

FIGURE 1. Percutaneous liver biopsy findings compatible with autoimmune hepatitis and hepatitis C virus infection. A, Portal tract with
interface hepatitis (H&E original magnification 200). B, Portal tract
with lymphocytic infiltrate suggestive of early lymphoid aggregate
formation. Reactive bile ducts are present (H&E original magnification
200). C, Lobular inflammation with spotty hepatocytes necrosis (H&E
original magnification 200). D, Closer view of portal tract with mild
interface hepatitis with plasma cells (H&E original magnification 400).

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Case Report

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Volume 61, Number 2, August 2015

40,000

400
Prednisone 20mg

350

35,000
30,000

300
Noncompliant

25,000

ALT (U/L)

250

20,000

200
Prednisone
10mg

Prednisone 15mg

150

15,000

Prednisone 7.5mg

Prednisone 10mg
Prednisone 5mg

100

10,000
5,000

50

0
0

12

16

20

24

28

32

36

40

44

48

74

88

95

144

Weeks of Treatment
HCV

ALT

FIGURE 2. Trend of alanine aminotransferase (ALT) and hepatitis C virus (HCV) RNA during treatment of HCV-AIH overlap syndrome.

On the basis of the clinical, laboratory, and pathologic

findings, a diagnosis of HCV-AIH type 2 overlap syndrome was
reached. The decision was made to begin treatment for HCV before
treating AIH, with concerns that first managing AIH with corticosteroids could precipitate acute liver failure (4). The patient was
given ribavirin 15 mg  kg1  day1 and weekly subcutaneous
pegylated IFN-2b, 60 mg/M2. Before treatment, HCV RNA was
36,100 IU/mL, with AST 124 U/L and ALT 171 U/L. She was a

rapid responder to the treatment with undetectable HCV RNA after

4 weeks of treatment (Fig. 2). She completed 48 weeks of antiviral
treatment and achieved SVR. After completing treatment for HCV,
AST and ALT increased to 369 and 401 U/L, respectively, and
quantitative IgG increased to 2.2 g/dL. The elevation of
liver enzymes likely reflected an AIH flare, and azathioprine
1 mg  kg1  day1 and prednisone 20 mg/day were given. Twelve
weeks later, AST and ALT had decreased to 117 and 132 U/L, and

TABLE 1. Review of published case reports on AIH-HCV overlap syndrome

Authors

Year of
publication

No.
patients

Age at
diagnosis, y

AIH
type

HCV
genotype

Initial
treatment

Secondary
treatment

Schiano
et al (2)

2001

Mean of 59

1 (6/7 patients
with
ASMA)

(2 nonresponders
with genotype 1)

Prednisone with
AZA or CsA

IFN  RBV

Peterson-Benz
et al (1)

2004

23

1b

Prednisone for
AIH at
50 mg/day

IFN-a2b
and RBV

Kogure
et al (4)

2007

27

1b

IFN-a2b
and RBV

Pulse steroids with

methylprednisolone

Azhar
et al (5)

2010

40

3a

Prednisone
and AZA

Oeda
et al (6)

2012

Mean of 50

2a, 1b

Prednisolone

AZA switched to
mycophenolate
mofetil because
of suboptimal
response, then
IFN RBV
IFN-a2b and RBV

Efe
et al (7)

2013

25 (20 with
HCV)

Mean of 48

1b (N 13),
1a (N 2),
2a (N 2),
2b (N 1),
3a (N 2)

Prednisone
 AZA

13/20 treated with

IFN  RBV
7 refused therapy

Length of
follow-up

Outcome
5/7 patients had
improvement in
ALT, IgG, and
histology, but not
viral eradication, 2/7
no response to CS
HCV RNA negative at
14 weeks
Relapse of AIH treated
with AZA CS
Fulminant hepatic
failure after 12 wk
of treatment for
HCV
RVR, SVR after 24 wk
Remission of AIH

HCV RNA negative at

8 wk
Remission of AIH
7/13 with SVR
6/13 nonresponders

Median
62 mo

8y

Not given

1y

3y

Not given

AIH autoimmune hepatitis; ALT alanine aminotransferase; ASMA anti-smooth muscle antibody; AZA azathioprine; CsA cyclosporine; CS corticosteroid; HCV hepatitis C
virus; IFN interferon; IgG immunoglobulin G; RBV ribavirin; RVR rapid virologic response; SVR sustained viral response.

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HCV RNA remained nondetectable. Prednisone was tapered and

HCV RNA remained negative (achieved SVR). Mild elevations in
liver enzymes during the next few months may have been the result
of noncompliance because the patient admitted to not taking her
medications, and pro-predict metabolite levels were subtherapeutic.
The patient is now 36 months post-HCV treatment with normal liver
enzymes, negative HCV RNA, and normal quantitative IgG. She
takes azathioprine and prednisone 5 mg/day.

DISCUSSION
Despite published reports on HCV and autoantibodies, HCVAIH overlap syndrome remains poorly elucidated and the treatment
approach continues to be controversial. To definitively diagnose
HCV-AIH overlap as a distinct entity, the existence of both diseases
must be confirmed independently (5,6). The adult literature has
favored initiating treatment for AIH followed by treatment for
HCV, because IFN can exacerbate AIH and even precipitate liver
failure (4). There is little evidence to support this approach in the
pediatric literature (Table 1).
This is the first case report of a pediatric patient with HCVAIH overlap syndrome. The diagnosis of overlap was based on HCV
viremia, persistently elevated autoantibodies, and liver histology that
demonstrated characteristics of both disease entities. The patient met
criteria for probable AIH according to 1999 IAIHG criteria, but
did not fulfill the AIH definition of the 2008 criteria; however, neither
scoring option is optimal in HCV-AIH because both include
absence of viral hepatitis as part of the diagnostic criteria (7).
The diagnosis of HCV-AIH was further confirmed by persistence of
elevated liver enzymes despite HCV eradication, response to steroids
and azathioprine, and relapse after remission.
Although the patient had a relatively low viral load at
presentation, subtype 1b has been shown to have lower rates of

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Case Report
SVR than subtype 1a (45% compared with 55%, P < 0.02) after
24 weeks of treatment with pegylated IFN and ribavirin (8). We had
success with treating HCV first and, depending on the clinic
scenario, would recommend doing this for future pediatric cases
of HCV-AIH, although more research and data are necessary.

REFERENCES
1. Peterson-Benz C, Kasper H, Dries K, et al. Differential efficacy of
corticosteroids and interferon in a patient with chronic hepatitis
C-autoimmune hepatitis overlap syndrome. Clin Gastroenterol Hepatol
2004;2:4403.
2. Schiano T, Te H, Thomas R, et al. Results of steroid-based therapy for the
hepatitis C-autoimmune hepatitis overlap syndrome. Am J Gastroenterol
2001;96:298491.
3. Fong TL, Valinluck B, Govindarajan S, et al. Short-term prednisone
therapy affects aminotransferase activity and hepatitis C virus RNA levels
in chronic hepatitis C. Gastroenterology 1994;107:1969.
4. Kogure T, Ueno Y, Fukushima K, 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;13:43947.
5. Azhar A, Niazi M, Tufail K, et al. A new approach for treatment of
hepatitis C in hepatitis C-autoimmune hepatitis overlap syndrome.
Gastroenterol Hepatol 2010;6:2336.
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7. Efe C, Wahlin S, Ozaslan E. Diagnostic difficulties, therapeutic strategies, and performance of scoring systems in patients with autoimmune
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8. Pellicelli A, Romano M, Stroffolini T, et al. HCV genotype 1a shows a
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BMC Gastroenterol 2012;12:1629.

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