CASE REPORT

Hepatitis C Virus-Autoimmune Hepatitis Overlap Syndrome in an Adolescent

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§

Danya Rosen, yJaime Chu, zRaffaella Morotti, Daniela Levanon, ySamantha Rose, jjSamantha Lee, and yRonen Arnon

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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 Children’s 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: [email protected]). 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

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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 0

4

8

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

7

Mean of 59

1 (6/7 patients with þ ASMA)

(2 nonresponders with genotype 1)

Prednisone with AZA or CsA

IFN  RBV

Peterson-Benz et al (1)

2004

1

23

2

1b

Prednisone for AIH at 50 mg/day

IFN-a2b and RBV

Kogure et al (4)

2007

1

27

2

1b

IFN-a2b and RBV

Pulse steroids with methylprednisolone

Azhar et al (5)

2010

1

40

1

3a

Prednisone and AZA

Oeda et al (6)

2012

2

Mean of 50

1

2a, 1b

Prednisolone

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

Efe et al (7)

2013

25 (20 with HCV)

Mean of 48

1b (N ¼ 13), 1a (N ¼ 2), 2a (N ¼ 2), 2b (N ¼ 1), 3a (N ¼ 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 þ 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 ¼ autoimmune hepatitis; ALT ¼ alanine aminotransferase; ASMA ¼ anti-smooth muscle antibody; AZA ¼ azathioprine; CsA ¼ cyclosporine; CS ¼ corticosteroid; HCV ¼ hepatitis C virus; IFN ¼ interferon; IgG ¼ immunoglobulin G; RBV ¼ ribavirin; RVR ¼ rapid virologic response; SVR ¼ 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;2:440–3. 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;96:2984–91. 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;107:196–9. 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;13:4394–7. 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;6:233–6. 6. Oeda S, Mizuta T, Isoda H, et al. Efficacy of pegylated interferon plus ribavirin in combination with corticosteroid for two cases of combined hepatitis C and autoimmune hepatitis. Clin J Gastroenterol 2012;5: 141–5. 7. Efe C, Wahlin S, Ozaslan E. Diagnostic difficulties, therapeutic strategies, and performance of scoring systems in patients with autoimmune hepatitis and concurrent hepatitis B/C. Scand J Gastroenterol 2013; 48:504–8. 8. Pellicelli A, Romano M, Stroffolini T, et al. HCV genotype 1a shows a better virological response to antiviral therapy than HCV genotype 1b. BMC Gastroenterol 2012;12:162–9.

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Hepatitis C Virus-Autoimmune Hepatitis Overlap Syndrome in an Adolescent.

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