Anti-mitochondrial antibody positive autoimmune hepatitis triggered by EBV infection in a young girl

Arab Journal of Gastroenterology 14 (2013) 130–132

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Case Report

Anti-mitochondrial antibody positive autoimmune hepatitis triggered by EBV infection in a young girl Omar I. Saadah a,⇑, Rana Y. Bokhary b a b

Department of Paediatrics, King Abdulaziz University, Jeddah, Saudi Arabia Department of Anatomical Pathology, King Abdulaziz University, Jeddah, Saudi Arabia

a r t i c l e

i n f o

Article history: Received 6 April 2012 Accepted 30 May 2013

Keywords: Autoimmune hepatitis Epstein Barr virus Anti-mitochondrial Child Saudi Arabia

a b s t r a c t Autoimmune hepatitis (AIH) is rare in children. Two types of childhood autoimmune hepatitis are recognized: AIH type 1 which is characterized by the presence of smooth muscle (SMA) and/or antinuclear (ANA) antibodies; and AIH type 2 which is positive for anti-liver kidney microsomal type 1 (anti-LKM1) antibody. Anti-mitochondrial antibody (AMA) is considered the hallmark for primary biliary cirrhosis (PBC) that occurs primarily in adult women and is characterized by destruction of the intralobular bile ducts and progression to cirrhosis and liver failure. Antimitochondrial-antibody-positive AIH is extremely rare in children. We report a 13 year old Saudi girl with type-1 AIH who had a strongly positive anti-mitochondrial antibody and no evidence of small bile duct disease in the liver biopsy. Ó 2013 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.

Introduction

Case report

Autoimmune liver disorders in children are inflammatory liver diseases. Histologically they are characterized by a dense mononuclear infiltrate in the portal tracts, and serologically by the presence of non-organ and liver specific autoantibodies as well as increased levels of transaminases and IgG, in the absence of known aetiology [1]. Two types of childhood autoimmune hepatitis (AIH) are recognized: AIH type 1 which is characterized by the presence of smooth muscle (SMA) and/or antinuclear (ANA) antibodies; and AIH type 2 which is positive for anti-liver kidney microsomal type 1 (anti-LKM-1) antibody [2]. Anti-mitochondrial antibody (AMA) is considered the hallmark for primary biliary cirrhosis (PBC) that occurs primarily in adult women and is characterized by destruction of the intralobular bile ducts that may eventually lead to cirrhosis and liver failure [3,4]. The occurrence of PBC in paediatric populations is rare [5]. The presence of AMA has been described in adults with autoimmune hepatitis with no evidence of bile duct damage [6], however, to the best of our knowledge the occurrence in children with AIH has been reported only once [7]. Herein, we report another case of antimitochondrial-antibodypositive AIH in a young girl that we think was potentially triggered by EBV infection.

A 13-year-old Saudi girl who had a history of progressive jaundice, itching and lethargy of 3 weeks duration; associated with changes in the colour of urine and stool; was first diagnosed at the age of 7 years (in July 2004). There was no history of previous operations, blood transfusion or recent use of hepatotoxic medications. Parents are first degree cousins. The mother had a history of autoimmune disease in the form of systemic lupus erythematosus. On physical examination, she had pallor, jaundice, cervical lymphadenopathy and hepatosplenomegaly. Her vital signs were normal. Basic laboratory investigations at presentation are shown in Table 1. Serum a1–antitrypsin, copper, and ceruloplasmin levels were normal. Serological screening for viral hepatitis which included hepatitis B surface antigen, hepatitis A and C, cytomegalovirus, and herpes simplex antibodies; was negative. IgG and IgM Epstein Barr Virus (EBV) antibodies were positive. Serum anti-nuclear antibody (ANA) was positive at 1:640, and serum anti-smooth muscle antibody (SMA) was weakly positive. Serum anti-liver kidney microsomal antibody (LKM-1) was negative. Anti-mitochondrial antibody (AMA) was not tested initially. Ultrasonography of the abdomen showed hepatosplenomegaly with coarse echotexture of the liver and no ascites. A liver biopsy was performed after correction of her deranged coagulation and it showed marked portal lymphocytic infiltrate with scattered plasma cells and significant portal-parenchymal interface activity (Fig. 1A). Mild lobular inflammation with scattered single-cell necrosis was observed (Fig. 1B). However,

⇑ Corresponding author. Address: Department of Paediatrics, Faculty of Medicine, King Abdulaziz University, P.O. Box 80215, Jeddah 21589, Jeddah, Saudi Arabia. Tel.: +966 (2) 6408203; fax: +966 (2) 6408353. E-mail address: [email protected] (O.I. Saadah).

1687-1979/$ - see front matter Ó 2013 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ajg.2013.05.006

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O.I. Saadah, R.Y. Bokhary / Arab Journal of Gastroenterology 14 (2013) 130–132 Table 1 Summary of the laboratory results. Reference range 3

Leukocytes count  10 /lL Haemoglobin (g/dl) Platelet count (103/lL) Prothrombin time (s) Activated partial thrombin time (s) Aspartate aminotransferase (IU/L) Alanine aminotransferase (IU/L) Alkaline phosphatise (IU/L) c-Glutamyl transferase (IU/L) Total bilirubin (lmol/L) Serum albumin (g/L) Serum globulin (g/L) Immunoglobulin G (g/L) Immunoglobulin M (g/L) Immunoglobulin A (g/L)

4–10 12–14 150–450 10–12 25–39 10–35 12–33 100–500 10–47 <17 36–40 23–35 5.4–16.1 0.5–1.9 0.8–2.8

1400

Result 4.8 8.4 443 18 73 1269 278 235 86 135 20 104 19.4 2.77 2.81

Transaminase level (IU/L)

Variable

1600

second flare up First presentation

Third flare up

1200 1000 800 600

First flare up

400 200 0 04

05

06

07

08

09

10

11

12

Follow up (years)

there was no evidence of bridging necrosis, giant-cell transformation, florid duct lesion, granulomas or fibrosis. Few hepatitic rosettes were observed in the parenchyma (Fig. 1C) with mild intracellular cholestasis (Fig. 1D). Taking in consideration the above mentioned parameters, the diagnosis of AIH was probable with a score of 13 according to the criteria published by the International Autoimmune Hepatitis Group [8]. And a score of six according to the most recent simplified criteria for the diagnosis of AIH was published by Hennes et al. [9]. Based on the liver biopsy findings; this patient was treated with corticosteroid dose of 2 mg/kg/day that showed improvement in the activity of liver enzymes. Similarly, the liver synthetic function was enhanced including albumin level and coagulation profile. Subsequently this patient was maintained on azathioprin and oral prednsiolone and the liver function was maintained within normal range. She had three episodes of flare up of her disease during the follow-up period. These were managed by corticosteroid pulse therapy (Fig. 2).

AST ALT

Fig. 2. Changes in the level of transaminases levels during follow up.

Repeated assessment in March 2010, at the age of 13, revealed normal liver functions test, albumin and globulin levels, and coagulation profile. Anti-nuclear antibody was positive at 1:320 with speckled pattern. Anti-mitochondrial antibody (M2), performed for the first time, was strongly positive. This unexpected finding suggested at the beginning the possibility of primary biliary cirrhosis or overlap syndrome. A repeat liver biopsy was performed and showed significant improvement in the portal inflammation with minimal interface hepatitis (Fig. 3A) and no parenchymal inflammation. Again there was no evidence of granulomas or florid duct lesions and the bile ducts were normal. However, there was mild expansion of the portal tracts with fibrosis and short periportal fibrous spikes were observed (Fig. 3B). These findings excluded both

Fig. 1. Initial liver biopsy. (A) Marked portal lymphoplasmacytic infiltrate with interface hepatitis (haematoxylin and eosin stain, 20 magnification). (B) Lobular necroinflammatory activity with rare parenchymal single-cell necrosis (haematoxylin and eosin stain, 20 magnification). (C) Pernchymal hepatitic rosettes (haematoxylin and eosin stain, 20 magnification). (D) Mild intracellular cholestasis.

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O.I. Saadah, R.Y. Bokhary / Arab Journal of Gastroenterology 14 (2013) 130–132

Her liver function tests have been normal apart from three episodes of flare up which were treated with pulse therapy of intravenous methylprednisolone. The liver biopsy that was performed at the age of 13 was better compared to the initial biopsy and both showed no evidence of bile duct damage or significant cholestais. However, the serological testing revealed the presence of ANA and strongly positive AMA. The paper of Gregorio et al. [7] was the first to report a 12 year old girl with AMA-positive AIH. Our patient fulfils the criteria for such a diagnosis as supported by the presence of high AMA titre and the absence of bile duct damage in the liver biopsy. Although rare in the paediatric age group [5], PBC may be observed in the presence of positive AMA. However, this disease usually presents with progressive cholestasis and intractable pruritus with associated high level of IgM and small bile duct disease in the liver biopsy which is not the situation in our patient. In summary, we are reporting an additional case of paediatric AMA-positive AIH. However, the long-term natural history remains unknown. With increased awareness among physicians more paediatric cases may be discovered. Conflict of interest The authors declared that there was no conflict of interest. References

Fig. 3. Repeated liver biopsy. (A) Significant improvement in the portal inflammation with minimal interface hepatitis and normal bile ducts (arrow showing the bile duct) (haematoxylin and eosin stain, 10 magnification). (B) Mild expansion of the portal tract with fibrosis and short periportal fibrous spikes (reticulin stain, 10 magnification).

first thought of possibilities and supported the diagnosis of antimitochondrial positive autoimmune hepatitis. Discussion Autoimmune hepatitis is rare in children. The long-term outcome is favourable if diagnosed and treated early with immunosuppressive therapy irrespective of presenting clinical, laboratory or histological features [10]. The pathogenesis of autoimmune hepatitis entails complex interactions between triggering factors, autoantigens, genetic predisposition, and immunoregulatory network. Implicated triggering factors are numerous and include toxins, medications, and infectious agents [11,12]. Viral infections have been proposed as a potential trigger to AIH. The strongest evidence is probably related to hepatitis A virus (HAV) infection [13,14]. AIH can also be triggered by HAV vaccine that contains the whole viral particles that are inactivated with formalin [15]. EBV has been reported as a potential trigger for AIH [16–18]. Other viruses such as CMV have been implicated [19–21]. Our patient had evidence of EBV infection in the form of positive IgG and IgM serology. The clinical presentation at the onset of the disease is suggestive of EBV infection with cervical lymphadenopathy and hepatosplenomegaly which disappeared during the follow-up. This patient has been followed up for 6 years and was kept on regular treatment with low dose prednisolone and azathioprine.

[1] Krawitt EL. Autoimmune hepatitis. N Engl J Med 2006;354(1):54–66. [2] Gregorio GV, Portmann B, Reid F, et al. Autoimmune hepatitis in childhood: a 20-year experience. Hepatology 1997;25(3):541–7. [3] Sherlock S, Scheuer PJ. The presentation and diagnosis of 100 patients with primary biliary cirrhosis. N Engl J Med 1973;289(13):674–8. [4] Kaplan MM. Primary biliary cirrhosis. N Engl J Med 1996;335(21):1570–80. [5] Dahlan Y, Smith L, Simmonds D, et al. Pediatric-onset primary biliary cirrhosis. Gastroenterology 2003;125(5):1476–9. [6] O’Brien C, Joshi S, Feld JJ, Guindi M, Dienes HP, Heathcote EJ. Long-term followup of antimitochondrial antibody-positive autoimmune hepatitis. Hepatology 2008;48(2):550–6. [7] Gregorio GV, Portmann B, Mowat AP, Vergani D, Mieli-Vergani G. A 12-yearold girl with antimitochondrial antibody-positive autoimmune hepatitis. J Hepatol 1997;27(4):751–4. [8] 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(5):929–38. [9] Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008;48(1):169–76. [10] Saadah OI, Smith AL, Hardikar W. Long-term outcome of autoimmune hepatitis in children. J Gastroenterol Hepatol 2001;16(11):1297–302. [11] Bjornsson E, Talwalkar J, Treeprasertsuk S, et al. Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology 2010;51(6):2040–8. [12] Watkins PB, Seeff LB. Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology 2006;43(3):618–31. [13] Huppertz HI, Treichel U, Gassel AM, Jeschke R, Meyer zum Buschenfelde KH. Autoimmune hepatitis following hepatitis A virus infection. J Hepatol 1995;23(2):204–8. [14] Singh G, Palaniappan S, Rotimi O, Hamlin PJ. Autoimmune hepatitis triggered by hepatitis A. Gut 2007;56(2):304. [15] Berry PA, Smith-Laing G. Hepatitis A vaccine associated with autoimmune hepatitis. World J Gastroenterol 2007;13(15):2238–9. [16] Nakajima S, Umebayashi H, Kurosawa R, et al. A case of autoimmune hepatitis needed to be differentiated from EBV hepatitis, in that the histology of liver biopsy specimen was useful for diagnosis. Nihon Rinsho Meneki Gakkai Kaishi 2005;28(3):154–8. [17] Vento S, Guella L, Mirandola F, et al. Epstein–Barr virus as a trigger for autoimmune hepatitis in susceptible individuals. Lancet 1995;346(8975):608–9. [18] Sevilla J, Del Carmen Escudero M, Jimenez R, et al. Severe systemic autoimmune disease associated with Epstein–Barr virus infection. J Pediatr Hematol Oncol 2004;26(12):831–3. [19] Castellote J, Guell E, Porta F. Autoimmune hepatitis following cytomegalovirus infection. Med Clin (Barc) 2001;117(2):76. [20] Mouelhi L, Debbeche R, Salem M, et al. Autoimmune hepatitis type 1 triggered by cytomegalovirus infection. One rare case report. Tunis Med 2010;88(9):674–7. [21] Toyoda-Akui M, Yokomori H, Kaneko F, et al. Association of an overlap syndrome of autoimmune hepatitis and primary biliary cirrhosis with cytomegalovirus infection. Int J Gen Med 2011;4:397–402.