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Postinfantile giant cell hepatitis associated with long-term elevated transaminase levels in treated Graves’ disease

      To the Editor:
      A 64-year-old woman presented with a 3-month history of fatigue, jaundice, abdominal distension, and orthopnea. She had persistently elevated transaminase levels that had been incidentally discovered 8 years before during thyroidectomy for Graves’ disease. They were attributed to her thyroid disease and remained elevated over the subsequent years.
      Her examination revealed icterus, stigmata of chronic liver disease, and an abdominal fluid wave without hepatosplenomegaly. Medications included thyroxine and a multivitamin. Laboratory data disclosed the following values: total bilirubin, 7.3 mg/dL (4.5 mg/dL conjugated); aspartate aminotransferase, 646 U/L; alanine aminotransferase, 372 U/L; alkaline phosphatase, 281 U/L; total protein, 4.5 mg/dL; albumin, 2.2 mg/dL; and ferritin, 500 ng/mL. Hepatitis B and C, antinuclear antibodies, and antimitochondrial serologies were negative, but anti–smooth muscle antibody serology was positive (1:80 titer). Thyroid-stimulating hormone level was 14 μIU/mL. Abdominal ultrasound revealed a normal heterogeneous liver, and a spleen sized at the upper limits of normal. Ascites analysis confirmed a noninfected transudative fluid. A liver biopsy revealed giant cell hepatitis and cirrhosis (Figure). Treatment for autoimmune hepatitis was initiated with oral prednisone, administered daily at 1.5 mg/kg. The patient’s transaminase levels improved initially; however, her clinical status deteriorated rapidly, and she died.
      Figure thumbnail gr1
      FigureLiver biopsy showing giant cell hepatitis and cirrhosis.
      Giant cell hepatitis encompasses a group of disorders with varying clinical presentations, etiologies, and other specific histologic findings (
      • Johnson S.J.
      • Mathew J.
      • MacSween R.N.
      • et al.
      Post-infantile giant cell hepatitis histological and immunohistochemical study.
      ,
      • Devaney K.
      • Goodman Z.D.
      • Ishak K.G.
      Postinfantile giant-cell transformation in hepatitis.
      ). Etiological factors include drugs (e.g., methotrexate), viruses (e.g., hepatitis A, B, and C; Epstein-Barr virus; paramyxoviruses), and autoimmune disorders, such as systemic lupus erythematosus (
      • Devaney K.
      • Goodman Z.D.
      • Ishak K.G.
      Postinfantile giant-cell transformation in hepatitis.
      ,
      • Cairns A.
      • McMahon R.F.
      Giant cell hepatitis associated with systemic lupus erythematosus.
      ,
      • Ben-Ari Z.
      • Broida E.
      • Monselise Y.
      • et al.
      Syncytial giant-cell hepatitis due to autoimmune hepatitis type II presenting as subfulminant hepatitis.
      ,
      • Phillips M.J.
      • Blendis L.M.
      • Poucell S.
      • et al.
      Syncytial giant-cell hepatitis sporadic hepatitis with distinctive pathological features, a severe clinical course, and paramyxoviral features.
      ,
      • Fimmel C.J.
      • Guo L.
      • Compans R.W.
      • et al.
      A case of syncytial giant cell hepatitis with features of a paramyxoviral infection.
      ). Adult hepatitis with extensive giant cell change is referred to as postinfantile giant cell hepatitis (
      • Johnson S.J.
      • Mathew J.
      • MacSween R.N.
      • et al.
      Post-infantile giant cell hepatitis histological and immunohistochemical study.
      ), which has been associated with high mortality and a rapidly progressive course in about half of patients, leading to death or the need for orthotopic liver transplantation (
      • Ben-Ari Z.
      • Broida E.
      • Monselise Y.
      • et al.
      Syncytial giant-cell hepatitis due to autoimmune hepatitis type II presenting as subfulminant hepatitis.
      ).
      We hypothesize that our patient had autoimmune hepatitis that eventually led to postinfantile giant cell hepatitis. What was striking was the 8-year history of asymptomatic elevated transaminase levels. In 29 patients with postinfantile giant cell hepatitis, only 3 had elevated transaminase levels for more than 1 year (
      • Johnson S.J.
      • Mathew J.
      • MacSween R.N.
      • et al.
      Post-infantile giant cell hepatitis histological and immunohistochemical study.
      ,
      • Devaney K.
      • Goodman Z.D.
      • Ishak K.G.
      Postinfantile giant-cell transformation in hepatitis.
      ). Most patients had elevated transaminase levels from 2 weeks to 8 months before diagnosis (
      • Devaney K.
      • Goodman Z.D.
      • Ishak K.G.
      Postinfantile giant-cell transformation in hepatitis.
      ).
      Another question raised was the association of thyroid disease and hepatitis, since our patient’s long-term elevated transaminase levels had been attributed to Graves’ disease. In hyperthyroidism, excess thyroid hormone causes hepatic tissue hypoxia owing to an increase in hepatic and splanchnic oxygen requirement (
      • Bayraktar M.
      • Van Thiel D.H.
      Abnormalities in measures of liver function and injury in thyroid disorders.
      ). Abnormalities of hepatic enzymes have been reported in as many as 76% of hyperthyroid patients, but the incidence of overt clinical hepatitis is less than 1% (
      • Thompson Jr, P.
      • Strum D.
      • Boehm T.
      • Wartofsky L.
      Abnormalities of liver function tests in thyrotoxicosis.
      ). Hypothyroidism also affects the liver by increasing bilirubin UDP-glucoronyl transferase activity, reducing p-nitrophenol transferase activity, reducing bile flow and excretion, and increasing the proportion of conjugated bilirubin (
      • Thompson Jr, P.
      • Strum D.
      • Boehm T.
      • Wartofsky L.
      Abnormalities of liver function tests in thyrotoxicosis.
      ). Notably, abnormalities in liver tests normalize once the thyroid disease is recognized and treated.
      Postinfantile giant cell hepatitis encompasses a heterogeneous group of disorders and should be considered in patients with long-standing hepatitis of unclear etiology, especially if associated with antecedent autoimmune disease.

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