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Azathioprine-Induced Lymphoma Manifesting as Fulminant Hepatic Failure

      Azathioprine and rheumatoid arthritis are known to be associated with an increased risk of the development of non-Hodgkin's lymphoma; however, the manifestation of fulminant hepatic failure is extremely uncommon in patients with non-Hodgkin's lymphoma. In this article, we describe a patient with rheumatoid arthritis who was taking azathioprine, in whom fulminant hepatic failure occurred because of massive lymphomatous infiltration of the liver.
      Liver involvement with non-Hodgkin's lymphoma is common. Autopsy studies report that the frequency of secondary involvement is as high as 30 to 70%.
      • Birrer MJ
      • Young RC
      Differential diagnosis of jaundice in lymphoma patients.
      Long-standing rheumatoid arthritis and long-term use of immunosuppressive drugs (for example, azathioprine) have previously been identified as risk factors for the development of non-Hodgkin's lymphoma.
      • Urowitz MB
      • Lee P
      The risks of antimalarial retinopathy, azathioprine lymphoma and methotrexate hepatotoxicity during the treatment of rheumatoid arthritis.
      Liver involvement is typically asymptomatic and suspected only because of biochemical signs of cholestasis. Jaundice is noted at the time of lymphoma manifestation in less than 0.3% of cases.
      • Rosenberg SA
      • Diamond HD
      • Jaslowitz B
      • Craver LF
      Lymphosarcoma: a review of 1269 cases.
      We describe a patient who was taking azathioprine for rheumatoid arthritis, who had development of fulminant hepatic failure due to lymphomatous liver involvement. Initial manifestations were jaundice and substantially abnormal results of liver function tests. She died 3 weeks after symptoms had developed.

      REPORT OF CASE

      A 50-year-old woman with a 15-year history of rheumatoid arthritis had been taking azathioprine for 5 years. The initial dosage of 150 mg per day provided excellent symptomatic control; however, the dosage was decreased to 100 mg daily after 2 years because of mild leukopenia. Other complications were not noted, and 6 months before admission, liver test results were normal (Table 1).
      Table 1Results of Liver Function Tests Performed Before and During Hospitalization of Patient With Lymphoma
      Results
      Test (normal range)6 mo before admissionDay 1Day 5Day 7
      Aspartate aminotransferase (12-31 U/L)251853201,150
      Alkaline phosphatase (84-218 U/L)180600650810
      Total bilirubin (0.1-1.1 mg/dL)0.58.220.221.3
      Prothrombin time (8-12 s)1111.515.320.6
      Two weeks before admission, the patient had epigastric pain, nausea, vomiting, and jaundice. Physical examination revealed severe jaundice and hepatomegaly; findings on the rest of her physical examination, including the neurologic examination, were normal. She had no evidence of intercurrent infection and no history of other hepatotoxic medication.
      Initial laboratory evaluation yielded a negative viral hepatitis screen (A, B, and C), normal complete blood cell count, and substantially abnormal liver test results (Table 1). Ultrasonography of the abdomen showed multiple nodular masses in both lobes of the liver with no bile duct dilatation or gallstones (Fig. 1). She was transferred to our institution for further assessment.
      Figure thumbnail gr1
      Fig. 1Abdominal ultrasonogram, showing multiple hypoechoic masses (arrows) within liver.
      On admission, the patient's physical condition was unchanged. Although hemodynamically stable, she had development of nonoliguric renal failure. An abdominal computed tomographic scan (without use of contrast medium) showed only retroperitoneal lymphadenopathy. The liver appeared normal. A liver biopsy yielded the diagnosis of anaplastic large cell lymphoma, T-cell pheno-type.
      Despite supportive therapy, the patient had development of encephalopathy and oliguria. The prothrombin time was substantially prolonged (Table 1) and did not correct with parenteral administration of vitamin K. Chemotherapy was initiated with high-dose methylprednisolone and nitrogen mustard. The patient became comatose, had development of disseminated intravascular coagulation, and died on the seventh hospital day.

      PATHOLOGIC FINDINGS

      Fine-needle aspiration biopsy of the liver demonstrated a core of hepatic tissue completely replaced by an infiltrate of pleomorphic, cytologically malignant large cells (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Fine-needle aspiration liver biopsy specimen, showing that anaplastic large cell lymphoma cells have effaced liver architecture and totally displaced hepatocytes. Note widespread pleomorphism of neoplastic cells including multinucleated cells. (Hematoxylin-eosin; original magnification, ×400.)
      Immunoperoxidase stains (Fig. 3) performed on formalin-fixed paraffin-embedded tissue sections showed that these large neoplastic cells were positive for CD45 (leukocyte common antigen), CD45RO (T-cell marker UCHL-1), and CD30 (BerH2) but negative for CD20 (B-cell marker L26). In situ hybridization studies, performed with use of a digoxigenin-labeled nuclear acid probe to Epstein-Barr virus-related nuclear RNA, were negative.
      Figure thumbnail gr3
      Fig. 3Immunoperoxidase stain with use of antibody to CD30 (BerH2), showing uniform, strong membrane staining of lymphoma cells. (Original magnification, ×400.)
      The data from the histomorphologic and immunopheno-typic studies were diagnostic for malignant lymphoma, anaplastic (CD30+) large cell type, T-cell phenotype.

      DISCUSSION

      Fulminant hepatic failure is an uncommon condition that usually manifests as a complication of viral hepatitis, autoimmune hepatitis, adverse drug reaction, or Wilson's disease.
      • Hoofnagle JH
      • Carithers Jr, RL
      • Shapiro C
      • Ascher N
      Fulminant hepatic failure: summary of a workshop.
      The development of fulminant hepatic failure due to lymphoma has been reported;
      • Salo J
      • Nomdedeu B
      • Bruguera M
      • Ordi J
      • Gines P
      • Castells A
      Acute liver failure due to non-Hodgkin's lymphoma.
      however, fulminant hepatic failure as the initial manifestation of lymphoma is very uncommon.
      • Colby TV
      • LaBrecque DR
      Lymphoreticular malignancy presenting as fulminant hepatic disease.
      Long-standing rheumatoid arthritis and long-term use of immunosuppressive drugs have previously been identified as risk factors for the development of non-Hodgkin's lymphoma.
      • Urowitz MB
      • Lee P
      The risks of antimalarial retinopathy, azathioprine lymphoma and methotrexate hepatotoxicity during the treatment of rheumatoid arthritis.
      The most firmly established cause of non-Hodgkin's lymphoma is immune impairment, including drug-induced (azathioprine and cyclosporine) and viral (human immunodeficiency virus).
      • Kinlen L
      Immunosuppressive therapy and acquired immunological disorders.
      Rheumatoid arthritis alone has been associated with a 2.5-fold increased risk of lymphoma. The risk is increased to 10-fold when the patient is taking azathioprine.
      • Kinlen L
      Immunosuppressive therapy and acquired immunological disorders.
      Typically, such lymphomas are of B-cell phenotype and are most often associated with Epstein-Barr virus infection.
      Our patient, who had been taking an immunosuppressive drug for 5 years for rheumatoid arthritis, had development of fulminant hepatic failure due to massive lymphomatous infiltration of the liver. The lymphoma was of anaplastic (CD30+) large cell type, T-cell phenotype, and was not associated with Epstein-Barr virus. To our knowledge, this is the first case of fulminant hepatic failure caused by a lymphoma in a patient with rheumatoid arthritis who was receiving long-term immunosuppressive therapy. In fact, none of the previous reports of lymphomas manifesting as fulminant hepatic failure have been associated with rheumatoid arthritis.
      Lymphoma manifesting as fulminant hepatic failure is an uncommon but deadly complication. The diagnostic approach in patients with rapidly deteriorating liver function must be aggressive. If lymphoma is a consideration, a liver biopsy should be performed early, especially if other causes of fulminant hepatic failure have been ruled out. Even if coagulopathy is present, a transjugular biopsy
      • McAfee JH
      • Keeffe EB
      • Lee RG
      • Rosch J
      Transjugular liver biopsy.
      should be attempted in order to obtain diagnostic tissue, inasmuch as chemotherapy may induce remission of the lymphoma if it is initiated before the development of liver failure.
      • Zafrani ES
      • Leclercq B
      • Vernant JP
      • Pinaudeau Y
      • Chomette G
      • Dhumeaux D
      Massive blastic infiltration of the liver: a cause of fulminant hepatic failure.
      Our patient's rapid clinical deterioration precluded successful treatment.
      Orthotopic liver transplantation, often the primary treatment of fulminant hepatic failure
      • Hoofnagle JH
      • Carithers Jr, RL
      • Shapiro C
      • Ascher N
      Fulminant hepatic failure: summary of a workshop.
      when supportive medical therapy has failed, is contraindicated in patients with lymphoma because of the potential systemic nature.

      CONCLUSION

      This report describes an unusual case of fulminant hepatic failure caused by anaplastic CD30+ large cell, T-cell lymphoma associated with long-term immunosuppressive therapy in a patient with rheumatoid arthritis.

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