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Excerpt
A 69-year-old man was admitted to our hospital because of general malaise, anorexia, jaundice and pruritus. He was given ticlopidine because of a cerebral infarction, after which, he presented with the above symptoms. Blood chemistries showed liver dysfunction and hyperbilirubinemia alanine transaminase (ALT), 455IU/L; asparate transaminase (AST), 190IU/l; total bilirubin, 8.2mg/dl; γ-glutamyltranspeptidase (γ-GTP), 806IU/L. Serological analysis was negative for HBsAg, HBsAb, HBeAg, HBeAb, IgM-HBc Ab, HCV Ab, and IgM-HA Ab. Anti-nuclear antibody was negative. An abdominal ultrasound scan showed normal liver and no evidence of obstructive jaundice. The patient was diagnosed with acute intrahepatic cholestasis induced by ticlopidine. Ticlopidine was discontinued, and the liver enzymes and T-bilirubin levels improved. However, a normocytic, normochronic anemia gradually developed, and reticulocytes disappeared. On the 16th day after admission, bone marrow smears showed marked depletion in the erythroblastic series (0.7%), with no abnormality in the granulocytic and megakaryocytic series. Based on these findings, the patient was diagnosed as having pure red cell aplasia (PRCA). As his hemoglobin concentration decreased rapidly, 5 units (2000 ml) of packed red cells were administered. Although no other treatment was given for anemia, hypoplasia of the erythroblastic series was transient and the anemia gradually improved. On the 35th day after admission, bone marrow smears showed improved eryhroblastic bone marrow series. Reticulocytes in the peripheral blood (5.2%) were present. On the 43rd day after admission, laparoscopy and biopsy of the liver was performed. Intrahepatic cholestasis was observed. The patient was diagnosed with acute intrahepatic cholestasis associated with pure red cell aplasia due to ticlopidine.
Ticlopidine is widely used for cerebrovascular or cardiovascular disease. Adverse effects of ticlopidine include allergic skin rash, gastrointestinal symptoms (nausea etc), bone marrow toxicity, and elevation of liver function tests. Ticlopidine induced mild elevations in serum liver enzymes are observed in some studies with a 1% to 2% incidence. The incidence of severe hepatitis is estimated at 0.0013%. Only a few cases of a severe cholestatic pattern of liver injury have been reported. In such cases, liver biopsies demonstrated centro-acinar cholestasis. 5 In our case, liver biopsy showed intrahepatic cholestasis, compatible with a drug-induced liver damage.
PRCA is an uncommon disease. It is almost always associated with a recent viral disease, although multiple causes have been described as a result of exposure to drugs or chemicals, infections, thymoma, or Adult Still Disease. 1 Reports associated PRCA with lamivudine, 3 HCV infection, 4 and acute hepatitis A. 2 The exact mechanism that causes the disorder is unknown, possibly associated with the immune system. Possible mechanisms for PRCA include IgG-mediated destruction in the presence of the offending drug and a direct effect on DNA synthesis. Autoantibody mechanisms also were proposed for the drug-induced blood cell dyscrasias.
The diagnosis of PRCA in this patient was based on the progression of normocytic, normochromic anemia with normal megakaryocyte and leukocyte counts and an absence of erythroid precursors. Ticlopidine induced acute cholestatic hepatitis complicated with pure red cell aplasia is rare.
