Hepatitis C virus (HCV) infection is a major public health issue. In developed countries, HCV accounts for 20% of cases of acute hepatitis, 70% of cases of chronic hepatitis, 40% of cases of end-stage cirrhosis, 60% of cases of hepatocellular carcinoma, and 30% of liver transplants . Moreover, extrahepatic manifestations of chronic HCV infection are clinically present in almost 40% of infected patients. These manifestations include essential mixed cryoglobulinemia, sicca syndrome, membranoproliferative glomerulonephritis, thrombocytopenia, and autoimmune hemolytic anemia (AIHA) .
Hepatitis-associated aplastic anemia (HAA) is a not uncommon syndrome in patients with bone marrow failure, with hepatitis documented in 2 to 5% of cases of aplastic anemia (AA) occurring in the West [3, 4] and 4 to 10% in the Far East . Characteristically, the HAA syndrome is more prevalent among young men. The hepatitis generally follows a benign course, but the onset of AA two to three months later is usually fatal if left untreated. HAA may be induced by the presence of HCV or hepatitis B virus infection, and also by infections with other viruses such as human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), transfusion-transmitted virus and echovirus . However, most cases of HAA are seronegative for the known hepatitis viruses, including hepatitis A, B, C, and G (GB virus C) . The clinical features of the syndrome and the patient's response to immunosuppressive treatment strongly indicate that the liver and marrow abnormalities in patients with HAA are immune-mediated [8, 9].
Pegylated interferon alpha 2a (PEG-IFN-α 2a) or 2b plus ribavirin is currently the standard regimen for patients with HCV infection. A wide range of adverse reactions, including flu-like symptoms, nausea, anorexia, diarrhea, psychiatric symptoms, alopecia, injection-site reactions, leukopenia, thrombocytopenia, hemolytic anemia, cough, dyspnea, rash, pruritus, insomnia, and ataxia, have been associated with PEG-IFN-α 2a plus ribavirin treatment. Treatment with interferon (IFN)-α has also been reported to trigger autoimmune phenomena in up to 3% of cases, with AIHA being the most prevalent and most significant phenomena seen in clinical practice . Furthermore, due to its inhibition of cellular growth, interference with oncogene expression and augmentation of lymphocyte cytotoxicity for target cells, IFN-α may cause bone marrow suppression, including potentially severe cytopenias and, very rarely, AA .
The primary observed serious adverse side effect of ribavirin treatment is hemolytic anemia. Ribavirin is an antiviral nucleoside analogue; the mechanism of ribavirin-induced hemolytic anemia has not been clearly established. Anemia is most likely related to extensive ribavirin accumulation in erythrocytes subsequent to active unidirectional transmembraneous transport. Ribavirin exerts its toxicity through an inhibition of intracellular energy metabolism and oxidative membrane damage, leading to an accelerated extravascular hemolysis by the reticulo-endothelial system . Lau et al. describe how ribavirin, following uptake into cells, is phosphorylated and converted to ribavirin triphosphates, which then must be dephosphorylated for elimination from the cells . However, because red blood cells lack dephosphorylation enzymes, ribavirin accumulates in cells and destroys them, causing hemolytic anemia. Severe anemia develops in about 10% of patients treated with ribavirin, and they require close monitoring of hemoglobin (Hb) levels and often ribavirin dose reduction, which may compromise sustained virologic response.
Herein, we report the development of AA in a patient with chronic HCV infection following treatment with PEG-IFN-α 2a plus ribavirin. By reviewing the literature on the subject and the course of the patient's disease, we have come to the conclusion that, on balance, the development of AA was a side effect of the patient's treatment with PEG-IFN-α 2a within a facilitating genetic and environmental background.