Ribavirin-Induced Pure Red-Cell Aplasia during Treatment of Chronic Hepatitis C
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《新英格兰医药杂志》
To the Editor: Interferon and ribavirin in combination are the standard treatment for chronic hepatitis C. Hematologic abnormalities, including thrombocytopenia and anemia, are major side effects.1 Ribavirin is closely associated with hemolytic anemia.2 We report a case of severe anemia due to acute pure red-cell aplasia during combination therapy, which rapidly improved after the discontinuation of ribavirin.
A 61-year-old man was admitted for treatment of chronic hepatitis C. He had received a blood transfusion after hemorrhoidectomy at the age of 30 years. Abnormal results on liver-function tests and antibody to hepatitis C virus (HCV) had been detected at a health checkup when the man was 55 years of age. His body weight was 75 kg, and physical examination showed only mild hepatomegaly. Laboratory tests demonstrated elevated alanine aminotransferase levels. The hemoglobin level and reticulocyte count were normal. A test for HCV RNA by the polymerase chain reaction was positive at a level above 850,000 IU per milliliter; the genotype was 1b. A liver biopsy showed chronic inflammation with portal fibrosis.
Treatment with interferon alfa-2b (Intron A, 6 million units) and ribavirin (Rebetol, 800 mg) was started. Eight weeks after the initiation of the treatment, the ribavirin dose was reduced to 600 mg per day because the hemoglobin level had decreased from 15.5 g per deciliter to 8.0 g per deciliter. Three weeks later, however, the hemoglobin level dropped to 6.0 g per deciliter even after the reduction in the dose of ribavirin. The reticulocyte count dropped from 7.8x104 per microliter to 0.2x104 per microliter. During the treatment, no changes in the indirect bilirubin, lactate dehydrogenase, or haptoglobin level were observed.
Bone marrow examination at week 12 showed mild hypocellularity without any morphologic abnormalities and a selective depletion of erythroid precursor cells (Figure 1). On the basis of these findings, a diagnosis of acute pure red-cell aplasia was made, and ribavirin was discontinued. Thereafter, the anemia and reticulocytopenia improved and had normalized by week 24. Administration of interferon was continued for 24 weeks and resulted in a sustained virologic response.
Figure 1. Findings on Microscopical Examination of Bone Marrow 12 Weeks after the Initiation of Combination Treatment with Interferon and Ribavirin (Wright–Giemsa Stain, x1000).
The nuclear cell count was 8.6x104 per microliter (normal range, 10x104 to 25x104 per microliter), and the ratio of myeloid to erythroid precursors was 5.8 (normal range, 2 to 4). No morphologic abnormalities were found in precursor cells.
Acute pure red-cell aplasia is characterized by rapidly progressive anemia with reticulocytopenia and is caused by viral infection, certain drugs, and nutritional disorders.3 Ribavirin induced dose-related anemia, erythroid hypoplasia, and vacuolization of erythroid precursors in rhesus monkeys, which disappeared after the discontinuation of ribavirin.4,5 We believe that our patient had acute pure red-cell aplasia caused by ribavirin used in the treatment of chronic hepatitis C. When anemia develops during treatment with interferon and ribavirin, the possibility of ribavirin-induced pure red-cell aplasia should be considered, and careful monitoring of the reticulocyte count is needed.
Naoki Tanaka, M.D., Ph.D.
Fumihiro Ishida, M.D., Ph.D.
Eiji Tanaka, M.D., Ph.D.
Shinshu University School of Medicine
Matsumoto 390-8621, Japan
etanaka@hsp.md.shinshu-u.ac.jp
References
Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology 2002;36:Suppl:S237-S244.
De Franceschi L, Fattovich G, Turrini F, et al. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology 2000;31:997-1004.
Erslev AJ. Pure red cell aplasia. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, eds. Williams hematology. 6th ed. New York: McGraw-Hill, 2001:391-8.
Canonico PG, Kastello MD, Cosgriff TM, et al. Hematological and bone marrow effects of ribavirin in rhesus monkeys. Toxicol Appl Pharmacol 1984;74:163-172.
Canonico PG, Kastello MD, Spears CT, Brown JR, Jackson EA, Jenkins DE. Effects of ribavirin on red blood cells. Toxicol Appl Pharmacol 1984;74:155-162.
A 61-year-old man was admitted for treatment of chronic hepatitis C. He had received a blood transfusion after hemorrhoidectomy at the age of 30 years. Abnormal results on liver-function tests and antibody to hepatitis C virus (HCV) had been detected at a health checkup when the man was 55 years of age. His body weight was 75 kg, and physical examination showed only mild hepatomegaly. Laboratory tests demonstrated elevated alanine aminotransferase levels. The hemoglobin level and reticulocyte count were normal. A test for HCV RNA by the polymerase chain reaction was positive at a level above 850,000 IU per milliliter; the genotype was 1b. A liver biopsy showed chronic inflammation with portal fibrosis.
Treatment with interferon alfa-2b (Intron A, 6 million units) and ribavirin (Rebetol, 800 mg) was started. Eight weeks after the initiation of the treatment, the ribavirin dose was reduced to 600 mg per day because the hemoglobin level had decreased from 15.5 g per deciliter to 8.0 g per deciliter. Three weeks later, however, the hemoglobin level dropped to 6.0 g per deciliter even after the reduction in the dose of ribavirin. The reticulocyte count dropped from 7.8x104 per microliter to 0.2x104 per microliter. During the treatment, no changes in the indirect bilirubin, lactate dehydrogenase, or haptoglobin level were observed.
Bone marrow examination at week 12 showed mild hypocellularity without any morphologic abnormalities and a selective depletion of erythroid precursor cells (Figure 1). On the basis of these findings, a diagnosis of acute pure red-cell aplasia was made, and ribavirin was discontinued. Thereafter, the anemia and reticulocytopenia improved and had normalized by week 24. Administration of interferon was continued for 24 weeks and resulted in a sustained virologic response.
Figure 1. Findings on Microscopical Examination of Bone Marrow 12 Weeks after the Initiation of Combination Treatment with Interferon and Ribavirin (Wright–Giemsa Stain, x1000).
The nuclear cell count was 8.6x104 per microliter (normal range, 10x104 to 25x104 per microliter), and the ratio of myeloid to erythroid precursors was 5.8 (normal range, 2 to 4). No morphologic abnormalities were found in precursor cells.
Acute pure red-cell aplasia is characterized by rapidly progressive anemia with reticulocytopenia and is caused by viral infection, certain drugs, and nutritional disorders.3 Ribavirin induced dose-related anemia, erythroid hypoplasia, and vacuolization of erythroid precursors in rhesus monkeys, which disappeared after the discontinuation of ribavirin.4,5 We believe that our patient had acute pure red-cell aplasia caused by ribavirin used in the treatment of chronic hepatitis C. When anemia develops during treatment with interferon and ribavirin, the possibility of ribavirin-induced pure red-cell aplasia should be considered, and careful monitoring of the reticulocyte count is needed.
Naoki Tanaka, M.D., Ph.D.
Fumihiro Ishida, M.D., Ph.D.
Eiji Tanaka, M.D., Ph.D.
Shinshu University School of Medicine
Matsumoto 390-8621, Japan
etanaka@hsp.md.shinshu-u.ac.jp
References
Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology 2002;36:Suppl:S237-S244.
De Franceschi L, Fattovich G, Turrini F, et al. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology 2000;31:997-1004.
Erslev AJ. Pure red cell aplasia. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, eds. Williams hematology. 6th ed. New York: McGraw-Hill, 2001:391-8.
Canonico PG, Kastello MD, Cosgriff TM, et al. Hematological and bone marrow effects of ribavirin in rhesus monkeys. Toxicol Appl Pharmacol 1984;74:163-172.
Canonico PG, Kastello MD, Spears CT, Brown JR, Jackson EA, Jenkins DE. Effects of ribavirin on red blood cells. Toxicol Appl Pharmacol 1984;74:155-162.