|Year : 2013 | Volume
| Issue : 1 | Page : 13-16
Evaluation of bone marrow examination in patients with hepatitis C virus infection
Inas A Asfour, Maryse S Ayoub, Nanees A.A. Magid, Ahmed A.I. Elsaharty
Department of Internal Medicine and Clinical Hematology, Ain Shams University, Cairo, Egypt
|Date of Submission||05-Oct-2012|
|Date of Acceptance||16-Oct-2012|
|Date of Web Publication||20-Jun-2014|
Maryse S Ayoub
Department of Internal Medicine and Clinical Hematology, Ain Shams University, 11344 Cairo
Source of Support: None, Conflict of Interest: None
Over 170 million individuals are infected with hepatitis C virus (HCV) worldwide. The report published by the Egyptian Demographic Health Survey stated that in Egypt, there is an overall anti-HCV antibody prevalence of 14.7% and the number of Egyptians estimated to be chronically infected was 9.8%. Hematological manifestations are among the most common extrahepatic manifestations of HCV infection. Patients with HCV infection can develop peripheral blood cell count abnormalities that are commonly attributed to hypersplenism, antiviral therapy, decreased thrombopoietin levels, and/or autoimmune mechanisms.
Aim of the work
Evaluation of bone marrow findings in patients infected with HCV presenting with peripheral blood cytopenias.
Material and Methods
This study was carried out on 35 patients with chronic HCV infection presenting with cytopenias. Patients were subjected to history taking, physical examination, and routine laboratory investigations together with bone marrow aspiration and trephine biopsy. Flow cytometry and cytogenetics analysis were carried out in selected patients.
Among the patients studied, B-cell non-Hodgkin lymphoma was the most commonly encountered disorder (31%), followed by idiopathic thrombocytopenic purpura (11%), acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, and hypersplenism (9% each), and autoimmune hemolytic leukemia (6%), and the least encountered disorders were anemia of chronic disease, aplastic anemia, CLL, myelofibrosis, Evan’s syndrome, and sideroblastic anemia (3% each).
B-cell non-Hodgkin lymphoma was the most frequently detected problem among the patients recruited (31%). There were significant data regarding relation of bone marrow dysplasia and fibrosis with age of patients.
Keywords: B-cell non-Hodgkin lymphoma, bone marrow, hepatitis C virus
|How to cite this article:|
Asfour IA, Ayoub MS, Magid NA, Elsaharty AA. Evaluation of bone marrow examination in patients with hepatitis C virus infection. Egypt J Haematol 2013;38:13-6
|How to cite this URL:|
Asfour IA, Ayoub MS, Magid NA, Elsaharty AA. Evaluation of bone marrow examination in patients with hepatitis C virus infection. Egypt J Haematol [serial online] 2013 [cited 2019 Dec 8];38:13-6. Available from: http://www.ehj.eg.net/text.asp?2013/38/1/13/134797
| Introduction|| |
Over 170 million individuals are infected with the hepatitis C virus (HCV) worldwide 1. The prevalence of hepatitis C is higher in some countries in Africa and Asia. The report published by the Egyptian Demographic Health Survey stated that in Egypt, there is an overall anti-HCV antibody prevalence of 14.7% (estimated to be about 12 million individuals), and the number of Egyptians estimated to be chronically infected was 9.8% (about 8 million individuals) 2. Viral persistence, mainly within hepatocytes, results in chronic hepatitis, progressive fibrosis with resultant cirrhosis, and an increased risk of hepatocellular carcinoma 3.
Hematological problems in HCV have diverse etiologies. Type II/III mixed cryoglobulinemia and non-Hodgkin B-cell lymphomas (such as diffuse large B-cell lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma) are among the most common pathologies 4.
It is believed that HCV can infect B lymphocytes, resulting in chronic antigenic stimulation and B-cell proliferation 5.
Also, patients with HCV develop peripheral blood cell abnormalities such as neutropenia and thrombocytopenia secondary to hypersplenism 6.
The aim of this study is to evaluate bone marrow findings in patients infected with HCV and presenting with peripheral blood cytopenias.
| Patients and methods|| |
This study was carried out on 35 adult patients with chronic HCV infection and cytopenia (whether monocytopenia, bicytopenia, or pancytopenia) in peripheral blood. The patients were selected from the Hematology, Hepatology, and Gastroenterology units at Ain Shams University Hospitals.
Patients under interferon therapy, patients with hepatocellular carcinoma, and patients with HCV infection acquired following blood transfusion among patients previously diagnosed with hematological problems were excluded from the study.
All patients were subjected to the following:
(1) History taking and clinical examination.
(2) Laboratory investigations:
(i) Complete blood picture.
(ii) Liver profile including: alanine aminotransferase, aspartate aminotransferase, total protein, serum albumin, total and direct serum bilirubin, prothrombin time, international normalized ratio.
(iii) Renal profile including blood urea nitrogen, serum creatinine, and serum uric acid.
(iv) Erythrocyte sedimentation rate.
(v) Lactate dehydrogenase enzyme.
(vi) Hepatitis C markers (anti-HCV antibody using the third-generation enzyme-linked immunosorbent assay technique).
(vii) HCV-RNA: using real-time PCR when possible.
(3) Radiological examination: abdominal ultrasonography and computerized tomography when indicated.
(4) Bone marrow examination involved:
(viii) Bone marrow aspiration: performed for all patients.
(ix) Bone marrow trephine biopsy for histopathological examination: for all lymphoma and dysplasia patients. Assessment of overall and each lineage bone marrow cellularity, evaluation for infiltration, fibrosis dysplasia, and iron store assessment were carried out.
(5) Flow cytometric immunophenotyping was carried out when indicated.
(6) Cytogenetics: (conventional and fluorescent in-situ hybridization) was carried out in certain patients when indicated.
The data were analyzed using the program statistical package for social science (SPSS Inc., Chicago, Illinois, USA) under windows version 11.0.1.
| Results|| |
This study was carried out on 35 patients. Fourteen patients were men, 21 patients were women, ranging in age from 20 to 70 years, mean age 45.8±12.5 years. Cytopenias were defined according to the WHO criteria; anemia was defined as hemoglobin less than 10 g/dl, thrombocytopenia as platelet count less than 100×109/l, and neutropenia as absolute neutrophil count less than 1.8×109/l in peripheral blood. Eight patients had pancytopenia, 15 patients had bicytopenia, six patients were anemic, three patients were neutropenic, and three patients had isolated thrombocytopenia [Table 1], [Table 2] and [Table 3].
[Table 4] shows that bone marrow fibrosis was prevalent in three (≈9%) cases. Immunophenotyping was carried out in 16 cases and showed abnormal results in 15 cases.
[Table 5] describes the spectrum of hematological findings found in patients recruited in this study: 11 patients (≈31%) had B-cell non-Hodgkin lymphoma (B-NHL), four patients (≈11%) had idiopathic thrombocytopenic purpura (ITP), one patient (≈3%) had anemia of chronic disease, one patient (≈3%) had aplastic anemia, two cases (≈6%) suffered from autoimmune hemolytic leukemia, three cases (≈9%) suffered from acute myeloid leukemias, three cases (≈9%) suffered from acute lymphoblastic leukemia, one case (≈3%) with chronic lymphocytic leukemia, three patients (≈9%) had hypercellular bone marrow secondary to hypersplenism, one patient (≈3%) had myelofibrosis, three patients (≈9%) had myelodysplastic syndrome (MDS), one patient (≈3%) had Evan’s syndrome, and one patient (≈3%) had sideroblastic anemia.
[Table 6] describes different types of non-Hodgkin lymphoma cases and their methods of detection.
|Table 6: Different types of non-Hodgkin lymphoma among the patients studied|
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[Table 7] presents abnormal results of immunophenotyping and their relation to the clinical diagnosis of different hematological manifestations among the groups studied. Conventional cytogenetics showed Philadelphia chromosome in one patient.
| Discussion|| |
HCV infection is a major public health problem worldwide, affecting an estimated 120–170 million individuals 7.
HCV is essentially a hepatotropic virus and infection caused by the virus evolves into a chronic state in ∼85% of patients as indicated by the persistence of HCV-RNA in serum. However, severe and long-term complications of chronic HCV infection such as liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma develop only in a proportion of infected patients after a period that may exceed 10–20 years 6.
Several extrahepatic manifestations have been reported in the natural history of HCV infection. Up to 40–74% of patients infected with HCV might develop at least one extrahepatic manifestation during the course of their disease 8.
Hematological manifestations are among the most common extrahepatic manifestations of HCV infection. Patients with HCV infection can develop peripheral blood cell count abnormalities that are commonly attributed to hypersplenism, antiviral therapy, decreased thrombopoietin levels, and/or autoimmune mechanisms 9.
HCV infection also has a well-documented association with type II/III mixed cryoglobulinemia and non-Hodgkin B-cell lymphomas (diffuse large B-cell lymphoma, lymphoplasmacytic lymphoma, and marginal zone lymphoma) 4.
B-NHLs were detected by immunophenotyping in 11 patients (≈31%) among 35 patients. Among these, five patients had lymphoplasmacytic lymphomas, three patients had small B-cell lymphoma, one patient had marginal zone lymphoma, one patient had diffuse large B-cell lymphoma, and one patient had anaplastic large B-cell lymphoma. However, in the study carried out by Hausfater et al. 10, three patients (≈15%) were found to have B-NHL among 20 patients with HCV infection, in contrast to the study published by Zukerman et al. 11, and the prevalence of HCV was found in 22% of 120 patients with B-NHL. This higher incidence of NHL in our study may be because of the higher incidence of HCV infection among Egyptian patients or the late discovery of infection after the appearance of hematological problems.
The relation between NHL and HCV has been explained by Curry et al. 12, who reported that HCV shows a cellular affinity for lymphocytes. Interactions between the virus and lymphocytes may occur through the viral envelope protein, which binds hepatocytes and lymphocytes. The interaction between HCV and lymphocytes directly affects the function of B-cells and may induce polyclonal activation.
Further support of the association between HCV infection and B-cell lymphoproliferation are the observations that anti-HCV viral therapy can result in regression of splenic marginal zone lymphoma 13.
Acute myeloid leukemia was found in two patients (5%) and chronic myeloid leukemia was detected by Philadelphia chromosome in conventional cytogenetics in one patient (≈3%) out of 35 patients and these results were close to the study published by Jeffery et al. 14, which showed that one patient (≈2%) was found to have chronic myeloid leukemia and two patients (≈4%) were found to have acute myeloid leukemia among 47 HCV patients.
ITP was found in four patients (≈11%) among 35 patients, whereas in the French study carried out by Hausfater et al. 10, five patients (≈25%) were found to have ITP among 20 patients infected with hepatitis C. These results were explained by Nagamine et al. 15, who concluded that chronic infection with HCV may induce a significant autoimmune reaction to platelets, leading to thrombocytopenia.
In this study, bone marrow iron stores were decreased in one patient (≈3%), increased in three patients (≈8%), and normal in 31 patients (≈89%) among 35 patients. This higher percentage of increased iron stores than their decrease is similar to the results published by Ying et al. 16, and it was found that HCV is associated with elevation in serum iron and iron stores in contrast to the study of Jeffery et al. 14, which found that seven patients (≈15%) had decreased iron stores, six patients (≈13%) had increased iron stores, and 34 patients (≈72%) had normal iron stores among 47 patients, with more patients with decreased than increased iron stores.
In the present study, the features of primary MDS were found in three patients (≈9%) among four patients with dysplastic features, and these dysplastic features were detected in patients ranging in age from 43 to 65 years, whereas in the study published by Jeffery et al. 14, two patients had primary MDS out of six patients with dysplastic features. The incidence of myelodysplasia among patients in our study increased significantly (P<0.05) with age and this is in agreement with the result reported by Timothy and Ghulam 17. HCV infection directly leads to dysmyelopoiesis, considering that the HCV virion has been detected in the bone marrow of chronically infected HCV patients as well as in peripheral circulating mononuclear cells. Also, we found that the age of the patients had a significant impact on bone marrow fibrosis, which was found to be positive in patients ranging in age from 43 to 65 years.
| Conclusion|| |
There was a wide variety of hematological diseases in patients with hepatitis C with peripheral cytopenias. B-NHL was the most frequently detected problem among recruited patients (31%). There were significant data regarding relation of bone marrow dysplasia and fibrosis with age of patients. Follow-up of hematological problems among patients with hepatitis C infection and assessment of their correlation with viral load are recommended.
| References|| |
|1.||Baldo V, Baldovin T, Trivello R, Floreani A. Epidemiology of HCV infection. Curr Pharm Des. 2008;14:1646–1654 |
|2.||El-Zanaty F, Way A Egypt demographic health survey 2008. 2009 Cairo Ministry of Health, El-Zanaty and Associates, and Macro International:241–250 |
|3.||Chang KM. Immunopathogenesis of hepatitis C virus infection. Clin Liver Dis. 2003;7:89–105 |
|4.||Neiters A, Kallinowski B, Brennan P, Ott M, Maynadie M, Benavente J, et al. Hepatitis C and risk of lymphoma: results of the European multicenter case control study EPILYMPH. Gastroenterology. 2006;131:1879–1886 |
|5.||Mehta SH, Brancati FL, Strathdee SA, Pankaw JS, Netski D, Coresh J, Szklo M, Thomas DL. Hepatitis C virus infection and incident type 2 diabetes. Hepatology. 2003;38:50–56 |
|6.||Seeff L. Natural history of chronic hepatitis C. Hepatology. 2002;36:S35–S46 |
|7.||Shepard C, Finelli L, Alter M. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis. 2005;5:558–567 |
|8.||Agnello V, De Rosa F. Extrahepatic disease manifestations of HCV infection: some current issues. J Hepatol. 2004;40:341–352 |
|9.||Afdhal N, Mchutchison J, Brown R, Jacobson I, Manns M, Poordad F. Thrombocytopenia associated with chronic liver disease. J Hepatol. 2008;48:1000–1007 |
|10.||Hausfater P, Cacoub P, Sterkers Y, Thibault V, Amoura Z, Nguyen L, et al. Hepatitis C virus infection and lymphoproliferative diseases: prospective study on 1576 patients in France. Am J Hematol. 2001;67:168–171 |
|11.||Zuckerman E, Zuckerman T, Levine AM, Douer D, Gutekunst k, Mizokami M, et al. Hepatitis C virus infection in patients with B-cell non-Hodgkin lymphoma. Ann Intern Med. 1997;127:423–428 |
|12.||Curry M, Golden ML, Doherty D, Degnan T, Norris S, Duffy M, et al. Expansion of innate CD5 positive B cells expressing high level of CD81 in hepatitis C virus infected liver. J Hepatol. 2003;38:642–650 |
|13.||Hermine O, Lefrere F, Bronowicki JP, Mariette X, Jondeau k, Saudreau V, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med. 2002;347:89–94 |
|14.||Jeffery MK, Bob G, Elizabeth MB, Hassan A, Nguyen TD, kreisel F, et al. Bone marrow biopsy in patients with hepatitis C virus infection: spectrum of findings and diagnostic utility. Am J Hematol. 2010;85:106–110 |
|15.||Nagamine T, Ohtuka T, Takehara K, Arai T, Takagi H, Mori M. Thrombocytopenia associated with hepatitis C viral infection. J Hepatol. 1996;25:135–140 |
|16.||Ying S, Richad WL, Herbert B. Association of hepatitis C virus infection with serum iron status: analysis of data from the Third National Health and Nutrition Examination Survey. Clin Infect Dis. 2005;40:834–841 |
|17.||Timothy JT, Ghulam JVictor Hoffbrand, et al. Myelodysplastic syndromes. Postgraduate Hematology. 20116th ed. Wiley-Blackwell:503–529 |
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]