Hepatitis-associated Aplastic Anemia Research Articles

Hepatitis-associated aplastic anaemia treated successfully with antilymphocyte globulin

Aplastic anaemia may occur following an acute attack of hepatitis. This is a rare condition, which if not recognized and promptly treated, may be fatal. Antilymphocyte globulin and allogeneic bone marrow transplantation have been used in the treatment of this condition. We report the case of a young man who developed severe aplastic anaemia following nonviral hepatitis.

Analysis of T-cell repertoire in hepatitis-associated aplastic anemia

AbstractHepatitis-associated aplastic anemia (HAA) is a syndrome of bone marrow failure following an acute attack of seronegative hepatitis. Clinical features and liver histology suggest a central role for an immune-mediated mechanism. To characterize the immune response, we investigated the T-cell repertoire (T-cell receptor [TCR] Vβ chain subfamily) of intrahepatic lymphocytes in HAA patients by TCR spectratyping. In 6 of 7 HAA liver samples, a broad skewing pattern in the 21 Vβ subfamilies tested was observed. In total, 62% ± 18% of HAA spectratypes showed a skewed pattern, similar to 68% ± 18% skewed spectratype patterns in 3 of 4 patients with confirmed viral hepatitis. Additionally, the T-cell repertoire had similarly low levels of complexity. In the peripheral blood lymphocytes (PBLs) of a separate group of HAA patients prior to treatment, 60% ± 15% skewed spectratypes were detected, compared with only 18% ± 8% skewed spectratypes in healthy controls. After successful immunosuppressive treatment, an apparent reversion to a normal T-cell repertoire with a corresponding significant increase in T-cell repertoire complexity was observed in the HAA samples. In conclusion, our data suggest an antigen-driven T-cell expansion in HAA and achievement of a normal T-cell repertoire during recovery from HAA. (Blood. 2004;103:4588-4593)

Investigation of SEN virus infection in patients with cryptogenic acute liver failure, hepatitis-associated aplastic anemia, or acute and chronic non-A-E hepatitis.

SEN virus (SENV) has been tentatively linked to transfusion-associated non-A-E hepatitis. We investigated SENV's role in unexplained hepatitis in other settings. Polymerase chain reaction amplification was used to detect 2 SENV variants (SENV-D and SENV-H) in 1706 patients and control subjects. SENV was detected in 54 (22%) of 248 patients with acute or chronic non-A-E hepatitis, 9 (35%) of 26 patients with hepatitis-associated aplastic anemia, and 0 of 17 patients with cryptogenic acute liver failure, compared with 150 (24%) of 621 control subjects with liver disease and 76 (10%) of 794 healthy control subjects. When controlling for geographic region, the prevalence of SENV among case and control subjects was not significantly different. The severity of acute or chronic hepatitis A, B, or C was not influenced by coexisting SENV infection. No etiological role for SENV in the cause of cryptogenic hepatitis could be demonstrated.

Prevalence of parvovirus B19 in liver tissue: no association with fulminant hepatitis or hepatitis-associated aplastic anemia.

Parvovirus B19 has been proposed as the etiological agent of fulminant hepatitis (FH) or hepatitis-associated aplastic anemia (HAA). We studied the prevalence of parvovirus B19 in liver-tissue samples from patients with FH and HAA and from control subjects. In the first study, parvovirus B19 DNA was detected by nested polymerase chain reaction (PCR) in 4 of 15 livers from patients with FH and in 3 of 22 livers from patients with nonviral hepatic disease. In a second confirmatory study, livers were tested for parvovirus B19 and its variant erythroviruses, V9 and A6. Tissues were also tested by reverse-transcriptase PCR for the presence of parvovirus B19 transcripts as a marker of viral replication. There was no significant difference in the prevalence of parvovirus B19 DNA in livers from patients with FH or HAA, compared with liver-tissue samples from patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection; parvovirus B19 transcripts were not detected. There was a significant increase (P<.1) in the prevalence of variant erythrovirus sequences in livers of patients with HBV or HCV hepatitis, the reason for which is currently unknown.

Hepatitis-associated aplastic anemia preceded by a hemophagocytic syndrome-like state

Hepatitis-associated aplastic anemia preceded by a hemophagocytic syndrome-like state

Aplastic anemia in the orient

Aplastic anemia (AA) is more common in Asia than in Europe or the United States. This may be due in part to the high incidence of hepatitis-associated AA in Asia. The management of AA has evolved rapidly in Japan during the last decade. Advances in the treatment of AA have largely been the result of prospective collaborative studies of immunosuppressive therapy and the large registry of bone marrow transplantation data. These studies have revealed several differences in clinical outcome between Western and Eastern patients, differences that may reflect the effects of genetic background on response to treatment or development of adverse effects.

Successful Bone Marrow Plus Cord Blood Stem Cell Transplantation in a Girl who Developed Myelodysplastic Syndrome from Hepatitis-associated Aplastic Anemia Treated with Long-term Immunosuppressants and Growth Factors

A 9-year-old girl who had hepatitis-associated aplastic anemia was treated intermittently with methylprednisolone pulse therapy and growth factors (granulocyte-colony stimulating factor (G-CSF), recombinant human erythropoietin (rhEpo) and cyclosporin A (CyA) for over two years. At this time, there was hematological improvement, but chromosome analysis revealed monosomy 7.After six months, there was progression to myelodysplastic syndrome (MDS) (stage in refractory anemia of excess blasts (RAEB)) with monosomy 7, monosomy 6, marker chromosome and with hematological deterioration.She received bone marrow (1.57×105 cells kg−1 (patient body weight)) plus cord blood cell (0.3×107 cells kg−1 (patient body weight)) transplantation from her brother, 2 years and 7 months after the diagnosis of hepatitis-associated aplastic anemia. Engraftment was achieved after two weeks, and acute graft-versus-host disease occurred in a mild form after four weeks. Hematological remission has been continuous for 20 months after bone marrow transplantation. Transformation of hepatitis-associated aplastic anemia to MDS with the monosomy 7, monosomy 6 and marker chromosome in this patient was considered to have been related to the administration of high doses of immunosuppressive drugs plus growth factors.

Successful Immunosuppressive Treatment for Hepatitis-Associated Aplastic Anemia

Successful Immunosuppressive Treatment for Hepatitis-Associated Aplastic Anemia

Lack of known hepatitis virus in hepatitis-associated aplastic anemia and outcome after bone marrow transplantation.

Viral infection has been shown to induce aplastic anemia, unidentified types of hepatitis being the most common cause for aplastic anemia-associated viral hepatitis. The survival rate for this group of patients after bone marrow transplantation with stem cells from an HLA-matched sibling is not well known. The aim of this study was to determine the prevalence of hepatitis G virus (HGV) and transfusion transmitted virus (TTV) infection in non-A, non-B, non-C hepatitis associated-aplastic anemia (HAAA) patients, and to define the role of bone marrow transplantation (BMT) as a therapeutic modality for this disease. Sixty-eight patients (43 males and 25 females) with aplastic anemia, underwent allogeneic BMT at the Hadassah University Hospital between 1981 and 1997. Onset of hepatitis was defined as jaundice and elevated alanine aminotransaminase (ALT) levels. Onset of aplastic anemia was defined as the first date on which varying degrees of pancytopenia occurred: hemoglobin level below 10 g/dl, WBC below 2 x 10(9)/l and low platelet count 10 x 10(10)/l. Serial serum samples from HAAA patients were assayed for virological and/or serological markers of hepatitis A, B, C, D, E, G viruses, TTV and parvovirus B19. Seventeen of the 68 patients with aplastic anemia (25%) suffered from hepatitis, 12 males and five females, ages 5 to 36 years. The mean interval between onset of hepatitis and first indication of aplastic anemia was 62 days (range 14-225 days). The development of aplastic anemia was unrelated to age, sex or severity of hepatitis. Ten of the 17 patients (59%) achieved complete ALT recovery prior to the diagnosis of aplastic anemia. Serum samples were available for 15 patients; none had evidence of acute or active hepatitis A, B, C, D, E, G and TTV virus infection at the time of diagnosis. Parvovirus B19 DNA sequences were not detectable in 10 of 12 tested cases; two positive results were detected in serum samples obtained after blood transfusion, making the analysis of these positive results difficult. All 17 patients underwent BMT. The mean post-BMT follow-up period was 38 months (range 1 day-123 months), five patients (30%) died 1 to 160 days post BMT, and 12 (70%) are alive 31 to 123 months after BMT. Relapsing hepatitis was not observed in any of the patients. In conclusion, HAAA is a disease of the young and the etiologic agent associated with HAAA remains unknown. HGV, TTV and parvovirus B19 sequences were not detected in any of the HAAA cases. The survival rate after BMT with stem cells from an HLA-matched sibling is similar to that for patients with non-hepatitis-associated aplastic anemia.

Hepatitis-associated aplastic anemia and acute parvovirus B19 infection: A report of two cases and a review of the literature

Hepatitis-associated aplastic anemia is rare in general, but occurs in up to 28% of patients receiving liver transplantation for fulminant non-A, non-B hepatitis. Cases are commonly young men with mild hepatitis but severe aplastic anemia. Although cases have been reported in association with hepatitis A, B, and C, most appear to be due to a non-A-B-C virus. We report two cases of acute hepatitis subsequently complicated by marrow hypoplasia in patients with acute parvovirus B19 infection. Hepatic manifestations of parvovirus B19 infection range from liver chemistry abnormalities to fulminant hepatic failure and aplastic anemia. Our cases demonstrate a less severe form of hepatitis-associated aplastic anemia, and together with other data, suggest that parvovirus B19 is at least one cause of hepatitis-associated aplastic anemia, and may be a heretofore underrecognized hepatotrophic virus.

Acute GB virus C/hepatitis G virus hepatitis preceding aplastic anemia

A novel virus, GB virus C/hepatitis G virus (GBV-C/HGV), is believed to be a member of the Flaviviridae and to be closely related to the hepatitis C virus (HCV), according to phylogenetical analysis. However, hepatitis-associated aplastic anemia (HA-AA) is known as a rare disease with a high mortality rate. In some reports, the role of GBV-C/HGV in causing HA-AA has been discussed. In this case report, we describe the detection of GBV-C/HGV RNA in a HA-AA patient. The patient, a 14-year-old male with no risk factors for hepatitis virus infection, developed acute idiopathic hepatitis and was diagnosed with aplastic anemia 6 months later. During the acute phase of hepatitis, GBV-C/HGV RNA was detected by the reverse transcription polymerase chain reaction, using specific primers derived from the 5′-untranslated region and became undetectable prior to the onset of aplastic anemia. HCV RNA and hepatitis B virus (HBV) DNA were not detected from the onset of hepatitis to that of aplastic anemia. These findings demonstrate that aplastic anemia occurred following acute GBV-C/HGV hepatitis in this patient. Therefore, GBV-C/HGV appears to be associated with aplastic anemia.

Hepatitis-Associated Aplastic Anemia

There is a well-recognized relationship between aplastic anemia and viral hepatitis. Clinically apparent hepatitis precedes aplastic anemia by a period of weeks to months. Hepatitis is an infrequent cause of aplastic anemia and is usually severe and fatal if untreated. The clinical features and, particularly the response to immunosuppressive therapy strongly suggest that immune mechanisms mediate the marrow aplasia. The cause of the hepatitis is unknown, but it does not appear to be due to any of the known hepatitis viruses. In this study we present two cases of hepatitis associated aplastic anemia (HAAA) at the ages of 10-11 years old. They both received immunosuppressive therapy, Anti thrombocytic globulin and Cyclosporine. They achieved a persistent clinicohematological remission.

Prevalence of GBV-C/HGV, a novel 'hepatitis' virus, in patients with aplastic anaemia.

GBV-C or hepatitis G virus (GBV-C/HGV) is a novel RNA virus with similarities to members of the Flaviviridae family, especially hepatitis C. Viral RNA is detected in about 1.5% of American blood donors, with higher prevalence in multiply transfused patients and in individuals with hepatitis or liver disease. Some cases of aplastic anaemia follow apparent non-A, non-B, non-C viral hepatitis, and GBV-C viraemia has been described in three case reports of hepatitis-associated aplastic anaemia. We tested clinical samples from patients with aplastic anaemia with or without recent hepatitis for the presence of GBV-C/HGV. Virus was detected in a total of 15/57 (26.3%) of patients with aplastic anaemia and 12/52 (23.1%) of multiply transfused control patients. Sequencing of the 188 base pair NS3 helicase PCR product in the serum of five individuals indicated the same high degree of sequence variation as has been seen among other isolates of the virus. GBV-C/HGV does not appear to be implicated in the aetiology of aplastic anaemia.

Hepatitis-associated aplastic anemia.

Hepatitis-associated aplastic anemia is a variant of aplastic anemia in which aplastic anemia follows an acute attack of hepatitis. The aplastic anemia, however, is often fatal if untreated. To characterize the illness, investigate the role of hepatitis viruses, and assess the response to immunosuppressive treatment, we studied patients with the syndrome who were referred to the National Institutes of Health (NIH). Standard hematologic and biochemical tests and measurements of bone marrow cellularity were used to monitor the patients' response to treatment. Serum was assayed for antibodies and antigens related to hepatitis A, B, and C viruses and for the RNA of hepatitis C and GB virus C by the polymerase chain reaction. All patients were treated with antithymocyte globulin and cyclosporine. Ten patients with hepatitis-associated aplastic anemia were referred to the NIH between 1990 and 1996; all had the typical features of this syndrome. There was evidence of activated CD8 T lymphocytes in the blood. Serologic tests for hepatitis A, B, and C viruses were negative; RNA of hepatitis C virus was undetectable in all patients, but RNA of GB virus C was detected in three patients. Seven of the patients responded to intensive immunosuppressive treatment; the three who did not respond all died within one year of treatment, two from complications of stem-cell or marrow transplantation. The hepatitis of the hepatitis-associated aplastic anemia does not appear to be caused by any of the known hepatitis viruses. We recommend immunosuppressive treatment for patients who do not have an HLA-matched related donor available for bone marrow transplantation. Several features of the syndrome suggest that it is mediated by immunopathologic mechanism.

Hepatitis-associated aplastic anemia: Virologic studies and long-term follow-up: D Myerson, H-P Kiem, CL Spurgeon, GB McDonald, Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA

Hepatitis-associated aplastic anemia: Virologic studies and long-term follow-up: D Myerson, H-P Kiem, CL Spurgeon, GB McDonald, Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA

Lack of evidence for a role of HCV in hepatitis-associated aplastic anaemia.

Hepatitis-associated aplastic anaemia (HAAA) is usually related to non-A, non-B hepatitis agents but the prevalence of anti-hepatitis C virus (HCV) antibodies is similar in HAAA and aplasia of other origins according to the results of the ELISA 1 assay. This fact could reflect either that HCV is not involved in HAAA or that HAAA-associated defective immune function could yield false negative assays despite on-going HCV infection. To test these hypotheses, we compared 19 patients with HAAA, including three ELISA 1-positive, to 23 patients with aplasia of known and unknown origin, including eight ELISA 1-positive, who were matched for age, sex and blood transfusion units. HCV infection was searched for by the second-generation recombinant-immunoblot assay (RIBA2), and by the polymerase chain reaction which detects HCV viraemia. HCV viraemia was detected in four among the 19 patients with HAAA and in six among the 23 patients with aplasia of other causes. HCV does not clearly appear responsible for hepatitis-associated aplastic anaemia which could be due to non-A, non-B, non-C hepatitis virus. HCV viraemia is frequent in severe aplastic anaemia, even without detectable anti-HCV antibodies, and reflects mainly transfusion-associated HCV infection.

Successful Bone Marrow Transplantation for a Child with Hepatitis-Associated Aplastic Anemia from an HLA DR Mismatched 7-Month-Old Brother

Successful Bone Marrow Transplantation for a Child with Hepatitis-Associated Aplastic Anemia from an HLA DR Mismatched 7-Month-Old Brother

漢方薬（小柴胡湯＋加味帰ひ湯）とメチルプレドニゾロン大量療法の併用が奏効した肝炎 再生不良性貧血症候群の１重症例

Abstract Combined treatment with high-dose methylprednisolone and Kampoherbal medicine (Xiao-Chai-Hu-Tang and Jia-Wei-Gui-Pi-Tang) brought about a striking clinical improvement in a 24-year-old woman with severe hepatitis-associated aplastic anemia. Laboratory findings on admission were summarized as follows: granulocytes 325/μl, erythrocytes 2, 450, 000/μl, platelets 10, 000/μl, bone marrow nucleated cells 27, 000/μl, and GPT 569IU/l. Neither anti-lymphocyte globulin, high-dose methylprednisolone alone nor oxymetholone was effective on any hematological finding although intravenous administration of high-dose glycyrrhizin improved the liver dysfunction. The patient needed repeated transfusions of leukocyte-poor washed red blood cells and HLA-matched platelet concentrates for a period of 1.5 years until the hematopoietic function recovered 3 months after combined treatment with high-dose methylprednisolone and Kampo-herbal medicine. Laboratory findings on discharge were as follows: granulocytes 1, 050/μl, erythrocytes 3, 460, 000/μl, reticulocytes 100, 000/μl, platelets 47, 000/μl, bone marrow nucleated cells 118, 000/μl, and GPT 52IU/l. Six months later hematopoietic depression recurred, and this combined treatment was performed again with favorable response.

Is Hepatitis C Virus Involved in Hepatitis-Associated Aplastic Anemia?

To determine whether hepatitis C virus is involved in hepatitis-associated aplastic anemia. Retrospective analysis. Bone marrow transplantation unit. One hundred and eighteen patients with severe aplastic anemia, including 19 with hepatitis-associated aplasia, 61 with aplastic anemia of undetermined cause, and 38 with aplastic anemia related to an inherited syndrome or an acquired etiology. There was no statistically significant difference in antihepatitis C virus antibodies between hepatitis-related aplastic anemia (15.8%; 95% CI, 4% to 36%) and aplasia of unknown (9.8%; CI, 5% to 22%) or known (7.9%; CI, 2% to 22%) cause. The antihepatitis C virus levels did not differ according to the cause of aplastic anemia. There was no relation between hepatitis C and hepatitis B virus serologies, regardless of cause. Hepatitis C virus is not a frequent cause of non-A, non-B hepatitis-associated aplastic anemia. Either a non-A, non-B, non-C hepatitis virus is involved in non-A, non-B hepatitis-related aplasia or hepatitis C virus prevalence is underestimated in patients with hepatitis-related aplasia, possibly as a result of immunologic defects.

Southwestern Internal Medicine Conference: Hepatitis C

The major cause of chronic post-transfusion hepatitis, the hepatitis C virus (HCV), has been identified. HCV is a single-stranded linear RNA virus with characteristics similar to the flaviviruses. A different agent, the hepatitis E virus, is associated with epidemic (enterically-transmitted) non-A, non-B hepatitis. At present, infection with HCV is recognized by the finding of anti-HCV antibodies, positive in up to 90% of patients with chronic non-A, non-B post-transfusion hepatitis. Antibodies to HCV are detected in 1% of normal volunteer blood donors and in the majority of donors implicated in post-transfusion hepatitis. HCV antibodies are also found in patients with autoimmune liver disease and hepatocellular carcinoma. Moreover, HCV infection may contribute to the pathogenesis of liver disease in alcoholic patients. The role of HCV infection in fulminant non-A, non-B hepatitis and hepatitis-associated aplastic anemia has not been elucidated as yet. Therapy of chronic non-A, non-B hepatitis with recombinant human alpha-interferon has been shown to improve or normalize aminotransferase levels in approximately 50% of patients, most of whom have evidence of HCV infection. However, relapse after cessation of treatment is common. In the future, screening blood for evidence of HCV infection may prevent most cases of non-A, non-B post-transfusion hepatitis.