Correspondence

Hepatitis-Associated Aplastic Anemia

N Engl J Med 1997; 337:424-425August 7, 1997

Article

To the Editor:

Brown et al. (April 10 issue)1 summarize the main features of hepatitis-associated aplastic anemia and conclude that the hepatitis in patients with this disorder is not likely to be caused by any of the known hepatitis viruses, including hepatitis G virus (HGV). These findings support recent reports questioning the role of HGV in liver disease.2,3 In their discussion, Brown et al. also mention that HGV did not appear to cause aplastic anemia.

The article by Brown et al. addresses two different issues: the role of HGV in causing liver disease and the role of HGV in causing aplastic anemia. We agree that HGV is most likely not associated with any liver disease. However, we would like to caution against premature conclusions regarding the role of HGV in causing aplastic anemia. The authors studied serum samples from only 10 patients with hepatitis-associated aplastic anemia and did not report on the prevalence of HGV in serum samples from patients with aplastic anemia not associated with hepatitis.

We have studied the prevalence of HGV RNA in a well-characterized cohort of 16 patients with hepatitis-associated aplastic anemia,4 as well as 47 concurrent patients with idiopathic aplastic anemia not related to hepatitis, who were matched for age, year of transplantation, and transfusion status. Our results confirmed that transfusions were the main source of HGV RNA in serum from both patients with hepatitis-associated aplastic anemia and those with idiopathic aplastic anemia (26.1 percent of 23 patients without transfusions and 67.5 percent of 40 with transfusions had positive tests for HGV RNA, P = 0.001). However, there was also an increased prevalence of HGV RNA in serum from patients with aplastic anemia who did not receive transfusions (26.1 percent), whether or not the anemia was associated with hepatitis (2 of 4 patients with hepatitis-associated aplastic anemia and 4 of 19 with idiopathic aplastic anemia had HGV RNA), as compared with the prevalence (1.7 percent) in serum from normal blood donors.5 These results suggest a possible role of HGV in the development of aplastic anemia in some patients. The findings also underscore the need for prospective studies of patients who have not received transfusions, in order to investigate the possible etiologic role of HGV in aplastic anemia.

Hans-Peter Kiem, M.D.
Rainer Storb, M.D.
George B. McDonald, M.D.
Fred Hutchinson Cancer Research Center, Seattle, WA 98104

5 References

1. 1

   Brown KE, Tisdale J, Barrett AJ, Dunbar CE, Young NS. Hepatitis-associated aplastic anemia. N Engl J Med 1997;336:1059-1064
   Full Text | Web of Science | Medline

2. 2

   Alter MJ, Gallagher M, Morris TT, et al. Acute non-A-E hepatitis in the United States and the role of hepatitis G virus infection. N Engl J Med 1997;336:741-746
   Full Text | Web of Science | Medline

3. 3

   Alter HJ, Nakatsuji Y, Melpolder J, et al. The incidence of transfusion-associated hepatitis G virus infection and its relation to liver disease. N Engl J Med 1997;336:747-754
   Full Text | Web of Science | Medline

4. 4

   Kiem H-P, McDonald GB, Myerson D, et al. Marrow transplantation for hepatitis-associated aplastic anemia: a follow-up of long-term survivors. Cesk Marfologie 1996;2:93-99
   

5. 5

   Kiem H-P, Myerson D, Spurgeon CL, Leisenring W, Storb R, McDonald GB. Prevalence of hepatitis G virus in patients with aplastic anemia. Blood (in press).
   

Author/Editor Response

The authors reply:

To the Editor: A possible relation between hepatitis GB virus C (GBV-C), also known as HGV, and aplastic anemia was first suggested by the reports of viremia in a few patients with bone marrow failure who had apparently not received transfusions at the time.1,2 Kiem et al. report viremia in two additional patients with hepatitis-associated aplastic anemia and four with idiopathic aplastic anemia. Although the specific viral cause of post-hepatitis aplastic anemia was not a major subject of our article, we have performed more extensive investigations of the relation of GBV-C to aplastic anemia.

GBV-C viral sequences were present in blood samples from 26 percent of 57 patients with aplastic anemia, as compared with 23 percent of 52 controls who had received multiple transfusions.3 Similar results have been reported by Moriyama et al.4 for patients with aplastic anemia and by other groups for patients who have received multiple blood transfusions because of other diseases. We would be interested to know whether Kiem et al. have determined the rate of hepatitis G viremia in controls with multiple transfusions. Gene-amplification techniques must be carefully controlled because of the susceptibility to contamination. Furthermore, in our experience some of the primers and probes used to detect HGV also have positive results in specimens containing Escherichia coli DNA sequences.

Neither we nor Moriyama et al. found GBV-C in patients with aplastic anemia who had not received transfusions. However, GBV-C is not transmitted only as a result of blood transfusion. The virus is highly prevalent in some normal populations: we found that almost 6 percent of normal Vietnamese persons had viral sequences in plasma,5 and a similar proportion of normal American children may also have viremia (unpublished data).

Efforts to establish a relation between GBV-C and any disease have been frustrating. A member of the expanding Flaviviridae family has been proposed as a candidate for a viral cause of aplastic anemia.6 However, GBV-C does not appear to be the agent responsible for either the common form of fulminant hepatitis of childhood or seronegative acute “viral” hepatitis. In our opinion, these syndromes and hepatitis-associated aplastic anemia probably share a single infectious cause. Hepatitis viruses commonly “travel” together, and GBV-C viremia may reflect exposure to another, as yet undiscovered pathogenic hepatitis virus.

Caution is indicated in the interpretation of laboratory results until we have a better understanding of GBV-C infection in humans and especially of the importance of viremia in apparently well adults and children.

Kevin E. Brown, M.D.
Neal S. Young, M.D.
National Heart, Lung, and Blood Institute, Bethesda, MD 20892

6 References

1. 1

   Byrnes JJ, Banks AT, Piatack M Jr, Kim JP. Hepatitis G-associated aplastic anaemia. Lancet 1996;348:472-472
   CrossRef | Web of Science | Medline

2. 2

   Zaidi Y, Chapman CS, Myint S. Aplastic anaemia after HGV infection. Lancet 1996;348:471-472
   CrossRef | Web of Science | Medline

3. 3

   Brown KE, Wong S, Young NS. Prevalence of GBV-C/HGV, a novel “hepatitis“ virus, in patients with aplastic anaemia. Br J Haematol 1997;97:492-496
   CrossRef | Web of Science | Medline

4. 4

   Moriyama K, Okamura T, Nakano S. Hepatitis GB virus C genome in the serum of aplastic anaemia patients receiving frequent blood transfusions. Br J Haematol 1997;96:864-867
   CrossRef | Web of Science | Medline

5. 5

   Brown KE, Wong S, Buu M, Binh TV, Be TV, Young NS. High prevalence of GB virus C/hepatitis G virus in healthy persons in Ho Chi Minh City, Vietnam. J Infect Dis 1997;175:450-453
   CrossRef | Web of Science | Medline

6. 6

   Young NS. Flaviviruses and bone marrow failure. JAMA 1990;263:3065-3068
   CrossRef | Web of Science | Medline

Citing Articles (3)

Citing Articles

1. 1

   P. F. Whitington, E. M. Alonso. (2001) Fulminant Hepatitis in Children: Evidence for an Unidentified Hepatitis Virus. Journal of Pediatric Gastroenterology and Nutrition 33:5, 529-536
   CrossRef

2. 2

   John Tung, Nedim Hadzic, Mark Layton, Alastair J. Baker, Anil Dhawan, Mohamed Rela, Nigel D. Heaton, Giorgina Mieli-Vergani. (2000) Bone Marrow Failure in Children With Acute Liver Failure. Journal of Pediatric Gastroenterology and Nutrition 31:5, 557-561
   CrossRef

3. 3

   Magdalena Robaczewska, Lucyna Cova, Anna J. Podhajska, Bogdan Falkiewicz. (1999) Hepatitis G virus: Molecular organization, methods of detection, prevalence, and disease association. International Journal of Infectious Diseases 3:4, 220-233
   CrossRef