Download PDF
Klin Padiatr 2020; 232(03): 151-158
DOI: 10.1055/a-1108-1553
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Hepatitis-associated Aplastic Anaemia in Children

Hepatitis-assoziierte aplastische Anämie im Kindesalter
Anne-Kathrin Böske
1   Clinic for Pediatric Nephrology, Hepatology and Metabolic Disorders, Hannover Medical School, Hannover, Germany
,
Annette Sander
2   Pediatric hematology and oncology, Hannover Medical School, Hannover, Germany
,
Karl-Walter Sykora
2   Pediatric hematology and oncology, Hannover Medical School, Hannover, Germany
,
Ulrich Baumann
1   Clinic for Pediatric Nephrology, Hepatology and Metabolic Disorders, Hannover Medical School, Hannover, Germany
,
Eva-Doreen Pfister
1   Clinic for Pediatric Nephrology, Hepatology and Metabolic Disorders, Hannover Medical School, Hannover, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
19 March 2020 (online)

Also available at
    Permissions and Reprints

Abstract

Background Children with idiopathic acute liver failure (IALF) are at a high risk of developing life-threatening bone marrow failure (BMF). The aim of the study was to describe the development, therapy and prognosis of this hepatitis-associated aplastic anaemia (HAAA) in comparison to isolated acquired aplastic anaemia.

Results We retrospectively found 18 patients (9 female) of HAAA between 1984 and 2017 with an age of 1.4–16.4 years. Fifteen of them fulfilled the SAA criteria, 3 had a bone marrow hypoplasia. Eleven of these children received liver transplantation (LTx) (these were 11 of 42 (26%) children receiving LTx for IALF), 6 patients recovered without LTx. The first signs of BMF, thrombocytopaenia and leucocytopaenia, occurred before LTx in all cases. During the follow-up period 8 patients reached haematological remission, 6 received haematopoietic stem cell transplantation (HSCT). Seven children died in a median of 304 days after the first symptoms mostly because of bleedings and infections. To date, extensive investigations failed to detect a genetically, viral or immunological aetiology. No AA was diagnosed in the 41 patients receiving liver transplants during the same period for ALF of known aetiology. As a comparison group, we collected the data of patients with isolated SAA. 73% achieved a remission after Immunosuppressive therapy (IST) without HSCT, and none of them died during the follow-up period.

Conclusion Blood counts should be examined early and regularly (0–22 days after onset) in patients with IALF. Aggressive treatment with LTx, IST and HSCT appears to improve the prognosis.

Zusammenfassung

Hintergrund Kinder mit akutem Leberversagen (ALV) unklarer Ätiologie haben ein hohes Risiko ein lebensbedrohliches Knochenmarkversagen zu entwickeln. Ziel dieser Studie war die Manifestation, Therapie und Prognose dieser Hepatitis-assoziierten aplastischen Anämie (HAAA) im Vergleich zur isolierten erworbenen aplastischen Anämie (AA) zu untersuchen.

Ergebnisse Wir fanden retrospektiv 18 Kinder (9 weiblich) mit HAAA zwischen 1984 und 2017 im Alter von 1,4–16,4 Jahren. Davon erfüllten 15 Patienten die SAA Kriterien, 3 zeigten eine Knochenmarkhypoplasie. Insgesamt 11 von 42 Kindern (26%), die bei ätiologisch unklarem ALV lebertransplantiert wurden, entwickelten ein Knochenmarkversagen. Weitere 6 Patienten erholten sich ohne Lebertransplantation (LTx). In allen Fällen zeigten sich die Erstsymptome des Knochenmarkversagens, Thrombopenie und Leukopenie, vor LTx. Innerhalb der Nachbeobachtungsdauer erreichten 8 Patienten eine Knochenmarkremission, 6 erhielten eine Hämatopoetische Stammzelltransplantation (HSCT). 7 Kinder verstarben im Median 304 Tage nach Erstmanifestation, hauptsächlich an Blutungen und Infektionen. Trotz umfangreicher Untersuchungen konnten keine genetischen, virologischen oder immunologischen Auslöser detektiert werden. Wir beobachteten keine Fälle von SAA unter den 41 Patienten die im gleichen Zeitraum bei ALV mit geklärter Ätiologie transplantiert wurden. Als Vergleichsgruppe sammelten wir die Daten von Patienten mit isolierter AA. 73% erreichten unter IST ohne HSCT eine Remission. Keiner dieser Patienten verstarb innerhalb der Nachbeobachtungsdauer.

Schlussfolgerung Bei Patienten mit HAAA müssen frühzeitig und regelmäßig (0–22 Tage nach Beginn) Blutbildkontrollen erfolgen. Eine intensive Therapie mit LTx, IST und HSCT scheint die Prognose zu verbessern.

Key words

acute liver failure - seronegative hepatitis - liver transplantation - aplastic anaemia - bone marrow failure - bone marrow transplantation/haematopoietic stem cell transplantation
 

  • References

  • 1 Al Nahdi N, Wiesinger H, Sutherland H. et al. Recurrent idiopathic acute hepatitis-associated aplastic anemia/pancytopenia fourteen years after initial episode. Ann Hepatol 2010; 9: 468-470
    CrossrefPubMedGoogle Scholar
  • 2 Babushok DV, Grignon AL, Li Y. et al. Disrupted lymphocyte homeostasis in hepatitis-associated acquired aplastic anemia is associated with short telomeres. Am J Hematol 2016; 91: 243-247
    CrossrefPubMedGoogle Scholar
  • 3 Bhaduri BR, Mieli-Vergani G. Fulminant hepatic failure: pediatric aspects. Semin Liver Dis 1996; 16: 349-355
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Brand K. Das Blaue Heft- Leitfaden Labordiagnostik, Institut für Klinische Chemie, Medizinische Hochschule Hannover. 2014
    PubMedGoogle Scholar
  • 5 Breakey VR, Meyn S, Ng V. et al. Hepatitis-associated aplastic anemia presenting as a familial bone marrow failure syndrome. J Pediatr Hematol Oncol 2009; 31: 884-887
    CrossrefPubMedGoogle Scholar
  • 6 Brown KE, Tisdale J, Barrett AJ. et al. Hepatitis-associated aplastic anemia. N Engl J Med 1997; 10 336: 1059-1064
    CrossrefPubMedGoogle Scholar
  • 7 Cattral MS, Langnas AN, Markin RS. et al. Aplastic anemia after liver transplantation for fulminant liver failure. Hepatology 1994; 20 813-818
    CrossrefPubMedGoogle Scholar
  • 8 Chen HF, Xu BX, Shen HS. et al. Efficacy and safety of immunosuppressive therapy in the treatment of seronegative hepatitis associated aplastic anemia. Drug Des Devel Ther 2014; 8: 1299-1305
    PubMedGoogle Scholar
  • 9 De Bruyne RM, Dhawan A. Bone marrow dysfunction following pediatric liver transplantation. Pediatr Transplant 2005; 9: 423-426
    CrossrefPubMedGoogle Scholar
  • 10 Fuhrer M, Bender-Gotze C, Ebell W. et al. Treatment of aplastic anemia- aims and development of the SAA 94 pilot protocol. Klin Padiatr 1994; 206: 289-295
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Gonzalez-Casas R, Garcia-Buey L, Jones EA. et al. Systematic review: hepatitis-associated aplastic anaemia- a syndrome associated with abnormal immunological function. Aliment Pharmacol Ther 2009; 30: 436-443
    CrossrefPubMedGoogle Scholar
  • 12 Goss JA, Schiller GJ, Martin P. et al. Aplastic anemia complicating orthotopic liver transplantation. Hepatology 1997; 26: 865-869
    CrossrefPubMedGoogle Scholar
  • 13 Hadzic N, Height S, Ball S. et al. Evolution in the management of acute liver failure-associated aplastic anaemia in children: a single centre experience. J Hepatol 2008; 48: 68-73
    CrossrefPubMedGoogle Scholar
  • 14 Herklotz R, Lüthi U, Ottiger C. et al. Referenzbereiche in der Hämatologie. Therapeutische Umschau 2006; 63: 5-24
    CrossrefPubMedGoogle Scholar
  • 15 Honkaniemi E, Gustafsson B, Fischler B. et al. Acquired aplastic anaemia in seven children with severe hepatitis with or without liver failure. Acta Paediatr 2007; 96: 1660-1664
    CrossrefPubMedGoogle Scholar
  • 16 Itterbeek P, Vandenberghe P, Nevens F. et al. Aplastic anemia after transplantation for non-A, non-B, non-C fulminant hepatic failure: case report and review of the literature. Transpl Int 2002; 15: 117-123
    PubMedGoogle Scholar
  • 17 Langnas AN, Markin RS, Cattral MS. et al. Parvovirus B19 as a possible causative agent of fulminant liver failure and associated aplastic anemia. Hepatology 1995; 22: 1661-1665
    PubMedGoogle Scholar
  • 18 Liang DC, Lin KH, Lin DT. et al. Post-hepatitic aplastic anaemia in children in Taiwan, a hepatitis prevalent area. Br J Haematol 1990; 74: 487-491
    CrossrefPubMedGoogle Scholar
  • 19 Locasciulli A, Bacigalupo A, Bruno B. et al. Hepatitis-associated aplastic anaemia: epidemiology and treatment results obtained in Europe. A report of The EBMT aplastic anaemia working party. Br J Haematol 2010; 149: 890-895
    CrossrefPubMedGoogle Scholar
  • 20 Lorenz E, Quaiser K. Panmyelopathy following epidemic hepatitis. Wien Med Wochenschr 1955; 105: 19-22
    PubMedGoogle Scholar
  • 21 Lu J, Basu A, Melenhorst JJ. et al. Analysis of T-cell repertoire in hepatitis-associated aplastic anemia. Blood 2004; 103: 4588-4593
    CrossrefPubMedGoogle Scholar
  • 22 Marsh JCW, Ball SE, Cavenagh J. et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol 2009; 147: 43-70
    CrossrefPubMedGoogle Scholar
  • 23 Molina RA, Katzir L, Rhee C. et al. Early evidence of bone marrow dysfunction in children with indeterminate fulminant hepatic failure who ultimately develop aplastic anemia. Am J Transplant 2004; 4: 1656-1661
    CrossrefPubMedGoogle Scholar
  • 24 Pardi DS, Romero Y, Mertz LE. et al. Hepatitis-associated aplastic anemia and acute parvovirus B19 infection: a report of two cases and a review of the literature. Am J Gastroenterol 1998; 93: 468-470
    PubMedGoogle Scholar
  • 25 Patel KR, Bertuch A, Sasa GS. et al. Features of Hepatitis in Hepatitis-associated Aplastic Anemia: Clinical and Histopathologic Study. J Pediatr Gastroenterol Nutr 2017; 64: e7-e12
    CrossrefPubMedGoogle Scholar
  • 26 Rasmussen LK, Stenbog EV, Kerndrup GB. et al. Autoimmune Hepatitis and Seronegative Hepatitis Associated With Myelodysplastic Syndrome in Children. J Pediatr Hematol Oncol 2016; 38: e274-e277
    CrossrefPubMedGoogle Scholar
  • 27 Schlitt HJ, Ringe B, Rodeck B. et al. Bone marrow dysfunction after liver transplantation for fulminant non-A, non-B hepatitis. High risk for young patients. Transplantation 1992; 54: 936-937
    CrossrefPubMedGoogle Scholar
  • 28 Squires RH, Shneider BL, Bucuvalas J. et al. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr 2006; 148: 652-658
    CrossrefPubMedGoogle Scholar
  • 29 Taylor S, Hu C, Pan DH. et al. Treatment of acquired aplastic anemia in patients with acute liver failure occurring concurrently: a case series. J Pediatr Hematol Oncol 2012; 34: e349-e352
    CrossrefPubMedGoogle Scholar
  • 30 Trey C, Davidson CS. The management of fulminant hepatic failure. Prog Liver Dis 1970; 3: 282-298
    PubMedGoogle Scholar
  • 31 Tung J, Hadzic N, Layton M. et al. Bone marrow failure in children with acute liver failure. J Pediatr Gastroenterol Nutr 2000; 31: 557-561
    CrossrefPubMedGoogle Scholar
  • 32 Tzakis AG, Arditi M, Whitington PF. et al. Aplastic anemia complicating orthotopic liver transplantation for non-A, non-B hepatitis. N Engl J Med 1988; 319: 393-396
    CrossrefPubMedGoogle Scholar
  • 33 Umemura T, Tanaka E, Ostapowicz G. et al. Investigation of SEN virus infection in patients with cryptogenic acute liver failure, hepatitis-associated aplastic anemia, or acute and chronic non-A-E hepatitis. J Infect Dis 2003; 188: 1545-1552
    CrossrefPubMedGoogle Scholar
  • 34 Wang H, Tu M, Fu R. et al. The clinical and immune characteristics of patients with hepatitis-associated aplastic anemia in China. PLoS One 2014; 9: e98142
    CrossrefPubMedGoogle Scholar
  • 35 Wong S, Young NS, Brown KE. Prevalence of parvovirus B19 in liver tissue: no association with fulminant hepatitis or hepatitis-associated aplastic anemia. J Infect Dis 2003; 187: 1581-1586
    CrossrefPubMedGoogle Scholar