Cytopenia first – hepatitis second: an unusual sequence in aplastic anemia

Key Clinical Message To the best of our knowledge, this is the first report of aplastic anemia (AA) preceding autoantibody‐negative autoimmune hepatitis (AIH) with successful treatment of both conditions with the same immunosuppressive regimen, resulting in hematopoietic reconstitution and remission of AIH.


Introduction
Aplastic anemia (AA) is a rare disorder arising from hematopoietic failure. It is characterized by bi-or tricytopenia and a hypocellular bone marrow in the absence of an abnormal infiltrate and no increase in reticulin. In most of the cases, the primary etiology remains unknown, while in <5% AA can be observed following an infection, in particular after hepatitis due to an unidentified pathogen. Patients with AA present with symptoms of anemia, neutropenia, and bleeding complications [1]. Depending on disease severity, patients' age, and the availability of a potential HLA-identical donor, different therapeutic strategies are favored. Immunosuppressive therapy (IST) with antithymocyte globulin (horse ATG) and cyclosporin (CSA) results in a hematologic recovery in 60-70% of patients and is considered the initial standard treatment besides bone marrow transplantation [1].
A switch in the IST to tacrolimus was indicated due to CSA-induced hypertensive emergency in March 2013. As hematologic indices were stable for more than 12 months following IST, tacrolimus was tapered down and discontinued by August 2014. On the last day of observation in May 2016, hematologic indices remained stable (ANC 1.8/nL, Hb 15.5 g/dL, PLT 78/nL, ARC 79/nL, LDH 181 U/L, PNH clone size of 1.9%).

Discussion
Aplastic anemia (AA) is a rare complication of hepatitis (<5%), affecting most often adolescent boys or young men [1]. The agent(s) responsible for hepatitis in these cases are not well defined. As signs and symptoms are rather unspecific for hepatitis, patients present with prodromal symptoms including fatigue, myalgia, arthralgia, recurrent episodes of fever, and jaundice 2-3 months prior to the onset of bone marrow failure.
In none of the reported cases of hepatitis-associated aplastic anemia (HAAA), AA was described to precede autoantibody-negative AIH. Therefore, we are able to demonstrate an unusual sequence, as AA being the primary immunological event, rather than the consequence of AIH.
Taking into account that HAAA remains uncommon, the majority of cases have been described as fulminate, with mortality rates up to 85%, making HAAA a challenging treatment decision [2]. In ≤7% of the patients with acute presentation, autoantibodies cannot be detected [3]. At initial presentation, a hypergammaglobulinemia might be absent, as seen in this patient. In general, patients with AIH respond well to corticosteroids (AEazathioprine) resulting in a significant improvement in the majority of patients [4]. In cases of treatment failure or drug intolerance, calcineurin inhibitors (CSA/tacrolimus) can be considered as salvage therapies [5,6]. The immunopathogenesis of HAAA being summarized by Rauff et al. concerning lymphocyte variations during this syndrome with the accumulation of activated cytotoxic T cells in the liver, defective monocyte to macrophage differentiation, and decreased circulating levels of interleukin-1, in addition to response to IST, suggests autoimmunity as the key mechanism [7]. The importance of activated CD8-positive lymphocytes and their cytotoxic effect to hematopoietic progenitor cells has been described by Kagan et al. [8]. As a possible antigenic overlap between hematopoietic stem cells and the liver compartment can be speculated [9], IST with the same IS strategy suggests a reasonable therapeutic approach for both immune-mediated AA and AIH.
Interferon-gamma, a mediator of hematopoietic suppression, being secreted by activated CD8-positive T cells, might plays an additional role [10].
Authorship FA: performed the research, designed the research study, analyzed the data, and wrote the manuscript. DF: performed the research and analyzed the data. UD: analyzed the data and wrote the manuscript. HAB: performed the research, contributed essential reagents or tools, analyzed the data, and wrote the manuscript. AR: performed the research, designed the research study, analyzed the data, and wrote the manuscript.