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Case Report

Case Report: An unusual case of severe autoimmune hemolytic anemia in untreated hepatitis C viral infection

[version 1; peer review: 1 approved, 1 approved with reservations]
PUBLISHED 01 Aug 2024
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Abstract

Patients with hepatitis C share a variety of anemia, including bleeding, nutritional deficiencies, and anemia of chronic disease. Autoimmune hemolytic anemia (AIHA) is usually reported with interferon-alpha and/or ribavirin treatment in hepatitis C virus (HCV) infections. We report an unusual case of AIHA occurring in a49-year-old patient with untreated hepatitis C infection who presented with functional anemia syndrome. Monospecific direct antiglobulin test showed the presence of anti-complement (C3d++). Cold agglutinin titer was 1/16 at 4°C. The patient improved following blood transfusion, steroid therapy and direct acting antivirals.

Keywords

Cold agglutinin- autoimmune hemolytic anemia- Chronic hepatitis C

Introduction

Chronic hepatitis C virus (HCV) infection is widely recognized as a cause of extrahepatic manifestations, including autoimmune disorders.14 Autoimmune hemolytic anemia (AIHA) is rare. Warm AIHA with HCV infection in treatment-naïve patients has been described either during interferon treatment or in treatment-naive patients.47 However, the association between AIHA due to cold agglutinin and untreated hepatitis C seems to be a rare situation, to the best of our knowledge only two cases have been reported.8,9 Herein, we present a case of HVC infection complicated by cold AIHA.

Case report

A 49-year-old man with a history of HVC diagnosed two months ago, presented with dyspnea and pallor. HCV belonged to the type 1a genotype and the viral load was 1.6 106 UI/ml. Fibroscan showed F2 hepatic fibrosis stage. No evidence of recent drug use was found. On admission, the patient was pale, polypneic, and tachycardic with mild hepatomegaly. The patient did not have splenomegaly or lymphadenopathy. Laboratory tests showed severe anemia with a low hemoglobin (Hb) level (4.2 g/dl), macrocytosis (MCV 120 fL), reticulocytosis (5.2%), and normal white blood cell and platelet counts. A peripheral blood smear showed anisocytosis and polychromasia with rare schizocytes. Hemolysis workup revealed elevated indirect bilirubin (84 μmol/l), high lactate dehydrogenase (LDH) (580 U/L), and low haptoglobin concentration (0.15 g/l). These findings were consistent with the diagnosis of hemolytic anemia.

The presence of anti-complement C3d++ was confirmed using a monospecific direct antiglobulin test (DAT- Low Ionic Strength Solution). Anti-immunoglobulin G antibodies were absent. Screening of the eluate was negative, and the cold agglutinin titer was 1/16 at 4°C. Hemoglobin electrophoresis results were normal. A bone marrow biopsy was performed to elucidate the underlying etiology of the patient’s AIHA and showed erythroid hyperplasia with no evidence of tumor lymphoma. Further investigations, including anti-smooth muscle, antinuclear antibodies, and anti-DNA antibodies, were negative. However, type III mixed cryoglobulinemia was also observed. Thoracic-abdominal computed tomography (CT) indicated that the underlying malignancy was ruled out. Serology results for hepatitis B and human immunodeficiency virus (HIV) were also negative. Based on the above findings, a diagnosis of AIHA due to cold agglutinin complicating untreated chronic hepatitis C was made. The patient required repeated packed RBC transfusions on admission. When the diagnosis of AIHA was confirmed, the patient received corticosteroid therapy (1.5 mg/kg/day) for six weeks. No additional blood transfusion was needed because a remarkable improvement in the Hb level was obtained (9.8 g/dl). After three months, the patient started HCV treatment with oral antiviral therapy. During the follow-up, the patient’s hematologic disorders were completely renormalized.

Discussion

HCV-related immune disorders are frequent secondary to the activation of the immune system.

HCV lymphotropism determines dysregulation of the immune system, facilitating clonal B-lymphocyte expansion and autoantibody production.10

This state represents a trigger in the pathogenesis of virus-related immune disorders both in systemic autoimmune diseases (Sjögren syndrome, rheumatoid arthritis, etc.) and in organ-specific autoimmune diseases (diabetes mellitus, thyroid disorders, etc.).11

A wide variety of hematologic disorders associated with HCV, such as anemia, neutropenia, and thrombocytopenia, are well documented and are usually associated with interferon (IFN) and ribavarin therapy.2,1214 It has been suggested that AIHA observed in untreated HCV infection occurs especially in cirrhotic patients, who have a higher prevalence of autoimmune diseases and respond well to corticosteroid therapy.12 However, HCV-related AIHA is uncommon in treatment-naive patients.4

Most cases previously reported in the literature describe warm AIHA with no history of autoimmune disorders.1419 Anemia was not associated with any other hematological disorders with a good response to steroid therapy.

However, the association between AIHA due to cold agglutinin and untreated hepatitis C seems rare. To the best of our knowledge, only two cases have been reported.8,9 In the latter, cold agglutinin-mediated hemolytic anemia occurred in 72- and 74-year-old men who were positive for type III mixed cryoglobulinemia, as in our patient. Mixed cryoglobulinemia is the most documented extrahepatic manifestation of HCV infection.20

A common hypothesis for HCV-related cryoglobulinemia is chronic antigen stimulation of the humoral immune system, with clonal b-lymphocyte expansion producing circulating immunocomplexes. It may also facilitate the development of autoimmune diseases and lymphoproliferative disorders. However, in our patient, as well as in the two published cases, there was no evidence of lymphoproliferative disorder.9

Our patient was diagnosed with cold agglutinins AIHA, including hemolytic anemia, reticulocytosis, elevated lactate dehydrogenase, hyperbilirubinemia, positive direct antiglobulin test (DAT), monospecific DAT positive for C3d, and negative for IgG and cold agglutinin titers ≥ 64. In our patient, the thermal amplitude, which is the highest temperature at which the antibody reacts with the antigen, at 4°C was useful for diagnosis, considering the cold agglutinin titer < 64.21

Cold agglutinins can adhere to red blood cells at low temperatures (complement activation). C3b-coated erythrocytes are removed by macrophages.22

Subsequently, it is imperative to rule out potential etiologies of cold agglutinin-induced AIHA, including medication side effects, systemic lupus erythematosus, and malignancy. In our patient and in two similar published cases, no etiology was found, except for HCV infection.

Pathogenesis of AIHA induced by infectious agents is still not well understood. Inflammatory state may explain this rare condition.23,24

Different treatment modalities are available for AIHA: corticosteroids, anti-CD20 (rituximab), Intravenous immunoglobulin (IVIG), and splenectomy. However, in cold AIHA, steroids are less effect in patients with cold AIHA compared with patients with warm AIHA.14,19,25 Our patient was a good responder to corticosteroids.

Steroids do not seem to show good results in all cases.8 In this situation, anti-CD20 or IVIG may be considered.26 However, it is important to note that the concomitant use of HCV antiretroviral drugs could explain the good response to corticosteroid therapy observed in our patient.

Conclusions

AIHA due to cold agglutinin is a very uncommon hematologic manifestation of HCV infection, particularly in treatment-naive patients. HCV seems to be mysterious, and further research is needed to elucidate the mechanisms of some related HCV autoimmune manifestations.

Consent

Patient gave an informed written consent to publish details regarding the case summary and its use in medical publications.

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CITE
how to cite this article
Debbabi H, Chakroun A, Elloumi H et al. Case Report: An unusual case of severe autoimmune hemolytic anemia in untreated hepatitis C viral infection [version 1; peer review: 1 approved, 1 approved with reservations]. F1000Research 2024, 13:863 (https://doi.org/10.12688/f1000research.148607.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Open Peer Review

Current Reviewer Status: ?
Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
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PUBLISHED 01 Aug 2024
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Reviewer Report 14 Oct 2024
Batbold Batsaikhan, Institute of Medical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia 
Approved
VIEWS 2
This case report is well written and included all necessary patient's condition. Also it is well described extrahepatic manifestations such as cryoglobulinemia. It is informative for practitioners that chronic HCV infection can be related with cold autoimmune hemolytic anemia. Authors ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Batsaikhan B. Reviewer Report For: Case Report: An unusual case of severe autoimmune hemolytic anemia in untreated hepatitis C viral infection [version 1; peer review: 1 approved, 1 approved with reservations]. F1000Research 2024, 13:863 (https://doi.org/10.5256/f1000research.162939.r324838)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Reviewer Report 01 Oct 2024
Madhumita Premkumar, Postgraduate Institute of Medical Education and Research,, Chandigarh, India 
Approved with Reservations
VIEWS 3
The authors present a single report of AIHA occurring in a 49-year-old patient with untreated hepatitis C infection who presented with 'functional' anemia syndrome. 

1. Please advise if it was appropriate  to start steroids without the cover ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Premkumar M. Reviewer Report For: Case Report: An unusual case of severe autoimmune hemolytic anemia in untreated hepatitis C viral infection [version 1; peer review: 1 approved, 1 approved with reservations]. F1000Research 2024, 13:863 (https://doi.org/10.5256/f1000research.162939.r324843)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

Comments on this article Comments (0)

Version 1
VERSION 1 PUBLISHED 01 Aug 2024
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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