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Hepatitis A virus infection is complicated by both pancytopenia and autoimmune hemolytic anemia (AIHA)

Introduction Hepatitis A infection affects liver tissue primarily and might have some extrahepatic manifestations. Hematologically, the extrahepatic manifestations include aplastic anemia, red cell aplasia, and thrombocytopenia. There were reports about pancytopenia among patients with Hepatitis A infections, however, its association with autoimmune hemolytic anemia is rare as in our case. Case presentation A 30-year-old male visited the emergency room with tiredness, unmeasured fever, and jaundice. He also mentioned that recently he had anorexia and weight loss without night sweating. Initial laboratory findings showed pancytopenia and marked elevation of AST and ALT. Direct Coombs and IgM anti-Hepatitis A virus were positive. Consequently, he was diagnosed with HAV complicated by both pancytopenia and AIHA and treated with prednisone (1 mg/kg) leading to significant improvement in his anemia. Discussion This report describes a case of acute viral hepatitis A complicated with severe autoimmune hemolytic anemia and pancytopenia, which was successfully treated by high dose (1 mg/kg/day) prednisolone therapy. Conclusion This case represents a rare case in the literature review that can increase the awareness of the wide range of complications of HAV and its association with pancytopenia and AIHA.


Introduction
The infection of the hepatitis A virus might manifest as an asymptomatic infection or mild one to severe, acute, or even fulminant hepatitis [1].
The clinical course of Hepatitis A infection doesn't complicate with a chronic phase or the development of cirrhosis. Moreover, its hematologic extrahepatic complications are rare, including hemolytic anemia, aplastic anemia, red cell aplasia, etc. [2][3][4]. In particular, pancytopenia related to hepatitis is a rare hematologic complication, and HAV has the lowest association with pancytopenia compared to other hepatitis viruses [5].
We experienced a case of HAV complicated by both pancytopenia and AIHA which was unreported previously in the literature.

Presentation of case
A 30-year-old male visited the emergency room on October 28, 2021 with tiredness and fatigue for 20 days. The complaint was associated with yellowing of the skin and darkening of the urine and unmeasured fever. He also mentioned that recently he had anorexia and weight loss without night sweating. He denies any hemorrhage or bruises. His other symptoms include headache, tinnitus, palpitations, and grade 3 (NYHA) exertional dyspnea. His past medical history is unremarkable except for the transfusion of 2 PRBCs two days before this visit. Also, he is a heavy smoker (20 cigarettes for 15 years).
Physical examination showed a pulse of 110/m and a temperature of 38 • C. Head and neck examination revealed the presence of pallor, jaundice, and jugular veins congestion without lymphadenopathy.
The heart examination was normal except for a systolic murmur grade 3/6. Abdominal examination shows hepatomegaly (liver span 16.5cm) without shifting dullness or splenomegaly. Additional findings Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; TTP, thrombotic thrombocytopenic purpura; DIC, disseminated intravascular coagulation.
include bilateral pitting edema in the lower limbs.
Hepatitis B virus surface antigen, IgM anti-HBC, hepatitis C virus (HCV) RNA, Western blot for HIV, and anti-HCV were all negative. IgM anti-Hepatitis A virus was positive.
Chest X-ray and CT scan of the abdomen and chest showed no remarkable findings except for hepatomegaly and a small amount of free fluid around the liver.
Bone marrow aspiration showed normocellular marrow. It revealed increased activity of the red chain with maturity (myeloid: erythroid = 1:3). Granulocyte's chain was in good differentiation with a little proportion of metamyelocytes Fig. 2.
Based on clinical and laboratory findings, we excluded the other possible diagnoses like coagulopathy, malignancies, and hypoproliferative disorders, the patient was diagnosed with Acute Hepatitis A with autoimmune hemolytic anemia. The patient completely accepted the management plan after explaining the benefits and harms of the transfusion therapy and corticosteroids, and excluding the contraindications of the given treatment, such as uncontrolled bleeding and active bleeding gastric ulcer. He was given 5 units of platelets, 5 units of PRBCs, supportive care, and oral prednisolone (1 mg/kg/day) for 7 days. The patient was treated in the hematology ward and his treatment adherence was ensured by ward nurses and he the treatment was well tolerated without any complications. His symptoms and laboratory results were gradually improved during hospitalization as shown in Table 1. The follow-up after three months revealed complete clinical recovery with the absence of the previous findings including pallor, Jaundice and the systolic murmur, however he denied to do the laboratory tests again.

Discussion
This report describes a case of acute viral hepatitis A complicated with severe autoimmune hemolytic anemia and pancytopenia, which was successfully treated by high dose (1 mg/kg/day) prednisolone therapy.
There have been a few reports of severe Coombs positive AIHA complicating acute viral hepatitis [6]. However, the infection of HAV complicated with severe AIHA with pancytopenia has not been reported.
One of the main challenges to diagnosing such a case is the unavailability of laboratory testing for viruses that might cause such type of Coombs positive hemolytic anemia (e.g., parvovirus) which leaves the place for uncertainty about the casual relationship. Moreover, the lack of scientific literature regarding this type of association formed a challenge in the work-up and identifying the prognosis. P. Valent et al. explained the concept of pancytopenia as a decrease in all peripheral bloodlines and can be associated with a wide range of life-threatening cases. For a definition, the cutoff values are Hemoglobin <12g/dl for non-pregnant women and <13 for men. Absolute neutrophil count <1800/μL. Platelet <150,000/μL. Adding that these cutoffs   AST, aspartate aminotransferase; ALT, alanine aminotransferase. a Prednisolone 60 mg/day was started one day after this finding. b Discharge day on prednisolone 60 mg per day administration.
depend on several factors like sex, age, sea level, and race [7]. According to them, the three main mechanisms of pancytopenia include: bone marrow infiltration disorders such as hematologic malignancies and myelofibrosis, or blood cell destruction as in DIC, TTP, and hypersplenism, or bone marrow aplasia such as nutritional disorders and infectious diseases (miliary tuberculosis, fungal infection), and the treatment should be considered according to the possible cause [7].
Another study by M. Michel et al. defined AIHA as a rare autoimmune condition in which autoantibodies directed toward RBC antigens lead to their accelerated destruction. The diagnosis of AIHA is usually based on the identification of anti-RBC autoantibodies using the direct antiglobulin test, and in most cases, reticulocytosis is accompanied. Corticosteroids are the cornerstone of the treatment, and splenectomy and rituximab are second lines. Rapid transfusion has a positive role in severe cases of anemia despite the risk of alloimmunization [8].
Other possible causes of pancytopenia include coagulopathy, malignancies, and hypoproliferative disorders. The absence of schistocytes and the normal values of prothrombin time (PT) and thromboplastin time (PTT) make coagulopathy unlikely [9]. The absence of abnormal cells on blood smear and the confirmation of this by bone marrow aspiration helped us to exclude hematologic malignancies [10]. Hypoproliferative conditions including those caused by medications and deficiencies of minerals and vitamins are diagnosed by bone marrow aspiration and biopsy and are associated with reticulocytopenia as opposed to our case [11].

Conclusion
We experienced an HAV case in a patient: who was previously healthy with no drug history, negative serology for HBV, HCV, HIV, which was complicated by both AIHA and pancytopenia, who was successfully treated with corticosteroid and initial transfusion. This should increase awareness about the association between different viral infections and AIHA.

Methods
The work has been reported in line with the SCARE 2020 criteria [12].

Sources of funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ethical approval
This case report didn't require review by ethics committee, alassad university hospital, Damascus university, damascus-Syria.

Consent of patient
Written informed consent was obtained from the patient of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Provenance and peer review
Not commissioned, externally peer-reviewed.

Author contribution
All authors have participated in writing and reviewing the manuscript.

Registration of research studies
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Declaration of competing interest
The authors have no Conflicts of Interest to declare.