Abstract
Hepatitis-associated aplastic anemia (HAAA) is a variant of bone marrow failure that usually follows an acute attack of hepatitis. It usually affects children and young adolescents and is uncommon in adults. The causative factor in the majority of cases remains unknown. The efficacy of immunosuppressive regimens suggests autoimmunity as a key mechanism of HAAA. Although rare, seronegative autoimmune hepatitis can be a cause of bone marrow failure.
A 43-year-old Caucasian male patient with a past medical history of hypertension was admitted due to abdominal pain of two-week duration and progressive jaundice. He denied alcohol, smoking, illicit drug use, foreign travel, recent bites, scrapes, or injuries. His medications included hydrochlorothiazide, lisinopril and hydrocodone/acetaminophen. On physical exam, there was right upper-quadrant tenderness and notable jaundice but no hepato-splenomegaly. Admission laboratory data showed transaminitis and pancytopenia without neutropenia. The white blood cell count was 3.7×103/µl, hemoglobin 13.6 mg/dl, platelets 69×103/µl, ALT 2451 IU/l, AST 1573 IU/l, total bilirubin 7.7 mg/dl, alkaline phosphatase 185 IU/l and lipase 172. Further investigations included serological markers of viral hepatitis which were negative. Urine histoplasma and Cryptococcus antigens were negative. Anti-nuclear, anti-smooth muscle, anti-LKM and anti-mitochondrial antibodies were negative. Serum immunoglobulins, ceruloplasmin, acetaminophen level, DIC panel and anti-tissue transglutaminase (anti-tTG) IgA were normal. Liver ultrasound, endoscopic ultrasound, and MRI of the liver did not show any acute process. A liver biopsy showed autoimmune hepatitis (AIH). Four weeks later, pancytopenia worsened with severe neutropenia, but showed significant improvement in transaminases. Laboratory data showed white blood cell count of 1.1×103/µl, absolute neutrophil count 418, hemoglobin 10.7 mg/dl, platelets 19×103/µl, ALT 164 IU/l, and AST 50 IU/l. Peripheral blood workup for pancytopenia was unremarkable. Bone marrow biopsy showed aplastic anemia. The patient was started on steroids, cyclosporine, and anti-thymocyte globulin (ATG). His counts improved after staring immunosuppressive therapy and his liver function returned to normal. Cyclosporine was stopped because patient developed microangiopathic hemolytic anemia. Three months after initiation of therapy, his counts were stable and immunosuppressive therapy was stopped. He required no further therapy or transfusion.
Aplastic anemia (AA) may develop in as many as 1 in 3 cases of seronegative clinically identifiable hepatitis. In most cases, the hepatitis is self-limiting, but the liver disease may be prolonged or recurrent. AA is characterized by diminished number or total lack of hematopoietic precursors in the bone marrow. In most cases, stem-cell failure is acquired as a consequence to exposure to ionizing radiation, environmental chemicals, drugs, or viruses. However, in some patients AA seems to be immune mediated, with active destruction of blood-forming cells. Up to 13% of patients are diagnosed with autoimmune hepatitis and have no typical antibodies or hypergammaglobulinemia at presentation. Our patient was seronegative for known hepatotoxic viruses. Although he had negative autoantibody markers, liver biopsy showed autoimmune hepatitis, thus confirming the diagnosis of seronegative autoimmune hepatitis (SAIH). Clinically, the disease presented as a protracted hepatitis with episodes of jaundice and very high transaminases. Usually bone marrow failure follows SAIH, but in our case the patient had mild bone marrow failure on admission and severe hepatitis. It is unknown whether the immune mediated mechanism targets the liver and bone marrow simultaneously or aplastic anemia is a consequence of SAIH. The hepatitis and aplastic anemia responded well to immunosuppressive therapy which confirmed autoimmunity as the etiology of aplastic anemia and hepatitis in our patient.
The major pathogenic mechanisms leading to the liver injury and bone marrow destruction in SAIH patients seem to have an immune nature. Patients with SAIH should be monitored carefully, and in the presence of cytopenia directed to hematologist. Early treatment of SAIH with corticosteroids could prevent development of end stage liver disease and aplastic anemia.
Disclosures
No relevant conflicts of interest to declare.
Autoimmune Hepatitis as a Unique Form of an Autoimmune Liver Disease: Immunological Aspects and Clinical Overview