A Unique Case Report Describing Association of HLA-DR β1* 0405 with Acute Non-Viral Hepatitis and Aplastic Anemia

HLA-DR β1* 0405 has been implicated in various autoimmune disorders including autoimmune hepatitis (Qiu DK et al, J Gastroenterol Hepatol 2003). T cell clones with HLA-DR β1* 0405 restricted stem cell toxicity has been demonstrated in patients with aplastic anemia (Nakao S et al, Blood 1997). We report a patient with acute non viral hepatitis and aplastic anemia who has HLA-DR β1* 0405 genotype which she shared with her HLA matched sibling who was diagnosed to have autoimmune hepatitis.

Case Report: A 23 year old South Asian lady presented in July of 2012 with acute hepatitis. Her liver function tests (LFTs) showed a total bilirubin of 9.8mg/dl, and aspartate transaminase (AST), alanine transaminase(ALT) of 1815 and 2327 U/L respectively. Screening for known acute hepatitis causing viruses was negative. She had no significant history of exposure to any drugs or toxins other than a three day course of ciprofloxacin two weeks earlier. Liver biopsy showed evidence of active hepatitis with chronic lymphocytic infiltrates in the portal triads and small areas of hepatic necrosis with neutrophilic infiltrates. She also had pancytopenia with hemoglobin (Hb) of 10.1 g/dl, white blood count (WBC) of 3.1 X10³/mm³ with absolute neutrophil count (ANC) of 2.1 X10³/mm³ and platelet count of 7 X10³/mm³. Bone marrow exam confirmed a hypocellular marrow with 10% cellularity. She was treated with high dose steroids with improvement of her liver function tests. Her cytopenias worsened and she was transferred to our tertiary care center for further management. At admission her WBC was 0.9 X10³ /mm³ with ANC of 0.1 X10³ /mm³, Hb of 10.1 g/dl and platelet count of 21 X 10³/mm³(after tranfusional support). A repeat bone marrow exam showed a marrow with <1% cellularity consistent with aplastic anemia. Her LFTs had improved with total bilirubin 2.6mg/dl, AST and ALT 131 and 667 U/L respectively and normalized four weeks later. Screening for autoimmune antibodies including Anti Nuclear Antibody (ANA), anti-mitochondrial antibody and anti-smooth muscle antibody was negative. Her HLA typing confirmed HLA DR*β 1 0405 genotype. Her sister was HLA identical and during donor screening was found to have elevated AST and ALT of 92 and 174 U/L respectively. She had normal blood counts. She was positive for both anti-smooth muscle and anti-mitochondrial antibodies and liver biopsy showed mixed inflammatory infiltrate in portal and lobular regions. She was initially excluded as a bone marrow donor secondary to diagnosis of autoimmune hepatitis. Patient was treated with immunosuppressive therapy consisting of equine antithymocyte globulin (Atgam), cyclosporine and methylprednisone without response at four months. She received allogeneinc bone marrow transplant from her HLA matched sister after conditioning with fludrabine and cyclophosphamide. Sibling donor with autoimmune hepatitis had normal liver function tests at the time of bone marrow harvest after receiving therapy with steroids for three months. The patient’s immediate post transplant course was complicated by respiratory failure requiring brief intubation and transient worsening of her LFTs. She developed severe thrombotic microangiopathy at 11 months post transplant with acute renal failure that was refractory to plasma exchange but responded well to therapy with rituximab. At 12 months post transplant patient had >95 % donor chimerism and was negative for anti-smooth muscle and anti-mitochondrial antibody screening. Patient is now 18 months post transplant and is off all immune suppression with normal blood counts, renal function and liver function tests.

Conclusion: HLA-DRβ1* 0405 restricted autoimmune T-cells may have a role to play in the pathogenesis of acute hepatitis and associated aplastic anemia. A successful bone marrow transplant could be carried out in a patient with hepatitis with aplastic anemia from HLA matched sibling donor with autoimmune hepatitis after the donor had received treatment with steroids.