Case Presentation: An 18 year old female with a history of cirrhosis due to autoimmune hepatitis on immunosuppressants presented with acute low back strain. On presentation, her vital sign was remarkable for heart rate of 129 bpm. Physical exam revealed splenomegaly with mild pedal edema and low back tenderness. Laboratory evaluation showed a hemoglobin of 10.4 g/dL and INR of 2.4, which was her baseline. Total bilirubin however was elevated at 5.1 mg/dL compared to her normal baseline. Conjugated bilirubin was 1.3 which necessitated further workup for unconjugated hyperbilirubinemia. Lactate dehydrogenase was mildly elevated at 376 U/L and haptoglobin level was less than 10 mg/dL that raised concern of slow hemolytic process despite stable hemoglobin. A direct coombs test was positive for both Ig G and C3b. Peripheral blood smear showed the presence of cold agglutinins in titers of 1:64. These findings suggested the presence of mixed (warm and cold) autoimmune hemolytic anemia (AIHA). Further investigation for any underlying cause was unremarkable except for her known autoimmune hepatitis with anti-nuclear antibody titers in the range of 1:160 with nucleolar pattern. Mycoplasma and Epstein-Barr virus antibodies, flow cytometry of peripheral blood, urine and serum electrophoresis turned up negative. Computed tomography of neck, chest, abdomen and pelvis revealed chronic splenic infarcts with splenomegaly without evidence of underlying malignancies or lymphoma. She remained asymptomatic and subsequently left the hospital against medical advice. About 3 weeks later when she was admitted for spontaneous bacterial peritonitis, the local temperatures had dropped from 83°F/70°F to 50°F/39°F over 2 days and she was noted to have a significant drop in her hemoglobin from 9.6 g/dL to 6.9 g/dL without signs of bleeding. After 1 unit of red blood cell transfusion and avoidance to cold exposure, her hemoglobin remained stable throughout the hospital course.
Discussion: AIHA is characterized by autoantibodies against RBC antigens that result in premature destruction of the cells and subsequent anemia. Its predominantly classified into warm (IgG subclass), cold (anti-C3) and mixed subtypes based on the direct Coombs test. Our patient tested positive for both the antibodies but predominantly exhibited the signs of cold agglutinin disease. Cold agglutinin disease is closely linked to lymphoma but our patient most likely developed AIHA secondary to longstanding autoimmune hepatitis as a few such cases have been reported in the literature. The only treatment is avoidance of cold exposure which was effective in our case. Steroids and Rituximab are usually reserved for symptomatic anemia due to mixed- or warm AIHA.
Conclusions: Unconjugated hyperbilirubinemia in otherwise asymptomatic patients still requires close attention as it could be a manifestation of an underlying slow hemolytic process including AIHA. Avoidance of cold exposure is part of the mainstay of the treatment in cold or mixed AIHA.