Increasing titers and changing specificities of antinuclear antibodies in patients with chronic liver disease who develop hepatocellular carcinoma

Abstract

Background: Patients with liver cirrhosis and chronic hepatitis are at high risk for development of hepatocellular carcinoma (HCC). In HCC and other malignant neoplasms, antinuclear antibodies (ANA) have been detected, but the clinical and biologic significance of these autoantibodies has not been established. This study documents changing ANA manifested as seroconversion from a negative to positive ANA status, increasing titers, and changing antibody specificities in patients in whom chronic liver disease has progressed to HCC.

Methods: Sera were collected from patients with chronic liver diseases and HCC in Japan. Indirect immunofluorescence was used to detect ANA, and Western blotting, two-dimensional immunoblotting, and enzyme-linked immunosorbent assay were used to characterize nuclear antigen-antibody systems.

Results: ANA were detected in 57 of 183 (31%) patients with HCC, a statistically higher frequency than in patients with the most common antecedent clinical conditions, liver cirrhosis (9 of 64 patients [14%]; P < 0.05) or chronic hepatitis (16 of 123 patients [13%]; P < 0.001). One patient with autoimmune hepatitis observed for 9 years had a decrease in ANA titer after therapy with corticosteroid and azathioprine and had a rebound increase in ANA titer associated with development of HCC. Immunologic assays demonstrated dramatic decreases in levels of autoantibodies to histones during therapy and the appearance of new autoantibodies coincident with HCC. Changes in ANA associated with the appearance of auto-antibodies of new specificities were documented in four other patients with chronic liver disease in whom HCC developed.

Conclusions: Changes in ANA, especially alterations in autoantibody specificities, are seen infrequently in systemic autoimmune diseases. It is possible that in HCC such changes in ANA might reflect autoimmune responses to intranuclear antigens that are perturbed in cellular transformation.