Increased T-cell sinusoidal lymphocytosis in liver biopsies in patients with chronic hepatitis C and mixed cryoglobulinemia

Abstract

Mixed cryoglobulinemia (MC) has a strong association with hepatitis C virus (HCV) infection and is associated with a higher degree of fibrosis and poor response to therapy. Currently, there are no known histological findings on liver biopsy that correlate with the presence of MC in HCV-infected patients, although we have occasionally noted prominent sinusoidal lymphocytosis in MC patients. The goal of this study is to determine whether sinusoidal lymphocytosis is a histological marker of MC in liver biopsies from patients with chronic hepatitis C. The liver clinic database at our institution was searched for chronic hepatitis C patients with MC who underwent liver biopsy during 1999-2005. Ten such cases were identified and were included in the study. Ten chronic hepatitis C MC-negative cases were matched for age and stage of fibrosis to serve as controls. Histological features (sinusoidal lymphocytes, inflammatory activity, acidophil bodies, and fibrosis stage) were evaluated in each biopsy. Clinical and laboratory data (serum protein electrophoresis, liver enzymes, hepatitis C viral load, treatment status, comorbidities, etc.) were also recorded. Formalin-fixed, paraffin-embedded sections were submitted for immunohistochemical analysis using antibodies against CD3, CD20, CD4, CD8, and CD68. Sinusoidal lymphocytes were counted in 5 hpf (40x) on hematoxylin and eosin (H&E) stain, and on CD3 and CD20 immunostains. The number of CD68+ Kupffer cells was also counted in a similar fashion. In the MC-positive versus MC-negative cases, mean fibrosis stage (2.4 vs. 2.4), inflammatory grade (1.7 vs. 2.1), lymphocyte count (359 vs. 128/5 hpf), and Kupffer cell count (239 vs. 220/5 HPF) were assessed. There was a significant increase in sinusoidal T-cell lymphocytes (P < 0.05) in MC-positive cases as compared to MC-negative cases. Nearly all sinusoidal lymphocytes were CD8-positive cells in both groups. Other histological parameters did not differ in the two groups. MC-positive cases tended to have a lower viral load as compared to controls (P= 0.059). The role of sinusoidal T cells in the pathogenesis of MC is currently unknown. It is unclear if the presence of these cells implies ongoing antigenic stimulation that may lead to increased risk of lymphoma. This feature may be an important clue to predict the presence of MC, an HCV-associated phenomenon that has important implications for response to treatment and disease progression.