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Infection with the hepatitis C virus (HCV) is present in more than 1% of the U.S. population, with about 3.5 million carriers and 400 million people infected worldwide; thus, approximately 3% of the world population. HCV infection is more often observed in its chronic stage, at least in the Western hemisphere. Most hepatitis C infections (~80%) manifest clinically during the chronic stage. Hepatitis C infection accounts for most cases of parentally transmitted viral hepatitis. Parenteral drug users account for 30 to 40% of all cases. In over 56% of hepatitis C cases, according to the Centers for Disease Control and Prevention CDC, no risk factors have been identified. Persistent HCV infection not only results in chronic hepatitis but also precedes cirrhosis and liver cancer. On the other hand, alcoholic cirrhosis is the end-stage disease of alcoholic liver disease (ALD). This is still the most common cause of liver cirrhosis in our society. Thus, studies dealing with the pathogenesis of both conditions are of special interest.

Regeneration and tolerance factor (RTF), whose gene was originally known as J6B7 (3), is located on the distal portion of human chromosome 12. By the labeled streptavidin biotin (LSAB+) kit peroxidase method we searched for RTF expression in the livers of patients with regenerating nodules who had alcoholic cirrhosis and hepatitis C, with or without cirrhosis. All specimen evaluations were based on morphologic criteria, and investigators were not aware of the final diagnosis prior to their histological assessment.

Because patients with chronic liver diseases are often immunocompromised we decided to investigate the expression of RTF in human liver in both conditions. Earlier studies from this laboratory have shown that the distribution of lymphocytes in the trophoblast-maternal interface is mimicked by findings in the peripheral blood (4). We found that in addition to being expressed in the surface markers, RTF is also expressed on lymphocytes in the peripheral blood. Because patients with chronic liver disease have peculiar patterns of expression on the lymphocytes in the organs involved, we began to study the expression of RTF on lymphocytes in the peripheral blood of our patients with ALD and HCV disease.

We examined 31 patients with HCV infection and 28 patients with alcoholic cirrhosis. The HCV infection included 10 patients with cirrhosis and 21 patients with chronic hepatitis. The histological material was obtained from patients under study in our local hospitals. From these groups of patients blood was available for flow cytometric studies from 14 patients with alcoholic cirrhosis and 24 HCV-seropositive individuals. In addition, 31 healthy individuals were used as controls.

The liver needle biopsy specimens from the 28 patients with alcoholic cirrhosis with negative serology for viral markers were in addition investigated by the immunoperoxidase method. All cases of alcoholic cirrhosis were well-established disease class B and C of the Pugh classification, with regenerative nodules (6). In the cases of patients with HCV infection, 10 exhibited regenerative nodules and 21 showed chronic hepatitis only. HCV genotypes were not available.

Flow cytometric analysis of RTF, CD38, and HLA-DR expression on T cells. Flow cytometric analysis showed that RTF expression on CD4⁺ or CD8⁺ T cells is significantly different between individuals with alcoholic cirrhosis (n = 14) and HCV-seropositive patients (n = 24). The results demonstrated that surface expression of RTF on T cells is upregulated in patients with alcoholic cirrhosis and downregulated in HCV-seropositive individuals compared to that of healthy subjects (Table 1). As shown in Table 1, the mean channel fluorescence (MCF) of RTF expression on CD4⁺ and CD8⁺ T cells from individuals with ALD was significantly higher than the MCF of RTF expression in HCV-seropositive individuals (P < 0.001). No correlation between viral load or current disease severity and RTF was identified.

RTF expression in regenerating hepatocytes by immunohistochemistry. By immunohistochemistry the RTF protein was shown to be expressed in the regenerating nodules of 26 patients with alcoholic cirrhosis, and only two such patients were negative for RTF expression. In patients with hepatitis C it was expressed in only two patients who had cirrhosis with regenerative nodules and the remainder of patients, were negative for RTF expression. All patients with chronic hepatitis C without cirrhosis failed to express this protein. We cannot explain the difference in expression patterns of RTF between the two groups of patients, but the difference may be of potential significance for diagnosis and prognosis in the understanding of the differences between the two disease processes.