Oval cell numbers in human chronic liver diseases are directly related to disease severity

Abstract

The risk of developing hepatocellular carcinoma is significantly increased in patients with genetic hemochromatosis, alcoholic liver disease, or chronic hepatitis C infection. The precise mechanisms underlying the development of hepatocellular carcinoma in these conditions are not well understood. Stem cells within the liver, termed oval cells, are involved in the pathogenesis of hepatocellular carcinoma in animal models and may be important in the development of hepatocellular carcinoma in human chronic liver diseases. The aims of this study were to determine whether oval cells could be detected in the liver of patients with genetic hemochromatosis, alcoholic liver disease, or chronic hepatitis C, and whether there is a relationship between the severity of the liver disease and the number of oval cells. Oval cells were detected using histology and immunohistochemistry in liver biopsies from patients with genetic hemochromatosis, alcoholic liver disease, or chronic hepatitis C. Oval cells were not observed in normal liver controls. Oval cell numbers increased significantly with the progression of disease severity from mild to severe in each of the diseases studied. We conclude that oval cells are frequently found in subjects with genetic hemochromatosis, alcoholic liver disease, or chronic hepatitis C. There is an association between severity of liver disease and increase in the number of oval cells consistent with the hypothesis that oval cell proliferation is associated with increased risk for development of hepatocellular carcinoma in chronic liver disease.

Figure 1.

Oval cell numbers in control subjects and those with chronic hepatitis C (n = 15), genetic hemochromatosis (n = 15), or alcoholic liver disease (n = 15) who had mild (n = 5 in each group), moderate (mod; n = 5 in each group), or severe (n = 5 in each group) liver disease. A: Oval cell numbers determined from staining for M2-PK. B: Oval cell numbers determined from staining for π-GST. Numbers below the x axis represent the mean ± SEM for each group. P < 0.01 compared with mild disease. P < 0.05 compared with moderate disease. Error bars show the SEM.

Figure 2.

Immunohistochemical staining of serial sections from a patient with severe genetic hemochromatosis. A portal tract (P) and hepatocytes containing fat droplets (F) are labeled in each of the serial sections for orientation purposes. A: Oval cells (arrow) identified by M2-PK staining (red). B: Oval cells (arrow) stained with antibody to CK 19 (red). Ductular epithelium and some M2-PK positive oval cells are seen staining positively for CK 19. C: Oval cells (arrow), biliary epithelium, and some hepatocytes are seen staining positively for π-GST (red). Fewer oval cells stain positively in comparison to M2-PK. The line represents 200 μm.

Figure 3.

Oval cells identified by M2-PK staining (red). A: A portal tract from a patient with mild genetic hemochromatosis. B: The boxed portal tract area in (A) magnified to demonstrate oval cell morphology. C: A portal tract from a patient with moderate chronic hepatitis C. D: The boxed portal tract in (C) has been magnified to demonstrate oval cell morphology. More oval cells are demonstrated in the moderate than in the mild disease cases. The line represents 200 μm.