metallothionein and Hepatitis--Chronic

The chronic form of primary hepatitis occurs commonly in dogs, and the etiology is rarely found. Metallothionein (MT) is a heavy metal-binding protein found in many organs, including the liver. MT was recently shown to enhance liver regeneration and decrease hepatic fibrosis in human beings. This study examined the expression of MT in 24 cases of chronic hepatitis in dogs using immunohistochemistry. To understand the role of MT as a determinant of hepatic inflammation, fibrosis, bile duct proliferation, and regeneration, we correlated its expression with histologic lesions of chronic hepatitis, such as hepatic inflammation, fibrosis, and bile duct proliferation, as well as hepatocellular growth fraction as measured by Ki67 immunolabeling. Hepatocellular growth fraction was used as a measure of hepatic regeneration. Regression analysis revealed a significant positive correlation between MT labeling intensity and growth fraction (r(2) = 0.29, P < .05). The percentage of MT-positive cells and the overall MT expression were both positively correlated with growth fraction (r(2) = 0.25 and 0.26, respectively; P < .05). A negative correlation was found between the overall MT labeling and fibrosis (r(2) = 0.18, P < .05). A similar trend of negative correlation was also found between the percentage of MT-positive cells and fibrosis, but the P value was not statistically significant (r(2) = 0.14, P = .0684). These findings suggest a protective role of MT in dogs affected by chronic hepatitis, similar to its role in human beings. These dogs may respond to treatment modules focusing on enhancing the expression of MT.

Topics: Animals; Bile Ducts; Cell Proliferation; Dogs; Gene Expression Regulation; Hepatitis, Chronic; Immunohistochemistry; Inflammation; Ki-67 Antigen; Liver; Liver Cirrhosis; Liver Diseases; Liver Regeneration; Metallothionein

Serum metal levels and their ratios are frequently reported to be good signals for diagnosing various diseases. These parameters are not always specific to the disease, however, it is necessary to use other serum parameters for an exact diagnosis. We examined whether the monitoring of these serum parameters such as metallothionein, copper, and zinc levels are useful in diagnosing hepatic disorders. Metallothionein levels of patients with liver cirrhosis and hepatocellular carcinoma were found to be significantly lower than those of patients with chronic hepatitis and those of controls. In contrast, copper levels of the patients with liver cirrhosis and hepatocellular carcinoma were significantly higher than those with chronic hepatitis and controls. Zinc levels of the patients with chronic hepatitis and hepatocellular carcinoma were lower than those of controls. Using these three parameters, we are introducing a new parameter, (Cu/Zn)/MT, by which we can discriminate between patients in the [control+miscellaneous diseases+chronic hepatitis] group and those in the [liver cirrhosis+hepatocellular carcinomal group. The new parameter does not, however, allow us to clearly distinguish between the liver cirrhosis and hepatocellular carcinoma groups. Multivariate discriminant analysis was found to be very useful, with combinations of two discriminant functions having been designed to discriminate both between chronic hepatitis and liver cirrhosis and between liver cirrhosis and hepatocellular carcinoma. This method recognizes the differences between hepatic disorder, including chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma groups. On the basis of these results, we propose here that the diagnosis of hepatic disorders should be made based on a combination of three serum levels such as those of metallothionein, copper, and zinc.

Topics: Carcinoma, Hepatocellular; Copper; Hepatitis, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Metallothionein; Metals; Multivariate Analysis; Statistics, Nonparametric; Zinc

Iron and copper deposition were examined in patients with chronic active viral hepatitis (CAH) and posthepatitic liver cirrhosis (LC) by Berlin blue, rhodanine, or Victoria blue staining and X-ray microanalysis. Considerable iron or copper deposition was demonstrated in the peripheral zones of hepatic lobules in both CAH (53% of specimens) and LC (63% of specimens). Frozen sections taken from the 2 CAH surgical sections with iron depositions were examined by photoncounting image analysis, and superoxide liberation from the metal granules were demonstrated. In areas of metal deposition, vacuolation of liver cell nuclei, accumulation of lipofuscin, and induction of metallothionein (69% of rhodanine- or Victoria blue-positive specimens) were often demonstrated, whereas induction of ferritin was found only in 14% of Berlin blue-positive specimens. The PCNA index was significantly lower in areas of metal deposition than in the adjacent areas without metal deposition, indicating lowered proliferative capability in the former. These results indicate that cell-mediated immune mechanisms causing the disturbance of bile secretion and heavy metal deposition in the peripheral zones of hepatic lobules may be involved in the progression of viral hepatitis from its acute phase to CAH and finally to LC phase, resulting in piecemeal necrosis. However, cholangitis could not be demonstrated in the present study.

Topics: Adult; Aged; Copper; Cytoplasmic Granules; Cytosol; Electron Probe Microanalysis; Female; Ferritins; Hepatitis, Chronic; Histocytochemistry; Humans; Immunohistochemistry; Iron; Lipofuscin; Liver; Liver Cirrhosis; Liver Neoplasms; Luminescent Measurements; Lysosomes; Male; Metallothionein; Microscopy, Electron; Middle Aged; Proliferating Cell Nuclear Antigen; Superoxides