Metallothionein Expression in Dogs With Chronic Hepatitis and Its Correlation With Hepatic Fibrosis, Inflammation, and Ki-67 Expression

Abstract

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.

Metallothionein Expression in Horses With Chronic Liver Disease and Its Correlation With Ki-67 Immunoreactivity

“…In our previous study, where MT was assessed in the diseased canine liver, Ki-67 expression within hepatocytes ranged from 0.4% to 25.2%. 44 It is possible that Ki-67 was absent because these cells reached the resting phase of the cell cycle and were no longer dividing. However, MT staining was observed within the nuclei of hepatocytes, suggesting that hepatocytes were regenerating, as MT immunostaining within the nucleus is associated with hepatocyte proliferation.…”

“…and A.L.A.) with a grading scheme modified after Sridharan et al 44 Hepatic inflammation was subjectively scored as 0, 1, 2, or 3 based on the assessment of the entire HE-stained section. A score of 0 indicated the absence of inflammatory cells; 1, the presence of inflammatory cells in <10% of the section; 2, 10% to 50%; and 3, >50%.…”

“…Recent work by our group showed a positive correlation between MT expression and hepatocyte regeneration and inflammation in chronic liver disease in dogs. 44 The present study aimed to examine the relationship between MT expression and hepatocellular proliferation in horses affected by chronic liver disease. The correlation between MT expression and common liver lesions (ie, degree of hepatic inflammation, fibrosis, and bile duct proliferation) was also assessed.…”

“…Recent work by our group showed a positive correlation between MT expression and hepatocyte regeneration and inflammation in chronic liver disease in dogs. 44…”