Nuclear ErbB2 Expression of Hepatocytes is Correlated with Distinct Histopathological Features

Background: ErbB2 is a prominent member of the epidermal growth factor receptor superfamily, a group of transmembrane receptors that mediate proliferation and cell growth in many tissues and are frequently investigated as oncogenic drivers and therapeutic targets in cancer. Besides transmembrane signaling, ErbB2 may also translocate into the nucleus and mediate distinct nuclear signaling effects, including DNA repair and cell cycle arrest. We recently demonstrated nuclear ErbB2 expression in hepatocytes, but it is still unclear, which disease conditions result in hepatocellular ErbB2 expression.

Methods: We analyzed 674 liver core needle biopsies from patients with hepatic dysfunction for immunohistochemical ErbB2 expression and correlated expression intensity with histopathological diagnosis and several histomorphological parameters: grades of fibrosis, steatosis, inflammation, cholestasis, occurrence of hepatocellular ballooning and Mallory-Denk-bodies.

Results: Hepatocellular ErbB2 positivity significantly correlated with increasing fibrosis grade and also with grade of chicken wire fibrosis. Furthermore, ErbB2 positivity correlated with inflammatory activity of steatohepatitis with particularly frequent and strong ErbB2 expression in alcoholic steatohepatitis compared to nonalcoholic steatohepatitis. Other hepatitides like viral hepatitis or autoimmune hepatitis were mostly ErbB2 negative. Interestingly, in case of steatohepatitis ErbB2 positivity was associated with low grade of steatosis, whereas in inflammation-free liver steatosis ErbB2 positivity was not correlated with grade of hepatocellular steatosis.

The histopathological finding of cholestasis (i.e. bilirubinostasis and cholate stasis), independently of disease background, frequently was accompanied with hepatocellular ErbB2 expression, too.

Moreover, ErbB2 positivity was significantly associated with hepatocellular ballooning and also with occurrence of Mallory-Denk-bodies.

Conclusion: Hepatocellular ErbB2 expression is correlated with several histomorphological features of hepatocellular dysfunction and damage like fibrosis, chicken wire fibrosis, cholestasis, hepatocellular ballooning and inflammatory activity of steatohepatitis. Of note, inflammation-associated hepatocellular ErbB2 expression was observed only in steatohepatitis, not in viral hepatitis or autoimmune hepatitis, although these hepatitides come along with significant hepatocellular damage, too. However, ErbB2 positivity is not only a result of alcoholic liver injury, but also occurs in diverse cholestatic liver conditions. Though, ErbB2 positivity may also serve as additional tool in histopathological differential diagnosis of liver disease. Moreover, further mechanistic studies on the role of ErbB2 expression on hepatocyte's fate have to be conducted in future.