Familial non-alcoholic steatohepatitis leading to hepatocellular carcinoma

Non-alcoholic steatohepatitis (NASH) has been associated with fibrosis that may progress to cirrhosis. The purpose of this study was to examine hepatocytes and perisinusoidal cells in liver biopsies of 3 families (3 males and 4 females) with non-cirrhotic and cirrhotic NASH to determine unique histological changes during a period of 2-7 years from diagnosis.

In this study, hepatocytes, stellate cells and Kupffer cells were analyzed using light and electron microscopy, and immunohistochemistry with specific anti-macrophage antibody staining of liver biopsies.

Body mass index of all patients was over 28, and all viral, metabolic markers were negative. Alcohol consumption was insignificant. In all liver biopsies, diffuse, non-zonal macrovesicular steatosis involved 40-70% of liver samples. The lobular hepatocytes showed prominent ballooning hepatocyte degeneration. No Mallory Denk hyaline bodies (MDBs) were observed in three of the patients. MDBs developed in ballooned hepatocytes of four individuals that also presented foci of lobular inflammation. The apoptotic bodies were stained by cytokeratin 18. The trichrome stain revealed portal to portal bridging fibrosis. In one family, there was a three-fold increase in relative numbers of perisinusoidal macrophages in the older sister with NASH compared to livers of the younger siblings. The special finding in livers of patients with NASH was accumulation of groups of perisinusoidal macrophages, which was not associated with focal necrosis.

Perisinusoidal macrophages appear to accumulate in NASH. It is possible that collections of macrophages are a response to chronic portal endotoxemia or lipotoxic activation of immuno-mediators. The persistent activation of these macrophages could lead to the chronic release of pro-inflammatory cytokines and contribute to chronic inflammation, fibrosis and cirrhosis leading to HCC.