Familial non-alcoholic steatohepatitis leading to hepatocellular carcinoma

Manuela G Neuman Prof; Lawrence B Cohen Dr; Stephen Malnick Dr

doi:10.1016/j.cbi.2020.109054

Familial non-alcoholic steatohepatitis leading to hepatocellular carcinoma

Chem Biol Interact. 2020 May 25:323:109054. doi: 10.1016/j.cbi.2020.109054. Epub 2020 Mar 23.

Authors

Manuela G Neuman Prof¹, Lawrence B Cohen Dr², Stephen Malnick Dr³

Affiliations

¹ In Vitro Drug Safety and Biotechnology, Canada; Department of Pharmacology & Toxicology, University of Toronto, Canada. Electronic address: manuela.neuman@utoronto.ca.
² Division of Gastroenterology, Sunnybrook Health Science Centre, Canada; Department of Medicine, University of Toronto, Toronto, Canada. Electronic address: lawrence.cohen@sunnybrook.ca.
³ Department of Internal Medicine, Kaplan Medical Centre, Affiliated to Hebrew University, Rehovot, Israel. Electronic address: stephen@malnick.net.

PMID: 32217109
DOI: 10.1016/j.cbi.2020.109054

Abstract

Background and aims: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Electron microscopy; Familial aggregation; Hepatocellular carcinoma; Non-alcoholic fatty liver disease.

MeSH terms

Adult
Biopsy
Carcinoma, Hepatocellular / etiology*
Carcinoma, Hepatocellular / pathology
Female
Hepatic Stellate Cells / pathology
Humans
Kupffer Cells / pathology
Lipid Droplets / metabolism
Liver / pathology
Liver / ultrastructure
Liver Neoplasms / etiology*
Liver Neoplasms / pathology
Male
Middle Aged
Non-alcoholic Fatty Liver Disease / complications*
Non-alcoholic Fatty Liver Disease / pathology