Hepatocellular Ballooning is Due to Highly Pronounced Glycogenosis Potentially Associated with Steatosis and Metabolic Reprogramming

Background and Aims: Hepatocellular ballooning is a com-mon finding in chronic liver disease, mainly characterized by rarefied cytoplasm that often contains Mallory-Denk bodies (MDB). Ballooning has mostly been attributed to degenera-tion but its striking resemblance to glycogenotic/steatotic changes characterizing preneoplastic hepatocellular lesions in animal models and chronic human liver diseases prompts the question whether ballooned hepatocytes (BH) are dam-aged cells on the path to death or rather viable cells, possibly involved in neoplastic development. Methods: Using speci-mens from 96 cirrhotic human livers, BH characteristics were assessed for their glycogen/lipid stores, enzyme activities, and proto-oncogenic signaling cascades by enzyme-and immunohistochemical approaches with serial paraffin and cryostat sections. Results: BH were present in 43.8% of cirrhotic livers. Particularly pronounced excess glycogen stor-age of (glycogenosis) and/or lipids (steatosis) were charac-teristic, ground glass features and MDB were often observed. Decreased glucose-6-phosphatase, increased glucose-6-phosphate dehydrogenase activity and altered immunore-activity of enzymes involved in glycolysis, lipid metabolism, and cholesterol biosynthesis were discovered. Furthermore, components of the insulin signaling cascade were upregulat-ed along with insulin dependent glucose transporter glucose transporter 4 and the v-akt murine thymoma viral oncogene homolog/mammalian target of rapamycin signaling pathway associated with de novo lipogenesis. Conclusions: BH are hallmarked by particularly pronounced glycogenosis with fac-ultative steatosis, many of their features being reminiscent of metabolic aberrations documented in preneoplastic hepa-tocellular lesions in experimental animals and chronic human liver diseases. Hence, BH are not damaged entities facing death but rather viable cells featuring metabolic reprogram-ming, indicative of a preneoplastic nature.