Hepatocellular Glycogenosis and Hepatic Neoplasms

Abstract

In a recent issue of Toxicologic Pathology, Floettmann et al. (2010) published an article titled ''Prolonged Inhibition of Glycogen Phosphorylase in Liver of Zucker Diabetic Fatty Rats Models Human Glycogen Storage Diseases.'' I have read these well-described observations, dealing with Zucker rats treated with the test compound GPi921 (2,3-, which has been designed to inhibit glycogen phosphorylase in patients afflicted with type 2 diabetes mellitus, with great interest. I do not disagree with the presentation of the results obtained, and I endorse the conclusion that ''although glycogen phosphorylase inhibitors are efficacious agents for the control of hyperglycemia, prolonged treatment might have the potential to cause significant clinical hepatic complications that resemble those seen in GSD and hepatic glycogenosis.'' This statement is certainly correct, but in their discussion and conclusion, the authors did not take into consideration a possible lifethreatening additional complication: the well-documented high risk of patients and experimental animals suffering from inborn or acquired hepatocellular glycogenosis (glycogen storage disease, GSD) to develop hepatocellular adenomas and carcinomas. I would like to bring this possible serious complication to your attention and ask you to further spread this knowledge by the publication of this letter in Toxicologic Pathology.

Comparative Histomorphological Review of Rat and Human Hepatocellular Proliferative Lesions

“…Clear cell foci: Clear cell areas of groups of hepatocytes can be observed in HCCs in both human and rodents 40 , 41 , 42 , 43 . Clear cell foci consisted of normal or enlarged groups of cells with prominent cell membranes and distinct cytoplasmic clear spaces surrounding a densely stained centrally located nucleus.…”

“…The role of clear cell foci in hepatocarcinogenesis is elusive and poorly described, although metabolic changes in carbohydrate metabolism have been associated with HCCs in both humans and rodents 41 , 42 , 44 , 45 , and therefore these foci, as observed in the rat liver, could play a role in liver tumor formation. The selected clear cell foci (n=9) were only found in the livers of male rats.…”

Glycogen controls Caenorhabditis elegans lifespan and resistance to oxidative stress

“…However, the excess glycogen observed in many disorders5152, including several types of glycogen-storage diseases and diabetes may be a root cause of concomitant pathologies. Patients with type I, VI and IX glycogen storage diseases accumulate high levels of glycogen and are at increased risk of developing cirrhosis, hepatocellular adenomas and carcinomas5152. The role of glycogen in development of these pathologies, however, has never been directly addressed.…”

Anti-hepatocellular carcinoma activity and mechanism of chemopreventive compounds: ursolic acid derivatives

“…Garcia-Compean et al (2009) held that insulin resistance could decrease cure rates in patients with chronic hepatitis C (CHC) and enhance liver fibrosis. In genetics, lacking of the enzyme glucose-6-phosphatase, which is essential for glucose release from liver glycogen, is also a cause of HCC and hepatic adenomas (Bannasch 2010).…”