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-dichloro-N-[(1R,2R)-1-[(hydroxyacetyl)amino]-2,3-dihydro-1H-inden-2-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide), 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 life-threatening 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.
It has been known for decades that human patients suffering from inborn hepatic GSD, mostly that of type I (von Gierke’s disease), which is due to a genetic defect in glucose-6-phosphatase, have an increased risk to develop hepatocellular adenomas and carcinomas when they pass through adolescence (Bannasch et al. 1984; Bianchi 1993; Limmer et al. 1988; Lerut et al. 2003; Mason and Anderson 1955; Wolfsdorf and Weinstein 2003; see the preceding for further literature). GSDs related to glycogen phosphorylase, namely, GSD VI (phosphorylase deficiency, Hers disease) and GSD IX (phosphorylase kinase deficiency), are much less frequent than GSD I, but even in these rare diseases hepatic adenomas have occasionally been observed in adolescence (Wolfsdorf and Weinstein 2003; Weinstein 2010). In addition, an acquired focal hepatic glycogenosis frequently occurs in human beings with various chronic liver diseases prone to develop hepatocellular adenomas and carcinomas (Altmann 1994; Bannasch and Klinge 1971; Bannasch et al. 1997; Su et al. 1997). Hepatic glycogenosis, which is usually focal but may also occupy almost the whole liver parenchyma, has been induced in different species, including human and nonhuman primates, by hepatocarcinogenic chemicals (Bannasch 1968; Bannasch, Mayer, and Hacker 1980; Cattan et al. 2000; Hacker et al. 1982; Moore and Kitagawa 1986; Nehrbass, Klimek, and Bannasch 1998; Williams et al. 1976), by oncogenic hepadnaviridae or subgenomic fragments of these viruses (Bannasch et al. 1995; Kim et al. 1991; Radaeva et al. 2000; Toshkov, Chisari, and Bannasch 1994), and by intrahepatic transplantation of pancreatic islets producing local hyperinsulinemia in the liver under diabetic conditions (Dombrowski, Bannasch, and Pfeifer 1997; Dombrowski, Mathieu, and Evert 2008). Compelling evidence for the preneoplastic nature of the focal hepatic glycogenosis (appearing as clear cell lesions in conventional, H&E-stained tissue sections) has been provided by many laboratories (Bannasch 1968; Bannasch, Mayer, and Hacker 1980; Bannasch et al. 1995; Cattan et al. 2000; Dombrowski, Bannasch, and Pfeifer 1997; Dombrowski, Mathieu, and Evert 2008; Hacker et al. 1982; Kim et al. 1991; Moore and Kitagawa 1986; Nehrbass, Klimek, and Bannasch 1998; Radaeva et al. 2000; Toshkov, Chisari, and Bannasch 1994; Williams et al. 1976; see the preceding for further literature). It has been demonstrated by biochemical approaches in situ in animal models of chemical, viral, and hormonal hepatocarcinogenesis, and in acquired human liver diseases, that the focal hepatic glycogenosis is regularly associated with a reduction in the activity of the two key enzymes involved in glycogen breakdown, namely, the glycogen phosphorylase and the glucose-6-phosphatase (Bannasch et al. 1984, 1997; Hacker et al. 1982; Moore and Kitagawa 1986, Toshkov, Chisari, and Bannasch 1994; Radaeva et al. 2000; Dombrowski, Bannasch, and Pfeifer 1997; Dombrowski, Mathieu, and Evert 2008). It would be of great interest to know whether the activity of glucose-6-phosphatase is reduced in addition to that of glycogen phosphorylase in the model presented by Floettmann and colleagues. In all experimental models of hepatocarcinogenesis, the transformation of the glycogenotic preneoplastic into the neoplastic cell populations requires a long lag period and is characterized by a fundamental metabolic shift resulting—among many other subcellular changes—in a gradual reduction of the glycogen initially stored in excess (Bannasch 1968; Bannasch, Mayer, and Hacker 1980; Bannasch et al. 1984, 1995; Moore and Kitagawa 1986; Radaeva et al. 2000; Toshkov, Chisari, and Bannasch 1994; Dombrowski, Bannasch, and Pfeifer 1997; Dombrowski, Mathieu, and Evert 2008). This metabolic shift is often accompanied by a transient accumulation of neutral fat. The storage of neutral fat in addition to glycogen observed by Floettmann et al. in Zucker diabetic fatty rats after treatment with the phosphorylase inhibitor GPi921 may be a similar phenomenon. The authors discussed that the “glucose-derived energy appeared to be shifted from glycogenosis to de novo lipogenesis” and felt that “drug holidays” might help to avoid fat accumulation and its adverse effects on the liver. It is important to realize, however, that it has been shown in the stop model of rat hepatocarcinogenesis that the transient storage of fat associated with the focal glycogenosis occurs only weeks and months after withdrawal of the carcinogen, indicating a persisting metabolic disturbance that is closely related to advanced preneoplasia or early neoplasia (Bannasch 1968; Bannasch, Mayer, and Hacker 1980; Bannasch et al. 1984). The metabolic aberrations in the acquired preneoplastic glycogenotic lesions are never limited to changes in the amount or activity of one enzyme such as glycogen phosphorylase but show a complex pattern resembling an effect of insulin (Bannasch, Klimek, and Mayer 1997; Bannasch et al. 1997; Dombrowski, Bannasch, and Pfeifer 1997; Dombrowski, Mathieu, and Evert 2008; Nehrbass, Klimek, and Bannasch 1998; Radaeva et al. 2000). This insulinomimetic effect appears to be the driving force for the gradual neoplastic transformation of the hepatocytes under various conditions. This may also apply to diabetes type 2, which as such confers an excess risk of primary liver cancer (Adami et al. 1996). Hence, the treatment of type 2 diabetic patients with a phosphorylase-inhibiting compound producing a hepatocellular glycogenosis in experimental animals, after a relatively short time of exposure, appears to be highly problematic. In any case, a hepatocarcinogenic effect of this compound has to be excluded in long-term animal studies in advance of any clinical application.