Abstract
In this commentary to the paper by Donadon V. et al (Clinical Medicine: Endocrinology and Diabetes. 2009;2:25–33.) the association and significance of insulin resistance with chronic liver disease are shortly reviewed and the molecular mechanisms underlying the diabetogenic and oncogenic potentials of advanced liver disease are summarized. Literature studies demonstrate that hepatocellular carcinoma (HCC) can be part of the natural history of NASH. HCCs in patients with features of metabolic syndrome as the only risk factor for liver disease have distinct morphological characteristics and mainly occur in the absence of significant fibrosis in the background liver. Moreover, data indicate that the presence of diabetes carries an approximately three to four-fold increased risk of HCC and such a risk is strongly increased by concurrent viral infections. Finally, the relationship between insulin resistance, steatosis and diabetes in NAFLD and HCV infection will be commented, along with the directions for future studies.
The Diabetogenic Potential of Advanced Liver Disease
Insulin resistance (IR) is a concept popular among diabetologists who, historically, have contributed to its most explicit conceptualization in the last two decades. 1 During the same time period, however, IR has also become of great current interest among hepatologists. This is essentially the result of IR playing a key-role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) 2 and being a cofactor of progression/impaired response to treatment in chronic hepatitis C. 3 Such close links between IR and two among the most common chronic liver disorders in western countries are likely to account for why diabetes almost invariably follows most chronic liver diseases. Moreover, they explain why cirrhosis, in particular, was depicted to be an overt diabetogenic condition a few years before Reaven had conceptualized the importance of IR in human disease. 4 Closing the circle, we now are aware that increasing stages of hepatic fibrosis are associated with increasing risks of developing type 2 diabetes via increasing levels of IR. The paper by Donadon 5 is further evidence for this pathogenic cascade of events.
The Oncogenic Potential of Advanced Liver Disease is Influenced by IR
Not only does insulin regulate glucose metabolism, but it is also directly and indirectly involved in the risk of promoting the development of cancer at various extrahepatic organ sites such as colon, prostate, and pancreas. 6 There is strong epidemiologic evidence linking the metabolic syndrome (MS) and hepatocellular carcinoma (HCC); the molecular mechanisms sustaining hepatic carcinogenesis in those with IR, however, are not completely understood. 7 Primary liver cancer might result from activation of the tumor suppressor PTEN, a phosphoinositide phosphatase regulating the PI3K/Akt signaling pathways and the dysregulated expression and activity of which critically affects hepatic insulin sensitivity, triggers the development of NAFLD and participates in the molecular pathogenesis of HCC.8,9 The Hydroxymethyl-glutaryl-CoA inhibitors statins exert pleiotropic actions in liver physiology and particularly on cholesterol-related cell signalling pathways. 10 On this basis, the recent finding that statin use is associated with a significant reduction in the risk of HCC among patients with diabetes 11 indirectly suggests that metabolic pathways such as synthesis of bile acids, sonic Hedgehog, Kras, and the Rho family, p21 and p27 cyclin-dependent kinase inhibitors and fibrogenesis could be additional potential mechanisms involved in hepatocarcinogenesis in diabetics.10,11
NASH, Cryptogenic Cirrhosis and HCC
Nonalcoholic steatohepatitis (NASH) is the most advanced histological form in the NAFLD spectrum. The association between NASH-cirrhosis–-sometimes indistinguishable from cryptogenic cirrhosis–-and HCC has been consistently confirmed by several studies summarized in Table 1.12–26 Such an association comes as no surprise given that cirrhosis of various etiologies is known to be a pre-cancerous condition 27 and NASH is indeed strongly associated with IR. 28 Overall, literature studies summarized in Table 1 demonstrate that HCC can be part of the natural history of NASH.12–26 HCCs in patients with features of MS as the only risk factor for liver disease have distinct morphological characteristics and mainly occur in the absence of significant fibrosis in the background liver.22,23 Awareness of these specific features of disease can be exploited to implement specific strategies aimed at obtaining earlier diagnoses and more effective treatment results. 26
Evidence for a relationship between NASH, cryptogenic cirrhosis and HCC.
Association of Diabetes, Steatosis and HCC
Population studies from Northern Italy have shown type 2 diabetic patients to have an increased risk of death from gastrointestinal diseases, particularly from liver cirrhosis after 5 years of follow-up and a higher risk of mortality from liver cancer after 10 years of follow-up, particularly in obese patients. 29 Such findings are strongly supported by several studies, summarized in Table 2.30–46 Data indicate that the presence of diabetes carries an approximatively three to four-fold increased risk of HCC.32,36,45 Moreover, the metabolic risk of diabetes is strongly potentiated by concurrent viral infections.31,37,44,45 Given that steatosis is a sensitive barometer of metabolic health, the association of steatosis with HCC risk is also biologically plausible35,43 although a study contrasts with such a view. 38
Evidence for an association between diabetes (or steatosis) and HCC.
The Relationship between Insulin Resistance, Steatosis and Diabetes in NAFLD and HCV Infection
Early stages of both NAFLD and HCV infection share steatosis as a common histologic feature and IR is a physiopathologic feature of both liver diseases. Such findings have generated interest in the possibility of transferring knowledge from one disease to the other. 47 In the transgenic mouse model expressing HCV core protein, IR anticipates the development of steatosis. Overt diabetes only occurs once these animals gain weight as a result of a high-fat diet. A high level of tumor necrosis factor-alpha, which acts by disturbing tyrosine phosphorylation of insulin receptor substrate-1 and is a common finding also in human chronic hepatitis C, is considered to be one of the bases of IR in the transgenic mice. 48 Studies conducted by short-term high fat feeding rats support the hypothesis that hepatic steatosis leads to hepatic insulin resistance by stimulating gluconeogenesis and activating PKC-epsilon and JNK1, which may interfere with tyrosine phosphorylation of IRS-1 and IRS-2 and impair the ability of insulin to activate glycogen synthase. 49 Our group recently compared the predictors of IR in HCV and NAFLD. Data show IR to be independently asssociated with BMI and triglyceridemia in NAFLD; male gender and fibrosis in chronic HCV infection. 50
Collectively, these animal and human studies have relevant clinical implications. On the HCV side, eradication of viral infection with combined IFN+ Ribavirin regimens, which is associated with prevention of fibrosis, has resulted in the prevention of the development of diabetes 51 although this finding has not been invariably confirmed. 52 On the NAFLD side, these patients are often glucose-intolerant or diabetics either at the first diagnosis or during follow-up.53–56 Furthermore, in a study conducted in patients with type 2 diabetes, a weight loss of only approximately 8 kg resulted in improved basal and insulin-stimulated hepatic glucose metabolism associated with an 80% reduction in intrahepatic lipid content. 57
Conclusions and Research Agenda
In conclusion, data reviewed here strongly support that advanced hepatic fibrosis is associated with diabetes and that diabetes increses the risk of developing HCC. Such a view is also confirmed in the study by Donadon. 5 Asssociation, however, does not prove causality. The paper by Donadon, owing to its cross-sectional design does not show which, between IR and HCC, comes first. 5 Prospective studies are, therefore, needed to address the issue whether those chronic liver disease patients who are more insulin-resistant are at an increased risk of developing HCC or if it is the presence of HCC per se that aggravates pre-existent IR. Moreover, given that most studies are based on patients with HCC rather than on diabetics, it is unclear whether a stricter metabolic control might be effective in preventing the development of HCC in these patients.
Disclosures
The authors report no conflicts of interest.
Footnotes
Acknowledgements
The authors are indebted to Mrs Jacqueline Mole for English editing of the manuscript.