Diabetes mellitus (DM) is a common comorbid condition in cirrhotic patients and those with hepatocellular carcinoma (HCC) likely because of deranged carbohydrate metabolism in the liver.1 DM is also a well-known risk factor for both chronic liver disease and HCC. To date, at least 10 case-controlled and five cohort studies have described a positive association between DM and HCC, with reports showing increased risk ratios of 2–3 : 1.2,3 However, whether DM adversely affects the long-term outcome of patients with HCC, particularly with respect to tumor recurrence following attempted therapy, remains controversial.
Undisputable factors contributing to a higher likelihood of recurrent HCC after potentially curative treatment include male gender, heavy alcohol consumption, tumor size, tumor differentiation, pretreatment alpha-fetoprotein, degree of liver fibrosis, and underlying etiology of liver disease/cirrhosis.3–6 A recent study of 90 Japanese with HCC showed that those with hepatitis C virus (HCV)-related disease and DM had decreased overall survival after surgical resection of their liver cancer.7 Interestingly, in the patient subgroup with DM, Child-Pugh B disease severity, and insulin therapy were significant predictive factors for HCC recurrence. Contrary to the results of this study, Huo et al. analyzed survival and tumor recurrence of 239 HCC patients according to glycemic status and underlying viral infection.8 Data from their 5-year follow-up revealed that patients with HCC and DM had decreased overall survival compared with those who were not diabetic, but there was no significant difference in tumor recurrence.8 However, diabetic patients with chronic hepatitis B virus (HBV) infection had poorer long-term outcomes compared with those with chronic HCV infection.8 In other studies, DM has been found to be a poor prognostic predictor only among those with small (≤ 5 cm) HCC without postoperative tumor recurrence; the increase in mortality was attributable to complications resulted from DM.9,10
In this issue of the Journal, Kawamura et al. present a study that examines the relationship between DM and recurrence for HCC in a small number of patients with non-B non-C hepatitis undergoing surgical resection or radiofrequency ablation.11 Twenty-two out of 40 patients (18 with DM), developed recurrent HCC during a median 4-year follow-up period. Although HCC recurrence rate was significantly higher in diabetic patients than in non-diabetics (hazard ratio: 4.61, 95% confidence interval: 1.5–13.9, P = 0.007), there was no significant difference in overall survival rate.11 Not surprisingly, the predictive factors for poor survival were serum albumin, prothrombin time, and age. Several points pertaining to the design and analysis of Kawamura.'s study warrant comment. The cohort was small and confined to non-viral related liver disease. Of note, a significant proportion of patients (19/40) had a history of excessive of alcohol consumption (lifetime intake > 500 kg). It would have been prudent to analyze this subgroup with respect to HCC recurrence and not just report on the lack of correlation between their overall survival and total ethanol intake. The severity of underlying steatosis or steatohepatitis in the group of patients with DM was also unknown. The authors report hyperlipidemia as an adverse prognostic factor but do not comment on whether this was associated with hyperglycemia and/or insulin resistance in their study cohort. Clarification of which patients with DM had undergone resection compared with non-surgical therapy (in this instance, radiofrequency ablation) would have been useful in the analyses, as it is possible that those with better glycemic control and underlying liver function would have been preferentially considered as candidates for surgery, thereby influencing outcomes.
Clinical studies aside, the underlying mechanisms behind the observation of increased HCC recurrence in diabetics are yet to be defined. Non-alcoholic fatty liver disease is detected in up to 70% of patients with type 2 DM.12,13 One of the mechanisms involved in the pathogenesis of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) is oxidative stress.13 Accumulation of fatty acids could upregulate peroxisome proliferator-activated receptor-alpha (PPAR-α), the one consequence of which is increased fatty acid oxidation by mitochondria, peroxisomes, and endoplasmic reticular pathways-generating reactive oxygen species.14 Sustained PPAR-α activation induces HCC in rodents lacking fatty acyl-CoA oxidase.14 In this context, the chronic deregulation of redox homeostasis may favor tumorigenesis, either indirectly through steatosis, the hepatic inflammatory response, and cellular proliferation or directly by inducing cancer-promoting mutations, such as in the p53 tumor suppressor gene.13,14
Here lies the challenge before us—does insulin resistance play an independent role in the pathogenesis of diabetes-related hepatic neoplasia or, is it purely an associated phenomenon? Chronic hyperinsulinemia associated with insulin resistance is a suggested risk factor for other gastrointestinal tract cancers, in particular, colon and pancreatic carcinomas.15 Insulin, by phosphorylating insulin receptor substrate 1 and mitogen-activated protein kinases,is a potent growth factor.16 Human and rat HCC cell lines that express insulin receptors can be stimulated to proliferate in a dose-dependent fashion by exposure to insulin at physiological concentrations.15,16 Moreover, insulin promotes the synthesis and biologic activity of insulin-like growth factor-1 (IGF-1), a peptide hormone that can also drive hepatocyte proliferation and inhibit apoptosis.16 The synthesis and biological availability of sex steroids may also be modulated by insulin.15 In breast and colon cancer, estrogens and androgens may play roles in oncogenesis through post-translational modification of p53, thereby altering tumor suppressor function.16,17 It is conceivable that these mechanisms may also operate in hepatocarcinogenesis. Interestingly, in the Komura study of patients with DM and HCV-related HCC,7 those being treated with insulin had increased HCC recurrence after surgical resection.
Finally, adipose tissue is not inert an organ as previously thought. Adipocytes secrete adipokines that modulate a variety of biological processes, including immunity, inflammation, angiogenesis, and extracellular matrix formation and degradation.13 Changes in circulating adipokine levels occur in DM and may also play a role in carcinogenesis. For example, there is mounting evidence to support a role of the immune system in recognizing and eliminating malignant cells. Natural killer T (NKT) cells are reduced and hypo-responsive.18 Such NKT cells have a crucial role in immunosurveillance and control of tumor progression. Whether insulin resistance, hyperinsulinemia, and hyperglycemia can specifically impair hepatic NKT function remains speculative but is clearly worthy of further investigation.
Plasma levels of adiponectin, an anti-inflammatory protein is synthesized and secreted almost exclusively by adipocytes, are inversely correlated with body mass index so that the values are decreased in obese individuals.19 Low plasma adiponectin levels occur in DM and metabolic syndrome. Two large epidemiological studies have demonstrated a relationship between hypoadiponectinemia and increased breast cancer risk that persisted even after adjustment for body mass index.20 Further, larger tumor size and more aggressive phenotype correlated with low serum adiponectin. Adiponectin also has growth-inhibiting activities on cancer cell lines, angiogenesis and may exert potent tumor suppressive effects in vivo.21
We await further prospective studies to establish the true impact of DM on the prognosis of HCC, and experimental work to elucidate the mechanistic role in hepatocarcinogenesis. Meanwhile, can we employ strategies to minimize the risk of HCC recurrence in patients with diabetes? The findings from the Kawamura paper in this issue of Journal of Gastroenterology and Hepatology and those of previous studies reinforce the importance of meticulous optimization of glycemic control during follow-up patients after definitive therapy for HCC. Such follow-up should include more than liver imaging and monitoring serum alpha-fetoprotein levels but also attempt to control diabetes as reflected by normal HbA1C levels, preferably by measures other than insulin.