In our meta-analysis of HCC incidence, DM was significantly associated with an 87% elevated risk of HCC occurrence. This positive association was not reversed across subgroup analyses, regardless of study quality, study area, study design, statistical adjustments, and year of publication (shown in ). Interestingly, we found a higher liver risk of cancer incidence associated with DM in Japan (HCV-related HCC area) than in other Asian countries (HBV-related HCC areas). This geographic variability may reflect differences in etiology and need to be further explored. Due to limited information available regarding effect modification between DM and other important risk factors in relation to HCC incident risk, we were not able to evaluate the possible interactions. Moreover, the results of the subgroup analyses by diabetes and outcome ascertainment were consistent with the comprehensive meta-analysis, supporting the argument that self-reported history of diabetes may be reasonably accurate 
Compared with incidence studies, mortality studies have less superiority in causal inference, especially in DM and HCC studies. Given the long latent time period between DM onset and HCC death, it is impossible that the relatively limited follow-up period is sufficient to clarify the effects of reverse causality. Furthermore, this relatively short duration of follow-up might not capture all mortality from HCC cases with longer survival time. Additionally, most population-based studies on HCC mortality ascertained death from HCC based on national vital statistics, where DM related death or associated death may not always be recorded on death certificates among cancer cases 
; hence this approach seemed to be unreliable. The combined result for HCC specific mortality of the 6 population-based studies, however, was similar to that for HCC incidence (HR
1.88, 95%CI: 1.39–2.55). This close similarity could be explained by long duration of follow-up, high quality of cancer death registries in the included mortality studies, and high HCC case-fatality of incident cases. Among those studies, the follow-up time ranged from 4 years to 25 years where 4 of the 6 studies reported more than 10 years of follow-up 
. Subgroup analyses showed that combined estimates for DM-associated HCC mortality varied across selected strata of different methodology of diabetes measurement, major confounder adjustment, and year of publication. These discrepancies may be partly due to the small number of studies within each stratum.
Despite the consistent findings from HCC incidence and specific mortality studies, several issues relating to casual inference on the association between DM and HCC should be noted. First, although it is almost certain that the diagnosis of diabetes preceded the diagnosis of HCC in cohort studies we analyzed, the possible reverse causality in some studies could not be ruled out because it was unknown as to whether diabetes preceded the underlying chronic liver disease, and in some cases diabetes might be caused by these chronic liver disease. In studies of DM and HCC incidence and specific mortality, only one 
excluded patients with known baseline liver disease from the cohort entry. Second, cohort studies in the analyses that had a relatively short duration of follow-up and/or examined younger populations were not well suited to evaluate the temporality, given the low incident HCC cases or power, and greater loss to follow-up in these studies. For example, two hospital-based 
and three population-based 
cohort studies reported an average follow-up period of no more than 4 years, however the time of follow-up in other studies was fairly long (>4years). Third, although most included studies considered major confounding factors such as HBV and HCV infection, body mass index, and alcohol drinking, the inability to adjust fully for other important risk factors, particularly for treatment modalities for diabetes, could have biased the results. Evidence show that some medications for diabetes such as metformin 
can decrease the risk of cancer, whereas use of exogenous insulin and insulin secretagogues such as sulfonylureas can increase the risk of cancer incidence and/or mortality 
. Lastly, the duration of diabetes at cohort entry is less clear across the studies where only one study 
evaluated a duration-response relationship (changes in RR for HCC according to different durations of diabetes). Consequently, we failed to evaluate such duration-response trends in our analysis and thus cannot draw a firm conclusion. Therefore, additional studies are warranted to better define the onset of diabetes in relationship to onset of liver disease, and to clarify how any excess risk conveyed by diabetes is mediated by duration and treatment modalities of diabetes.
Although reported associations between pre-existing DM and mortality in patients with cancer have been inconsistent and varied with site, our results indicate that DM is associated with cancer prognosis. Having pre-existing DM increased the risk of all-cause mortality, recurrence after HCC treatment, and hepatic decomposition. The risk of all-cause mortality increased by 38% in patients with diabetes compared to those without diabetes. The magnitude of association only increased when analysis was restricted to high quality studies (49%) and remained consistent amongst studies adjusting for major confounders. Although our results indicate that pre-existing DM portends an elevated all-cause mortality, it is important to note that these data do not necessarily suggest a causal relationship. Such elevated risk could be associated with DM due to increased risk of complications, morbidity, and mortality associated with diabetes itself. We were unable to analyze the data further to assess mortality risks excluding DM-related causes of mortality because most of the studies involved in the analysis assessed overall survival and all-cause mortality. Of the six studies analyzed, only one study confined analysis to cancer related deaths, excluding DM related causes of death 
, in which the authors found that a positive association remained between DM and cancer mortality with or without the inclusion of DM-related deaths. Additionally, poor prognosis amongst patients with pre-existing DM may be attributable to a multitude of interactions and factors. These factors include tumoral factors such as size, extent of liver damage/cirrhotic factors, tumor recurrence, and DM-associated factors such as insulin intolerance 
. One study found that DM was a poor prognostic indicator of long-term survival in patients with tumors <5 cm due to the occurrence of DM-related deaths 
. Moreover, most patients with HCC have liver cirrhosis as a result of long term chronic liver disease. Diabetes may accelerate mortality by accelerating liver fibrosis, inflammation with increased inflammatory markers and cytokines resulting in severe liver failure 
and poor cancer prognosis 
. Also, it is possible that pre-existing diabetes may potentiate the incidence of bacterial infections in cirrhotic patients which has been shown to increase mortality 
. However, the pathophysiology underlying cancer prognosis and diabetes remains uncertain and requires further investigation 
. It is important to note that our analysis of hepatic decomposition was limited to few studies and should be interpreted with caution.
We observed that the risk estimate for HCC specific mortality was higher than all-cause mortality in patients with pre-existing diabetes. The elevated mortality risk may be attributed to risk related to HCC treatment and not necessarily due to the natural progression of HCC. The etiology of HCC is complex and influences treatment options available. Although treatment vary world-wide, first line treatment of early stage HCC is surgical resection, liver transplantation, and ablative therapies all with curative intent. For patients with intermediate stage disease with multifocal lesions and without vascular invasion, the treatment option is transcatheter arterial chemoembolization (TACE) 
. Theoretically, liver transplantation is ideal because it removes the tumor along with accompanying liver disease. Due to a shortage of donor livers and long waiting times for transplantation, most clinicians advocate for surgical resection. However, complications of surgery include decreased liver function, inadequate liver remnant and hepatic decomposition, all of which may impact prognosis. Additionally, patients with pre-existing DM and HCC have liver cirrhosis and thus decreased liver function, and/or other diabetes related comorbidities making them poor candidates for surgery or more aggressive treatments resulting in a worse prognosis 
. Overall, it is difficult to distinguish death from treatment related liver failure, other treatment related complications, diabetes or HCC. Analyzing studies across time periods, we found that mortality risks have declined when comparing current studies with earlier studies. This slight decline may be a result of improvements with diabetes management, glucose control 
as well as HCC classification, identification of therapeutic targets, and prognosis 
Although diabetes was found to be significantly associated with recurrence of HCC after treatment, when restricted to patients who received curative surgery only, the significant association disappeared. The attenuation of risk may result from inherent characteristics of surgery. It is commonly accepted that HCC recurrence is not a result of inadequate resection but more a result of microscopic tumor foci or due to microscopic dissemination of neoplastic cells during surgical procedures 
It remains unclear whether diabetes is directly associated with mortality in cancer patients, if it's more of an underlying biologic factor that alters cancer risk such hyperinsulinemia, or whether the cancer-diabetes association is indirect and a result of common risk factors such as obesity. In order to better understand the relationship, it is important to consider levels of insulin, glucose, and other diabetes related biomarkers such as adiponectin. Also, it is pertinent to understand duration of disease and disease management as these factors may also impact diabetes and/or cancer prognosis and outcome 
. In addition to pre-existing DM and associated DM comorbidities, other influences on HCC prognosis and HCC treatment response may also include the treatment and management of DM itself. Diabetic treatments may influence HCC prognosis by creating an environment of hyperinsulinemia. One study found insulin therapy for diabetic patients with advanced HCC resulted in a higher recurrence after hepatic resection 
. Similarly, sulfonylurea agents provide glycemic control but also create an environment of hyperinsulinemia 
. Thus, high insulin, rather than high glucose, may be an important contributing factor of HCC progression and impact how cells respond to HCC treatment 
The key strength of our meta-analysis is that our results were based on cohort studies, thus ensuring that DM diagnosis preceded the hepatocellular carcinoma and have less recall bias due to its prospective nature. Nonetheless, some limitations should be mentioned. First, substantial heterogeneity was found across the component studies. This was partly because of different study areas, study designs, statistical adjustments and methods of diabetes and outcome assessment in each study according to subgroup analyses. However, heterogeneity still existed in many subgroups, indicating that other factors may explain this heterogeneity. Second, publication bias was detected in the meta-analysis of all-cause mortality, however, the adjusted estimate based on trim and fill method had a slightly decrease and could not reverse the significant positive association, and no publication bias was found in other parts.
Implications and conclusions
In this meta-analysis, we found an increased risk of HCC in patients with diabetes mellitus. This finding underscores the need for preventative measures of diabetes management including weight control, promotion of measures to increase physical activity, and maintenance of a healthy diet. We also found that pre-existing DM is associated with adverse outcomes in hepatocellular carcinoma throughout its entire proceeding, from occurrence, progression, and to mortality. While the mechanism underlying the association between DM and prognosis remains unclear, it is important to monitor patients for post-operative recurrence, post-operative complications and hepatic decomposition.
Future studies should therefore 1) investigate how preexisting diabetes influences clinical decisions and how patients with DM diagnosed with HCC respond to varying treatment modalities for the latter; 2) determine the role of DM treatment in response to HCC treatment and prognosis, and 3) clarify the pathophysiology underlying liver cancer prognosis and diabetes. In addition, the effect of treatments and duration of diabetes should be taken into account in future etiological research.