Metabolic syndrome and liver-related events: a systematic review and meta-analysis

Because of a significant increase in the incidence and mortality of hepatocellular carcinoma (HCC), this cancer has become one of the most common malignancies and a major cause of death worldwide. In recent years, chronic liver disease has become a major cause of death in the United States, causing a large number of deaths every year, according to national life statistics. All the cirrhotic complications, HCC, and/or liver-related mortality were called LREs. And liver-related death is defined as death related to hepatic events [1]. Viral hepatitis and excessive drinking have been identified as the major risk factors for LREs, but risk factors for approximately 5 to 30% of HCC cases remain to be identified [2, 3]. Metabolic syndrome (MetS) patients have a high risk of cardiovascular disease. In addition, there is increasing evidence that patients with chronic liver disease are at risk of a higher rate of diagnosis of MetS or diabetes mellitus [4]. Recent studies have shown that MetS might have additional associations with liver disease. Liver cancer is the most severe liver disease. Although MetS is known to promote liver cancer, there is little evidence of whether MetS is associated with cirrhosis, liver failure, liver fibrosis, and death from liver causes.

MetS has become a major public health focus worldwide, and it is related to the occurrence of obesity and the diabetes pandemic. MetS components are a series of risk factors for cardiovascular diseases and it has become an increasingly severe problem globally [5]. The risk factors comprising MetS include obesity, abnormal blood sugar, Increased blood pressure, elevated triglyceride levels, decreased high-density lipoprotein cholesterol levels [6]. Several studies have described the relationship between MetS and diabetes and liver cancer [5], but few have investigated the LREs. The article intended to address this knowledge gap. Recent cohort studies have attempted to further understand the temporal relationship between these factors and to validate previous findings. However, there are few data on the association of LREs and MetS factors, which include obesity, diabetes and MetS.

In this study, we conducted a systematic review and meta-analysis to assess all available evidence to identify an association between MetS and LREs. We additionally analyzed related factors.

Figure 1 details our search steps. A total of 1,561,457 individuals were included in the study. Overall, we identified 8400 studies from different databases, including 4559 studies from PubMed, 173 studies from the Cochrane database, and 3668 studies from EMABASE. After reading the abstract, we initially considered 173 publications to be relevant. Among them, we excluded 25 comments, 2 letters, 7 meta-analysis, 25 comments, 1 unreported HCC, and 94 lacking risk estimates. A total of 19 studies (18 cohort studies and one case-control study) were included in the final analysis [1, 6, 9‐25].

In the meta-analysis of 19 studies including 1,561,457 patients with MetS, 16 studies found a statistically significant positive association, while 3 studies showed a negative association. After we removed the negative study indicated by the random-effects model to have affected the results, we also found that MetS significantly increased the risk of LREs. Therefore, the negative study did not change the finding.

The results also indicated that preexisting MetS confers a statistically significant 1.56- or 2.23-fold increased risk for LREs that is independent of other risk factors, an association also observed for its components. MetS can promote the occurrence of cardiovascular diseases, coronary heart disease and other diseases, and the degree of association between MetS and liver cancer is similar to the former [26, 27]. Nonalcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH), insulin resistance, and several metabolic abnormalities are closely related, thus suggesting a link between metabolic factors and cancer of the liver.

The findings from our study suggested a 1.33- or 2.33-fold increased risk of HCC development in patients with MetS. In addition, the study also demonstrated a 1.55- or 3.74-fold increased risk of liver-related death in patients with MetS. Our results together indicate that MetS is associated with a moderately increased risk of LRE.

Analysis of related factors showed an overall 115% increase in risk of LREs in HBV-positive cases (RR: 2.15, 95% CI: 1.02–4.53). For HBV-negative cases, the probability indicated a 85% increase in risk (RR: 1.85, 95% CI: 1.53–2.24). This conclusion is consistent with viral hepatitis having been identified as a major risk factors for LREs [2, 3], because over time, patients infected with viral hepatitis develop cirrhosis and, eventually, HCC.

And there was some article showed the pooled RR for HCV subjects with IR was 1.89 (95% CI, 1.54–2.33). It is because the presence of the HCV core protein will increase the level of tumor necrosis factor-α, further leading to proteasomal degradation of the insulin receptor substrate, ultimately altering insulin function and promoting the development of IR. At the same time, IR further causes lipid accumulation in the liver and production of reactive oxygen species, and indirectly activates stellate cells, eventually leading to the occurrence of liver fibrosis [28].

The related factor analysis also indicated that non-Asian MetS populations are more likely than Asian populations to have LREs. There was a 73% increase in risk of LREs for Asians and an 112% increase for non-Asians. The reason for this result is not yet clear, and more research is needed to provide an explanation. It is possible that the economy and the typical non-Western diet in Asia may explain the lower risk of MetS. And for Asian, the HBV vaccine is being recommended widespread. Meanwhile, the incidence of T2DM is lower in the Asian population, and it may have influenced the results. Some studies have reported that up to 90% of obese people in Europe have some degree of fatty degeneration in their liver and overweight increases the risk of HCC. The observed association between excess body weight and the increased risk of liver disease seems to support the reports that liver disease in obese individuals may be mediated through the development of NAFLD and NASH [12].

Our study suggests a relationship between MetS and LREs, but the mechanism that links the two is not fully understood. MetS is likely to be a proxy for other cancer risk factors, such as low physical activity, intake of high caloric food producing a high quantity of heat, high dietary fat intake, low fiber intake, and oxidative stress [29].The mechanisms by which DM induces HCC are related to insulin-like growth factor I (IGF-I) or insulin-like growth factor-binding protein-3 (IGFBP-3) [6]. The presence of insulin resistance and hepatic steatosis may support the hypothesis that diabetes promotes HCC, while the growth of insulin-like growth factor-1, the increase in leptin, the decrease in adiponectin and the imbalance of pro-inflammatory/anti-inflammatory cytokines are supported the appeal opinion [30]. There are several articles that study oxidative stress, cytokine effects, and other factors that contribute to the development of NAFLD. And because of the interaction between many metabolic factors, the study of their contribution to liver disease and liver cancer is more complicated. For example, deposition of free fatty acids and their metabolites in liver tissue is associated with hyperinsulinemia and insulin resistance, and they further promote hepatic steatosis [26].

Moreover, diabetic people have a higher risk of HCV infection, and diabetes is also associated with hyperinsulinemia. Both MetS and LREs are a problem worldwide, and growing evidence shows a relationship between MetS and an increased risk of LREs [31]. Insulin resistance and obesity are often thought to be linked to cancer, and diabetes is an independent prognostic factor for several common human malignancies, such as breast, colorectal, and prostate cancer [32, 33]. Therefore, a link between MetS and cancer is also possible. Previous studies have shown that coexisting MetS in Chronic hepatitis B (CHB) patients increases the risk of different kinds of liver complications, such as liver fibrosis progression and liver cirrhosis [34]. The role of diabetes in liver cancer has been extensively studied, and a variety of biological mechanisms support an association [35‐38]. For example, diabetes can affect the recurrence of liver cancer through hyperinsulinemia, hyperglycemia, or chronic inflammation.

A previous meta-analysis has described a relationship between hypertension and cancer, thus suggesting that hypertension is associated with an increased risk of cancer death [26]. That study found that people with an average blood pressure of up to one in five have a cancer risk 2.8 times more than those with the lowest blood pressure. Another meta-analysis has examined the relationship between liver cancer and diabetes. Most studies have shown a significant increase in risk, with a combined risk ratio of 2.5 (95% CI, 1.9–3.2) [39]. The above studies show that hypertension and diabetes as metabolic risk factors are significantly associated with the risk of liver disease, and decreasing the risk of MetS may also contribute to the long-term reduction of liver disease.

There are several limitations that should be considered when interpreting the findings of our meta-analysis. First, there are multiple factors that were not considered in the combined RR analysis, such as dietary habits, HCC family history, and other genetic risk factors, owing to the unavailability of these variables in the original study. Second, for diabetes and liver cancer risk meta-analysis, we referred data from observational studies, while those studies may have lower heterogeneity. Third, because chronic liver disease can also cause diabetes, the link between diabetes and HCC may not be exact. Fourth, different controls on confounding factors also influenced the results. Finally, the meta-analysis was limited to English-language studies, which might have introduced publication bias.

However, our study has several strengths; for example, this article included more data than previous studies and examined links between MetS and cirrhosis, as well as liver-related deaths, among other factors. We also analyzed the geographic region and the population for hepatitis B and other parameters. The all cohort studies in our meta-analysis are of high quality and were able to detect potential associations and eliminate the possibility of recall and selection bias.

In conclusion, this population-based study showed that MetS is an important risk factor for the development of liver disease. Therefore, the control of the globally prevalent MetS may help reduce liver disease. At the same time, the metabolic syndrome and related factors are introduced in the paper. Trying to avoid these risk factors is a better treatment. More well-designed randomized controlled trials or prospective cohort or retrospective cohort studies are urgently needed to improve understanding of this risk.