Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?

Abstract

Non-alcoholic fatty liver disease (NAFLD), comprising a spectrum of conditions ranging from pure steatosis to steatohepatitis and cirrhosis, has reached epidemic proportions and represents the most common cause of chronic liver disease in the community. The prevalence of NAFLD has been estimated to be between 20% and 30% in the general population, but this value is much higher (∼70-80%) in type 2 diabetic patients, who are also at higher risk of developing advanced fibrosis and cirrhosis. Increasing recognition of the importance of NAFLD and its strong relationship with the metabolic syndrome has stimulated an interest in the possible role of NAFLD in the development of cardiovascular disease (CVD). Several epidemiological studies indicate that NAFLD, especially in its more severe forms, is linked to an increased risk of CVD, independently of underlying cardiometabolic risk factors. This suggests that NAFLD is not merely a marker of CVD, but may also be actively involved in its pathogenesis. The possible molecular mediators linking NAFLD and CVD include the release of pro-atherogenic factors from the liver (C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 and other inflammatory cytokines) as well as the contribution of NAFLD per se to whole-body insulin resistance and atherogenic dyslipidemia, in turn favouring CVD progression. The clinical impact of NAFLD on CVD risk deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.

Elevated Serum Gamma-glutamyl Transpeptidase Levels and Fatty Liver Strongly Predict the Presence of Carotid Plaque

“…In this context, studies have been conducted to determine whether an elevated serum GGT level and fatty liver are predictive of future CVD events. Some studies have examined the impact of elevated serum GGT levels on all-cause and CVD mortality and showed positive results 14,15) , and similar results have been reported regarding the relationship between fatty liver and CVD events 16) . Notably, one study found that the serum GGT levels are significantly associated with all-cause and CVD mortality in men and that this association is stronger among those with increased echogenicity of the liver parenchyma, known as the US sign of fatty liver 17) .…”

External validation of the fatty liver index and lipid accumulation product indices, using 1H-magnetic resonance spectroscopy, to identify hepatic steatosis in healthy controls and obese, insulin-resistant individuals

“…Only histological examination or proton magnetic resonance spectroscopy ( 1 H-MRS) can quantitatively assess liver fat (more exactly, hepatocellular lipid content) (3,4). Non-invasive algorithms based on metabolic and anthropometric variables, such as the fatty liver index (FLI), lipid accumulation product (LAP), the hepatic steatosis index (HIS) and the Finnish Diabetes Risk Score (FINDRISC) (6,7,8,9,10,11), have been used as a screening test for hepatic steatosis and identify potential patients for further clinical investigation or for epidemiologic studies. They have been applied in various clinical populations to assess prevalence of NAFLD (12) and to provide prognostic information about incident risk of metabolic syndrome and type 2 diabetes, cardiovascular disease and risk of mortality in various sub-groups (13,14,15,16,17,18).…”

Modulation of glycosphingolipid metabolism significantly improves hepatic insulin sensitivity and reverses hepatic steatosis in mice

“…Candidates in this respect are low-grade inflammation throughout the body and fatty liver, both of which occur in concurrent obesity. 2,3 The proinflammatory environment that exists in adipose tissue of the majority of obese individuals 4 is thought to precede insulin resistance by enhancing deregulation of adipose tissue, leading to adipocyte cell death. 5 Subsequently, increased amounts of free fatty acids coming from the inflamed adipose tissue reach the liver, where they decrease insulin sensitivity.…”