Abstract
BackgroundType 2 diabetes mellitus (T2DM) is a strong risk factor for liver fibrosis in non-alcoholic fatty liver disease (NAFLD). It remains uncertain why T2DM increases the risk of liver fibrosis. It has been suggested that growth differentiation factor-15 (GDF-15) concentrations increase the risk of liver fibrosis. We aimed to investigate (a) whether GDF-15 concentrations were associated with liver fibrosis and involved in the relationship between T2DM and liver fibrosis and (b) what factors linked with T2DM are associated with increased GDF-15 concentrations.MethodsNinety-nine patients with NAFLD (61% men, 42.4% T2DM) were studied. Serum GDF-15 concentrations were measured by electro-chemiluminescence immunoassay. Vibration-controlled transient elastography (VCTE)-validated thresholds were used to assess liver fibrosis. Regression modelling, receiver operator characteristic curve analysis and Sobel test statistics were used to test associations, risk predictors and the involvement of GDF-15 in the relationship between T2DM and liver fibrosis, respectively.ResultsPatients with NAFLD and T2DM (n = 42) had higher serum GDF-15 concentrations [mean (SD): 1271.0 (902.1) vs. 640.3 (332.5) pg/ml, p < 0.0001], and a higher proportion had VCTE assessed ≥F2 fibrosis (48.8 vs. 23.2%, p = 0.01) than those without T2DM. GDF-15 was independently associated with liver fibrosis (p = 0.001), and GDF-15 was the most important single factor predicting ≥F2 or ≥F3 fibrosis (≥F2 fibrosis AUROC 0.75, (95% CI 0.63–0.86), p < 0.001, with sensitivity, specificity, positive predictive (PPV) and negative predictive (NPV) values of 56.3%, 86.9%, 69.2% and 79.1%, respectively). GDF-15 was involved in the association between T2DM and ≥F2 fibrosis (Sobel test statistic 2.90, p = 0.004). Other factors associated with T2DM explained 60% of the variance in GDF-15 concentrations (p < 0.0001). HbA1c concentrations alone explained 30% of the variance (p < 0.0001).ConclusionsGDF-15 concentrations are a predictor of liver fibrosis and potentially involved in the association between T2DM and liver fibrosis in NAFLD. HbA1c concentrations explain a large proportion of the variance in GDF-15 concentrations.
Highlights
Non-alcoholic liver disease (NAFLD) is a ‘multisystem’ disease that increases the risk of type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD) [1], and chronic kidney disease (CKD) [2]
In patients with non-alcoholic fatty liver disease (NAFLD) and Type 2 diabetes mellitus (T2DM), liver Vibration-controlled transient elastography (VCTE)-derived kPa measurements were significantly higher and there was a greater prevalence of ≥F2 and ≥F3 liver fibrosis, compared to counterparts without T2DM
Fasting glucose and haemoglobin A1c (HbA1c) concentrations were higher in patients with NAFLD and T2DM, whereas
Summary
Non-alcoholic liver disease (NAFLD) is a ‘multisystem’ disease that increases the risk of type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD) [1], and chronic kidney disease (CKD) [2]. A recent multicentre transcriptomic study demonstrated that hepatic GDF-15 expression was positively associated with NAFLD severity and GDF-15 expression was significantly higher in patients with advanced liver fibrosis [10]. Growing evidence suggests that GDF-15 may have pro-fibrogenic effects within the liver and other tissues [13,14,15] Taken together, these studies suggest that increased GDF-15 concentrations may increase the risk of liver fibrosis. These studies suggest that increased GDF-15 concentrations may increase the risk of liver fibrosis It is not known whether circulating GDF-15 concentrations are potentially involved in the known relationship between T2DM and liver fibrosis in patients with NAFLD. Type 2 diabetes mellitus (T2DM) is a strong risk factor for liver fibrosis in non-alcoholic fatty liver disease (NAFLD). HbA1c concentrations explain a large proportion of the variance in GDF-15 concentrations
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