Steatohepatitis and liver fibrosis are predicted by the characteristics of very low density lipoprotein in nonalcoholic fatty liver disease

Abstract

Background & aims: A major challenge in the management of nonalcoholic fatty liver disease (NAFLD) is to identify patients with nonalcoholic steatohepatitis (NASH) and early liver fibrosis. The progression of NAFLD is accompanied by distinctive changes in very low density lipoprotein (VLDL), a lipoprotein particle produced exclusively in the liver. Herein, we sought to determine the characteristics of VLDL profiles associated with NASH and liver fibrosis.

Methods: We evaluated VLDL profiles of 128 patients from a single centre NAFLD registry, and examined VLDL size, total and subclass VLDL concentrations in relation to NAFLD activity score (NAS), steatohepatitis and liver fibrosis as determined by liver biopsy.

Results: A near linear relationship was observed between mean VLDL particle size and NAFLD activity score (NAS). In multivariate models, VLDL particle size was significantly associated with both NAS and NASH, after adjustment for BMI and diabetes. A decrease in small VLDL particle concentration was associated with more advanced liver fibrosis. In receiver operative characteristic analyses, mean VLDL size performed similarly to cytokeratin 18 in predicting NASH, whereas small VLDL particle concentration had similar performance to NAFLD fibrosis score in predicting stage 2 or above liver fibrosis.

Conclusions: The increase in mean VLDL size in NASH and decrease in small VLDL particle concentration in liver fibrosis likely reflect changes in the number and state of hepatocytes associated with NASH and fibrosis. In addition to its value in risk stratification of cardiovascular diseases, circulating VLDL profile may provide information for the staging of NAFLD disease severity.

Keywords: lipoprotein metabolism; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; very low density lipoprotein.

Fig. 1

Characteristics of VLDL changes associated with NASH and liver fibrosis. (A) Mean VLDL size measured in nm plotted over NAS score. (B) CK18 concentration over NAS score. (C) The changes of VLDL subclass ratios to total VLDL at different stages of liver fibrosis. Dark gray, medium gray and white bars represent the percentage of large, medium and small VLDL particles respectively. P values were calculated by Student’s t-test. Error bars represent standard deviation in A, B and 25–75% IQR in C.

Fig. 2

ROC curves for NASH and significant liver fibrosis. (A) Comparison of mean VLDL size (black) and CK18 (gray) in predicting NASH. (B) Comparison of small VLDL concentration (black) and NFS (gray dash) in predicting significant liver fibrosis (stage 2 or above). The predicted AUROC with its 95% CI was shown below each panel.

Fig. 3

Proposed VLDL profile changes in association with NAFLD disease progression. This hypothesis highlights the relationship between circulating VLDL profile and the state of hepatocytes in the liver parenchyma. An increase in the ratio of metabolically stressed hepatocytes in the setting of NASH produces more large VLDL particles. The development of significant liver fibrosis leads to the loss of hepatocytes, especially healthy ones, leading to decreased concentration of small VLDL particles.