Background:

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and is strongly associated with obesity, dyslipidemia and insulin resistance. NAFLD often presents as simple steatosis (NAFL) but can progress to non-alcoholic steatohepatitis (NASH) and fibrosis. Current non-invasive biomarkers are not tailored to identify significant (⩾ F2) fibrosis, although recent guidelines recommend a stringent follow-up of this patient population. We and others have reported on the role of pathological angiogenesis in the pathogenesis of NAFLD, highlighting pro-angiogenic factors as potential diagnostic markers.

Objective:

To investigate the applicability of angiogenic and endothelial dysfunction markers as non-invasive diagnostic tools for NASH or NASH-associated fibrosis in obese patients.

Methods:

In a prospective cross-sectional study, male patients undergoing bariatric surgery (n= 61) and control patients (n= 35) were recruited. Serum protein levels and visceral adipose tissue gene expression of endothelial dysfunction and angiogenic markers were analyzed by multiplex bead-based assay and quantitative RT-PCR, respectively. For validation, we recruited a second cohort of patients undergoing bariatric surgery (n= 40) and a cohort of NAFLD patients from our outpatient clinic (n= 30).

Results:

We identified serum vascular cell adhesion molecule-1 (VCAM-1) as an independent predictor for⩾ F2 fibrosis (median 14.0 vs 8.7 ng ml− 1 in patients with and without significant fibrosis; P< 0.0001) with an area under the receiver-operating characteristics (AUROC) curve of 0.80. The cutoff point of 13.2 ng ml− 1 showed a sensitivity of 80% and specificity of 83%. In line with these results, VCAM-1 visceral adipose tissue gene expression was also elevated in patients with fibrosis (P= 0.030). In the bariatric surgery and clinical validation cohorts, VCAM-1 displayed similar AUROCs of 0.89 and 0.85, respectively.

Conclusions:

VCAM-1 levels are able to accurately predict significant (⩾ F2) fibrosis in NAFLD patients.

Introduction

As a result of the obesity pandemic, non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. NAFLD is the hepatic manifestation of obesity and a precursor of and independent risk factor for type 2 diabetes. 1, 2, 3 NAFLD comprises a spectrum of disease that ranges from hepatocellular steatosis without necro-inflammation (NAFL) to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and even hepatocellular carcinoma. In addition, NAFLD is an independent risk factor for cardiovascular disease, with recent studies unequivocally showing an increased cardiovascular mortality in NAFLD patients. 4, 5 The global prevalence of NAFLD and NASH is around 25% and 3%, respectively, although this rises to an estimated 90% and 25%, respectively, in severely obese patients. 3, 6