Diagnostic algorithm to detect NASH and fibrosis in NAFLD patients with low NAFLD fibrosis score or liver stiffness

Non-alcoholic steatohepatitis (NASH) and fibrosis play critical roles for the prognosis of patients with non-alcoholic fatty liver disease (NAFLD), making it important to identify patients at higher risk of NASH and fibrosis for optimal disease management. The NAFLD fibrosis score (NFS) and transient elastography (TE) have been suggested as initial diagnostic approach to exclude advanced fibrosis. However, there is increasing evidence that also patients with NASH and early fibrosis are at significant risk of disease progression and complications, emphasizing the need for improved non-invasive risk stratification in NAFLD. Because hepatocyte apoptosis plays an early role in NASH pathogenesis, we evaluated whether the apoptosis biomarker M30, a neo-antigen generated by caspase-mediated keratin-18 cleavage, might identify NAFLD patients who are at risk of NASH and fibrosis despite low NFS or TE values. Serum M30 levels were assessed by ELISA in combination with NFS and/or TE in a cohort of 103 biopsy-proven NAFLD patients. The majority of patients with low NFS (cut-off value < -1.455) revealed increased M30 levels (> 200 U/L) and more than 70% of them had NASH, mostly with histological signs of fibrosis. Vice versa, most patients with NFS < -1.455 but non-elevated M30 levels showed no NASH. NASH was also detected in most patients with indeterminate NFS (-1.455 to 0.676) but elevated M30 levels, from which 90% showed fibrosis. Similar results were obtained when using TE instead of NFS. In conclusion, the combination of the M30 biomarker with NFS or TE enables a more reliable identification of patients with increased risk of progressed NAFLD and improves patient stratification.