Autophagy-related gene expression is associated with fibrosis severity in chronic hepatitis B and fatty liver disease

Autophagy regulates hepatocyte survival, stellate cell activation and inflammation, but its transcriptional correlates in human liver fibrosis are poorly defined. In liver biopsy transcriptomes from 124 patients with chronic hepatitis B, 20 autophagy-related genes differed nominally between fibrotic and non-fibrotic tissue. Co-expression network analysis prioritized CCL2 , MYC , CDKN1A and CAPN2 , whose expression correlated with immune cell signatures and was positively associated with fibrosis stage after adjustment for inflammation grade, age and sex. An exploratory 15-gene neural-network classifier had an apparent area under the receiver operating characteristic curve (AUC) of 0.982; bootstrap validation of a re-implemented development procedure gave an optimism-corrected AUC of 0.865, and the classifier had an AUC of 0.833 (95% confidence interval, 0.556–1.000) in whole blood from six healthy individuals and six with hepatitis B-related cirrhosis. In two independent cohorts with non-alcoholic fatty liver disease, expression of CCL2 , CAPN2 and CDKN1A , but not MYC , was higher in advanced than in mild fibrosis (n = 72), and that of all four genes was higher in fibrotic than in non-fibrotic liver (n = 112), largely owing to cirrhotic samples. These genes warrant further study as markers of fibrosis severity; their cellular sources and roles in fibrosis are unknown.