Serum N-terminal DDR1: A Novel Diagnostic Marker of Liver Fibrosis Severity

The expression of discoidin domain receptor 1 (DDR1) is commonly up-regulated and undergoes collagen-induced ectodomain (N-terminal) shedding during the progression of liver fibrosis. This study aimed to evaluate the clinical utility of N-terminal DDR1 as a diagnostic biomarker for liver fibrosis.

N-terminal DDR1 shedding was evaluated using cell lines, liver fibrosis mouse models, clinical data of 298 patients collected from February 2019 to June 2020. The clinical data were divided into test and validation cohorts to evaluate the diagnostic performance of serum N-terminal DDR1.

Time- and dosage-dependent N-terminal DDR1 shedding stimulated by collagen I was observed in a hepatocyte cell line model. The type I collagen deposition and serum N-terminal DDR1 levels concurrently increased in the development of liver fibrosis in mouse models. Clinical data demonstrated a significant diagnostic power of serum N-terminal DDR1 levels as an accurate biomarker of liver fibrosis and cirrhosis. The diagnostic performance was further increased when applying N-DDR1/albumin ratio, achieving area under the curve of 0.790, 0.802, 0.879, and 0.865 for detecting histological fibrosis stages F ≥2, F ≥3, F 4 with liver biopsy as a reference method, and cirrhosis according to imaging techniques, respectively. With a cut-off of 55.6, a sensitivity, specificity, positive predictive value, and negative predictive value of 82.7%,76.6%, 67.4%, and 88.3% were achieved for the detection of cirrhosis.

Serum N-terminal DDR1 appears to be a novel diagnostic marker for liver fibrosis.