A simple in silico strategy identifies candidate biomarkers for the diagnosis of liver fibrosis in morbidly obese subjects

Abstract

Background & Aims Non‐alcoholic fatty liver disease (NAFLD) is a chronic liver disorder, tightly associated with obesity. The histological spectrum of the disease ranges from simple steatosis to steatohepatitis, with different stages of fibrosis, and fibrosis stage is the most significant predictor of mortality in NAFLD. Liver biopsy continues to be the gold standard for its diagnosis and reliable non‐invasive diagnostic tools are unavailable. We investigated the accuracy of candidate proteins, identified by an in silico approach, as biomarkers for diagnosis of fibrosis. Methods Seventy‐one morbidly obese (MO) subjects with biopsy‐proven NAFLD were enrolled, and the cohort was subdivided according to minimal (F0/F1) or moderate (F2/F3) fibrosis. The plasmatic level of CD44 antigen (CD44), secreted protein acidic and rich in cysteine (SPARC), epidermal growth factor receptor (EGFR) and insulin‐like growth factor 2 (IGF2) were determined by ELISA. Significant associations between plasmatic levels and histological fibrosis were determined by correlation analysis and the diagnostic accuracy by the area under receiver operating characteristic curves (AUROC). Results Eighty‐two percentage of the subjects had F0/F1 and 18% with F2/F3 fibrosis. Plasmatic levels of IGF2, EGFR and their ratio (EGFR/IGF2) were associated with liver fibrosis, correlating inversely for IGF2 (P < .006) and directly (P < .018; P < .0001) for EGFR and EGFR/IGF2 respectively. The IGF2 marker had the best diagnostic accuracy for moderate fibrosis (AUROC 0.83), followed by EGFR/IGF2 ratio (AUROC 0.79) and EGFR (AUROC 0.71). Conclusions Our study supports the potential utility of IGF2 and EGFR as non‐invasive diagnostic biomarkers for liver fibrosis in morbidly obese subjects.

Global epidemiology of non‐alcoholic fatty liver disease/non‐alcoholic steatohepatitis: What we need in the future

“…This “ideal test” would help clinicians identify and follow‐up patients with NASH, predicting the response to therapy and the risk of disease progression . Many studies have identified potential biomarkers to predict disease activity for the whole spectrum of NAFLD: a) cell death and apoptosis biomarkers, including caspase‐generated CK‐18 fragment (CK‐18); b) the fibroblast growth factor 21 (FGF21); c) insulin‐like growth factor 2 (IGF‐2) and the epidermal growth factor receptor (EGFR) . These biomarkers are expected to improve the ability to stratify disease severity in NAFLD and may identify additional pathways to target for treatment .…”

“…9,21 In addition, there is also a need to develop and validate a simple, F I G U R E 1 Extrahepatic complications of non-alcoholic fatty liver disease (FGF21); c) insulin-like growth factor 2 (IGF-2) and the epidermal growth factor receptor (EGFR). [25][26][27][28][29] These biomarkers are expected to improve the ability to stratify disease severity in NAFLD and may identify additional pathways to target for treatment. 28 However, despite several available studies, an accurate and reproducible noninvasive method to diagnose NAFLD/NASH, which could be used for screening in the general population or for patient follow-up has still not been identified.…”

Ficolin-2 Plasma Level Assesses Liver Fibrosis in Non-Alcoholic Fatty Liver Disease

“…Diabetes was diagnosed according to the ESC-EASD guidelines [ 28 ]. Blood-based tests of liver fibrosis such as FIB-4, APRI, FORNS, and NFS were calculated as described [ 29 ].…”

Ficolin-2 Plasma Levels Assesses Liver Fibrosis in Non-Alcoholic Fatty Liver Disease

“…Diabetes was diagnosed according to the ESC-EASD guidelines [14]. Blood-based tests of liver fibrosis such as FIB-4, APRI, FORNS, and NFS were calculated as described [15].…”