Serum Immunoreactive Collagen IV detected by Monoclonal Antibodies as a Marker of Severe Fibrosis in Patients with Non- Alcoholic Fatty Liver Disease

Abstract

Background & Aims: The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. We evaluated serum collagen IV as a direct non-invasive marker of severe liver fibrosis in NAFLD.Methods: The study included 148 NAFLD and 187 chronic hepatitis C patients in whom histological severity of liver fibrosis was evaluated. The utility of serum collagen IV measured by immune-mediated agglutination using two types of monoclonal antibodies for distinguishing severe fibrosis (≥ stage 3 and ≥ F3) from non-to-moderate fibrosis in NAFLD or chronic hepatitis C was assessed in comparison to serum hyaluronic acid or other indirect fibrosis markers.Results: Multiple logistic regression analysis showed that serum collagen IV was significantly associated with severe fibrosis in NAFLD (odds ratio: 1.21, p<0.001) but not in chronic hepatitis C. For distinguishing severe fibrosis in NAFLD, collagen IV showed the largest area under the receiver-operating characteristic curve (0.827, 95%CI: 0.746-0.908) followed by FIB-4 (0.805, 95%CI: 0.728-0.890); in chronic hepatitis C, those for FIB-4 (0.813, 95%CI: 0.748-0.878) and collagen IV (0.770, 95%CI: 0.683-0.857) were the largest and smallest, respectively. To detect severe fibrosis in NAFLD, a cutoff of collagen IV > 177 exhibited 77.1% sensitivity, 84.0% specificity, 76.5% positive predictive value, and 84.0% negative predictive value. Combined with a cutoff of FIB-4 > 2.09, the negative and positive predictive values, and specificity for detecting severe fibrosis in NAFLD increased further.Conclusion: Collagen IV is a reliable marker for distinguishing severe liver fibrosis from non-to-moderate fibrosis in NAFLD but not chronic hepatitis C.

Classification of patients with non‐alcoholic fatty liver disease using rapid immunoassay of serum type IV collagen compared with liver histology and other fibrosis markers

“…Hyaluronic acid is elevated in advanced fibrosis in patients with NASH, but the capacity of HA to differentiate patients with mild fibrosis from those with advanced fibrosis was inferior to that of type IV collagen . Hyaluronic acid is synthesized in hepatic stellate cells and degraded by sinusoidal endothelial cells in the liver .…”

Hyaluronic acid as a biomarker of fibrosis in chronic liver diseases of different etiologies

“…In one study collagen type IV proved to have similar value in distinguishing F0–2 fibrosis from F3–F4 in NAFLD (AUC=0.827, HA had an AUC=0.774). When comparing serum values between CHC and NAFLD patients, HA was higher in CHC patients while type IV collagen did not have a significant difference [ 44 ]. In the study by Sakugawa et al again both markers could differentiate between stage 0–2 fibrosis and stage 3 or 4.…”

Recombinant soluble gp130 protein reduces DEN-induced primary hepatocellular carcinoma in mice

“…Type IV collagen staining is another strong indicator of liver fibrosis formation and very low level of type IV collagen can be detected in liver tissue under normal physiological conditions 18 19 20 21 22 . A heavy accumulation of type IV collagen in the livers of DEN-treated mice was observed in our experiments using immunohistochemical staining.…”