Evaluation of the biomarker candidate MFAP4 for non-invasive assessment of hepatic fibrosis in hepatitis C patients

J Transl Med. 2016 Jul 4;14(1):201. doi: 10.1186/s12967-016-0952-3.

Abstract

Background: The human microfibrillar-associated protein 4 (MFAP4) is located to extracellular matrix fibers and plays a role in disease-related tissue remodeling. Previously, we identified MFAP4 as a serum biomarker candidate for hepatic fibrosis and cirrhosis in hepatitis C patients. The aim of the present study was to elucidate the potential of MFAP4 as biomarker for hepatic fibrosis with a focus on the differentiation of no to moderate (F0-F2) and severe fibrosis stages and cirrhosis (F3 and F4, Desmet-Scheuer scoring system).

Methods: MFAP4 levels were measured using an AlphaLISA immunoassay in a retrospective study including n = 542 hepatitis C patients. We applied a univariate logistic regression model based on MFAP4 serum levels and furthermore derived a multivariate model including also age and gender. Youden-optimal cutoffs for binary classification were determined for both models without restrictions and considering a lower limit of 80 % sensitivity (correct classification of F3 and F4), respectively. To assess the generalization error, leave-one-out cross validation (LOOCV) was performed.

Results: MFAP4 levels were shown to differ between no to moderate fibrosis stages F0-F2 and severe stages (F3 and F4) with high statistical significance (t test on log scale, p value <2.2·10(-16)). In the LOOCV, the univariate classification resulted in 85.8 % sensitivity and 54.9 % specificity while the multivariate model yielded 81.3 % sensitivity and 61.5 % specificity (restricted approaches).

Conclusions: We confirmed the applicability of MFAP4 as a novel serum biomarker for assessment of hepatic fibrosis and identification of high-risk patients with severe fibrosis stages in hepatitis C. The combination of MFAP4 with existing tests might lead to a more accurate non-invasive diagnosis of hepatic fibrosis and allow a cost-effective disease management in the era of new direct acting antivirals.

Keywords: Cirrhosis; Direct acting antivirals; Hepatic fibrosis; Hepatitis C; Microfibrillar-associated protein 4; Serum biomarker.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analysis of Variance
  • Biomarkers / metabolism
  • Carrier Proteins / metabolism*
  • Cohort Studies
  • Extracellular Matrix Proteins / metabolism*
  • Female
  • Glycoproteins / metabolism*
  • Hepatitis C / complications*
  • Hepatitis C / diagnosis
  • Hepatitis C / metabolism*
  • Humans
  • Liver Cirrhosis / complications*
  • Liver Cirrhosis / diagnosis
  • Liver Cirrhosis / metabolism*
  • Logistic Models
  • Male
  • Middle Aged
  • Multivariate Analysis
  • ROC Curve
  • Sensitivity and Specificity

Substances

  • Biomarkers
  • Carrier Proteins
  • Extracellular Matrix Proteins
  • Glycoproteins
  • MFAP4 protein, human