Microfibrillar-Associated Protein 4: A Potential Biomarker for Screening for Liver Fibrosis in a Mixed Patient Cohort

Sækmose, Susanne Gjørup; Mössner, Belinda Klemmensen; Christensen, Peer Brehm; Lindvig, Kristoffer; Schlosser, Anders; Holst, René; Barington, Torben; Holmskov, Uffe; Sørensen, Grith Lykke

doi:10.1371/journal.pone.0140418

Cited by 36 publications

(33 citation statements)

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“…The risk of hepatic carcinogenesis may persist in those with cirrhosis or severe fibrosis, in spite of achieving sustained viral response after antiviral treatment [5]. Our results revealed a significant increase in serum level of MFAP-4 in patients with HCV-related cirrhosis compared to the control group, and this data is in agreement with many reports [22,25,26]. Additionally, our data revealed a highly significant increase in serum MFAP4 in HCC patients compared to the control group, but the serum level of MFAP4 was non-significantly increased in HCC patients compared to cirrhotic patients.…”

Section: Discussionsupporting

confidence: 92%

“…Patients with higher amounts of elastin fiber have significantly a higher risk of HCC development [24]. Furthermore, systemic MFAP4 increases significantly with progressive fibrosis stage among HCV infected patients [25] and can be used as a biomarker to assess hepatic fibrosis in HCV patients [26]. However, MFAP4 has not been evaluated before in HCC.…”

Section: Introductionmentioning

confidence: 99%

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Potential Role of Microfibrillar-Associated Protein 4, Fibrotic Indices and Oxidative Stress in Hepatocellular Carcinoma

et al. 2018

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Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. In an attempt to understand some potential mechanisms of persistence and oncogenicity of Hepatitis C virus (HCV)-related HCC, microfibrillar-associated protein 4 (MFAP4), fibrotic indices and oxidative status biomarkers were assessed in the sera of 50 patients with HCV-associated HCC, 25 patients with HCV-related liver cirrhosis and 15 healthy individuals. Serum oxidized Coenzyme Q10 (CoQ10) and malondialdehyde showed significant elevation in HCC patients compared to the control group (p < 0.001), as well as cirrhotic patients (p < 0.05 and p < 0.001, respectively), while serum glutathione content and superoxide dismutase activity were significantly decreased in HCC patients compared to the control group (p < 0.001). Serum MFAP4, aspartate aminotransferase to platelet ratio index (APRI), fibrosis index based on the 4 factors (FIB-4) and Forns index showed significant increase in HCC patients compared to the control group (p < 0.001), while only APRI and FIB-4 were significantly different between HCC and cirrhotic patients (p < 0.05), with a sensitivity of 86% and 92%, respectively, at cut off ≥0.7 for APRI and ≥1.57 for FIB-4. Therefore, increasing oxidative stress and fibrosis might mediate HCV induced cirrhosis and HCC. APRI and FIB-4 may be used as a simple non-expensive formula for the screening of HCC rather than MFAP4.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Potential Role of Microfibrillar-Associated Protein 4, Fibrotic Indices and Oxidative Stress in Hepatocellular Carcinoma

et al. 2018

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“…However, MAFP4 concentration in the plasma of patients with chronic hepatitis and cirrhosis is increased and positively correlates with liver stiffness measured by transient elastography. The increase in plasma MFAP4 level in patients with liver disease is higher than that observed in patients with heart or other diseases (Sækmose et al, 2013, 2015). …”

Section: Elastic Fibers In the Diagnosis Of Liver Diseasesmentioning

confidence: 82%

Elastin in the Liver

Kanta

2016

Front. Physiol.

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A characteristic feature of liver cirrhosis is the accumulation of large amounts of connective tissue with the prevailing content of type I collagen. Elastin is a minor connective tissue component in normal liver but it is actively synthesized by hepatic stellate cells and portal fibroblasts in diseased liver. The accumulation of elastic fibers in later stages of liver fibrosis may contribute to the decreasing reversibility of the disease with advancing time. Elastin is formed by polymerization of tropoelastin monomers. It is an amorphous protein highly resistant to the action of proteases that forms the core of elastic fibers. Microfibrils surrounding the core are composed of fibrillins that bind a number of proteins involved in fiber formation. They include microfibril-associated glycoproteins (MAGPs), microfibrillar-associated proteins (MFAPs) and fibulins. Lysyl oxidase (LOX) and lysyl oxidase-like proteins (LOXLs) are responsible for tropoelastin cross-linking and polymerization. TGF-β complexes attached to microfibrils release this cytokine and influence the behavior of the cells in the neighborhood. The role of TGF-β as the main profibrotic cytokine in the liver is well-known and the release of the cytokines of TGF-β superfamily from their storage in elastic fibers may affect the course of fibrosis. Elastic fibers are often studied in the tissues where they provide elasticity and resilience but their role is no longer viewed as purely mechanical. Tropoelastin, elastin polymer and elastin peptides resulting from partial elastin degradation influence fibroblastic and inflammatory cells as well as angiogenesis. A similar role may be performed by elastin in the liver. This article reviews the results of the research of liver elastic fibers on the background of the present knowledge of elastin biochemistry and physiology. The regulation of liver elastin synthesis and degradation may be important for the outcome of liver fibrosis.

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“…The performance of the univariate model y uni solely based on MFAP4 measurements was compared to the performance of a multivariate model y multi that additionally accounts for age and gender of the patients. For these additional covariates, previous studies have shown an association with MFAP4 serum levels [ 20 , 21 ]. After fitting the respective model, a cutoff was determined in order to define a binary classification rule for the assignment of samples to the group of either F0–F2 or F3 and F4.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2016

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BackgroundThe 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).MethodsMFAP4 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.ResultsMFAP4 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).ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0952-3) contains supplementary material, which is available to authorized users.

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Microfibrillar-Associated Protein 4: A Potential Biomarker for Screening for Liver Fibrosis in a Mixed Patient Cohort

Cited by 36 publications

References 31 publications

Potential Role of Microfibrillar-Associated Protein 4, Fibrotic Indices and Oxidative Stress in Hepatocellular Carcinoma

Potential Role of Microfibrillar-Associated Protein 4, Fibrotic Indices and Oxidative Stress in Hepatocellular Carcinoma

Elastin in the Liver

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

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