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Candidate Biomarkers of Liver Fibrosis: A Concise, Pathophysiology-oriented Review

  • Mattia Bellan*,1,2,3,
  • Luigi Mario Castello1,4 and
  • Mario Pirisi1,5
Journal of Clinical and Translational Hepatology   2018;6(3):317-325

doi: 10.14218/JCTH.2018.00006

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Citation: Bellan M, Castello LM, Pirisi M. Candidate Biomarkers of Liver Fibrosis: A Concise, Pathophysiology-oriented Review. J Clin Transl Hepatol. 2018;6(3):317-325. doi: 10.14218/JCTH.2018.00006.

Abstract

Repair of sustained liver injury results in fibrosis (i.e. the accumulation of extracellular matrix proteins), and ultimately the complete distortion of parenchymal architecture of the liver, which we call cirrhosis. Detecting and staging of fibrosis is thus a mainstay in the management of chronic liver diseases, since many clinically relevant decisions, such as starting treatment and/or monitoring for complications including hepatocellular carcinoma, may depend on it. The gold standard for fibrosis staging is liver biopsy, the role of which, however, is questioned nowadays because of cost, hazards and poor acceptance by patients. On the other hand, imaging techniques and/or measurement of direct and indirect serum markers have not proved to be completely satisfactory under all circumstances as alternatives to liver biopsy. Making progress in this field is now more crucial than ever, since treatments for established fibrosis appear on the horizon. Fine dissection of the pathways involved in the pathophysiology of liver diseases has put forward several novel candidate biomarkers of liver fibrosis, such as growth arrest-specific6, Mac-2-binding protein, osteopontin, placental growth factor, growth/differentiation factor 15 and hepatocyte growth factor. All molecules have been suggested to have potential to complement or substitute methods currently used to stage liver diseases. Here, we review the pros and cons for their use in this setting.

Keywords

Liver fibrosis, Staging, Biomarkers, Gas6, HGF, PlGF

Introduction

Hepatic fibrosis is the overly exuberant accumulation of extracellular matrix proteins, including collagen, typically triggered by chronic injury of the liver parenchyma with an inflammatory component. This process, analogous to wound healing, may disrupt the hepatic architecture and results in hepatocellular dysfunction and portal hypertension, two of the main features of cirrhosis.1,2 Indeed, to the multiplicity of factors (viral, toxic, genetic, nutritional, etc.) causing liver diseases, the counterpart is a relative monotony of pathological features, including degeneration and necrosis of hepatocytes, replacement of liver parenchyma by fibrotic tissue and regenerative nodules and loss of liver function. These events are in fact the result of the activation of common pro-inflammatory and pro-fibrotic pathways.3–5

Accurately defining the fibrosis stage reached by a patient along the course of his/her disease is of quintessential clinical importance, since crucial decisions, such as starting monitoring for complications (i.e. esophageal varices or hepatocellular carcinoma (HCC)), depend on it. Unfortunately, the medical history and physical examination do not always provide reliable clues for the detection of advanced fibrosis, since the classical signs of liver diseases are commonly absent or subtle in early cirrhosis.6,7 The gold standard for fibrosis detection and quantification is liver biopsy, a procedure poorly accepted by patients, who perceive it as unduly aggressive and risky.8 In the past decade, several methods to stage chronic liver disease noninvasively have been proposed or are under evaluation/validation. They fall into the following two broad categories: a) imaging techniques, and b) serum markers, sometimes combined into artificial intelligence algorithms.9

Though the noninvasive alternatives have largely replaced liver biopsy for many indications, they also have pitfalls. Ultrasonography, for example, can suggest the presence of fibrosis and cirrhosis but it is neither sensitive nor specific in doing it, performing significantly better only in late stages of liver cirrhosis, when the signs of portal hypertension develop.10 Computed tomography and magnetic resonance are more sensitive and specific, but they are also burdened by high costs and inadequate inter-rater reliability among different radiologists; moreover, the extensive use of computed tomography scan is limited by radiological risks.11 Finally, transient elastography, besides requiring expensive equipment, maybe inaccurate in obese patients and may lead to over-estimation of fibrosis in patients with high necroinflammatory activity.12 Being the result of the sum of inflammation and fibrosis in the liver parenchyma, liver stiffness per se may not be the ideal candidate to monitor for fibrosis regression.

The ability of the liver to either produce or modify hundreds of chemicals has long been exploited to estimate, from the changes in their blood concentration, the degree to which liver function is impaired and/or organ damage is extensive. Indeed, liver biochemistry panels are included in almost all laboratory routines, being informative, relatively cheap and prone to repeat testing. Conceptually, fibrosis makes no exception. By-products spilling in the blood as a result of the deposition of excess extracellular matrix can be taken as a proxy measure of what is occurring in the liver parenchyma.

Alternatively, patients can be profiled based on artificial intelligence algorithms that produce scores by combining different parameters, including demographics and blood cell counts, such as the aspartate aminotransferase-to-platelet ratio (APRI),13 fibrosis-414 or Fibro index.15 Unfortunately, neither the former nor the latter approach have produced highly accurate results for liver fibrosis assessment to date,16 and their use in clinical practice is not comparable to that of prognostic scores, such as the Child-Pugh-Turcotte classification system17 and the Model for End-stage Liver Disease score.18 In this context, we also need to account for some derived scores, such as FibroMeter19 and FibroTest,20 which include more specific blood tests that are not routinely available. Again, the lines of evidence about their reliability and cost-effectiveness are not enough to support their use in clinical practice.

There is always room for improvement. Recently, for example, the use of nt-pro-brain natriuretic peptide and copeptin, prognostic biomarkers in patients with heart failure,21,22 has been extended to liver cirrhosis;23,24 their concentrations in blood bear a strict relationship to the hemodynamic changes that parallel the progression of liver disease. With putative treatments for liver fibrosis appearing on the horizon, the race to discover the holy grail of a liquid biopsy able to monitor its progression and regression is on. In the present paper we will review current lines of evidence supporting the use of some of the less known but still promising novel biomarkers for the detection of fibrosis in patients with chronic liver diseases.

Growth arrest-specific 6 (Gas6)

Gas6 is the circulating ligand of three different tyrosine kinase receptors, collectively named TAM, an acronym for Tyro3, Axl and MerTK. The human gene was cloned in 1993 and encodes for a vitamin K-dependent protein which is expressed in different tissues, such as the gut, bone marrow, endothelial cells and fibroblasts.25–27 The Gas6/TAM system is highly pleiotropic and has many biological functions. Gas6 and TAM regulate cell growth and they have been claimed as potential actors in oncogenesis.28 Moreover, Gas6 and TAM are implied in the activity of the immune system. MerTK and Axl have been isolated from circulating monocytes and tissue macrophages,29,30 and their activation by Gas6 down-regulates the expression of pro-inflammatory cytokines.31 Furthermore, this system is directly involved in the clearance of apoptotic bodies. In fact, Gas6 recognizes phosphatidylserine, a lipid normally expressed on the inner face of the plasma membrane and exposed on the external membrane during apoptosis; by doing it, Gas6 bridges this lipid with TAM receptors, driving macrophages to the recognition of apoptotic cells and to their subsequent phagocytosis.32

It is, therefore, not surprising that a dysfunction of this system has been linked to the development of autoimmune and degenerative diseases, since an impaired clearance of apoptotic bodies and an inappropriate inflammatory response are considered critical for the deranged immune response observed in these conditions. On these premises, Gas6 and TAM have been found to be related to rheumatoid arthritis,33 connective tissue diseases,34,35 Alzheimer’s disease36 and multiple sclerosis.37 Furthermore, TAM are involved in hemostasis, also being receptors of protein S, a master regulator of the coagulative cascade; Gas6 seems to play a complementary role in platelet function38 and it has been proposed as a biomarker for the diagnosis of pulmonary embolism.39

More recently, the Gas6/TAM interaction has been described to be relevant in inflammatory and repair processes of the liver; in fact, Gas6 seems to play a protective role in response to liver injury. After an acute or chronic injury, repair involves macrophages and hepatic stellate cells (HSCs) activated into myofibroblastic cells (HSCs/MFBs), which produce cytokines and matrix proteins. It has been shown in animal models that Gas6 expression by macrophages, HSCs and HSCs/MFBs is significantly up-regulated in injured areas. In this context, Gas6 exerts an anti-apoptotic effect on both HSCs and HSCs/MFBs, acting as a survival factor for these cells, probably supporting transient HSC/MFB accumulation during liver healing.40

Consistent with this finding, in Gas6−/− knock-out (KO) mice, a defective wound healing after carbon tetrachloride-induced liver damage has been reported, with reduced Kupffer cell activation and decreased macrophage and HSC/MFB recruitment in damaged areas.41 Similarly, Gas6−/− KO mice are more prone to severe liver damage after ischemia/reperfusion injury and the administration of recombinant Gas6 has a protective role either in wild-type or in KO mice.42 This protective role is played at the expense of a fibrogenic effect, however. In fact, Gas6-deficient mice also exhibited reduced liver fibrosis as a consequence of defective macrophage recruitment, inflammatory response and HSC/MFB activation compared with wild-type animals.43

Bárcena et al.44 recently demonstrated that blockade of the Gas6/Axl pathway down-regulates HSC activation, collagen deposition and liver fibrogenesis, even postulating a potential therapeutic role for Axl inhibition in the prevention of liver fibrosis. In the same paper, the authors firstly observed a correlation between Gas6 plasma concentration and the progression of liver disease in a group of patients affected by alcoholic liver disease and in a group of hepatitis C virus (HCV)-infected subjects. According to these authors, Gas6 concentrations were significantly higher in patients than in healthy controls and progressively increased from F0/F1 to compensated and finally to decompensated cirrhosis.44 However, the activity of Gas6 in this context probably also implies the activation of MerTK, as suggested by the observation that a specific polymorphism of its gene, associated with lower intrahepatic expression of MerTK, is protective against F2-F4 fibrosis in patients with nonalcoholic fatty liver disease (NAFLD).45

On these premises our group recently published a paper demonstrating that Gas6 plasma concentration directly correlates with liver stiffness assessed by liver elastography and is higher in patients with higher degrees of fibrosis assessed by liver biopsy. The diagnostic accuracy was comparable to that of liver elastography.46 Of note, Gas6 is also able to predict one of the most relevant complications of liver cirrhosis, esophageal varices.47

Mac-2 binding protein (M2BP)

Amongst the most promising molecules identified by proteomics as a candidate marker of fibrosis is M2BP.48 M2BP is a 90-kDa glycoprotein, able to promote cell adhesion and to bind selectively to several collagen types and fibronectin, as well as to galectin-3 (formerly known as Mac-2). This protein is secreted by different cell types and, interestingly, it oligomerizes in large ring structures. It has been shown that the biological behavior of M2BP is modified by liver disease progression as a consequence of changes in N-glycosylation; on this basis, a specific test has been developed by Japanese investigators using a Wisteria floribunda agglutinin lectin probe which is able to discriminate this altered N-glycans profile of M2BP. Therefore, Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) has been proposed as a unique glycobiomarker associated with progression of liver disease.49

Since its development, this test has been evaluated in many cohorts of patients with chronic liver diseases of different etiologies. Serum level of WFA+-M2BP has been validated as a marker of liver fibrosis in HCV50,51 and hepatitis B virus (HBV)52 infected subjects, in NAFLD,53 in primary biliary cirrhosis,54 and in autoimmune hepatitis.55 Moreover, serum levels of WFA+-M2BP are predictive of the development of HCC in patients affected by chronic HCV-related liver disease. In fact, in HCV infected subjects, the 10-year cumulative risk of HCC rises from 1.1% to 54.1% for different, increasing thresholds of WFA+-M2BP plasma concentrations.56 Similarly, WFA+-M2BP plasma concentration was an independent risk factor for HCC in a retrospective cohort of 1323 patients affected by chronic HBV-related liver disease. Along a median follow-up period of 60.3 months, 52 (3.9%) patients developed HCC. In multivariate analysis, WFA+-M2BP predicted HCC development with an adjusted hazard ratio of 1.143 (95% confidence interval: 1.139–1.829), together with male sex and diabetes. Interestingly, the predictive value of WFA+-M2BP is even higher in patients without cirrhosis. These findings suggest a potential role for WFA+-M2BP in the surveillance strategies for HCC development in the clinical course of chronic liver diseases.57

Although growing evidence links M2BP to liver fibrosis, it is still not clear whether the increase of its plasma concentration is a simple epiphenomenon or if this molecule plays a pathogenetic role. Recently, an increasing proportion of WFA+-M2BP-positive cells has been shown in liver sections for increasing degrees of fibrosis. According to recent lines of evidence, HSCs are the main cell type responsible for WFA+-M2BP secretion, and probably the interaction of M2BP with Mac-2 expressing Kupffer cells possibly contributing to α-smooth muscle actin expression.58

However, M2BP is not a disease-specific marker. First of all, it seems to mark fibrotic processes in general. Increased WFA+-M2BP plasma concentrations have been described in idiopathic pulmonary fibrosis and in chronic pancreatitis.59,60 Finally, M2BP probably has a role in cell transformation and cancer spreading. Therefore, many authors have investigated M2BP concentrations in different neoplastic conditions. A role for this biomarker has been postulated and proved for lung,61,62 prostate,63,64 pancreatic,65 gastric66 and colorectal cancer.67

Osteopontin (OPN)

OPN is a 32-kDa secreted, extracellular matrix glycosylated phosphoprotein, encoded by a gene located on chromosome 4 (4q13). OPN is characterized by a wide conformational flexibility due to extensive posttranslational modification and leading to heterogeneity in phosphorylation, glycosylation and sulphation;68 this feature confers OPN different functions, depending on the microenvironment in which it acts. As a pleotropic cytokine, OPN is involved in different physiological and pathological processes, including inflammation,69 cancer progression69,70 and wound healing.71 Many data in the literature confirm OPN as a major determinant of liver fibrosis, both in animal models and in humans, regardless to the cause of liver damage.72

In 2012, Urtasun et al.73 demonstrated that mice over-expressing the OPN gene develop liver fibrosis spontaneously; these Authors found that the effect is mediated by PI3K/pAkt/NF-κB activation which follows the interaction between OPN and αvß3 integrin on the HSC surface, with consequent collagen-I up-regulation and fibrosis formation.73 OPN also plays an important role in fibrillar collagen deposition at periportal spaces, mediated through the activation of oval cells (OCs).OPN prompts OCs to differentiate into biliary epithelial cells (BECs) and causes an inflammatory response, called ductular reaction, which involves BECs and inflammatory cells in the portal tract interface. The ductular reaction is characterized by the production of different molecules that sustain portal fibrosis via the activation of extracellular matrix, HSCs and portal fibroblasts.

Wang et al.74 studied the role of OPN in fibrogenesis using two murine models of chronic liver injury, based on chronic thioacetamide administration and common bile duct ligation both in wild-type and OPN null mice. The results pointed out that OPN is a major determinant of the dysregulated response to liver injury that leads to liver fibrosis. The Authors discovered that OPN−/− mice develop less OC and BEC proliferation, less ductular reaction and less collagen-I deposition with respect to wild-type mice. In vitro experiments confirmed the ability of OPN for increasing OC and BEC proliferation. In summary, these findings indicate that OPN, via its interaction with extracellular matrix and adhesion molecules, is an important activator of different cell populations and of the matrix leading to OC proliferation, ductular reaction and fibrogenesis. In this scenario, activated HSCs seem to exert a positive feedback on ductular reaction, inducing a vicious circle in which OPN is involved with a pivotal role. The Authors’ hypothesis is that OPN may be one of the major mediators inducing an inflammatory milieu that guides OC proliferation and differentiation, collagen-I up-regulation and TGF-ß over-expression.74 A recent study confirmed this hypothesis and identified the high-mobility group box-1, a chromosomal protein involved in DNA replication, as the mediator of the OPN induced collagen-I up-regulation.75

These preclinical studies support the use of OPN as a biomarker of fibrosis, of portal hypertension and of adverse outcome in patients affected by chronic liver disease. Several clinical studies confirmed this hypothesis and suggested the use of OPN as a biomarker of liver fibrosis in HBV chronic infection,76 HCV chronic infection77 and in alcohol-induced liver disease.78 A strong correlation between OPN plasma concentration and the degree of fibrosis, evaluated by liver biopsy, was found by Matsue et al.79 in a population of 115 HCV infected patients; they divided their patients into five groups according to the histological degree of fibrosis (F0, F1, F2, F3 and F4) and evaluated serum concentrations of different biomarkers (platelet count, and OPN, hyaluronic acid and collagen IV concentrations) and computed scores as APRI and Fibro-Test. In this study, OPN presented as the best diagnostic marker for fibrosis; its plasma concentration, in fact, was significantly different in all the comparisons between groups and the receiver operating characteristic curves allowed for identification of OPN cut-offs able to distinguish F1 versus F2/F3/F4 patients (OPN: 83 ng/mL; area under the curve (AUC): 0.997), F1/F2 versus F3/F4 patients (OPN: 124 ng/mL; AUC: 0.999) and F1/F2/F3 versus F4 patients (OPN: 152 ng/mL; AUC: 0.945). None of the other parameters considered gave similar results and the Authors concluded that OPN is an independent predictor of the extent of liver fibrosis in HCV patients and could be used as a non-invasive biomarker to assess the grade of fibrosis in HCV patients. Its use could help to reduce the number of liver biopsies.79

Other studies evaluated the relationship between OPN and the presence of complications of cirrhosis, as portal hypertension. In 2016, for example, a study involving 154 cirrhotic patients, mainly affected by alcoholic cirrhosis, demonstrated a relationship between OPN plasma concentration and the hepatic venous pressure gradient (HVPG) measured with the classic wedge technique. The Authors found that OPN plasma concentration was significantly increased in cirrhotic patients with respect to controls (107 vs. 55 ng/mL respectively). Within cirrhotics, OPN plasma concentration showed a statistically significant correlation with HVPG upon linear regression analysis. A cut-off value of OPN set at 80 ng/mL showed a sensitivity of 75% and a specificity of 63% in identifying patients with a HVPG of >10 mmHg (AUC: 0.763). Setting the OPN cut-off at 90 ng/mL, the data allowed for identification of patients at high risk for variceal bleeding (i.e. patients with HVPG >12 mmHg) with a sensitivity of 71% and a specificity of 62% (AUC: 0.72). These Authors also evaluated the prognostic value of OPN, with a mean follow-up time of 3.7± 2.6 years. Kaplan-Meier curves analysis showed a significantly superior cumulative probability of survival in patients with OPN <80 ng/dL with respect to patients with OPN above this cut-off value (56% vs. 37% respectively with an odds ratio of 2.23). The same trend was confirmed upon stratifying of patients using HVPG (above or below 10 mmHg; odds ratio: 2.92).

Overall, these data demonstrate the direct involvement of OPN in the scarring process affecting the liver and the strong correlation between the OPN plasma concentration and the liver fibrosis progression. Other recent studies have pointed out the role of OPN in the development and progression of HCC.80

In conclusion, OPN seems to be a reliable biomarker for the noninvasive staging of liver fibrosis in different chronic liver diseases; moreover, since many lines of evidence support its important role in the pathophysiology of fibrosis, it is tempting to speculate in favor of a possible role for the OPN/collagen-I axis as a target for future anti-fibrotic therapies.

Placental growth factor (PlGF)

PlGF is a member of the vascular endothelial growth factor family, discovered and cloned in the early ‘90s.81 PlGF acts as a pro-angiogenic factor, enhancing the proliferation, migration and survival of endothelial cells. Moreover, it stimulates proliferation of mesenchymal fibroblasts and regulates the contractile response of mural cells, organized around the endothelium. Finally, PlGF activates and attracts macrophages, which in turn release angiogenic and lymphangiogenic factors and interferes with dendritic cell differentiation and accumulation, as well as with antigen recognition. PlGF and its pathway have been claimed as potentially relevant in many different human diseases. One of the most promising applications is chronic liver disease.82 The first paper linking PlGF to liver fibrosis was published in 2005, when Salcedo-Mora et al.83 reported an increased PlGF plasma concentration in patients with HCV-related chronic liver disease with respect to healthy controls. More recently, the threshold of 20.2 pg/mL was reported to be 79% sensitive and 63% specific for liver fibrosis ≥F2.84

Interestingly, PlGF blockade does not affect the healthy vasculature, thus limiting potential adverse reactions.85 Van Steenkiste et al.,86 in 2011, reported a significant reduction in angiogenesis, arteriogenesis, inflammation, fibrosis, and portal hypertension in cirrhotic PlGF KO mice compared to wild-type mice; similar results were obtained by pharmacologically inhibiting PlGF.86 These findings have been recently confirmed; PlGF expression by HSCs is up-regulated in the carbon tetrachloride-induced rodent model of liver cirrhosis, as well as in cirrhotic patients. The knock-down of PlGF attenuates liver fibrosis. In fact, while 8 weeks after the carbon tetrachloride challenge of wild-type mice led to a remarkable extent of fibrosis, PlGF KO mice exhibited thinner septa, mild portal or pericellular fibrosis of the liver, and more preserved hepatic parenchyma. This was paralleled by a reduction in angiogenesis and in HSC proliferation and activation.87 On this basis, PlGF blockade has been postulated as a potentially promising therapeutic target for the treatment of chronic liver diseases.88

Growth differentiation factor 15 (GDF15)

GDF15 is a member of the TGF-β cytokine superfamily, cloned in 1997 and also known by the name of macrophage inhibitory cytokine 1.89 Its gene is located on chromosome 19p12–13.1 and codifies for a 40-kDa propeptide, cleaved in the endoplasmic reticulum to release a 25-kDa active circulating dimeric protein.90 Proinflammatory cytokines (i.e. TNFα or interleukin-6) induce GDF15mRNA expression in activated macrophages, which suggests that GDF15 could act as an autocrine inhibitor during the inflammatory response. Probably, the suppression of proinflammatory cytokines plays a role in the induction of immunotolerance towards the fetus; in fact, GDF15 is expressed by the placenta in large amounts under physiological conditions, with increasing concentrations as pregnancy progresses.91 Moreover, low serum levels of GDF15 between the 6th and 13th week of gestation may predict miscarriage.92

Beside this postulated physiological activity, GDF15 induction has been observed in different pathological conditions, its gene being over-expressed in response to diverse cellular stress signals, such as hypoxia/anoxia, inflammation, acute tissue injuries, and development of neoplasia. On these bases, it has been studied as a biomarker for different diseases. The greatest amount of evidence links GDF15 to cardiovascular diseases and cancer. In fact, higher GDF15 plasma concentrations have been associated to a poor prognosis in myocardial infarction, pulmonary thromboembolism and chronic heart failure but it has also been related to cancer invasiveness, metastases and prognosis.93

In the last few years, several observations have hinted at a potential role of this growth factor in chronic liver disease. First of all, GDF15 expression in vitro in hepatoma cells is dramatically enhanced by HCV infection, both at the mRNA and the protein level. Moreover, higher GDF15 plasma concentrations are observed in patients affected by HCV and HBV with respect to that in healthy controls.94 Considering what is known about GDF15 physiology, this finding probably testifies a response to the stress induced by viral infection and to the consequent liver inflammation. As a further clue, an increase in GDF15 expression has also been reported in mice subjected to bile duct injury.95 A recent paper smartly elucidated the role of GDF15 in liver pathology using animal models. GDF15 is exclusively expressed by hepatocytes and not by HSCs or by liver-resident macrophages. When hepatocytes are stressed by different stimuli, i.e. alcohol or carbon tetrachloride, the expression of GDF15 gene is enhanced.

Despite being synthesized only by hepatocytes, GDF15 also has effects on HSCs and Kupffer cells. In fact, recombinant GDF15 significantly decreases the lipopolysaccharide-induced pro-inflammatory cytokines production by Kupffer cells. Moreover, when Kupffer cells are co-cultured with GDF15 KO hepatocytes, the lipopolysaccharide-induced proinflammatory signature is significantly enhanced with respect to co-culture with wild-type hepatocytes. This suggests an important paracrine activity for GDF15. Finally, GDF15 deficiency in GDF15 KO mice enhances alcohol and carbon tetrachloride-induced liver damage and fibrosis.96 Taken together, these findings support the hypothesis that different insults to liver parenchyma lead to the increase of GDF15 expression and, consequently, enhance its plasma levels; as such, GDF15 would play a hepato-protective role. This makes GDF15 potentially promising as a diagnostic biomarker of liver damage.

Nonetheless, although raised in cases of viral hepatitis, GDF15 plasma concentration is a stronger marker of advanced liver disease. In fact, in a study by Liu et al.,97 GDF15 was significantly increased in HBV and HCV infected subjects with respect to healthy controls, but the plasma concentrations were 3 to 6 times higher in patients affected by liver cirrhosis and HCC. Similarly, GDF15 is increased in cases of alcoholic liver cirrhosis98 and in patients with advanced, biopsy-proven, liver fibrosis in NAFLD.99

To the best of our knowledge, GDF15 has been tested as diagnostic biomarker in two different studies. Lee et al.100 have demonstrated that GDF15 is able to predict chronic hepatitis, compensated liver cirrhosis and decompensated liver cirrhosis, with an increasing degree of diagnostic accuracy. More interestingly for the purpose of the present review, in a European cohort of 834 patients, GDF15 was 94% sensitive and 67% specific for the detection of a significant liver fibrosis (≥F2, assessed by liver biopsy).84

Hepatocyte growth factor (HGF)

HGF is secreted by mesenchymal cells and cleaved by extracellular proteases into a heterodimer composed by a 69-kDa α chain and 34-kDa β chain.101 Its receptor, tyrosine-protein kinase Met (c-MET),is a class IV receptor tyrosine kinase implicated in many physiological and pathological conditions. c-MET is present on the surface of epithelial cells of multiple organs including liver, pancreas, prostate, kidney, lung and bronchus.102 Consequently, although originally identified and cloned as a potent mitogen for hepatocytes, HGF is a strong protective and trophic factor for many tissues and organs. For example, HGF plays a direct role in the proliferation and differentiation of erythroid progenitors.103 Moreover, HGF has a crucial role in wound healing and tissue repair, being for example a protective, antifibrotic agent for lung,104 kidney105,106 and heart107 as well.

On the other hand, over-activation of the HGF/c-MET pathway has been shown in the pathogenesis and in the prognosis of many different neoplastic conditions. c-MET is a proto-oncogene, since an altered form, causing constitutive kinase activity, has been cloned as a transforming factor from a chemically-induced human osteosarcoma cell line.108 Furthermore, a germline mutation of c-MET has been identified as the cause of familial cases of hereditary papillary renal cell carcinomas.109 Finally, c-MET over-expression is associated with a poor prognosis in many human tumors, such as colorectal, ovarian and breast cancers.110

With regard to liver physiology and pathology, HGF is an important hepato-protective and pro-regenerative factor during liver injuries. The main intrahepatic source of HGF is Kupffer cells; local pro-inflammatory cytokines expressed as a consequence of liver damage are responsible for HGF gene up-regulation.111 According to many pre-clinical data, HGF is a promising therapeutic tool for liver diseases. In fact, different experiments have been performed, including gene therapy, transfection of mesenchymal cells over-expressing HGF and the use of recombinant HGF. Independently from the strategy adopted, HGF was able to suppress the development of liver cirrhosis after toxic damage in experimental rats112,113 and cholestatic damage,114 to prevent liver failure115 and, in contrast to its anti-apoptotic activity on hepatocytes, to exert an inhibitory and pro-apoptotic effect on HCC cells.116

As occurs for other hepato-protective molecules, the local production of HGF is increased during chronic liver disease, paralleling its increase in plasma concentration. Higher blood concentrations of HGF have been found in cirrhotic patients compared to controls and alcoholics without liver cirrhosis. Moreover, significantly higher concentrations of HGF have been observed in patients with Child class C liver cirrhosis compared to patients with Child class A liver cirrhosis.117 Furthermore, HGF plasma concentrations are able to effectively distinguish liver cirrhosis from mild fibrosis in HCV infected subjects.118 On these bases, HGF has been postulated as a promising biomarker of liver fibrosis. According to a recent study, HGF performs well as a biomarker of chronic liver disease progression. In fact, it showed a 97% sensitivity and a 64% specificity in the detection of a histological F2 or higher stage of liver fibrosis.84

However, it should be noted that HGF is not hepato-specific and its plasma concentration is increased in different pathological conditions.119–121

Conclusions

The staging of liver fibrosis is of great importance in the management of chronic liver diseases, but it is made difficult by the inaccuracy of the methods currently available. This is why the search for circulating biomarkers is clinically relevant. Moreover, chronic liver diseases, though multifactorial, share common pathways leading to fibrosis and cirrhosis, which are still largely unknown. The discovery of novel biomarkers of liver fibrosis is, therefore, not only potentially promising from a clinical point of view but could even contribute to deepening our knowledge about the biological mechanisms underlying the development of liver fibrosis. Finally, the current treatment strategies are essentially based on the removal of the cause, subsiding the fibrotic process; a better knowledge of the mechanisms beyond the development of liver cirrhosis could also give us the opportunity to develop new drugs directly targeting liver fibrosis.

In the last decades, dozens of putative molecules have been proposed to monitor the clinical course of liver diseases. In the present paper we have presented some of the most promising, reviewing their biology and the line of evidence supporting their use in clinical practice. These biomarkers share some common pros and cons. First and foremost, they can be tested easily, safely and inexpensively, overcoming some of the main issues of the methods currently available (i.e. liver biopsy and imaging techniques). These features make them particularly suitable for repeat measurements and, therefore, for monitoring patients during the clinical course of their disease.

However, none of them is organ-specific. Their plasma concentrations are generally increased not only as a consequence of the development of liver fibrosis but also in several other different conditions. Furthermore, hepatic and renal clearance can interfere with circulating plasma levels. On these premises, their routine use in clinical practice cannot be currently supported. Other studies are required in the near future to better validate these biomarkers, the use of which cannot be established without a good selection of patients undergoing tests of the dosages, to lower the number of false positive subjects.

In the present paper we have reviewed the evidence about the use of six different potential biomarkers of liver fibrosis. In Table 1, we compared the diagnostic performance of these molecules. We included those papers in which the diagnostic performance has been analyzed with respect to the gold standard - the liver biopsy. It is evident that the comparison between the different markers is difficult because different scoring systems have been used and different etiologies of liver disease have been considered. However, the majority of papers have evaluated the ability of the different molecules to identify severe fibrosis.

Table 1.

Diagnostic value of candidate biomarkers of liver fibrosis

ValueSensSpecPredictive valueAUCPublication, yearRefEtiologyDefinition of fibrosis
Gas630 ng/mL84%56%N/A0.734Bellan et al. 201646Mixed, 92% viralIshak ≤1
42 ng/mL64%95%N/A0.788Bellan et al. 201646Ishak ≥4
M2BP2.21 C.O.I.88.2%78.7%PPV 58.9%, NPV 94.5%0.812Toshima et al. 201550HCVMetavir ≥3
1.00 C.O.I.67%70%PPV 53%, NPV 81%0.680Nakamura et al. 201752HBVIshak ≥3
2.00 C.O.I.69%74%PPV 57%, NPV 83%0.795Nakamura et al. 201752HCVIshak ≥3
1.57 C.O.I.85.9%74.6%N/A0.879Abe et al. 201553NAFLDMetavir ≥3
1.40 C.O.I.83%90%PPV 69%, NPV 95%0.933Umemura et al. 201554PBCMetavir ≥3
3.70 C.O.I.64.3%83.3%N/A0.747Nishikawa et al. 201655Autoimmune hepatitisMetavir ≥3
OPN2.9 ng/mL96.4%94.1%N/A0.957Huang et al. 201077HCVMetavir ≥3
124 ng/mL97.1%100%N/A0.997Matsue et al. 201579HCVMetavir ≥3
PlGF20.2 pg/mL79%63%N/A0.758Krawczyk et al. 201784MixedDesmet Scheuer ≥2
21.9 pg/mLN/AN/AN/A0.771Krawczyk et al. 201784MixedDesmet Scheuer ≥3
GDF151582.8 pg/mL94%67%N/A0.854Krawczyk et al. 201784MixedDesmet Scheuer ≥2
1563.7 pg/mLN/AN/AN/A0.901Krawczyk et al. 201784MixedDesmet Scheuer ≥3
HGF2598 pg/mL97%64%N/A0.849Krawczyk et al. 201784MixedDesmet Scheuer ≥2
2085.7 pg/mLN/AN/AN/A0.888Krawczyk et al. 201784MixedDesmet Scheuer ≥3

Abbreviations: AUC, area under the curve; C.O.I., cut-off index; M2BP, Mac-2 binding protein; GDF15, growth differentiation factor 15; HGF, hepatocyte growth factor; N/A, not available; NPV, negative predictive value; OPN, osteopontin; PlGF, placental growth factor; PPV, positive predictive value; Sens, sensitivity; Spec, specificity.

Moreover, it is reasonable that these novel biomarkers might find their best use within more complex algorithms rather than in the simple measurement of their plasma concentration. For example, the combined use of PlGF, HGF and GDF15 has been recently tested. The sensitivity and specificity of at least one marker positive for fibrosis stage F2 or higher was 84% and 72%, respectively, resulting in a positive predictive value of 89% and a negative predictive value of 63%. Moreover, the use of this approach was effective in identifying 50% of those patients with a significant degree of fibrosis, who would have been missed by a strategy based only on transient elastography.84 Similar future studies will establish which combination of biomarkers will prove to represent a breakthrough for the non-invasive assessment of fibrosis.

Abbreviations

APRI: 

aspartate aminotransferase-to-platelet ratio

AUC: 

area under the curve

BEC: 

biliary epithelial cell

c-Met: 

tyrosine protein kinase Met

GAS6: 

growth arrest-specific 6

GDF15: 

growth differentiation factor 15

HBV: 

hepatitis B virus

HCC: 

hepatocellular carcinoma

HCV: 

hepatitis C virus

HGF: 

hepatocyte growth factor

HSC: 

hepatic stellate cell

HVPG: 

hepatic venous pressure gradient

KO: 

knock-out

M2BP: 

mac-2 binding protein

MFB: 

myofibroblastic cell

NAFLD: 

nonalcoholic fatty liver disease

OC: 

oval cell

OPN: 

osteopontin

PlGF: 

placental growth factor

WFA+-M2BP: 

Wisteria floribunda agglutinin-positive Mac-2 binding protein

Declarations

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Contributed equally in study design, manuscript drafting and manuscript revision (MB, LMC, MP).

References

  1. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115:209-218 View Article PubMed/NCBI
  2. Friedman SL. Liver fibrosis – from bench to bedside. J Hepatol 2003;38:S38-S53 View Article PubMed/NCBI
  3. Zhou WC, Zhang QB, Qiao L. Pathogenesis of liver cirrhosis. World J Gastroenterol 2014;20:7312-7324 View Article PubMed/NCBI
  4. Wanless IR, Nakashima E, Sherman M. Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis. Arch Pathol Lab Med 2000;124:1599-1607 View Article PubMed/NCBI
  5. Ferrell L. Liver pathology: cirrhosis, hepatitis, and primary liver tumors. Update and diagnostic problems. Mod Pathol 2000;13:679-704 View Article PubMed/NCBI
  6. de Bruyn G, Graviss EA. A systematic review of the diagnostic accuracy of physical examination for the detection of cirrhosis. BMC Med Inform Decis Mak 2001;1:6 View Article PubMed/NCBI
  7. Udell JA, Wang CS, Tinmouth J, FitzGerald JM, Ayas NT, Simel DL. Does this patient with liver disease have cirrhosis?. JAMA 2012;307:832-842 View Article PubMed/NCBI
  8. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2014;60:392-420 View Article PubMed/NCBI
  9. Tapper EB, Lok AS. Use of liver imaging and biopsy in clinical practice. N Engl J Med 2017;377:756-768 View Article PubMed/NCBI
  10. Allan R, Thoirs K, Phillips M. Accuracy of ultrasound to identify chronic liver disease. World J Gastroenterol 2010;16:3510-3520 View Article PubMed/NCBI
  11. Venkatesh SK, Yin M, Takahashi N, Glockner JF, Talwalkar JA, Ehman RL. Non-invasive detection of liver fibrosis: MR imaging features vs. MR elastography. Abdom Imaging 2015;40:766-775 View Article PubMed/NCBI
  12. Arena U, Vizzutti F, Corti G, Ambu S, Stasi C, Bresci S. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology 2008;47:380-384 View Article PubMed/NCBI
  13. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003;38:518-526 View Article PubMed/NCBI
  14. Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43:1317-1325 View Article PubMed/NCBI
  15. Koda M, Matunaga Y, Kawakami M, Kishimoto Y, Suou T, Murawaki Y. FibroIndex, a practical index for predicting significant fibrosis in patients with chronic hepatitis C. Hepatology 2007;45:297-306 View Article PubMed/NCBI
  16. Nallagangula KS, Nagaraj SK, Venkataswamy L, Chandrappa M. Liver fibrosis: a compilation on the biomarkers status and their significance during disease progression. Future Sci OA 2017;4:FSO250 View Article PubMed/NCBI
  17. Child CG, Turcotte JG. The liver and portal hypertension. Philadelphia: Saunders; 1964, 50-64 View Article PubMed/NCBI
  18. Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL. A model to predict survival in patients with end-stage liver disease. Hepatology 2001;33:464-470 View Article PubMed/NCBI
  19. Calès P, Boursier J, Oberti F, Hubert I, Gallois Y, Rousselet MC. FibroMeters: a family of blood tests for liver fibrosis. Gastroenterol Clin Biol 2008;32:40-51 View Article PubMed/NCBI
  20. Rossi E, Adams L, Prins A, Bulsara M, de Boer B, Garas G. Validation of the FibroTest biochemical markers score in assessing liver fibrosis in hepatitis C patients. Clin Chem 2003;49:450-454 View Article PubMed/NCBI
  21. Vetrone F, Santarelli S, Russo V, Lalle I, De Berardinis B, Magrini L. Copeptin decrease from admission to discharge has favorable prognostic value for 90-day events in patients admitted with dyspnea. Clin Chem Lab Med 2014;52:1457-1464 View Article PubMed/NCBI
  22. Winther JA, Brynildsen J, Høiseth AD, Strand H, Følling I, Christensen G. Prognostic and diagnostic significance of copeptin in acute exacerbation of chronic obstructive pulmonary disease and acute heart failure: data from the ACE 2 study. Respir Res 2017;18:184 View Article PubMed/NCBI
  23. Solà E, Kerbert AJ, Verspaget HW, Moreira R, Pose E, Ruiz P. Plasma copeptin as biomarker of disease progression and prognosis in cirrhosis. J Hepatol 2016;65:914-920 View Article PubMed/NCBI
  24. Licata A, Corrao S, Petta S, Genco C, Cardillo M, Calvaruso V. NT pro BNP plasma level and atrial volume are linked to the severity of liver cirrhosis. PLoS One 2013;8:e68364 View Article PubMed/NCBI
  25. Manfioletti G, Brancolini C, Avanzi G, Schneider C. The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Mol Cell Biol 1993;13:4976-4985 View Article PubMed/NCBI
  26. Avanzi GC, Gallicchio M, Cavalloni G, Gammaitoni L, Leone F, Rosina A. GAS6, the ligand of Axl and Rse receptors, is expressed in hematopoietic tissue but lacks mitogenic activity. Exp Hematol 1997;25:1219-1226 View Article PubMed/NCBI
  27. Melaragno MG, Wuthrich DA, Poppa V, Gill D, Lindner V, Berk BC. Increased expression of Axl tyrosine kinase after vascular injury and regulation by G protein-coupled receptor agonists in rats. Circ Res 1998;83:697-704 View Article PubMed/NCBI
  28. Wu G, Ma Z, Hu W, Wang D, Gong B, Fan C. Molecular insights of Gas6/TAM in cancer development and therapy. Cell Death Dis 2017;8:e2700 View Article PubMed/NCBI
  29. Graham DK, Dawson TL, Mullaney DL, Snodgrass HR, Earp HS. Cloning and mRNA expression analysis of a novel human protooncogene, c-mer. Cell Growth Differ 1994;5:647-657 View Article PubMed/NCBI
  30. Neubauer A, Fiebeler A, Graham DK, O’Bryan JP, Schmidt CA, Barckow P. Expression of axl, a transforming receptor tyrosine kinase, in normal and malignant hematopoiesis. Blood 1994;84:1931-1941 View Article PubMed/NCBI
  31. Alciato F, Sainaghi PP, Sola D, Castello L, Avanzi GC. TNF-alpha, IL-6, and IL-1 expression is inhibited by GAS6 in monocytes/macrophages. J Leukoc Biol 2010;87:869-875 View Article PubMed/NCBI
  32. Scott RS, McMahon EJ, Pop SM, Reap EA, Caricchio R, Cohen PL. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 2001;411:207-211 View Article PubMed/NCBI
  33. Kurowska-Stolarska M, Alivernini S, Melchor EG, Elmesmari A, Tolusso B, Tange C. MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis. Nat Commun 2017;8:15877 View Article PubMed/NCBI
  34. Jung JY, Suh CH. Incomplete clearance of apoptotic cells in systemic lupus erythematosus: pathogenic role and potential biomarker. Int J Rheum Dis 2015;18:294-303 View Article PubMed/NCBI
  35. Chen CH, Chen HC, Chang CC, Peng YJ, Lee CH, Shieh YS. Growth arrest-specific 6 protein in patients with sjögren syndrome: determination of the plasma level and expression in the labial salivary gland. PLoS One 2015;10:e0139955 View Article PubMed/NCBI
  36. Sainaghi PP, Bellan M, Lombino F, Alciato F, Carecchio M, Galimberti D. Growth arrest specific 6 concentration is increased in the cerebrospinal fluid of patients with alzheimer’s disease. J Alzheimers Dis 2017;55:59-65 View Article PubMed/NCBI
  37. Bellan M, Pirisi M, Sainaghi PP. The Gas6/TAM system and multiple sclerosis. Int J Mol Sci 2016;17:1807 View Article PubMed/NCBI
  38. van der Meer JH, van der Poll T, van ‘t Veer C. TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis. Blood 2014;123:2460-2469 View Article PubMed/NCBI
  39. Sainaghi PP, Alciato F, Carnieletto S, Castello L, Bergamasco L, Sola D. Gas6 evaluation in patients with acute dyspnea due to suspected pulmonary embolism. Respir Med 2009;103:589-594 View Article PubMed/NCBI
  40. Lafdil F, Chobert MN, Couchie D, Brouillet A, Zafrani ES, Mavier P. Induction of Gas6 protein in CCl4-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells. Hepatology 2006;44:228-239 View Article PubMed/NCBI
  41. Lafdil F, Chobert MN, Deveaux V, Zafrani ES, Mavier P, Nakano T. Growth arrest-specific protein 6 deficiency impairs liver tissue repair after acute toxic hepatitis in mice. J Hepatol 2009;51:55-66 View Article PubMed/NCBI
  42. Llacuna L, Bárcena C, Bellido-Martín L, Fernández L, Stefanovic M, Marí M. Growth arrest-specific protein 6 is hepatoprotective against murine ischemia/reperfusion injury. Hepatology 2010;52:1371-1379 View Article PubMed/NCBI
  43. Fourcot A, Couchie D, Chobert MN, Zafrani ES, Mavier P, Laperche Y. Gas6 deficiency prevents liver inflammation, steatohepatitis, and fibrosis in mice. Am J Physiol Gastrointest Liver Physiol 2011;300:G1043-G1053 View Article PubMed/NCBI
  44. Bárcena C, Stefanovic M, Tutusaus A, Joannas L, Menéndez A, García-Ruiz C. Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation. J Hepatol 2015;63:670-678 View Article PubMed/NCBI
  45. Petta S, Valenti L, Marra F, Grimaudo S, Tripodo C, Bugianesi E. MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease. J Hepatol 2016;64:682-690 View Article PubMed/NCBI
  46. Bellan M, Pogliani G, Marconi C, Minisini R, Franzosi L, Alciato F. Gas6 as a putative noninvasive biomarker of hepatic fibrosis. Biomark Med 2016;10:1241-1249 View Article PubMed/NCBI
  47. Bellan M, Sainaghi PP, Minh MT, Minisini R, Molinari L, Baldrighi M. Gas6 as a predictor of esophageal varices in patients affected by hepatitis C virus related-chronic liver disease. Biomark Med 2018;12:27-34 View Article PubMed/NCBI
  48. Cheung KJ, Tilleman K, Deforce D, Colle I, Van Vlierberghe H. The HCV serum proteome: a search for fibrosis protein markers. J Viral Hepat 2009;16:418-429 View Article PubMed/NCBI
  49. Kuno A, Ikehara Y, Tanaka Y, Ito K, Matsuda A, Sekiya S. A serum “sweet-doughnut” protein facilitates fibrosis evaluation and therapy assessment in patients with viral hepatitis. Sci Rep 2013;3:1065 View Article PubMed/NCBI
  50. Toshima T, Shirabe K, Ikegami T, Yoshizumi T, Kuno A, Togayachi A. A novel serum marker, glycosylated Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+)-M2BP), for assessing liver fibrosis. J Gastroenterol 2015;50:76-84 View Article PubMed/NCBI
  51. Xu H, Kong W, Liu L, Chi X, Wang X, Wu R. Accuracy of M2BPGi, compared with Fibro Scan®, in analysis of liver fibrosis in patients with hepatitis C. BMC Gastroenterol 2017;17:62 View Article PubMed/NCBI
  52. Nakamura M, Kanda T, Jiang X, Haga Y, Takahashi K, Wu S. Serum microRNA-122 and Wisteria floribunda agglutinin-positive Mac-2 binding protein are useful tools for liquid biopsy of the patients with hepatitis B virus and advanced liver fibrosis. PLoS One 2017;12:e0177302 View Article PubMed/NCBI
  53. Abe M, Miyake T, Kuno A, Imai Y, Sawai Y, Hino K. Association between Wisteria floribunda agglutinin-positive Mac-2 binding protein and the fibrosis stage of non-alcoholic fatty liver disease. J Gastroenterol 2015;50:776-784 View Article PubMed/NCBI
  54. Umemura T, Joshita S, Sekiguchi T, Usami Y, Shibata S, Kimura T. Serum wisteria floribunda agglutinin-positive Mac-2-binding protein level predicts liver fibrosis and prognosis in primary biliary cirrhosis. Am J Gastroenterol 2015;110:857-864 View Article PubMed/NCBI
  55. Nishikawa H, Enomoto H, Iwata Y, Hasegawa K, Nakano C, Takata R. Clinical significance of serum Wisteria floribunda agglutinin positive Mac-2-binding protein level and high-sensitivity C-reactive protein concentration in autoimmune hepatitis. Hepatol Res 2016;46:613-621 View Article PubMed/NCBI
  56. Yamasaki K, Tateyama M, Abiru S, Komori A, Nagaoka S, Saeki A. Elevated serum levels of Wisteria floribunda agglutinin-positive human Mac-2 binding protein predict the development of hepatocellular carcinoma in hepatitis C patients. Hepatology 2014;60:1563-1570 View Article PubMed/NCBI
  57. Kim SU, Heo JY, Kim BK, Park JY, Kim DY, Han KH. Wisteria floribunda agglutinin-positive human Mac-2 binding protein predicts the risk of HBV-related liver cancer development. Liver Int 2017;37:879-887 View Article PubMed/NCBI
  58. Bekki Y, Yoshizumi T, Shimoda S, Itoh S, Harimoto N, Ikegami T. Hepatic stellate cells secreting WFA+ -M2BP: Its role in biological interactions with Kupffer cells. J Gastroenterol Hepatol 2017;32:1387-1393 View Article PubMed/NCBI
  59. Kono M, Nakamura Y, Oyama Y, Mori K, Hozumi H, Karayama M. Increased levels of serum Wisteria floribunda agglutinin-positive Mac-2 binding protein in idiopathic pulmonary fibrosis. Respir Med 2016;115:46-52 View Article PubMed/NCBI
  60. Fujiyama T, Ito T, Ueda K, Tachibana Y, Yasunaga K, Miki M. Serum levels of Wisteria floribunda agglutinin-positive Mac-2 binding protein reflect the severity of chronic pancreatitis. J Dig Dis 2017;18:302-308 View Article PubMed/NCBI
  61. Ozaki Y, Kontani K, Hanaoka J, Chano T, Teramoto K, Tezuka N. Expression and immunogenicity of a tumor-associated antigen, 90K/Mac-2 binding protein, in lung carcinoma. Cancer 2002;95:1954-1962 View Article PubMed/NCBI
  62. Marchetti A, Tinari N, Buttitta F, Chella A, Angeletti CA, Sacco R. Expression of 90K (Mac-2 BP) correlates with distant metastasis and predicts survival in stage I non-small cell lung cancer patients. Cancer Res 2002;62:2535-2539 View Article PubMed/NCBI
  63. Bair EL, Nagle RB, Ulmer TA, Laferté S, Bowden GT. 90K/Mac-2 binding protein is expressed in prostate cancer and induces promatrilysin expression. Prostate 2006;66:283-293 View Article PubMed/NCBI
  64. Hu J, He J, Kuang Y, Wang Z, Sun Z, Zhu H. Expression and significance of 90K/Mac-2BP in prostate cancer. Exp Ther Med 2013;5:181-184 View Article PubMed/NCBI
  65. Waragai Y, Suzuki R, Takagi T, Sugimoto M, Asama H, Watanabe K. Clinical significance of serum Wisteria floribunda agglutinin-positive Mac-2 binding protein in pancreatic ductal adenocarcinoma. Pancreatology 2016;16:1044-1050 View Article PubMed/NCBI
  66. Park YP, Choi SC, Kim JH, Song EY, Kim JW, Yoon DY. Up-regulation of Mac-2 binding protein by hTERT in gastric cancer. Int J Cancer 2007;120:813-820 View Article PubMed/NCBI
  67. Wu CC, Huang YS, Lee LY, Liang Y, Tang RP, Chang YS. Overexpression and elevated plasma level of tumor-associated antigen 90K/Mac-2 binding protein in colorectal carcinoma. Proteomics Clin Appl 2008;2:1586-1595 View Article PubMed/NCBI
  68. Kurzbach D, Platzer G, Schwarz TC, Henen MA, Konrat R, Hinderberger D. Cooperative unfolding of compact conformations of the intrinsically disordered protein osteopontin. Biochemistry 2013;52:5167-5175 View Article PubMed/NCBI
  69. Castello LM, Raineri D, Salmi L, Clemente N, Vaschetto R, Quaglia M. Osteopontin at the crossroads of inflammation and tumor progression. Mediators Inflamm 2017;2017:4049098 View Article PubMed/NCBI
  70. Shi L, Wang X. Role of osteopontin in lung cancer evolution and heterogeneity. Semin Cell Dev Biol 2017;64:40-47 View Article PubMed/NCBI
  71. Lund SA, Giachelli CM, Scatena M. The role of osteopontin in inflammatory processes. J Cell Commun Signal 2009;3:311-322 View Article PubMed/NCBI
  72. Wen Y, Jeong S, Xia Q, Kong X. Role of osteopontin in liver diseases. Int J Biol Sci 2016;12:1121-1128 View Article PubMed/NCBI
  73. Urtasun R, Lopategi A, George J, Leung TM, Lu Y, Wang X. Osteopontin, an oxidant stress sensitive cytokine, up-regulates collagen-I via integrin α(V)β(3) engagement and PI3K/pAkt/NFκB signaling. Hepatology 2012;55:594-608 View Article PubMed/NCBI
  74. Wang X, Lopategi A, Ge X, Lu Y, Kitamura N, Urtasun R. Osteopontin induces ductular reaction contributing to liver fibrosis. Gut 2014;63:1805-1818 View Article PubMed/NCBI
  75. Arriazu E, Ge X, Leung TM, Magdaleno F, Lopategi A, Lu Y. Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury. Gut 2017;66:1123-1137 View Article PubMed/NCBI
  76. Zhao L, Li T, Wang Y, Pan Y, Ning H, Hui X. Elevated plasma osteopontin level is predictive of cirrhosis in patients with hepatitis B infection. Int J Clin Pract 2008;62:1056-1062 View Article PubMed/NCBI
  77. Huang W, Zhu G, Huang M, Lou G, Liu Y, Wang S. Plasma osteopontin concentration correlates with the severity of hepatic fibrosis and inflammation in HCV-infected subjects. Clin Chim Acta 2010;411:675-678 View Article PubMed/NCBI
  78. Patouraux S, Bonnafous S, Voican CS, Anty R, Saint-Paul MC, Rosenthal-Allieri MA. The osteopontin level in liver, adipose tissue and serum is correlated with fibrosis in patients with alcoholic liver disease. PLoS One 2012;7:e35612 View Article PubMed/NCBI
  79. Matsue Y, Tsutsumi M, Hayashi N, Saito T, Tsuchishima M, Toshikuni N. Serum osteopontin predicts degree of hepatic fibrosis and serves as a biomarker in patients with hepatitis C virus infection. PLoS One 2015;10:e0118744 View Article PubMed/NCBI
  80. Cabiati M, Gaggini M, Cesare MM, Caselli C, De Simone P, Filipponi F. Osteopontin in hepatocellular carcinoma: A possible biomarker for diagnosis and follow-up. Cytokine 2017;99:59-65 View Article PubMed/NCBI
  81. Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A 1991;88:9267-9271 View Article PubMed/NCBI
  82. Dewerchin M, Carmeliet P. PlGF: a multitasking cytokine with disease-restricted activity. Cold Spring Harb Perspect Med 2012;2:a011056 View Article PubMed/NCBI
  83. Salcedo Mora X, Sanz-Cameno P, Medina J, Martín-Vílchez S, García-Buey L, Borque MJ. Association between angiogenesis soluble factors and disease progression markers in chronic hepatitis C patients. Rev Esp Enferm Dig 2005;97:699-706 View Article PubMed/NCBI
  84. Krawczyk M, Zimmermann S, Hess G, Holz R, Dauer M, Raedle J. Panel of three novel serum markers predicts liver stiffness and fibrosis stages in patients with chronic liver disease. PLoS One 2017;12:e0173506 View Article PubMed/NCBI
  85. Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 2007;131:463-475 View Article PubMed/NCBI
  86. Van Steenkiste C, Ribera J, Geerts A, Pauta M, Tugues S, Casteleyn C. Inhibition of placental growth factor activity reduces the severity of fibrosis, inflammation, and portal hypertension in cirrhotic mice. Hepatology 2011;53:1629-1640 View Article PubMed/NCBI
  87. Li X, Yao QY, Liu HC, Jin QW, Xu BL, Zhang SC. Placental growth factor silencing ameliorates liver fibrosis and angiogenesis and inhibits activation of hepatic stellate cells in a murine model of chronic liver disease. J Cell Mol Med 2017;21:2370-2385 View Article PubMed/NCBI
  88. Li X, Jin Q, Yao Q, Zhou Y, Zou Y, Li Z. Placental growth factor contributes to liver inflammation, angiogenesis, fibrosis in mice by promoting hepatic macrophage recruitment and activation. Front Immunol 2017;8:801 View Article PubMed/NCBI
  89. Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A 1997;94:11514-11519 View Article PubMed/NCBI
  90. Eling TE, Baek SJ, Shim M, Lee CH. NSAID activated gene (NAG-1), a modulator of tumorigenesis. J Biochem Mol Biol 2006;39:649-655 View Article PubMed/NCBI
  91. Moore AG, Brown DA, Fairlie WD, Bauskin AR, Brown PK, Munier ML. The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. J Clin Endocrinol Metab 2000;85:4781-4788 View Article PubMed/NCBI
  92. Tong S, Marjono B, Brown DA, Mulvey S, Breit SN, Manuelpillai U. Serum concentrations of macrophage inhibitory cytokine 1 (MIC 1) as a predictor of miscarriage. Lancet 2004;363:129-130 View Article PubMed/NCBI
  93. Corre J, Hébraud B, Bourin P. Concise review: growth differentiation factor 15 in pathology: a clinical role?. Stem Cells Transl Med 2013;2:946-952 View Article PubMed/NCBI
  94. Si Y, Liu X, Cheng M, Wang M, Gong Q, Yang Y. Growth differentiation factor 15 is induced by hepatitis C virus infection and regulates hepatocellular carcinoma-related genes. PLoS One 2011;6:e19967 View Article PubMed/NCBI
  95. Koniaris LG. Induction of MIC-1/growth differentiation factor-15 following bile duct injury. J Gastrointest Surg 2003;7:901-905 View Article PubMed/NCBI
  96. Chung HK, Kim JT, Kim HW, Kwon M, Kim SY, Shong M. GDF15 deficiency exacerbates chronic alcohol- and carbon tetrachloride-induced liver injury. Sci Rep 2017;7:17238 View Article PubMed/NCBI
  97. Liu X, Chi X, Gong Q, Gao L, Niu Y, Chi X. Association of serum level of growth differentiation factor 15 with liver cirrhosis and hepatocellular carcinoma. PLoS One 2015;10:e0127518 View Article PubMed/NCBI
  98. Prystupa A, Kiciński P, Luchowska-Kocot D, Błażewicz A, Niedziałek J, Mizerski G. Association between serum selenium concentrations and levels of proinflammatory and profibrotic cytokines-interleukin-6 and growth differentiation factor-15, in patients with alcoholic liver cirrhosis. Int J Environ Res Public Health 2017;14:437 View Article PubMed/NCBI
  99. Koo BK, Um SH, Seo DS, Joo SK, Bae JM, Park JH. Growth differentiation factor 15 predicts advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease. Liver Int 2018;38:695-705 View Article PubMed/NCBI
  100. Lee ES, Kim SH, Kim HJ, Kim KH, Lee BS, Ku BJ. Growth differentiation factor 15 predicts chronic liver disease severity. Gut Liver 2017;11:276-282 View Article PubMed/NCBI
  101. Miyazawa K, Tsubouchi H, Naka D, Takahashi K, Okigaki M, Arakaki N. Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor. Biochem Biophys Res Commun 1989;163:967-973 View Article PubMed/NCBI
  102. Comoglio PM, Giordano S, Trusolino L. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 2008;7:504-516 View Article PubMed/NCBI
  103. Galimi F, Bagnara GP, Bonsi L, Cottone E, Follenzi A, Simeone A. Hepatocyte growth factor induces proliferation and differentiation of multipotent and erythroid hemopoietic progenitors. J Cell Biol 1994;127:1743-1754 View Article PubMed/NCBI
  104. Cahill EF, Kennelly H, Carty F, Mahon BP, English K. Hepatocyte growth factor is required for mesenchymal stromal cell protection against bleomycin-induced pulmonary fibrosis. Stem Cells Transl Med 2016;5:1307-1318 View Article PubMed/NCBI
  105. Stewart N, Chade AR. Renoprotective effects of hepatocyte growth factor in the stenotic kidney. Am J Physiol Renal Physiol 2013;304:F625-F633 View Article PubMed/NCBI
  106. Esposito C, Parrilla B, Cornacchia F, Grosjean F, Mangione F, Serpieri N. The antifibrogenic effect of hepatocyte growth factor (HGF) on renal tubular (HK-2) cells is dependent on cell growth. Growth Factors 2009;27:173-180 View Article PubMed/NCBI
  107. Gallo S, Sala V, Gatti S, Crepaldi T. Cellular and molecular mechanisms of HGF/Met in the cardiovascular system. Clin Sci (Lond) 2015;129:1173-1193 View Article PubMed/NCBI
  108. Cooper CS, Park M, Blair DG, Tainsky MA, Huebner K, Croce CM. Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature 1984;311:29-33 View Article PubMed/NCBI
  109. Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 1997;16:68-73 View Article PubMed/NCBI
  110. Petrini I. Biology of MET: a double life between normal tissue repair and tumor progression. Ann Transl Med 2015;3:82 View Article PubMed/NCBI
  111. Matsumoto K, Nakamura T. Hepatocyte growth factor: molecular structure and implications for a central role in liver regeneration. J Gastroenterol Hepatol 1991;6:509-519 View Article PubMed/NCBI
  112. Matsuda Y, Matsumoto K, Ichida T, Nakamura T. Hepatocyte growth factor suppresses the onset of liver cirrhosis and abrogates lethal hepatic dysfunction in rats. J Biochem 1995;118:643-649 View Article PubMed/NCBI
  113. Lai L, Chen J, Wei X, Huang M, Hu X, Yang R. Transplantation of MSCs overexpressing HGF into a rat model of liver fibrosis. Mol Imaging Biol 2016;18:43-51 View Article PubMed/NCBI
  114. Li Z, Mizuno S, Nakamura T. Antinecrotic and antiapoptotic effects of hepatocyte growth factor on cholestatic hepatitis in a mouse model of bile-obstructive diseases. Am J Physiol Gastrointest Liver Physiol 2007;292:G639-G646 View Article PubMed/NCBI
  115. Kosai K, Matsumoto K, Funakoshi H, Nakamura T. Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice. Hepatology 1999;30:151-159 View Article PubMed/NCBI
  116. Yuge K, Takahashi T, Nagano S, Terazaki Y, Murofushi Y, Ushikoshi H. Adenoviral gene transduction of hepatocyte growth factor elicits inhibitory effects for hepatoma. Int J Oncol 2005;27:77-85 View Article PubMed/NCBI
  117. Prystupa A, Kiciński P, Sak J, Boguszewska-Czubara A, Toruń-Jurkowska A, Załuska W. Proinflammatory cytokines (IL-1α, IL-6) and hepatocyte growth factor in patients with alcoholic liver cirrhosis. Gastroenterol Res Pract 2015;2015:532615 View Article PubMed/NCBI
  118. Andersen ES, Ruhwald M, Moessner B, Christensen PB, Andersen O, Eugen-Olsen J. Twelve potential fibrosis markers to differentiate mild liver fibrosis from cirrhosis in patients infected with chronic hepatitis C genotype 1. Eur J Clin Microbiol Infect Dis 2011;30:761-766 View Article PubMed/NCBI
  119. Yamanouchi H, Fujita J, Yoshinouchi T, Hojo S, Kamei T, Yamadori I. Measurement of hepatocyte growth factor in serum and bronchoalveolar lavage fluid in patients with pulmonary fibrosis. Respir Med 1998;92:273-278 View Article PubMed/NCBI
  120. Konopka A, Janas J, Piotrowski W, Stepińska J. Hepatocyte growth factor—a new marker for prognosis in acute coronary syndrome. Growth Factors 2010;28:75-81 View Article PubMed/NCBI
  121. Wader KF, Fagerli UM, Holt RU, Stordal B, Børset M, Sundan A. Elevated serum concentrations of activated hepatocyte growth factor activator in patients with multiple myeloma. Eur J Haematol 2008;81:380-383 View Article PubMed/NCBI

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