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Biomarkers of hepatic fibrosis, fibrogenesis and genetic pre-disposition pending between fiction and reality.

Gressner OA, Weiskirchen R, Gressner AM - J. Cell. Mol. Med. (2007 Sep-Oct)

Bottom Line: Many of them, however, proved to be disappointing with regard to sensitivity and specificity.The translation of genetic pre-disposition biomarkers into clinical practice has not yet started, but some polymorphisms indicate a link to progression and outcome of fibrogenesis.Parallel to serum markers non-invasive physical techniques, for example, transient elastography, are developed, which can be combined with serum tests and profiling of serum proteins and glycans.

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Central Laboratory, RWTH-University Hospital, Aachen, Germany. agressner@ukaachen.de

ABSTRACT
Fibrosis is a frequent, life-threatening complication of most chronic liver diseases. Despite major achievements in the understanding of its pathogenesis, the translation of this knowledge into clinical practice is still limited. In particular, non-invasive and reliable (serum-) biomarkers indicating the activity of fibrogenesis are scarce. Class I biomarkers are defined as serum components having a direct relation to the mechanism of fibrogenesis, either as secreted matrix-related components of activated hepatic stellate cells and fibroblasts or as mediators of extracellular matrix (ECM) synthesis or turnover. They reflect primarily the activity of the fibrogenic process. Many of them, however, proved to be disappointing with regard to sensitivity and specificity. Up to now hyaluronan turned out to be the relative best type I serum marker. Class II biomarkers comprise in general rather simple standard laboratory tests, which are grouped into panels. They fulfil most criteria for detection and staging of fibrosis and to a lesser extent grading of fibrogenic activity. More than 20 scores are currently available, among which Fibrotest is the most popular one. However, the diagnostic use of many of these scores is still limited and standardization of the assays is only partially realized. Combining of panel markers in sequential algorithms might increase their diagnostic validity. The translation of genetic pre-disposition biomarkers into clinical practice has not yet started, but some polymorphisms indicate a link to progression and outcome of fibrogenesis. Parallel to serum markers non-invasive physical techniques, for example, transient elastography, are developed, which can be combined with serum tests and profiling of serum proteins and glycans.

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Network of resident liver cells (red) and inflammatory non-liver resident cells (black) with hepatic stellate cells in the process of activation and transdifferentiation to myofibroblasts. Major molecular mediators are indicated. The influx of inflammatory and immune competent cells from the circulation into the damaged liver tissue is illustrated. Secreted products of resident liver cells leading to biochemical changes in blood of liver fibrotic patients are exemplified. Abbreviations: AcAld, acetalde-hyde; α2M, α2-macroglobulin; CTGF, connective tissue growth factor; EGF, epidermal growth factor; ET-1, endothelin-1; HNE, 4-hydroxynonenal; HSC, hepatic stellate cells; ICAM-1, intercellular adhesion molecule-1; IGFBP, IGF-binding proteins; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor.
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fig02: Network of resident liver cells (red) and inflammatory non-liver resident cells (black) with hepatic stellate cells in the process of activation and transdifferentiation to myofibroblasts. Major molecular mediators are indicated. The influx of inflammatory and immune competent cells from the circulation into the damaged liver tissue is illustrated. Secreted products of resident liver cells leading to biochemical changes in blood of liver fibrotic patients are exemplified. Abbreviations: AcAld, acetalde-hyde; α2M, α2-macroglobulin; CTGF, connective tissue growth factor; EGF, epidermal growth factor; ET-1, endothelin-1; HNE, 4-hydroxynonenal; HSC, hepatic stellate cells; ICAM-1, intercellular adhesion molecule-1; IGFBP, IGF-binding proteins; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor.

Mentions: The molecular mediators of the complex cellular network between stellate cells, resident liver cells, platelets and invaded inflammatory cells are mostly known (Fig. 2). The fibrogenic master cytokine is transforming growth factor (TGF)-β[10, 27] followed by platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), endothelin-1, angiotensin II and certain fibroblast growth factors, but also non-peptide signalling components, such as acetalde-hyde (in alcoholic fibrosis) and reactive oxygen species and H2O2 are noteworthy [11]. The bioactive, 25 kD TGF-β homodimer not only activates HSC, but stimulates ECM synthesis in HSC/MFB and fibrob-lasts/fibrocytes. Furthermore, TGF-β is a driving cytokine of EMT, stimulates chemokine (receptor) expression, apoptosis of hepatocytes (a pre-requisite for fibrogenesis) and decreases ECM catabolism by down-regulation of matrix metallo-proteinases (MMPs) and up-regulation of tissue inhibitor of met-alloproteinase (TIMPs), the specific tissue inhibitors of MMPs [28]. Several other functions of TGF-β are known including a strong immunosuppressive effect, mitogenic or anti-proliferative actions (depending on the cell type), regulation of cell differentiation and tumour suppression in the early stage. Thus, there is a need to regulate the activity of TGF-β sensitively by extracellular proteolytic activation of a large molecular weight precursor (large latent TGF-β complex). The latent TGF-β complex is the primary secretion product of TGF-β, which can be covalently fixed in the fibrotic ECM by a transglutaminase-dependent reaction. Bioactive TGF-β is released by proteolytic truncation of the complex. Furthermore, bone morphogenetic protein-7 (BMP-7), a member of the TGF-β gene superfamily, is a potent antagonist of TGF-β, for example, an inhibitor of TGF-β-driven EMT and apoptosis [26, 29]. BMP-7 reverses TGF-β signalling, which occurs via phosphorylated Smad proteins transferring the signal from the serine-threonine-kinase receptors to the Smad-binding elements in the promoter region of TGF-β target genes. One of these TGF-β-dependent genes is that of connective tissue growth factor (CTGF/CCN2), a cysteine-rich, secreted, 38 kD multi-domain protein, which has an important role as a downstream modulator of TGF-β effects [30, 31]. CTGF synthesis is not limited to HSC and (MFB). Instead, TGF-β-dependent CTGF gene expression and secretion was recently shown to occur in hepato-cytes in culture and in experimental liver fibrosis [32]. Additional antagonists of TGF-β are synthetic and naturally occurring PPAR-γ agonists like prostaglandin J2 (PGJ2), thiazolidone and triterpenoids [33]. These chemicals might gain therapeutic application in human fibrosis. Due to its multiple functions TGF-β is termed ‘plasticity-factor’, notifying its extensive cross-talk with other cytokines and signalling pathways, for example, p38 MAP kinases, ERK and JNK.


Biomarkers of hepatic fibrosis, fibrogenesis and genetic pre-disposition pending between fiction and reality.

Gressner OA, Weiskirchen R, Gressner AM - J. Cell. Mol. Med. (2007 Sep-Oct)

Network of resident liver cells (red) and inflammatory non-liver resident cells (black) with hepatic stellate cells in the process of activation and transdifferentiation to myofibroblasts. Major molecular mediators are indicated. The influx of inflammatory and immune competent cells from the circulation into the damaged liver tissue is illustrated. Secreted products of resident liver cells leading to biochemical changes in blood of liver fibrotic patients are exemplified. Abbreviations: AcAld, acetalde-hyde; α2M, α2-macroglobulin; CTGF, connective tissue growth factor; EGF, epidermal growth factor; ET-1, endothelin-1; HNE, 4-hydroxynonenal; HSC, hepatic stellate cells; ICAM-1, intercellular adhesion molecule-1; IGFBP, IGF-binding proteins; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401271&req=5

fig02: Network of resident liver cells (red) and inflammatory non-liver resident cells (black) with hepatic stellate cells in the process of activation and transdifferentiation to myofibroblasts. Major molecular mediators are indicated. The influx of inflammatory and immune competent cells from the circulation into the damaged liver tissue is illustrated. Secreted products of resident liver cells leading to biochemical changes in blood of liver fibrotic patients are exemplified. Abbreviations: AcAld, acetalde-hyde; α2M, α2-macroglobulin; CTGF, connective tissue growth factor; EGF, epidermal growth factor; ET-1, endothelin-1; HNE, 4-hydroxynonenal; HSC, hepatic stellate cells; ICAM-1, intercellular adhesion molecule-1; IGFBP, IGF-binding proteins; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor.
Mentions: The molecular mediators of the complex cellular network between stellate cells, resident liver cells, platelets and invaded inflammatory cells are mostly known (Fig. 2). The fibrogenic master cytokine is transforming growth factor (TGF)-β[10, 27] followed by platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), endothelin-1, angiotensin II and certain fibroblast growth factors, but also non-peptide signalling components, such as acetalde-hyde (in alcoholic fibrosis) and reactive oxygen species and H2O2 are noteworthy [11]. The bioactive, 25 kD TGF-β homodimer not only activates HSC, but stimulates ECM synthesis in HSC/MFB and fibrob-lasts/fibrocytes. Furthermore, TGF-β is a driving cytokine of EMT, stimulates chemokine (receptor) expression, apoptosis of hepatocytes (a pre-requisite for fibrogenesis) and decreases ECM catabolism by down-regulation of matrix metallo-proteinases (MMPs) and up-regulation of tissue inhibitor of met-alloproteinase (TIMPs), the specific tissue inhibitors of MMPs [28]. Several other functions of TGF-β are known including a strong immunosuppressive effect, mitogenic or anti-proliferative actions (depending on the cell type), regulation of cell differentiation and tumour suppression in the early stage. Thus, there is a need to regulate the activity of TGF-β sensitively by extracellular proteolytic activation of a large molecular weight precursor (large latent TGF-β complex). The latent TGF-β complex is the primary secretion product of TGF-β, which can be covalently fixed in the fibrotic ECM by a transglutaminase-dependent reaction. Bioactive TGF-β is released by proteolytic truncation of the complex. Furthermore, bone morphogenetic protein-7 (BMP-7), a member of the TGF-β gene superfamily, is a potent antagonist of TGF-β, for example, an inhibitor of TGF-β-driven EMT and apoptosis [26, 29]. BMP-7 reverses TGF-β signalling, which occurs via phosphorylated Smad proteins transferring the signal from the serine-threonine-kinase receptors to the Smad-binding elements in the promoter region of TGF-β target genes. One of these TGF-β-dependent genes is that of connective tissue growth factor (CTGF/CCN2), a cysteine-rich, secreted, 38 kD multi-domain protein, which has an important role as a downstream modulator of TGF-β effects [30, 31]. CTGF synthesis is not limited to HSC and (MFB). Instead, TGF-β-dependent CTGF gene expression and secretion was recently shown to occur in hepato-cytes in culture and in experimental liver fibrosis [32]. Additional antagonists of TGF-β are synthetic and naturally occurring PPAR-γ agonists like prostaglandin J2 (PGJ2), thiazolidone and triterpenoids [33]. These chemicals might gain therapeutic application in human fibrosis. Due to its multiple functions TGF-β is termed ‘plasticity-factor’, notifying its extensive cross-talk with other cytokines and signalling pathways, for example, p38 MAP kinases, ERK and JNK.

Bottom Line: Many of them, however, proved to be disappointing with regard to sensitivity and specificity.The translation of genetic pre-disposition biomarkers into clinical practice has not yet started, but some polymorphisms indicate a link to progression and outcome of fibrogenesis.Parallel to serum markers non-invasive physical techniques, for example, transient elastography, are developed, which can be combined with serum tests and profiling of serum proteins and glycans.

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Central Laboratory, RWTH-University Hospital, Aachen, Germany. agressner@ukaachen.de

ABSTRACT
Fibrosis is a frequent, life-threatening complication of most chronic liver diseases. Despite major achievements in the understanding of its pathogenesis, the translation of this knowledge into clinical practice is still limited. In particular, non-invasive and reliable (serum-) biomarkers indicating the activity of fibrogenesis are scarce. Class I biomarkers are defined as serum components having a direct relation to the mechanism of fibrogenesis, either as secreted matrix-related components of activated hepatic stellate cells and fibroblasts or as mediators of extracellular matrix (ECM) synthesis or turnover. They reflect primarily the activity of the fibrogenic process. Many of them, however, proved to be disappointing with regard to sensitivity and specificity. Up to now hyaluronan turned out to be the relative best type I serum marker. Class II biomarkers comprise in general rather simple standard laboratory tests, which are grouped into panels. They fulfil most criteria for detection and staging of fibrosis and to a lesser extent grading of fibrogenic activity. More than 20 scores are currently available, among which Fibrotest is the most popular one. However, the diagnostic use of many of these scores is still limited and standardization of the assays is only partially realized. Combining of panel markers in sequential algorithms might increase their diagnostic validity. The translation of genetic pre-disposition biomarkers into clinical practice has not yet started, but some polymorphisms indicate a link to progression and outcome of fibrogenesis. Parallel to serum markers non-invasive physical techniques, for example, transient elastography, are developed, which can be combined with serum tests and profiling of serum proteins and glycans.

Show MeSH
Related in: MedlinePlus