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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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Schematic presentation of the pathogenetic sequence of liver fibrosis and cirrhosis based on the activation of hepatic stellate cells (HSC) and transdifferentiation to matrix-synthesizing myofibroblasts (MFB). The inset of the electron micrograph shows retinoid-filled lipid droplets of HSC indenting the nucleus. Surrogate pathogenetic mechanisms contributing to the expansion of the myofibroblast pool in fibrotic liver are indicated: epithelial-mesenchymal-transition (EMT) of biliary epithelial cells or even hepatocytes, transformation of circulating monocytes at the site of injury to fibroblasts and the influx of bone marrow-derived fibrocytes into damaged tissue. Examples of serum biomarkers reflecting the pathogenetic sequence are given, but a considerable overlap is noticeable. Abbreviations: see Table 2, CRP, C-reactive protein; CSF, colony-stimulating factor; CTGF, connective tissue growth factor; GLDH, glutamate-dehydrogenase; PIVKA, prothrombin induced by vitamin K absence
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fig01: Schematic presentation of the pathogenetic sequence of liver fibrosis and cirrhosis based on the activation of hepatic stellate cells (HSC) and transdifferentiation to matrix-synthesizing myofibroblasts (MFB). The inset of the electron micrograph shows retinoid-filled lipid droplets of HSC indenting the nucleus. Surrogate pathogenetic mechanisms contributing to the expansion of the myofibroblast pool in fibrotic liver are indicated: epithelial-mesenchymal-transition (EMT) of biliary epithelial cells or even hepatocytes, transformation of circulating monocytes at the site of injury to fibroblasts and the influx of bone marrow-derived fibrocytes into damaged tissue. Examples of serum biomarkers reflecting the pathogenetic sequence are given, but a considerable overlap is noticeable. Abbreviations: see Table 2, CRP, C-reactive protein; CSF, colony-stimulating factor; CTGF, connective tissue growth factor; GLDH, glutamate-dehydrogenase; PIVKA, prothrombin induced by vitamin K absence

Mentions: Current knowledge ascribes liver-specific pericytes, that is, HSC, a major role in ECM production and re-modelling [7–10]. HSC, formerly termed vitamin A-storing cells, fat-storing cells, lipocytes or Ito-cells are located in the sub-endothelial space of Disse in close proximity to hepatocytes embracing with starlike extensions (spines) the sinusoidal endothelial tube [11]. They express some heterogeneity and represent about 15% of total resident liver cells and about 30% of non-parenchymal cells including Kupffer cells, sinusoidal endothelial cells and pit cells [12]. The ultra-structural features are characterized by large triacylglycerol-filled vacuoles containing retinoids [11, 13]. Besides their function as major vitamin A storage sites [14], that is, around 85% of liver vitamin A is located in this cell type, HSC were recently identified as antigen-presenting cells (APC) [15, 16] and are likely to have additional functions in liver cell renewal, regeneration, immunoregulation, angiogenesis and vascular re-modelling [17]. Their dominant role in fibrogenesis is based on their ability to change the phenotype from retinoid-storing, resting cells to contractile, smooth-muscle α-actin positive, vitamin A-depleted myofibroblasts (MFB) with a strongly developed endoplasmic reticulum and Golgi-apparatus if HSC are challenged by necro-inflammatory stimuli [1, 18]. Myofibroblasts synthesize and secrete virtually all of the matrix components found in ECM of the fibrotic liver (Fig. 1). This, however, does not rule out the contribution of other cell types and mechanisms to enhance matrix production in chronically inflamed liver tissue. The role of portal (MFB), in particular in biliary fibrosis, has been emphasized [19, 20] and, recently, the influx on bone-marrow-derived fibrocytes [21]via the circulation into the damaged tissue has been shown [22–24] Similarly, circulating monocytes, monocyte-like and mesenchymal stem cells have the potential to change to fibroblasts and other cell types if the appropriate microenvironment is provided [25]. Furthermore, actual research is focused on the possibility of epithelial-mesenchymal transition (EMT) [26], which describes the transition of biliary epithe-lial cells or even of hepatocytes to fibroblasts, which participate actively in the generation of fibrotic ECM. However, the role of EMT in liver fibrogenesis is still under debate, but is well established in lung and kidney fibrosis [26].


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)

Schematic presentation of the pathogenetic sequence of liver fibrosis and cirrhosis based on the activation of hepatic stellate cells (HSC) and transdifferentiation to matrix-synthesizing myofibroblasts (MFB). The inset of the electron micrograph shows retinoid-filled lipid droplets of HSC indenting the nucleus. Surrogate pathogenetic mechanisms contributing to the expansion of the myofibroblast pool in fibrotic liver are indicated: epithelial-mesenchymal-transition (EMT) of biliary epithelial cells or even hepatocytes, transformation of circulating monocytes at the site of injury to fibroblasts and the influx of bone marrow-derived fibrocytes into damaged tissue. Examples of serum biomarkers reflecting the pathogenetic sequence are given, but a considerable overlap is noticeable. Abbreviations: see Table 2, CRP, C-reactive protein; CSF, colony-stimulating factor; CTGF, connective tissue growth factor; GLDH, glutamate-dehydrogenase; PIVKA, prothrombin induced by vitamin K absence
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4401271&req=5

fig01: Schematic presentation of the pathogenetic sequence of liver fibrosis and cirrhosis based on the activation of hepatic stellate cells (HSC) and transdifferentiation to matrix-synthesizing myofibroblasts (MFB). The inset of the electron micrograph shows retinoid-filled lipid droplets of HSC indenting the nucleus. Surrogate pathogenetic mechanisms contributing to the expansion of the myofibroblast pool in fibrotic liver are indicated: epithelial-mesenchymal-transition (EMT) of biliary epithelial cells or even hepatocytes, transformation of circulating monocytes at the site of injury to fibroblasts and the influx of bone marrow-derived fibrocytes into damaged tissue. Examples of serum biomarkers reflecting the pathogenetic sequence are given, but a considerable overlap is noticeable. Abbreviations: see Table 2, CRP, C-reactive protein; CSF, colony-stimulating factor; CTGF, connective tissue growth factor; GLDH, glutamate-dehydrogenase; PIVKA, prothrombin induced by vitamin K absence
Mentions: Current knowledge ascribes liver-specific pericytes, that is, HSC, a major role in ECM production and re-modelling [7–10]. HSC, formerly termed vitamin A-storing cells, fat-storing cells, lipocytes or Ito-cells are located in the sub-endothelial space of Disse in close proximity to hepatocytes embracing with starlike extensions (spines) the sinusoidal endothelial tube [11]. They express some heterogeneity and represent about 15% of total resident liver cells and about 30% of non-parenchymal cells including Kupffer cells, sinusoidal endothelial cells and pit cells [12]. The ultra-structural features are characterized by large triacylglycerol-filled vacuoles containing retinoids [11, 13]. Besides their function as major vitamin A storage sites [14], that is, around 85% of liver vitamin A is located in this cell type, HSC were recently identified as antigen-presenting cells (APC) [15, 16] and are likely to have additional functions in liver cell renewal, regeneration, immunoregulation, angiogenesis and vascular re-modelling [17]. Their dominant role in fibrogenesis is based on their ability to change the phenotype from retinoid-storing, resting cells to contractile, smooth-muscle α-actin positive, vitamin A-depleted myofibroblasts (MFB) with a strongly developed endoplasmic reticulum and Golgi-apparatus if HSC are challenged by necro-inflammatory stimuli [1, 18]. Myofibroblasts synthesize and secrete virtually all of the matrix components found in ECM of the fibrotic liver (Fig. 1). This, however, does not rule out the contribution of other cell types and mechanisms to enhance matrix production in chronically inflamed liver tissue. The role of portal (MFB), in particular in biliary fibrosis, has been emphasized [19, 20] and, recently, the influx on bone-marrow-derived fibrocytes [21]via the circulation into the damaged tissue has been shown [22–24] Similarly, circulating monocytes, monocyte-like and mesenchymal stem cells have the potential to change to fibroblasts and other cell types if the appropriate microenvironment is provided [25]. Furthermore, actual research is focused on the possibility of epithelial-mesenchymal transition (EMT) [26], which describes the transition of biliary epithe-lial cells or even of hepatocytes to fibroblasts, which participate actively in the generation of fibrotic ECM. However, the role of EMT in liver fibrogenesis is still under debate, but is well established in lung and kidney fibrosis [26].

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