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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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Pathobiochemical mechanisms of elevation of class I biomarkers of fibrosis exemplified by collagens hyaluronan and laminin, respectively. Increased production by activated hepatic stellate cells due to paracrine stimulation via TGF-β by interacting cells, mechanical stress and hypoxia leads to stimulated secretion and consecutive deposition as incomplete basement membranes in the space of Disse and perisinusoidal fibrosis. As a consequence of newly developed sub-endothelial basement membrane and cellular insufficiency, the clearance function of the sinusoidal compartment for circulating matrix components is decreased and intrahepatic hemodynamic resistance is elevated. The latter leads to perihepatic shunting of blood reducing further the elimination of matrix components and their fragments from the blood.
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fig03: Pathobiochemical mechanisms of elevation of class I biomarkers of fibrosis exemplified by collagens hyaluronan and laminin, respectively. Increased production by activated hepatic stellate cells due to paracrine stimulation via TGF-β by interacting cells, mechanical stress and hypoxia leads to stimulated secretion and consecutive deposition as incomplete basement membranes in the space of Disse and perisinusoidal fibrosis. As a consequence of newly developed sub-endothelial basement membrane and cellular insufficiency, the clearance function of the sinusoidal compartment for circulating matrix components is decreased and intrahepatic hemodynamic resistance is elevated. The latter leads to perihepatic shunting of blood reducing further the elimination of matrix components and their fragments from the blood.

Mentions: This group of fibrogenic biomarkers comprises mainly secretion products of activated HSC and portal (MFB), i.e., matrix components, ECM-related enzymes, TGF-β-dependent export proteins of hepatocytes and mediators of ECM-synthesis or turnover (Table 1). The elevation of these components in the circulation is due to increased expression of ECM-components in the fibrotic tissue (e.g. by HSC) and fractional spillover into the systemic bloodstream. Additionally, reduced clearance by Kupffer cells, sinusoidal endothelial cells or hepatocytes, for example, by perihepatic blood shunting or decrease of scavenger receptor functions of the respective cell types contributes to their elevation in blood (Fig. 3). Some of the previously recommended enzymes of collagen metabolism (e.g. prolylhydroxylase, lysyloxidase, -hydroxylase, collagen peptidase) have nowadays only anecdotic character because their activities in serum do not reflect reliably matrix synthesis, but cell necrosis (Table 1). In addition, their measurement is laborious and costly involving radio-enzymatic, mostly not standardized, cumbersome assays [34]. Similarly, catabolic enzymes of the glycoprotein and proteogly-can metabolism, such as -glucuronidase and N-acetyl- -D-glucosaminidase have not convinced as biomarkers of liver fibrosis. Summarizing the plenitude of existing literature, only a few class I fibrosis biomarkers have reached a certain clinical importance [35–37]. In several studies, hyaluronan (formerly termed hyaluronic acid) currently proves to be the relative best class I biomarker of fibrosis having sensitivities and specificities of 86–100% and 88%, respectively, if cirrhosis in non-alcoholic fatty liver disease (NAFLD) [38] and other etiologies are considered [39]. The diagnostic power of hyaluronan is based on the high negative predictive value (98–100%) at a cut-off concentration of 60 μg/l, which is significantly higher than the positive predictive value of 61%. Promising diagnostic sensitivity and negative predictive value can be ascribed to the stimulated synthesis of hyaluronan in activated HSC [40], its direct secretion into the sinusoidal bloodstream, and the short half-lifetime of 2–9 min in the circulation, which is prolonged in disease conditions by a reduced clearance in the sinusoidal endothelial cells [41]. Of the several pro-collagen and collagen fragments proposed as biomarkers [35] only the aminoterminal propeptide of type III pro-collagen (PIIINP) has reached a limited, but no widespread and continuous clinical application [42]. Reported sensitivities and specificities vary considerably around 76–78% and 71–81%, respectively, which can be increased if combined with additional collagen fragment markers. It should be noticed that PII-INP, hyaluronan and several other class I fibrosis markers are not disease-specific, because elevations are also reported for rheumatoid diseases, chronic pancreatitis, lung fibrosis, scleroderma and others. A series of other studies was focused on the clinical significance of the elevated P1-fragment of the large molecular weight basement membrane glycoprotein laminin [43]. It was reported to be a predictor of portal hypertension, because a positive correlation was noticed between the portal venous pressure and the increase of the P1-laminin fragment in blood [44]. Positive and negative predictive values are given with 0.77 and 0.85, respectively, sensitivity and specificity with 87% and 74%, respectively [44]. If combined with hyaluronan [45] or aminoterminal pro-peptide of type III pro-collagen [46], the diagnostic criteria for assessing portal hypertension can be further improved.


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)

Pathobiochemical mechanisms of elevation of class I biomarkers of fibrosis exemplified by collagens hyaluronan and laminin, respectively. Increased production by activated hepatic stellate cells due to paracrine stimulation via TGF-β by interacting cells, mechanical stress and hypoxia leads to stimulated secretion and consecutive deposition as incomplete basement membranes in the space of Disse and perisinusoidal fibrosis. As a consequence of newly developed sub-endothelial basement membrane and cellular insufficiency, the clearance function of the sinusoidal compartment for circulating matrix components is decreased and intrahepatic hemodynamic resistance is elevated. The latter leads to perihepatic shunting of blood reducing further the elimination of matrix components and their fragments from the blood.
© Copyright Policy
Related In: Results  -  Collection

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

fig03: Pathobiochemical mechanisms of elevation of class I biomarkers of fibrosis exemplified by collagens hyaluronan and laminin, respectively. Increased production by activated hepatic stellate cells due to paracrine stimulation via TGF-β by interacting cells, mechanical stress and hypoxia leads to stimulated secretion and consecutive deposition as incomplete basement membranes in the space of Disse and perisinusoidal fibrosis. As a consequence of newly developed sub-endothelial basement membrane and cellular insufficiency, the clearance function of the sinusoidal compartment for circulating matrix components is decreased and intrahepatic hemodynamic resistance is elevated. The latter leads to perihepatic shunting of blood reducing further the elimination of matrix components and their fragments from the blood.
Mentions: This group of fibrogenic biomarkers comprises mainly secretion products of activated HSC and portal (MFB), i.e., matrix components, ECM-related enzymes, TGF-β-dependent export proteins of hepatocytes and mediators of ECM-synthesis or turnover (Table 1). The elevation of these components in the circulation is due to increased expression of ECM-components in the fibrotic tissue (e.g. by HSC) and fractional spillover into the systemic bloodstream. Additionally, reduced clearance by Kupffer cells, sinusoidal endothelial cells or hepatocytes, for example, by perihepatic blood shunting or decrease of scavenger receptor functions of the respective cell types contributes to their elevation in blood (Fig. 3). Some of the previously recommended enzymes of collagen metabolism (e.g. prolylhydroxylase, lysyloxidase, -hydroxylase, collagen peptidase) have nowadays only anecdotic character because their activities in serum do not reflect reliably matrix synthesis, but cell necrosis (Table 1). In addition, their measurement is laborious and costly involving radio-enzymatic, mostly not standardized, cumbersome assays [34]. Similarly, catabolic enzymes of the glycoprotein and proteogly-can metabolism, such as -glucuronidase and N-acetyl- -D-glucosaminidase have not convinced as biomarkers of liver fibrosis. Summarizing the plenitude of existing literature, only a few class I fibrosis biomarkers have reached a certain clinical importance [35–37]. In several studies, hyaluronan (formerly termed hyaluronic acid) currently proves to be the relative best class I biomarker of fibrosis having sensitivities and specificities of 86–100% and 88%, respectively, if cirrhosis in non-alcoholic fatty liver disease (NAFLD) [38] and other etiologies are considered [39]. The diagnostic power of hyaluronan is based on the high negative predictive value (98–100%) at a cut-off concentration of 60 μg/l, which is significantly higher than the positive predictive value of 61%. Promising diagnostic sensitivity and negative predictive value can be ascribed to the stimulated synthesis of hyaluronan in activated HSC [40], its direct secretion into the sinusoidal bloodstream, and the short half-lifetime of 2–9 min in the circulation, which is prolonged in disease conditions by a reduced clearance in the sinusoidal endothelial cells [41]. Of the several pro-collagen and collagen fragments proposed as biomarkers [35] only the aminoterminal propeptide of type III pro-collagen (PIIINP) has reached a limited, but no widespread and continuous clinical application [42]. Reported sensitivities and specificities vary considerably around 76–78% and 71–81%, respectively, which can be increased if combined with additional collagen fragment markers. It should be noticed that PII-INP, hyaluronan and several other class I fibrosis markers are not disease-specific, because elevations are also reported for rheumatoid diseases, chronic pancreatitis, lung fibrosis, scleroderma and others. A series of other studies was focused on the clinical significance of the elevated P1-fragment of the large molecular weight basement membrane glycoprotein laminin [43]. It was reported to be a predictor of portal hypertension, because a positive correlation was noticed between the portal venous pressure and the increase of the P1-laminin fragment in blood [44]. Positive and negative predictive values are given with 0.77 and 0.85, respectively, sensitivity and specificity with 87% and 74%, respectively [44]. If combined with hyaluronan [45] or aminoterminal pro-peptide of type III pro-collagen [46], the diagnostic criteria for assessing portal hypertension can be further improved.

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