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Some direct markers of fibrosis and their actions
Associated with matrix deposition
Procollagen I and III
Hyaluronic acid
Transforming growth factor- beta 1
YKL-40 ( chondrex )
Collagen precursors ; mature collagen integrates into the ECM
A glycosaminoglycan ; a component of the ECM produced by hepatic stellate cells
Non-collagenous component of the ECM , which is deposited in the basement membrane of the liver and produced by stellate cells
Pleiotropic cytokine involved in tissue growth , differentiation , ECM production and the immune response
Member of the chitinase family of enzymes
Associated with matrix degradation
Matrix metalloproteinases ( MMPs )
Type IV collagen
Structurally related proteolytic enzymes that mediate the degradation of the ECM and the basal membranes
Inhibit MMP actions
Secreted during interstitial filament metabolism
and tend to be elevated when there is high inflammatory activity . When there is minimal inflammation , extensive matrix deposition might therefore not be detected . These markers are not liver specific and serum levels also depend on their clearance rates , which are influenced by the dysfunction of endothelial cells , impaired biliary excretion or renal function . 2
Indirect markers Indirect markers of fibrosis include molecules that are released into the blood due to inflammation and molecules that are excreted or synthesised by the liver and reflect alterations in hepatic function .
What makes the ‘ ideal ’ marker ? The ‘ ideal ’ marker for liver fibrosis would be :
• Highly sensitive and specific in identifying the different stages of fibrosis
• Able to monitor disease deterioration / progression as part of the natural development of liver disease or treatment regimens
• Not prone to false-positive results ; for example , in inflammation related to non-hepatic diseases
• Readily available , safe , cost-effective , and reproducible .
A single ‘ ideal ’ marker would not be possible , but several markers have been identified as useful indicators of fibrosis when used in combination .
Combined panels of indirect markers of liver fibrosis Table 3 summarises some of the indirect serorological combination panels available .
AST / ALT ratio This is a commonly available marker that can be used routinely ; however , the specificity and clinical utility in predicting fibrosis or cirrhosis are low .
AST-to-platelet ratio index ( APRI ) APRI is calculated as : ( AST / upper limit of normal range )/ platelet count ( 109 / l ) × 100 . It was developed as a marker to assess fibrosis in HIV – HCV co-infected patients and can identify significant fibrosis with a moderate degree of accuracy but is less accurate in differentiating intermediate fibrosis from mild or severe fibrosis .
Forns index The Forns index uses four clinical parameters : age of the patient ; platelet count ; cholesterol levels ; and GGT . This tool is useful in differentiating patients with mild ( F0 – F1 ) fibrosis from those with severe fibrosis , but it is less accurate in predicting more advanced fibrosis or cirrhosis .
FIB-4 score This score combines platelet count , ALT , AST and age , and was developed to assess fibrosis in HIV – HCV co-infected patients ; it has a sensitivity of about 70 % and can be used in routine clinical practice .
NAFLD fibrosis score The non-alcoholic fatty liver disease ( NAFLD ) fibrosis score is a simple scoring panel that includes age , hyperglycaemia , body mass index , platelet count , albumin , and AST / ALT . It can predict significant fibrosis in NAFLD patients , reducing the requirement for invasive liver biopsy .
ELF This panel includes HA , amino-terminal propeptide of type III collagen , and TIMP . ELF is useful in accurately diagnosing significant fibrosis in about 90 % of NAFLD patients .
FibroTest / FibroSure This is the most validated algorithm and is calculated using age , sex , and results for serum haptoglobin , α2-macroglobulin , apolipoprotein A1 , GGT , and bilirubin . It is used to assess fibrosis and necroinflammatory activity in various liver diseases . The sensitivity and specificity values for FibroTest based detection of primary severe fibrosis were found to be 75 % and 85 %, respectively . 10
FibroMeter It is a combination of seven parameters : platelet count , prothrombin index , AST , γ2 macroglobulin , hyaluronate , blood urea nitrogen , and age . FibroMeter determines the extent of liver fibrosis as a percentage of fibrous tissue within the liver . FibroMeter has two main diagnostic targets : the stage of fibrosis corresponding to the METAVIR system ; and the amount of fibrosis , which corresponds to morphometric determinations of the fibrotic area .
Imaging techniques Transient elastography ( TE ) FibroScan is an ultrasound-based technology employing TE whereby stiffness of liver parenchyma is assessed using
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