Non-invasive Markers of Liver Fibrosis
[TGF-β], tumour necrosis factor-α [TNF-α], interferon-γ [IFN-γ], fibroblast growth factor [FGF] and interleukin-10 [IL-10]), which provokes an increased synthesis of ECM constituents, glycoproteins and polysaccharides, such as hyaluronic acid (HA), elastin and fibronectin, in addition to an increase in enzymes involved in ECM synthesis (lysyl oxidase, propyl-hydroxylase and lysyl hydroxylase) and its degradation, such as matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). This process causes an increase in the maturation and degradation products of collagen and their precursors, the propeptides generated by the process of maturation of these molecules and their incorporation into the fibrotic tissue as the propeptides of types I, III and IV collagen.
Among all these direct biochemical serum markers, HA, TIMP-1 and amino-terminal propeptide of type III procollagen (PIIINP) have been shown to be the most promising.
HA is an integral component of the ECM. There is a good correlation between HA levels and the severity of liver disease. However, whereas HA has an excellent ability to identify the F4 stage, it is less useful for differentiating the early stages of fibrosis.29–34
On the other
Finally, PIIINP is a good predictor of fibrosis in HCV patients, but its capacity to differentiate F4 and the early stages of fibrosis is less than that of HA.32–35
hand, TIMP-1 is one of the four tissue inhibitors of MMPs. It has been reported that high levels of MMPs and TIMPs correlate well with cirrhosis.33–36
Several indexes have been
developed using a combination of direct and surrogate biochemical markers for liver fibrosis.
FibroSpect
This index includes the identification of three parameters: HA, TIMP-1 and α2-macroglobulin. FibroSpect was evaluated by the group of McHutchinson in a retrospective study of 696 patients with HCV.37
The
analysis allowed differentiation of those patients with chronic HCV with moderate or severe fibrosis from those who had no or mild fibrosis. However, it was not possible to distinguish between the different stages of fibrosis.
Serum Hyaluronic Acid, Aspartate Aminotransferase and Albumin
This biomarker was developed using HA, AST and albumin. As well as other biomarker tests, the serum HA, AST and albumin (SHASTA) index accurately classified mild and advanced fibrosis in a cohort of 95 patients co-infected with HIV/HCV.38
Hepascore
This index of liver fibrosis is based on levels of four serum markers: total bilirubin, GGT, HA and α2-macroglobulin, age and sex. The Hepascore allows differentiation between advanced fibrosis and cirrhosis.39
European Trial of Hepatic Fibrosis
Several mathematical algorithms that only combine direct biochemical markers have been developed. A few years ago, the European Liver Fibrosis Group conducted an international multicentre study in a cohort of 1,021 patients with chronic hepatitis C, non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease. They analysed the performance of an algorithm, the enhanced liver fibrosis (ELF) panel, which includes age and combines the serum levels of HA, PIIINP and TIMP-1. It was found that this algorithm could identify patients with mild fibrosis or its absence, distinguishing
EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW
patients with significant liver fibrosis in a wide range of chronic liver disease. The accuracy of this algorithm was similar to the score on the reading of liver biopsies of patients by three expert liver pathologists. Therefore, the authors concluded that this algorithm could be used with similar accuracy in the evaluation of chronic liver disease of different aetiologies.40
A study published in 2008 validated the Original European Liver Fibrosis (OELF – originally reported as the European Liver Fibrosis) score and the simplified ELF score, which includes the three markers mentioned but does not consider age in a cohort of patients with NAFLD. There were no significant differences in the results obtained by both algorithms in each of the different stages of fibrosis. Furthermore, they compared the performance of the ELF score with different serum markers according to the stage of fibrosis. Independently of the level of fibrosis, ELF algorithm performance was higher than that offered by other serum markers.41 In this regard, direct biochemical markers have been validated in paediatric non-alcoholic fatty liver disease,42 cirrhosis,43
primary biliary alcoholic liver disease44 during antiviral treatment.45
We have recently validated and compared the diagnostic performance of several non-invasive tests for predicting severity and to assess changes in liver fibrosis after antiviral treatment.46
and patients infected with HCV
The
performance of Forns’ score, APRI, FIB-4 index and ELF score was validated in 340 patients undergoing antiviral therapy. These scores were determined 24 weeks after treatment in 161 patients. We concluded that simple panel markers and the ELF score are accurate at identifying significant fibrosis and cirrhosis in chronic HCV. Moreover, a decrease in the ELF score after antiviral treatment reflects the impact of viral clearance on hepatic ECM and probably on the improvement in liver fibrosis.
Surrogate biochemical markers27,47 have shown limitations in patients
receiving LT because some of the variables included can be altered by causes not related to fibrosis progression. Preliminary data in the LT setting have suggested that the use of direct biochemical markers of fibrosis might be useful to identify patients infected with HCV with rapid fibrosis progression after LT.48
In another study, published in
2010, we described that the serum markers HA, TIMP-1 and PIIINP measured six months after LT can accurately discriminate between patients with mild and progressive hepatitis C recurrence after LT. The most important finding was that the values of the algorithm at six months can predict which patients will develop liver fibrosis one year after transplantation. It was found that the diagnostic accuracy of the algorithm to identify patients at risk of significant fibrosis six months after transplantation was significantly higher than the assessment of transaminases and the APRI and Benlloch scores. These results support the use of direct serum markers in monitoring patients with recurrent hepatitis C in the first months after transplantation and allow therapeutic decisions at an early stage.49
As described above, many non-invasive biochemical serum markers of liver fibrosis with similar diagnostic power to identify patients with advanced liver disease are currently available. However, it is necessary to improve the diagnostic accuracy of these non-invasive biomarkers with prospective studies before they can completely replace liver biopsy, particularly in the early stages of liver fibrosis and in monitoring the progression of the disease. n
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