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Noninvasive Markers of Liver Fibrosis
 
 
  "Stepwise combination algorithms of non-invasive markers to diagnose significant fibrosis in chronic hepatitis C"
 
Journal of Hepatology April 2006
 
Giada Sebastiania, Alessandro Varioa, Maria Guidob, Franco Noventaa, Mario Plebanic, Roberta Pistisa, Alessia Ferraria, Alfredo Albertia
a Department of Clinical and Experimental Medicine, University of Padova, via Giustiniani, 35100 Padova, Italy
b Department of Oncological and Surgical Sciences, University of Padova, Padova, Italy
c Department of Laboratory Medicine, University of Padova, Padova, Italy
 
Following the main article are 2 interesting letters to the editor with additional useful information.
 
"....Several non-invasive markers of liver fibrosis have been described but their use in place of liver biopsy is still controversial and not universally accepted due to still unsatisfactory diagnostic accuracy. Indeed, some of these methods, like APRI and Forns' index, leave many patients unclassified and all of them do not exceed 80-85% diagnostic accuracy.... As a consequence, many patients still need to have a liver biopsy taken and in those classified without biopsy misdiagnosis is expected to occur in at least 15-20%, a figure that is considered inadequate by many clinicians..... These markers have other limitations.... Our results indicate that the diagnostic performance of these non-invasive markers of liver fibrosis can be greatly improved by combining them in stepwise algorithms..... The algorithm we have developed for identifying patients with significant fibrosis (F≥2) among HCV carriers with elevated ALT had indeed more than 94% diagnostic accuracy with around 50% reduction in the number of liver biopsies needed.... We have also developed an algorithm for identifying patients with significant fibrosis among HCV carriers with PNALT (normal ALT).....there is abundant evidence in the literature that around 15-30% of them may have significant fibrosis and a definitive indication to antiviral therapy.... The algorithm we have developed to identify cirrhosis showed around 95% diagnostic accuracy and allowed to save 65-70% of liver biopsies..."
 
ABSTRACT

Background/Aims: In chronic hepatitis C, biopsy is the gold standard for assessment of liver fibrosis. Non-invasive markers have been proposed but their use is limited by diagnostic accuracy. Our aim was to increase the diagnostic performance of non-invasive markers of liver fibrosis by combining them in sequential algorithms.
 
Methods: One hundred and ninety patients with chronic hepatitis C were evaluated for AST to platelets ratio (APRI), Forns' index and Fibrotest at the time of liver biopsy and stepwise combination algorithms were developed and validated prospectively in 100 additional patients.
 
Results: Three algorithms were developed: (1) significant fibrosis (F≥2 by METAVIR) was identified with high diagnostic performance (>94% accuracy) using APRI as screening test, followed by Fibrotest in APRI non-classified cases and restricting liver biopsy to patients classified F0-F1 by non-invasive tests. (2) A slightly modified algorithm had similar performance when applied to hepatitis C carriers with normal ALT. (3) Identification of cirrhosis (95% accuracy) was achieved using a dedicated algorithm with different cut-off, reducing by 60-70% the liver biopsies needed.
 
Conclusions: Stepwise combination of non-invasive markers of liver fibrosis improves the diagnostic performance in chronic hepatitis C. Need for liver biopsy is reduced by 50-70% but cannot be completely avoided.
 
Introduction
Chronic infection with hepatitis C virus remains a major health problem with around 200 million individuals affected worldwide [1]. The natural course of chronic hepatitis C is characterised by progressive fibrosis in the inflamed liver with structural and hemodynamic changes leading to cirrhosis, which is followed by end-stage complications [2]. Accordingly, the prognostic evaluation and clinical management of still compensated chronic hepatitis C is largely based on assessment of the type and degree of liver fibrosis and several semiquantitative scoring systems have been proposed and validated [3], [4], [5], [6]. Liver biopsy is the gold standard for fibrosis staging in chronic hepatitis C as in many other chronic liver diseases. However, liver biopsy is invasive and complications occur in 0.6-5% of patients [7], [8], [9]. Moreover, liver biopsy is costly and requires hospitalisation of at least 6-18h [10]. Finally, recent studies performed in chronic hepatitis C have demonstrated that inadequate liver biopsy sample size frequently leads to underestimation of fibrosis stage [11], [12]. Furthermore, laparoscopic studies have shown that cirrhosis is missed by percutaneous liver biopsy in 10-30% of the cases [13], [14], [15]. For all these reasons a great interest and many studies have been recently dedicated to the development of non-invasive markers as surrogates of liver biopsy. These non-invasive markers include the AST to platelet ratio index (APRI) proposed by Wai et al., the Forns' index based on age, platelets, ΓGT and cholesterol and more sophisticated model like Fibrotest [16], [17], [18]. Fibrotest is based on five serological parameters including bilirubin, ΓGT, apolipoprotein A1 (ApoA1), alfa-2-macroglobulin (A2M) and haptoglobin [18]. These different methods have been usually applied individually in the different validation studies. All of them have limitations. APRI and Forns' index leave many patients unclassified while Fibrotest is more expensive and uses two uncommon parameters. Furthermore, the diagnostic accuracy of most methods has not exceed 80-85% [12]. There are no published studies in which these non-invasive markers of liver fibrosis have been combined in the attempt to improve diagnostic accuracy. We have here measured APRI, Forns' index and Fibrotest in a consecutive series of patients with chronic hepatitis C. Having first assessed the diagnostic accuracy of each individual method using liver biopsy as gold standard, we have then combined them with the aim of defining stepwise algorithms of higher diagnostic accuracy to be used in most common clinical scenarios, i.e. for identifying cases with significant fibrosis and those with cirrhosis among patients presenting with chronic HCV infection.
 
Patients and methods
Patients

This study included two cohorts of consecutive patients with a recent diagnosis of chronic hepatitis C who underwent percutaneous liver biopsy at the Department of Clinical and Experimental Medicine at the University of Padova. The first cohort (training set) included 190 patients seen between March 2003 and June 2004. The second cohort (validation set) consisted of 100 consecutive patients seen between July 2004 and April 2005. All patients were positive for serum HCV-RNA by polymerase chain reaction and had compensated chronic HCV infection. The exclusion criteria were any other cause of chronic liver disease, co-infection with HBV or HIV and co-morbidities that could confound the results of the non-invasive markers adopted. These included current alcohol intake (>20g/die), haemolysis, Gilbert's syndrome. All biopsies were obtained with 16G Menghini type needle. To limit the risk of fibrosis underestimation, patients with biopsy samples shorter than 1.5cm or containing less than seven portal tracts were excluded [19]. According to these criteria, 76 patients with chronic hepatitis C were excluded. Informed consent was obtained from all patients participating in the study, that was conducted according to the rules of the Declaration of Helsinki.
 
Discussion
Staging of hepatic fibrosis is fundamental for clinical management of chronic hepatitis C. Patients showing F≥2 stage by METAVIR are at significant risk of developing cirrhosis within 5-10 years and are considered to have priority for antiviral therapy in all International and National guidelines and recommendations [1], [2], [21]. On the other hand, many experts believe that therapy is not mandatory in patients with no or minimal fibrosis (F0-F1), particularly when the chance of achieving a favourable response is not high, like in patients with contraindications or with poor motivation towards therapy, patients with high viral load or difficult-to-treat HCV genotypes [1]. Furthermore, assessment of the risk-benefit ratio of antiviral therapy has always been to consider the stage of liver disease in the presence of any contraindication. Thus, a liver biopsy is often necessary to assess prognosis and to decide management. Several non-invasive markers of liver fibrosis have been described but their use in place of liver biopsy is still controversial and not universally accepted due to still unsatisfactory diagnostic accuracy. Indeed, some of these methods, like APRI and Forns' index, leave many patients unclassified and all of them do not exceed 80-85% diagnostic accuracy [15], [16], [22], [23], [24]. As a consequence, many patients still need to have a liver biopsy taken and in those classified without biopsy misdiagnosis is expected to occur in at least 15-20%, a figure that is considered inadequate by many clinicians [1], [21], [25], [26]. These markers have other limitations. Most of them, such as APRI and Forns' index, are not able to identify individual stages of fibrosis. APRI cannot be completely standardised due to the variability of measurement and normality ranges of AST in different laboratories [24]. The performance of Forns' index might be modified in patients infected by HCV-3 because of lower cholesterol levels [22]. In our series cholesterol levels were indeed significantly lower in patients with HCV-3 but the diagnostic performance of Forns' index was similar in HCV-3 and non-3, probably due to the low prevalence of HCV-3 in our series. Our results indicate that the diagnostic performance of these non-invasive markers of liver fibrosis can be greatly improved by combining them in stepwise algorithms. The algorithm we have developed for identifying patients with significant fibrosis (F≥2) among HCV carriers with elevated ALT had indeed more than 94% diagnostic accuracy with around 50% reduction in the number of liver biopsies needed both in the training and in the validation cohort. We have also developed an algorithm for identifying patients with significant fibrosis among HCV carriers with PNALT. This category has not been considered in most previous studies of non-invasive markers of fibrosis. However, there is abundant evidence in the literature that around 15-30% of them may have significant fibrosis and a definitive indication to antiviral therapy [27], particularly when considering the favourable results recently reported with PEG-interferon alfa-2a plus ribavirin combination therapy [28]. The slightly modified algorithm developed for significant fibrosis in these patients had similar performance to that of patients with elevated ALT. Forns' index was excluded from this stepwise algorithm because of the minimal impact on further reducing liver biopsies needed. It should be here underlined that the prevalence of significant fibrosis (F≥2) was in our series of patients with PNALT somehow higher than that usually reported in the literature [28]. This most likely was due to the attitude in our centre to perform more frequently a liver biopsy in these patients when ALT levels are in the upper part of the normal range. Furthermore, we included only liver biopsy specimens of adequate size and Colloredo et al [11]. have recently shown that the use of larger samples favours identification of higher stages of liver fibrosis. The rather high prevalence of patients with significant fibrosis in our series with and without elevated ALT should be taken into account when considering the performance of the combined algorithms described. Indeed our algorithms depend on the PPV of the non-invasive markers used and may therefore perform less well when applied to clinical settings with lower prevalence of significant fibrosis, where the negative rather than positive predictive value might be more important.
 
Another algorithm was developed to diagnose cirrhosis. Identification of cirrhosis in chronic hepatitis C is extremely important since patients who have reached this stage need specific management, including closer monitoring for complications and hepatocellular carcinoma. Furthermore, patients with cirrhosis may be expected to have reduced response and tolerability during antiviral therapy. The algorithm we have developed to identify cirrhosis showed around 95% diagnostic accuracy and allowed to save 65-70% of liver biopsies. Again, these performances appear superior to those reported previously for individual non-invasive markers of cirrhosis. The drastic reduction in liver biopsies needed and the fact that our algorithm requires this invasive procedure in patients with low chance of having cirrhosis are particularly important since the risk of liver biopsy complications is increased in cirrhotics [7], [9].
 
The diagnostic algorithms we have described may not only reduce the risk of liver biopsy, but may also have competitive cost-benefit ratio compared to other approaches since, although they require APRI and Fibrotest to be done, the cost of these parameters are clearly inferior to that of liver biopsy.
 
Recently, high diagnostic accuracy for detection of significant fibrosis and cirrhosis has been reported for the combination of Fibrotest with Fibroscan, that is based on the measurement of hepatic stiffness by transient elastography [29], [30]. However, this approach requires availability of a complex instrument, with limited access and costs that most likely exceed those of our more simple and accessible algorithms.
 
Many studies have also been dedicated to evaluation of direct markers of fibrogenesis, i.e. of extracellular matrix in the liver. The potential clinical utility of such markers appears interesting and innovative, as they could be used not only to stage liver fibrosis, but also to assess the rate of liver fibrogenesis, and also to estimate and monitor the efficacy of and the response to antifibrotic drugs. However, these ambitious goals have not been yet fully achieved for clinical application. Moreover, some combination panels of matrix markers have been recently developed but the diagnostic performance described appears unsatisfactory in hepatitis C, with around 75-80% accuracy [31], [32].
 
In conclusion, we have developed and validated simple algorithms of elevated diagnostic accuracy to identify significant fibrosis and cirrhosis in patients with hepatitis C. These algorithms that are based on stepwise use of previously described non-invasive markers of liver fibrosis still require liver biopsy in a limited number of patients. These algorithms that are expected to have optimised performance in clinical settings with high prevalence of significant fibrosis may be useful for the clinical management of patients with chronic HCV infection.
 
Methods
Histological assessment

Liver biopsies were fixed in formalin and embedded in paraffin. The slides were stained with hematoxylin-eosin, van Gieson stain for collagen, PAS after diastase digestion and Perls' Prussian blue method. The slides were evaluated by a single, independent Pathologist (M.G.) who was unaware of clinical data. Fibrosis was scored according to the METAVIR system [5]. Intra-observer agreement was assessed, using k statistics, by re-evaluating a subset of 50 randomly chosen samples: k value was higher than 0.90.
 
Non-invasive markers
All patients were evaluated for APRI, Forns' index and Fibrotest using fasting serum samples obtained at the time of liver biopsy. For this purpose platelet count, AST, ALT, ΓGT, cholesterol levels, haptoglobin, ApoA1, A2M, total bilirubin were routinely determined using validated methods. All the patients were also tested for prothrombin time (international normalised ratio, INR), albumin, viral load (Amplicor; Roche, Diagnostic Systems, Basel, Switzerland) and HCV genotype (InnoLipa; Innogenetics, Bayer, Ghent, Belgium). APRI and Forns' index were calculated using cut-off values indicated in the original reports [16], [17]. Fibrotest results were kindly provided by T. Poynard, Universite Paris VI, Paris, France.
 
Statistical tools
Descriptive results were expressed as mean±SD or number (percentage) of patients with a condition. The t-test or non-parametric Mann-Whitney test was used to compare quantitative data and the ƒÔ2-test was applied for comparison of frequency data. P-values less than 0.05 were considered significant. The diagnostic performance of the non-invasive methods for liver fibrosis was measured as sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, likelihood ratios (LR). Sensitivity, specificity, PPV, NPV and accuracy were expressed as percentage. The diagnostic value of the three methods was assessed by calculating the areas under the curves (AUC) and their corresponding 95% confidence intervals (CI). The diagnostic algorithms combining the non-invasive methods were developed by modelling the best algorithm for liver fibrosis in different clinical scenarios, as described in Section 3.
 
Results
 
The main demographic, laboratory and histological features of the two sets of patients are summarized in Table 1. The mean length of liver specimens was 1.77±0.31cm and mean complete portal tracts number was 11.03±3.17. Baseline characteristics of patients were comparable for all parameters considered. Around 34 and 28% of patients in the training and in the validation set, respectively, had chronic hepatitis C with persistently normal ALT (PNALT) as defined by at least three normal values 2 months apart over 6 months [20]. The two sets had all fibrosis stages represented.
 
Diagnostic performance of individual non-invasive methods in the training set The first analysis was aimed to determine the diagnostic performance of the three non-invasive methods in detecting significant fibrosis as defined by METAVIR fibrosis stage ≥F2. In this analysis, patients with elevated ALT and with PNALT were considered separately. The corresponding results are shown in Table 2, Table 3.
 

Table2Per-1.gif

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In patients with elevated transaminases, Fibrotest classified all cases while both APRI and Forns' index were unable to classify almost half of the patients. APRI had the best PPV with the 1.5 cut-off and the best NPV with the 0.5 cut-off. It also showed the best accuracy in patients classified by the 0.5 cut-off. Fibrotest showed slightly better AUC but the difference against Forns and APRI was not significant. Around 10% of patients were infected by HCV-3 and showed significantly lower cholesterol levels compared to cases infected with HCV non-3 (140.7±41.1 vs 175.1±33.9mg/dL, P=0.003). However, the diagnostic performance of Forns' index, which includes cholesterol, was similar in HCV-3 and non-3 (70 vs 72.9%).
 
The results obtained with the same set of tests applied to patients with PNALT are shown in Table 3. Fibrotest could again classify all patients while both Forns' index and APRI showed a significant percentage of unclassified cases (44% for the former and 26% for the latter). Fibrotest had the best NPV and good accuracy. APRI showed the best AUC and accuracy with the 0.5 cut-off. Forns' index and APRI showed excellent PPV.
 
The diagnostic accuracy of APRI and Fibrotest in detecting cirrhosis (F4 by METAVIR) was also assessed in the training set (Table 4). Forns' index was not considered since it does not discriminate between significant fibrosis and cirrhosis. Fibrotest was able to classify all patients while APRI could not classify almost half of them. APRI had rather high NPV (86.7%). Overall, Fibrotest had the best performance scores for all parameters considered.
 

Table4-3.gif

Optimised combination algorithms
Having defined the individual diagnostic performance of the three non-invasive markers of fibrosis, we have then combined them in stepwise algorithms aimed to achieve optimised diagnostic performance (accuracy >90%) while minimising the number of liver biopsies needed. These algorithms were developed in the training set on the basis mainly of the PPV or NPV of each marker and then validated in the validation set. Three different pretest clinical scenarios were chosen for the development of these algorithms. The first scenario was for patients with elevated ALT with the aims of identifying all those with significant fibrosis (F≥2 by METAVIR) and a clear indication to antiviral treatment and of minimising the number of over-diagnosed cases and the number of liver biopsies needed. The same modelling was performed for patients with PNALT. In the third scenario, the algorithm was modelled to optimise identification of cirrhosis with the aim of detecting all patients with cirrhosis, and of minimising over-diagnosis and the number of liver biopsies needed. The best diagnostic algorithm for each of these three scenarios is reported in Fig. 1a-c. The results and performance of each algorithm in the training and in the validation set are described in Table 5.

Table5-4.gif

In patients with elevated transaminases, the best diagnostic algorithm was to first calculate APRI (best PPV) in all patients and then to perform Fibrotest in those not classified by APRI (51%). Patients classified F≥2 in either test (51%) did not need biopsy due to the high PPV. However, patients showing F0-F1 by APRI (31%) or by Fibrotest (18%) had to undergo liver biopsy due to the low NPV of both methods and to the relatively low performance of Fibrotest in improving diagnosis in patients classified F0-F1 by APRI (data not shown). With this algorithm we obtained 94% accuracy and saved around 50% liver biopsies. When Fibrotest was applied alone in our series, the accuracy was reduced to 74% with 43% saved liver biopsies.
 
In patients with PNALT, the best algorithm used again APRI in all patients followed by Fibrotest in those who resulted F0-F1 or unclassified by APRI. Patients who resulted F0-F1 by Fibrotest needed liver biopsy while those classified as F≥2 by any test could be diagnosed as significant fibrosis with high accuracy without liver biopsy.
 
In the third clinical scenario the best algorithm to identify cirrhosis was to perform APRI in all patients. Those classified by APRI as F0-F1 did not need further evaluation due to the high NPV. For all other cases the following step was to perform Fibrotest and then to take a liver biopsy in those classified F2-F3 by Fibrotest. In cases classified F0-F1 by Fibrotest, cirrhosis could be excluded with very high NPV and cases classified as F4 by Fibrotest could be diagnosed as cirrhotic without liver biopsy.
 
Table 5 describes the results obtained when these algorithms were applied to the training and to the validation sets, with indication of the number of each test that had to be performed in a cohort of 100 patients, and of the number of saved liver biopsies and of misdiagnosed cases. The algorithm for detecting significant fibrosis (F≥2 by METAVIR) in patients with elevated ALT reached 94% accuracy in both the training and validation set, with no underestimation of fibrosis, limited overestimation (5-6%), and saving around 50% of liver biopsies. Similar performances were calculated for the algorithm developed for identifying significant fibrosis in patients with PNALT. The algorithm developed to identify cirrhosis also had 93-95% accuracy, with virtually no misdiagnosis and required liver biopsy in only around one third of cases.
 
Evolving practices of non-invasive markers of liver fibrosis in patients with chronic hepatitis C in France: Time for new guidelines?
 
Jnl of Hepatology
In Press
published online 18 December 2006.
 
Laurent Castera
Jacques Denis
Gerard Babany
Francoise Roudot-Thoraval
Services d'Hepato-Gastroenterologie, Centre Hosiptalier, Universitaire de Bordeaux, Bordeaux, France
Service d'Hepato-Gastroenterologie, Centre Hospitalier Sud Francilien, Corbeil, France
Produits Roche, Neuilly sur Seine, France
Departement de Sante Publique, AP-HP, Hopital Henri Mondor, Creteil, France
 
To the Editor:
 
We read with interest the article by Sebastiani et al. [1] proposing stepwise algorithms combining non-invasive markers for the diagnosis of significant fibrosis in patients with chronic hepatitis C (CHC). We agree with the authors that combining methods may improve diagnostic accuracy. Indeed, we have also recently proposed an algorithm combining transient elastography (FibroScan), a new technology allowing measurement of liver stiffness, and FibroTest[2] as first-line assessment of liver fibrosis in patients with CHC [3]. Based on this algorithm, liver biopsy examination could have been avoided in more than 75% of patients for the diagnosis of significant fibrosis. It can be anticipated that non-invasive markers of fibrosis will become an important tool in clinical practice in the near future [4]. However, no guidelines regarding the use of these markers are currently available and international consensus reports [5], [6] still recommend liver biopsy as mandatory before starting antiviral therapy in CHC patients.
 
We conducted a nationwide survey aimed at evaluating, in the absence of guidelines, the current practices of non-invasive markers of fibrosis in nave patients with CHC and elevated transaminases in France. A questionnaire was sent to all French hepatologists taking care of CHC patients in April 2006. By July, 546 responses (65%) were received (public practice (n=265), academic hospitals (n=147), non-academic hospitals (n=118), private practice (n=153), both (n=128)). FibroTest was the most widely used marker (81% of respondants for 66% of their patients), then FibroScan (32% for 60% of their patients), and dosage of hyaluronate (17%). Liver biopsy was still performed systematically by 4% of respondants whereas it was not done anymore by 3%. The respondants estimated that liver biopsy was still necessary for the following: presence of comorbidities such as alcohol abuse or overweight (72%), discrepancy between FibroScan and FibroTest or discrepancy between markers and clinical judgement (72%), initiation of antiviral therapy in patients infected by HCV genotype 1 (48%) or 4 (30%), and suspicion of cirrhosis (44%). It was estimated that the use of non-invasive markers resulted in a reduced need for liver biopsy in at least (or more than) 50% of patients by 52% of respondants and in 25-50% of patients by 25% (Fig. 1). In addition, 55% of respondants considered that the use of non-invasive markers increased the number of treated patients (by 35%). Finally, updated guidelines for the use of non-invasive markers in clinical practice were required by 95% of respondants.
 
Fig. 1. Impact of the use of non-invasive markers on the need for liver biopsy in patients with chronic hepatitis C in France according to the type of practice.

Change-5.gif

The results of the present study clearly show that non-invasive markers of fibrosis are widely used in routine clinical practice in France, resulting in a significant decrease in the need for liver biopsy. They also emphasize the urgent need for new guidelines, as requested by almost all respondants. We agree, however, with Sebastiani et al. [7] that with an expected rate of misdiagnosis of at least 20%, non-invasive markers will likely reduce but not substitute the need for liver biopsy. Thus, the most rationale way of using them would be that of a compromise in which non-invasive markers would be first used to classify those patients in whom they perform with high accuracy, limiting liver biopsy to the subset in whom precise non-invasive diagnosis is not possible, due to causes of misinterpretation of non-invasive test and/or need for other histological diagnosis.
 
Non-invasive markers of liver fibrosis: How to use them in clinical practice?
 
Journal of Hepatology
In Press
 
Giada Sebastiani, Alfredo Alberti
published online 18 December 2006.
 
To the Editor:
 
We fully agree with Castera et al. [1] regarding the need to develop and validate guidelines for the use of non-invasive markers of liver fibrosis in clinical practice. Castera et al. referred to a nationwide survey among French hepatologists, indicating that in France, Fibrotest is the most used marker, followed by Fibroscan and hyaluronan. Liver biopsy was still performed systematically by only 4% of respondants. Liver biopsy was considered still necessary in case of discrepancy between Fibroscan and Fibrotest. Interestingly, guidelines for the use of non-invasive markers in clinical practice were required by 95% of respondants. Similarly, a recent survey assessing the consensus among Italian hepatologists about when and how to take a liver biopsy in CHC showed a great divergence in the management of the same group of patients, indicating the need to better define the role of biopsy and of non-invasive markers [2]. Our studies describing sequential algorithms based on the use of APRI, Fibrotest [3], [4] clearly indicate that liver biopsy cannot be completely avoided when a precise definition of the stage of liver fibrosis is needed in patients chronically infected with HCV or HBV. This may still be essential for treatment decisions in special populations of patients, such as those with high viraemia, or with contraindications, with normal ALT or not highly motivated. In these cases, as well as in many others, the distinction among minimal, intermediate or advanced fibrosis may greatly help in directing management. Available data indicate that non-invasive markers of fibrosis and liver biopsy should be considered as agonists and not antagonists towards the common goal of correctly classifying the stage of liver fibrosis [5]. This is also true for the combined use of Fibrotest and Fibroscan, as reported by Castera et al. [6]. We completely agree with these authors that the most accurate non-invasive markers should be used as first line assessment, limiting liver biopsy to the cases in which they do not agree or have low predictive value. Priority should be given to large scale validation studies of these algorithms in different patient populations inclusive of all major etiologies of chronic liver disease and most frequent cofactors which may affect the diagnostic performance of fibrosis markers.
 
References
[1] [1]Castera L, Denis J, Babany G, Francoise Roudot-Thoraval. Evolving practices of non-invasive markers of liver fibrosis in patients with chronic hepatitis C in France: time for new guidelines? J Hepatol, in press.
 
[2] [2]Almasio PL, Niero M, Angioli D, Ascione A, Gullini S, Minoli G, et al.. Experts' opinions on the role of liver biopsy in HCV infection: a Delphi survey by the Italian Association of Hospital Gastroenterologists (A.I.G.O.). J Hepatol. 2005;43:381-387. Abstract | Full Text | Full-Text PDF (117 KB) | MEDLINE | CrossRef
 
[3] [3]Sebastiani G, Vario A, Guido M, Noventa F, Plebani M, Pistis R, et al.. Stepwise combination algorithms of non-invasive markers to diagnose significant fibrosis in chronic hepatitis C. J Hepatol. 2006;44:686-693. Abstract | Full Text | Full-Text PDF (175 KB) | MEDLINE | CrossRef
 
[4] [4]Sebastiani G, Vario A, Guido M, Alberti A. Sequential algorithms combining non-invasive markers and biopsy for the assessment of liver fibrosis in chronic hepatitis B. World J Gastroenterol, in press.
 
[5] [5]Sebastiani G, Alberti A. Non invasive fibrosis biomarkers reduce but not substitute the need for liver biopsy. World J Gastroenterol. 2006;12:3682-3694. MEDLINE
 
[6] [6]Castera L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, et al.. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology. 2005;128:343-350. Abstract | Full Text | Full-Text PDF (257 KB) | MEDLINE | CrossRef
 
Department of Clinical and Experimental Medicine, University of Padova, and Venetian Institute of Molecular Medicine, Padova, Italy
 
 
 
 
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