Serum markers of non-invasive fibrosis in chronic hepatitis C virus infection

MATTER: Liver biopsy is recommended for the management of patients infected by hepatitis C virus (HCV) and is currently the gold standard in assessing liver histology. It's an invasive test prone to complications with a morbidity rate of 0.3 to 0.6% and a mortality rate up to 0.05%. Since the last decade, researchers developed non invasifs biomarkers of liver fibrosis as an alternative to liver biopsy. These scores are based on different algorithms with various combinations of biomarkers issued from extra-cellular matrix, serum and cells. CURRENT EVENTS: The diagnostic performance of these scores, estimated by the AUROC for significant fibrosis (>F2), in patients with chronic hepatitis C reach 0.78 to 0.90 for the most accurate. In HIV-HCV co-infected patients and patients with hepatitis C cirrhosis the diagnostic performance of these scores reach 0.74 to 0.88 and 0.73 to 0.97 respectively. PERSPECTIVES: Liver fibrosis biomarkers constitutes an alternative to liver biopsy due to their non invasive approach, their easy reproducibility and accuracy. However, these scores must be used only after a validation in multicentric independent studies. The future is based on the comparison and validation of these scores after laboratory methods standardization.     

Comparison of non-invasive assessment to diagnose liver fibrosis in chronic hepatitis B and C patients

Abstract

Objective. Chronic viral hepatitis B and C cause liver fibrosis, leading to cirrhosis. Fibrosis assessment is essential to establish prognosis and treatment indication. We compared seven non-invasive tests, separately and in combination, in chronic hepatitis patients to detect early stages of fibrosis according to the Metavir score in liver biopsy. Material and methods. Galactose and methacetin breath tests (GBT and MBT), biomarkers (hyaluronic acid (HA), aspartate aminotransferase platelet ratio index (APRI), FibroTest, and Fib-4) and transient elastography (TE) were evaluated in 89 patients. Additionally, 31 healthy controls were included for evaluation of breath tests and biomarkers. Results. Serum markers (HA, APRI, FibroTest, and Fib-4) and elastography significantly distinguished non-cirrhotic (F0123) from cirrhotic (F4) patients (p < 0.001, p = 0.015, p < 0.001, p = 0.005, p = 0.006, respectively). GBT, HA, APRI, FibroTest, Fib-4, and TE detected F01 from F234 (p = 0.04, p = 0.011, p = 0.009, p < 0.001, p < 0.001, and p < 0.001, respectively). A combination of different tests (TE, HA, and FibroTest) improved the performance statistically, area under the curve (AUC) = 0.87 for F234, 0.92 for F34, and 0.90 for F4. Conclusion. HA, APRI, FibroTest, Fib-4, and TE reliably distinguish non-cirrhotic and cirrhotic patients. Except for MBT, all tests discriminate between mild and moderate fibrosis. As single tests: FibroTest, Fib-4, and TE were the most accurate for detecting early fibrosis; combining different non-invasive tests increased the accuracy for detection of liver fibrosis to such an extent and thus might be acceptable to replace liver biopsy.     

Sequential algorithms combining non-invasive markers and biopsy for the assessment of liver fibrosis in chronic hepatitis B

AIM： To assess the performance of several noninvasive markers and of our recently proposed stepwise combination algorithms to diagnose significant fibrosis （F ≥ 2 by METAVIR） and cirrhosis （F4 by METAVIR） in chronic hepatitis B （CHB）.
METHODS： One hundred and ten consecutive patients （80 males, 30 females, mean age： 42.6 ± 11.3） with CHB undergoing diagnostic liver biopsy were included. AST-to-Platelet ratio （APRI）, Forns＇ index, AST-to-ALT Ratio, Goteborg University Cirrhosis Index （GUCD, Hui＇s model and Fibrotest were measured on the day of liver biopsy. The performance of these methods and of sequential algorithms combining Fibrotest, APRI and biopsy was defined by positive （PPV） and negative （NPV） predictive values, accuracy and area under the curve （AUC）.
RESULTS： PPV for significant fibrosis was excellent （100%） with Forns and high （〉 92%） with APR1, GUCI, Fibrotest and Hui. However, significant fibrosis could not be excluded by any marker （NPV 〈 65%）. Fibretest had the best PPV and NPV for cirrhosis （87% and 90%, respectively）. Fibrotest showed the best AUC for both significant fibrosis and cirrhosis （0.85 and 0.76, respectively）. Stepwise combination algorithms of APR1, Fibrotest and biopsy showed excellent performance （0.96 AUC, 100% NPV） for significant fibrosis and 0.95 AUC, 98% NPV for cirrhosis, with 50%-80% reduced need for liver biopsy.
CONCLUSION： In CHB sequential combination of APRI, Fibrotest and liver biopsy greatly improves the diagnostic performance of the single non-invasive markers. Need for liver biopsy is reduced by 50%-80% but cannot be completely avoided. Non-invasive markers and biopsy should be considered as agonists and not antagonists towards the common goal of estimating liver fibrosis.     

Evaluation of a panel of non-invasive serum markers to differentiate mild from moderate-to-advanced liver fibrosis in chronic hepatitis C patients

BACKGROUND/AIMS: In chronic hepatitis C (CHC) infection, a liver biopsy provides important information that guides treatment decisions, but is invasive, expensive and associated with possible complications. Extracellular matrix remodeling proteins may be useful non-invasive markers of fibrosis. The aim of this study was to evaluate the diagnostic accuracy of a panel of these markers in CHC patients, develop a predictive algorithm that differentiates no/mild (METAVIR F0-F1) from moderate/severe (F2-F4) fibrosis, and validate the model in external cohorts. METHODS: A combination of matrix markers were initially evaluated and optimized in 294 CHC patients from a single center, and validated in an external cohort of 402 patients. RESULTS: Hyaluronic acid, TIMP-1 and alpha2-macroglobulin were selected as having the best predictive accuracy for F2-F4 fibrosis (combined AUROC = 0.831). At an index cut-off >0.36 and prevalence for F2-F4 of 52%, results in all 696 patients indicated positive and negative predictive values of 74.3 and 75.8% with an accuracy of 75%. CONCLUSIONS: The three-marker panel may reliably differentiate CHC patients with moderate/severe fibrosis from those with no/mild fibrosis, although accurate delineation between stages was not possible. Prospective studies are required to determine the potential utility of the marker panel in guiding treatment decisions and following disease progression.     

Evaluation of non-invasive fibrosis indices in Mexican patients with chronic hepatitis C

Background: Among the many methods proposed to predict the presence of fibrosis in patients with chronic hepatitis C are the indices models obtained from serum biochemical tests, the aspartate aminotransferase-toplatelet ratio index (APRI) and the Forns index (FI). Objective: To compare the diagnostic accuracy of the Forns index and APRI for predicting cirrhosis. Methods: We included 105 patients with chronic hepatitis C and a liver biopsy. The FI and APRI were calculated from the biochemical tests of each patient. Receivers operating characteristic (ROC) curves were calculated to determine the best cutoff to discriminate between cirrhosis (F4), advanced fibrosis (F3-F4), and portal fibrosis (F1) according to the Knodell score. Diagnostic accuracy was assessed by obtaining sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) for each of the indices. Results: ROC curves showed that the best cutoff for predicting cirrhosis (F4) for the FI is >7.64, with Sn 62.5% and Sp 91.8% (Area under the curve, AUC = 0.881), for advanced fibrosis (F3 - F4) the best cutoff value is >6.93 with Sn 42.9% and Sp 89.6% (AUC = 0.772). An APRI value of >1.74 was the best predictor for F4 with Sn 75% and Sp 82% (AUC = 0.799), and a cutoff value of >1.7 for predicting F3-F4 with Sn 47.6% and Sp 85.4% (AUC = 0.768). Conclusions: The results confirm the utility of both the FI and APRI for predicting advanced fibrosis and cirrhosis.     

Fibro-check: a combination of direct and indirect markers for liver fibrosis staging in chronic hepatitis C patients

Background and rationale for the study. The assessment of liver fibrosis provides useful information not only for diagnosis but also for therapeutic decision. This study was concerned with determining the levels of collagen III and its degrading enzyme matrix metalloproteinase-1 (MMP-1) as direct and complementary markers for liver fibrosis staging.Results. A total of 269 chronic hepatitis C patients constituted this study. Western blotting was used for identifying collagen III and MMP-1 in serum samples. As a result, collagen III and MMP-1 were identified, respectively, at 70 and 245 kDa using their respective mono-specific antibodies. These two markers were quantified in sera of patients using ELISA. Next, Fibro-check was constructed combining collagen III and MMP-1 together with other indirect markers which reflect alteration in hepatic functions that proved useful to stage liver fibrosis. Fibro-check produced area under the receiver-operating characteristic curve (AUC) 0.91 and 0.83 for significant (F2-F4) and cirrhosis (F4), respectively. Additionally, we estimated the performance of Fibro-check in comparison with aspartate to platelet ratio index (APRI) and fibrosis index. Fibro-check seems to be more efficient than both of them. Fibro-check was then applied to the validation study to test its accuracy and reproducibility showing AUCs 0.90 for F2-F4 and 0.86 for F4.Conclusions. Fibro-check combining ‘direct’ and ‘indirect’ markers using a mathematical formula may improve the staging of liver fibrosis with a high degree of accuracy and seems more efficient than APRI and Fibrosis index in this group of Egyptian patients.     

Successful treatment with telaprevir‐based regimens for chronic hepatitis C results in significant improvements to serum markers of liver fibrosis

Patients infected with hepatitis C virus (HCV) have differing levels of liver health when they initiate treatment. We sought to quantify whether liver health improves following successful treatment with telaprevir‐based antiviral regimens. We performed a retrospective analysis of data generated from one Phase 2 and two Phase 3 telaprevir clinical studies. 1208 patients treated with a telaprevir‐based regimen were included in the analysis. Patients were grouped according to their baseline Metavir score (F0–F1, F2 and F3–F4) and whether or not they attained sustained virologic response (SVR). Scores from four biomarker tests, FibroTest, APRI, FIB‐4 and Forns' Score, were monitored both before and after HCV treatment. All four of these tests differentiated the fibrosis stage as determined by Metavir score at baseline. Consistent with previous studies, patients who attained SVR exhibited significant improvements in scores from each of these tests after treatment. These improvements remained significant even when patients were grouped according to their baseline Metavir score. On average, the scores from different tests exhibited differential improvements following SVR. Improvements in APRI scores corresponded to complete fibrosis regression (i.e. a Metavir stage of F0‐F1). In contrast, improvements in scores from Forns' Score, FIB‐4 and FibroTest were more modest (i.e. fibrosis regression of less than a Metavir stage). Overall, these results demonstrated that attaining SVR with a telaprevir‐based regimen led to significant improvements in liver health as determined by four biomarker tests. However, not all correlations observed between noninvasive markers and fibrosis stage at baseline hold after SVR is attained.     

A simple approach to noninvasively identifying significant fibrosis in chronic hepatitis C patients in clinical practice

BACKGROUND: Identification of the presence of significant fibrosis is an important part of the diagnostic work-up of patients with chronic hepatitis C (CHC). AIM: To evaluate the performance of the aspartate to alanine aminotransferase ratio (AST/ALT ratio) and platelet count in reducing the number of liver biopsies and diagnosing the presence/absence of significant fibrosis in a large cohort of patients with CHC seen at 2 tertiary referral centers. METHODS: Liver biopsies of 409 patients with CHC were evaluated. Staging was carried out by means of the Ishak and METAVIR scores in the Italian and US series, respectively. Prevalence of significant fibrosis was 43%. Receiver operating characteristic curves were used to identify AST/ALT ratio and platelet count cutoffs with the highest accuracy for the diagnosis of significant fibrosis. These cutoffs were used to devise a diagnostic algorithm for reducing the number of liver biopsies and diagnosing/ruling out significant fibrosis. RESULTS: AST/ALT ratios increased and platelet counts decreased as liver fibrosis worsened. Both AST/ALT ratio (c-index=0.747) and platelet count (c-index=0.733) had high accuracy for the diagnosis of significant fibrosis. The use of AST/ALT ratio and platelet count cutoffs in a diagnostic algorithm would have avoided liver biopsy in 68.9% of the patients and would have correctly identified the absence/presence of significant fibrosis in 80.5% of these cases. CONCLUSIONS: In clinical practice, the use of simple, reproducible, and inexpensive parameters such as the AST/ALT ratio and platelet count can reduce the need for liver biopsy in a substantial proportion of patients with CHC.     

综合预测模型FibroTest对慢性乙型肝炎肝纤维化的诊断价值

目的探讨综合预测模型FibroTest对慢性乙型肝炎肝纤维化的诊断价值。方法留取2002年8月至2005年12月北京大学第一医院、安阳市第五人民医院和无锡市传染病医院的123例行肝活检的慢性乙型肝炎患者的血清,检测α2-巨球蛋白、结合珠蛋白、载脂蛋白-AⅠ、记录总胆红素和谷氨酰转肽酶的数值,并根据其结果结合患者的年龄和性别计算出FibroTest的数值。根据肝纤维化分期设定3个判定点,分别为显著纤维化(S2~S4期),严重纤维化(S3~S4期)和肝硬化(S4期)。以肝活检病理结果为金标准绘制出FibroTest的受试者工作特征曲线,计算曲线下面积(AUC),并与用天冬氨酸转氨酶-血小板比值指数(APRI)计算出的AUC进行比较,评价其对慢性乙型肝炎肝硬化的诊断价值。结果123例肝活检患者中S0期25例(20.3%);S1期27例(22.0%);S2期31例(25.2%);S3期29例(23.6%);S4期11例(8.9%),即显著纤维化者(S2~S4期)71例(57.7%),严重纤维化者(S3~S4期)40例(32.5%),肝硬化者(S4期)11例(8.9%)。FibroTest对3个判定点的AUC值分别为0.814(95%CI:0.740~0.888,P<0.01),0.824(95%CI:0.749~0.898,P<0.01),0.723(95%CI:0.575~0.870,P=0.015)。而APRI对3种不同程度肝纤维化的AUC值分别为0.715(95%CI:0.625~0.805,P=0.001),0.725(95%CI:0.631~0.818,P=0.002)和0.646(95%CI:0.497~0.795,P>0.05)。结论Fi-broTest可以准确地估计慢性乙型肝炎患者有无显著纤维化,可使45.5%的患者避免进行肝脏活检,并保证87.5%的诊断准确率。     

Concordance of non-invasive mechanical and serum tests for liver fibrosis evaluation in chronic hepatitis C

AIM To determine the sensitivity and specificity of liver stiffness measurement(LSM) and serum markers(SM) for liver fibrosis evaluation in chronic hepatitis C.METHODS Between 2012 and 2014,81 consecutive hepatitis C virus(HCV) patients had METAVIR score from liver biopsy compared with concurrent results from LSM [transient elastography(TE) [FibroS can~/ARFI technology(Virtual Touch~)] and SM [FIB-4/aspartate aminotransferase-toplatelet ratio index(APRI)].The diagnostic performance of these tests was assessed using receiver operating characteristic curves.The optimal cut-off levels of each test were chosen to define fibrosis stages F ≥ 2,F ≥ 3 and F = 4.The Kappa index set the concordance analysis.RESULTS Fifty point six percent were female and the median age was 51 years(30-78).Fifty-six patients(70%) weretreatment-na?ve.The optimal cut-off values for predicting F ≥ 2 stage fibrosis assessed by TE were 6.6 kP a,for acoustic radiation force impulse(ARFI) 1.22 m/s,for APRI 0.75 and for FIB-4 1.47.For F ≥ 3 TE was 8.9 kP a,ARFI was 1.48 m/s,APRI was 0.75,and FIB-4 was 2.For F = 4,TE was 12.2 kP a,ARFI was 1.77 m/s,APRI was 1.46,and FIB-4 was 3.91.The APRI could not distinguish between F2 and F3,P = 0.92.The negative predictive value for F = 4 for TE and ARFI was 100%.Kappa index values for F ≥ 3 METAVIR score for TE,ARFI and FIB-4 were 0.687,0.606 and 0.654,respectively.This demonstrates strong concordance between all three screening methods,and moderate to strong concordance between them and APRI(Kappa index = 0.507).CONCLUSION Given the costs and accessibility of LSM methods,and the similarity with the outcomes of SM,we suggest that FIB-4 as well as TE and ARFI may be useful indicators of the degree of liver fibrosis.This is of particular importance to developing countries.     

Non-invasive markers for the prediction of fibrosis in chronic hepatitis C infection.

Liver fibrosis occurs as a result of chronic liver injury and is the hallmark of chronic liver disease. The final stage of progressive liver fibrosis is cirrhosis, which is implicated in portal hypertension, end-stage liver disease and hepatocellular carcinoma. Liver biopsy has historically been the gold standard test for the assessment of liver fibrosis for liver diseases such as viral hepatitis, autoimmune hepatitis and primary biliary cirrhosis. Improved serological tests have enhanced the diagnosis of these conditions and reduced the need for liver biopsy. Liver biopsy is unpopular among patients and clinicians. It is associated with morbidity and mortality, and in addition is subject to sampling error, inter- and intra-observer variability. There is therefore a need for non-invasive markers of liver fibrosis that are accurate, reliable, cheap and easy to use. The aim of this review is to examine the different non-invasive methods that can be used to estimate the severity of fibrosis. The methods evaluated include clinical examination, routine laboratory investigations, imaging tests, specialized tests of liver function and finally serum extra-cellular matrix markers of fibrosis. The review mainly focuses on fibrogenesis in the context of chronic hepatitis C infection.