Chronic hepatitis C infection — Noninvasive assessment of liver fibrosis in the era of direct acting antivirals

Significant advancements in the diagnosis and treatment of chronic hepatitis C infection and its associated fibrosis have revolutionized treatment of these patients over the last several years. Liver biopsy, the gold standard diagnostic method for evaluating liver fibrosis level, was routinely used prior to initiation of hepatitis C therapy, placing patients at an inherent risk of adverse events. The recent advent of noninvasive serologic and nonserologic measures of hepatic fibrosis level has reduced the need for liver biopsy significantly, thereby minimizing its associated risks. These noninvasive methods have been extensively studied in the era of interferon therapies and are increasingly recognized in the realm of direct acting antiviral agents as well. Their validation of use after having achieved a sustained virologic response is yet to occur, but the future remains promising.This review focuses on the various non-invasive diagnostic modalities of liver fibrosis and discusses how they can be applied to the care of patients undergoing direct acting antiviral therapy for hepatitis C. In the constantly evolving landscape of hepatitis C therapy, the review underscores the important prognostic value of fibrosis staging prior to HCV treatment and suggests potential uses for non-invasive fibrosis assessment following successful HCV eradication.     

Biomarkers of Fibrosis and Fibrosis Progression in Chronic Hepatitis C

The majority of patients exposed to the hepatitis C virus develop chronic infection. The morbidity and mortality associated with chronic hepatitis C (CHC) is a consequence of progressive liver fibrosis, leading to cirrhosis, decompensated liver disease and hepatocellular carcinoma. As fibrosis is the key determinant of prognosis and influences treatment decisions and enrolment in surveillance programs, accurate assessment of fibrosis is crucial in the management of CHC. Currently liver biopsy is the ??gold standard?? for fibrosis assessment, but has a number of limitations including morbidity and mortality, sampling error and inter/intra-observer variability. The identification of non-invasive biomarkers of fibrosis has expanded rapidly over the last 10?years, providing an attractive alternative to liver biopsy. This article will review non-invasive biomarkers (serum biochemistry, imaging-based and genetic) for the assessment of fibrosis and fibrosis progression in CHC.     

Checkmate to liver biopsy in chronic hepatitis C?

Liver biopsy (LB) has traditionally been considered the gold standard for pretreatment evaluation of liver fibrosis in patients with chronic hepatitis C (CHC). However, LB is an invasive procedure with several shortcomings (intra- and interobserver variability of histopathological interpretation, sampling errors, high cost) and the risk of rare but potentially life-threatening complications. In addition, LB is poorly accepted by patients and it is not suitable for repeated evaluation. Furthermore, the prevalence of CHC makes LB unrealistic to be performed in all patients with this disease who are candidates for antiviral therapy. The above-mentioned drawbacks of LB have led to the development of noninvasive methods for the assessment of liver fibrosis. Several noninvasive methods, ranging from serum marker assays to advanced imaging techniques, have proved to be excellent tools for the evaluation of liver fibrosis in patients with CHC, whereas the value of LB as a gold standard for staging fibrosis prior to antiviral therapy has become questionable for clinicians. Despite significant resistance from those in favor of LB, noninvasive methods for pretreatment assessment of liver fibrosis in patients with CHC have become part of routine clinical practice. With protease inhibitors-based triple therapy already available and substantial improvement in sustained virological response, the time has come to move forward to noninvasiveness, with no risks for the patient and, thus, no need for LB in the assessment of liver fibrosis in the decision making for antiviral therapy in CHC.     

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.     

Non-invasive assessment of liver fibrosis in chronic liver diseases： Implementation in clinical practice and decisional algorithms

Chronic hepatitis B and C together with alcoholic and non-alcoholic fatty liver diseases represent the major causes of progressive liver disease that can eventually evolve into cirrhosis and its end-stage complications, including decompensation, bleeding and liver cancer. Formation and accumulation of fibrosis in the liver is the common pathway that leads to an evolutive liver disease. Precise definition of liver fibrosis stage is essential for management of the patient in clinical practice since the presence of bridging fibrosis represents a strong indication for antiviral therapy for chronic viral hepatitis, while cirrhosis requires a specific follow-up including screening for esophageal varices and hepatocellular carcinoma. Liver biopsy has always represented the standard of reference for assessment of hepatic fibrosis but it has some limitations being invasive, costly and prone to sampling errors. Recently blood markers and instrumental methods have been proposed for the non-invasive assessment of liver fibrosis. However, there are still some doubts as to their implementation in clinical practice and a real consensus on how and when to use them is not still available. This is due to an unsatisfactory accuracy for some of them,and to an incomplete validation for others. Some studies suggest that performance of non-invasive methods for liver fibrosis assessment may increase when they are combined. Combination algorithms of non-invasive methods for assessing liver fibrosis may represent a rational and reliable approach to implement non-invasive assessment of liver fibrosis in clinical practice and to reduce rather than abolish liver biopsies.     

Staging Fibrosis in Chronic Viral Hepatitis

Staging fibrosis accurately has always been a challenge in viral hepatitis and other liver diseases. Liver biopsy is an imperfect gold standard due to its intra and interobserver agreement limitations and additional characteristics such as its safety and cost. Hence, non-invasive tests have been developed to stage liver fibrosis. In addition to serological biomarkers, physical tests with reasonable accuracy are available and adopted in the daily clinic regarding viral hepatitis fibrosis staging. In this review, we discuss the published data regarding the staging of liver fibrosis in chronic hepatitis B and C, emphasizing non-invasive markers of fibrosis, both serological and physical. Moreover, we also discuss a persistent central gap, the evaluation of liver fibrosis after HCV cure.     

Is liver biopsy still needed in children with chronic viral hepatitis?

Liver biopsy is a standard method used for obtaining liver tissue for histopathological evaluation. Since reliable serological and virological tests are currently available, liver biopsy is no longer needed for the etiological diagnosis of chronic hepatitis B and C. However, liver histology remains the gold standard as a prognostic tool, providing information about the liver disease progression(grading of necroinflammatory activity and staging of fibrosis) and serving clinicians in the management and therapeutic decisions. In general, histopathological evaluation is indicated before starting the antiviral treatment. Main limitations of the liver biopsy include its invasive and painful procedure, sampling errors and the inter- and intra-observer variability. In addition, indications for the liver biopsy in pediatric patients with chronic viral hepatitis were questioned recently, and efforts have been made toward the development of non-invasive methods as an alternative to the liver biopsy. The most commonly used methods are novel imaging studies(elastography) and combinations of biomarkers. However, to date, none of these tests was validated in children with chronic viral hepatitis. In this review, we present the current status of the liver biopsy in the management of chronic viral hepatitis B and C in pediatric population, including specific indications, complications, contraindications, problems, limitations, and alternative non-invasive methods.     

Hepatitis delta virus: Disease assessment and stratification

Hepatitis D virus (HDV) causes one of the most severe forms of hepatitis in people with chronic hepatitis B (CHB) infection. Timely and accurate assessment of hepatitis delta virus (HDV) and disease stratification is mandatory for thorough pre-therapeutic evaluation for prioritizing treatment and outcome prediction. Viral biomarkers associated with HDV and hepatitis B virus (HBV) are crucial to aid in diagnosis, and monitoring of serum viral nucleic acids for both viruses is recommended. Liver biopsy remains the gold standard for staging of liver fibrosis and grading of histological activity and should remain central for diagnostic purposes, but is also of importance for research to enhance our understanding of HDV. The emergence of novel non-invasive tests for the assessment of liver fibrosis in HDV patients coupled with the well-recognized potential complications of liver biopsy has resulted in reduced utility of liver biopsy in clinical practice. Preliminary data suggest that these emerging non-invasive modalities appear to be reliable, and their use is supported, similar to other viral hepatitis. Nevertheless, further validation is required before their widespread adoption into clinical practice.     

Chronic hepatitis C virus infection:Serum biomarkers in predicting liver damage

Currently, a major clinical challenge in the management of the increasing number of hepatitis C virus(HCV) infected patients is determining the best means for evaluating liver impairment. Prognosis and treatment of chronic hepatitis C(CHC) are partly dependent on the assessment of histological activity, namely cell necrosis and inflammation, and the degree of liver fibrosis. These parameters can be provided by liver biopsy; however, in addition to the risks related to an invasive procedure, liver biopsy has been associated with sampling error mostly due to suboptimal biopsy size. To avoid these pitfalls, several markers have been proposed as non-invasive alternatives for the diagnosis of liver damage. Distinct approaches among the currently available non-invasive methods are(1) the physical ones based on imaging techniques; and(2) the biological ones based on serum biomarkers. In this review, we discuss these approaches with special focus on currently available non-invasive serum markers. We will discuss:(1) class?Ⅰ?serum biomarkers individually and as combined panels, particularly those that mirror the metabolism of liver extracellular matrix turnover and/or fibrogenic cell changes;(2) class Ⅱ biomarkers that are indirect serum markers and are based on the evaluation of common functional alterations in the liver; and(3) biomarkers of liver cell death, since hepatocyte apoptosis plays a significant role in the pathogenesis of HCV infection. We highlight in this review the evidence behind the use of these markers and assess the diagnostic accuracy as well as advantages, limitations, and application in clinical practice of each test for predicting liver damage in CHC.     

Noninvasive assessment of liver fibrosis in patients with chronic hepatitis B

Infection with hepatitis B virus is an important healthproblem worldwide:it affects more than 350 millionpeople and is a leading cause of liver-related morbidity,accounting for 1 million deaths annually.Hepatic fibrosis is a consequence of the accumulation of extracellular matrix components in the liver.An accurate diagnosis of liver fibrosis is essential for the management of chronic liver disease.Liver biopsy has been considered the gold standard for diagnosing disease,grading necroinflammatory activity,and staging fibrosis.However,liver biopsy is unsuitable for repeated evaluations because it is invasive and can cause major complications,including death.Several noninvasive evaluations have been introduced for the assessment of liver fibrosis:serum biomarkers,combined indices or scores,and imaging techniques including transient elastography,acoustic radiation force impulse,real-time tissue elastography,and magnetic resonance elastography.Here,we review the recent progress of noninvasive assessment of liver fibrosis in patients with chronic hepatitis B.Most noninvasive evaluations for liver fibrosis have been validated first in patients with chronic hepatitis C,and later in those with chronic hepatitis B.The establishment of a noninvasive assessment of liver fibrosis is urgently needed to aid in the management of this leading cause of chronic liver disease.     

Non-invasive diagnosis of hepatitis B virus-related cirrhosis

Chronic hepatitis B(CHB)infection is a major public health problem associated with significant morbidity and mortality worldwide.Twenty-three percent of patients with CHB progress naturally to liver cirrhosis,which was earlier thought to be irreversible.However,it is now known that cirrhosis can in fact be reversed by treatment with oral anti-nucleotide drugs.Thus,early and accurate diagnosis of cirrhosis is important to allow an appropriate treatment strategy to be chosen and to predict the prognosis of patients with CHB.Liver biopsy is the reference standard for assessment of liver fibrosis.However,the method is invasive,and is associated with pain and complications that can be fatal.In addition,intra-and inter-observer variability compromises the accuracy of liver biopsy data.Only small tissue samples are obtained and fibrosis is heterogeneous in such samples.This confounds the two types of observer variability mentioned above.Such limitations have encouraged development of non-invasive methods for assessment of fibrosis.These include measurements of serum biomarkers of fibrosis;and assessment of liver stiffness via transient elastography,acoustic radiation force impulse imaging,real-time elastography,or magnetic resonance elastography.Although significant advances have been made,most work to date has addressed the diagnostic utility of these techniques in the context of cirrhosis caused by chronic hepatitis C infection.In the present review,we examine the advantages afforded by use of non-invasive methods to diagnose cirrhosis in patients with CHB infections and the utility of such methods in clinical practice.     

Non invasive fibrosis biomarkers reduce but not substitute the need for liver biopsy

Chronic liver diseases are very common worldwide, particularly those linked to viral hepatitis and to alcoholic and non-alcoholic fatty liver. Their natural history is variable and long-term evolution differs in individual patients. Optimised clinical management of compensated chronic liver diseases requires precise definition of the stage of liver fibrosis, the main determinant of prognosis and of most therapeutic decisions. Liver biopsy is the gold standard for assessment of hepatic fibrosis. However, it is invasive with possible complications, costly and prone to sampling errors. Many non-invasive markers of liver fibrosis have been recently proposed and assessed in the clinical setting as surrogates of liver biopsy. Direct markers are based on biochemical parameters directly linked to fibrogenesis while indirect markers use simple or more sophisticated parameters that correlate with liver fibrosis stages. Non-invasive markers of liver fibrosis have been tested in different forms of chronic liver disease and showed variable diagnostic performance, but accuracy rarely was above 75%-80%. Better results were obtained when markers were combined. On this line, we have recently proposed a set of algorithms that combine sequentially indirect non-invasive markers of liver fibrosis, reaching 90%-95% diagnostic accuracy with significant reduction in the need for liver biopsy. Based on available evidence, it can be anticipated that non-invasive markers of liver fibrosis and their combined use will soon become a most useful tool in the clinical management of many forms of chronic liver disease. However, their implementation is expected to reduce, but not to completely eliminate, the need for liver biopsy.     

AST to platelet ratio index (APRI) for the noninvasive evaluation of liver fibrosis: Original Article

Liver biopsy is the recognized gold standard for liver fibrosis staging. The aspartate aminotransferase to platelet ratio index (APRI) has been proposed as a noninvasive and readily available tool for the assessment of liver fibrosis in chronic hepatitis C (CHC). This study aimed to validate, in a Mexican tertiary health care setting, the diagnostic usefulness of APRI in CHC, nonalcoholic fatty liver disease (NAFLD) and autoimmune hepatitis (AIH). In an observational, cross-sectional, comparative and retrolective fashion, consecutive patients with CHC, NAFLD or AIH were evaluated. Fibrosis was staged using the METAVIR scale. Receiver operating characteristic ROC curves were constructed for significant fibrosis, advanced fibrosis and cirrhosis. One-hundred-sixty-four CHC, 30 NAFLD and 42 AIH patients were evaluated. For the diagnosis of significant fibrosis, APRI values delimited an area under de ROC curve (AUC) of 0.776 in CHC, 0.564 in NAFLD, and 0.602 in AIH patients. For advanced fibrosis, the AUCs were 0.803, 0.568 and 0.532 in CHC, NAFLD and AIH patients, respectively. For cirrhosis, AUCs were 0.830 and 0.599 in CHC and AIH patients. In conclusion, APRI can be a useful noninvasive alternative for the diagnosis of significant fibrosis and cirrhosis in our CHC patients. APRI values of ≤ 0.3 and ≤ 0.5 rule out significant fibrosis and cirrhosis, and a value of ≥ 1.5 rules in significant fibrosis. In patients with NAFLD, APRI values tend to increase with the degree of fibrosis, suggesting that it could be useful in this disease. APRI appears to be of no value in patients with AIH.     

miRNAs as Potential Biomarkers for Viral Hepatitis B and C

Around 257 million people are living with hepatitis B virus (HBV) chronic infection and 71 million with hepatitis C virus (HCV) chronic infection. Both HBV and HCV infections can lead to liver complications such as cirrhosis and hepatocellular carcinoma (HCC). To take care of these chronically infected patients, one strategy is to diagnose the early stage of fibrosis in order to treat them as soon as possible to decrease the risk of HCC development. microRNAs (or miRNAs) are small non-coding RNAs which regulate many cellular processes in metazoans. Their expressions were frequently modulated by up- or down-regulation during fibrosis progression. In the serum of patients with HBV chronic infection (CHB), miR-122 and miR-185 expressions are increased, while miR-29, -143, -21 and miR-223 expressions are decreased during fibrosis progression. In the serum of patients with HCV chronic infection (CHC), miR-143 and miR-223 expressions are increased, while miR-122 expression is decreased during fibrosis progression. This review aims to summarize current knowledge of principal miRNAs modulation involved in fibrosis progression during chronic hepatitis B/C infections. Furthermore, we also discuss the potential use of miRNAs as non-invasive biomarkers to diagnose fibrosis with the intention of prioritizing patients with advanced fibrosis for treatment and surveillance.     

Non-invasive diagnosis of liver fibrosis in chronic hepatitis C

Assessment of liver fibrosis in chronic hepatitis C virus(HCV)infection is considered a relevant part of patient care and key for decision making.Although liver biopsy has been considered the gold standard for staging liver fibrosis,it is an invasive technique and subject to sampling errors and significant intra-and inter-observer variability.Over the last decade,several noninvasive markers were proposed for liver fibrosis diagnosis in chronic HCV infection,with variable performance.Besides the clear advantage of being noninvasive,a more objective interpretation of test results may overcome the mentioned intra-and inter-observer variability of liver biopsy.In addition,these tests can theoretically offer a more accurate view of fibrogenic events occurring in the entire liver with the advantage of providing frequent fibrosis evaluation without additional risk.However,in general,these tests show low accuracy in discriminating between intermediate stages of fibrosis and may be influenced by several hepatic and extrahepatic conditions.These methods are either serum markers(usually combined in a mathematical model)or imaging modalities that can be used separately or combined in algorithms to improve accuracy.In this review we will discuss the different noninvasive methods that are currently available for the evaluation of liver fibrosis in chronic hepatitis C,their advantages,limitations and application in clinical practice.     

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.     

瞬时弹性成像在肝纤维化无创性诊断中的应用

肝组织活检是目前肝纤维化疾病诊断的金指标,但具有局限性。近年来,无创性诊断方法的确立已成为国内外学者关注的热点。目前临床常用多种血清纤维化指标进行肝纤维化的评价,但其敏感性和特异性尚无法令人满意。国外研制出瞬时弹性测定的方法用于肝纤维化评估,此文对FibroScan在肝纤维化无创性诊断的研究进展进行综述。     

Prediction of liver fibrosis in human immunodeficiency virus/hepatitis C virus coinfected patients by simple non-invasive indexes

BACKGROUND: Liver biopsy is an invasive technique with associated major complications. There is no information on the validity of five non-invasive indexes based on routinely available parameters, estimated and validated in hepatitis C virus (HCV) monoinfected patients, in human immunodeficiency virus (HIV)/HCV coinfected patients. AIM: To validate these predictive models of liver fibrosis in HIV/HCV coinfected patients. PATIENTS: A total of 357 (90%) of 398 patients from five hospitals were investigated, who underwent liver biopsy and who had complete data to validate all of the models considered. METHODS: The predictive accuracy of the indexes was tested by measuring areas under the receiver operating characteristic curves. Diagnostic accuracy was calculated by estimating sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values. RESULTS: The models performed better when liver biopsies>or=15 mm were used as reference. In this setting, the Forns and Wai indexes, models aimed at discriminating significant fibrosis, showed PPV of 94% and 87%, respectively. Using these models, 27-34% of patients could benefit from exclusion of liver biopsy. If both models were applied sequentially, 41% of liver biopsies could be spared. The indexes aimed at predicting cirrhosis achieved NPV of up to 100%. However, they showed very low PPV. CONCLUSIONS: The diagnostic accuracy of these models was lower in HIV/HCV coinfected patients than in the validation studies performed in HCV monoinfected patients. However, simple fibrosis tests may render liver biopsy unnecessary in deciding anti-HCV treatment in over one third of patients with HIV infection and chronic hepatitis C.     

Transient elastography for liver fibrosis diagnosis

Liver biopsy is considered the “golden standard” for assessment of hepatic fibrosis. However, the procedure has limitations because of inconvenience and rare but serious complications as bleeding. Furthermore, sampling errors are frequent, and interobserver variability often poses problems.Recently, a modified ultrasound scanner (transient elastography) has been developed to assess fibrosis. The device measures liver elasticity, which correlates well with the degree of fibrosis. Studies have shown that transient elastography is more accurate in diagnosing cirrhosis than minor to moderate fibrosis. Most of the studies have been conducted on patients with chronic hepatitis but a few studies have also covered fibrosis and cirrhosis due to other etiologies, and they also demonstrate the high sensitivity and specificity. Transient elastography for assessment of fibrosis may turn out to be a valuable diagnostic procedure and follow-up of patients with chronic liver diseases.