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Patel K, Asrani SK, Fiel MI, Levine D, Leung DH, Duarte-Rojo A, Dranoff JA, Nayfeh T, Hasan B, Taddei TH, Alsawaf Y, Saadi S, Majzoub AM, Manolopoulos A, Alzuabi M, Ding J, Sofiyeva N, Murad MH, Alsawas M, Rockey DC, Sterling RK. Accuracy of blood-based biomarkers for staging liver fibrosis in chronic liver disease: A systematic review supporting the AASLD Practice Guideline. Hepatology 2025; 81:358-379. [PMID: 38489517 DOI: 10.1097/hep.0000000000000842] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 02/19/2024] [Indexed: 03/17/2024]
Abstract
BACKGROUND AND AIMS Blood-based biomarkers have been proposed as an alternative to liver biopsy for noninvasive liver disease assessment in chronic liver disease. Our aims for this systematic review were to evaluate the diagnostic utility of selected blood-based tests either alone, or in combination, for identifying significant fibrosis (F2-4), advanced fibrosis (F3-4), and cirrhosis (F4), as compared to biopsy in chronic liver disease. APPROACH AND RESULTS We included a comprehensive search of databases including Ovid MEDLINE(R), EMBASE, Cochrane Database, and Scopus through to April 2022. Two independent reviewers selected 286 studies with 103,162 patients. The most frequently identified studies included the simple aspartate aminotransferase-to-platelet ratio index and fibrosis (FIB)-4 markers (with low-to-moderate risk of bias) in HBV and HCV, HIV-HCV/HBV coinfection, and NAFLD. Positive (LR+) and negative (LR-) likelihood ratios across direct and indirect biomarker tests for HCV and HBV for F2-4, F3-4, or F4 were 1.66-6.25 and 0.23-0.80, 1.89-5.24 and 0.12-0.64, and 1.32-7.15 and 0.15-0.86, respectively; LR+ and LR- for NAFLD F2-4, F3-4, and F4 were 2.65-3.37 and 0.37-0.39, 2.25-6.76 and 0.07-0.87, and 3.90 and 0.15, respectively. Overall, the proportional odds ratio indicated FIB-4 <1.45 was better than aspartate aminotransferase-to-platelet ratio index <0.5 for F2-4. FIB-4 >3.25 was also better than aspartate aminotransferase-to-platelet ratio index >1.5 for F3-4 and F4. There was limited data for combined tests. CONCLUSIONS Blood-based biomarkers are associated with small-to-moderate change in pretest probability for diagnosing F2-4, F3-4, and F4 in viral hepatitis, HIV-HCV coinfection, and NAFLD, with limited comparative or combination studies for other chronic liver diseases.
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Affiliation(s)
- Keyur Patel
- Department of Medcine, Division of Gastroenterology and Hepatology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Sumeet K Asrani
- Department of Medicine, Division of Hepatology, Baylor University Medical Center, Dallas, Texas, USA
| | - Maria Isabel Fiel
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Deborah Levine
- Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Daniel H Leung
- Department of Pediatrics, Baylor College of Medicine and Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Hospital, Houston, Texas, USA
| | - Andres Duarte-Rojo
- Division of Gastroenterology and Hepatology, Northwestern Medicine and Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Jonathan A Dranoff
- Yale School of Medicine, Department of Internal Medicine, Section of Digestive Diseases, New Haven, Connecticut, USA
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Tarek Nayfeh
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Bashar Hasan
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Tamar H Taddei
- Yale School of Medicine, Department of Internal Medicine, Section of Digestive Diseases, New Haven, Connecticut, USA
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Yahya Alsawaf
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Samer Saadi
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | | | | | - Muayad Alzuabi
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Jingyi Ding
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Nigar Sofiyeva
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Mohammad H Murad
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Mouaz Alsawas
- Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
- Department of Medicine, Section of Hepatology, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Don C Rockey
- Department of Medicine, Digestive Disease Research Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Richard K Sterling
- Department of Medicine, Section of Hepatology, Virginia Commonwealth University, Richmond, Virginia, USA
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Nallagangula KS, Nagaraj SK, Venkataswamy L, Chandrappa M. Liver fibrosis: a compilation on the biomarkers status and their significance during disease progression. Future Sci OA 2018; 4:FSO250. [PMID: 29255622 PMCID: PMC5729599 DOI: 10.4155/fsoa-2017-0083] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 09/06/2017] [Indexed: 02/08/2023] Open
Abstract
Liver fibrosis occurs in response to different etiologies of chronic liver injury. Diagnosing degree of liver fibrosis is a crucial step in evaluation of severity of the disease. An invasive liver biopsy is the gold standard method associated with pain and complications. Biomarkers to detect liver fibrosis include direct markers of extracellular matrix turnover and indirect markers as a reflection of liver dysfunction. Although a single marker may not be useful for successful management, a mathematical equation combining tests might be effective. The main purpose of this review is to understand the diagnostic accuracy of biomarkers and scoring systems for liver fibrosis. Advances in -omics approach have generated clinically significant biomarker candidates for liver fibrosis that need further evaluation.
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Affiliation(s)
| | - Shashidhar Kurpad Nagaraj
- Department of Biochemistry, Sri Devaraj Urs Medical College, SDUAHER, Tamaka, Kolar, Karnataka, India
| | - Lakshmaiah Venkataswamy
- Department of Medicine, Sri Devaraj Urs MedicalCollege, SDUAHER, Tamaka, Kolar, Karnataka, India
| | - Muninarayana Chandrappa
- Department of Community Medicine, Sri DevarajUrs Medical College, SDUAHER, Tamaka, Kolar, Karnataka, India
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Bichoupan K, Tandon N, Martel-Laferriere V, Patel NM, Sachs D, Ng M, Schonfeld EA, Pappas A, Crismale J, Stivala A, Khaitova V, Gardenier D, Linderman M, Olson W, Perumalswami PV, Schiano TD, Odin JA, Liu LU, Dieterich DT, Branch AD. Factors associated with success of telaprevir- and boceprevir-based triple therapy for hepatitis C virus infection. World J Hepatol 2017; 9:551-561. [PMID: 28469811 PMCID: PMC5395804 DOI: 10.4254/wjh.v9.i11.551] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 03/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate new therapies for hepatitis C virus (HCV), data about real-world outcomes are needed.
METHODS Outcomes of 223 patients with genotype 1 HCV who started telaprevir- or boceprevir-based triple therapy (May 2011-March 2012) at the Mount Sinai Medical Center were analyzed. Human immunodeficiency virus-positive patients and patients who received a liver transplant were excluded. Factors associated with sustained virological response (SVR24) and relapse were analyzed by univariable and multivariable logistic regression as well as classification and regression trees. Fast virological response (FVR) was defined as undetectable HCV RNA at week-4 (telaprevir) or week-8 (boceprevir).
RESULTS The median age was 57 years, 18% were black, 44% had advanced fibrosis/cirrhosis (FIB-4 ≥ 3.25). Only 42% (94/223) of patients achieved SVR24 on an intention-to-treat basis. In a model that included platelets, SVR24 was associated with white race [odds ratio (OR) = 5.92, 95% confidence interval (CI): 2.34-14.96], HCV sub-genotype 1b (OR = 2.81, 95%CI: 1.45-5.44), platelet count (OR = 1.10, per x 104 cells/μL, 95%CI: 1.05-1.16), and IL28B CC genotype (OR = 3.54, 95%CI: 1.19-10.53). Platelet counts > 135 x 103/μL were the strongest predictor of SVR by classification and regression tree. Relapse occurred in 25% (27/104) of patients with an end-of-treatment response and was associated with non-FVR (OR = 4.77, 95%CI: 1.68-13.56), HCV sub-genotype 1a (OR = 5.20; 95%CI: 1.40-18.97), and FIB-4 ≥ 3.25 (OR = 2.77; 95%CI: 1.07-7.22).
CONCLUSION The SVR rate was 42% with telaprevir- or boceprevir-based triple therapy in real-world practice. Low platelets and advanced fibrosis were associated with treatment failure and relapse.
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Tama M, Naylor P, Patel S, Altawil J, Gulati D, Antaki F, Mutchnick MG, Ehrinpreis M. Overestimate of Fibrosis by FIBROSpect® II in African Americans Complicates the Management of their Chronic Hepatitis C. J Clin Transl Hepatol 2016; 4:12-9. [PMID: 27047767 PMCID: PMC4807138 DOI: 10.14218/jcth.2015.00053] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2015] [Revised: 02/02/2016] [Accepted: 02/04/2016] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Evaluation of advanced fibrosis in patients with hepatitis C virus (HCV) infection is used to facilitate decisions on treatment strategy and to initiate additional screening measures. Unfortunately, most studies have predominately Caucasian (Cau) patients and may not be as relevant for African Americans (AA). AIMS This study specifically addresses the issue of defining minimal vs. significant fibrosis in African Americans (AA) with chronic hepatitis C (CHC) using noninvasive assays. METHODS All patients (n = 319) seen between 1 January 2008 and 30 June 2013 for whom a FibroSpect II® (FSII) assay was performed and had data for calculation of aspartate aminotransferase (AST) platelet ratio index (APRI) and Fibrosis-4 (FIB-4) were identified using the medical records. RESULTS When liver biopsy score and FSII assay results for the AA patients with CHC were compared, 31% of AA had advanced FSII fibrosis scores (F2-F4) despite a biopsy score of F0-F1. In contrast, 10% of Cau over-scored. The AA false positive rate was 14% for APRI and 34% for FIB-4. Combining FSII with either APRI (7% false positive) or FIB-4 (10% false positive) improved the false positive rate in AA to 7% (FSII + APRI) and 10% (FSII + FIB-4) but reduced the sensitivity for significant fibrosis. CONCLUSIONS The FSII assay overestimates fibrosis in AA and should be used with caution since these patients may not have significant fibrosis. If the APRI or FIB-4 assay is combined with the FSII assay, minimal fibrosis in AA can be defined without subjecting the patients to a subsequent biopsy.
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Affiliation(s)
- Maher Tama
- Wayne State University School of Medicine, Department of Internal Medicine, Division of Gastroenterology, Detroit, MI, USA
| | - Paul Naylor
- Wayne State University School of Medicine, Department of Internal Medicine, Division of Gastroenterology, Detroit, MI, USA
- Correspondence to: Paul Naylor, Gastroenterology, 603 Hudson Bldg, Harper University Hospital, 3990 John R, Detroit, MI 48201, USA. Tel: +1-313-745-8601, Fax: +1-313-745-8843, E-mail:
| | - Suhag Patel
- Wayne State University School of Medicine, Department of Internal Medicine, Division of Gastroenterology, Detroit, MI, USA
| | - Johnny Altawil
- Wayne State University School of Medicine, Department of Internal Medicine, Division of Gastroenterology, Detroit, MI, USA
| | - Dhiraj Gulati
- Wayne State University School of Medicine, Department of Internal Medicine, Division of Gastroenterology, Detroit, MI, USA
| | - Fadi Antaki
- Wayne State University School of Medicine, Department of Internal Medicine, Division of Gastroenterology, Detroit, MI, USA
| | - Milton G. Mutchnick
- Wayne State University School of Medicine, Department of Internal Medicine, Division of Gastroenterology, Detroit, MI, USA
| | - Murray Ehrinpreis
- Wayne State University School of Medicine, Department of Internal Medicine, Division of Gastroenterology, Detroit, MI, USA
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Zhou Y, Sun L, Wang X, Zhou L, Li J, Liu M, Wang F, Peng J, Gui X, Zhao H, Reichenbach N, Zhou D, Ho WZ. Heroin use promotes HCV infection and dysregulates HCV-related circulating microRNAs. J Neuroimmune Pharmacol 2015; 10:102-10. [PMID: 25572448 DOI: 10.1007/s11481-014-9577-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 12/23/2014] [Indexed: 01/22/2023]
Abstract
Hepatitis C virus (HCV) infection is common among injection drug users (IDUs). There is accumulating evidence that circulating microRNAs (miRNAs) are associated with HCV infection and disease progression. The present study was undertaken to determine the in vivo impact of heroin use on HCV infection and HCV-related circulating miRNA expression. Using the blood specimens from four groups of the study subjects (HCV-infected individuals, heroin users with/without HCV infection, and healthy volunteers), we found that HCV-infected heroin users had significantly higher viral load than HCV-infected non-heroin users (p = 0.0004). Measurement of HCV-related circulating miRNAs in plasma showed that miRs-122, 141, 29a, 29b, and 29c were significantly increased in the heroin users with HCV infection, whereas miR-351, an HCV inhibitory miRNA, was significantly decreased in heroin users as compared to control subjects. Further investigation identified a negative correlation between the plasma levels of miR-29 family members and severity of HCV infection based on aspartate aminotransferase to platelet ratio index (APRI). In addition, heroin use and/or HCV infection also dysregulated a panel of plasma miRNAs. Taken together, these data for the first time revealed in vivo evidence that heroin use and/or HCV infection alter circulating miRNAs, which provides a novel mechanism for the impaired innate anti-HCV immunity among IDUs.
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Affiliation(s)
- Yu Zhou
- Department of Pathology and Laboratory Medicine, Temple University School of Medicine, 3500 N. Broad St., Philadelphia, PA, 19140, USA
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Crossan C, Tsochatzis EA, Longworth L, Gurusamy K, Davidson B, Rodríguez-Perálvarez M, Mantzoukis K, O'Brien J, Thalassinos E, Papastergiou V, Burroughs A. Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation. Health Technol Assess 2015; 19:1-vi. [PMID: 25633908 PMCID: PMC4781028 DOI: 10.3310/hta19090] [Citation(s) in RCA: 109] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver biopsy is the reference standard for diagnosing the extent of fibrosis in chronic liver disease; however, it is invasive, with the potential for serious complications. Alternatives to biopsy include non-invasive liver tests (NILTs); however, the cost-effectiveness of these needs to be established. OBJECTIVE To assess the diagnostic accuracy and cost-effectiveness of NILTs in patients with chronic liver disease. DATA SOURCES We searched various databases from 1998 to April 2012, recent conference proceedings and reference lists. METHODS We included studies that assessed the diagnostic accuracy of NILTs using liver biopsy as the reference standard. Diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was conducted using the bivariate random-effects model with correlation between sensitivity and specificity (whenever possible). Decision models were used to evaluate the cost-effectiveness of the NILTs. Expected costs were estimated using a NHS perspective and health outcomes were measured as quality-adjusted life-years (QALYs). Markov models were developed to estimate long-term costs and QALYs following testing, and antiviral treatment where indicated, for chronic hepatitis B (HBV) and chronic hepatitis C (HCV). NILTs were compared with each other, sequential testing strategies, biopsy and strategies including no testing. For alcoholic liver disease (ALD), we assessed the cost-effectiveness of NILTs in the context of potentially increasing abstinence from alcohol. Owing to a lack of data and treatments specifically for fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), the analysis was limited to an incremental cost per correct diagnosis. An analysis of NILTs to identify patients with cirrhosis for increased monitoring was also conducted. RESULTS Given a cost-effectiveness threshold of £20,000 per QALY, treating everyone with HCV without prior testing was cost-effective with an incremental cost-effectiveness ratio (ICER) of £9204. This was robust in most sensitivity analyses but sensitive to the extent of treatment benefit for patients with mild fibrosis. For HBV [hepatitis B e antigen (HBeAg)-negative)] this strategy had an ICER of £28,137, which was cost-effective only if the upper bound of the standard UK cost-effectiveness threshold range (£30,000) is acceptable. For HBeAg-positive disease, two NILTs applied sequentially (hyaluronic acid and magnetic resonance elastography) were cost-effective at a £20,000 threshold (ICER: £19,612); however, the results were highly uncertain, with several test strategies having similar expected outcomes and costs. For patients with ALD, liver biopsy was the cost-effective strategy, with an ICER of £822. LIMITATIONS A substantial number of tests had only one study from which diagnostic accuracy was derived; therefore, there is a high risk of bias. Most NILTs did not have validated cut-offs for diagnosis of specific fibrosis stages. The findings of the ALD model were dependent on assuptions about abstinence rates assumptions and the modelling approach for NAFLD was hindered by the lack of evidence on clinically effective treatments. CONCLUSIONS Treating everyone without NILTs is cost-effective for patients with HCV, but only for HBeAg-negative if the higher cost-effectiveness threshold is appropriate. For HBeAg-positive, two NILTs applied sequentially were cost-effective but highly uncertain. Further evidence for treatment effectiveness is required for ALD and NAFLD. STUDY REGISTRATION This study is registered as PROSPERO CRD42011001561. FUNDING The National Institute for Health Research Health Technology Assessment programme.
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Affiliation(s)
- Catriona Crossan
- Health Economics Research Group, Brunel University London, Uxbridge, UK
| | - Emmanuel A Tsochatzis
- Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Louise Longworth
- Health Economics Research Group, Brunel University London, Uxbridge, UK
| | | | | | - Manuel Rodríguez-Perálvarez
- Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Konstantinos Mantzoukis
- Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Julia O'Brien
- Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Evangelos Thalassinos
- Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Vassilios Papastergiou
- Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Andrew Burroughs
- Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
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Impact of contacting study authors to obtain additional data for systematic reviews: diagnostic accuracy studies for hepatic fibrosis. Syst Rev 2014; 3:107. [PMID: 25239493 PMCID: PMC4185334 DOI: 10.1186/2046-4053-3-107] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 08/29/2014] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Seventeen of 172 included studies in a recent systematic review of blood tests for hepatic fibrosis or cirrhosis reported diagnostic accuracy results discordant from 2 × 2 tables, and 60 studies reported inadequate data to construct 2 × 2 tables. This study explores the yield of contacting authors of diagnostic accuracy studies and impact on the systematic review findings. METHODS Sixty-six corresponding authors were sent letters requesting additional information or clarification of data from 77 studies. Data received from the authors were synthesized with data included in the previous review, and diagnostic accuracy sensitivities, specificities, and positive and likelihood ratios were recalculated. RESULTS Of the 66 authors, 68% were successfully contacted and 42% provided additional data for 29 out of 77 studies (38%). All authors who provided data at all did so by the third emailed request (ten authors provided data after one request). Authors of more recent studies were more likely to be located and provide data compared to authors of older studies. The effects of requests for additional data on the conclusions regarding the utility of blood tests to identify patients with clinically significant fibrosis or cirrhosis were generally small for ten out of 12 tests. Additional data resulted in reclassification (using median likelihood ratio estimates) from less useful to moderately useful or vice versa for the remaining two blood tests and enabled the calculation of an estimate for a third blood test for which previously the data had been insufficient to do so. We did not identify a clear pattern for the directional impact of additional data on estimates of diagnostic accuracy. CONCLUSIONS We successfully contacted and received results from 42% of authors who provided data for 38% of included studies. Contacting authors of studies evaluating the diagnostic accuracy of serum biomarkers for hepatic fibrosis and cirrhosis in hepatitis C patients impacted conclusions regarding diagnostic utility for two blood tests and enabled the calculation of an estimate for a third blood test. Despite relatively extensive efforts, we were unable to obtain data to resolve discrepancies or complete 2 × 2 tables for 62% of studies.
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Abstract
Liver fibrosis is the final common pathway for almost all causes of chronic liver injury. Liver fibrosis is now known to be a dynamic process having significant potential for resolution. Therefore, fibrosis prediction is an essential part of the assessment and management of patients with chronic liver disease. As such, there is strong demand for reliable liver biomarkers that provide insight into disease etiology, diagnosis, therapy, and prognosis in lieu of more invasive approaches such as liver biopsy. Current diagnostic strategies range from use of serum biomarkers to more advanced imaging techniques including transient elastography and magnetic resonance imaging. In addition to these modalities, there are other approaches including the use of novel, but yet to be validated, biomarkers. In this chapter, we discuss the biomarkers of liver fibrosis including the use of invasive and noninvasive biomarkers and disease-specific biomarkers in various chronic liver diseases.
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Schiavon LDL, Narciso-Schiavon JL, Carvalho-Filho RJD. Non-invasive diagnosis of liver fibrosis in chronic hepatitis C. World J Gastroenterol 2014; 20:2854-2866. [PMID: 24659877 PMCID: PMC3961992 DOI: 10.3748/wjg.v20.i11.2854] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/10/2013] [Accepted: 01/14/2014] [Indexed: 02/06/2023] Open
Abstract
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 extra-hepatic 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.
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Bonekamp D, Bonekamp S, Ou HY, Torbenson MS, Corona-Villalobos CP, Mezey E, Kamel IR. Assessing liver fibrosis: Comparison of arterial enhancement fraction and diffusion-weighted imaging. J Magn Reson Imaging 2013; 40:1137-46. [DOI: 10.1002/jmri.24472] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 09/12/2013] [Indexed: 12/21/2022] Open
Affiliation(s)
- David Bonekamp
- Russell H. Morgan Department of Radiology and Radiological Science; The Johns Hopkins Hospital; Baltimore Maryland USA
| | - Susanne Bonekamp
- Russell H. Morgan Department of Radiology and Radiological Science; The Johns Hopkins Hospital; Baltimore Maryland USA
| | - Hsin-You Ou
- Russell H. Morgan Department of Radiology and Radiological Science; The Johns Hopkins Hospital; Baltimore Maryland USA
- Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College; Niao-Sung Kaohsiung Taiwan
| | - Michael S. Torbenson
- Department of Pathology; Johns Hopkins University; School of Medicine; Baltimore Maryland USA
| | | | - Esteban Mezey
- Department of Medicine; Johns Hopkins University, Sheikh Zayed Tower, School of Medicine; Baltimore Maryland USA
| | - Ihab R. Kamel
- Russell H. Morgan Department of Radiology and Radiological Science; The Johns Hopkins Hospital; Baltimore Maryland USA
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Abd El Rihim AY, Omar RF, Fathalah W, El Attar I, Hafez HA, Ibrahim W. Role of fibroscan and APRI in detection of liver fibrosis: a systematic review and meta-analysis. Arab J Gastroenterol 2013; 14:44-50. [PMID: 23820499 DOI: 10.1016/j.ajg.2013.05.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Revised: 03/23/2013] [Accepted: 05/09/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND STUDY AIMS Fibroscan and APRI are promising noninvasive alternatives to liver biopsy for detecting hepatic fibrosis. However, their overall test performance in various settings remains questionable. The aim of our study was to perform a systematic review and meta-analysis of diagnostic accuracy studies comparing fibroscan and APRI with liver biopsy for hepatic fibrosis. PATIENTS AND METHODS Electronic and manual bibliographic searches to identify potential studies were performed. Selection of studies was based on reported accuracy of fibroscan and APRI compared with liver biopsy. Data extraction was performed independently by two reviewers. Meta-analysis combined the sensitivities, specificities, and likelihood ratios of individual studies. Extent and reasons for heterogeneity were assessed. RESULTS 23 studies for fibroscan and 20 studies for APRI in full publication were identified. For patients with stage IV fibrosis (cirrhosis), the pooled estimates for sensitivity of fibroscan were 83.4% (95% confidence interval [CI], 71.7-95.0%) and specificity 92.4% (95% CI, 85.6-99.2%). For patients with stage IV fibrosis (cirrhosis), the pooled estimates for sensitivity of APRI at cutoff point of 1.5 were 66.5% (95% CI, 25.0-100%) and specificity 71.7% (95% CI, 35.0-100%). Diagnostic threshold bias was identified as an important cause of heterogeneity for pooled results in both patient groups. CONCLUSIONS Fibroscan and APRI appear to be clinically useful tests for detecting cirrhosis however not useful tools in early stages of fibrosis.
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An Elevated Arterial Enhancement Fraction Is Associated With Clinical and Imaging Indices of Liver Fibrosis and Cirrhosis. J Comput Assist Tomogr 2012. [DOI: 10.1097/rct.0b013e3182702ee3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Avgerinos ED, Kadoglou NPE, Moulakakis KG, Giannakopoulos TG, Liapis CD. Current role of biomarkers in carotid disease: a systematic review. Int J Stroke 2011; 6:337-45. [PMID: 21745345 DOI: 10.1111/j.1747-4949.2011.00623.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND AND PURPOSE Accumulating evidence suggests that carotid plaque vulnerability can be used as a determinant of ischemic stroke risk stratification and carotid intervention. Novel markers of high-risk carotid plaque in patients are needed. SUMMARY OF REVIEW Advances in cellular and molecular pathophysiology, the demand for accurately predicting carotid risk, and choosing the optimal prevention strategy are stimulating great interest in the development of novel surrogate markers. Biomarkers in cardiovascular disease are expected to predict the natural history, clinical outcomes, and the efficacy of disease-modifying interventions. We aimed to review the literature regarding clinical data on novel serum biomarkers related to ischemic cerebrovascular events associated with carotid artery disease. We provide background information on the biomarkers related to all aspects of carotid disease: natural history, carotid intervention strategies for symptomatic and asymptomatic patients, perioperative risk prediction, and their therapeutic implications. CONCLUSION At present, heterogeneous data support evidence that biological markers can help existing practices to more accurately assess patients at risk for stroke. Randomized-controlled trials for carotid artery disease and carotid intervention, incorporating biomarkers, are needed.
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Affiliation(s)
- Efthimios D Avgerinos
- Department of Vascular Surgery, Attikon University Hospital, Medical School, Athens, Greece
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Abstract
Fibrosis prediction is an essential part of the assessment and management of patients with chronic liver disease. Blood-based biomarkers offer a number of advantages over the traditional standard of fibrosis assessment of liver biopsy, including safety, cost-savings and wide spread accessibility. Current biomarker algorithms include indirect surrogate measures of fibrosis, including aminotransaminases and platelet count, or direct measures of fibrinogenesis or fibrinolysis such as hyaluronic acid and tissue inhibitor of metalloproteinase-1. A number of algorithms have now been validated across a range of chronic liver disease including chronic viral hepatitis, alcoholic and non-alcoholic fatty liver disease. Furthermore, several models have been demonstrated to be dynamic to changes in fibrosis over time and are predictive of liver-related survival and overall survival to a greater degree than liver biopsy. Current limitations of biomarker models include a significant indeterminate range, and a predictive ability that is limited to only a few stages of fibrosis. Utilization of these biomarker models requires knowledge of patient co-morbidities which may produce false positive or negative results in a small proportion of individuals. Furthermore, knowledge of the underlying prevalence of fibrosis in the patient population is required for interpretation of the positive or negative predictive values of a test result. Novel proteins identified by proteomic technology and genetic polymorphisms from genome association studies offer the possibility for further refinement and individualization of biomarker fibrosis models in the future.
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Affiliation(s)
- Leon A Adams
- School of Medicine and Pharmacology, University of Western Australia, Nedlands, WA 6009,, Australia.
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15
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Giannakopoulos TG, Avgerinos ED, Moulakakis KG, Kadoglou NP, Preza O, Papapetrou A, Papasideris C, Liapis CD. Biomarkers for diagnosis of the vulnerable atherosclerotic plaque. Interv Cardiol 2011. [DOI: 10.2217/ica.11.11] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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16
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Blanco F, Barreiro P, Ryan P, Vispo E, Martín-Carbonero L, Tuma P, Labarga P, Medrano J, González-Lahoz J, Soriano V. Risk factors for advanced liver fibrosis in HIV-infected individuals: role of antiretroviral drugs and insulin resistance. J Viral Hepat 2011; 18:11-6. [PMID: 20088890 DOI: 10.1111/j.1365-2893.2009.01261.x] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Liver damage may result from multiple factors in HIV-infected patients. The availability of reliable noninvasive tools to measure liver fibrosis has permitted the screening of large patient populations. Cross-sectional study of all consecutive HIV outpatients who underwent examination by transient elastometry (FibroScan) at one HIV reference clinic during 2007. Advanced liver fibrosis (ALF) was defined as hepatic stiffness >9.5 kilopascals, which corresponds to Metavir stages F3-F4 in the liver biopsy. A total of 681 consecutive HIV-infected patients (64% injecting drug users; mean age 43; 78% male; 98% on antiretroviral therapy) had at least one valid FibroScan evaluation. ALF was diagnosed in 215 (32%) of them. In the univariate analysis, ALF was significantly associated with older age, low CD4 counts, chronic hepatitis C, past alcohol abuse, elevated ALT, high triglycerides, low cholesterol, high homeostasis model assessment (HOMA) index and exposure to didanosine and/or stavudine. In a multivariate model (OR, 95% CI), chronic hepatitis C (2.83, 1.57-5.08), past alcohol abuse (2.26, 1.37-3.74), exposure to didanosine and/or stavudine (1.85, 1.14-3.01), high HOMA index (1.25, 1.04-1.51), older age (1.09, 1.05-1.14) and elevated ALT (1.04, 1.03-1.06) remained as independently associated with ALF. Therefore, in addition to chronic hepatitis C and alcohol abuse, insulin resistance and/or exposure to dideoxy-nucleosides may contribute to ALF in HIV-infected patients.
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Affiliation(s)
- F Blanco
- Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain
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17
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Mummadi RR, Petersen JR, Xiao SY, Snyder N. Role of simple biomarkers in predicting fibrosis progression in HCV infection. World J Gastroenterol 2010; 16:5710-5. [PMID: 21128320 PMCID: PMC2997986 DOI: 10.3748/wjg.v16.i45.5710] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the accuracy of the aspartate aminotransferase (AST)/Platelet Ratio Index (APRI) and FIB-4, in predicting longitudinal changes in liver histology in hepatitis C virus (HCV) patients.
METHODS: Patients that underwent repeat liver biopsies at least 1 year apart from 1999 to 2007 were identified. Liver fibrosis was staged on needle core biopsies evaluated by a single expert liver pathologist. Only laboratory values within 3 mo of the liver biopsies were used.
RESULTS: Thirty-six patients met the inclusion criteria with 50% stage 1 on initial biopsy, 25% stage 2, and 22% stage 3. Nineteen of 36 (53%) had progression of fibrosis on repeat biopsies, while 16 (44%) showed no change in stage, and one (3%) showed improvement. Patients that showed progression of fibrosis had significantly higher alanine aminotransferase and aspartate aminotransferase levels than the group that did not show progression. A significant correlation was seen between change in stage of fibrosis and change in APRI (r² = 0.39, P = 0.00001) and a change in FIB-4 (r² = 0.31, P = 0.00004). A change in APRI (ΔAPRI) of 0.18 had 80% positive predictive value (PPV) and 67% negative predictive value (NPV) for progression of fibrosis. A change in FIB-4 (ΔFIB-4) of 0.39 had 75% PPV and 75% NPV for predicting progression of fibrosis.
CONCLUSION: ΔAPRI and ΔFIB-4 parallel changes in fibrosis progression, and could be useful tools for clinicians in following patients with active chronic HCV infection.
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18
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El-Attar MM, Ahmed MAH, Shehata Hasan M, Aly MA, Nasr AM. Spontaneous viral clearance of chronic HCV infection in Upper Egypt: A community-based study with a 10year follow-up. Arab J Gastroenterol 2010. [DOI: 10.1016/j.ajg.2010.10.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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19
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Hessien MH, El-Sharkawi IM, El-Barbary AA, El-Beltagy DM, Snyder N. Non-invasive index of liver fibrosis induced by alcohol, thioacetamide and Schistosomal infection in mice. BMC Gastroenterol 2010; 10:53. [PMID: 20515488 PMCID: PMC2894747 DOI: 10.1186/1471-230x-10-53] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2009] [Accepted: 06/01/2010] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Non invasive approaches will likely be increasing utilized to assess liver fibrosis. This work provides a new non invasive index to predict liver fibrosis induced in mice. METHODS Fibrosis was generated by thioacetamide (TAA), chronic intake of ethanol, or infection with S. mansoni in 240 mice. Both progression and regression of fibrosis (after treatment with silymarin and/or praziquantel) were monitored. The following methods were employed: (i) The METAVIR system was utilized to grade and stage liver inflammation and fibosis; (ii) Determination of hepatic hydroxyproline and collagen; and (iii) Derivation of a new hepatic fibrosis index from the induced changes, and its prospective validation in a group of 70 mice. RESULTS The index is composed of 4 serum variable including total proteins, gamma-GT, bilirubin and reduced glutathione (GSH), measured in diseased, treated and normal mice. These parameters were highly correlated with both the histological stage and the grade. They were combined in a logarithmic formula, which non-invasively scores the severity of liver fibrosis through a range (0 to 2), starting with healthy liver (corresponding to stage 0) to advanced fibrosis (corresponding stage 3).Receiver operating characteristic curves (ROC) for the accuracy of the index to predict the histological stages demonstrated that the areas under the curve (AUC) were 0.954, 0.979 and 0.99 for index values corresponding to histological stages 1, 2 and 3, respectively. Also, the index was correlated with stage and grade, (0.947 and 0.859, respectively). The cut off values that cover the range between stages 0-1, 1-2 and 2-3 are 0.4, 1.12 and 1.79, respectively. The results in the validation group confirmed the accuracy of the test. The AUROC was 0.869 and there was good correlation with the stage of fibrosis and grade of inflammation. CONCLUSION The index fulfils the basic criteria of non-invasive marker of liver fibrosis since it is liver-specific, easy to implement, reliable, and inexpensive. It proved to be accurate in discriminating precirrhotic stages.
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Affiliation(s)
- Mohamed H Hessien
- Department of Chemistry, Faculty of Science, Tanta University, Tanta 31111, Egypt
| | | | - Ahmed A El-Barbary
- Department of Chemistry, Faculty of Science, Tanta University, Tanta 31111, Egypt
| | - Doha M El-Beltagy
- Department of Chemistry, Faculty of Science, Tanta University, Tanta 31111, Egypt
| | - Ned Snyder
- Division of Gastroenterology at the University of Texas Medical Branch (UTMB) in Galveston, TX: 77555, USA
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20
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Cooke JP, Wilson AM. Biomarkers of peripheral arterial disease. J Am Coll Cardiol 2010; 55:2017-23. [PMID: 20447524 PMCID: PMC3157958 DOI: 10.1016/j.jacc.2009.08.090] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2009] [Revised: 07/22/2009] [Accepted: 08/16/2009] [Indexed: 10/19/2022]
Abstract
Atherosclerotic arterial occlusive disease affecting the lower extremities is also known as peripheral artery disease (PAD). This disorder affects 8 to 12 million individuals in the U.S. and is increasingly prevalent in Europe and Asia. Unfortunately, most patients are not diagnosed and are not optimally treated. A blood test for PAD, if sufficiently sensitive and specific, would be expected to improve recognition and treatment of these individuals. Even a biomarker panel of moderate sensitivity and specificity for PAD could refine risk stratification to select individuals for diagnostic vascular examination. Alternatively, biomarkers for PAD may be useful in determining prognosis, the risk for progression, or the response to therapy. Finally, the discovery of biomarkers associated with PAD may provide novel insights into the pathophysiology of PAD and new therapeutic avenues to pursue. Biomarkers may be derived from studies of the genome, transcriptome, proteome, or metabolome. The focus of this review is on proteomic biomarkers associated with PAD.
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Affiliation(s)
- John P Cooke
- Division of Cardiovascular Medicine, Stanford University, Stanford, California 94305-5406, USA.
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21
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Smith JO, Sterling RK. Systematic review: non-invasive methods of fibrosis analysis in chronic hepatitis C. Aliment Pharmacol Ther 2009; 30:557-76. [PMID: 19519733 DOI: 10.1111/j.1365-2036.2009.04062.x] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Accurate determination of the presence and degree of liver fibrosis is essential for prognosis and for planning treatment of patients with chronic hepatitis C virus (HCV). Non-invasive methods of assessing fibrosis have been developed to reduce the need for biopsy. AIM To perform a review of these non-invasive measures and their ability to replace biopsy for assessing hepatic fibrosis in patients with chronic HCV. METHODS A systematic review of PUBMED and EMBASE was performed through 2008 using the following search terms: HCV, liver, elastography, hepatitis, Fibroscan, SPECT, noninvasive liver fibrosis, ultrasonography, Doppler, MRI, Fibrotest, Fibrosure, Actitest, APRI, Forns and breath tests, alone or in combination. RESULTS We identified 151 studies: 87 using biochemical, 57 imaging and seven breath tests either alone or in combination. CONCLUSIONS Great strides are being made in the development of accurate non-invasive methods for determination of fibrosis. Although no single non-invasive test or model developed to date can match that information obtained from actual histology (i.e. inflammation, fibrosis, steatosis), combinations of two modalities of non-invasive methods can reliably differentiate between minimal and significant fibrosis, and thereby avoid liver biopsy in a significant percentage of patients.
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Affiliation(s)
- J O Smith
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University Health System, Richmond, VA 23298-0341, USA
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22
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Patel K, Benhamou Y, Yoshida EM, Kaita KD, Zeuzem S, Torbenson M, Pulkstenis E, Subramanian GM, McHutchison JG. An independent and prospective comparison of two commercial fibrosis marker panels (HCV FibroSURE and FIBROSpect II) during albinterferon alfa-2b combination therapy for chronic hepatitis C. J Viral Hepat 2009; 16:178-86. [PMID: 19175870 DOI: 10.1111/j.1365-2893.2008.01062.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Noninvasive markers that accurately follow changes in fibrosis may provide alternatives to liver biopsy for assessment of histological endpoints of antiviral therapy in chronic hepatitis C (CHC). This study compared two commercially available serum marker panels (HCV FibroSURE and FIBROSpect II) during interferon-based therapy. Ninety-five interferon-naïve patients with genotype 1 CHC were enrolled in a phase 2b, active-controlled study of albinterferon alfa-2b/ribavirin for 48 weeks. Proprietary and simple biochemical marker panels were independently evaluated in serum before and during the study. Baseline liver biopsies were evaluated for METAVIR fibrosis by a single pathologist. Index scores were obtained for HCV FibroSURE (n = 84) and FIBROSpect II (n = 95); mean biopsy length: 17.8 +/- 8.0 mm. For detecting fibrosis stages 2-4 (prevalence 23% [22/95] and 21% [18/84]), HCV FibroSURE and FIBROSpect II indicated high sensitivity (1.00 and 0.95, respectively), lower but comparable specificity (0.61 and 0.66, respectively), and a good area under the receiver operating characteristic curve (0.89 and 0.90, respectively). Simple indices had high indeterminate rates (31-40%) at baseline. Patients with a sustained virological response had lower baseline scores than nonresponders, and reduced median percent changes in index scores for HCV FibroSURE (-20.0%vs 2.9%; P = 0.14) and FIBROS Spect II (-6.8%vs 18.4%; P = 0.05). The panels demonstrated comparable performance characteristics for differentiating mild from moderate-severe stage disease in CHC. Lower index scores at baseline that continue to decline likely reflect reduced fibrogenesis activity in patients with successful antiviral responses to therapy.
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Affiliation(s)
- K Patel
- Duke Clinical Research Institute and Duke University Medical Center, Durham, NC 27715, USA.
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Poynard T, Morra R, Ingiliz P, Imbert-Bismut F, Thabut D, Messous D, Munteanu M, Massard J, Benhamou Y, Ratziu V. Biomarkers of liver fibrosis. Adv Clin Chem 2008; 46:131-60. [PMID: 19004189 DOI: 10.1016/s0065-2423(08)00404-6] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Liver biopsy, due to its limitations and risks, is an imperfect gold standard for assessing the severity of the most frequent chronic liver diseases. This chapter summarized the advantages and the limits of the available biomarkers of liver fibrosis. Among a total of 2237 references, a total of 14 validated biomarkers have been identified between 1991 and 2007. Nine were not patented and five were patented. FibroTest (FT) was the most studied test with 33 different populations including 6549 patients and 925 controls. The mean diagnostic value for the diagnosis of advanced fibrosis assessed using standardized area under the receiver operating characteristics (ROC) curves was 0.84 [95% confidence interval (CI), 0.83-0.86], without significant difference between the causes of liver disease, hepatitis C, hepatitis B, alcoholic or nonalcoholic fatty liver disease. High-risk profiles of false negative/positive of FT are present in 3% of populations, mainly Gilbert syndrome, hemolysis, and acute inflammation. FT has higher accuracy than aspartate aminotransferase/platelets ratio index (APRI), the most used nonpatented test. No significant difference has been observed between the five patented tests. A quality score has been assessed in order to compare the quality of fibrosis biomarkers. Neither biomarkers nor biopsy are sufficient alone to take definitive decision in a given patient and all the clinical and biological data must be taken into account. Due to the evidence-based data, health authorities in some countries have already approved validated biomarkers as first-line procedure for the staging of liver fibrosis. This overview of evidence-based data suggests that biomarkers could be used as an alternative to liver biopsy for the assessment of fibrosis stage in the four more common chronic liver diseases: C virus (HCV), hepatitis B virus (HBV), hepatitis nonalcoholic fatty liver disease (NAFLD), and alcoholic liver disease (ALD). Neither biomarkers nor biopsy are sufficient alone to take definitive decision in a given patient and all the clinical and biological data must be taken into account.
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Affiliation(s)
- Thierry Poynard
- Service d'Hépato-Gastroentérologie, Groupe Hospitalier Pitié-Salpêtrière, Université Paris VI, CNRS ESA 8067 Paris, France.
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Abstract
AIM: To determine the most frequent etiologies of hepatic epithelioid granulomas, and whether there was an association with chronic hepatitis C virus (HCV).
METHODS: Both a retrospective review of the pathology database of liver biopsies at our institution from 1996 through 2006 as well as data from a prospective study of hepatic fibrosis markers and liver biopsies from 2003 to 2006 were reviewed to identify cases of hepatic epithelioid granulomas. Appropriate charts, liver biopsy slides, and laboratory data were reviewed to determine all possible associations. The diagnosis of HCV was based on a positive HCV RNA.
RESULTS: There were 4578 liver biopsies and 36 (0.79%) had at least one epithelioid granuloma. HCV was the most common association. Fourteen patients had HCV, and in nine, there were no concurrent conditions known to be associated with hepatic granulomas. Prior interferon therapy and crystalloid substances from illicit intravenous injections did not account for the finding. There were hepatic epithelioid granulomas in 3 of 241 patients (1.24%) with known chronic HCV enrolled in the prospective study of hepatic fibrosis markers.
CONCLUSION: Although uncommon, hepatic granulomas may be part of the histological spectrum of chronic HCV. When epithelioid granulomas are found on the liver biopsy of someone with HCV, other clinically appropriate studies should be done, but if nothing else is found, the clinician can be comfortable with an HCV association.
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Fung ET, Wilson AM, Zhang F, Harris N, Edwards KA, Olin JW, Cooke JP. A biomarker panel for peripheral arterial disease. Vasc Med 2008; 13:217-24. [PMID: 18687758 PMCID: PMC3133945 DOI: 10.1177/1358863x08089276] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Peripheral arterial disease (PAD) is common, but often not diagnosed. A biomarker index would be useful to raise suspicion of PAD, so as to trigger appropriate vascular testing and management. The study comprised 540 individuals: 197 individuals with both coronary artery disease and peripheral arterial disease (CAD + PAD); 81 with CAD only; and 262 with no hemodynamically significant disease (NHSD) of the coronary or peripheral arteries. Multiple linear regression was performed to generate a biomarker panel score that could predict ankle-brachial index (ABI). Logistic regression was used to investigate the relationship between disease status and the panel score as well as other risk factors (e.g. age, diabetes status, smoking status). ROC analysis was performed to test the prediction power of the biomarker panel score. Among the plasma markers tested, beta 2 microglobulin (beta2M) and cystatin C had the highest correlation with ABI, and higher than any of the conventional risk factors of age, smoking status, and diabetes status. A biomarker panel score derived from beta2M, cystatin C, hsCRP, and glucose had an increased association with PAD status (OR = 12.4, 95% confidence interval (CI) 6.6-23.5 for highest vs lowest quartile), which was still significant after adjusting for known risk factors (OR = 7.3, 95% CI 3.6-14.9 for highest vs lowest quartile). In conclusion, after taking into account the traditional risk factors for PAD, a biomarker panel comprising beta2M, cystatin C, hsCRP, and glucose adds useful information to assess the risk of disease.
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Trang T, Petersen JR, Snyder N. Non-invasive markers of hepatic fibrosis in patients co-infected with HCV and HIV: comparison of the APRI and FIB-4 index. Clin Chim Acta 2008; 397:51-4. [PMID: 18692034 DOI: 10.1016/j.cca.2008.07.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2008] [Revised: 07/14/2008] [Accepted: 07/14/2008] [Indexed: 12/11/2022]
Abstract
INTRODUCTION The APRI and FIB-4 index are markers that have been proposed for the evaluation of hepatic fibrosis in patients co-infected with HIV and HCV. METHODS We retrospectively compared these 2 indices in 81 co-infected patients staged by liver biopsy. RESULTS The FIB-4 index was superior to the APRI for the differentiation of mild from significant fibrosis in both predictive values and area under the receiver operator curve (AUROC). The tests were comparable for the differentiation of mild/moderate from advanced fibrosis. CONCLUSION These tests could be used to evaluate co-infected patients for treatment, and exclude those that do not need periodic screening for hepatocellular carcinoma.
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Affiliation(s)
- Tony Trang
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA
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Liver biopsy versus noninvasive testing in chronic hepatitis C: Where do we stand in 2008? ACTA ACUST UNITED AC 2008. [DOI: 10.1007/s11901-008-0008-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Correlation of FIBROSpect II with histologic and morphometric evaluation of liver fibrosis in chronic hepatitis C. Clin Gastroenterol Hepatol 2008; 6:242-7. [PMID: 18187364 DOI: 10.1016/j.cgh.2007.11.009] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Accurate disease staging in chronic hepatitis C (CHC) infection helps guide treatment and may provide prognostic information. Liver biopsies are invasive, costly, and associated with morbidity. We hypothesized that a noninvasive test of liver fibrosis can accurately stage liver fibrosis. We prospectively evaluated the FIBROSpect II (FSII) biomarker panel versus pathology assessment and a quantitative measure of fibrosis. METHODS Liver biopsy specimens and serum were obtained from 252 CHC patients, including 50 posttransplant, from 3 tertiary centers. Biopsy specimens were scored centrally and independently at each site, along with central quantification of fibrosis by digitized morphometry. Serum tests were performed blinded to clinical or histologic evaluation. RESULTS The mean biopsy specimen length was 1.95 +/- 0.87 cm; prevalence of stage F2 through F4 fibrosis was 77%. Agreement between central and site readings for individual stages was modest (k = 0.674), with concordant readings in 106 of 248 (43%) biopsy specimens. The area under the receiver operating characteristic curve for FSII and morphometry for stages F2 through F4 for concordant biopsy specimens were 0.823 and 0.728, respectively. Sensitivity and specificity for FSII were 83.5% and 66.7%, respectively, with an accuracy of 80.2%. The aspartate aminotransferase to platelet ratio index sensitivity and specificity for predicting F2 through F4 were 30.4% and 100%, respectively, the indeterminate rate was 40.4%, and the accuracy rate was 48.4%. The accuracy of FSII in concordant biopsy specimens in the posttransplant cohort was 73%. CONCLUSIONS Serum biomarkers can differentiate mild from moderate-to-severe fibrosis. This prospective study validates the performance characteristics of FSII in CHC patients and a posttransplant cohort. Assessing the diagnostic utility of biomarkers is limited by variability in methods to quantify fibrosis and poor interobserver agreement for histologic staging.
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Harrison SA. Is the FIBROSpect II® index effective for determining the stage of fibrosis in patients with chronic hepatitis C? ACTA ACUST UNITED AC 2007; 5:138-9. [DOI: 10.1038/ncpgasthep1035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2007] [Accepted: 10/15/2007] [Indexed: 11/09/2022]
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