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Causse X, Potier P, Valéry A, Labadie H, Macaigne G, Cadranel J, Fontanges T, Mouna L, Roque‐Afonso A. Predictive Factors for HBsAg Loss in Chronic HBeAg-Negative Hepatitis B Virus Infection: Insights From a 5-Year French Cohort. J Viral Hepat 2025; 32:e14041. [PMID: 39673688 PMCID: PMC11646079 DOI: 10.1111/jvh.14041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 11/20/2024] [Accepted: 11/23/2024] [Indexed: 12/16/2024]
Abstract
Prognostic factors for the long-term evolution of chronic hepatitis B e antigen (HBeAg)-negative hepatitis B virus (HBV) infection may vary depending on local epidemiology. We aimed to identify these factors in France, where the epidemiology is influenced by diverse immigration. Hepatitis B surface antigen (HBsAg)-positive, HBeAg-negative adults with normal transaminase levels and viral loads < 20,000 IU/mL for 1 year, without viral co-infection or advanced liver disease, were enrolled for a 5-year follow-up. A total of 564 patients were recruited from 23 centres (54.4% women, mean age 42.3 ± 12 years, 47.7% from sub-Saharan Africa). HBV DNA was detectable but < 2000 IU/mL for most (71.3%). Genotypes E (27.8%) and A (20.0%) were predominant. The mean HBsAg titre was 3.8 ± 3.4 log IU/mL, > 1000 IU/mL in 60% of cases, and higher in genotype E (p < 0.0001). During follow-up, 18 patients received antiviral treatment, 9 for viral reactivation (0.3% per year) and 9 preemptively. HBsAg loss occurred in 39 patients (1.4% per year). These patients were older (p < 0.0001), more frequently treated for dyslipidemia, hypertension or diabetes (p < 0.05), and had lower baseline HBV DNA (p = 0.0112) and HBsAg (p < 0.0001), but similar levels of HBcrAg compared to those who did not clear HBsAg. Baseline HBsAg was the only independent predictor of HBsAg loss (p = 0.009). In this cohort, HBsAg < 153 IU/mL predicted clearance with 87% sensitivity and specificity. In conclusion, baseline HBsAg accurately predicted seroclearance at 5 years in patients with chronic HBeAg-negative infection, regardless of genotype, sex, or geographical origin, indicating that this marker is widely applicable for reducing the frequency of patient monitoring.
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Affiliation(s)
- Xavier Causse
- Service d'Hépato‐Gastroentérologie et d'Oncologie DigestiveCentre Hospitalier Universitaire d'OrléansOrléansFrance
| | - Pascal Potier
- Service d'Hépato‐Gastroentérologie et d'Oncologie DigestiveCentre Hospitalier Universitaire d'OrléansOrléansFrance
- Département d'Information MédicaleCentre Hospitalier Universitaire d'OrléansOrléansFrance
| | - Antoine Valéry
- Département d'Information MédicaleCentre Hospitalier Universitaire d'OrléansOrléansFrance
| | - Hélène Labadie
- Service d'Hépato‐GastroentérologieCentre Hospitalier de Saint DenisSaint DenisFrance
| | - Gilles Macaigne
- Groupe Hospitalier Intercommunal Le Raincy‐MontfermeilService d'Hépato‐GastroentérologieLe Raincy MontfermeilFrance
| | | | | | - Lina Mouna
- Inserm U1193, Assistance Publique‐Hôpitaux de Paris, Hôpital Paul Brousse, Service de VirologieUniversité Paris‐SaclayVillejuifFrance
| | - Anne‐Marie Roque‐Afonso
- Inserm U1193, Assistance Publique‐Hôpitaux de Paris, Hôpital Paul Brousse, Service de VirologieUniversité Paris‐SaclayVillejuifFrance
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Sghaier I, Zidi S, Mouelhi L, Ghazoueni E, Brochot E, Almawi WY, Loueslati BY. TLR3 and TLR4 SNP variants in the liver disease resulting from hepatitis B virus and hepatitis C virus infection. Br J Biomed Sci 2018; 76:35-41. [PMID: 30421643 DOI: 10.1080/09674845.2018.1547179] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Chronic infection with hepatitis B (HBV) and C virus (HCV) is linked with a pro-inflammatory state, predisposing to cirrhosis and liver cancer, particularly hepatocellular carcinoma (HCC). A role for Toll-like receptor (TLR) signalling in hepatocarcinogenesis was recently documented. We hypothesised a link TLR3 and TLR4 polymorphisms and HCC, as surrogates for the significance of TLR signalling in the promotion and initiation of HCC. MATERIALS AND METHODS We recruited 174 HCV-infected patients, 100 HBV-infected patients and 360 healthy control subjects. TLR3 (rs3775290) and TLR4 (rs4986790) genotyping was done by PCR-restriction fragment length polymorphisms (PCR-RFLP), LFTs and AFP by standard routine techniques. Liver fibrosis was assessed clinically by the Fibrotest and Actitest. RESULT The TLR3 rs3775290 minor T genotype was linked with increased risk of chronic HBV (P = 0.05) and HCV (P = 0.031) infection. The TLR4 rs4986790 minor G genotype was linked with significantly increased risk for HBV/HCV chronic infection (P < 0.001). Subgroups analyses indicated decreased risk of HBV-related HCC in relation to TLR3 rs3775290 CC/CT genotype (P = 0.022), with increased risk ascribed to the minor (T) allele (P = 0.04). Likewise, TLR4 rs4985790 minor (GG) genotype was positively associated with HBV-linked HCC (P < 0.001). Furthermore, a link between TLR3 TT (P < 0.001) andTLR4 GG (P = 0.04) minor genotypes was noted in relation to increased risk of HCV-related disease. CONCLUSION TLR3 and TLR4 polymorphisms are promising biomarkers of liver cirrhosis and cancer associated with HBV and HCV infection.
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Affiliation(s)
- I Sghaier
- a Faculty of Sciences of Tunis , University of Tunis El Manar , Tunis , Tunisia
| | - S Zidi
- a Faculty of Sciences of Tunis , University of Tunis El Manar , Tunis , Tunisia
| | - L Mouelhi
- b Hepato-Gastro-Enterology department , Charles Nicolle Hospital , Tunis , Tunisia
| | - E Ghazoueni
- c Laboratory of Immunology , Military Hospital of Tunis , Tunis , Tunisia
| | - E Brochot
- d Department of Virology , Amiens University Medical Centre , Amiens , France.,e Virology Research Unit, EA 4294 , Jules Verne University of Picardie , Amiens , France
| | - W Y Almawi
- f Faculty of Sciences of Tunis, Laboratory of Mycology , University of Tunis El Manar , Tunis , Tunisia
| | - B Y Loueslati
- f Faculty of Sciences of Tunis, Laboratory of Mycology , University of Tunis El Manar , Tunis , Tunisia
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Serum Cytokeratin 18 M30 Levels in Chronic Hepatitis B Reflect Both Phase and Histological Activities of Disease. Mediators Inflamm 2017; 2017:3480234. [PMID: 28827897 PMCID: PMC5554581 DOI: 10.1155/2017/3480234] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 07/02/2017] [Accepted: 07/09/2017] [Indexed: 01/06/2023] Open
Abstract
Chronic hepatitis B has highly a dynamic course with significant fluctuations of HBV-DNA and ALT impeding assessment of disease activity. New biomarkers of inflammatory versus noninflammatory stages of HBV infection are urgently needed. Cytokeratin 18 epitope M30 (M30 CK-18) is a sensitive marker of cell death. We aimed to investigate an association between serum M30 CK-18 and histological activity and phase of HBV infection. 150 Caucasian patients with HBV-infection were included in the study. Serum M30 CK-18 levels reflected phase of disease, being significantly higher in both HBeAg(+) and HBeAg(−) hepatitis B in comparison to HBsAg(+) carrier groups. The highest serum M30 CK-18 levels were observed in subjects with the most advanced stages of HBV. Moreover, its serum concentrations correlated with both inflammatory activity and fibrosis advancement (ANOVA P < 0.001). Importantly, serum M30 CK-18 levels were able to discriminate patients with mild versus moderate-advanced fibrosis (AUC: 0.86) and mild versus active liver inflammation (AUC: 0.79). M30 CK-18 serum concentration has good sensitivity and specificity in discriminating mild versus moderate/severe fibrosis and inflammation even in patients with normal ALT activity. This study suggests M30 CK-18 as a potential noninvasive marker of disease activity and also a marker of phase of persistent HBV infection.
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EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol 2015; 63:237-64. [PMID: 25911335 DOI: 10.1016/j.jhep.2015.04.006] [Citation(s) in RCA: 1307] [Impact Index Per Article: 130.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 04/09/2015] [Indexed: 02/06/2023]
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Ferraioli G, Filice C, Castera L, Choi BI, Sporea I, Wilson SR, Cosgrove D, Dietrich CF, Amy D, Bamber JC, Barr R, Chou YH, Ding H, Farrokh A, Friedrich-Rust M, Hall TJ, Nakashima K, Nightingale KR, Palmeri ML, Schafer F, Shiina T, Suzuki S, Kudo M. WFUMB guidelines and recommendations for clinical use of ultrasound elastography: Part 3: liver. ULTRASOUND IN MEDICINE & BIOLOGY 2015; 41:1161-79. [PMID: 25800942 DOI: 10.1016/j.ultrasmedbio.2015.03.007] [Citation(s) in RCA: 471] [Impact Index Per Article: 47.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
The World Federation for Ultrasound in Medicine and Biology (WFUMB) has produced these guidelines for the use of elastography techniques in liver disease. For each available technique, the reproducibility, results, and limitations are analyzed, and recommendations are given. Finally, recommendations based on the international literature and the findings of the WFUMB expert group are established as answers to common questions. The document has a clinical perspective and is aimed at assessing the usefulness of elastography in the management of liver diseases.
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Affiliation(s)
- Giovanna Ferraioli
- Ultrasound Unit, Department of Infectious Diseases, Fondazione IRCCS Policlinico S. Matteo, School of Medicine, University of Pavia, Pavia, Italy
| | - Carlo Filice
- Ultrasound Unit, Department of Infectious Diseases, Fondazione IRCCS Policlinico S. Matteo, School of Medicine, University of Pavia, Pavia, Italy
| | - Laurent Castera
- Service d'Hépatologie, Hôpital Beaujon, Clichy, Assistance Publique-Hôpitaux de Paris, INSERM U 773 CRB3, Université Denis Diderot Paris-VII, Paris, France
| | - Byung Ihn Choi
- Department of Radiology, Seoul National University Hospital, Seoul, Korea
| | - Ioan Sporea
- Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy, Timişoara, Romania
| | - Stephanie R Wilson
- Department of Diagnostic Imaging, Foothills Medical Centre, University of Calgary, Calgary, AB, Canada
| | - David Cosgrove
- Division of Radiology, Imperial and Kings Colleges, London, UK
| | | | - Dominique Amy
- Breast Center, 21 ave V. Hugo, 13100 Aix-en-Provence, France
| | - Jeffrey C Bamber
- Joint Department of Physics, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
| | - Richard Barr
- Department of Radiology, Northeastern Ohio Medical University, Rootstown, Ohio and Radiology Consultants Inc., Youngstown, Ohio, USA
| | - Yi-Hong Chou
- Department of Radiology, Veterans General Hospital and National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Hong Ding
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Andre Farrokh
- Department of Gynecology and Obstetrics, Franziskus Hospital, Bielefeld, Germany
| | - Mireen Friedrich-Rust
- Department of Internal Medicine 1, J. W. Goethe University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Timothy J Hall
- Department of Medical Physics, University of Wisconsin, Madison, WI, USA
| | | | | | - Mark L Palmeri
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Fritz Schafer
- Department of Breast Imaging and Interventions, University Hospital Schleswig-Holstein Campus, Kiel, Germany
| | - Tsuyoshi Shiina
- Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinichi Suzuki
- Department of Endocrinology and Surgery, Fukushima University, Fukushima, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Japan.
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Traoré F, Gormally E, Villar S, Friesen MD, Groopman JD, Vernet G, Diallo S, Hainaut P, Maiga MY. Molecular characteristics of Hepatitis B and chronic liver disease in a cohort of HB carriers from Bamako, Mali. BMC Infect Dis 2015; 15:180. [PMID: 25886382 PMCID: PMC4403772 DOI: 10.1186/s12879-015-0916-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Accepted: 03/27/2015] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Hepatitis B (HB) infection is common in Mali. However, there is little information on molecular and biochemical characteristics of HB carriers. METHODS A group of 1466 adult volunteers was recruited in the district of Bamako. Confirmed HB carriers were tested for HB viral load by quantitative PCR and HBV was genotyped by sequencing of HBS. Fibrosis and hepatitis activity were measured using the Fibrotest-Actitest. A mutation of TP53 at codon 249 (R249S), specific for exposure to aflatoxin, was detected in cell-free DNA extracted from plasma. RESULTS Overall, 276 subjects were HBsAg-positive (18.8%). Among 152 subjects tested for HBV load, 49 (32.2%) had over 10(4) copies/mL and 16 (10.5%) had levels below the limit of detection. The E genotype was found in 91.1% of carriers. Fibrotest scores ≥ F2 were observed in 52 subjects (35.4%). Actitest scores ≥ A2 were detected in 15 subjects (10.2%) and were correlated with Fibrotest scores (p = 0.0006). Among 105 subjects tested, 60% had detectable levels of R249S copies (>40 copies/mL plasma). CONCLUSION Chronic HB carriage in adults in Bamako district is well over epidemic threshold. About 1/3 of carriers have moderate to severe liver fibrosis and 60% have detectable aflatoxin-related TP53 R249S mutation. These results support introduction of anti-HB therapies to reduce the progression towards severe liver disease.
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Affiliation(s)
- Fatou Traoré
- Centre d'Infectiologie Charles Mérieux, Bamako, République du Mali.
| | - Emmanuelle Gormally
- Université de Lyon, UMRS 449 ; Laboratoire de Biologie générale, Université Catholique de Lyon ; Reproduction et développement comparé, EPHE, Lyon, France.
| | | | - Marlin D Friesen
- Bloomberg School of Public Health, Johns Hopkins University, Baltimore, USA.
| | - John D Groopman
- Bloomberg School of Public Health, Johns Hopkins University, Baltimore, USA.
| | - Guy Vernet
- Laboratoire des Pathogènes Emergents Fondation Mérieux, Lyon, France.
- Centre Pasteur du Cameroun, Yaoundé, Cameroun.
| | | | - Pierre Hainaut
- International Prevention Research Institute, Lyon, France.
| | - Moussa Y Maiga
- Service de Gastroentérologie et Hépatologie, Centre Hospitalier Universitaire Gabriel Touré, Bamako, République du Mali.
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Pais R, Rusu E, Zilisteanu D, Circiumaru A, Micu L, Voiculescu M, Poynard T, Ratziu V. Prevalence of steatosis and insulin resistance in patients with chronic hepatitis B compared with chronic hepatitis C and non-alcoholic fatty liver disease. Eur J Intern Med 2015; 26:30-6. [PMID: 25553983 DOI: 10.1016/j.ejim.2014.12.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2014] [Revised: 10/25/2014] [Accepted: 12/01/2014] [Indexed: 02/07/2023]
Abstract
UNLABELLED The association of NAFLD with chronic hepatitis C (CHC) has been extensively studied but little is known about its coexistence with chronic hepatitis B (CHB). AIMS To investigate the prevalence and determinants of steatosis and insulin resistance (IR) in CHB and its consequences on liver injury compared with CHC and NAFLD. METHODS Patients with CHB (N=110), CHC (N=111) and NAFLD (N=136) were evaluated by biomarkers of steatosis (SteatoTest>0.38 as a surrogate for steatosis >5%), IR (HOMA-IR>2.7 as a surrogate for IR) and fibrosis (FibroTest>0.48 as a surrogate for significant fibrosis, ≥F2). RESULTS HOMA-IR gradually increased in CHB, CHC and NAFLD: 2.3±1.8; 3±2.6 and 3.8±2.7 (p<0.001). The prevalence of steatosis >5% was 21% (CHB), 43% (CHC) and 82% (NAFLD), (p<0.001). The prevalence of fibrosis≥F2 was 10% (CHB), 42% (CHC) and 21% (NAFLD), p<0.001. In CHB, IR was related to host and not viral factors. CHB patients with steatosis had higher BMI (29±5.7kg/m(2) vs. 24±4kg/m(2), p<0.001), waist circumference (96±14cm vs. 84±11cm, p=0.001) and HOMA-IR (3.9±2.6 vs. 1.8±1.2, p<0.001) than those without steatosis. HOMA-IR independently predicted steatosis in CHB (OR=1.9, 95% CI, 1.09-3.27, p<0.05) and CHC (OR=1.38; 95% CI, 1.07-1.78, p<0.02). In CHB, metabolic risk factors and HOMA-IR were not associated with significant fibrosis. HOMA-IR was an independent predictor of fibrosis in CHC. CONCLUSIONS Steatosis may co-exist in CHB patients but with a lower prevalence than in CHC and NAFLD. In CHB steatosis is related to host and not viral factors, and is not associated with the severity of fibrosis.
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Affiliation(s)
- Raluca Pais
- Université Pierre et Marie Curie, Hôpital Pitié Salpêtrière, Paris, France; INSERM, UMRS 938, Paris, France.
| | - Elena Rusu
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania; Clinic of Internal Medicine and Nephrology, Fundeni Clinical Institute, Bucharest, Romania.
| | - Diana Zilisteanu
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania; Clinic of Internal Medicine and Nephrology, Fundeni Clinical Institute, Bucharest, Romania.
| | - Alexandra Circiumaru
- Clinic of Internal Medicine and Nephrology, Fundeni Clinical Institute, Bucharest, Romania.
| | - Laurentiu Micu
- Clinic of Internal Medicine and Nephrology, Fundeni Clinical Institute, Bucharest, Romania.
| | - Mihai Voiculescu
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania; Clinic of Internal Medicine and Nephrology, Fundeni Clinical Institute, Bucharest, Romania.
| | - Thierry Poynard
- Université Pierre et Marie Curie, Hôpital Pitié Salpêtrière, Paris, France; INSERM, UMRS 938, Paris, France.
| | - Vlad Ratziu
- Université Pierre et Marie Curie, Hôpital Pitié Salpêtrière, Paris, France; INSERM, UMRS 938, Paris, France.
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Poynard T, Vergniol J, Ngo Y, Foucher J, Thibault V, Munteanu M, Merrouche W, Lebray P, Rudler M, Deckmyn O, Perazzo H, Thabut D, Ratziu V, de Ledinghen V. Staging chronic hepatitis B into seven categories, defining inactive carriers and assessing treatment impact using a fibrosis biomarker (FibroTest®) and elastography (FibroScan®). J Hepatol 2014; 61:994-1003. [PMID: 25016224 DOI: 10.1016/j.jhep.2014.06.027] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 06/16/2014] [Accepted: 06/20/2014] [Indexed: 12/30/2022]
Abstract
BACKGROUND & AIMS The first aim was to extend the validation of FibroTest® (FT) and transient elastography (TE) as markers of occurrence of cirrhosis without complications (F4.1), oesophageal varices (F4.2), and severe complications (F4.3) in patients with chronic hepatitis B (CHB). The second aim was to validate a previous definition of an inactive carrier based on normal FT and ActiTest® (normal-FT-AT). The third aim was to assess the long-term dynamics of fibrosis in patients with sustained virological response. METHODS The 10-year updated individual data of 1434 patients were pooled from two prospective cohorts. RESULTS Of the 1312 patients without a history of complications, varices had occurred after 10 years in 14 patients (F4.2, incidence of 1.7%, 95% CI [0.6-2.8]), and severe complications in 25 (F4.3 3.7% [1.8-5.7]), including hepatocellular carcinoma (HCC) in 21 (3.7% [1.5-5.8]). Using Cox-multivariate analysis adjusted for treatment, viral load, HBeAg status and ALT, FT, and TE were predictive of liver complications (n=37; AUROC=0.83 [0.71-0.90]; p<0.0001) and (n=8/844; AUROC=0.82 [0.72-0.89]; p<0.0001) respectively. Normal FT-AT better identified patients with lower fibrosis progression than the ALT-based standard: 3/163 (1.8%) vs. 16/181 (8.8%; p=0.004) in the Paris cohort, and 5/195 (2.6%) vs. 15/228 (6.6%; p=0.05) in the Bordeaux cohort. Of the 582 responders, 23 had complications (incidence 6.2% [3.2-9.1]) including 19 HCC (5.8% [2.6-9.0]) and 10 with varices (2.6% [0.8-4.4]). Of the 138 responders with advanced fibrosis, only 31% (15-47%) had fibrosis regression. CONCLUSIONS FibroTest® and TE identified three categories of cirrhosis with increasing morbidity. Normal FibroTest® and ActiTest® were better able to identify inactive hepatitis B carriers than the standard definition. Despite virological response, the overall incidence of cirrhosis increased, with a remaining 5.8% risk of HCC.
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Affiliation(s)
- Thierry Poynard
- Assistance Publique Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière, Paris, France; University Pierre et Marie Curie (UPMC) University of Paris VI, Paris, France; INSERM, UMRS 938, Paris, France.
| | | | - Yen Ngo
- BioPredictive, Paris, France
| | | | - Vincent Thibault
- Assistance Publique Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | | | | | - Pascal Lebray
- Assistance Publique Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Marika Rudler
- Assistance Publique Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | | | - Hugo Perazzo
- Assistance Publique Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Dominique Thabut
- Assistance Publique Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Vlad Ratziu
- Assistance Publique Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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Branchi F, Conti CB, Baccarin A, Lampertico P, Conte D, Fraquelli M. Non-invasive assessment of liver fibrosis in chronic hepatitis B. World J Gastroenterol 2014; 20:14568-14580. [PMID: 25356021 PMCID: PMC4209524 DOI: 10.3748/wjg.v20.i40.14568] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2013] [Revised: 01/10/2014] [Accepted: 06/05/2014] [Indexed: 02/06/2023] Open
Abstract
The goal of this review is to provide a comprehensive picture of the role, clinical applications and future perspectives of the most widely used non-invasive techniques for the evaluation of hepatitis B virus (HBV) infection. During the past decade many non-invasive methods have been developed to reduce the need for liver biopsy in staging fibrosis and to overcome whenever possible its limitations, mainly: invasiveness, costs, low reproducibility, poor acceptance by patients. Elastographic techniques conceived to assess liver stiffness, in particular transient elastography, and the most commonly used biological markers will be assessed against their respective role and limitations in staging hepatic fibrosis. Recent evidence highlights that both liver stiffness and some bio-chemical markers correlate with survival and major clinical end-points such as liver decompensation, development of hepatocellular carcinoma and portal hypertension. Thus the non-invasive techniques here discussed can play a major role in the management of patients with chronic HBV-related hepatitis. Given their prognostic value, transient elastography and some bio-chemical markers can be used to better categorize patients with advanced fibrosis and cirrhosis and assign them to different classes of risk for clinically relevant outcomes. Very recent data indicates that the combined measurements of liver and spleen stiffness enable the reliable prediction of portal hypertension and esophageal varices development.
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Enomoto M, Morikawa H, Tamori A, Kawada N. Noninvasive assessment of liver fibrosis in patients with chronic hepatitis B. World J Gastroenterol 2014; 20:12031-12038. [PMID: 25232240 PMCID: PMC4161791 DOI: 10.3748/wjg.v20.i34.12031] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 02/09/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Infection with hepatitis B virus is an important health problem worldwide: it affects more than 350 million people 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.
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Bessone F. Re-appraisal of old and new diagnostic tools in the current management of chronic hepatitis B. Liver Int 2014; 34:991-1000. [PMID: 25098191 DOI: 10.1111/liv.12499] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Accepted: 02/05/2014] [Indexed: 12/11/2022]
Abstract
Hepatitis B virus (HBV) is a very complex and intricate DNA structure associated with a particular genomic organization and replication cycle. However, many years of investigations allowed clarification of the real HBV natural history, through a deeper knowledge of the behavior of HBV antigens and viral structures. Several of the old diagnostic tools, such as HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) determinations, gained prominence now, since the variation of both HBsAg and HBeAg plasma levels was shown to predict treatment response. In addition, the availability of more sensitive methods, such as HBV DNA detection by real-time PCR, has improved the current knowledge of the relationships between HBV replication levels and the natural history of the disease. It is now well established that some HBV genotypes are associated with a better response to treatment with pegylated interferon. Despite the widely accepted value of liver biopsy as a staging tool, transient elastography is being increasingly acknowledged as a non-invasive method to assess liver stiffness, chiefly for detection of advanced fibrosis. Current international guidelines for the management of chronic hepatitis B have provided several accurate biochemical and serological criteria for selecting patients for treatment, allowing a higher number of cases to be enrolled into antiviral therapy. This review describes the different serological markers used for the study of HBV and their clinical significance. It also deals with methods used for detection of genotypes and HBV DNA, emphasizing the effectiveness of such determinations for both patient selection and chronic hepatitis B therapy/monitoring.
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Affiliation(s)
- Fernando Bessone
- Gastroenterology and Hepatology Department, School of Medicine, University of Rosario, Rosario, Santa Fe, Argentina
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12
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Vergniol J, Boursier J, Coutzac C, Bertrais S, Foucher J, Angel C, Chermak F, Hubert IF, Merrouche W, Oberti F, de Lédinghen V, Calès P. Evolution of noninvasive tests of liver fibrosis is associated with prognosis in patients with chronic hepatitis C. Hepatology 2014; 60:65-76. [PMID: 24519328 DOI: 10.1002/hep.27069] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Accepted: 02/06/2014] [Indexed: 12/13/2022]
Abstract
UNLABELLED No data are available about the prediction of long-term survival using repeated noninvasive tests of liver fibrosis in chronic hepatitis C (CHC). We aimed to assess the prognostic value of 3-year liver stiffness measurement (LSM), aspartate aminotransferase to platelet ratio index (APRI), and fibrosis 4 (FIB-4) evolution in CHC. CHC patients with two LSM (1,000-1,500 days interval) were prospectively included. Blood fibrosis tests APRI and FIB-4 were calculated the day of baseline (bLSM) and follow-up (fLSM) LSM. Evolution of fibrosis tests was expressed as delta: (follow-up-baseline results)/duration. Date and cause of death were recorded during follow-up that started the day of fLSM. In all, 1,025 patients were included. Median follow-up after fLSM was 38.0 months (interquartile range [IQR]: 27.7-46.1) during which 35 patients died (14 liver-related death) and seven had liver transplantation. Prognostic accuracy (Harrell C-index) of multivariate models including baseline and delta results was not significantly different between LSM and FIB-4 (P ≥ 0.24), whereas FIB-4 provided more accurate prognostic models than APRI (P = 0.03). By multivariate analysis including LSM variables, overall survival was independently predicted by bLSM, delta (dLSM), and sustained virological response (SVR). Prognosis was excellent in patients having bLSM <7 kPa, SVR, or no increase (<1 kPa/year) in 7-14 kPa bLSM. Prognosis was significantly impaired in patients with an increase (≥ 1 kPa/year) in 7-14 kPa bLSM, or decrease (≤ 0 kPa/year) in ≥ 14 kPa bLSM (P = 0.949 between these two groups). Patients with an increase (>0 kPa/year) in ≥ 14 kPa bLSM had the worst prognosis. Baseline and delta FIB-4 also identified patient subgroups with significantly different prognosis. CONCLUSION Three-year evolution of noninvasive tests of liver fibrosis has a strong prognostic value in CHC patients. These tests should be repeated to monitor patients and predict their outcome.
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Affiliation(s)
- Julien Vergniol
- Centre d'Investigation de la Fibrose hépatique, Hôpital Haut-Lévêque, Centre Hospitalier Universitaire de Bordeaux, Pessac, France
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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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Pang JXQ, Zimmer S, Niu S, Crotty P, Tracey J, Pradhan F, Shaheen AAM, Coffin CS, Heitman SJ, Kaplan GG, Swain MG, Myers RP. Liver stiffness by transient elastography predicts liver-related complications and mortality in patients with chronic liver disease. PLoS One 2014; 9:e95776. [PMID: 24755824 PMCID: PMC3995722 DOI: 10.1371/journal.pone.0095776] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 03/29/2014] [Indexed: 12/18/2022] Open
Abstract
Background Liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) is a validated method for noninvasively staging liver fibrosis. Most hepatic complications occur in patients with advanced fibrosis. Our objective was to determine the ability of LSM by TE to predict hepatic complications and mortality in a large cohort of patients with chronic liver disease. Methods In consecutive adults who underwent LSM by TE between July 2008 and June 2011, we used Cox regression to determine the independent association between liver stiffness and death or hepatic complications (decompensation, hepatocellular carcinoma, and liver transplantation). The performance of LSM to predict complications was determined using the c-statistic. Results Among 2,052 patients (median age 51 years, 65% with hepatitis B or C), 87 patients (4.2%) died or developed a hepatic complication during a median follow-up period of 15.6 months (interquartile range, 11.0–23.5 months). Patients with complications had higher median liver stiffness than those without complications (13.5 vs. 6.0 kPa; P<0.00005). The 2-year incidence rates of death or hepatic complications were 2.6%, 9%, 19%, and 34% in patients with liver stiffness <10, 10–19.9, 20–39.9, and ≥40 kPa, respectively (P<0.00005). After adjustment for potential confounders, liver stiffness by TE was an independent predictor of complications (hazard ratio [HR] 1.05 per kPa; 95% confidence interval [CI] 1.03–1.06). The c-statistic of liver-stiffness for predicting complications was 0.80 (95% CI 0.75–0.85). A liver stiffness below 20 kPa effectively excluded complications (specificity 93%, negative predictive value 97%); however, the positive predictive value of higher results was sub-optimal (20%). Conclusions Liver stiffness by TE accurately predicts the risk of death or hepatic complications in patients with chronic liver disease. TE may facilitate the estimation of prognosis and guide management of these patients.
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Affiliation(s)
- Jack X. Q. Pang
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Scott Zimmer
- Medical Services, Alberta Health Services, Calgary, Alberta, Canada
| | - Sophia Niu
- Medical Services, Alberta Health Services, Calgary, Alberta, Canada
| | - Pam Crotty
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Jenna Tracey
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Faruq Pradhan
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Abdel Aziz M. Shaheen
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Carla S. Coffin
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Steven J. Heitman
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Gilaad G. Kaplan
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Mark G. Swain
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Robert P. Myers
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
- * E-mail:
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15
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Castera L. Hepatitis B: are non-invasive markers of liver fibrosis reliable? Liver Int 2014; 34 Suppl 1:91-6. [PMID: 24373084 DOI: 10.1111/liv.12393] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 10/25/2013] [Indexed: 02/06/2023]
Abstract
Liver biopsy, which was traditionally considered to be the gold standard for the staging of fibrosis, has been challenged in the past decade by non-invasive techniques. These techniques rely on two distinct but complementary approaches: a 'biological' approach, based on the quantification of biomarkers of fibrosis in serum, and a 'physical' approach, based on the measurement of liver stiffness using elastography-based technologies. Advantages of serum biomarkers include their high applicability (>95%) and good reproducibility. However, as none are liver specific their results can be influenced by comorbid conditions (risk of false positive results with FibroTest in patients with Gilbert's syndrome or with APRI in case of acute hepatitis). Transient elastograpy has the advantages of being a user's friendly procedure that can be performed at the bedside or in an outpatient clinic with high performance for detecting cirrhosis. However, its applicability is lower (80%) than that of serum biomarker (particularly in case of ascites, obesity and limited operator experience) with the risk of false positive results in case of ALT flares. Although these non-invasive methods were initially developed and validated in patients with chronic hepatitis C, they are now increasingly used in patients with hepatitis B, reducing the need for liver biopsy.
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Affiliation(s)
- Laurent Castera
- Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, INSERM U773 CRB 3, Université Denis Diderot, Paris-7, Clichy, France
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Impact of genetic heterogeneity in polymerase of hepatitis B virus on dynamics of viral load and hepatitis B progression. PLoS One 2013; 8:e70169. [PMID: 23936156 PMCID: PMC3728348 DOI: 10.1371/journal.pone.0070169] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 06/17/2013] [Indexed: 12/14/2022] Open
Abstract
Objective The hepatitis B virus (HBV)-polymerase region overlaps pre-S/S genes with high epitope density and plays an essential role in viral replication. We investigated whether genetic variation in the polymerase region determined long-term dynamics of viral load and the risk of hepatitis B progression in a population-based cohort study. Methods We sequenced the HBV-polymerase region using baseline plasma from treatment-naïve individuals with HBV-DNA levels≥1000 copies/mL in a longitudinal viral-load study of participants with chronic HBV infection followed-up for 17 years, and obtained sequences from 575 participants (80% with HBV genotype Ba and 17% with Ce). Results Patterns of viral sequence diversity across phases (i.e., immune-tolerant, immune-clearance, non/low replicative, and hepatitis B e antigen (HBeAg)-negative hepatitis phases) of HBV-infection, which were associated with viral and clinical features at baseline and during follow-up, were similar between HBV genotypes, despite greater diversity for genotype Ce vs. Ba. Irrespective of genotypes, however, HBeAg-negative participants had 1.5-to-2-fold higher levels of sequence diversity than HBeAg-positive participants (P<0.0001). Furthermore, levels of viral genetic divergence from the population consensus sequence, estimated by numbers of nucleotide substitutions, were inversely associated with long-term viral load even in HBeAg-negative participants. A mixed model developed through analysis of the entire HBV-polymerase region identified 153 viral load-associated single nucleotide polymorphisms in overall and 136 in HBeAg-negative participants, with distinct profiles between HBV genotypes. These polymorphisms were most evident at sites within or flanking T-cell epitopes. Seven polymorphisms revealed associations with both enhanced viral load and a more than 4-fold increased risk of hepatocellular carcinoma and/or liver cirrhosis. Conclusions The data highlight a role of viral genetic divergence in the natural course of HBV-infection. Interindividual differences in the long-term dynamics of viral load is not only associated with accumulation of mutations in HBV-polymerase region, but differences in specific viral polymorphisms which differ between genotypes.
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de Lédinghen V, Vergniol J, Barthe C, Foucher J, Chermak F, Le Bail B, Merrouche W, Bernard PH. Non-invasive tests for fibrosis and liver stiffness predict 5-year survival of patients chronically infected with hepatitis B virus. Aliment Pharmacol Ther 2013; 37:979-88. [PMID: 23557139 DOI: 10.1111/apt.12307] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Revised: 01/03/2013] [Accepted: 03/19/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Liver stiffness and non-invasive tests predict overall survival in chronic hepatitis C. However, in patients chronically infected with hepatitis B virus (HBV), only the association between liver stiffness and the risk of hepatocellular carcinoma has been published. AIM To evaluate the 5-year prognostic value of liver stiffness, non-invasive tests of liver fibrosis, and liver biopsy, to predict overall survival in chronic hepatitis B. METHODS In a consecutive cohort, we prospectively assessed fibrosis, with liver stiffness, FibroTest, APRI, FIB-4 and liver biopsy (if indicated). We examined death and liver transplantation during a 5-year follow-up, and factors associated with overall survival. RESULTS A total of 600 patients (men 64%, mean age 42 years, inactive carriers 36%) with chronic hepatitis B were included. At 5 years, 25 patients were dead (13 liver-related deaths) and four patients had liver transplantation. Overall survival was 94.1% and survival without liver-related death 96.3%. No liver-related death was observed in inactive carriers. Survival was significantly decreased in patients diagnosed with severe fibrosis, whatever the non-invasive method used (P < 0.0001), or liver biopsy (P = 0.02). Patients' prognosis decreased as liver stiffness and FibroTest increased. In multivariate analysis, FibroTest and liver stiffness had the highest hazard ratio with survival. The association persisted after adjustment on age, necro-inflammatory histological activity presumed by ActiTest and treatment. CONCLUSIONS Liver stiffness measurement or FibroTest can predict survival in chronic HBV infection. Thus, these tools may help physicians to early assess prognosis and discuss specific treatments, such as liver transplantation.
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Affiliation(s)
- V de Lédinghen
- Centre d'Investigation de la Fibrose hépatique, Hôpital Haut-Lévêque, CHU Bordeaux, Pessac, France.
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Castera L. Noninvasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology 2012; 142:1293-1302.e4. [PMID: 22537436 DOI: 10.1053/j.gastro.2012.02.017] [Citation(s) in RCA: 433] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2011] [Revised: 02/08/2012] [Accepted: 02/09/2012] [Indexed: 12/13/2022]
Abstract
The prognosis and management of patients with chronic viral hepatitis B and C depend on the amount and progression of liver fibrosis and the risk for cirrhosis. Liver biopsy, traditionally considered to be the reference standard for staging of fibrosis, has been challenged over the past decade by the development of noninvasive methodologies. These methods rely on distinct but complementary approaches: a biologic approach, which quantifies serum levels of biomarkers of fibrosis, and a physical approach, which measures liver stiffness by ultrasound or magnetic resonance elastography. Noninvasive methods were initially studied and validated in patients with chronic hepatitis C but are now used increasingly for patients with hepatitis B, reducing the need for liver biopsy analysis. We review the advantages and limitations of the noninvasive methods used to manage patients with chronic viral hepatitis B or C infection.
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Affiliation(s)
- Laurent Castera
- Department of Hepatology, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Inserm U773 CRB3, Université Denis Diderot Paris-7, Clichy, France.
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Poynard T, Lassailly G, Diaz E, Clement K, Caïazzo R, Tordjman J, Munteanu M, Perazzo H, Demol B, Callafe R, Pattou F, Charlotte F, Bedossa P, Mathurin P, Ratziu V. Performance of biomarkers FibroTest, ActiTest, SteatoTest, and NashTest in patients with severe obesity: meta analysis of individual patient data. PLoS One 2012; 7:e30325. [PMID: 22431959 PMCID: PMC3303768 DOI: 10.1371/journal.pone.0030325] [Citation(s) in RCA: 97] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2011] [Accepted: 12/19/2011] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Liver biopsy is considered as the gold standard for assessing non-alcoholic fatty liver disease (NAFLD) histologic lesions in patients with severe obesity. The aim of this study was to perform an overview of 3 studies which assessed the performance of non-invasive markers of fibrosis (FibroTest), steatosis (SteatoTest) and steato-hepatitis (NashTest, ActiTest) in these patients. METHODS 494 patients with interpretable biopsy and biomarkers using of three prospective cohorts of patients with severe obesity (BMI >35 kg/m2) were included. Histology (NAS score) and the biochemical measurements were blinded to any other characteristics. The area under the ROC curves (AUROC), sensitivity, specificity, positive and negative predictive values were assessed. Weighted AUROC (wAUROC Obuchowski method) was used to prevent multiple testing and spectrum effect. Two meta-analyses were performed; one used the individual patient, and the other a classical meta-analysis. RESULTS Prevalence of advanced fibrosis (bridging) was 9.9%, advanced steatosis (>33%) 54.2%, and steato-hepatitis (NAS score >4) 17.2%. The mean wAUROCs were: FibroTest for advanced fibrosis (95%CI; significance) = 0.85 (0.83-0.87; P<0.0001); SteatoTest for advanced steatosis = 0.80 (0.79-0.83); and ActiTest for steato-hepatitis = 0.84 (0.82-0.86; P<0.0001). Using the classical meta-analysis (random effect model) the mean AUROCs were: FibroTest = 0.72 (0.63-0.79; P<0.0001); SteatoTest = 0.71 (0.66-0.75; P<0.0001); and ActiTest = 0.74 (0.68-0.79; P<0.0001). Despite more metabolic risk factors in one cohort, results were similar according to gender, presence of diabetes and between the 3 cohorts. CONCLUSION In patients with severe obesity, a significant diagnostic performance of FibroTest, SteatoTest and ActiTest was observed for liver lesions.
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Poynard T, de Ledinghen V, Zarski JP, Stanciu C, Munteanu M, Vergniol J, France J, Trifan A, Le Naour G, Vaillant JC, Ratziu V, Charlotte F. Relative performances of FibroTest, Fibroscan, and biopsy for the assessment of the stage of liver fibrosis in patients with chronic hepatitis C: a step toward the truth in the absence of a gold standard. J Hepatol 2012; 56:541-8. [PMID: 21889468 DOI: 10.1016/j.jhep.2011.08.007] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2011] [Revised: 07/30/2011] [Accepted: 08/09/2011] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Liver fibrosis stage is traditionally assessed with biopsy, an imperfect gold standard. Two widely used techniques, FibroTest®, and liver stiffness measurement (LSM) using Fibroscan® have been validated using biopsy, and therefore the true performances of these estimates are still unknown in the absence of a perfect reference. The aim was to assess the relative accuracy of FibroTest, LSM, and biopsy using methods without gold standard in patients with chronic hepatitis C (CHC) and controls. METHODS A total of 1289 patients with CHC and 604 healthy volunteers, with assessment of fibrosis stage by the three techniques, and alanine aminotransferase (ALT) taken as a control test, were analyzed by latent class method with random effects. In the volunteers, the false positive risk of biopsy was obtained from a large surgical sample of four normal livers. RESULTS The latent class model with random effects permitted to conciliate the observed data and estimates of test performances. For advanced fibrosis, the specificity/sensitivity was for FibroTest 0.93/0.70, LSM 0.96/0.45, ALT 0.79/0.78 and biopsy 0.67/0.63, and for cirrhosis FibroTest 0.87/0.41, LSM 0.93/0.39, ALT 0.78/0.08 and biopsy 0.95/0.51. The analysis of the discordances between pairs suggested that the variability of the model was mainly related to the discordances between biopsy and LSM (residuals>10; p<0.0001). CONCLUSIONS A method without the use of a gold standard confirmed the accuracy of FibroTest and Fibroscan for the diagnosis of advanced fibrosis and cirrhosis in patients with chronic hepatitis C. The variability of the model was mostly due to the discordances between Fibroscan and biopsy.
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Sebastiani G, Castera L, Halfon P, Pol S, Mangia A, Di Marco V, Pirisi M, Voiculescu M, Bourliere M, Alberti A. The impact of liver disease aetiology and the stages of hepatic fibrosis on the performance of non-invasive fibrosis biomarkers: an international study of 2411 cases. Aliment Pharmacol Ther 2011; 34:1202-16. [PMID: 21981787 DOI: 10.1111/j.1365-2036.2011.04861.x] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Performance of non-invasive fibrosis biomarkers may be influenced by aetiology of chronic liver disease (CLD) and the stages of hepatic fibrosis, but large-scale studies are pending. AIM To investigate the effect of aetiogy and stages of hepatic fibrosis on the performance of fibrosis biomarkers. METHODS A total of 2411 patients with compensated CLD (HCV=75.1%, HBV=10.5%, NASH=7.9%, HIV/HCV=6.5%) were consecutively enrolled in 9 centres. APRI, Forns'index, Lok index, AST-to-ALT ratio, Fib-4, platelets and Fibrotest-Fibrosure were tested against liver biopsy, considered the gold standard. The effect of the stages of hepatic fibrosis to diagnose significant fibrosis and cirrhosis (≥F2 and F4 respectively) was investigated through difference between advanced and non-advanced fibrosis stages (DANA). Performance was expressed as observed area under the ROC curve (ObAUROC) and AUROC adjusted for DANA (AdjAUROC). RESULTS Performance of APRI and Fibrotest-Fibrosure was higher than other biomarkers. In all aetiologies, AdjAUROC was higher than ObAUROC. APRI showed its best performance in HCV monoinfected cases, with an AdjAUROC of 0.77 and 0.83 for ≥F2 and F4 respectively. In HBV and non-alcoholic steatohepatitis (NASH) patients, its performance was poor (AdjAUROC <0.70). Performance of Fibrotest-Fibrosure was good in all aetiologies for both ≥F2 and F4 (AdjAUROC >0.73), except for ≥F2 in NASH (AdjAUROC = 0.64). Performance of all biomarkers was reduced in HCV cases with normal ALT. CONCLUSIONS Aetiology is a major factor influencing the performance of liver fibrosis biomarkers. Even after correction for DANA, APRI and Fibrotest-Fibrosure exhibit the best performance. However, liver biopsy is not replaceable, especially to diagnose ≥F2 and in HCV carriers with normal ALT.
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Affiliation(s)
- G Sebastiani
- VIMM-Venetian Institute of Molecular Medicine, Padua, Italy
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Poynard T, Ngo Y, Perazzo H, Munteanu M, Lebray P, Moussalli J, Thabut D, Benhamou Y, Ratziu V. Prognostic value of liver fibrosis biomarkers: a meta-analysis. Gastroenterol Hepatol (N Y) 2011; 7:445-54. [PMID: 22298979 PMCID: PMC3264893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
AIMS AND METHODS Several serum biomarkers such as FibroTest, aspartate transaminase-platelet ratio index (APRI), FIB-4, and liver stiffness measurement by FibroScan have been validated as alternatives to biopsy for the diagnosis of fibrosis in patients with chronic liver disease. This paper aims to assess the 5-year prognostic values of these biomarkers. A meta-analysis combined all published prognostic studies. Baseline biopsy and APRI data were used as references. RESULTS Only 3 biomarkers had several prognostic validations: FibroTest (4 studies; 2,396 patients), APRI (5 studies; 2,422 patients), and FIB-4 (3 studies; 1,184 patients). For the prediction of survival without liver-related death, the areas under the receiver operating characteristic curves (AUROCs) were 0.86 for biopsy (95% confidence interval [CI], 0.77-0.95), 0.88 for FibroTest (95% CI, 0.79-0.98), 0.73 for FIB-4 (95% CI, 0.62-0.85), and 0.66 for APRI (95% CI, 0.57-0.75). APRI had a significantly lower prognostic value versus biopsy, with a mean difference between AUROCs of -0.21 (95% CI, -0.33 to -0.10; P<.001); FIB-4 had a significantly lower prognostic value versus biopsy, with a mean difference between AUROCs of -0.21 (95% CI, -0.20 to -0.02; P=.02). Only FibroTest did not show a significant difference in prognostic value versus biopsy, with a mean difference in AUROCs of +0.02 (95% CI, -0.05 to +0.09; P=.85). CONCLUSION FibroTest is a validated biomarker for the prognosis of patients with chronic liver disease.
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Affiliation(s)
- Thierry Poynard
- Drs. Poynard, Perazzo, Lebray, Moussalli, Thabut, Benhamou, and Ratziu are affiliated with the Department of Hepato-Gastroenterology at the APHP UPMC Liver Center in Paris, France. Drs. Ngo and Munteanu are affiliated with Biopredictive in Paris, France
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Poynard T, Ngo Y, Munteanu M, Thabut D, Ratziu V. Noninvasive Markers of Hepatic Fibrosis in Chronic Hepatitis B. CURRENT HEPATITIS REPORTS 2011; 10:87-97. [PMID: 21654911 PMCID: PMC3085108 DOI: 10.1007/s11901-011-0096-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
A serum biomarker (FibroTest; Biopredictive, Paris, France; FibroSure; LabCorp, Burlington, USA) and liver stiffness measurement (LSM) by Fibroscan (Echosens, Paris, France) have been extensively validated in chronic hepatitis C. This review updates the clinical validation of serum biomarkers and LSM in patients with chronic hepatitis B (CHB). One meta-analysis combined all published studies and another used a database combining FibroTest individual data. Sensitivity analysis assessed the impact of several factors, including authors' independence, length of biopsy, ethnicity, hepatitis B early antigen status, viral load, and alanine aminotransferase value. Only two biomarkers had several validations: FibroTest (8 studies, 1,842 patients), and Fibroscan (5 studies, 618 patients). For the diagnosis of advanced fibrosis, the standardized area under the receiver operating curve was 0.84 (0.79-0.86) for FibroTest and 0.89 (0.83-0.96) for LSM, without significant difference. No significant factors of variability were identified for FibroTest's performance. In conclusion, FibroTest and LSM were the most validated biomarkers of fibrosis in CHB. However, the reliability of Fibroscan must be better assessed.
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Affiliation(s)
- Thierry Poynard
- Assistance Publique Hôpitaux de Paris-University Pierre et Marie Curie, Liver Center, Groupe Hospitalier Pitié Salpêtrière, 75013 Paris, France
| | - Yen Ngo
- Biopredictive, 40 Rue du Bac, 75007 Paris, France
| | | | - Dominique Thabut
- Assistance Publique Hôpitaux de Paris-University Pierre et Marie Curie, Liver Center, Groupe Hospitalier Pitié Salpêtrière, 75013 Paris, France
| | - Vlad Ratziu
- Assistance Publique Hôpitaux de Paris-University Pierre et Marie Curie, Liver Center, Groupe Hospitalier Pitié Salpêtrière, 75013 Paris, France
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Vergniol J, Foucher J, Terrebonne E, Bernard PH, le Bail B, Merrouche W, Couzigou P, de Ledinghen V. Noninvasive tests for fibrosis and liver stiffness predict 5-year outcomes of patients with chronic hepatitis C. Gastroenterology 2011; 140:1970-9, 1979.e1-3. [PMID: 21376047 DOI: 10.1053/j.gastro.2011.02.058] [Citation(s) in RCA: 308] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2010] [Revised: 01/25/2011] [Accepted: 02/18/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Liver stiffness can be measured noninvasively to assess liver fibrosis in patients with chronic hepatitis C. In patients with chronic liver diseases, level of fibrosis predicts liver-related complications and survival. We evaluated the abilities of liver stiffness, results from noninvasive tests for fibrosis, and liver biopsy analyses to predict overall survival or survival without liver-related death with a 5-year period. METHODS In a consecutive cohort of 1457 patients with chronic hepatitis C, we assessed fibrosis and, on the same day, liver stiffness, performed noninvasive tests of fibrosis (FibroTest, the aspartate aminotransferase to platelet ratio index, FIB-4), and analyzed liver biopsy samples. We analyzed data on death, liver-related death, and liver transplantation collected during a 5-year follow-up period. RESULTS At 5 years, 77 patients had died (39 liver-related deaths) and 16 patients had undergone liver transplantation. Overall survival was 91.7% and survival without liver-related death was 94.4%. Survival was significantly decreased among patients diagnosed with severe fibrosis, regardless of the noninvasive method of analysis. All methods were able to predict shorter survival times in this large population; liver stiffness and results of FibroTest had higher predictive values. Patient outcomes worsened as liver stiffness and FibroTest values increased. Prognostic values of stiffness (P<.0001) and FibroTest results (P<.0001) remained after they were adjusted for treatment response, patient age, and estimates of necroinflammatory grade. CONCLUSIONS Noninvasive tests for liver fibrosis (measurement of liver stiffness or FibroTest) can predict 5-year survival of patients with chronic hepatitis C. These tools might help physicians determine prognosis at earlier stages and discuss specific treatments, such as liver transplantation.
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Affiliation(s)
- Julien Vergniol
- Centre d'Investigation de la Fibrose hépatique, Hôpital Haut-Lévêque, CHU Bordeaux, Pessac, France
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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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M'Kada H, Munteanu M, Perazzo H, Ngo Y, Ramanujam N, Imbert-Bismut F, Ratziu V, Bonnefont-Rousselot D, Souberbielle B, Schuppe-Koistinen I, Poynard T. What are the best reference values for a normal serum alanine transaminase activity (ALT)? Impact on the presumed prevalence of drug induced liver injury (DILI). Regul Toxicol Pharmacol 2011; 60:290-5. [PMID: 21539883 DOI: 10.1016/j.yrtph.2011.04.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Revised: 04/02/2011] [Accepted: 04/02/2011] [Indexed: 01/03/2023]
Abstract
BACKGROUND In clinical research, the definition of the upper limit of normal (ULN) is rarely detailed. For alanine transaminase (ALT), there are several definitions of ULN-ALT but no recognized global reference. Furthermore the inter-laboratory variability of results expressed using ULN-ALT is higher than using the actual value of ULN expressed in IU/L. Regulatory agencies still use ULN-ALT for the definition of drug adverse events such as drug induced liver disease (DILI). METHODS We applied two extreme definitions of ULN-ALT (26 and 66 IU/L) in two populations with different liver disease risk: 7463 consecutive volunteers representative a low risk population, and 6865 consecutive patients hospitalized in a tertiary referral center. The same assay technique was used for both populations on fresh plasma in the same laboratory. RESULTS In the low risk population the liver disease estimates ranged from 0% to 1.99% according to ULN-ALT definition and gender; prevalence of liver disease as defined by Temple's criteria (3×ULN) decreased significantly with increased ULN-ALT threshold and prevalence of liver disease was lower in females compared to males (all P<0.001). In the high risk population the estimates of liver disease prevalence ranged from 0.78% to 15.85%; disease prevalence using both Temple's corollary and Hy's law criteria (3×ULN-ALT and bilirubin >34 μmol/L) decreased significantly with increased ULN-ALT threshold and females compared to males. In the low risk population the two major factors associated with ULN variability were gender and BMI. CONCLUSION Artificial statistical modifications of the procedures chosen for the ULN-ALT definition change dramatically the prevalence of DILI estimates. A consensus in liver disease definitions seems mandatory for DILI studies in order to prevent misleading conclusions.
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Affiliation(s)
- Helmi M'Kada
- Assistance Publique Hôpitaux de Paris UPMC Liver Center, Paris, France
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Castéra L, Bernard PH, Le Bail B, Foucher J, Trimoulet P, Merrouche W, Couzigou P, de Lédinghen V. Transient elastography and biomarkers for liver fibrosis assessment and follow-up of inactive hepatitis B carriers. Aliment Pharmacol Ther 2011; 33:455-65. [PMID: 21235598 DOI: 10.1111/j.1365-2036.2010.04547.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Non invasive methods for fibrosis evaluation remain to be validated longitudinally in hepatitis B. AIM To evaluate longitudinally transient elastography (TE) and biomarkers for liver fibrosis assessment and follow-up of hepatitis B virus (HBV) inactive carriers. METHODS Three hundred and twenty-nine consecutive HBeAg-negative HBV patients (201 inactive carriers) who underwent TE, Fibrotest and aspartate to platelet ratio index (APRI) the same day were studied. RESULTS TE (median 4.8 vs. 6.8 kPa, P < 0.0001), Fibrotest (0.16 vs. 0.35, P < 0.0001) and APRI values (0.28 vs. 0.43, P < 0.0001) were significantly lower in inactive carriers than in the remaining patients whereas they did not differ among inactive carriers according to HBV DNA levels. In 82 inactive carriers with repeated examinations, although differences were observed among individual patients, TE values did not differ significantly over time (median intra-patient changes at end of follow-up relative to baseline: -0.2 kPa, P = 0.12). Conversely, significant fluctuations were observed for Fibrotest (+0.03, P = 0.012) and APRI (-0.01, P < 0.05). Eleven inactive carriers (5.5%) had initial elevated TE values (>7.2 kPa) confirmed during follow-up in two with significant fibrosis (F2 and F3) on liver biopsy. CONCLUSION Non-invasive tools, particularly TE, could be useful, in addition to HBV DNA and transaminase levels, for follow-up of HBV inactive carriers as well as better selection of patients who require a liver biopsy.
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Affiliation(s)
- L Castéra
- Hôpital Haut-Lévêque, Centre Hospitalier Universitaire Bordeaux, Pessac, France.
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Poynard T, Munteanu M, Colombo M, Bruix J, Schiff E, Terg R, Flamm S, Moreno-Otero R, Carrilho F, Schmidt W, Berg T, McGarrity T, Heathcote EJ, Gonçales F, Diago M, Craxi A, Silva M, Boparai N, Griffel L, Burroughs M, Brass C, Albrecht J. FibroTest is an independent predictor of virologic response in chronic hepatitis C patients retreated with pegylated interferon alfa-2b and ribavirin in the EPIC³ program. J Hepatol 2011; 54:227-35. [PMID: 21056496 DOI: 10.1016/j.jhep.2010.06.038] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2010] [Revised: 06/16/2010] [Accepted: 06/22/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS EPIC-3 is a prospective, international study that has demonstrated the efficacy of PEG-IFN alfa-2b plus weight-based ribavirin in patients with chronic hepatitis C and significant fibrosis who previously failed any interferon-alfa/ribavirin therapy. The aim of the present study was to assess FibroTest (FT), a validated non-invasive marker of fibrosis in treatment-naive patients, as a possible alternative to biopsy as the baseline predictor of subsequent early virologic (EVR) and sustained virologic response (SVR) in previously treated patients. METHODS Of 2312 patients enrolled, 1459 had an available baseline FT, biopsy, and complete data. Uni- (UV) and multi-variable (MV) analyses were performed using FT and biopsy. RESULTS Baseline characteristics were similar as in the overall population; METAVIR stage: 28% F2, 29% F3, and 43% F4, previous relapsers 29%, previous PEG-IFN regimen 41%, high baseline viral load (BVL) 64%. 506 patients (35%) had undetectable HCV-RNA at TW12 (TW12neg), with 58% achieving SVR. The accuracy of FT was similar to that in naive patients: AUROC curve for the diagnosis of F4 vs F2=0.80 (p<0.00001). Five baseline factors were associated (p<0.001) with SVR in UV and MV analyses (odds ratio: UV/MV): fibrosis stage estimated using FT (4.5/5.9) or biopsy (1.5/1.6), genotype 2/3 (4.5/5.1), BVL (1.5/1.3), prior relapse (1.6/1.6), previous treatment with non-PEG-IFN (2.6/2.0). These same factors were associated (p ≤ 0.001) with EVR. Among patients TW12neg, two independent factors remained highly predictive of SVR by MV analysis (p ≤ 0.001): genotype 2/3 (odds ratio=2.9), fibrosis estimated with FT (4.3) or by biopsy (1.5). CONCLUSIONS FibroTest at baseline is a possible non-invasive alternative to biopsy for the prediction of EVR at 12 weeks and SVR, in patients with previous failures and advanced fibrosis, retreated with PEG-IFN alfa-2b and ribavirin.
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Thabut D, Moreau R, Lebrec D. Noninvasive assessment of portal hypertension in patients with cirrhosis. Hepatology 2011; 53:683-94. [PMID: 21274889 DOI: 10.1002/hep.24129] [Citation(s) in RCA: 106] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Severe portal hypertension is responsible for complications and death. Although measurement of the hepatic venous pressure gradient is the most accurate method for evaluating the presence and severity of portal hypertension, this technique is considered invasive and is not routinely performed in all centers. Several noninvasive techniques have been proposed to measure portal hypertension. Certain methods evaluate elements related to the pathogenesis of portal hypertension through the measurement of hyperkinetic syndrome, for example, or they investigate the development of hepatic fibrosis through the measurement of increased intrahepatic vascular resistance. Other methods evaluate the clinical consequences of portal hypertension, such as the presence of esophageal varices or the development of portosystemic shunts. Methods evaluating increased hepatic vascular resistance are fairly accurate and mainly involve the detection of hepatic fibrosis by serum markers and transient elastography. The radiological assessment of hyperkinetic syndrome probably has value but is still under investigation. The assessment of severe portal hypertension by the presence of varices may be performed with simple tools such as biological assays, computed tomography, and esophageal capsules. More sophisticated procedures seem promising but are still under development. Screening tools for large populations must be simple, whereas more complicated procedures could help in the follow-up of already diagnosed patients. Although most of these noninvasive methods effectively identify severe portal hypertension, methods for diagnosing moderate portal hypertension need to be developed; this shows that further investigation is needed in this field.
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Affiliation(s)
- Dominique Thabut
- Institut National de la Santé et de la Recherche Médicale Unité 773, Centre de Recherche Biomédicale Bichat-Beaujon, Paris, France
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Munteanu M, Hermeziu B, Bismut FI, Poynard T. Performance of the FibroTest cannot be accurately estimated in nine paediatric patients with advanced fibrosis. ACTA ACUST UNITED AC 2011; 43:159-60. [PMID: 21235307 DOI: 10.3109/00365548.2010.513013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Parkes J, Guha IN, Roderick P, Harris S, Cross R, Manos MM, Irving W, Zaitoun A, Wheatley M, Ryder S, Rosenberg W. Enhanced Liver Fibrosis (ELF) test accurately identifies liver fibrosis in patients with chronic hepatitis C. J Viral Hepat 2011; 18:23-31. [PMID: 20196799 DOI: 10.1111/j.1365-2893.2009.01263.x] [Citation(s) in RCA: 132] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Assessment of liver fibrosis is important in determining prognosis and evaluating interventions. Due to limitations of accuracy and patient hazard of liver biopsy, non-invasive methods have been sought to provide information on liver fibrosis, including the European liver fibrosis (ELF) test, shown to have good diagnostic accuracy for the detection of moderate and severe fibrosis. Access to independent cohorts of patients has provided an opportunity to explore if this test could be simplified. This paper reports the simplification of the ELF test and its ability to identity severity of liver fibrosis in external validation studies in patients with chronic hepatitis C (CHC). Paired biopsy and serum samples from 347 naïve patients with CHC in three independent cohorts were analysed. Diagnostic performance characteristics were derived (AUROC, sensitivity and specificity, predictive values), and clinical utility modelling performed to determine the proportion of biopsies that could have been avoided if ELF test was used in this patient group. It was possible to simplify the original ELF test without loss of performance and the new algorithm is reported. The simplified ELF test was able to predict severe fibrosis [pooled AUROC of 0.85 (95% CI 0.81-0.89)] and using clinical utility modelling to predict severe fibrosis (Ishak stages 4-6; METAVIR stages 3 and 4) 81% of biopsies could have been avoided (65% correctly). Issues of spectrum effect in diagnostic test evaluations are discussed. In chronic hepatitis C a simplified ELF test can detect severe liver fibrosis with good accuracy.
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Affiliation(s)
- J Parkes
- Public Health Sciences & Medical Statistics, University of Southampton, UK.
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Laparoscopic findings of reddish markings predict hepatocellular carcinoma in patients with hepatitis B virus-related liver disease. J Gastroenterol 2010; 45:1172-82. [PMID: 20549250 DOI: 10.1007/s00535-010-0266-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2010] [Accepted: 05/18/2010] [Indexed: 02/04/2023]
Abstract
BACKGROUND For patients with chronic hepatitis due to hepatitis B virus (HBV), factors predicting hepatocellular carcinoma (HCC) other than high levels of HBV-DNA and alanine aminotransferase (ALT) are needed to prevent HCC development, as many patients with chronic HBV infection fulfill these conditions. The purpose of this study was to clarify factors predictive of HCC development for those patients. METHODS The study was a systematic cohort analysis of 303 consecutive patients with hepatitis B e-antigen, receiving laparoscopic examination for assessment of liver disease. Laparoscopic, histological, and clinical characteristics were investigated as related to HCC development. RESULTS HCC occurred in 27 patients during a mean follow-up of 8.0 ± 5.0 years, at the age of 37-72 years. Significant associations with HCC development were shown for liver cirrhosis, histological activity grade, reddish markings, and older age. Multivariate analysis revealed that HCC development was strongly associated with older age and male gender (P = 0.002 and P = 0.043, respectively). HCC occurred more frequently in patients of age ≥30 years even with early stage than in patients of age <30 years (P = 0.031). Severe reddish markings, a laparoscopic finding of widespread parenchymal destruction, were highly associated with HCC development in patients of age ≥30 years at diagnosis (odds ratio = 1.67, P = 0.034), while histological activity grade and ALT level were not (P = 0.075 and P = 0.69, respectively). CONCLUSIONS HCC development is associated with older age, male gender, and liver cirrhosis. Reddish markings, rather than histological activity or ALT level, can be useful to predict HCC for HBV patients of age ≥30 years.
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Poynard T, Ngo Y, Munteanu M, Thabut D, Massard J, Moussalli J, Varaud A, Benhamou Y, Ratziu V. Biomarkers of liver injury for hepatitis clinical trials: a meta-analysis of longitudinal studies. Antivir Ther 2010; 15:617-31. [PMID: 20587855 DOI: 10.3851/imp1570] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Liver biopsy and virological end points are standard references for assessing the effect of viral hepatitis treatments. We aimed to review evidence-based published data of biomarkers that have been validated as non-invasive alternatives to biopsy as end points for HBV and HCV infection trials. METHODS Studies were included if there were at least two repeated estimates of fibrosis per patient using biomarkers with at least two studies and a control group. Meta-analysis of the percentage of fibrosis progression per year (pFPy) was performed. RESULTS Two biomarkers were included, FibroTest and liver stiffness measurement (LSM; FibroScan. A total of 1,413 patients with chronic hepatitis C (11 populations) and 772 with chronic hepatitis B (6 populations) were analysed. In a comparison of HCV patients with controls, the FibroTest pFPy was -18% (95% confidence interval [CI] -23--14; P<0.001) in treated patients and the LSM pFPy was -15% (95% CI -28--1; P=0.01), both with differences according to virological responses. In HBV patients, there was a significant decrease of the pFPy only in patients with baseline advanced fibrosis (mean difference -5% [95% CI -10--0.1]; P=0.02). In patients with advanced fibrosis, stratified by virological response, there were similar differences between pFPy estimated either using FibroTest or biopsy, both in HCV and HBV infections. Repeated LSM in HBV patients had an early variability related to necroinflammatory activity. CONCLUSIONS In patients with chronic hepatitis C and B, the treatment effect on fibrosis progression rate was similarly estimated using FibroTest or biopsy. The same concordance was observed for FibroScan but with a possible overestimation of the fibrosis regression during the first weeks of treatment.
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Affiliation(s)
- Thierry Poynard
- University Pierre and Marie Curie Liver Center, Paris, France.
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Friedrich-Rust M, Rosenberg W, Parkes J, Herrmann E, Zeuzem S, Sarrazin C. Comparison of ELF, FibroTest and FibroScan for the non-invasive assessment of liver fibrosis. BMC Gastroenterol 2010; 10:103. [PMID: 20828377 PMCID: PMC2944336 DOI: 10.1186/1471-230x-10-103] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2010] [Accepted: 09/09/2010] [Indexed: 02/07/2023] Open
Abstract
Background FibroTest (FT) is the most frequently used serum fibrosis marker and consists of an algorithm of five fibrosis markers (alfa2-macroglobulin, apolipoproteinA1, haptoglobin, GGT, bilirubin). The Enhanced Liver Fibrosis (ELF) test consists of an algorithm of three fibrosis markers (hyaluronic acid, amino-terminal propeptide-of-type-III-collagen, tissue-inhibitor of matrix-metaloproteinase-1). While a systematic review has shown comparable results for both individual markers, there has been no direct comparison of both markers. Methods In the present study, the ELF-test was analyzed retrospectively in patients with chronic liver disease, who received a liver biopsy, transient elastography (TE) and the FibroTest using histology as the reference method. Histology was classified according to METAVIR and the Ludwig's classification (F0-F4) for patients with chronic hepatitis C and B virus (HCV, HBV) infection and primary biliary cirrhosis (PBC), respectively. Results Seventy-four patients were analysed: 36 with HCV, 10 with HBV, and 28 with PBC. The accuracy (AUROC) for the diagnosis of significant fibrosis (F≥2) for ELF and FibroTest was 0.78 (95%CI:0.67-0.89) and 0.69 (95%-CI:0.57-0.82), respectively (difference not statistically significant, n.s.). The AUROC for the diagnosis of liver cirrhosis was 0.92 (95%CI:0.83-1,00), and 0.91 (95%CI:0.83-0.99), respectively (n.s.). For 66 patients with reliable TE measurements the AUROC for the diagnosis of significant fibrosis (cirrhosis) for TE, ELF and FT were 0.80 (0.94), 0.76 (0.92), and 0.67 (0.91), respectively (n.s.). Conclusion FibroTest and ELF can be performed with comparable diagnostic accuracy for the non-invasive staging of liver fibrosis. Serum tests are informative in a higher proportion of patients than transient elastography.
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Affiliation(s)
- Mireen Friedrich-Rust
- Department of Internal Medicine 1, JW Goethe-University Hospital, Frankfurt, Germany
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Liu HB, Zhou JP, Zhang Y, Lv XH, Wang W. Prediction on liver fibrosis using different APRI thresholds when patient age is a categorical marker in patients with chronic hepatitis B. Clin Chim Acta 2010; 412:33-7. [PMID: 20828546 DOI: 10.1016/j.cca.2010.08.032] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2010] [Revised: 08/21/2010] [Accepted: 08/23/2010] [Indexed: 12/17/2022]
Abstract
BACKGROUND Patient age as a predictive variable plays an important role in some indices and models. It was hypothesized that patient age might be a categorical marker. METHODS We collected the data of 623 CHB patients with liver biopsies. Two-hundred fifty-two patients could provide the duration of HBsAg-positive. RESULTS The positive correlation between duration of HBsAg-positive and patient age was statistically significant (r = 0.487, P < 0.001). When the cutoff value of patient age was 33.5 y, the best accuracy for liver fibrosis could be obtained. If we could use APRI threshold value of 0.11 for patients with age ≤ 35 and 0.18 for those > 35 y, we could correctly identify 110 CHB patients with insignificant fibrosis which were free of liver biopsy. For all CHB patients based on the APRI threshold of 0.11, 75 patients could be safely predicted as insignificant fibrosis. CONCLUSIONS Many more CHB patients with insignificant fibrosis could be free of liver biopsy when we used different APRI threshold values based on patient age, especially in patients with > 35 y. The study indicated that more attention should be paid to the influence of patient age on fibrosis.
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Affiliation(s)
- Hong-Bo Liu
- School of Public Health, China Medical University, Shenyang, China.
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Wang D, Wang Q, Shan F, Liu B, Lu C. Identification of the risk for liver fibrosis on CHB patients using an artificial neural network based on routine and serum markers. BMC Infect Dis 2010; 10:251. [PMID: 20735842 PMCID: PMC2939639 DOI: 10.1186/1471-2334-10-251] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2009] [Accepted: 08/24/2010] [Indexed: 12/14/2022] Open
Abstract
Background Liver fibrosis progression is commonly found in patients with CHB. Liver biopsy is a gold standard for identifying the extent of liver fibrosis, but has many draw-backs. It is essential to construct a noninvasive model to predict the levels of risk for liver fibrosis. It would provide very useful information to help reduce the number of liver biopsies of CHB patients. Methods 339 chronic hepatitis B patients with HBsAg-positive were investigated retrospectively, and divided at random into 2 subsets with twice as many patients in the training set as in the validation set; 116 additional patients were consequently enrolled in the study as the testing set. A three-layer artificial neural network was developed using a Bayesian learning algorithm. Sensitivity and ROC analysis were performed to explain the importance of input variables and the performance of the neural network. Results There were 329 patients without significant fibrosis and 126 with significant fibrosis in the study. All markers except gender, HB, ALP and TP were found to be statistically significant factors associated with significant fibrosis. The sensitivity analysis showed that the most important factors in the predictive model were age, AST, platelet, and GGT, and the influence on the output variable among coal miners were 22.3-24.6%. The AUROC in 3 sets was 0.883, 0.884, and 0.920. In the testing set, for a decision threshold of 0.33, sensitivity and negative predictive values were 100% and all CHB patients with significant fibrosis would be identified. Conclusions The artificial neural network model based on routine and serum markers would predict the risk for liver fibrosis with a high accuracy. 47.4% of CHB patients at a decision threshold of 0.33 would be free of liver biopsy and wouldn't be missed.
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Affiliation(s)
- Danan Wang
- Institute of Immunology, China Medical University, Shenyang, Liaoning, China
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Duarte-Rojo A, Feld JJ. Hepatitis B Biomarkers: Clinical Significance of the Old and the New. ACTA ACUST UNITED AC 2010. [DOI: 10.1007/s11901-010-0053-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Ratziu V. Serum fibrosis markers: death by validation or a leap of faith? J Hepatol 2010; 53:222-4. [PMID: 20546961 DOI: 10.1016/j.jhep.2010.04.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2010] [Accepted: 04/27/2010] [Indexed: 01/06/2023]
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El-Shabrawi MH, Mohsen NA, Sherif MM, El-Karaksy HM, Abou-Yosef H, El-Sayed HM, Riad H, Bahaa N, Isa M, El-Hennawy A. Noninvasive assessment of hepatic fibrosis and necroinflammatory activity in Egyptian children with chronic hepatitis C virus infection using FibroTest and ActiTest. Eur J Gastroenterol Hepatol 2010; 22:946-951. [PMID: 20110820 DOI: 10.1097/meg.0b013e328336ec84] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatic fibrosis. Liver biopsy, because of its limitations and risks, might be considered an imperfect gold standard for assessing the severity of chronic liver diseases. In this study, we aimed to prospectively validate FibroTest (FT) and ActiTest (AT) as noninvasive serum biochemical markers for assessment of the degree of hepatic fibrosis and necroinflammatory activity respectively, in pediatric patients with chronic HCV infection and compare them to liver biopsy. METHODS Fifty patients, aged 2 to 18 years, with chronic HCV infection were prospectively enrolled. Two assessments were carried out, within 24-h duration, one of a liver biopsy specimen and the other FT and AT measured in serum sample. FINDINGS A highly significant linear trend and correlation were found between FT-related fibrosis and fibrosis stage by METAVIR scoring on histopathological examination. A highly significant correlation was also found between AT and necroinflammatory histological activity using METAVIR as well. The FT area under the receiver operating characteristic curve (AUROC) is 0.97, SE=0.02 which can diagnose patients with mild stage of fibrosis, thus discriminating them from those with no (or minimal) fibrosis. The AT can successfully discriminate between patients with moderate activity and those with mild activity with AUROC=0.93, SE=0.06. CONCLUSION FT and AT are potential noninvasive methods for assessment of hepatic fibrosis and necroinflammatory activity in pediatric patients with chronic HCV infection in comparison with liver biopsy.
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Noninvasive markers to diagnose cirrhosis in patients with HBeAg positive chronic hepatitis: Do new biomarkers improve the accuracy? Clin Biochem 2010; 43:877-81. [PMID: 20433821 DOI: 10.1016/j.clinbiochem.2010.04.063] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2009] [Revised: 04/13/2010] [Accepted: 04/14/2010] [Indexed: 12/19/2022]
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Assessment of Allograft Fibrosis by Transient Elastography and Noninvasive Biomarker Scoring Systems in Liver Transplant Patients. Transplantation 2010; 89:983-93. [DOI: 10.1097/tp.0b013e3181cc66ca] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Poynard T, Lebray P, Ingiliz P, Varaut A, Varsat B, Ngo Y, Norha P, Munteanu M, Drane F, Messous D, Bismut FI, Carrau JP, Massard J, Ratziu V, Giordanella JP. Prevalence of liver fibrosis and risk factors in a general population using non-invasive biomarkers (FibroTest). BMC Gastroenterol 2010; 10:40. [PMID: 20412588 PMCID: PMC2864202 DOI: 10.1186/1471-230x-10-40] [Citation(s) in RCA: 156] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2009] [Accepted: 04/22/2010] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND FibroTest and elastography have been validated as biomarkers of liver fibrosis in the most frequent chronic liver diseases and in the fibrosis screening of patients with diabetes. One challenge was to use them for estimating the prevalence of fibrosis, identifying independent risk factors and to propose screening strategies in the general population. METHODS We prospectively studied 7,463 consecutive subjects aged 40 years or older. Subjects with presumed advanced fibrosis (FibroTest greater than 0.48) were re-investigated in a tertiary center. RESULTS The sample characteristics were similar to those of the French population. FibroTest was interpretable in 99.6%. The prevalence of presumed fibrosis was 2.8%, (209/7,463), including cirrhosis in 0.3% (25/7,463); 105/209 (50%) subjects with presumed fibrosis accepted re-investigation. Fibrosis was confirmed in 50, still suspected in 27, indeterminate in 25 and not confirmed with false positive FibroTest or false negative elastography in 3 subjects. False negative rate of FibroTest estimated using elastography was 0.4% (3/766). The attributable causes for confirmed fibrosis were both alcoholic and nonalcoholic fatty liver disease (NAFLD) in 66%, NAFLD in 13%, alcohol in 9%, HCV in 6%, and other in 6%. Factors independently associated (all P < 0.003) with confirmed fibrosis were age, male gender, waist circumference, HCV antibody and alcohol consumption estimated using carbohydrate-deficient transferrin, enabling efficient screening-oriented strategies to be compared and proposed. CONCLUSIONS Biomarkers have permitted to estimate prevalence of advanced fibrosis around 2.8% in a general population aged 40 years or older, and several risk factors which may be used for the validation of selective or non-selective screening strategies.
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Affiliation(s)
- Thierry Poynard
- APHP-UPMC-Liver Center, Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France
| | - Pascal Lebray
- APHP-UPMC-Liver Center, Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France
| | - Patrick Ingiliz
- APHP-UPMC-Liver Center, Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France
| | - Anne Varaut
- APHP-UPMC-Liver Center, Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France
| | | | - Yen Ngo
- APHP-UPMC-Liver Center, Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France
| | - Pascal Norha
- APHP-UPMC-Liver Center, Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France
| | | | | | - Djamila Messous
- Biochemistry Unit, Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France
| | - Françoise Imbert Bismut
- Biochemistry Unit, Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France
| | | | - Julien Massard
- APHP-UPMC-Liver Center, Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France
| | - Vlad Ratziu
- APHP-UPMC-Liver Center, Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France
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Bonino F, Piratvisuth T, Brunetto MR, Liaw YF. Diagnostic markers of chronic hepatitis B infection and disease. Antivir Ther 2010; 15 Suppl 3:35-44. [PMID: 21041902 DOI: 10.3851/imp1622] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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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. Assessment of liver fibrosis: noninvasive means. Saudi J Gastroenterol 2009. [PMID: 19568532 DOI: 10.4103/1319-] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Liver biopsy, owing to its limitations and risks, is an imperfect gold standard for assessing the severity of the most frequent chronic liver diseases chronic hepatitis C (HCV), B (HBV) non alcoholic (NAFLD) and alcoholic (ALD) fatty liver diseases. This review summarizes the advantages and the limits of the available biomarkers of liver fibrosis. Among a total of 2,237 references, a total of 14 validated serum biomarkers have been identified between 1991 and 2008. Nine were not patented and five were patented. Two alternatives to liver biopsy were the most evaluated FibroTest and Fibroscan. For FibroTest, there was a total of 38 different populations including 7,985 subjects with both FibroTest and biopsy (4,600 HCV, 1,580 HBV, 267 NAFLD, 524 ALD, and 1014 mixed). For Fibroscan, there was a total of 11 published studies including 2,260 subjects (1,466 HCV, 95 cholestatic liver disease, and 699 mixed). For FibroTest, the mean diagnostic value for the diagnosis of advanced fibrosis assessed using standardized area under the ROC curves was 0.84 (95% confidence interval 0.83-0.86), without a significant difference between the causes of liver disease, hepatitis C, hepatitis B, and alcoholic or non alcoholic fatty liver disease. High-risk profiles of false negative/false positive of FibroTest, mainly Gilbert syndrome, hemolysis and acute inflammation, are present in 3% of the populations. In case of discordance between biopsy and FibroTest, half of the failures can be due to biopsy; the prognostic value of FibroTest is at least similar to that of biopsy in HCV, HBV and ALD. In conclusion this overview of evidence-based data suggests that biomarkers could be used as an alternative to liver biopsy for the first line assessment of fibrosis stage in the four most common chronic liver diseases, namely HCV, HBV, NAFLD and ALD. Neither biomarkers nor biopsy alone is sufficient for taking a definite decision in a given patient; all the clinical and biological data must be taken into account. There is no evidence based data justifying biopsy as a first line estimate of liver fibrosis. Health authorities in some countries have already approved validated biomarkers as the first line procedure for the staging of liver fibrosis.
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Affiliation(s)
- Thierry Poynard
- Service d'Hépato-Gastroentérologie, Groupe Hospitalier Pitié-Salpêtrière, Université Paris VI, CNRS ESA 8149 Paris, France.
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Gressner OA, Beer N, Jodlowski A, Gressner AM. Impact of quality control accepted inter-laboratory variations on calculated Fibrotest/Actitest scores for the non-invasive biochemical assessment of liver fibrosis. Clin Chim Acta 2009; 409:90-5. [DOI: 10.1016/j.cca.2009.09.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2009] [Revised: 08/20/2009] [Accepted: 09/02/2009] [Indexed: 01/06/2023]
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Poynard T, Muntenau M, Morra R, Ngo Y, Imbert-Bismut F, Thabut D, Messous D, Massard J, Lebray P, Moussalli J, Benhamou Y, Ratziu V. Methodological aspects of the interpretation of non-invasive biomarkers of liver fibrosis: a 2008 update. ACTA ACUST UNITED AC 2009; 32:8-21. [PMID: 18973843 DOI: 10.1016/s0399-8320(08)73990-3] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
This review summarizes the methodological aspects of the interpretation of non-invasive biomarkers in liver fibrosis. A scoring system has been updated to better compare the quality of fibrosis biomarkers. Several methodological issues are related to the classical methodology using biopsy, as this is considered the gold standard. However, from evidence-based data, it appears that the methodology needs to change to prevent flawed conclusions among key opinion leaders as well as in obsolete guidelines. As waiting for the perfect biomarker for the diagnosis of advanced fibrosis to come along is probably a waste of time, in the meantime, methods can be improved. The main proposals for improving the methodology are, to take into account the spectrum bias, to assess accuracy between adjacent stages, to compare biomarkers in the same patient, to assess the cause of failure among discordant cases and to use specific statistical methods adapted for imperfect gold standards.
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Affiliation(s)
- T Poynard
- APHP Service d'Hépato-Gastroentérologie, Groupe Hospitalier Pitié-Salpêtrière, Université Paris 6, CNRS ESA 8149 Paris, France.
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Abstract
FibroTest (FT) is a biomarker of liver fibrosis initially validated in patients with chronic hepatitis C (CHC) and subsequently assessed in other frequent liver diseases, including chronic hepatitis B (CHB), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). The primary aim of the present study was to update a previous meta-analysis of FT diagnostic value, and to summarize its advantages and limitations. The secondary aim was to provide an overview of the prognostic value of FT in CHC, CHB and ALD. For diagnostic value, the main endpoint was the FT area under the ROC curves (AUROCs) for the diagnosis of bridging fibrosis (F2/F3/F4 vs F0/F1), standardized for the spectrum of fibrosis. Sensitivity analysis integrated the non-standardized observed AUROCs, the independency of authors, size (length) of biopsy, prospective design, correctness of procedures, co-morbidities, and timelag between biopsy and serum sampling. For prognostic value, the main endpoint was the FT AUROC for the prognostic value of liver complications or death related to liver disease. A total of 38 diagnostic studies were included, which pooled 7985 subjects who had undergone both FT and biopsy (4600 HCV, 1580 HBV, 267 NAFLD, 524 ALD and 1014 mixed). The mean standardized AUROC was 0.84 (95% CI, 0.83-0.86), with no differences in terms of causes of liver disease: HCV 0.84 (0.82-0.87); HBV 0.81 (0.78-0.83); NAFLD 0.84 (0.76-0.92); ALD 0.87 (0.82-0.92); and mixed 0.85 (0.81-0.89). Three prognostic studies were also included. FT was found to have higher or similar prognostic value compared with biopsy in patients with CHC, CHB or ALD. FibroTest is an effective alternative to biopsy in patients with chronic hepatitis C or B, ALD or NAFLD. Indeed, the prognostic performance of FibroTest was at least as accurate as that of biopsy in patients with chronic hepatitis C or B, or ALD.
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Popov Y, Schuppan D. Targeting liver fibrosis: strategies for development and validation of antifibrotic therapies. Hepatology 2009; 50:1294-306. [PMID: 19711424 DOI: 10.1002/hep.23123] [Citation(s) in RCA: 252] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We have made striking progress in our understanding of the biochemistry and cell biology that underlies liver fibrosis and cirrhosis, including the development of strategies and agents to prevent and reverse fibrosis. However, translation of this knowledge into clinical practice has been hampered by (1) the limitation of many in vitro and in vivo models to confirm mechanisms and to test antifibrotic agents, and (2) the lack of sensitive methodologies to quantify the degree of liver fibrosis and the dynamics of fibrosis progression or reversal in patients. Furthermore, whereas cirrhosis and subsequent decompensation are accepted hard clinical endpoints, fibrosis and fibrosis progression alone are merely plausible surrogates for future clinical deterioration. In this review we focus on an optimized strategy for preclinical antifibrotic drug development and highlight the current and future techniques that permit noninvasive assessment and quantification of liver fibrosis and fibrogenesis. The availability of such noninvasive methodologies will serve as the pacemaker for the clinical development and validation of potent antifibrotic agents.
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Affiliation(s)
- Yury Popov
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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