Research ArticleStaging chronic hepatitis C in seven categories using fibrosis biomarker (FibroTest™) and transient elastography (FibroScan®)
Introduction
Fibrosis progression is the earlier estimate of severity in patients with chronic hepatitis C (CHC) [1]. Before the stage of cirrhosis, the estimates of fibrosis progression mainly used transition rates between successive stages from normal liver (F0) to cirrhosis (F4), defined by histological score such as the METAVIR scoring system [1], [2]. The last stage F4 included patients with a wide range of severity. As stated by Garcia-Tsao et al., “there was a need to move beyond the characterization of cirrhosis as a single stage and instead, thinking of cirrhosis as a series of critical steps that culminate in hepatic decompensation” [3].
In CHC, FibroTest™ (FT) and transient elastography (TE) have been validated as markers of METAVIR fibrosis stages from F0 to F4 using biopsy [4], [5], [6], [7], [8], of liver fibrosis progression [9], [10] or regression [10], [11] but also validated as prognostic quantitative markers for occurrence of liver related complications, survival without liver related death, and overall survival [12], [13], [14], [15], [16], [17]. In these studies the performances of FT and TE were at least similar to those of biopsy for predicting overall survival and liver related complications. However due to the low incidence of each severe complication at 5 years (Supplementary Table 1), more patients and longer follow-up were needed to assess the specific performance of FT and TE for predicting separately the occurrence of varices, variceal bleeding, hepatic insufficiency (ascites, encephalopathy, or jaundice) and hepatocellular carcinoma.
The aim of the present study was to assess the performance of FT and TE for predicting the main steps in fibrosis progression, from F0 to death. The “seven stages spectrum”, included the 4 non-cirrhotic stages and the 3 critical steps in cirrhosis [3]: F4.1 defined as cirrhosis without varices or severe events, F4.2 defined as the presence of varices without severe events and F4.3 defined by the occurrence of the first severe event. Previously, F4.3 was defined as the occurrence of the following severe events: variceal hemorrhage, and hepatic insufficiency (ascites, encephalopathy, or jaundice the three clinical signs of decompensation in the Child-Turcotte classification) [3]. As primary liver cancer (PLC including hepatocellular carcinoma or cholangiocarcinoma) is the main cause of death in CHC, even in sustained virological responders (SVR) [11], we included also PLC in the stage F4.3 definition.
Section snippets
Materials and methods
To assess the prognostic values of FT and TE on a large sample of CHC with a wide severity spectrum we analyzed the updated individual data of three prospective cohorts called “EPIC”, “Paris”, and “Bordeaux” cohorts (Fig. 1). The cohorts’ characteristics were detailed in previous publications [11], [12], [13], [18] and in the Supplementary data.
The cohorts’ protocols were approved by the appropriate institutional review boards, regulatory agencies and conducted in accordance with principles of
Characteristics of patients (Table 1)
A total of 3927 patients without complications at baseline were pooled.
In the EPIC cohort and in comparison with the two other cohorts, patients had twice more advanced fibrosis, were all previous non-responders, older, and with more genotype 1. Their characteristics were similar to those of the EPIC overall group, and also without significant difference on primary endpoints between randomized groups [16], 286 received maintenance therapy and 288 were observed.
In the Paris cohort and in
Discussion
In patients with chronic hepatitis C both FT and TE, have been extensively validated for the diagnosis of advanced fibrosis stages [4], [5], [6], [7], [8], [9], [10], [11], [12], [13] and prediction of mortality [12], [13], [14], [15], [16], [17]. Due to the low incidence of events in previous studies (Supplementary Table 1), larger cohorts and a longer follow-up were needed to assess the performance of biomarkers for each complication [24].
The strength of the present study is that it
Conclusion
In conclusion, predetermined cut-offs of FibroTest™ and transient elastography (when reliable) permits to rank the severity of chronic hepatitis C in “seven stages”, from no-fibrosis to death, with three stages in cirrhotic patients with increasing morbidity and mortality.
Conflict of interest
TP is the inventor of patented FibroTest™, with a capital interest in BioPredictive the company marketing this test (FibroSure™ in USA). The patents belong to the French Public Organization “Assistance Publique Hopitaux de Paris”.
YN, MM, OD are full employees of BioPredictive, the company marketing FibroTest™.
The other authors have nothing to declare.
Authors’ contribution
TP: Study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; obtained funding, technical, or material support; study supervision.
JV, YN, MM, WM, MC, VT, ES, CB, JA, MR, OD, PL, and DT: Acquisition of data; analysis and interpretation of data.
VR: Acquisition of data; analysis and interpretation of data; critical revision of the manuscript for
References (33)
- et al.
Natural history of liver fibrosis progression in patients with chronic hepatitis C
Lancet
(1997) - et al.
Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy
J Hepatol
(2011) - et al.
Validation of liver fibrosis biomarker (FibroTest™) for assessing liver fibrosis progression: proof of concept and first application in a large population
J Hepatol
(2012) - et al.
Liver stiffness accurately predicts portal hypertension related complications in patients with chronic liver disease: a prospective study
J Hepatol
(2011) - et al.
Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular carcinoma in cirrhotic patients with chronic hepatitis C
Gastroenterology
(2011) - et al.
Prospective comparison of transient elastography, FibroTest™, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C
Gastroenterology
(2005) - et al.
Rates and risk factors of liver fibrosis progression in persons with chronic hepatitis C
J Hepatol
(2001) - et al.
Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores
J Hepatol
(2009) - et al.
Measurement of spleen stiffness to evaluate portal hypertension and the presence of esophageal varices in patients with HCV-related cirrhosis
Gastroenterology
(2012) - et al.
Performances of Elasto-FibroTest™ (®), a combination between FibroTest™ (®) and liver stiffness measurements for assessing the stage of liver fibrosis in patients with chronic hepatitis C
Clin Res Hepatol Gastroenterol
(2012)
FibroTest™ (®) and FibroScan (®) performances revisited in patients with chronic hepatitis C. Impact of the spectrum effect and the applicability rate
Clin Res Hepatol Gastroenterol
Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression
Hepatology
Now there are many (stages) where before there was one: in search of a pathophysiological classification of cirrhosis
Hepatology
EASL Clinical Practice Guidelines: management of hepatitis C virus infection
J Hepatol
Meta-analyses of FibroTest™ diagnostic value in chronic liver disease
BMC Gastroenterol
Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review
Ann Intern Med
Cited by (95)
Non-invasive tools for compensated advanced chronic liver disease and portal hypertension after Baveno VII – an update
2023, Digestive and Liver DiseaseBiomechanical changes in the liver tissue induced by a mouse model of multiple sclerosis (EAE) and the effect of anti-VLA-4 mAb treatment
2022, Archives of Biochemistry and BiophysicsClinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity
2021, Journal of HepatologyCitation Excerpt :Prior to the start of DAA therapy, the presence of cirrhosis was determined by liver biopsy or non-invasive measures of fibrosis. Cirrhosis was defined by a liver biopsy showing a METAVIR score of F4, a transient elastography result of ≥13.0 kPa, or at least 2 of the following: esophageal varices; platelet count below 140∗109/L; liver imaging showing a nodular liver, signs of portal hypertension, or ascites; non-invasive serum panels compatible with fibrosis stage 4 (FIB-4 >3.25, APRI >2 or FibroTest [BioPredictive, Paris, France] ≥0.75).18–21 Baseline Child-Pugh score was calculated within 2 months of DAA initiation.
Input of serum haptoglobin fucosylation profile in the diagnosis of hepatocellular carcinoma in patients with non-cirrhotic liver disease: Input of serum haptoglobin fucosylation profile
2020, Clinics and Research in Hepatology and GastroenterologyCitation Excerpt :Most published HCC risk scores have included histological cirrhosis as a major component, which is a limitation due to the adverse events and the cost of biopsy. The FibroTest is a validated fibrosis biomarker which can replace a biopsy to determine the presence or absence of cirrhosis when constructing new tests [23,24]. The diagnosis of HCC was based on non-invasive imaging, including multiphasic computed tomography (CT) and magnetic resonance imaging (MRI), and on histological examination by an experienced pathologist [7,8].