Direct Comparison of the Specialised Blood Fibrosis Tests FibroMeterV2G and Enhanced Liver Fibrosis Score in Patients With Non-alcoholic Fatty Liver Disease From Tertiary Care Centres

Maeva Guillaume; Valerie Moal; Cyrielle Delabaudiere; Floraine Zuberbuhler; Marie-Angèle Robic; Adrien Lannes; Sophie Metivier; Frederic Oberti; Pierre Gourdy; Isabelle Fouchard-Hubert; Janick Selves; Sophie Michalak; Jean-Marie Peron; Paul Cales; Christophe Bureau; Jerome Boursier

Disclosures

Aliment Pharmacol Ther. 2019;50(11):1214-1222. 

In This Article

Abstract and Introduction

Abstract

Background: The Enhanced Liver Fibrosis score (ELF) and the FibroMeterV2G are two specialized blood fibrosis tests which include direct markers of liver fibrosis. They have been shown to be more accurate than the simple blood fibrosis tests FIB4 and the non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS).

Aims: To directly compare the accuracies of ELF and FibroMeterV2G for the non-invasive diagnosis of liver fibrosis in NAFLD.

Methods: Four hundred and seventeen patients with biopsy-proven NAFLD were enrolled from two tertiary care centres. Four blood fibrosis tests were calculated: ELF, FibroMeterV2G, NFS, and FIB4. Advanced fibrosis F3/4 on liver biopsy (NASH CRN scoring) was the primary endpoint.

Results: Areas under the receiver operating characteristic (AUROC) curve for advanced fibrosis were not significantly different between the direct markers of liver fibrosis (hyaluronate, PIIINP, TIMP-1, alpha2-macroglobulin) and the simple blood fibrosis tests NFS and FIB4. ELF (0.793 ± 0.022) and FibroMeterV2G (0.804 ± 0.021) had significantly higher AUROC than NFS (0.722 ± 0.025, P < .010) and FIB4 (0.739 ± 0.024, P < .020). AUROC for advanced fibrosis and Obuchowski index were not significantly different between ELF and FibroMeterV2G. Algorithms using first ELF or FibroMeterV2G and then liver biopsy in case of undetermined diagnosis provided high diagnostic accuracy for advanced fibrosis: 90% sensitivity, 90% specificity, 93% negative predictive value, 85% positive predictive value, and 90% correct classification. In these algorithms, the rate of liver biopsy was 45.3% with ELF versus 39.3% with FibroMeterV2G (P = .065).

Conclusions: ELF and FibroMeterV2G have equal accuracy and perform better than the simple FIB4 and NFS tests for the non-invasive diagnosis of advanced liver fibrosis in patients with NAFLD from tertiary care centres.

Introduction

Non-alcoholic fatty liver disease (NAFLD) has become the primary cause of chronic liver disease worldwide and the prevalence is as high as 25% in the general population.[1,2] Liver steatosis is the hallmark feature of NAFLD and approximately 20% of the patients develop non-alcoholic steatohepatitis (NASH) defined by the additional presence of hepatocyte ballooning degeneration and lobular inflammation.[3] NASH is the aggressive form of the disease with progressive liver fibrosis leading to cirrhosis and liver-related complications.[4] Of all the liver lesions described in NAFLD, only liver fibrosis is independently associated with patient outcome.[5,6] A recent meta-analysis has demonstrated that the prognosis in NAFLD is impaired as of stage 2 fibrosis with an exponential increase during the transition to stage F3 (bridging fibrosis) then F4 (cirrhosis).[7]

There is currently no approved pharmacological treatment for NAFLD/NASH. Many new drugs are being developed, four of which have already reached the phase III level of clinical trials.[8] The current international guidelines state that pharmacological treatments should be proposed to patients with NASH and fibrosis,[9] particularly those with bridging fibrosis or cirrhosis.[10] Therefore, once the new drugs are in the market, a challenge for physicians will be to accurately identify the subset of patients who are eligible for these therapies. Liver biopsy, the reference for evaluating liver lesions in NAFLD, cannot be proposed as a first-line procedure in all NAFLD patients because of its invasiveness and the associated costs. Therefore, there is a crucial need for non-invasive tests capable of accurately targeting advanced F3/4 liver fibrosis in NAFLD.[10,11]

Considering that they are simple and widely available, blood fibrosis tests are a very attractive option to facilitate the identification of NAFLD patients with advanced liver fibrosis.[12] Blood fibrosis tests include "simple" tests that combine common indirect markers of liver fibrosis, and "specialized" tests that use direct markers of liver fibrosis.[13] FibroMeters (Echosens) is a family of blood fibrosis tests specifically developed for each cause of chronic liver disease (Table S1). The FibroMeterNAFLD, developed for the diagnosis of advanced fibrosis in NAFLD,[14] includes common blood markers: AST, ALT, platelets, glucose, and ferritin. Independent studies have confirmed the good diagnostic accuracy of the FibroMeterNAFLD (Table 1). Some of these works showed the FibroMeterNAFLD to have an accuracy comparable to the simple blood fibrosis tests FIB4 and NAFLD fibrosis score (NFS),[15–17] whereas other works found the FibroMeterNAFLD to be significantly more accurate.[17,18] The FibroMeterV2G, developed for the diagnosis of significant fibrosis in chronic hepatitis C,[19] includes both indirect (AST, urea, platelets, prothrombin time) and direct (hyaluronate, alpha2-macroglobulin) markers of liver fibrosis. We have recently compared the FibroMeterNAFLD, the FibroMeterV2G, four simple blood fibrosis tests (APRI, FIB4, BARD, NFS) and two other specialized blood fibrosis tests (Fibrotest, Hepascore) in a large cohort of 452 biopsy-proven NAFLD patients.[20] Results showed that specialized tests were more accurate than simple tests and, among specialized tests, FibroMeterV2G was the most accurate with area under the receiver operating characteristic (AUROC) reaching 0.82 for advanced fibrosis. Paradoxically, the FibroMeterV2G initially developed in chronic hepatitis C was more accurate in NAFLD than the specifically dedicated FibroMeterNAFLD. Indeed, the FibroMeterV2G includes alpha2-macroglobulin and hyaluronate, two direct markers that are individually very well correlated to liver fibrosis stages whatever the underlying chronic liver disease, while FibroMeterNAFLD uses only indirect and less accurate markers of liver fibrosis.

The Enhanced Liver Fibrosis (ELF) score (Siemens Healthineers) is another specialized blood fibrosis test.[21] ELF has shown very good accuracy for the non-invasive diagnosis of advanced fibrosis in NAFLD but studies had small sample size,[22–25] were non-independent,[26] or were restricted to paediatric[27,28] or bariatric[29,30] cohorts (Table 2). A large series has been very recently published but it was conducted in a highly selected population that included patients who were candidates for therapeutic trials targeting advanced fibrosis or cirrhosis.[31] Finally, there is little data concerning the diagnostic accuracy of ELF in large series of patients from hepatology clinics.

The aim of this work was to compare the diagnostic accuracy of the FibroMeterV2G and ELF tests in a large cohort of NAFLD patients included in the setting of hepatology clinics from tertiary centres, with liver biopsy used as the reference for liver fibrosis staging.

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