<scp>ELF</scp> score ≥9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis and histological activity

Fagan, Kevin J.; Pretorius, Carel J.; Horsfall, Leigh; Irvine, Katharine M.; Wilgen, Urs; Choi, K.; Fletcher, Linda M.; Tate, Jill; Melino, Michelle; Nusrat, Sharmin; Miller, Gregory; Clouston, Andrew D.; Ballard, Emma; O’Rourke, Peter; Lampe, Guy; Ungerer, Jacobus P.J.; Powell, Elizabeth E.

doi:10.1111/liv.12760

Cited by 67 publications

(99 citation statements)

References 33 publications

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“…The cohort is the sub-set of a previously reported cohort of 536 consecutive patients[8] for whom sufficient, non-hemolyzed serum remained for multiplex ELISA analysis. Fasted serum collected at the time of liver biopsy was stored at -80°C prior to analysis.…”

Section: Methodsmentioning

confidence: 99%

“…The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the Institution's human research committee. Diagnosis of liver disease was based on standard biochemical and serological assays and consensus histological assessment of the liver biopsy by 2 blinded, experienced pathologists (ADC and GL) as previously reported [8]. Eighty-five % of liver biopsies were ≥15 mm in length or showed definite cirrhosis (98% of biopsies were ≥10 mm).…”

Section: Methodsmentioning

confidence: 99%

“…Weight, height, age, serum biochemistry (AST, ALT) and platelet counts were obtained from the medical record and used to calculate the AST to Platelet Ratio Index (APRI)[1] and Fibrosis-4 score (FIB4)[1]. An ADVIA Centaur XP system (Siemens Healthcare Diagnostics, New York, USA) was used to measure serum HA, PIIINP and TIMP1 and calculate the ELF score [8]. …”

Section: Methodsmentioning

confidence: 99%

“…However, a recent meta-analysis of nine studies evaluating the ELF test reported median sensitivity/specificity values of 78%/76% for advanced fibrosis, although the data-driven diagnostic cut-offs applied in different studies were a major cause of heterogeneity[7]. Using the ELF manufacturer’s cut-off for advanced fibrosis (≥9.8), we demonstrated 92% specificity and 74% sensitivity for the detection of advanced fibrosis in a mixed etiology CLD cohort[8]. …”

Section: Introductionmentioning

confidence: 95%

“…More recently, unbiased approaches have been undertaken, including protein[9] and metabolite[10] profiling, with the goal of discovering novel biomarkers that improve the diagnostic accuracy of the currently available tests and provide new insights into mechanisms of disease pathogenesis. The aim of this study was to identify novel serum biomarkers of advanced liver fibrosis (METAVIR fibrosis stage 3 or 4 on liver biopsy) using multiplex ELISA-profiling, including cytokines, chemokines, and matrix remodelling factors, in a mixed etiology cohort of CLD patients with known ELF scores[8]; and to evaluate their diagnostic accuracy using liver biopsy as the reference. The underlying rationale for this approach was that, since fibrogenesis involves activation of many liver cell types in response to injury, factors reflecting different pathological processes (eg hepatitis/inflammation or metabolic perturbations, in addition to matrix remodelling) could provide an optimal biomarker panel.…”

Section: Introductionmentioning

confidence: 99%

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Multiplex Serum Protein Analysis Identifies Novel Biomarkers of Advanced Fibrosis in Patients with Chronic Liver Disease with the Potential to Improve Diagnostic Accuracy of Established Biomarkers

et al. 2016

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Background and AimsNon-invasive markers of liver fibrosis are urgently required, especially for use in non-specialist settings. The aim of this study was to identify novel serum biomarkers of advanced fibrosis.MethodsWe performed an unbiased screen of 120 serum analytes including cytokines, chemokines and proteases in 70 patients (35 without fibrosis, 35 with cirrhosis on biopsy), and selected a panel of 44 candidate biomarkers, which were subsequently measured in a mixed-etiology cohort of 432 patients with known serum HA, PIIINP and TIMP1 (which comprise the validated Enhanced Liver Fibrosis (ELF) test). Multivariate logistic regression modelling was used to generate models for the prediction of advanced or significant fibrosis (METAVIR ≥F3 and ≥F2, respectively); in addition to identifying biomarkers of disease activity and steatohepatitis.ResultsSeventeen analytes were significantly differentially expressed between patients with no advanced fibrosis and patients with advanced fibrosis, the most significant being hyaluronic acid (HA) and matrix metalloproteinase (MMP) 7 (p = 2.9E-41 and p = 1.0E-26, respectively). The optimal model for the prediction of advanced fibrosis comprised HA, MMP7, MMP1, alphafetoprotein (AFP) and the AST to platelet ratio index (APRI). We demonstrate enhanced diagnostic accuracy (AUROC = 0.938) compared to a model comprising HA, PIIINP and TIMP1 alone (ELF) (AUROC = 0.898, p<0.0001, De Long’s test).ConclusionsWe have identified novel serum biomarkers of advanced liver fibrosis, which have the potential to enhance the diagnostic accuracy of established biomarkers. Our data suggest MMP7 is a valuable indicator of advanced fibrosis and may play a role in liver fibrogenesis.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Multiplex Serum Protein Analysis Identifies Novel Biomarkers of Advanced Fibrosis in Patients with Chronic Liver Disease with the Potential to Improve Diagnostic Accuracy of Established Biomarkers

et al. 2016

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Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science

et al. 2018

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Nonalcoholic steatohepatitis (NASH) is an important cause of liver-related morbidity and mortality. There are no approved therapies and the results of clinical trials have been difficult to compare due to inconsistent definitions of relevant disease parameters in patients with NASH. The natural course of the disease has not been rigorously characterized particularly with respect to the contributions of underlying obesity, type 2 diabetes and other comorbidities and the treatments provided to these comorbidities. Efforts to perform analyses of pooled data are limited by heterogeneous case definitions used across studies to define disease states. There remains a major unmet need in the field to develop standardized definitions for populations for interventional trials. Such definitions are expected to impact how endpoints for clinical trials are constructed. The Liver Forum is a multi-stakeholder effort including US and European regulatory agencies, academic investigators, professional and patient representative organizations and industry to catalyze therapeutic development for NASH by developing potential solutions to barriers to development. The Case Definitions Working Group was established by The Liver Forum to evaluate the validity of case definitions for populations to be included in clinical trials for NASH from a regulatory science perspective. Based on such analyses, specific recommendations are provided noting the strengths and weaknesses of the case definitions along with knowledge gaps that require additional study.

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A Pragmatic Approach Identifies a High Rate of Nonalcoholic Fatty Liver Disease With Advanced Fibrosis in Diabetes Clinics and At‐Risk Populations in Primary Care

Patel

Hossain

Horsfall

et al. 2018

Hepatology Communications

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Noninvasive serum biomarkers (nonalcoholic fatty liver disease fibrosis score [NFS], fibrosis 4 score [FIB‐4], or enhanced liver fibrosis [ELF] test) are recommended as first‐line tools to determine the risk of advanced fibrosis in nonalcoholic fatty liver disease. We aimed to assess the utility of a pragmatic approach to screening for clinically significant fibrosis in primary care and diabetes clinics. We recruited 252 patients from an endocrine clinic or primary care facility. Anthropometric measurements, ELF test, ultrasound, and liver stiffness measurements (LSMs) were performed. Clinically significant fibrosis was defined as LSM ≥8.2 kPa or ELF ≥9.8. A subgroup of patients underwent liver biopsy (n = 48) or had imaging diagnostic of cirrhosis (n = 14). Patients were 57.3 ± 12.3 years old with a high prevalence of metabolic syndrome (84.5%), type 2 diabetes (82.5%), and body mass index (BMI) ≥40 kg/m2 (21.8%). LSM met quality criteria in 230 (91.3%) patients. NFS and FIB‐4 combined had a high negative predictive value (90.0%) for excluding LSM ≥8.2 kPa. However, 84.1% of patients had indeterminate or high NFS or FIB‐4 scores requiring further assessment. LSM ≥8.2 kPa and ELF ≥9.8 were present in 31.3% and 28.6% of patients, respectively. Following adjustment for age, BMI, sex, and presence of advanced fibrosis, older age was independently associated with ELF ≥9.8 (adjusted odds ratio, 1.14; 95% confidence interval, 1.06‐1.24), whereas increasing BMI was independently associated with LSM ≥8.2 kPa (adjusted odds ratio, 1.15; 95% confidence interval, 1.01‐1.30). Concordant LSM <8.2 kPa and ELF <9.8 and concordant LSM ≥8.2 kPa and ELF ≥9.8 had a high negative predictive value (91.7%) and positive predictive value (95.8%) for excluding and identifying clinically significant fibrosis, respectively. Conclusion: Simple scoring tools alone lack accuracy. LSM accuracy is influenced by severe obesity, whereas age impacts the ELF test. Further studies are required to confirm whether combining LSM and ELF may enhance accuracy and confidence in identifying clinically significant fibrosis. (Hepatology Communications 2018; 00:000‐000)

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ELF score ≥9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis and histological activity

Cited by 67 publications

References 33 publications

Multiplex Serum Protein Analysis Identifies Novel Biomarkers of Advanced Fibrosis in Patients with Chronic Liver Disease with the Potential to Improve Diagnostic Accuracy of Established Biomarkers

Multiplex Serum Protein Analysis Identifies Novel Biomarkers of Advanced Fibrosis in Patients with Chronic Liver Disease with the Potential to Improve Diagnostic Accuracy of Established Biomarkers

Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science

A Pragmatic Approach Identifies a High Rate of Nonalcoholic Fatty Liver Disease With Advanced Fibrosis in Diabetes Clinics and At‐Risk Populations in Primary Care

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