ELF Score Research Articles

Efficacy and safety of the FGF19 analog aldafermin for the treatment of nonalcoholic steatohepatitis (NASH): A GRADE assessed systematic review and Meta-Analysis

Background: Non-alcoholic fatty liver disease (NAFLD) is increasingly concerning due to its rising prevalence. It encompasses conditions from simple steatosis to severe non-alcoholic steatohepatitis (NASH), posing risks such as fibrosis, cirrhosis, or hepatocellular carcinoma if untreated. This systematic review and meta-analysis aims to assess aldafermin, an FGF-19 analog, for efficacy and safety in NASH patients. Methods: Eligible studies were identified by searching PubMed, Cochrane Library, and Google Scholar, resulting in 1115 studies. Three RCTs were included. Risk of bias was assessed using the Cochrane Risk of Bias tool, and data synthesis utilized Review Manager software. Certainty of evidence was evaluated with the GRADE approach. Results: In the 3 mg dose group, aldafermin significantly improved various parameters. The ELF score decreased notably (pooled MD: -0.46, 95% CI -0.64 to -0.28; P<0.00001). Additionally, fibrosis improvement without NASH worsening showed a pooled MD of 8.15 (95% CI -3.62 to 19.93; P<0.17), and fibrosis improvement with NASH resolution displayed a pooled MD of 10.16 (95% CI 1.68 to 18.64; P=0.02). Furthermore, significant reductions were noted in absolute AST levels (pooled MD: -13.40, 95% CI -18.66 to -8.14; P<0.00001) and absolute ALT levels (pooled MD: -19.92, 95% CI -27.08 to -12.75; P<0.00001), suggesting improved liver function. Conclusion: The meta-analysis indicates that aldafermin, particularly, the 3 mg dose, shows significant efficacy in improving liver histology and biochemical markers in NASH patients compared to placebo along with a satisfactory safety profile.

Non-invasive fibrosis markers are useful in predicting the presence of varices in compensated cirrhosis and variceal bleeding in decompensated cirrhosis.

This study aims to investigate the effectiveness of non-invasive fibrosis markers in predicting varices in compensated advanced chronic liver disease patients and variceal bleeding in decompensated cirrhotic patients. Between 1 July 2020-2021, 137 newly diagnosed cirrhosis patients (67 females/70 males; mean age: 53.35) were included in the study. The diagnosis of cirrhosis was made based on clinical, laboratory, imaging, and, if available, biopsy findings. Laboratory and clinical parameters, including lysyl oxidase-like protein 2 (LOXL2), were recorded for all patients. Commonly used noninvasive fibrosis scores were calculated, and endoscopies were performed to assess varices. All patients were followed up for 12 months, and variceal bleeding events were recorded. Parameters that could predict the presence of varices and variceal bleeding were identified using appropriate statistical methods. Out of the 137 cirrhotic patients, 55 were in the compensated stage and 82 were in the decompensated stage. Varices were detected in 36 (65%) of the compensated cirrhotic patients. It was found that a variceal score derived from spleen size and the ELF score could be used to predict varices (AUC: 0.83). Variceal bleeding developed in 26 (31%) of the patients with decompensated cirrhosis. It was determined that a scoring system derived from albumin, spleen size, LOXL2 level, and the Lok index could be used to predict variceal bleeding in this patient group (AUC: 0.845). This study demonstrates that, besides device-dependent examinations, non-invasive fibrosis scores and various serum parameters can predict varices and variceal bleeding in cirrhotic patients.

Serologic extracellular matrix remodeling markers are related to fibrosis stage and prognosis in a phase 2b trial of simtuzumab in patients with primary sclerosing cholangitis.

Novel noninvasive predictors of disease severity and prognosis in primary sclerosing cholangitis (PSC) are needed. This study evaluated the ability of extracellular matrix remodeling markers to diagnose fibrosis stage and predict PSC-related fibrosis progression and clinical events. Liver histology and serum markers of collagen formation (propeptide of type III collagen [Pro-C3], propeptide of type IV collagen, propeptide of type V collagen), collagen degradation (type III collagen matrix metalloproteinase degradation product and type IV collagen matrix metalloproteinase degradation product), and fibrosis (enhanced liver fibrosis [ELF] score and its components [metalloproteinase-1, type III procollagen, hyaluronic acid]) were assessed in samples from baseline to week 96 in patients with PSC enrolled in a study evaluating simtuzumab (NCT01672853). Diagnostic performance for advanced fibrosis (Ishak stages 3-6) and cirrhosis (Ishak stages 5-6) was evaluated by logistic regression and AUROC. Prognostic performance for PSC-related clinical events and fibrosis progression was assessed by AUROC and Wilcoxon rank-sum test. Among 234 patients, 51% had advanced fibrosis and 11% had cirrhosis at baseline. Baseline Pro-C3 and ELF score and its components provided moderate diagnostic ability for discrimination of advanced fibrosis (AUROC 0.73-0.78) and cirrhosis (AUROC 0.73-0.81). Baseline Pro-C3, ELF score, and type III procollagen provided a moderate prognosis for PSC-related clinical events (AUROC 0.70-0.71). Among patients without cirrhosis at baseline, median changes in Pro-C3 and ELF score to week 96 were higher in those with than without progression to cirrhosis (both p < 0.001). Pro-C3 correlated with fibrosis stage, and Pro-C3 and ELF score provided discrimination of advanced fibrosis and cirrhosis and predicted PSC-related events and fibrosis progression. The results support the clinical utility of Pro-C3 and ELF score for staging and as prognostic markers in PSC.

Role of the fatty pancreatic infiltration in pancreatic oncogenesis

Although pancreatic precancerous lesions are known to be related to obesity and fatty pancreatic infiltration, the mechanisms remain unclear. We assessed the role of fatty infiltration in the process of pancreatic oncogenesis and obesity. A combined transcriptomic, lipidomic and pathological approach was used to explore neoplastic transformations. Intralobular (ILF) and extralobular (ELF) lipidomic profiles were analyzed to search for lipids associated with pancreatic intraepithelial neoplasia (PanINs) and obesity; the effect of ILF and ELF on acinar tissue and the histopathological aspects of pancreatic parenchyma changes in obese (OB) and non-obese patients. This study showed that the lipid composition of ILF was different from that of ELF. ILF was related to obesity and ELF-specific lipids were correlated to PanINs. Acinar cells were shown to have different phenotypes depending on the presence and proximity to ILF in OB patients. Several lipid metabolic pathways, oxidative stress and inflammatory pathways were upregulated in acinar tissue during ILF infiltration in OB patients. Early acinar transformations, called acinar nodules (AN) were linked to obesity but not ELF or ILF suggesting that they are the first reversible precancerous pancreatic lesions to occur in OB patients. On the other hand, the number of PanINs was higher in OB patients and was positively correlated to ILF and ELF scores as well as to fibrosis. Our study suggests that two types of fat infiltration must be distinguished, ELF and ILF. ILF plays a major role in acinar modifications and the development of precancerous lesions associated with obesity, while ELF may play a role in the progression of PDAC.

A prospective study on the prevalence of MASLD in people with type-2 diabetes in the community. Cost effectiveness of screening strategies.

As screening for the liver disease and risk-stratification pathways are not established in patients with type-2 diabetes mellitus (T2DM), we evaluated the diagnostic performance and the cost-utility of different screening strategies for MASLD in the community. Consecutive patients with T2DM from primary care underwent screening for liver diseases, ultrasound, ELF score and transient elastography (TE). Five strategies were compared to the standard of care: ultrasound plus abnormal liver function tests (LFTs), Fibrosis score-4 (FIB-4), NAFLD fibrosis score, Enhanced liver fibrosis test (ELF) and TE. Standard of care was defined as abnormal LFTs prompting referral to hospital. A Markov model was built based on the fibrosis stage, defined by TE. We generated the cost per quality-adjusted life year (QALY) gained and calculated the incremental cost-effectiveness ratio (ICER) over a lifetime horizon. Of 300 patients, 287 were included: 64% (186) had MASLD and 10% (28) had other causes of liver disease. Patients with significant fibrosis, advanced fibrosis, and cirrhosis due to MASLD were 17% (50/287), 11% (31/287) and 3% (8/287), respectively. Among those with significant fibrosis classified by LSM≥8.1 kPa, false negatives were 54% from ELF and 38% from FIB-4. On multivariate analysis, waist circumference, BMI, AST levels and education rank were independent predictors of significant and advanced fibrosis. All the screening strategies were associated with QALY gains, with TE (148.73 years) having the most substantial gains, followed by FIB-4 (134.07 years), ELF (131.68 years) and NAFLD fibrosis score (121.25 years). In the cost-utility analysis, ICER was £2480/QALY for TE, £2541.24/QALY for ELF and £2059.98/QALY for FIB-4. Screening for MASLD in the diabetic population in primary care is cost-effective and should become part of a holistic assessment. However, traditional screening strategies, including FIB-4 and ELF, underestimate the presence of significant liver disease in this setting.

Analytical performance of the Enhanced Liver Fibrosis (ELF) Test on the Atellica IM Analyzer

BackgroundThe Enhanced Liver Fibrosis (ELFTM) Test comprises 3 direct serum markers of fibrosis—hyaluronic acid (HA), amino-terminal pro-peptide of type III procollagen (PIIINP), and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1)—whose results are combined in an algorithm to generate the ELF score. Outside the U.S., the ELF Test and score are CE marked for assessment of liver fibrosis severity in patients with signs, symptoms, or risk factors of chronic liver disease to support diagnosis of fibrosis staging or prognosis for likelihood of progression to cirrhosis and liver-related clinical events. In the U.S., the FDA granted de novo marketing authorization to aid prognostic evaluation of disease progression (to cirrhosis and liver-related clinical events) in nonalcoholic steatohepatitis patients with advanced liver fibrosis. We describe the analytical performance of the ELF analytes and score on the Atellica® IM Analyzer. MethodsClinical and Laboratory Standards Institute protocols were followed for detection capability (limits of blank [LoB], detection [LoD], and quantitation [LoQ]), precision, interference, linearity, hook effect, and ELF reference interval. ResultsAll parameters met predetermined requirements: HA (LoB 1.00 ng/mL, LoD 2.00 ng/mL, LoQ 3.00 ng/mL); PIIINP (LoB 0.50 ng/mL, LoD 0.75 ng/mL, LoQ 1.00 ng/mL); TIMP-1 (LoB 3.0 ng/mL, LoD 4.0 ng/mL, LoQ 5.0 ng/mL). Across the 3 assays, repeatability was ≤5.4% CV; within-lab precision was ≤8.5% CV. ELF score repeatability was ≤0.6% CV, within-lab precision ≤1.3% CV, and reproducibility ≤1.1% CV. Good correlation was obtained between the Atellica IM ELF and ADVIA Centaur ELF Tests (y = 1.01x − 0.22, r = 0.997). Assays were linear across analytical measuring ranges. ConclusionsAnalytical performance validation results for the ELF Test and ELF score were excellent making the test acceptable for routine clinical use.

P018 Non-alcoholic fatty liver disease in spondyloarthritis: identifying patients on therapy at high risk of serious liver disease

Abstract Background/Aims People with Spondyloarthritis (SpA), especially those with psoriatic disease (PsD) [psoriasis (PsO) and psoriatic arthritis (PsA)], are at higher risk of non-alcoholic fatty liver disease (NAFLD) due to increased prevalence of metabolic syndrome, obesity, hypertension, dyslipidaemia and disease-specific factors such as duration/ severity of psoriasis. There is significant concern that both synthetic and biological DMARDs (including methotrexate) may worsen liver function in PsD patients with NAFLD. The Leeds Teaching Hospitals Trust (LTHT) NAFLD pathway uses three screening tools (ELF, FIB-4 and fibroscanning) to identify those needing further investigation/ treatment by hepatology. However, the pathway is not validated in PsD. Our aim was to survey the prevalence of liver disease in our PsD population and explore the performance of our hepatology referral pathway. Methods We audited consecutive patients referred from the Leeds Specialist SpA service at LTHT with persistently abnormal ALT, whom the consultant Rheumatologist felt required Hepatology referral for suspected NAFLD. Data collected were: age, sex, BMI, history of diabetes, ALT, AST, platelets, albumin, hepatitis B and C, ELF score, FIB-4 score, fibroscan score, abdominal ultrasound, liver biopsy result and final hepatology diagnosis (NAFLD, fibrosis/cirrhosis or other). Results 72 patients were included; 84.2% had PsD (61/72), and 15.8% (11/62) had ‘Other’ forms of SpA (including axial spondyloarthritis, enteropathic arthritis, etc). Baseline characteristics, drug treatment and liver biochemistry/virology were similar between PsD and Other arthritis groups (Table 1) except for age which was lower in the Other. The average ELF scores were similar between PsD and Other, however FIB-4 scores were higher in PsD, and was associated with higher rates of fibrosis/cirrhosis (Table 1). FIB-4 &amp;gt;1.3, but not ELF&amp;gt;9.5, was statistically significantly associated with a high fibroscan score (p = 0.038 and p = 0.443 respectively). Conclusion PsD patients had higher rates of significant fibrosis/cirrhosis compared with patients with Other SpAs. FIB-4 was better than ELF for identifying which PsD patients required fibroscan and further investigation to exclude significant fibrosis/ cirrhosis. These findings will now be validated in a larger prospective study. Disclosure S.R. Harrison: None. U. Nandasoma: None. R. Parker: None. C. Chimakurthi: None. P. Laws: None. A. Barr: None. C. Vandevelde: None. H. Marzo-Ortega: None. J. Freeston: None.

P162 Biosamples from VEDOSS patients show classic pathological signs of Scleroderma:Opportunity for a biological diagnosis of disease

Abstract Background/Aims The VEDOSS study has recently indicated that more than 50% of patients affected by Raynaud’s phenomenon (RP) and specific SSc anti-nuclear antibodies (ANA) and/or nailfold videocapillaroscopy changes (NVC) (sRP) satisfied ACR/EULAR 2013 criteria within 5 years, indicating a window of opportunity for early detection of SSc. Here we aimed to determine whether sera, skin or dermal fibroblasts cultured from VEDOSS patients showed any biological hallmark of SSc. Methods VEDOSS patients were enrolled in the national inception cohort for patients at risk of Scleroderma (Kennedy Cohort, n = 64) . Sera were tested for IFN-inducible chemokines and biomarker of extracellular matrix turnover (ELF test) and compared to Healthy control (HC) and SSc sera (n = 56, 64, respectively). 3mm skin punch biopsies were taken from the forearms of 12 VEDOSS patients, and 5 healthy controls and 6 SSc patients. Biopsies were analysed for haematoxylin and eosin (H&amp;E), masson trichrome staining (MT) and immunohistological (IHC) staining for CD45. A dermatopathologist blinded to clinical features undertook the analysis. A probabilistic image analysis model was used to detect areas of immunopositivity (CD45) and collagen staining (MT) within the samples, using HeteroGenius Medical Imaging Manager colour analysis. In addition, 7 biopsies along with 2 healthy control and 3 SSc, were used to explant fibroblasts cultures. mRNA and protein were isolated from primary fibroblasts and processed for RT-qPCR and western blotting analyses. Results Skin biopsies from VEDOSS patients showed evidence of fibrosis and increased collagen bundles within the dermis evidenced in H&amp;E and MT staining, as usually seen in SSc, compared to HC. IHC showed increased number of CD45+ cells in VEDOSS. Semiquantitative analysis of histopathological samples indicated a significant correlation between MT and CD45 staining for VEDOSS (R = 0.8828 P = 0.0016). In vitro, fibroblasts from VEDOSS patients showed an average 5-fold higher collagen mRNA levels compared to HC fibroblasts, at a similar range to that seen in SSc fibroblasts, confirmed at protein level via western blotting. Sera from VEDOSS patients showed significantly higher IFN-inducible chemokines compared to HC and an intermediate levels compared to SSc [Mean (STDV) HC = 4.69(0.29) vs. VEDOSS= 4.93 (0.39); SSc= 5.30 (0.54)]. ELF score was within normal range for most patients with SRP and showed no statistical difference to HC. Conclusion Although pilot in nature, this study suggests that patients with no clinical signs of skin fibrosis in their forearms already show biomarker signs of SSc both in their sera, skin biopsies and fibroblast level. Our data indicate that skin thickening is a late manifestation of SSc pathogenesis and early window of opportunity of patients with VEDOSS could be targeted for immune intervention and antifibrotic intervention. Disclosure R.L. ross: None. E. Clarke: None. W. Merchant: None. I. Georgiou: None. P. Mulipa: None. A. Carriero: None. G. Abignano: None. A. herrick: None. C. Denton: None. N. Riobo-Del Galdo: None. F. Del Galdo: Consultancies; FDG received consultancies and research support from Abbvie, AstraZeneca, Boheringer-Ingelheim, Capella, Chemomab, Ergomed, Janssen, Kymab, Mitsubishi-Tanabe.

A randomized, double-blind, placebo-controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis

Efruxifermin has shown clinical efficacy in patients with non-alcoholic steatohepatitis (NASH) and F1-F3 fibrosis. The primary objective of the BALANCED Cohort C was to assess the safety and tolerability of efruxifermin in patients with compensated NASH cirrhosis. Patients with NASH and stage 4 fibrosis (n= 30) were randomized 2:1 to receive efruxifermin 50mg (n= 20) or placebo (n= 10) once-weekly for 16 weeks. The primary endpoint was safety and tolerability of efruxifermin. Secondary and exploratory endpoints included evaluation of non-invasive markers of liver injury and fibrosis, glucose and lipid metabolism, and changes in histology in a subset of patients who consented to end-of-study liver biopsy. Efruxifermin was safe and well-tolerated; most adverse events (AEs) were grade 1 (n= 7, 23.3%) or grade 2 (n= 19, 63.3%). The most frequent AEs were gastrointestinal, including transient, mild to moderate diarrhea, and/or nausea. Significant improvements were noted in key markers of liver injury (alanine aminotransferase) and glucose and lipid metabolism. Sixteen-week treatment with efruxifermin was associated with significant reductions in non-invasive markers of fibrosis including Pro-C3 (least squares mean change from baseline [LSMCFB]-9μg/L efruxifermin vs.-3.4μg/L placebo; p= 0.0130) and ELF score (-0.4 efruxifermin vs.+0.4 placebo; p= 0.0036), with a trend towards reduced liver stiffness (LSMCFB-5.7kPa efruxifermin vs.-1.1kPa placebo; n.s.). Of 12 efruxifermin-treated patients with liver biopsy after 16 weeks, 4 (33%) achieved fibrosis improvement of at least one stage without worsening of NASH, while an additional 3 (25%) achieved resolution of NASH, compared to 0 of 5 placebo-treated patients. Efruxifermin appeared safe and well-tolerated with encouraging improvements in markers of liver injury, fibrosis, and glucose and lipid metabolism following 16 weeks of treatment, warranting confirmation in larger and longer term studies. Cirrhosis resulting from non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease, represents a major unmet medical need. Currently there are no approved drugs for the treatment of NASH. This proof-of-concept randomized, double-blind clinical trial demonstrated the potential therapeutic benefit of efruxifermin treatment compared to placebo in patients with cirrhosis due to NASH. NCT03976401.

Enhanced liver fibrosis score as a noninvasive biomarker in hepatitis C virus patients after direct-acting antiviral agents.

Background: In more than 90% of chronic viral hepatitis C (HCV) patients treated with direct-acting antiviral agents (DAAs), a sustained viral response (SVR) was observed. Unfortunately, there are subgroups of subjects who display enduring liver fibrosis and are at high risk of developing hepatocellular carcinoma (HCC). Thus, liver fibrosis evaluation during the follow-up of these patients plays a pivotal role. The gold standard to evaluate hepatic fibrosis is liver biopsy, which is an invasive procedure. Imaging techniques and serum biomarkers have been proposed as safer and cheaper procedures. Objectives: In this study, we evaluated the concordance of transient elastography (TE) with ELF score ( enhanced liver fibrosis) in a cohort of patients with HCV before and after direct-acting antiviral (DAAs) treatment. ELF score has been validated in other chronic liver diseases; the evidence is not available in HCV patients treated with DAAs. Study design: We prospectively recruited all consecutive HCV patient candidates for DAAs therapy at the University of Naples “Federico II” between April 2015 and July 2016. TE and ELF scores were assessed at baseline, at SVR24, and at SVR48. Results: One-hundred-nineteen patients were treated with DAAs, and 94.1% of them reached SVR. A total of 55.5% of patients were males with a mean age of 64.7 ± 9.6 years. TE results revealed that 12 patients (10%) had F1-2 mild/moderate fibrosis, and 107 (90%) had F3-4 advanced fibrosis. At baseline, SVR24, and SVR48, the concordance between ELF test and TE was poor: 0.11 (p = 0.086), 0.15 (p = 0.124), and 0.034 (p = 0.002), respectively. However, at SVR24 and SVR48, both methods showed a significant amelioration of liver fibrosis compared to baseline (p < 0.001). In addition, both ELF index and TE were significantly associated with portal hypertension at baseline, but not with varices and ascites. Conclusions: Our findings suggested that ELF test could predict changes in liver fibrosis, independently of TE. In case of TE unavailability, ELF score could represent an appropriate tool. Notably, in the context of the COVID-19 pandemic, ELF testing should be encouraged to reduce unnecessary access to the hospital and prolonged physical contact.

FRI048 - The combination of the ELF and FIB-4 scores have high predictive performance for significant fibrosis in patients with NAFLD

FRI048 - The combination of the ELF and FIB-4 scores have high predictive performance for significant fibrosis in patients with NAFLD

Enhanced Liver Fibrosis Score as a Biomarker for Vascular Damage Assessment in Patients with Takayasu Arteritis-A Pilot Study.

Takayasu Arteritis (TA) is characterized by granulomatous panarteritis, vessel wall fibrosis, and irreversible vascular impairment. The aim of this study is to explore the usefulness of the Enhanced Liver Fibrosis score (ELF), procollagen-III aminoterminal propeptide (PIIINP), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), and hyaluronic acid (HA) in assessing vascular damage in TA patients. ELF, PIIINP, TIMP-1, and HA were measured in 24 TA patients, and the results were correlated with the clinical damage indexes (VDI and TADS), an imaging damage score (CARDS), and disease activity scores (NIH and ITAS2010). A mean ELF score 8.42 (±1.12) and values higher than 7.7 (cut-off for liver fibrosis) in 21/24 (87.5%) of patients were detected. The VDI and TADS correlated significantly to ELF (p < 0.01). Additionally, a strong association across ELF and CARDS (p < 0.0001), PIIINP and CARDS (p < 0.001), and HA and CARDS (p < 0.001) was observed. No correlations of the tested biomarkers with inflammatory parameters, NIH, and ITAS2010 scores were found. To our knowledge, this is the first study that suggests the association of the serum biomarkers PIIINP, HA, and ELF score with damage but not with disease activity in TA patients. The ELF score and PIIINP may be useful biomarkers reflecting an ongoing fibrotic process and quantifying vascular damage.

Defining Primary Sclerosing Cholangitis: Results From an International Primary Sclerosing Cholangitis Study Group Consensus Process

Defining Primary Sclerosing Cholangitis: Results From an International Primary Sclerosing Cholangitis Study Group Consensus Process

Relationship of ELF and PIIINP With Liver Histology and Response to Vitamin E or Pioglitazone in the PIVENS Trial.

Enhanced liver fibrosis score (ELF) and one of its components, amino‐terminal propeptide of type III procollagen (PIIINP) are promising noninvasive biomarkers of liver histology in patients with nonalcoholic steatohepatitis (NASH). We evaluated the association of ELF and PIIINP with fibrosis stages at baseline and end of treatment (EOT) with vitamin E or pioglitazone in the PIVENS trial (Pioglitazone vs. Vitamin E vs. Placebo for the Treatment of Nondiabetic Patients With NASH) and characterized ELF and PIIINP changes and their associations with changes in the histological endpoints. ELF and PIIINP were measured at baseline and weeks 16, 48, and 96 on sera from 243 PIVENS participants. Baseline and EOT ELF were significantly associated with fibrosis stage (P < 0.001). The area under the curve for ELF’s detection of clinically significant and advanced fibrosis in baseline biopsies was 0.74 and 0.79, respectively (P < 0.001). There was a significant drop in ELF score at weeks 48 and 96 in patients who achieved the NAFLD activity score (NAS)–based primary end point (P = 0.007) but not in those who experienced NASH resolution (P = 0.24) or fibrosis improvement (P = 0.50). Change in PIIINP was significantly associated with NASH resolution and improvement in NAS‐based histological endpoint and fibrosis (P < 0.05 for all). Over the study period, both ELF and PIIINP significantly decreased with vitamin E (P < 0.05), but only PIIINP decreased with pioglitazone (P < 0.001). Conclusion: ELF is significantly associated with clinically significant and advanced fibrosis in patients with NASH, but its longitudinal changes were not associated with improvement in fibrosis or NASH resolution. PIIINP, one of its components, appears promising for identifying longitudinal histologic changes in patients with NASH and is worthy of further investigation.

Liver stiffness measured by two-dimensional shear-wave elastography predicts hepatic vein pressure gradient at high values in liver transplant candidates with advanced liver cirrhosis.

Liver stiffness is a reliable non-invasive predictor of Hepatic Venous Pressure Gradient (HVPG) above 10 mm Hg. However, it failed to predict higher thresholds of HVPG. Our aim was to investigate whether liver stiffness and selected previously published non-invasive blood biomarkers could predict higher HVPG thresholds in liver transplant candidates without ongoing alcohol use. One hundred and nine liver transplant candidates with liver cirrhosis of various aetiologies underwent direct HVPG measurement, liver stiffness measurement by 2D shear-wave elastography (Aixplorer Multiwave, Supersonic Imagine, France) and assessment of blood HVPG biomarkers (osteopontin, VCAM-1, IL-6, TNF-α, IL-1ra/IL-1F3 and ELF score). The correlation between liver stiffness and HVPG was linear up to 30 mm Hg of HVPG (r = 0.765, p < 0.0001). The regression lines had similar slopes for HVPG values below and above 16 mm Hg (p > 0.05) and the correlation in patients with HVPG <16 mm Hg (r = 0.456, p = 0.01) was similar to patients with HVPG ≥ 16 mm Hg (r = 0.499, p < 0.0001). The correlation was similar in the subgroup patients with alcoholic (r = 0.718, p < 0.0001), NASH (r = 0.740, p = 0.008), cryptogenic (r = 0.648, p = 0,0377), cholestatic and autoimmune (r = 0.706, p < 0.0001) and viral cirrhosis (r = 0.756, p < 0.0001). Liver stiffness distinguished patients with HVPG above 16, and 20 mm Hg with AUROCs 0.90243, and 0.86824, sensitivity 0.7656, and 0.7027, and specificity 0.9333, and 0.8750. All studied blood biomarkers correlated better with liver stiffness than with HVPG and their AUROCs did not exceed 0.8 at both HVPG thresholds. Therefore, a composite predictor superior to liver stiffness could not be established. We conclude that liver stiffness is a clinically reliable predictor of higher HVPG thresholds in non-drinking subjects with advanced liver cirrhosis.

Equilibrium CT Texture Analysis for the Evaluation of Hepatic Fibrosis: Preliminary Evaluation against Histopathology and Extracellular Volume Fraction.

Background: Evaluate equilibrium contrast-enhanced CT (EQ-CT) texture analysis (EQ-CTTA) against histologically-quantified fibrosis, serum-based enhanced liver fibrosis panel (ELF) and imaging-based extracellular volume fraction (ECV) in chronic hepatitis. Methods: This study was a re-analysis of image data from a previous prospective study. Pre- and equilibrium-phase post-IV contrast CT datasets were collected from patients with chronic hepatitis with contemporaneous liver biopsy and serum ELF measurement between April 2011 and July 2013. Biopsy samples were analysed to derive collagen proportionate area (CPA). EQ-CTTA was performed with a filtration histogram technique using texture analysis software, with texture quantification using statistical and histogram-based metrics (mean, skewness, standard deviation, entropy, etc.). Association between pre-contrast and EQ-CTTA against CPA, ECV and ELF was evaluated using Spearman’s rank correlation coefficient (rs). Results: Complete datasets collected in 29 patients (16 male; 13 female), mean age (range): 49 (22–66 years). Liver ECV, CPA and ELF had a median (interquartile range) of 0.26 (0.24–0.29); 5.0 (3.0–13.7) and 9.71 (8.39–10.92). Difference in segment VII hepatic CTTA (medium texture scale) between EQ-CT and pre-contrast images was significantly and positively associated with ELF score (mean: rs = 0.69, p < 0.001; skewness: rs = 0.57, p = 0.007). Significant negative associations were observed between pre-contrast and EQ-CT whole hepatic CTTA (coarse texture scale) with CPA (pre-contrast, SD: rs = −0.66, p < 0.001) and ECV (EQ-CT, entropy: rs = −0.58, p = 0.006). Conclusions: Hepatic EQ-CTTA demonstrates significant association with validated markers of liver fibrosis, suggesting a role in non-invasive quantification of severity in diffuse fibrosis.

Fibroscan® and ELF score in the study of fibrosis in obese patients with chronic liver disease: A preliminary study

Developing carbon based anode materials for alkali and alkaline earth metal ion batteries is important for the development of non-Li metal ion batteries. From density functional theory calculations, we studied alkali metal (Li, Na, K, and Rb) and alkaline earth metal (Be, Mg, Ca, Sr, and Ba) ions adsorption on penta-graphene (PG), which is a novel two dimensional (2D) carbon isomer composed of both sp2 and sp3 hybridized C-atoms. Strong correlations are observed between the adsorption energy and the electronegativity of the M-atoms, namely, smaller electronegativity corresponds to lower adsorption energy. The suitable Ca-ion intercalation potential (~117 mV), metallic electronic structures of Ca-ion adsorbed PG, low Ca-ion diffusion energy barriers (0.36 eV to 0.51 eV), and high specific capacity (1487.6 mAh/g) suggest that PG can be applied as an excellent anode material for Ca-ion batteries.

Comparison and correlation of fibrosis stage assessment by collagen proportionate area (CPA) and the ELF panel in patients with chronic liver disease

BackgroundFibrosis progression is the common consequence of most chronic liver diseases. AimsTo evaluate the performance of Collagen Proportionate Area (CPA) and ELF using Ishak’s score in patients with chronic liver diseases. MethodsRetrospective analysis of medical data from patients on whom a liver biopsy was performed as part of the diagnostic assessment. CPA was calculated by using digital image analysis and then compared with Ishak and ELF scores. Results143 patients (84 men (59%); mean age 48.8 ± 12.8 years) were evaluated. Patients were mainly affected by viral hepatitis (92 HCV and 8 HBV). CPA and ELF values increased with worsening Ishak stage (P < 0.001) and their median values were significantly different among Ishak stages (P < 0.001). There was a significant correlation between CPA and ELF (r = 0.5). In AUROC analysis, CPA and ELF had similar diagnostic accuracy in identifying cirrhosis, but CPA had higher diagnostic accuracy than ELF in identifying significant or absent fibrosis. High ELF scores were observed in non-cirrhotic patients who suffered non-liver related deaths. ConclusionsThis study demonstrated that CPA and ELF values successfully identified patients with advanced fibrosis or cirrhosis, thus confirming the role of ELF as a clinical method for non-invasive assessment of fibrosis stage in chronic hepatitis.

Using machine learning techniques to generate laboratory diagnostic pathways—a case study

Background: Diagnostic pathways are based on expert rules (“if…then…else”), which can be visualized as decision trees. Machine learning algorithms may be used to validate existing or to suggest potential new decision trees. Methods: We present and compare two machine learning algorithms, which automatically generate decision trees from laboratory data. The underlying functions (rpart and ctree) are included in the free statistical software environment R (www.r-project.org). Results: Using input data from a published study on hepatitis C patients, we demonstrate that both algorithms are easy to apply and produce plausible decision trees. These algorithms confirm common knowledge about the power of laboratory testing to detect liver fibrosis and cirrhosis. For example, we show that conventional measurands such as choline esterase or albumin can separate cases with no or slight fibrosis from those with severe fibrosis and cirrhosis, while intermediate stages are often misclassified. Addition of the newer ELF score to the test panel makes decision trees simpler and may improve the quality of classification. Validation of the automatic decision trees with the leave-one-out method shows that the accuracy of all models created by machine learning is significantly higher than pure guessing. However, small changes of the input data result in markedly deviant decision trees, which need to be validated further with respect to clinical plausibility. Conclusions: The machine learning algorithms presented here can support but do not replace the medical expert when designing decision trees for diagnostic pathways.

Interim assessment of liver damage in patients with sickle cell disease using new non-invasive techniques.

We explored transient elastography (TE) and enhanced liver fibrosis (ELF™ ) score with standard markers of liver function to assess liver damage in 193 well patients with sickle cell disease (SCD). Patients with HbSS or HbSβ0 thalassaemia (sickle cell anaemia, SCA; N=134), had significantly higher TE results and ELF scores than those with HbSC (N=49) disease (TE, 6·8 vs. 5·3, P<0·0001 and ELF, 9·2 vs. 8·6 P<0·0001). In SCA patients, TE and ELF correlated significantly with age and all serum liver function tests (LFTs). Additionally, (weak) positive correlation was found with lactate dehydrogenase (TE: r=0·24, P=0·004; ELF: r=0·26 P=0·002), and (weak) negative correlation with haemoglobin (TE: r=-0·25, P=0·002; ELF: r=-0·25 P=0·004). In HbSC patients, correlations were weaker or not significant between TE or ELF, and serum LFTs. All markers of iron loading correlated with TE values when corrected for sickle genotype (serum ferritin, β=0·25, P<0·0001, total blood transfusion units, β=0·25, P<0·0001 and LIC β=0·32, P=0·046). The exploratory study suggests that, while TE could have a role, the utility of ELF score in monitoring liver damage in SCD, needs further longitudinal studies.