Inflammation and fibrosis in chronic liver diseases including non-alcoholic fatty liver disease and hepatitis C

At present chronic liver disease (CLD), the third commonest cause of premature death in the United Kingdom is detected late, when interventions are ineffective, resulting in considerable morbidity and mortality. Injury to the liver, the largest solid organ in the body, leads to a cascade of inflammatory events. Chronic inflammation leads to the activation of hepatic stellate cells that undergo trans-differentiation to become myofibroblasts, the main extra-cellular matrix producing cells in the liver; over time increased extra-cellular matrix production results in the formation of liver fibrosis. Although fibrogenesis may be viewed as having evolved as a “wound healing” process that preserves tissue integrity, sustained chronic fibrosis can become pathogenic culminating in CLD, cirrhosis and its associated complications. As the reference standard for detecting liver fibrosis, liver biopsy, is invasive and has an associated morbidity, the diagnostic assessment of CLD by non-invasive testing is attractive. Accordingly, in this review the mechanisms by which liver inflammation and fibrosis develop in chronic liver diseases are explored to identify appropriate and meaningful diagnostic targets for clinical practice. Due to differing disease prevalence and treatment efficacy, disease specific diagnostic targets are required to optimally manage individual CLDs such as non-alcoholic fatty liver disease and chronic hepatitis C infection. To facilitate this, a review of the pathogenesis of both conditions is also conducted. Finally, the evidence for hepatic fibrosis regression and the mechanisms by which this occurs are discussed, including the current use of antifibrotic therapy

Systematic review: Investigating the prognostic performance of four non‐invasive tests in alcohol‐related liver disease

BACKGROUND/AIMS: Mortality of Alcohol-related-Liver-Disease (ArLD) is increasing, and liver fibrosis stage is the best mortality predictor. Non-invasive-tests (NIT) are increasingly used to detect fibrosis, but their value as prognostic tests in chronic liver disease (CLD), and in particular in ArLD is less well recognized. We aimed to describe the prognostic performance of four widely used NITs (FIB4, ELF test, FibroScan and FibroTest) in ArLD. METHODS: Applying systematic-review methodology, four databases were searched from inception to May 2020. Inclusion/exclusion criteria were applied to search using MeSH terms and keywords. First and second reviewers independently screened results, extracted data and performed risk-of-bias assessment using Quality-In-Prognostic-Studies (QUIPS) tool. RESULTS: Searches produced 25,088 articles. After initial screening, 1,020 articles were reviewed independently by both reviewers. Eleven articles remained after screening for eligibility: one on ELF, four on FibroScan, four on FIB4, one on FIB4+FibroScan and one on FibroTest+FIB4. Area-Under-Receiving-Operator-Characteristics-curves (AUROCS) for outcome-prediction ranged from: 0.65-0.76 for FibroScan, 0.64-0.83 for FIB4, 0.69-0.79 for FibroTest and 0.72-0.85 for ELF. Studies scored low-moderate risk of bias for most domains, but high-risk in confounding/statistical reporting domains. The results were heterogeneous for outcomes and reporting, making pooling of data unfeasible. CONCLUSIONS: This systematic-review returned eleven papers, six of which were conference-abstracts and one unpublished manuscript. Whilst the heterogeneity of studies precluded direct comparisons of NITs, each NIT performed well in individual studies in predicting prognosis in ArLD (AUROCs >0.7 in each NIT category), and may add value to prognostication in clinical practice

Uncovering unsuspected advanced liver fibrosis in patients referred to alcohol nurse specialists using the ELF test

BBackground and aims: Alcohol use disorders (AUD) cause 7.2% of UK hospital admissions/year. Most are not managed by hepatologists and liver disease may be missed. We used the Enhanced Liver Fibrosis (ELF) test to investigate prevalence and associations of occult advanced liver fibrosis in AUD patients not known to have liver fibrosis. / Methods: Liver fibrosis was assessed using ELF in prospective patients referred to the Royal Free Hospital Alcohol Specialist Nurse (November 2018–December 2019). Known cases of liver disease were excluded. Patient demographics, blood tests, imaging data and alcohol histories recorded. Advanced fibrosis was categorised as ELF ≥ 10.5. / Results: The study included 99 patients (69% male, mean age 53.1 ± 14.4) with median alcohol intake 140 units/week (IQR 80.9–280), and a mean duration of harmful drinking of 15 years (IQR 10–27.5). The commonest reason for admission was symptomatic alcohol withdrawal (36%). The median ELF score was 9.62, range 6.87–13.78. An ELF score ≥ 10.5 was recorded in 28/99 (29%) patients, of whom 28.6% had normal liver tests. Within previous 5-years, 76% had attended A&E without assessment of liver disease. The ELF score was not associated with recent alcohol intake (p = 0.081), or inflammation (p = 0.574). / Conclusion: Over a quarter of patients with AUD had previously undetected advanced liver fibrosis assessed by ELF testing. ELF was not associated with liver inflammation or recent alcohol intake. The majority had recent missed opportunities for investigating liver disease. We recommend clinicians use non-invasive tests to assess liver fibrosis in patients admitted to hospital with AUD

Relationship of Enhanced Liver Fibrosis Score with Pediatric Nonalcoholic Fatty Liver Disease Histology and Response to Vitamin E or Metformin

OBJECTIVES: To study the diagnostic performance of the enhanced liver fibrosis score (ELF) for detecting different stages of fibrosis and its usefulness in detecting histologic response to vitamin E or metformin in children with nonalcoholic fatty liver disease who participated in the Vitamin E or Metformin for the Treatment Of NAFLD In Children (TONIC) trial. STUDY DESIGN: ELF was measured at baseline and weeks 24, 48, and 96 on sera from 166 TONIC participants. Associations between ELF with baseline and end of trial (EOT) fibrosis stages and other histologic features were assessed using χ2 tests and logistic regression models. RESULTS: ELF was significantly associated with severity of fibrosis at baseline and EOT. ELF areas under the curve for discriminating patients with clinically significant and advanced fibrosis were 0.70 (95% CI, 0.60-0.80) and 0.79 (95% CI, 0.69-0.89), respectively. A 1-unit decrease in ELF at EOT was associated with overall histologic improvement (OR, 1.86; 95% CI, 1.11-3.14; P = .02), resolution of steatohepatitis (OR, 1.88; 95% CI, 1.09-3.25; P = .02), improvement in steatosis grade (OR, 1.76; 95% CI, 1.06-2.82; P = .03), and hepatocellular ballooning (OR, 1.79; 95% CI, 1.06-3.00; P = .03), but not with improvement in fibrosis stage (OR, 1.26; 95% CI, 0.78-2.03; P = .34). CONCLUSIONS: ELF was associated with fibrosis stage in children who participated in TONIC. Although not associated with improvement in fibrosis, a decrease in ELF at EOT was associated with Nonalcoholic Steatohepatitis resolution and improvement in nonalcoholic fatty liver disease histology. ELF may be a useful noninvasive test to monitor treatment response in children with nonalcoholic fatty liver disease

Association between skirt size and chronic liver disease in post-menopausal women: a prospective cohort study within the United Kingdom Trial of Ovarian Cancer Screening (UKCTOCS)

BACKGROUND: We investigated the association between self-reported skirt size (SS) and change in SS, and incidence of chronic liver disease (CLD) in a prospective cohort study of women recruited to the UKCTOCS trial. METHODS: Women recruited to UKCTOCS in England without documented CLD self-reported their current UK SS during trial participation and were asked to recall their SS when aged in 20s (via completion of a questionnaire 3-5 years after recruitment). Participants were followed up via electronic health record linkage and hazard ratios (HR) calculated for incident liver-related events (LRE). RESULTS: Three hundred twenty-two (0.3%) of 94,124 women experienced a first LRE. Compared to SS ≤ 16, rates of LRE were higher in the SS ≥ 18 groups (both when aged in 20s and at questionnaire completion). Event rates were higher if there was no change in SS or an increase in SS, compared to a decrease in SS. In the models adjusted for potential confounders, HRs for LRE were higher in the groups of women reporting SS ≥ 18 both when aged in 20s (HR = 1.39 (95% CI; 0.87-2.23)) and at questionnaire completion (HR = 1.37 (95% CI; 1.07-1.75)). Compared to a decrease in SS, HRs were higher in the no change (HR = 1.78 (95% CI; 0.95-3.34)) and increase (HR = 1.80 (95% CI; 1.01-3.21)) groups. CONCLUSION: CLD is associated with high SS and an increase in SS over time. These data suggest SS can be used in simple public health messages about communicating the risk of liver disease. TRIAL REGISTRATION: UKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978 . Registered 06/04/2000

Exploring changing attitudes to non-invasive liver fibrosis tests in secondary care pathways: comparison of two national surveys

INTRODUCTION: The increasing availability of non-invasive tests (NITs) has created the opportunity to explore their use in improving risk stratification of advanced liver disease. The study aimed to determine the attitudes and practices among UK secondary care specialists, focusing primarily on attitudes to fibrosis assessment and the use of NITs. METHODS: Two web-based surveys were circulated, first between 2014 and 2015 (survey 1), and again in 2021 (survey 2). The surveys were promoted via the British Society of Gastroenterology, the British Association for the Study of the Liver and using Twitter. RESULTS: In survey 1, 215 healthcare professionals (HCPs) completed the online survey. 112 HCPs completed survey 2. 71 acute UK trusts were represented in survey 1 compared with 60 trusts in survey 2. Between the two surveys, the proportion of HCPs performing fibrosis assessment in all or nearly all cases rose from 45.1% to 74.1% (χ2=25.01; p<0.0001). 46.5% (n=33/71) respondents in acute services reported the use of NITs in clinical pathways in survey 1, rising to 70.0% (n=42/60) in survey 2 (χ2=7.35; p=0.007). Availability of tests has increased but is not universal. The proportion reporting availability as a barrier to uptake fell from 57.2% of responses in survey 1 to 38.4% in 2021 χ2=11.01; p=0.0009). CONCLUSION: Between 2014 and 2021, the role of NITs in fibrosis assessment has risen substantially, as has the proportion of clinicians using NITs in clinical pathways to assess risk of liver disease. Poor access to NITs remains the predominant barrier

How Valid Are Measures of Children’s Self-Concept/ Self-Esteem? Factors and Content Validity in Three Widely Used Scales

Children’s self-esteem/self-concept, a core psychological construct, has been measured in an overwhelming number of studies, and the widespread use of such measures should indicate they have well-established content validity, internal consistency and factor structures. This study, sampling a demographically representative cohort in late childhood/early adolescence in Dublin, Ireland (total n = 651), examined three major self-esteem/self-concept scales designed for late childhood/early adolescence: Piers-Harris Self-Concept Scale for Children 2 (Piers et al. 2002), Self-Description Questionnaire I (Marsh 1992) and Self-Perception Profile for Children (Harter 1985). It also examined findings in light of the salient self factors identified by participants in a linked mixed-methods study. The factor structure of Piers-Harris Self-Concept Scale was not replicated. The Self-Description Questionnaire I and Self-Perception Profile for Children were replicated only in part although in similar ways. In all three scales, a global/ appearance self evaluation factor accounted for the largest variance in factor analyses. Sport/athletic ability, school ability, school enjoyment, maths and reading ability/enjoyment, behaviour, peer popularity, and parent factors were also identified but did not always reflect existing scale structures. Notably, the factors extracted, or items present in these scales, often did not reflect young people’s priorities, such as friendship over popularity, the importance of family and extended family members, and the significance of incremental personal mastery in activities rather than assessing oneself as comparatively good at preferred activities. The findings raise questions about how self-esteem/self-concept scales are used and interpreted in research with children and young people

Equilibrium Contrast-enhanced CT Imaging to Evaluate Hepatic Fibrosis: Initial Validation by Comparison with Histopathologic Sampling

Purpose To prospectively evaluate hepatic extracellular volume (ECV) fraction measurement at equilibrium computed tomographic (CT) imaging compared with both fibrosis quantified with histologic analysis and the enhanced liver fibrosis panel (ELF) in a cohort of patients with chronic hepatitis. Materials and Methods This prospective study was approved by the regional ethics committee. All patients gave fully informed written consent. Forty patients with a clinical indication for liver biopsy were prospectively recruited for liver ECV quantitation at equilibrium CT imaging. Biopsy samples underwent digital image analysis and assessment of collagen content expressed as the collagen-proportionate area (CPA). Spearman correlation was used to evaluate association between ECV, ELF, and CPA. Multiple regression analysis was used to test prediction of CPA by a model that combined ECV and ELF. ECV, ELF score, and CPA were compared with Ishak stage by using the Kruskal-Wallis test. Results Complete ECV, ELF, and CPA were available in 33 patients. Liver ECV, CPA, and ELF had a median of 0.26 (interquartile range [IQR], 0.24-0.29), 5.0 (IQR, 3.0-15.0), and 9.71 (IQR, 8.14-10.92), respectively. Hepatic ECV demonstrated good association with CPA (r = 0.64; P < .001) and ELF score (r = 0.38; P < .027), with no significant difference in strength of correlation (P = .177). The regression model that combined ELF and ECV achieved good prediction of CPA (R(2) = 0.67; P < .001). Significant variation in ECV and ELF was seen between fibrosis stage groups. Conclusion Hepatic ECV measured with equilibrium CT imaging is associated with biopsy-derived CPA and serum ELF-validated markers of liver fibrosis. This suggests that equilibrium CT imaging can quantify diffuse fibrosis in chronic liver disease. (©) RSNA, 2014

Performance of Enhanced Liver Fibrosis test and comparison with transient elastography in the identification of liver fibrosis in patients with chronic hepatitis B infection

Assessment of liver fibrosis is important in determining prognosis, disease progression and need for treatment in patients with chronic hepatitis B (CHB). Limitations to the use of liver biopsy in assessing fibrosis are well recognized, and noninvasive tests are being increasingly evaluated including transient elastography (TE) and serum markers such as the Enhanced Liver Fibrosis (ELF) test. We assessed performance of ELF and TE in detecting liver fibrosis with reference to liver histology in a cohort of patients with CHB (n = 182), and compared the performance of these modalities. Median age was 46 and mean AST 70 IU/L. Cirrhosis was reported in 20% of liver biopsies. Both modalities performed well in assessing fibrosis at all stages. Area under receiver operator characteristic (AUROC) curves for detecting METAVIR fibrosis stages F ≥ 1, F ≥ 2, F ≥ 3 and F4 were 0.77, 0.82, 0.80 and 0.83 for ELF and 0.86, 0.86, 0.90 and 0.95 for TE. TE performed significantly better in the assessment of severe fibrosis (AUROC 0.80 for ELF and 0.90 for TE, P < 0.01) and cirrhosis (0.83 for ELF and 0.95 for TE, P < 0.01). This study demonstrates that ELF has good performance in detection of liver fibrosis in patients with CHB, and when compared, TE performs better in detection of severe fibrosis/cirrhosis. © 2013 John Wiley & Sons Ltd

Effective selection of informative SNPs and classification on the HapMap genotype data

<p>Abstract</p> <p>Background</p> <p>Since the single nucleotide polymorphisms (SNPs) are genetic variations which determine the difference between any two unrelated individuals, the SNPs can be used to identify the correct source population of an individual. For efficient population identification with the HapMap genotype data, as few informative SNPs as possible are required from the original 4 million SNPs. Recently, Park <it>et al.</it> (2006) adopted the nearest shrunken centroid method to classify the three populations, i.e., Utah residents with ancestry from Northern and Western Europe (CEU), Yoruba in Ibadan, Nigeria in West Africa (YRI), and Han Chinese in Beijing together with Japanese in Tokyo (CHB+JPT), from which 100,736 SNPs were obtained and the top 82 SNPs could completely classify the three populations.</p> <p>Results</p> <p>In this paper, we propose to first rank each feature (SNP) using a ranking measure, i.e., a modified t-test or F-statistics. Then from the ranking list, we form different feature subsets by sequentially choosing different numbers of features (e.g., 1, 2, 3, ..., 100.) with top ranking values, train and test them by a classifier, e.g., the support vector machine (SVM), thereby finding one subset which has the highest classification accuracy. Compared to the classification method of Park <it>et al.</it>, we obtain a better result, i.e., good classification of the 3 populations using on average 64 SNPs.</p> <p>Conclusion</p> <p>Experimental results show that the both of the modified t-test and F-statistics method are very effective in ranking SNPs about their classification capabilities. Combined with the SVM classifier, a desirable feature subset (with the minimum size and most informativeness) can be quickly found in the greedy manner after ranking all SNPs. Our method is able to identify a very small number of important SNPs that can determine the populations of individuals.</p