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 CONCLUSIONS: This systematic-review returned eleven papers, six of which were conference-abstracts and one unpublished manuscript.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

Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: We aimed to develop and evaluate a pathway for management of patients with non-alcoholic fatty liver disease (NAFLD) using blood tests to stratify patients in primary care to improve detection of cases of advanced fibrosis and cirrhosis, and avoid unnecessary referrals to secondary care. METHODS: This was a prospective longitudinal cohort study with before-and-after analysis and comparison to unexposed controls. We used a two-step algorithm combining the use of FIB-4 followed by the ELF test if required RESULTS: In total, 3,012 patients were analysed. Use of the pathway detected 5 times more cases of advanced fibrosis (Kleiner F3) and cirrhosis (OR=5.18; 95%CI=2.97 to 9.04; p<0.0001). Unnecessary referrals from primary care to secondary care fell by 81% (OR=0.193; 95%CI 0.111 to 0.337; p<0.0001). Three times more cases of cirrhosis were diagnosed (OR=3.14; 95%CI=1.57 to 24; p=0.00011). Although it was used for only 48% of referrals, significant benefits were observed across all referrals from the practices exposed to the pathway. Unnecessary referrals fell by 77% (OR=0.23; 95% CI=0.658 to 0.082; p=0.006) with a 4-fold improvement in detection of cases of advanced fibrosis and cirrhosis (OR=4.32; 95% CI=1.52 to 12.25; p=0.006). Compared to referrals made before introduction of the pathway, unnecessary referrals fell from 79/83 referrals (95.2%) to 107/152 (70.4%) representing an 88% reduction in unnecessary referrals when the pathway was followed (OR=0.12; 95%CI=0.042 to 0.349; p<0.0001). CONCLUSIONS: The use of non-invasive blood tests for liver fibrosis to stratify patients with NAFLD improves the detection of cases of advanced fibrosis and cirrhosis and reduces unnecessary referrals to secondary care of patients with lesser degrees of liver fibrosis. This strategy improves resource use and benefits patients. LAY SUMMARY: Non-alcoholic fatty liver disease effects up to 30% of the population but only a minority of cases develop liver disease. Our study has shown that established blood tests can be used in primary care to stratify patients with fatty liver disease to reduce unnecessary referrals by 80% and improve the detection of cases of advanced fibrosis 5 fold and cirrhosis 3 fold

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

Biomarkers of Hepatic Fibrosis in Chronic Hepatitis C A Comparison of 10 Biomarkers Using 2 Different Assays for Hyaluronic Acid

Background: Advancing fibrosis is regarded as the most important factor when stratifying patients with chronic hepatitis C for retreatment. Goals: (1) To compare the performance of 10 biomarkers of fibrosis, including patented tests, among patients with chronic hepatitis C and treatment failure; and (2) to assess the impact on biomarker performance of using 2 different assays of hyaluronic acid (HA). Study: For 80 patients, liver histology (Metavir) was compared with biomarker scores using sera obtained within 6 months of liver biopsy (indirect biomarkers: AST:ALT ratio, APRI, Forns index, FIB-4, Fibrometer V3G; direct biomarkers: ELF, Fibrospect II, Hyaluronic acid-HA, Fibrometer V2G, Hepascore). Direct biomarker scores were calculated using 2 validated assays for HA (ELISA and radiometric). Results: Using the ELISA assay for HA to calculate the direct panels, all 10 of the biomarkers exhibited comparable overall discriminatory performance (unweighted Obuchowski measure, ordROC 0.92-0.94, P-value> 0.05) except AST:ALT ratio and APRI (ordROC 0.86-0.88, P-value< 0.05). For the detection of moderate (F2-4) and advanced (F3-4) fibrosis, the AUROC of Fibrometer 2G were significantly higher than AST:ALT ratio and APRI but none of the other biomarkers. Good correlation was observed between the 2 HA assays (intraclass correlation coefficient= 0.873) with the ELISA assay exhibiting superior diagnostic performance (ordROC 0.92 vs. 0.88, P-value= 0.003). Importantly, the performance of many of the direct biomarkers at their diagnostic thresholds was heavily influenced by the choice of HA assay. Conclusions: Although many biomarkers exhibited good diagnostic performance for the detection of advancing fibrosis, our results indicate that diagnostic performance may be significantly affected by the selection of individual component assays

Hepatitis C virus cell-cell transmission and resistance to direct-acting antiviral agents

Hepatitis C virus (HCV) is transmitted between hepatocytes via classical cell entry but also uses direct cell-cell transfer to infect neighboring hepatocytes. Viral cell-cell transmission has been shown to play an important role in viral persistence allowing evasion from neutralizing antibodies. In contrast, the role of HCV cell-cell transmission for antiviral resistance is unknown. Aiming to address this question we investigated the phenotype of HCV strains exhibiting resistance to direct-acting antivirals (DAAs) in state-of-the-art model systems for cell-cell transmission and spread. Using HCV genotype 2 as a model virus, we show that cell-cell transmission is the main route of viral spread of DAA-resistant HCV. Cell-cell transmission of DAA-resistant viruses results in viral persistence and thus hampers viral eradication. We also show that blocking cell-cell transmission using host-targeting entry inhibitors (HTEIs) was highly effective in inhibiting viral dissemination of resistant genotype 2 viruses. Combining HTEIs with DAAs prevented antiviral resistance and led to rapid elimination of the virus in cell culture model. In conclusion, our work provides evidence that cell-cell transmission plays an important role in dissemination and maintenance of resistant variants in cell culture models. Blocking virus cell-cell transmission prevents emergence of drug resistance in persistent viral infection including resistance to HCV DAAs

Validation of terminal peptide of procollagen III for the detection and assessment of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease

Liver biopsy is the reference standard for the detection of nonalcoholic steatohepatitis (NASH) within nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify a biomarker of NASH in patients without significant fibrosis. In all, 172 patients from two centers with biopsy-proven NAFLD were included in this study. Eighty-four patients from a single center were included as a derivation cohort and 88 patients from a second center were included as a validation cohort. Serum samples were tested for candidate markers of fibrosis and inflammation alongside hematological and biochemical markers. Among patients without advanced fibrosis, terminal peptide of procollagen III (PIIINP) was the only marker found to be associated with a histological diagnosis of NASH in both cohorts. PIIINP also correlated with the total NAFLD activity score (NAS) and its constituent components (P < 0.001). Area under receiver operating characteristic curve (AUROC) for PIIINP in discriminating between NASH and simple steatosis (SS) was 0.77-0.82 in patients with F0-2 fibrosis and 0.82-0.84 in patients with F0-3 fibrosis. PIIINP was elevated in patients with advanced fibrosis, the overwhelming majority of whom had NASH. When incorporating patients with all degrees of fibrosis from both cohorts, PIIINP was able to discriminate between patients with SS and those with NASH or advanced fibrosis with AUROC 0.85-0.87. Conclusion: PIIINP discriminates between SS and NASH or advanced fibrosis. The use of a single biomarker in this context will be of clinical utility in detecting the minority of patients with NAFLD who have NASH or advanced fibrosis related to NASH.Sudeep Tanwar, Paul M. Trembling, Indra N. Guha, Julie Parkes, Philip Kaye, Alastair D. Burt, Stephen D. Ryder, Guruprasad P. Aithal, Christopher P. Day, and William M. Rosenber

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.</p