The detection of fibrosis within nonalcoholic fatty liver disease (NAFLD) is important for ascertaining prognosis and the stratification of patients for emerging therapeutic intervention. We ...validated the Original European Liver Fibrosis panel (OELF) and a simplified algorithm not containing age, the Enhanced Liver fibrosis panel (ELF), in an independent cohort of patients with NAFLD. Furthermore, we explored whether the addition of simple markers to the existing panel test could improve diagnostic performance. One hundred ninety‐six consecutively recruited patients from 2 centers were included in the validation study. The diagnostic accuracy of the discriminant scores of the ELF panel, simple markers, and a combined panel were compared using receiver operator curves, predictive values, and a clinical utility model. The ELF panel had an area under the curve (AUC) of 0.90 for distinguishing severe fibrosis, 0.82 for moderate fibrosis, and 0.76 for no fibrosis. Simplification of the algorithm by removing age did not alter diagnostic performance. Addition of simple markers to the panel improved diagnostic performance with AUCs of 0.98, 0.93, and 0.84 for the detection of severe fibrosis, moderate fibrosis, and no fibrosis, respectively. The clinical utility model showed that 82% and 88% of liver biopsies could be potentially avoided for the diagnosis of severe fibrosis using ELF and the combined panel, respectively. The ELF panel has good diagnostic accuracy in an independent validation cohort of patients with NAFLD. The addition of established simple markers augments the diagnostic performance across different stages of fibrosis, which will potentially allow superior stratification of patients with NAFLD for emerging therapeutic strategies. (HEPATOLOGY 2007.)
Given the high global prevalence of nonalcoholic fatty liver disease (NAFLD), the need for relevant noninvasive biomarkers and algorithms to accurately stage disease severity is a critical unmet ...medical need. Identifying those with advanced fibrosis (≥ F3) is the most crucial, as these individuals have the greatest risk of adverse, long‐term, liver‐related outcomes. We aimed to investigate the role of PRO‐C3 (a marker of type III collagen formation) as a biomarker for advanced fibrosis in NAFLD. We measured PRO‐C3 by enzyme‐linked immunosorbent assay in two large independent cohorts with extensive clinical phenotyping and liver biopsy: 150 in the derivation and 281 in the validation cohort. A PRO‐C3‐based fibrosis algorithm that included age, presence of diabetes, PRO‐C3, and platelet count (ADAPT) was developed. PRO‐C3 increased with fibrosis stage (Rho 0.50; P < 0.0001) and was independently associated with advanced fibrosis (odds ratio = 1.05; 95% confidence interval CI 1.02‐1.08; P = 0.003). ADAPT showed areas under the receiver operating characteristics curve of 0.86 (95% CI 0.79‐0.91) in the derivation and 0.87 in the validation cohort (95% CI 0.83‐0.91) for advanced fibrosis. This was superior to the existing fibrosis scores, aspartate aminotransferase to platelet ratio index (APRI), FIB‐4, and NAFLD fibrosis score (NFS) in most comparisons. Conclusion: PRO‐C3 is an independent predictor of fibrosis stage in NAFLD. A PRO‐C3‐based score (ADAPT) accurately identifies patients with NAFLD and advanced fibrosis and is superior to APRI, FIB‐4, and NFS.
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•Assessment of MRI parameters in a single scan session.•Higher liver T1 and reduced liver perfusion with increasing disease severity and clinical outcomes.•Reduced renal cortex T1 ...linked to disease severity and clinical outcomes.
Advancing liver disease results in deleterious changes in a number of critical organs. The ability to measure structure, blood flow and tissue perfusion within multiple organs in a single scan has implications for determining the balance of benefit vs. harm for therapies. Our aim was to establish the feasibility of magnetic resonance imaging (MRI) to assess changes in Compensated Cirrhosis (CC), and relate this to disease severity and future liver-related outcomes (LROs).
A total of 60 patients with CC, 40 healthy volunteers and 7 patients with decompensated cirrhosis were recruited. In a single scan session, MRI measures comprised phase-contrast MRI vessel blood flow, arterial spin labelling tissue perfusion, T1 longitudinal relaxation time, heart rate, cardiac index, and volume assessment of the liver, spleen and kidneys. We explored the association between MRI parameters and disease severity, analysing differences in baseline MRI parameters in the 11 (18%) patients with CC who experienced future LROs.
In the liver, compositional changes were reflected by increased T1 in progressive disease (p <0.001) and an increase in liver volume in CC (p = 0.006), with associated progressive reduction in liver (p <0.001) and splenic (p <0.001) perfusion. A significant reduction in renal cortex T1 and increase in cardiac index and superior mesenteric arterial blood flow was seen with increasing disease severity. Baseline liver T1 (p = 0.01), liver perfusion (p <0.01), and renal cortex T1 (p <0.01) were significantly different in patients with CC who subsequently developed negative LROs.
MRI enables the contemporaneous assessment of organs in liver cirrhosis in a single scan without the requirement for a contrast agent. MRI parameters of liver T1, renal T1, hepatic and splenic perfusion, and superior mesenteric arterial blood flow were related to the risk of LROs.
This study assesses the changes to structure, blood flow and perfusion that occur in the key organs (liver, spleen and kidney) associated with severe liver disease (Compensated Cirrhosis), using magnetic resonance imaging. The magnetic resonance imaging measures which changed with disease severity and were related to negative liver-related clinical outcomes are described.
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•Optimal liver stiffness thresholds for community-based screening of at-risk patients are 9.1–9.5 kPa for fibrosis (stages ≥F2).•Transient elastography is a cost-effective ...intervention for identifying patients with liver fibrosis in primary care.•Between 2,500 to 6,500 PPP-adjusted euros are needed to gain an extra year of life, adjusted for quality of life.•The survival effect of screening is most pronounced for the identification of significant (≥F2) fibrosis.
Non-alcoholic fatty liver disease and alcohol-related liver disease pose an important challenge to current clinical healthcare pathways because of the large number of at-risk patients. Therefore, we aimed to explore the cost-effectiveness of transient elastography (TE) as a screening method to detect liver fibrosis in a primary care pathway.
Cost-effectiveness analysis was performed using real-life individual patient data from 6 independent prospective cohorts (5 from Europe and 1 from Asia). A diagnostic algorithm with conditional inference trees was developed to explore the relationships between liver stiffness, socio-demographics, comorbidities, and hepatic fibrosis, the latter assessed by fibrosis scores (FIB-4, NFS) and liver biopsies in a subset of 352 patients. We compared the incremental cost-effectiveness of a screening strategy against standard of care alongside the numbers needed to screen to diagnose a patient with fibrosis stage ≥F2.
The data set encompassed 6,295 participants (mean age 55 ± 12 years, BMI 27 ± 5 kg/m2, liver stiffness 5.6 ± 5.0 kPa). A 9.1 kPa TE cut-off provided the best accuracy for the diagnosis of significant fibrosis (≥F2) in general population settings, whereas a threshold of 9.5 kPa was optimal for populations at-risk of alcohol-related liver disease. TE with the proposed cut-offs outperformed fibrosis scores in terms of accuracy. Screening with TE was cost-effective with mean incremental cost-effectiveness ratios ranging from 2,570 €/QALY (95% CI 2,456–2,683) for a population at-risk of alcohol-related liver disease (age ≥45 years) to 6,217 €/QALY (95% CI 5,832–6,601) in the general population. Overall, there was a 12% chance of TE screening being cost saving across countries and populations.
Screening for liver fibrosis with TE in primary care is a cost-effective intervention for European and Asian populations and may even be cost saving.
The lack of optimized public health screening strategies for the detection of liver fibrosis in adults without known liver disease presents a major healthcare challenge. Analyses from 6 independent international cohorts, with transient elastography measurements, show that a community-based risk-stratification strategy for alcohol-related and non-alcoholic fatty liver diseases is cost-effective and potentially cost saving for our healthcare systems, as it leads to earlier identification of patients.
Chronic hepatitis C (CHC) is characterised by hepatic fibrosis, used as a proxy measure of prognosis. Liver biopsy is a flawed reference standard and serum markers of fibrosis offer an attractive ...alternative.
A systematic review was conducted to assess the performance of panels of serum markers of hepatic fibrosis in CHC, incorporating analyses placing markers in a clinical context.
14 studies were included with 10 different panels. Median AUC in validation populations was 0.77 and training populations 0.81. Likelihood ratios (LR) ranged from −LR 0.1 to 0.9, + LR 1.2 to 33.1, diagnostic odds ratios (DOR) were 9.0 (median) with a range of 5 to 27- mostly below values of robust tests. Tests perform with either high sensitivity with low specificity or vice versa. Cut-off levels that gave clinically relevant predictive values for the presence/absence of significant fibrosis were applicable to 35% of the population.
Serum markers can rule-in or rule-out fibrosis in up to 35% of patients, but cannot differentiate stages of fibrosis reliably. Improvement of index and reference test in needed including evaluation of clinical outcomes as reference. Improved test reporting is needed to derive LR and DOR as performance indicators.
Abstract Background The liver is known to be structurally abnormal in long-standing Fontan circulation. The degree of liver dysfunction associated with such abnormalities is however largely unknown. ...We assessed structural changes (serum fibrosis markers) and function (indocyanine green clearance (ICG)) in Fontan patients. Methods 21 stable Fontan patients were prospectively assessed and compared with 8 histologically proven compensated viral cirrhotic patients. All subjects had standard liver profile, “Enhanced Liver Fibrosis” (ELF) score (including hyaluronic acid, aminoterminal type III procollagen peptide P3NP and tissue inhibitor of metalloproteinase TIMP-1 levels), and ICG using the LiMON Device. Plasma disappearance rate (PDR) and 15-minute retention (R15) were recorded after ICG infusion. Results Indocyanine clearance and retention (PDR and R15) were similar between Fontan and compensated cirrhotic patients (17 ± 5 vs 18 ± 6 (p = 0.75) and 11 ± 10 vs 10 ± 10 (p = 0.75)), as was degree of fibrosis (7.97 ± 1.16 vs 9.0 ± 1.43, p = NS). There was a positive correlation between PDR and ELF (R = 0.77, p = 0.028) as well as R15 and ELF (R = 0.905, p = 0.002) in the viral cirrhotics but not in the Fontan group. (R = − 0.243, p = 0.302; and R = 0.226, p = 0.338). PDR (17 ± 5) and R15 (11 ± 10) were not significantly different in Fontan as compared with the established cirrhotics. Conclusions Fontan patients have similar global hepatic function and fibrosis as compared with viral cirrhotic patients. However in Fontan patients, fibrosis was not closely correlated with global liver function, whereas viral cirrhotic patients exhibited a close correlation between function and fibrosis.
Noninvasive biomarkers of liver fibrosis represent an intense area of research with the goals of improving patient care, disease stratification, and aiding the development of future antifibrotic ...therapies. Despite the rapid progress in recent years, there remain questions about how diagnostic studies are designed, statistical methods to account for spectrum bias, clinically relevant thresholds of fibrosis that should be delineated, how diagnostics can be improved, and strengthening the reference test to judge emerging biomarkers. This review discusses the current methods to address these issues and where further progress is needed. (HEPATOLOGY 2011;)
ObjectivesThe increasing incidence of chronic liver disease (CLD) in the UK may be attributed to a rise in preventable risk factors, including hazardous alcohol use and type 2 diabetes. Transient ...elastography (TE) can rapidly stratify risk of CLD in primary care populations and provide an opportunity to raise patient awareness of risk factors.This study explores patients’ experiences of TE screening in a primary care setting. In addition, patient awareness of CLD risk is explored.Study design and settingThis study used a qualitative process evaluation of a community screening pathway for CLD (Nottingham, UK). Participants completed semistructured interviews, which were audio-recorded, transcribed verbatim and analysed thematically.ParticipantsTwenty adults were purposively recruited 6 months to 2 years after TE screening. Inclusion criteria included (1) hazardous alcohol use, (2) type 2 diabetes and/or (3) persistently elevated liver enzymes without known cause.ResultsUndergoing TE in primary care was seen as acceptable to most participants. Hazardous alcohol use was identified as the primary cause of CLD; no participants were aware of metabolic risk factors. TE improved understanding of personal risk factors and prompted contemplation of lifestyle changes across all TE stratifications. However, participants’ perceptions of risk were altered by the healthcare providers’ communication of TE scores.ConclusionsHigh acceptability of TE, regardless of the risk factor, provides strong support for inclusion of TE stratification in primary care. Findings highlight the positive impact of receiving TE on risk awareness. Future clinical iterations should improve the structure and communication of TE results to patients.
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