BACKGROUND: Liver biopsy is the reference standard for diagnosing the extent of fibrosis in chronic liver disease; however, it is invasive, with the potential for serious complications. Alternatives to biopsy include non-invasive liver tests (NILTs); however, the cost-effectiveness of these needs to be established. OBJECTIVE: To assess the diagnostic accuracy and cost-effectiveness of NILTs in patients with chronic liver disease. DATA SOURCES: We searched various databases from 1998 to April 2012, recent conference proceedings and reference lists. METHODS: We included studies that assessed the diagnostic accuracy of NILTs using liver biopsy as the reference standard. Diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was conducted using the bivariate random-effects model with correlation between sensitivity and specificity (whenever possible). Decision models were used to evaluate the cost-effectiveness of the NILTs. Expected costs were estimated using a NHS perspective and health outcomes were measured as quality-adjusted life-years (QALYs). Markov models were developed to estimate long-term costs and QALYs following testing, and antiviral treatment where indicated, for chronic hepatitis B (HBV) and chronic hepatitis C (HCV). NILTs were compared with each other, sequential testing strategies, biopsy and strategies including no testing. For alcoholic liver disease (ALD), we assessed the cost-effectiveness of NILTs in the context of potentially increasing abstinence from alcohol. Owing to a lack of data and treatments specifically for fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), the analysis was limited to an incremental cost per correct diagnosis. An analysis of NILTs to identify patients with cirrhosis for increased monitoring was also conducted. RESULTS: Given a cost-effectiveness threshold of £20,000 per QALY, treating everyone with HCV without prior testing was cost-effective with an incremental cost-effectiveness ratio (ICER) of £9204. This was robust in most sensitivity analyses but sensitive to the extent of treatment benefit for patients with mild fibrosis. For HBV [hepatitis B e antigen (HBeAg)-negative)] this strategy had an ICER of £28,137, which was cost-effective only if the upper bound of the standard UK cost-effectiveness threshold range (£30,000) is acceptable. For HBeAg-positive disease, two NILTs applied sequentially (hyaluronic acid and magnetic resonance elastography) were cost-effective at a £20,000 threshold (ICER: £19,612); however, the results were highly uncertain, with several test strategies having similar expected outcomes and costs. For patients with ALD, liver biopsy was the cost-effective strategy, with an ICER of £822. LIMITATIONS: A substantial number of tests had only one study from which diagnostic accuracy was derived; therefore, there is a high risk of bias. Most NILTs did not have validated cut-offs for diagnosis of specific fibrosis stages. The findings of the ALD model were dependent on assuptions about abstinence rates assumptions and the modelling approach for NAFLD was hindered by the lack of evidence on clinically effective treatments. CONCLUSIONS: Treating everyone without NILTs is cost-effective for patients with HCV, but only for HBeAg-negative if the higher cost-effectiveness threshold is appropriate. For HBeAg-positive, two NILTs applied sequentially were cost-effective but highly uncertain. Further evidence for treatment effectiveness is required for ALD and NAFLD. STUDY REGISTRATION: This study is registered as PROSPERO CRD42011001561. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

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Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation

The presence and degree of hepatic fibrosis is crucial in order to make therapeutic decisions and predict clinical outcomes. Currently, the place of liver biopsy as the standard of reference for assessing liver fibrosis has been challenged by the increasing awareness of a number of drawbacks related to its use (invasiveness, sampling error, inter-/intraobserver variability). In parallel with this, noninvasive assessment of liver fibrosis has experienced explosive growth in recent years and a wide spectrum of noninvasive methods ranging from serum assays to imaging techniques have been developed. Some are validated methods, such as the Fibrotest/ Fibrosure and transient elastography in Europe, and are gaining a growing role in routine clinical practice, especially in chronic hepatitis C. Large-scale validation is awaited in the setting of other chronic liver diseases. However, noninvasive tests used to detect significant fibrosis and cirrhosis, the two major clinical endpoints, are not yet at a level of performance suitable for routine diagnostic tests, and there is still no perfect surrogate or method able to completely replace an optimal liver biopsy. This article aims to review current noninvasive tests for the assessment of liver fibrosis and the perspectives for their rational use in clinical practice.

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Non-invasive assessment of liver fibrosis

https://www.journal-of-hepatology.eu/article/S0168-8278(12)00962-2/pdf

Progression of liver fibrosis in post-transplant hepatitis C: mechanisms, assessment and treatment.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/lt.22460

Ultrasound-based transient elastography for the detection of hepatic fibrosis in patients with recurrent hepatitis C virus after liver transplantation: a systematic review and meta-analysis.

Background 
The enhanced liver fibrosis test (ELF) has been shown to accurately predict significant liver fibrosis in several liver diseases.


Aims 
To perform a meta-analysis to assess the performance of the ELF test for the assessment of liver fibrosis.


Study 
Electronic and manual searches were performed to identify studies of the ELF test. After methodological quality assessment and data extraction, pooled estimates of the sensitivity, specificity, area under the receiver operating characteristic curve (AUROC), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and summary receiver operating characteristics (sROC) were assessed systematically. The extent of heterogeneity and reasons for it were assessed.


Results 
Nine studies were identified for analysis. The pooled sensitivity, specificity, positive LR, negative LR, and DOR values of ELF test, for assessment of significant liver fibrosis, were 83% (95% CI = 0.80–0.86), 73% (95% CI = 0.69–0.77), 4.00 (95% CI = 2.50–6.39), 0.24 (95% CI = 0.17–0.34), and 16.10 (95% CI = 8.27–31.34), respectively; and, for evaluation of severe liver fibrosis, were 78% (95% CI = 0.74–0.81), 76% (95% CI = 0.73–0.78), 4.39 (95% CI = 2.76–6.97), 0.27 (95% CI = 0.16–0.46), and 16.01 (95% CI: 7.15–35.82), respectively; and, for estimation of cirrhosis, were 80% (95% CI = 0.75–0.85), 71% (95% CI = 0.68–0.74), 3.13 (95% CI = 2.01–4.87), 0.29 (95% CI = 0.19–0.44), and 14.09 (95% CI: 5.43–36.59), respectively.


Conclusions 
The ELF test shows good performance and considerable diagnostic value for the prediction of histological fibrosis stage.

/pdf/the-performance-of-enhanced-liver-fibrosis-elf-test-for-the-2uwvbl7bfh.pdf

The Performance of Enhanced Liver Fibrosis (ELF) Test for the Staging of Liver Fibrosis: A Meta-Analysis

Kamphues C, Lotz K, Rocken C, Berg T, Eurich D, Pratschke J, Neuhaus P, Neumann UP. Chances and limitations of non-invasive tests in the assessment of liver fibrosis in liver transplant patients. Clin Transplant 2009 DOI:10.1111/j.1399-0012.2009.01152.x © 2009 John Wiley & Sons A/S.



Abstract:  Because fibrosis progression resulting in liver cirrhosis represents the main reason for graft lost in patients after liver transplantation, an early detection of liver fibrosis is crucial. In recent years, several non-invasive tests for the assessment of liver fibrosis have been developed. We prospectively assessed the stage of liver fibrosis of 135 liver transplant patients (94 hepatitis C virus [HCV], 41 alcoholic cirrhosis) using liver biopsy, transient elastography, and serum markers. In the HCV group, the area under the receiver operating characteristic curve (AUROC) for diagnosis of significant fibrosis (F ≥ 2) and cirrhosis (F = 4) was 0.81 (negative predictive value [NPV] = 0.58, positive predictive value [PPV] = 0.9) and 0.87 (NPV = 0.94, PPV = 0.56), respectively. In the alcoholic cirrhosis group, significant fibrosis (F ≥ 2) was diagnosed with an AUROC of 0.83 (NPV = 1.00, PPV = 0.23). In both groups, higher AUROC values were reached in patients with a body mass index of <25 kg/m2, and both serum markers showed no significant correlation to liver fibrosis. The transient elastography is a reliable test for exclusion of liver cirrhosis in HCV transplant and significant liver fibrosis in alcoholic transplant patients. For the diagnosis of significant liver fibrosis in HCV transplant patients, the transient elastography reaches good results but cannot replace liver biopsy. Both serum markers AST-to-platelet ratio index and FIB-4 are not feasible to assess liver fibrosis in liver transplant patients.

Katharina Lotz

Papers

Chances and limitations of non‐invasive tests in the assessment of liver fibrosis in liver transplant patients