Non-invasive diagnostic assessment tools for the detection of liver fibrosis in patients with suspected alcohol-related liver disease: a systematic review and economic evaluation
ABSTRACT Excessive alcohol consumption may lead to the development of alcohol-related liver disease (ALD). Liver biopsy may be used in patients with suspected ALD to confirm the diagnosis, exclude other or additional liver pathologies, and provide accurate staging of the degree of liver injury in order to enable the prediction of prognosis and inform treatment decisions. However, as it is an invasive procedure that carries the risk of morbidity and mortality, current UK guidance recommends that biopsy is not required to confirm the diagnosis in patients with a high clinical suspicion of ALD in whom blood tests have excluded other causes of liver disease, unless it is necessary to confirm a diagnosis of acute alcoholic hepatitis in order to inform specific treatment decisions.
To evaluate the diagnostic accuracy, cost-effectiveness, and effect on patient outcomes of four non-invasive tests for liver fibrosis [the Enhanced Liver Fibrosis (ELF™) test (Siemens Healthcare Diagnostic Inc., Tarrytown, NY, USA), FibroTest (BioPredictive, Paris, France), FibroMAX (BioPredictive, Paris, France) and transient elastography (FibroScan(®); produced by EchoSens, Paris, France and distributed in the UK by Artemis Medical Ltd, Kent, UK)] in patients suspected of having ALD.
A systematic review was undertaken to identify studies reporting the diagnostic and prognostic accuracy of the ELF test, FibroTest, FibroMAX, and FibroScan for the identification of liver fibrosis and associated conditions in patients with suspected ALD. The following databases were searched in January 2010: MEDLINE (from 1950 to January 2010), MEDLINE In-Process & Other Non-Indexed Citations (from 1950 to January 2010), EMBASE (from 1980 to January 2010), Cochrane Database of Systematic Reviews (from 1996 to January 2010), Cochrane Central Register of Controlled Trials (from 1898 to January 2010), Cochrane Methodology Register (from 1904 to January 2010), Database of Abstracts of Reviews of Effects (from 1995 to January 2010), HTA Database (from 1995 to January 2010), NHS Economic Evaluation Database (from 1995 to January 2010), Cumulative Index to Nursing and Allied Health Literature (from 1982 to January 2010), Web of Knowledge and Science Citation Index (from 1969 to January 2010).
Study quality was assessed using the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) checklist. Owing to the heterogeneity of the studies, no formal meta-analysis was undertaken. A de novo mathematical model was constructed to estimate the incremental costs and incremental quality-adjusted life-years (QALYs) associated with alternative strategies compared with a biopsy-all strategy. The tests are assessed first as a replacement for liver biopsy, and secondly as an additional test prior to liver biopsy. Thirty-six scenarios were assessed for each non-invasive test strategy, which varied the sensitivity of biopsy, the anxiety associated with biopsy, sensitivity and specificity values and whether or not the biopsy was percutaneous or transjugular. For each scenario, threshold levels were reported where biopsying all patients was more cost-effective than the strategy for two parameters (the decreased level of abstinence associated with the strategy compared with biopsying all and the level of incidental QALY gain associated with biopsy).
No studies were identified that specifically assessed the ELF test, although a study was identified that evaluated the diagnostic accuracy of the European Liver Fibrosis Test (essentially, the ELF test with the addition of age to the algorithm) compared with biopsy. Three studies of FibroTest, no relevant studies of FibroMax, and six studies of FibroScan assessing accuracy compared with biopsy in patients with known or suspected alcohol-related liver disease were identified. In all studies, the number of patients with suspected ALD was small, meaning that the estimated sensitivities and specificities were not robust. No conclusive estimate of the cost per QALY of each non-invasive test could be provided. Scenarios exist in which each of the strategies analysed is more cost-effective than biopsying all patients and, in contrast, scenarios exist in which each strategy is less cost-effective than biopsying all patients.
Study selection and data analysis were undertaken by one reviewer.
No conclusive result can be provided on the most cost-effective strategy until further data are available. A large number of parameters require data; however, the following are selected as being of most importance: (1) the sensitivity and specificity of each non-invasive liver test (NILT) against biopsy at validated and pre-selected cut-off thresholds; (2) the influence of potential confounding variables such as current drinking behaviour and the degree of hepatic inflammation on the performance of NILTs; and (3) the likelihood, and magnitude, of decreases in abstinence rates associated with a diagnosis of significant ALD by diagnostic modality and the incidental gains in QALYs that may be associated with biopsy.
The National Institute for Health Research Technology Assessment programme.
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ABSTRACT: Liver fibrosis is characterized by accumulation of extracellular matrix. Our previous study found that osteopontin (OPN) increased in plasma of cirrhotic patients and indicative of cirrhosis staging. The present study was designed to investigate the expression of OPN in liver tissues and plasma of cirrhotic patients and further explore the role of OPN in human hepatic stellate cell (HSC) activation. We used immunohistochemical staining and enzyme-linked immunosorbent assay to evaluate the expression level of OPN in liver tissues and plasma from cirrhotic patients, respectively. We produced lentivirus particles and infected target cell to manipulate OPN expression. Infection efficiency was determined by real-time RT-PCR and western blot. Cell proliferation was determined using CCK8 assay, and phenotypes of HSC activation were determined by real-time RT-PCR. OPN promoter activity was determined by dual luciferase reporter assay. We found that OPN expression in human cirrhotic liver tissues was upregulated compared to normal controls. In addition, its expression correlated with Child-Pugh classification, MELD score and the occurrence of complications. We further explored OPN level in patients' plasma and showed that its level correlated with transforming growth factor-β1 (TGF-β1). In human HSC cell line LX-2, we found that change of OPN expression level could not only affect the proliferation of cells but also the TGF-β1 mediated HSC activation. Moreover, OPN was increased by TGF-β1 stimulation and regulated by TGF-β1 at transcription level. OPN is upregulated in liver tissues and plasma of cirrhotic patients and promotes TGF-β1 mediated HSC activation.Digestive Diseases and Sciences 06/2012; 57(11):2883-91. DOI:10.1007/s10620-012-2248-7
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ABSTRACT: Fibrosis is a hallmark histologic event of chronic liver diseases and is characterized by the excessive accumulation and reorganization of the extracellular matrix (ECM). The gold standard for assessment of fibrosis is liver biopsy. As this procedure has various limitations, including risk of patient injury and sampling error, a non-invasive serum marker for liver fibrosis is desirable. The increasing understanding of the pathogenesis of hepatic fibrosis has suggested several markers which could be useful indicators of hepatic fibrogenesis and fibrosis. These markers include serum markers of liver function, ECM synthesis, fibrolytic processes, ECM degradation and fibrogenesis related cytokines. Recently, neo-epitopes, which are post-translational modifications of proteins, have been successfully used in bone and cartilage diseases which are characterized by extensive ECM remodeling. Increasing numbers of studies are being undertaken to identify neo-epitopes generated during liver fibrosis, and which ultimately might be useful for diagnosing and monitoring fibrogenesis. To date, the metalloproteinases generated fragment of collagen I, III, IV and VI have been proven to be elevated in two rat models of fibrosis. This review summarizes the recent efforts that have been made to identify potentially reliable non-invasive serum markers. We used the recently proposed BIPED (Burden of disease, Investigative, Prognostic, Efficacy and Diagnostic) system to characterize potential serum markers and neo-epitope markers that have been identified to date.Biomarker insights 07/2012; 7:105-17. DOI:10.4137/BMI.S10009
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ABSTRACT: The prognosis and clinical management of patients with chronic liver diseases are closely related to the severity of liver fibrosis. Liver biopsy is considered the gold standard for the staging of liver fibrosis. However, it is an invasive test sometimes related to complications. This study aimed to assess the diagnostic value of enhanced liver fibrosis (ELF) test to predict liver fibrosis in patients with chronic hepatitis C. This study included 162 patients with liver disease and 67 healthy controls. Hyaluronic acid, tissue inhibitor of matrix metalloproteinase type 1, and amino-terminal propeptide type III procollagen were measured by enzyme-linked immunosorbent assay with the ELF test ADVIA Centaur® (Siemens Healthcare Diagnostics Inc.). Fibrosis stage was determined using the Metavir scoring system. In our study, for the diagnosis of significant fibrosis (Metavir F≥2) a cut-off value >7.72 provides a sensitivity of 93.0% and a specificity of 83.0%. The areas under the receiver operator characteristic curve, sensitivity, specificity, and positive and negative predictive values were 0.94, 93.3%, 81.0%, 93.3%, and 81.0%, respectively (P<0.001). For the diagnosis of cirrhosis (Metavir F=4) a cut-off value >9.3 provides a sensitivity of 93.0% and a specificity of 86.0%. The areas under the receiver operator characteristic curve, sensitivity, specificity, and positive and negative predictive values were 0.94, 79.1%, 90.8%, 75.6%, and 92.3%, respectively (P<0.001). The ELF test is a promising non-invasive method for assessing liver fibrosis in patients with chronic hepatitis C. It is effective in the diagnosis of both fibrosis and cirrhosis.Hepatobiliary & pancreatic diseases international: HBPD INT 10/2013; 12(5):500-507. DOI:10.1016/S1499-3872(13)60079-X