These articles have been accepted for publication in the British Journal of Dermatology and are currently being edited and typeset. Readers should note that articles published below have been fully refereed, but have not been through the copy-editing and proof correction process. Wiley-Blackwell and the British Association of Dermatologists cannot be held responsible for errors or consequences arising from the use of information contained in these articles; nor do the views and opinions expressed necessarily reflect those of Wiley-Blackwell or the British Association of Dermatologists
Accepted Date: 10-Feb-2014 Article Type: Systematic Review
Diagnostic accuracy of non-invasive markers of liver fibrosis in patients with psoriasis taking methotrexate: A systematic review and meta-analysis Running head: Non-invasive markers of liver fibrosis (38 characters with spaces) Authors: C.M. Maybury1, E. Samarasekera2, A. Douiri3, J.N. Barker1, C.H. Smith1,4
1
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine,
King’s College London School of Medicine, King’s College London, London, UK 2
National Clinical Guideline Centre, Royal College of Physicians of London, 11 St
Andrews Place, London NW1 4LE, UK. 3
Department of Public Health Sciences, School of Medicine, King’s College
London, Capitol House, 42 Weston St London SE1 3QD, UK. 4
St John’s Institute of Dermatology, Guys and St Thomas’ NHS Foundation Trust, London, UK
Corresponding author: Professor Catherine Smith, St John's Institute of Dermatology, 9th floor Tower Wing, Guys Hospital, London. Email: [email protected] Telephone: 0207 188 6410 Acknowledgement: Some of this work was undertaken by the National Clinical Guideline Centre, which received funding from the National Institute for Health and Clinical Excellence (NICE). CM, CS, JB and AD acknowledge financial support from the Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King’s College Hospital NHS Foundation Trust. There are no conflicts of interest.
What’s already known about this topic? •
Methotrexate may confer an increased risk of liver fibrosis in people with psoriasis and suspected liver fibrosis is a common reason for treatment discontinuation.
•
There is uncertainty about the best method to identify liver fibrosis in this population and clinical practice varies.
What does this study add? •
Liver function tests (LFTs) demonstrate low diagnostic accuracy for the detection of fibrosis.
•
Likelihood ratios for P3NP were suboptimal for it to be considered a ‘good test.’
•
Larger studies are needed to further assess newer tests (including Fibroscan®) in the review population.
Abstract Background People with psoriasis taking methotrexate may be at increased risk of developing liver fibrosis compared to the general population. Non-invasive methods of detecting fibrosis have been widely adopted but their clinical utility is uncertain. Objectives To evaluate the diagnostic accuracy of non-invasive methods to detect fibrosis compared to liver biopsy (reference standard) in people with psoriasis taking methotrexate.
Methods A systematic search using MEDLINE, Embase, CINAHL, the Cochrane Library and Clinical Trials Register was performed. Diagnostic cohorts or case-control studies of adults taking or being considered for methotrexate therapy were considered. Study quality was evaluated using the Quality Assessment for Diagnostic Accuracy Studies tool (QUADAS-2). Pooled data analysis was performed using RevMan 5.1. Predictive analysis was conducted using Bayesian Markov chain Monte Carlo MCMC simulation. Results 17 studies were included. Sensitivity and specificity were 38% and 83% for standard liver function tests (LFTs), 74% and 77% for Procollagen-3 N-terminal Peptide (P3NP), 60% and 80% for Fibroscan®, 55% and 49% for ultrasound. Confidence in these results is limited due to low quality data; old, small studies displayed significant selection bias and significant variation in the prevalence of fibrosis.
No studies were identified
evaluating recently developed markers. Conclusions The clinical utility of LFTs, P3NP and liver ultrasound is poor and if used in isolation, will miss a significant number of patients with liver fibrosis. Larger prospective studies in this population are required to validate newer methods including Fibroscan®. Words: 237
Introduction Description of the health problem: Psoriasis and risk of liver fibrosis. Liver fibrosis is a major public health concern. Two large cohort studies have indicated that patients with psoriasis are at increased risk of liver fibrosis and death from liver disease (1, 2). This risk is probably due to a combination of non-alcoholic fatty liver disease (NAFLD) (3, 4), alcohol (5) and possibly methotrexate (6). Earlier detection of fibrosis would provide an opportunity to reverse the progression of disease (7) and prevent the practice of dermatologists stopping methotrexate, (an efficacious and cheap drug) unnecessarily. Variation in current guidelines Liver biopsy remains the ‘gold standard’ (8) method for detecting fibrosis despite being an unpleasant, hazardous and expensive test (9, 10). The American Academy of Dermatology (AAD) guidelines (Supplementary Tables 2-4), recommend monitoring for liver disease with standard liver function tests and biopsy (11). Whereas British (12) and European (13) guidelines (Supplementary Table 5) recommend monitoring with Procollagen-3 N-Terminal Peptide (P3NP) progressing to biopsy if multiple results are abnormal. Non-invasive methods to detect liver fibrosis To date the lack of accurate, reproducible and easily applied methods for fibrosis assessment has been a major limitation in both the clinical management and research
of liver disease in this patient population(14). Current non-invasive methods range from serum assays to imaging as depicted in Figure One. Aims of study The aim is to evaluate the diagnostic accuracy of non-invasive methods to detect fibrosis in people with psoriasis either being considered for treatment with methotrexate or currently taking methotrexate compared to liver biopsy. Materials and methods Literature search Searches were undertaken by an information specialist (JC) from inception until October 2012. Searches were made of English-language literature on MEDLINE, Embase, CINAHL, the Cochrane Library and Clinical Trials Register (Search terms, Table 1). Study selection, design and inclusion/exclusion criteria Observational studies to assess the accuracy of non-invasive tools to detect liver fibrosis or cirrhosis were considered. No limitations were made according to sample size or age. Studies were excluded if there was insufficient data to construct a 2x2 table, there were methodological limitations, or the incorrect population was evaluated. The population was people with psoriasis considered for, or being treated with methotrexate. Studies that considered mixed populations of patients with psoriasis, psoriatic arthritis and rheumatoid arthritis were excluded.
Index tests and reference standard Index tests were all methods of investigating liver fibrosis including imaging and serum markers of fibrosis. A P3NP level of >4.2mcg/l was considered abnormal (15). As there is no universal agreement on ‘abnormal’ liver biochemistry and imaging, any published ‘abnormal’ result was accepted. Liver biopsy was used as the reference standard. For our analysis any definition of fibrosis was accepted, irrespective of the histological classification system used. (In the case of Roenigk (16) and Metavir (17) systems, we accepted Roenigk Grade 3a and above or at least Metavir Grade F2.) Studies that limited the definition to at least marked fibrosis were excluded as they may overestimate sensitivity by removing the more difficult to diagnose milder end of the fibrosis spectrum. Fibrosis and cirrhosis were considered together as many studies did not give the number with fibrosis and cirrhosis separately. We searched for studies which included biopsies performed whilst patients were taking methotrexate. If studies included biopsy data separated into ‘pre’ and ‘during’ methotrexate, we extracted data taken from patients during treatment. Outcomes Tables of diagnostic test performance (i.e. numbers of true-positives (TP), true negatives (TN), false positives (FP) and false negatives (FN)) were constructed. Outcomes were statistical measures of diagnostic accuracy and utility: Sensitivity: The probability of someone with a disease having a positive test result, (true positive rate).
Specificity: The probability of someone without the disease having a negative test result, (true negative rate). Positive Likelihood ratio (LR+ve): How much more likely a positive test will be found in a person with the disease than without it. Negative Likelihood ratio (LR-ve): How much more likely a negative test is to be found in a person without the condition (18). A ‘good test’ would demonstrate sensitivity and specificity as close to 100% as possible. Likelihood ratios further from 1 provide greater evidence for presence or absence of disease. LRs >10 and 10) (19), when (theoretically) used in combination, positive LRs significantly improved and would be considered useful as a diagnostic pathway: 11.6 for P3NP+LFTs,13.5 for P3NP+Fibroscan®,30.5 for P3NP+LFT+Fibroscan®, and 134.3 for P3NP+P3NP+P3NP. It is important to stress that these results only give an indication of possible outcomes if the tests were to be used in combination based our on review data. P3NP performed three times had the best probability to rule-in the disease. Discussion Main findings Standard LFTs We show that standard liver function tests, the most commonly requested liver tests in hospital and community practice, demonstrate low diagnostic accuracy for the detection of liver fibrosis. Pooled sensitivity of 38% is very low and would indicate that many cases of fibrosis would be missed if standard LFTs were the only screening method used. These tests are currently recommended by the AAD to guide clinicians as to which patients to refer for biopsy and based on our data this recommendation should be reconsidered.
P3NP P3NP showed the best levels of diagnostic accuracy of the tests evaluated in our review; however the P3NP studies showed significant ascertainment bias and likelihood ratios were suboptimal for us to consider P3NP as a ‘good test.’ We know that P3NP has limitations as a diagnostic test: P3NP reflects active fibrogenesis so may not detect an already cirrhotic liver, nor is it liver-specific with elevated levels reported in arthritis (42), post myocardial infarction (43) and during normal puberty (44). The P3NP studies included did not adequately assess the prevalence of nor the impact of psoriatic arthritis on test performance, which was a significant limitation. To illustrate this point, in one case series of 170 patients with normal liver biopsies (excluded from this review due to insufficient reporting) 4% of patients with skin psoriasis alone had raised levels of P3NP compared with 38% of patients with a diagnosis of psoriatic arthritis (45). Fibroscan® Fibroscan® is increasingly used to identify possible fibrosis and performed reasonably well (pooled sensitivity 60% and specificity 80%) but was only assessed by two small studies comprising a total of 34 patients (37, 40). Strengths of the study Our review was performed in a well-defined population, using the gold standard of biopsy as a reference standard. We performed both pooled and Bayesian statistics which yielded similar results, strengthening their validity. A previous smaller systematic review by Montaudie et al evaluated P3NP,Fibrotest and Fibroscan. Their review did not analyse standard LFTs or other imaging methods (46). The incidence of fibrosis they
reported and the results for sensitivity and specificity of P3NP were similar to our findings. Weaknesses The majority of studies in our review were old and small. There were few studies for the majority of tests limiting the strength of our results. Importantly, there was significant ascertainment bias: research was performed in tertiary centres and the study population was far more likely to have liver fibrosis than the wider population of psoriasis patients taking methotrexate. Although liver biopsy is the gold standard for fibrosis evaluation, its use as a reference standard has several methodological limitations which may influence the results of noninvasive tests (47). The variability in the distribution of fibrosis within the liver produces inevitable sampling variability (48) and combined with the difficulty of obtaining an adequate biopsy sample, these factors may result in underestimation of the diagnostic accuracy of non-invasive markers (49). The variety of histological scoring systems employed introduces a risk of heterogeneity in the biopsy results and this is likely to underlie the very wide variation in the prevalence of fibrosis and cirrhosis (6.9-69.5%) reported thus the use of clinical outcomes as an alternative reference standard to biopsy has been mooted (47). Other factors to explain the reported variation in disease prevalence include population differences with regards to psoriasis disease severity and co-morbidities. Although most studies were conducted at tertiary centres, disease scores were not stated. A recent large population-based study demonstrated that in patients with psoriasis, the risk of
developing liver disease increased with increasing psoriasis disease severity (OR 1.29 for mild vs. 1.69 for severe psoriasis) (50). Cytokines and oxidative stress involved in the inflammatory process are known to predispose to steatohepatitis a precursor to fibrosis and cirrhosis (51, 52), and therefore disease severity could influence the predictive value of diagnostic tests but we were unable to assess this. Metabolic syndrome is common in psoriasis (and more so in severe disease) (53) and increases the incidence of cirrhosis (54-56); however because the prevalence of metabolic syndrome was underreported we were unable to evaluate its impact on test performance. Non-invasive markers in other chronic liver diseases The pathophyisiology of liver fibrosis (in terms of hepatocytes involved, distribution of disease in the liver and rate of progression) varies dependent on the cause, (whether it be alcohol, hepatitis B etc). Therefore individual test performance may be altered by the underlying disease process. This is why tests need to be validated in specific disease populations. However research in other groups remains important to illustrate the strengths and weaknesses of tests and is the starting point for validation studies in the psoriasis population(14). If we consider the non-invasive methods already discussed, a recent meta-analysis to compare ALT to biopsy in patients with chronic hepatitis b reported that approximately one fifth of patients with significant fibrosis have normal levels of ALT, supporting our evidence that this is a poor test to detect fibrosis(57) a result echoed in a large study of patients referred to hepatology with abnormal LFTs: “ ALT was essentially the same in
subjects with either no fibrosis, fibrosis, or cirrhosis or in subjects who died in the study population. A high ALT was not a useful discriminator for the severity of liver disease”(58). P3NP is not used in isolation as a non-invasive test in other chronic liver diseases and therefore we could not find a systematic review to address its utility for comparison, however it is being explored as a biomarker in combined panels such as the ‘Traffic light test’(58) and the ELF (Enhanced Liver Fibrosis) panel (59) which are showing promising results. A novel algorithm (Fib-4) derived from ALT, AST, platelet count and age has also performed well in hepatitis b and c(60). In a meta-analysis of patients with chronic hepatitis B (N=1625), Fibroscan® showed a sensitivity of 74.3% and specificity of 78.3% to detect fibrosis. (This related to an Area Under Receiver Operating Characteristic Curve (AUROC) of 0.859. AUROC>0.8 indicates a good diagnostic performance with diagnostic accuracy improving closer to 1.) The accuracy of Fibroscan® improved for the detection of cirrhosis, (sensitivity 84.5%, specificity 81.5%, AUROC 0.929.) Similar levels of accuracy were seen in another meta-analysis of Fibroscan® in hepatitis C patients (AUROC 0.84 for significant fibrosis, 0.94 for cirrhosis) (61). These figures are more impressive than our results and warrant formal evaluation in a larger study of the psoriasis population. Conclusion Our data do not support the use of standard LFTs to identify fibrosis or the use of P3NP in isolation as a monitoring tool. At present no individual test can replace biopsy if the diagnosis of fibrosis is suspected. However as our modelling exercise showed, when combined the likelihood ratios for non-invasive tests increase significantly. It is likely that in the future several tests (for example an imaging method and a combined panel of
biomarkers) will be used together to ‘triage’ patients, reducing the number referred for biopsy. In particular Fibroscan® and new combined panels such as ELF deserve validation in the psoriasis population at risk of liver disease. Furthermore an agreement of the most appropriate histological scoring system or an agreement to adopt a surrogate reference standard (possibly composed of clinical outcomes) would aid future analysis of non-invasive tests in this cohort. Acknowledgements •
This work was partly undertaken by the National Clinical Guideline Centre which received funding from the National Institute for Health and Clinical Excellence. The views expressed in this publication are those of the authors and not the Institute.
•
We thank Jill Cobb at the National Clinical Guideline Centre for assistance with literature searching.
•
We thank John W Stevens (Bsc PhD) at the Centre for Bayesian Statistics in Health Economics, University of Sheffield for assistance with the creation of bivariate forest plots.
•
We thank Professor Amar Paul Dhillon, Professor of Histopathology, University College London for his advice regarding the histological classification of liver fibrosis and cirrhosis.
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Liver scintigraphy
Liver biopsy
Within 2 weeks
Patients with psoriasis taking MTX (UK; N = 28)
simultaneously
Ho et al 1986
Prospecti ve case series
Patients with psoriasis taking MTX selected for biopsy due to total MTX dose/abnormal LFTs (Singapore; N = 18)
Alanine aminotransfera se
Liver biopsy
Unclear
LenlerRetrospec Patients with psoriasis taking MTX Petersen tive case with biopsy proven liver fibrosis or et al series cirrhosis 1982 (Denmark; N = 45)
Galactose tolerance test
Liver biopsy
Unclear
Maurice et al 2005
Retrospec Patients with psoriasis taking MTX tive case with >1 biopsy. series (UK; N = 34)
P3NP
Liver biopsy
Unclear
Mc Henry et al 1992
Retrospec Patients with psoriasis taking MTX tive case requiring a liver biopsy (either prior series to starting MTX or after every 11.5g) (UK; N = 63)
Liver scintigraphy
Liver biopsy
Within 4 weeks
Mitchell et al 1987
Prospecti ve case series
Ultrasound and liver scintigraphy
Liver biopsy
Within 24 hours
Newman et al 1989
Retrospec Patients with psoriasis taking MTX tive case resistant to other drugs & previous series liver biopsy before/during MTX (USA; N = 168)
Liver function tests
Liver biopsy
Within 3 days
Patients with psoriasis taking MTX for >12/12 and >0.5g cumulative dose MTX who were candidates for liver biopsy (UK; N = 49)
O'Conno r et al 1989
Retrospec Patients with psoriasis taking MTX, tive case who had a biopsy following MTX series (USA; N = 50)
Liver function tests
Liver biopsy
Within 7 days
Paramso Prospecti thy et al ve case 1988 control study
Patients with psoriasis taking MTX (UK; N = 15)
Liver function tests and antipyrine clearance
Liver biopsy
Unclear
Risteli 1988
Prospecti ve case series
Patients with psoriasis taking MTX for >6/12 months (Denmark; N = 24)
P3NP
Liver biopsy
Unclear
Zacharia e 1989
Retrospec Patients with psoriasis taking MTX tive case (Denmark; N = 84) series
P3NP
Liver biopsy
Unclear
Zacharia e et al 2001
Retrospec Patients with psoriasis taking MTX tive case who had a biopsy without fibrosis series and a normal P3NP (Denmark; N = 70)
P3NP
Liver biopsy
Unclear
*All studies were performed in a hospital setting
Table 3: Quality assessment of Diagnostic Accuracy Tool (QUADAS-2)
QUADAS-2: Critical appraisal of Diagnostic Test Accuracy DOMAIN 1: PATIENT SELECTION 1. Was a consecutive or random sample of patients enrolled? 2. Did the study include difficult to diagnose patients? 3. Could the selection of patients have introduced bias? 4. Are there concerns that the included patients and setting do not match the question?
DOMAIN 2: INDEX TEST 1. Were the index test results interpreted without knowledge of the results of the reference standard? 2. Did the study pre-specify the threshold for a positive result? 3. Could methods used to conduct or interpret the index test have introduced bias? 4. Are there concerns that the test technology, test methods and interpretation do not match the question?
DOMAIN 3: REFERENCE STANDARD 1. Is the reference standard likely to correctly classify the target condition? 2. Were the reference standard results interpreted without knowledge of the results of the index test? 3. Could methods used to conduct or interpret the reference standard have introduced bias? 4. Are there concerns that the target condition as defined by the reference standard does not match the question?
DOMAIN 4: FLOW AND TIMING 1. Was there an appropriate interval between index test and reference standard? 2. Did all patients receive a reference standard? 3. Did patients receive the same reference standard? 4. Were all patients included in the analysis?
Table 4 QUADAS-2 Study summary table
Study
Newman O’Connor Ho L- Petersen Paramsothy Geronemus McHenry Mitchell Coulson Boffa Zachariae 01 Maurice Berends Risteli/Zachariae 89 Bray Almeyda Creswell ☺Low Risk ? Unclear Risk High Risk
PATIENT SELECTION ? ? ☺ ? ? ☺ ? ? ? ? ☺ ? ? ? ?
RISK OF BIAS INDEX REFERENCE TEST STANDARD ? ☺ ? ? ? ? ☺ ☺ ☺ ? ? ☺ ☺ ☺ ☺ ? ?
☺ ☺ ☺
FLOW AND TIMING
APPLICABILITY CONCERNS PATIENT INDEX REFERENCE SELECTION TEST STANDARD
? ☺
☺ ☺
☺ ☺
? ? ☺ ☺ ☺
? ? ? ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺
? ☺ ☺
? ?
? ? ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺
? ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺
? ? ☺ ☺ ? ☺
☺ ☺ ☺ ? ? ☺ ☺ ☺ ☺ ☺ ? ☺ ☺ ☺ ☺ ☺ ☺
Indirect Biomarkers
Direct Biomarkers Combinational panels
Staging of fibrosis Proteomics profiles
Liver Biopsy Liver imaging
Forest Plot 1: Standard Liver function tests
Forest Plot 2: P3NP
Forest plots of (1) standard LFTs (ALT, AST, GGT, Bilirubin) and (2) P3NP with liver biopsy as reference test.
The squares represent the calculated specificity and sensitivity of one test within a study; the black line is the 95% confidence interval. The area of each square is proportional to the study's weight in the meta-analysis. The overall meta-analysed sensitivity and specificity is plotted as a diamond, the lateral points of which indicate confidence intervals for this estimate. Pooled (classical) and predictive (Bayesian) summaries shown at the bottom in bold.
Statistics summary 1
Test
Pooled sensitivity
Pooled Specificity
Pooled positive likelihood ratio
LFTs
0.38 (0.29-0.47)
0.83 (0.78-0.87)
2.04 (1.51 -2.76) 0.79 (0.65-0.96)
P3NP
0.74 (0.63-1.0)
0.77 (0.72-0.81)
5.32 (1.99 14.22)
0.35 (0.20-0.60)
Fibroscan
0.60 (0.15-0.95)
0.80 (0.59-0.93)
2.65 (1.03-6.82)
0.54 (0.21-1.36)
Ultrasound
0.55 (0.38-0.71)
0.49 (0.37-0.62)
0.81 (0.66-0.98)
3.23 (0.04263.99)
Radionuclide (scintigraphy) scans
0.60 (0.39-0.79)
0.77 (0.69-0.84)
2.51 (1.19-5.30)
0.62 (0.38-1.01)
Pooled negative likelihood ratio
AST recommended by US guidelines to stratify patients for biopsy was evaluated by 3 studies (39, 40, 43) (N=235) and demonstrated sensitivity 20-43%, specificity 86-100%, LR-ve1.4-1.5. 1 study (42) analysed the galactose tolerance test (N=45). Sensitivity 14%, specificity 94% LR+ve 2.19. LR-ve 1.1
Accepted Date: 10-Feb-2014 Article Type: Systematic Review
Diagnostic accuracy of non-invasive markers of liver fibrosis in patients with psoriasis taking methotrexate: A systematic review and meta-analysis Running head: Non-invasive markers of liver fibrosis (38 characters with spaces) Authors: C.M. Maybury1, E. Samarasekera2, A. Douiri3, J.N. Barker1, C.H. Smith1,4
1
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine,
King’s College London School of Medicine, King’s College London, London, UK 2
National Clinical Guideline Centre, Royal College of Physicians of London, 11 St
Andrews Place, London NW1 4LE, UK. 3
Department of Public Health Sciences, School of Medicine, King’s College
London, Capitol House, 42 Weston St London SE1 3QD, UK. 4
St John’s Institute of Dermatology, Guys and St Thomas’ NHS Foundation Trust, London, UK
Corresponding author: Professor Catherine Smith, St John's Institute of Dermatology, 9th floor Tower Wing, Guys Hospital, London. Email: [email protected] Telephone: 0207 188 6410 Acknowledgement: Some of this work was undertaken by the National Clinical Guideline Centre, which received funding from the National Institute for Health and Clinical Excellence (NICE). CM, CS, JB and AD acknowledge financial support from the Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King’s College Hospital NHS Foundation Trust. There are no conflicts of interest.
What’s already known about this topic? •
Methotrexate may confer an increased risk of liver fibrosis in people with psoriasis and suspected liver fibrosis is a common reason for treatment discontinuation.
•
There is uncertainty about the best method to identify liver fibrosis in this population and clinical practice varies.
What does this study add? •
Liver function tests (LFTs) demonstrate low diagnostic accuracy for the detection of fibrosis.
•
Likelihood ratios for P3NP were suboptimal for it to be considered a ‘good test.’
•
Larger studies are needed to further assess newer tests (including Fibroscan®) in the review population.
Abstract Background People with psoriasis taking methotrexate may be at increased risk of developing liver fibrosis compared to the general population. Non-invasive methods of detecting fibrosis have been widely adopted but their clinical utility is uncertain. Objectives To evaluate the diagnostic accuracy of non-invasive methods to detect fibrosis compared to liver biopsy (reference standard) in people with psoriasis taking methotrexate.
Methods A systematic search using MEDLINE, Embase, CINAHL, the Cochrane Library and Clinical Trials Register was performed. Diagnostic cohorts or case-control studies of adults taking or being considered for methotrexate therapy were considered. Study quality was evaluated using the Quality Assessment for Diagnostic Accuracy Studies tool (QUADAS-2). Pooled data analysis was performed using RevMan 5.1. Predictive analysis was conducted using Bayesian Markov chain Monte Carlo MCMC simulation. Results 17 studies were included. Sensitivity and specificity were 38% and 83% for standard liver function tests (LFTs), 74% and 77% for Procollagen-3 N-terminal Peptide (P3NP), 60% and 80% for Fibroscan®, 55% and 49% for ultrasound. Confidence in these results is limited due to low quality data; old, small studies displayed significant selection bias and significant variation in the prevalence of fibrosis.
No studies were identified
evaluating recently developed markers. Conclusions The clinical utility of LFTs, P3NP and liver ultrasound is poor and if used in isolation, will miss a significant number of patients with liver fibrosis. Larger prospective studies in this population are required to validate newer methods including Fibroscan®. Words: 237
Introduction Description of the health problem: Psoriasis and risk of liver fibrosis. Liver fibrosis is a major public health concern. Two large cohort studies have indicated that patients with psoriasis are at increased risk of liver fibrosis and death from liver disease (1, 2). This risk is probably due to a combination of non-alcoholic fatty liver disease (NAFLD) (3, 4), alcohol (5) and possibly methotrexate (6). Earlier detection of fibrosis would provide an opportunity to reverse the progression of disease (7) and prevent the practice of dermatologists stopping methotrexate, (an efficacious and cheap drug) unnecessarily. Variation in current guidelines Liver biopsy remains the ‘gold standard’ (8) method for detecting fibrosis despite being an unpleasant, hazardous and expensive test (9, 10). The American Academy of Dermatology (AAD) guidelines (Supplementary Tables 2-4), recommend monitoring for liver disease with standard liver function tests and biopsy (11). Whereas British (12) and European (13) guidelines (Supplementary Table 5) recommend monitoring with Procollagen-3 N-Terminal Peptide (P3NP) progressing to biopsy if multiple results are abnormal. Non-invasive methods to detect liver fibrosis To date the lack of accurate, reproducible and easily applied methods for fibrosis assessment has been a major limitation in both the clinical management and research
of liver disease in this patient population(14). Current non-invasive methods range from serum assays to imaging as depicted in Figure One. Aims of study The aim is to evaluate the diagnostic accuracy of non-invasive methods to detect fibrosis in people with psoriasis either being considered for treatment with methotrexate or currently taking methotrexate compared to liver biopsy. Materials and methods Literature search Searches were undertaken by an information specialist (JC) from inception until October 2012. Searches were made of English-language literature on MEDLINE, Embase, CINAHL, the Cochrane Library and Clinical Trials Register (Search terms, Table 1). Study selection, design and inclusion/exclusion criteria Observational studies to assess the accuracy of non-invasive tools to detect liver fibrosis or cirrhosis were considered. No limitations were made according to sample size or age. Studies were excluded if there was insufficient data to construct a 2x2 table, there were methodological limitations, or the incorrect population was evaluated. The population was people with psoriasis considered for, or being treated with methotrexate. Studies that considered mixed populations of patients with psoriasis, psoriatic arthritis and rheumatoid arthritis were excluded.
Index tests and reference standard Index tests were all methods of investigating liver fibrosis including imaging and serum markers of fibrosis. A P3NP level of >4.2mcg/l was considered abnormal (15). As there is no universal agreement on ‘abnormal’ liver biochemistry and imaging, any published ‘abnormal’ result was accepted. Liver biopsy was used as the reference standard. For our analysis any definition of fibrosis was accepted, irrespective of the histological classification system used. (In the case of Roenigk (16) and Metavir (17) systems, we accepted Roenigk Grade 3a and above or at least Metavir Grade F2.) Studies that limited the definition to at least marked fibrosis were excluded as they may overestimate sensitivity by removing the more difficult to diagnose milder end of the fibrosis spectrum. Fibrosis and cirrhosis were considered together as many studies did not give the number with fibrosis and cirrhosis separately. We searched for studies which included biopsies performed whilst patients were taking methotrexate. If studies included biopsy data separated into ‘pre’ and ‘during’ methotrexate, we extracted data taken from patients during treatment. Outcomes Tables of diagnostic test performance (i.e. numbers of true-positives (TP), true negatives (TN), false positives (FP) and false negatives (FN)) were constructed. Outcomes were statistical measures of diagnostic accuracy and utility: Sensitivity: The probability of someone with a disease having a positive test result, (true positive rate).
Specificity: The probability of someone without the disease having a negative test result, (true negative rate). Positive Likelihood ratio (LR+ve): How much more likely a positive test will be found in a person with the disease than without it. Negative Likelihood ratio (LR-ve): How much more likely a negative test is to be found in a person without the condition (18). A ‘good test’ would demonstrate sensitivity and specificity as close to 100% as possible. Likelihood ratios further from 1 provide greater evidence for presence or absence of disease. LRs >10 and 10) (19), when (theoretically) used in combination, positive LRs significantly improved and would be considered useful as a diagnostic pathway: 11.6 for P3NP+LFTs,13.5 for P3NP+Fibroscan®,30.5 for P3NP+LFT+Fibroscan®, and 134.3 for P3NP+P3NP+P3NP. It is important to stress that these results only give an indication of possible outcomes if the tests were to be used in combination based our on review data. P3NP performed three times had the best probability to rule-in the disease. Discussion Main findings Standard LFTs We show that standard liver function tests, the most commonly requested liver tests in hospital and community practice, demonstrate low diagnostic accuracy for the detection of liver fibrosis. Pooled sensitivity of 38% is very low and would indicate that many cases of fibrosis would be missed if standard LFTs were the only screening method used. These tests are currently recommended by the AAD to guide clinicians as to which patients to refer for biopsy and based on our data this recommendation should be reconsidered.
P3NP P3NP showed the best levels of diagnostic accuracy of the tests evaluated in our review; however the P3NP studies showed significant ascertainment bias and likelihood ratios were suboptimal for us to consider P3NP as a ‘good test.’ We know that P3NP has limitations as a diagnostic test: P3NP reflects active fibrogenesis so may not detect an already cirrhotic liver, nor is it liver-specific with elevated levels reported in arthritis (42), post myocardial infarction (43) and during normal puberty (44). The P3NP studies included did not adequately assess the prevalence of nor the impact of psoriatic arthritis on test performance, which was a significant limitation. To illustrate this point, in one case series of 170 patients with normal liver biopsies (excluded from this review due to insufficient reporting) 4% of patients with skin psoriasis alone had raised levels of P3NP compared with 38% of patients with a diagnosis of psoriatic arthritis (45). Fibroscan® Fibroscan® is increasingly used to identify possible fibrosis and performed reasonably well (pooled sensitivity 60% and specificity 80%) but was only assessed by two small studies comprising a total of 34 patients (37, 40). Strengths of the study Our review was performed in a well-defined population, using the gold standard of biopsy as a reference standard. We performed both pooled and Bayesian statistics which yielded similar results, strengthening their validity. A previous smaller systematic review by Montaudie et al evaluated P3NP,Fibrotest and Fibroscan. Their review did not analyse standard LFTs or other imaging methods (46). The incidence of fibrosis they
reported and the results for sensitivity and specificity of P3NP were similar to our findings. Weaknesses The majority of studies in our review were old and small. There were few studies for the majority of tests limiting the strength of our results. Importantly, there was significant ascertainment bias: research was performed in tertiary centres and the study population was far more likely to have liver fibrosis than the wider population of psoriasis patients taking methotrexate. Although liver biopsy is the gold standard for fibrosis evaluation, its use as a reference standard has several methodological limitations which may influence the results of noninvasive tests (47). The variability in the distribution of fibrosis within the liver produces inevitable sampling variability (48) and combined with the difficulty of obtaining an adequate biopsy sample, these factors may result in underestimation of the diagnostic accuracy of non-invasive markers (49). The variety of histological scoring systems employed introduces a risk of heterogeneity in the biopsy results and this is likely to underlie the very wide variation in the prevalence of fibrosis and cirrhosis (6.9-69.5%) reported thus the use of clinical outcomes as an alternative reference standard to biopsy has been mooted (47). Other factors to explain the reported variation in disease prevalence include population differences with regards to psoriasis disease severity and co-morbidities. Although most studies were conducted at tertiary centres, disease scores were not stated. A recent large population-based study demonstrated that in patients with psoriasis, the risk of
developing liver disease increased with increasing psoriasis disease severity (OR 1.29 for mild vs. 1.69 for severe psoriasis) (50). Cytokines and oxidative stress involved in the inflammatory process are known to predispose to steatohepatitis a precursor to fibrosis and cirrhosis (51, 52), and therefore disease severity could influence the predictive value of diagnostic tests but we were unable to assess this. Metabolic syndrome is common in psoriasis (and more so in severe disease) (53) and increases the incidence of cirrhosis (54-56); however because the prevalence of metabolic syndrome was underreported we were unable to evaluate its impact on test performance. Non-invasive markers in other chronic liver diseases The pathophyisiology of liver fibrosis (in terms of hepatocytes involved, distribution of disease in the liver and rate of progression) varies dependent on the cause, (whether it be alcohol, hepatitis B etc). Therefore individual test performance may be altered by the underlying disease process. This is why tests need to be validated in specific disease populations. However research in other groups remains important to illustrate the strengths and weaknesses of tests and is the starting point for validation studies in the psoriasis population(14). If we consider the non-invasive methods already discussed, a recent meta-analysis to compare ALT to biopsy in patients with chronic hepatitis b reported that approximately one fifth of patients with significant fibrosis have normal levels of ALT, supporting our evidence that this is a poor test to detect fibrosis(57) a result echoed in a large study of patients referred to hepatology with abnormal LFTs: “ ALT was essentially the same in
subjects with either no fibrosis, fibrosis, or cirrhosis or in subjects who died in the study population. A high ALT was not a useful discriminator for the severity of liver disease”(58). P3NP is not used in isolation as a non-invasive test in other chronic liver diseases and therefore we could not find a systematic review to address its utility for comparison, however it is being explored as a biomarker in combined panels such as the ‘Traffic light test’(58) and the ELF (Enhanced Liver Fibrosis) panel (59) which are showing promising results. A novel algorithm (Fib-4) derived from ALT, AST, platelet count and age has also performed well in hepatitis b and c(60). In a meta-analysis of patients with chronic hepatitis B (N=1625), Fibroscan® showed a sensitivity of 74.3% and specificity of 78.3% to detect fibrosis. (This related to an Area Under Receiver Operating Characteristic Curve (AUROC) of 0.859. AUROC>0.8 indicates a good diagnostic performance with diagnostic accuracy improving closer to 1.) The accuracy of Fibroscan® improved for the detection of cirrhosis, (sensitivity 84.5%, specificity 81.5%, AUROC 0.929.) Similar levels of accuracy were seen in another meta-analysis of Fibroscan® in hepatitis C patients (AUROC 0.84 for significant fibrosis, 0.94 for cirrhosis) (61). These figures are more impressive than our results and warrant formal evaluation in a larger study of the psoriasis population. Conclusion Our data do not support the use of standard LFTs to identify fibrosis or the use of P3NP in isolation as a monitoring tool. At present no individual test can replace biopsy if the diagnosis of fibrosis is suspected. However as our modelling exercise showed, when combined the likelihood ratios for non-invasive tests increase significantly. It is likely that in the future several tests (for example an imaging method and a combined panel of
biomarkers) will be used together to ‘triage’ patients, reducing the number referred for biopsy. In particular Fibroscan® and new combined panels such as ELF deserve validation in the psoriasis population at risk of liver disease. Furthermore an agreement of the most appropriate histological scoring system or an agreement to adopt a surrogate reference standard (possibly composed of clinical outcomes) would aid future analysis of non-invasive tests in this cohort. Acknowledgements •
This work was partly undertaken by the National Clinical Guideline Centre which received funding from the National Institute for Health and Clinical Excellence. The views expressed in this publication are those of the authors and not the Institute.
•
We thank Jill Cobb at the National Clinical Guideline Centre for assistance with literature searching.
•
We thank John W Stevens (Bsc PhD) at the Centre for Bayesian Statistics in Health Economics, University of Sheffield for assistance with the creation of bivariate forest plots.
•
We thank Professor Amar Paul Dhillon, Professor of Histopathology, University College London for his advice regarding the histological classification of liver fibrosis and cirrhosis.
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34. Risteli J, Sogaard H, Oikarinen A, Risteli L, Karvonen J, Zachariae H. Aminoterminal propeptide of type III procollagen in methotrexate-induced liver fibrosis and cirrhosis. The British journal of dermatology. 1988 Sep;119(3):321-5. PubMed PMID: 3179204. Epub 1988/09/01. eng. 35. Zachariae H, Heickendorff L, Sogaard H. The value of amino-terminal propeptide of type III procollagen in routine screening for methotrexateinduced liver fibrosis: a 10-year follow-up. The British journal of dermatology. 2001 Jan;144(1):100-3. PubMed PMID: 11167689. Epub 2001/02/13. eng. 36. Maurice PD, Maddox AJ, Green CA, Tatnall F, Schofield JK, Stott DJ. Monitoring patients on methotrexate: hepatic fibrosis not seen in patients with normal serum assays of aminoterminal peptide of type III procollagen. The British journal of dermatology. 2005 Mar;152(3):451-8. PubMed PMID: 15787813. Epub 2005/03/25. eng. 37. Berends MA, Snoek J, de Jong EM, Van Krieken JH, de Knegt RJ, van Oijen MG, et al. Biochemical and biophysical assessment of MTXinduced liver fibrosis in psoriasis patients: Fibrotest predicts the presence and Fibroscan predicts the absence of significant liver fibrosis. Liver international : official journal of the International Association for the Study of the Liver. 2007 Jun;27(5):639-45. PubMed PMID: 17498249. Epub 2007/05/15. eng. 38. Almeyda J, Barnardo D, Baker H, Levene GM, Landells JW. Structural and functional abnormalities of the liver in psoriasis before and during methotrexate therapy. The British journal of dermatology. 1972 Dec;87(6):623-31. PubMed PMID: 4648805. 39. Creswell SN, Burrows D. Liver biopsies in psoriatics--complications and evaluation. Int J Dermatol. 1980 May;19(4):217-9. PubMed PMID: 7399795. Epub 1980/05/01. eng. 40. Bray APJJ, Barnova I, Przemioslo R, Kennedy CTC. Liver fibrosis screening for patients with psoriasis taking methotrexate: A cross-sectional study comparing transient elastography and liver biopsy. British Journal of Dermatology. 2012 May;166(5):1125-7. PubMed PMID: 2012242593. 41. Berends MAM, Snoek J, De Jong EMGJ, Van Krieken JH, De Knegt RJ, van Oijen MGH, et al. Biochemical and biophysical assessment of MTX-induced liver fibrosis in psoriasis patients: Fibrotest predicts the presence and Fibroscan predicts the absence of significant liver fibrosis. Liver International. 2007 June;27(5):639-45. PubMed PMID: 2007360077. 42. Horslev-Petersen K, Saxne T, Haar D, Thomsen BS, Bentsen KD, Junker P, et al. The aminoterminal-type-III procollagen peptide and proteoglycans in serum and synovial fluid of patients with rheumatoid
arthritis or reactive arthritis. Rheumatology international. 1988;8(1):1-9. PubMed PMID: 3259005. Epub 1988/01/01. eng. 43. Fertin M, Dubois E, Belliard A, Amouyel P, Pinet F, Bauters C. Usefulness of circulating biomarkers for the prediction of left ventricular remodeling after myocardial infarction. The American journal of cardiology. 2012 Jul 15;110(2):277-83. PubMed PMID: 22482862. Epub 2012/04/10. eng. 44. Crofton PM, Wade JC, Taylor MR, Holland CV. Serum concentrations of carboxyl-terminal propeptide of type I procollagen, amino-terminal propeptide of type III procollagen, cross-linked carboxyl-terminal telopeptide of type I collagen, and their interrelationships in schoolchildren. Clinical chemistry. 1997 Sep;43(9):1577-81. PubMed PMID: 9299936. Epub 1997/09/23. eng. 45. Zachariae H, Aslam HM, Bjerring P, Sogaard H, Zachariae E, Heickendorff L. Serum aminoterminal propeptide of type III procollagen in psoriasis and psoriatic arthritis: relation to liver fibrosis and arthritis. J Am Acad Dermatol. 1991 Jul;25(1 Pt 1):50-3. PubMed PMID: 1880254. Epub 1991/07/01. eng. 46. Montaudie H, Sbidian E, Paul C, Maza A, Gallini A, Aractingi S, et al. Methotrexate in psoriasis: A systematic review of treatment modalities, incidence, risk factors and monitoring of liver toxicity. Journal of the European Academy of Dermatology and Venereology. 2011 May;25(SUPPL. 2):12-8. PubMed PMID: 2011144411. 47. Parkes J, Guha IN, Roderick P, Rosenberg W. Performance of serum marker panels for liver fibrosis in chronic hepatitis C. J Hepatol. 2006 Mar;44(3):462-74. PubMed PMID: 16427156. Epub 2006/01/24. eng. 48. Bedossa P, Dargère D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003 Dec;38(6):1449-57. PubMed PMID: 14647056. eng. 49. Poynard T, Munteanu M, Imbert-Bismut F, Charlotte F, Thabut D, Le Calvez S, et al. Prospective analysis of discordant results between biochemical markers and biopsy in patients with chronic hepatitis C. Clinical chemistry. 2004 Aug;50(8):1344-55. PubMed PMID: 15192028. eng. 50. Yeung H, Takeshita J, Mehta NN, Kimmel SE, Ogdie A, Margolis DJ, et al. Psoriasis severity and the prevalence of major medical comorbidity: a population-based study. JAMA Dermatol. 2013 Oct;149(10):1173-9. PubMed PMID: 23925466. Pubmed Central PMCID: PMC3800487. eng. 51. Organisation WG, editor World Gastroenterology Organisation Global Guideline: Nonalcoholic Fatty Liver Disease
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Liver scintigraphy
Liver biopsy
Within 2 weeks
Patients with psoriasis taking MTX (UK; N = 28)
simultaneously
Ho et al 1986
Prospecti ve case series
Patients with psoriasis taking MTX selected for biopsy due to total MTX dose/abnormal LFTs (Singapore; N = 18)
Alanine aminotransfera se
Liver biopsy
Unclear
LenlerRetrospec Patients with psoriasis taking MTX Petersen tive case with biopsy proven liver fibrosis or et al series cirrhosis 1982 (Denmark; N = 45)
Galactose tolerance test
Liver biopsy
Unclear
Maurice et al 2005
Retrospec Patients with psoriasis taking MTX tive case with >1 biopsy. series (UK; N = 34)
P3NP
Liver biopsy
Unclear
Mc Henry et al 1992
Retrospec Patients with psoriasis taking MTX tive case requiring a liver biopsy (either prior series to starting MTX or after every 11.5g) (UK; N = 63)
Liver scintigraphy
Liver biopsy
Within 4 weeks
Mitchell et al 1987
Prospecti ve case series
Ultrasound and liver scintigraphy
Liver biopsy
Within 24 hours
Newman et al 1989
Retrospec Patients with psoriasis taking MTX tive case resistant to other drugs & previous series liver biopsy before/during MTX (USA; N = 168)
Liver function tests
Liver biopsy
Within 3 days
Patients with psoriasis taking MTX for >12/12 and >0.5g cumulative dose MTX who were candidates for liver biopsy (UK; N = 49)
O'Conno r et al 1989
Retrospec Patients with psoriasis taking MTX, tive case who had a biopsy following MTX series (USA; N = 50)
Liver function tests
Liver biopsy
Within 7 days
Paramso Prospecti thy et al ve case 1988 control study
Patients with psoriasis taking MTX (UK; N = 15)
Liver function tests and antipyrine clearance
Liver biopsy
Unclear
Risteli 1988
Prospecti ve case series
Patients with psoriasis taking MTX for >6/12 months (Denmark; N = 24)
P3NP
Liver biopsy
Unclear
Zacharia e 1989
Retrospec Patients with psoriasis taking MTX tive case (Denmark; N = 84) series
P3NP
Liver biopsy
Unclear
Zacharia e et al 2001
Retrospec Patients with psoriasis taking MTX tive case who had a biopsy without fibrosis series and a normal P3NP (Denmark; N = 70)
P3NP
Liver biopsy
Unclear
*All studies were performed in a hospital setting
Table 3: Quality assessment of Diagnostic Accuracy Tool (QUADAS-2)
QUADAS-2: Critical appraisal of Diagnostic Test Accuracy DOMAIN 1: PATIENT SELECTION 1. Was a consecutive or random sample of patients enrolled? 2. Did the study include difficult to diagnose patients? 3. Could the selection of patients have introduced bias? 4. Are there concerns that the included patients and setting do not match the question?
DOMAIN 2: INDEX TEST 1. Were the index test results interpreted without knowledge of the results of the reference standard? 2. Did the study pre-specify the threshold for a positive result? 3. Could methods used to conduct or interpret the index test have introduced bias? 4. Are there concerns that the test technology, test methods and interpretation do not match the question?
DOMAIN 3: REFERENCE STANDARD 1. Is the reference standard likely to correctly classify the target condition? 2. Were the reference standard results interpreted without knowledge of the results of the index test? 3. Could methods used to conduct or interpret the reference standard have introduced bias? 4. Are there concerns that the target condition as defined by the reference standard does not match the question?
DOMAIN 4: FLOW AND TIMING 1. Was there an appropriate interval between index test and reference standard? 2. Did all patients receive a reference standard? 3. Did patients receive the same reference standard? 4. Were all patients included in the analysis?
Table 4 QUADAS-2 Study summary table
Study
Newman O’Connor Ho L- Petersen Paramsothy Geronemus McHenry Mitchell Coulson Boffa Zachariae 01 Maurice Berends Risteli/Zachariae 89 Bray Almeyda Creswell ☺Low Risk ? Unclear Risk High Risk
PATIENT SELECTION ? ? ☺ ? ? ☺ ? ? ? ? ☺ ? ? ? ?
RISK OF BIAS INDEX REFERENCE TEST STANDARD ? ☺ ? ? ? ? ☺ ☺ ☺ ? ? ☺ ☺ ☺ ☺ ? ?
☺ ☺ ☺
FLOW AND TIMING
APPLICABILITY CONCERNS PATIENT INDEX REFERENCE SELECTION TEST STANDARD
? ☺
☺ ☺
☺ ☺
? ? ☺ ☺ ☺
? ? ? ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺
? ☺ ☺
? ?
? ? ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺
? ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺
? ? ☺ ☺ ? ☺
☺ ☺ ☺ ? ? ☺ ☺ ☺ ☺ ☺ ? ☺ ☺ ☺ ☺ ☺ ☺
Indirect Biomarkers
Direct Biomarkers Combinational panels
Staging of fibrosis Proteomics profiles
Liver Biopsy Liver imaging
Forest Plot 1: Standard Liver function tests
Forest Plot 2: P3NP
Forest plots of (1) standard LFTs (ALT, AST, GGT, Bilirubin) and (2) P3NP with liver biopsy as reference test.
The squares represent the calculated specificity and sensitivity of one test within a study; the black line is the 95% confidence interval. The area of each square is proportional to the study's weight in the meta-analysis. The overall meta-analysed sensitivity and specificity is plotted as a diamond, the lateral points of which indicate confidence intervals for this estimate. Pooled (classical) and predictive (Bayesian) summaries shown at the bottom in bold.
Statistics summary 1
Test
Pooled sensitivity
Pooled Specificity
Pooled positive likelihood ratio
LFTs
0.38 (0.29-0.47)
0.83 (0.78-0.87)
2.04 (1.51 -2.76) 0.79 (0.65-0.96)
P3NP
0.74 (0.63-1.0)
0.77 (0.72-0.81)
5.32 (1.99 14.22)
0.35 (0.20-0.60)
Fibroscan
0.60 (0.15-0.95)
0.80 (0.59-0.93)
2.65 (1.03-6.82)
0.54 (0.21-1.36)
Ultrasound
0.55 (0.38-0.71)
0.49 (0.37-0.62)
0.81 (0.66-0.98)
3.23 (0.04263.99)
Radionuclide (scintigraphy) scans
0.60 (0.39-0.79)
0.77 (0.69-0.84)
2.51 (1.19-5.30)
0.62 (0.38-1.01)
Pooled negative likelihood ratio
AST recommended by US guidelines to stratify patients for biopsy was evaluated by 3 studies (39, 40, 43) (N=235) and demonstrated sensitivity 20-43%, specificity 86-100%, LR-ve1.4-1.5. 1 study (42) analysed the galactose tolerance test (N=45). Sensitivity 14%, specificity 94% LR+ve 2.19. LR-ve 1.1
