Elsevier

Journal of Hepatology

Volume 44, Issue 3, March 2006, Pages 462-474
Journal of Hepatology

Performance of serum marker panels for liver fibrosis in chronic hepatitis C

https://doi.org/10.1016/j.jhep.2005.10.019Get rights and content

Background/Aims

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.

Methods

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.

Results

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.

Conclusions

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.

Introduction

Chronic hepatitis C (CHC) is recognised as a major healthcare problem with a worldwide prevalence of over 200 million [1]. Prevalence is increasing, and estimates of the future burden of CHC predict at least a three-fold rise in cirrhosis by 2020 [2], [3]. CHC is characterised by hepatic fibrosis which may progress to cirrhosis with all the attendant long-term complications of liver disease including death. Clinicians and patients require accurate information about the degree of fibrosis to guide management decisions, predict outcome and monitor disease.

Liver biopsy has been the reference test for the assessment of hepatic fibrosis, but has limitations including small but significant morbidity and mortality rates, sampling error, inter- and intra-observer variation in pathology reporting, and provision of a static picture of liver architecture in a dynamic disease process [4], [5], [6], [7], [8].

Serum markers of liver fibrosis offer an attractive alternative to liver biopsy, as they are less invasive than biopsy, may allow dynamic calibration of fibrosis, and may be more cost effective. A systematic review of single or multiple serum markers versus histology in assessing fibrosis in CHC was conducted up to 2002 [9]. The diagnostic accuracy appeared greatest and most promising in the studies using a panel of markers. We have built on this work and have performed a systematic review to assess the diagnostic performance of panels of serum markers of fibrosis in CHC.

Section snippets

Methods

The review was conducted following accepted principles [10], [11]. A systematic literature search was performed to ascertain the performance of panels of surrogate markers of fibrosis in Hepatitis C. Sources searched included:

  • Electronic databases 1985–October 2004: Cochrane Library 2004 MEDLINE, EMBASE using a search strategy derived from the literature [11], [12]. (Available from authors.) Search terms were added following initial searches as appropriate.

  • Relevant websites: American Association

Inclusion criteria

Studies were included if:

  • they evaluated panels of ≥2 serum markers;

  • allowed extraction of data for interferon naïve patients with CHC;

  • were written in English;

  • were systematic reviews, meta-analyses or studies of diagnostic tests;

  • they used liver biopsy as a reference standard;

  • they included >30 participants (as smaller studies will be underpowered to produce precise estimates of test performance and would be more likely to produce zero denominator effects in 2×2 table. Confidence intervals would be

Exclusion criteria

Studies were excluded if:

  • data on hepatitis C were not separately extractable;

  • study did not produce a composite score;

  • study used single markers;

  • study did not use liver biopsy as reference test;

  • less than 30 participants.

Quality assessment strategy

The quality of included studies was assessed using the quality assessment of diagnostic accuracy studies (QADAS) tool [13] (Appendix A).

Results

The electronic search yielded 2766 abstracts which were read in full. Twenty-five full papers were retrieved of which 11 were excluded leaving 14 studies in separate populations to be included in the review (see Table 1). Reasons for exclusion were:

  • single markers: four papers;

  • less than 30 participants: four papers;

  • no reference test: one paper

In addition two reviews were identified; a systematic review of all serum markers and an overview of two markers (Fibrotest and Actitest) [9], [19]. All

Results from studies differentiating (F0/F1 vs F2/F3/F4)

For those studies presenting data on mild versus moderate/severe fibrosis, 10 studies presented data at several thresholds and had sufficient information to permit the derivation of true positive, true negative, false positive, and false negative (Table 2). The number of thresholds presented for each test varied.

AUC for Receiver Operating Characteristic (ROC) curves were presented in 13/14 studies. For most studies the AUC varies between training and validation sets with performance generally

Results from studies differentiating (F0/F1/F2/F3 vs F4)

In studies that reported results for F0, 1, 2, 3 vs F4 (i.e. no cirrhosis versus cirrhosis) all of the surrogate markers performed at a higher level, with the AUC and sensitivity and specificity being greater at all thresholds (Table 3).

Discussion

We identified 14 primary studies evaluating the diagnostic performance of serum markers of liver fibrosis in CHC, using 10 different combinations of serum markers. Whilst all studies recruited patients from specialist clinics, there was variation between studies in population characteristics, prevalence of severe fibrosis, and methods of test validation. Most studies reported AUC in differentiating mild/no fibrosis and significant fibrosis with the median value in validation populations being

Conclusion

This review provides an update of published evidence of the diagnostic performance of serum markers of fibrosis in CHC, novel summative analyses, and using methods adaptable by clinicians, demonstrates the clinical utility of markers to inform use in practice. It highlights methodological limitations of commonly used performance measures and suggests alternatives. Although informative in a minority of patients with CHC, the tests have a place in assessment of fibrosis to rule-in or rule-out

Acknowledgements

Jacqueline Dinnes for statistical and methodological advice. We thank the anonymous reviewers and editors for constructive comments.

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