Gastroenterology

Gastroenterology

Volume 127, Issue 6, December 2004, Pages 1704-1713
Gastroenterology

Clinical-liver, pancreas, and biliary tract
Serum markers detect the presence of liver fibrosis: A cohort study

https://doi.org/10.1053/j.gastro.2004.08.052Get rights and content

Background & Aims: Histologic examination of a liver biopsy specimen is regarded as the reference standard for detecting liver fibrosis. Biopsy can be painful and hazardous, and assessment is subjective and prone to sampling error. We developed a panel of sensitive automated immunoassays to detect matrix constituents and mediators of matrix remodeling in serum to evaluate their performance in the detection of liver fibrosis. Methods: In an international multicenter cohort study, serum levels of 9 surrogate markers of liver fibrosis were compared with fibrosis stage in liver biopsy specimens obtained from 1021 subjects with chronic liver disease. Discriminant analysis of a test set of samples was used to identify an algorithm combining age, hyaluronic acid, amino-terminal propeptide of type III collagen, and tissue inhibitor of matrix metalloproteinase 1 that was subsequently evaluated using a validation set of biopsy specimens and serum samples. Results: The algorithm detected fibrosis (sensitivity, 90%) and accurately detected the absence of fibrosis (negative predictive value for significant fibrosis, 92%; area under the curve of a receiver operating characteristic plot, .804; standard error, .02; P < .0001; 95% confidence interval, .758–.851). Performance was excellent for alcoholic liver disease and nonalcoholic fatty liver disease. The algorithm performed equally well in comparison with each of the pathologists. In contrast, pathologists’ agreement over histologic scores ranged from very good to moderate (κ = .97–.46). Conclusions: Assessment of liver fibrosis with multiple serum markers used in combination is sensitive, specific, and reproducible, suggesting they may be used in conjunction with liver biopsy to assess a range of chronic liver diseases.

Section snippets

Materials and methods

The study and study protocols were approved by the UK South and West Multicentre Research Ethics Committee (MREC 98/6/08) and the local research ethics committees (m140/98) at all participating sites.

We have investigated the relationship among levels of 9 serum fibrosis markers and liver fibrosis assessed by histologic examination of liver biopsy specimens from 1021 prospectively recruited subjects obtained as part of the investigation of chronic liver disease at 13 centers between 1998 and

Results

The primary aim of the study was to investigate the ability of serum markers to identify significant histologic fibrosis. The mean, median, and SEM for each marker in GT and GV were determined. A multivariate analysis of variance indicated that there were no differences between groups for all markers taken together (Hotelling’s T = .01, F = 1.14, df1 = 9, df2 = 911, P = .33). An examination of the associated individual t tests showed no significant differences between the groups on any

Discussion

We have defined an algorithm combining serum markers of liver fibrosis that can be used to exclude significant fibrosis with sensitivity in excess of 90% or to detect significant fibrosis with specificity in excess of 90% by adopting different test thresholds. In addition, the algorithm can detect cirrhosis with sensitivity in excess of 90%. The algorithm achieved a similar level of sensitivity and specificity when compared with the scoring of 3 different pathologists, providing evidence that

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Supported by Bayer Healthcare AG (Leverkusen, Germany). This study is an investigator-initiated study funded by Bayer AG. M.B. and M.V. are employees of Bayer HealthCare AG. R.T. is an independent statistical analyst engaged by Bayer HealthCare AG. A.B., S.H., and T.R. received grant support from Bayer AG.

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