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Blood Tests to Diagnose Fibrosis or Cirrhosis in Patients With Chronic Hepatitis C Virus Infection: A Systematic Review

Roger Chou, MD; and Ngoc Wasson, MPH
[+] Article and Author Information

From Oregon Health & Science University, Portland, Oregon.

Disclaimer: The findings and conclusions in this article are those of the authors, who are responsible for its content, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or the U.S. Department of Health and Human Services.

Acknowledgment: The authors thank Tracy Dana, MLS; AHRQ Task Order Officer Christine Chang, MD, MPH; and USPSTF Medical Officer Iris Mabry-Hernandez, MD, MPH.

Grant Support: By AHRQ (contract 290-2007-10057-I, task order 8), Rockville, Maryland.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-3007.

Requests for Single Reprints: Roger Chou, MD, Oregon Health & Science University, Mail Code BICC, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239-3098; e-mail, chour@ohsu.edu.

Current Author Addresses: Drs. Chou and Wasson: Oregon Health & Science University, Mail Code BICC, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239-3098.

Author Contributions: Conception and design: R. Chou.

Analysis and interpretation of the data: R. Chou.

Drafting of the article: R. Chou.

Critical revision of the article for important intellectual content: R. Chou.

Final approval of the article: R. Chou.

Provision of study materials or patients: R. Chou.

Statistical expertise: R. Chou.

Obtaining of funding: R. Chou.

Administrative, technical, or logistic support: R. Chou, N. Wasson.

Collection and assembly of data: R. Chou, N. Wasson.


Ann Intern Med. 2013;158(11):807-820. doi:10.7326/0003-4819-158-11-201306040-00005
Text Size: A A A

This article has been corrected. The original version (PDF) is appended to this article as a supplement.

Background: Many blood tests have been proposed as alternatives to liver biopsy for identifying fibrosis or cirrhosis.

Purpose: To evaluate the diagnostic accuracy of blood tests to identify fibrosis or cirrhosis in patients with hepatitis C virus (HCV) infection.

Data Sources: MEDLINE (1947 to January 2013), the Cochrane Library, and reference lists.

Study Selection: Studies that compared the diagnostic accuracy of blood tests with that of liver biopsy.

Data Extraction: Investigators abstracted and checked study details and quality by using predefined criteria.

Data Synthesis: 172 studies evaluated diagnostic accuracy. For identifying clinically significant fibrosis, the platelet count, age–platelet index, aspartate aminotransferase–platelet ratio index (APRI), FibroIndex, FibroTest, and Forns index had median positive likelihood ratios of 5 to 10 at commonly used cutoffs and areas under the receiver-operating characteristic curve (AUROCs) of 0.70 or greater (range, 0.71 to 0.86). For identifying cirrhosis, the platelet count, age–platelet index, APRI, and Hepascore had median positive likelihood ratios of 5 to 10 and AUROCs of 0.80 or greater (range, 0.80 to 0.91). The Göteborg University Cirrhosis Index and the Lok index had slightly lower positive likelihood ratios (4.8 and 4.4, respectively). In direct comparisons, the APRI was associated with a slightly lower AUROC than the FibroTest for identifying fibrosis and a substantially higher AUROC than the aspartate aminotransferase–alanine aminotransferase ratio for identifying fibrosis or cirrhosis.

Limitation: Only English-language articles were included, and most studies had methodological limitations, including failure to describe blinded interpretation of liver biopsy specimens and inadequate description of enrollment methods.

Conclusion: Many blood tests are moderately useful for identifying clinically significant fibrosis or cirrhosis in HCV-infected patients.

Primary Funding Source: Agency for Healthcare Research and Quality.

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Comment
Posted on June 10, 2013
Thierry Poynard, Mona Munteanu, vlad Ratziu
AP-HP UPMC Paris Liver Center, BioPredictive
Conflict of Interest: TP is a consultant and has a capital interest in BioPredictive the company marketing FibroTest. The patents belong to the French Public Organization “Assistance Publique Hopitaux de Paris”.

We read with a great interest the systematic review of blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection [1] updating, 11 years after, the previous high quality review [2] on this topic. Despite the authors discussed the limitations of using biopsy as a perfect reference, they missed the opportunity to review the evidence based data on prognostic performances of blood tests. In the absence of true gold standard, one more reliable method to compare the performance of tests in the diagnosis of cirrhosis is to use morbidity and mortality as the reference [3]. Using this methodology FibroTest had greater 5-year prognostic value than APRI (Table) [4,5] and Forns index [5].  

In this overview there was another omission, which was unfair for the FibroTest versus APRI comparisons. Contrarily to the authors' statement there were not 2 but 3 studies estimating Obuchowski measure. In this missing reference FibroTest had a very higher performance for all pair-wise comparisons between stages versus APRI (P<0.000] [4] (Table). This is not a detail as Obuchowski measure included the test's performance for cirrhosis staging. Therefore, from published evidence during the overview period, FibroTest had a significantly better performance than APRI for the diagnosis of fibrosis stages, including cirrhosis.

 

Thierry Poynard, Mona Munteanu, Vlad Ratziu.

 

AP-HP UPMC Paris Liver Center, BioPredictive, Paris France

Possible conflict of interest:

TP is a consultant and has a capital interest in BioPredictive the company marketing FibroTest. The patents belong to the French Public Organization “Assistance Publique Hopitaux de Paris”.

MM is a full employee of BioPredictive.

VR has no conflict of interest.

References

[1]. Chou R, Wasson N. Blood tests to diagnose fibrosis or cirrhosis in patients

with chronic hepatitis C virus infection: a systematic review. Ann Intern Med.

2013;158:807-20.

[2]. Gebo KA, Herlong HF, Torbenson MS, Jenckes MW, Chander G, Ghanem KG, et al. Role of liver biopsy in management of chronic hepatitis C: a systematic review. Hepatology. 2002;36:S161-72.

[3]. Poynard T, Ngo Y, Perazzo H, Munteanu M, Lebray P, Moussalli J, et al. Prognostic value of liver fibrosis biomarkers: a meta-analysis. Gastroenterol Hepatol (N Y). 2011;7:445-54.

[4]. Ngo Y, Munteanu M, Messous D, Charlotte F, Imbert-Bismut F, Thabut D, et al. A prospective analysis of the prognostic value of biomarkers (FibroTest) in patients with chronic hepatitis C. Clin Chem. 2006;52:1887-96.

[5]. Vergniol J, Foucher J, Terrebonne E, Bernard PH, le Bail B, Merrouche W, et al. Noninvasive tests for fibrosis and liver stiffness predict 5-year outcomes of patients with chronic hepatitis C. Gastroenterology. 2011;140:1970-9.

 

Author, year

Endpoint

FibroTest

APRI

P value

Ngo, 2006

Survival without liver complications (n=537)

0.96 (0.93-0.97)

0.82 (0.66-0.91)

0.03

Vergniol, 2011

Overall survival (n=663)

0.80 (0.69–0.87)

0.66 (0.55–0.75)

0.02

Vergniol, 2011

Obuchowski measure (n=633)

0.861 (0.007

0.814 (0.007)

<0.0001

 

AUROC for liver fibrosis diagnosis is useful but not sufficient
Posted on June 29, 2013
Paul Calès (1), Victor de Ledinghen (2), Jérôme Guéchot (3)
1 - Liver-Gastroenterology Department, CHU Angers, Angers, France, HIFIH laboratory, UPRES 3859, SFR 4208, LUNAM University, Angers, France. 2 - Liver-Gastroenterology Department, Pessac University Ho
Conflict of Interest: Paul Calès is a consultant for BioLiveScale Inc. that has a license for FibroMeter from Angers University. BioLiveScale had no role in the present study. The other authors have no conflicts of interest to declare.

We thank Roger Chou and Ngoc Wasson for their impressive work (1). We would like to comment on some aspects. The authors introduce the selected studies as those comparing the diagnostic accuracy of blood tests with that of liver biopsy while most of the studies evaluated diagnostic accuracy of tests using liver biopsy as reference standard. This precision is important since biopsy is an imperfect gold standard. As the main judgment criterion was based on AUROC, the AUROC interpretation should have taken into account the misclassification rate of liver biopsy as already demonstrated (2).Table 1 contains errors regarding test compositions: FibroMeter includes hyaluronate, but not ALT and GGT, and 8 markers, not 9; Fibrotest includes sex and age. Table 2 is the most important as it deals with the main judgment criterion (significant fibrosis). We are surprised by the discrepancy in the number of studies analyzed between that table and those that follow (3 studies on FibroMeter in Table 2 versus 8 in Table 4). Consistency would have been improved by considering all available studies.The diagnostic target is important to consider. Almost all blood tests were constructed with significant fibrosis as diagnostic target. Therefore, in accuracy evaluations, caution should be exercised when interpreting other diagnostic targets (cirrhosis). For example, in the FibroMeter constructed for cirrhosis (CirrhoMeter) marker coefficients were specific (3), explaining in part why CirrhoMeter accuracy was the highest in Table 3. It should be emphasized that this review is biased by the fact that negative results are frequently not published. For instance, the authors concluded to the high strength of evidence of the AST:ALT ratio diagnostic value, although its diagnostic value is very low when aminotransferase activities are adequately measured. Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, is a coenzyme in all transamination reactions. Supplementation with PLP increases both aminotransferases measurements, mainly ALT and to a lesser extent AST, so that the AST:ALT ratio is almost constant. Since B6 deficiency is observed in a significant percentage of patients, including those with liver disease, it is recommended to include PLP in AST and ALT measurements to better reflect the liver’s cytolytic state. Finally, we think that evaluating accuracy for binary diagnoses is useful but not sufficient. Other characteristics should be evaluated including prognostic performance (4), reproducibility, robustness, reliability and prediction, as well as the accuracy and precision of fibrosis classification used in clinical practice (5).

References

1. Chou R, Wasson N. Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review. Annals of internal medicine. 2013;158(11):807-20.

2. Mehta SH, Lau B, Afdhal NH, Thomas DL. Exceeding the limits of liver histology markers. J Hepatol. 2009;50(1):36-41.

3. Boursier J, Bacq Y, Halfon P, Leroy V, de Ledinghen V, de Muret A, et al. Improved diagnostic accuracy of blood tests for severe fibrosis and cirrhosis in chronic hepatitis C. Eur J Gastroenterol Hepatol. 2009;21(1):28-38.

4. Vergniol J, Foucher J, Terrebonne E, Bernard PH, le Bail B, Merrouche W, et al. Noninvasive tests for fibrosis and liver stiffness predict 5-year outcomes of patients with chronic hepatitis C. Gastroenterology. 2011;140(7):1970-9, 9 e1-3.

5. Boursier J, Bertrais S, Oberti F, Gallois Y, Fouchard-Hubert I, Rousselet MC, et al. Comparison of accuracy of fibrosis degree classifications by liver biopsy and non-invasive tests in chronic hepatitis C. BMC Gastroenterol. 2011;11:132.

In response
Posted on July 16, 2013
Roger Chou
Oregon Health & Science University
Conflict of Interest: Funding received from the Agency for Healthcare Research and Quality

In response:Although liver biopsy has limitations, such as sampling error and variability in interpretation, it remains the reference standard for evaluating hepatic fibrosis in almost all diagnostic studies. As we reported, results were largely unchanged when analyses were restricted to studies using adequate biopsy specimens (defined as length >15 mm and >5 portal tracts in the absence of cirrhosis).

We focused on diagnostic rather than prognostic accuracy since determination of fibrosis stage at the time of biopsy impacts clinical decisions regarding treatment, and there are few studies on prognostic performance (6 in a recent meta-analysis (1)) compared with diagnostic accuracy (172 in our review). Two of the three results in the Table presented by Poynard and colleagues were excluded because they evaluated prognosis (2, 3); one study (3) also reported a difference of 0.05 favoring the Fibrotest over the APRI for diagnosis of fibrosis stage based on the area under the receiver operating curve (AUROC) using the Obuchowski method, consistent with our results based on the standard AUROC (median difference 0.03).

Cales and colleagues suggest inconsistency in how we utilized data. To clarify, we used all available data, but the number of studies providing information for various measures of diagnostic accuracy differed. In addition, as described in our methods, some analyses were restricted to studies that directly compared two or more blood tests. We evaluated these studies separately because empiric research indicates that results based on direct comparisons differ from results based on noncomparative studies, and may be more suited for understanding comparative diagnostic test performance (4).

We reported diagnostic accuracy for significant fibrosis and cirrhosis separately, based on the specific thresholds used to define a positive test for the target condition, as well as any modifications of the blood test for the target condition. Potential inaccuracies in aminotransferase measurements related to low pyridoxal 5’-phosphate (PLP) levels would reflect results expected in clinical practice, since PLP levels are not routinely obtained. Reporting bias can affect any systematic review, though data on the extent and effects of reporting bias in diagnostic test reviews are very limited.

As noted by Cales and colleagues, we inadvertently omitted age and sex as component items of the Fibrotest. In addition, the Fibrometer includes 8 (not 9) items, excluding the alanine aminotransferase level. Gamma-glutamyl transferase (GGT) was listed as a component because it replaced hyaluronic acid in the 3rd generation Fibrometer test (5).

References

(1) Poynard T, Ngo Y, Perazzo H, Munteanu M, et al. Prognostic value of liver fibrosis biomarkers: a meta-analysis. Gastroenterol Hepatol 2011;7:445-54.

(2) Takwoingi Y, Leeflang MM, Deeks JJ. Empirical evidence of the importance of comparative studies of diagnostic test accuracy. Ann Intern Med 2013;158:544-54.

(3) Ngo Y, Munteanu M, Messous D, Charlotte F, et al. A prospective analysis of the prognostic value of biomarkers (Fibrotest)in patients with chronic hepatitis C. Clin Chem 2006;52:1887-96.

(4) Vergniol J, Foucher J, Terrebonne E, Bernhard P.H., et al. Noninvasive tests for fibrosis and liver stiffness predict 5-year outcomes of patients with chronic hepatitis C. Gastroenterol 2011;140:1970-9.

(5) Cales P, Boursier J, Bertrais S, Oberti F, et al. Optimization and robustness of blood tests for liver fibrosis and cirrhosis. Clin Biochem 2010;43:1315-22.

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