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Annals of Internal Medicine
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
Background: Many blood tests have been proposed as alternatives
let count, age–platelet index, APRI, and Hepascore had median to liver biopsy for identifying fibrosis or cirrhosis.
positive likelihood ratios of 5 to 10 and AUROCs of 0.80 or greater(range, 0.80 to 0.91). The Go¨teborg University Cirrhosis Index and Purpose: To evaluate the diagnostic accuracy of blood tests to
the Lok index had slightly lower positive likelihood ratios (4.8 and identify fibrosis or cirrhosis in patients with hepatitis C virus (HCV) 4.4, respectively). In direct comparisons, the APRI was associated with a slightly lower AUROC than the FibroTest for identifying Data Sources: MEDLINE (1947 to January 2013), the Cochrane
fibrosis and a substantially higher AUROC than the aspartate ami- notransferase–alanine aminotransferase ratio for identifying fibrosisor cirrhosis.
Study Selection: Studies that compared the diagnostic accuracy of
blood tests with that of liver biopsy.
Limitation: Only English-language articles were included, and most
studies had methodological limitations, including failure to describe
Data Extraction: Investigators abstracted and checked study details
blinded interpretation of liver biopsy specimens and inadequate and quality by using predefined criteria.
Data Synthesis: 172 studies evaluated diagnostic accuracy. For
Conclusion: Many blood tests are moderately useful for identifying
identifying clinically significant fibrosis, the platelet count, age– clinically significant fibrosis or cirrhosis in HCV-infected patients.
platelet index, aspartate aminotransferase–platelet ratio index Primary Funding Source: Agency for Healthcare Research and
(APRI), FibroIndex, FibroTest, and Forns index had median positive likelihood ratios of 5 to 10 at commonly used cutoffs and areasunder the receiver-operating characteristic curve (AUROCs) of 0.70 Ann Intern Med. 2013;158:807-820.
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or greater (range, 0.71 to 0.86). For identifying cirrhosis, the plate- For author affiliations, see end of text.
The prevalence of anti–hepatitis C virus (HCV) anti- pass patients at lower risk for disease progression, calling
body in the United States is about 1.6% (1). Approx- into question the need to obtain detailed pretreatment imately three quarters of persons with anti-HCV antibody prognostic information with an invasive test. Therefore, have viremia, indicating chronic infection. Hepatitis C biopsy is no longer recommended in all HCV-infected pa- virus–related liver disease is the most common reason for tients before antiviral treatment (11). However, given the liver transplantation among American adults and a leading adverse effects and costs associated with current antiviral cause of hepatocellular carcinoma, and it is associated with therapies, knowing the degree of liver fibrosis can still pro- about 15 000 deaths annually (2–5).
vide important information and allow for more informed The natural course of HCV infection varies. The best treatment decisions. Ideally, methods for assessing liver fi- predictor of disease progression is the degree of liver fibro- brosis would be accurate without exposing patients to the sis. In patients with minimal or no fibrosis and inflamma- potential harms and discomfort of biopsy. Many blood tion, the risk for progression to severe fibrosis or cirrhosis tests have been proposed as alternatives to liver biopsy, over the next 10 to 20 years is low (6). Those with bridging ranging from single tests to more complicated indices fibrosis are at high risk for progression to cirrhosis. Most based on multiple tests (Table 1).
major complications of chronic HCV infection occur in The purpose of this article is to review the evidence on the accuracy of blood tests to diagnose fibrosis in patients The goal of antiviral therapy is to eradicate viremia with chronic HCV infection. This review was conducted as and prevent the long-term complications associated with part of a larger review commissioned by the Agency for chronic HCV infection. Previously, liver biopsy was rec- Healthcare Research and Quality (AHRQ) on HCV ommended before antiviral therapy because treatment was primarily targeted to patients at higher risk for disease pro-gression (8). Although biopsy remains the reference stan-dard for assessing liver histology, it is subject to sampling error; variability in interpretation; and such complicationsas bleeding, severe pain, and infection (9, 10). In addition, Web-Only
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Review Blood Tests for Fibrosis or Cirrhosis in HCV Infection Table 1. Blood Indices for Assessing Presence of Fibrosis or Cirrhosis in Patients With Hepatitis C Virus Infection
Index (Reference)
Platelet
Other Components
Prothrombin index, presence of ascites, and presence of spider angiomata Hyaluronic acid, N-terminal propeptide of type II collagen, and TIMP-1 Sex, ␣2-macroglobulin level, prothrombin time, GGT level, and urea level Alkaline phosphatase, bilirubin, and albumin levels Total cholesterol level, insulin resistance, and alcohol intake TIMP-1, ␣2-macroglobulin, and hyaluronic acid levels ␣2-Macroglobulin, haptoglobin, apolipoprotein A-I, GGT, and total bilirubin levels (␥-globulin in original version) ␣2-Macroglobulin level, hyaluronic acid level, GGT level, total bilirubin Prothrombin time, right hepatic lobe atrophy, splenomegaly, and caudate Haptoglobin, ␣2-macroglobulin, TIMP-1, MMP-2, and GGT levels ␣2-Macroglobulin, GGT, and hyaluronic acid levels ALT ϭ alanine aminotransferase; APRI ϭ AST–platelet ratio index; AST ϭ aspartate aminotransferase; ELF ϭ enhanced liver fibrosis; GGT ϭ ␥-glutamyltransferase; GUCI ϭ Göteborg University Cirrhosis Index; HALT-C ϭ Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis; INR ϭ international normalized ratio; MMP-1 ϭ matrix metalloproteinase-1; MMP-2 ϭ matrix metalloproteinase-2; NIHCED ϭ Non-Invasive Hepatitis-C–Related Cirrhosis Early Detection; PIIIP ϭ procollagen III propeptide; TIMP-1 ϭ tissue metalloproteinase inhibitor 1.
* Patented and available commercially as a proprietary panel of tests.
† Removed for simplified ELF index.
Study Selection
At least 2 reviewers independently evaluated each We developed a review protocol with the following key study to determine inclusion eligibility. We selected studies question: What is the accuracy of blood tests for diagnosing of HCV-infected patients that compared the accuracy of fibrosis or cirrhosis in patients with chronic HCV infection? blood tests with that of liver biopsy for diagnosing fibrosis Detailed methods and data for the review are available in the or cirrhosis. We restricted inclusion to English-language full report (42). The protocol was developed using a standard- articles and excluded studies published only as abstracts.
ized process with input from experts and the public.
We also excluded studies of posttransplant patients, pa-tients co-infected with HIV or hepatitis B virus, patients Data Sources and Searches
receiving hemodialysis, and children.
We searched Ovid MEDLINE (1947 to January 2013), EMBASE, the Cochrane Library, Scopus, and Data Abstraction and Quality Rating
PsycINFO. The MEDLINE search strategy for blood tests One investigator abstracted details about study design, is shown in Appendix Table 1 (available at www.annals
patient population, setting, interventions, analysis, follow- .org). We supplemented electronic searches by reviewing up, and results, and a second investigator reviewed data for reference lists of retrieved articles.
accuracy. Two investigators independently applied pre- 808 4 June 2013 Annals of Internal Medicine Volume 158 • Number 11
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Blood Tests for Fibrosis or Cirrhosis in HCV Infection Review defined criteria (43– 45) to assess the quality of each study ratios from individual studies (50). The positive likelihood as good, fair, or poor. Discrepancies were resolved through ratio [sensitivity/(1 Ϫ specificity)] is the odds of fibrosis or consensus. We rated the quality of each diagnostic accuracy cirrhosis among patients with a positive test result (51).
study on the basis of whether it evaluated a representative The negative likelihood ratio [(1 Ϫ sensitivity)/specificity] spectrum of patients, enrolled a random or consecutive is the odds among patients with a negative result. We sep- sample of patients meeting predefined criteria, used a cred- arately summarized the difference in AUROCs from the ible reference standard, applied the same reference standard subgroup of studies that directly compared 2 or more to all patients, reported the proportion of patients with uninterpretable or unobtainable reference standard tests, To avoid double counting of data when calculating interpreted the reference standard independently from the medians, we excluded duplicative results from the same test under evaluation, and predefined test cutoff thresholds population reported in different publications. When the (44, 45). For studies of blood indices, we also recorded degree of overlap was partial or unclear, we included both whether results were from the original sample and analysis sets of data but performed sensitivity analyses that excluded used to develop the index. Such results can overestimate studies with potential overlap. We also performed sensitiv- diagnostic accuracy because the model and test cutoffs are ity analyses that excluded poor-quality studies, results fitted to the observed data. If such studies then applied the based on the original sample and analysis used to develop index to a separate validation sample, we abstracted results an index, studies with discrepancies between calculated and for the development and validation samples separately.
reported measures of diagnostic accuracy, studies of pa-tients with normal aminotransferase levels, and studies that Data Synthesis
did not restrict analysis to adequate biopsy specimens For studies on diagnostic accuracy, we created 2 ϫ 2 (length Ͼ15 mm and Ͼ5 portal tracts in the absence of tables based on the sample size, prevalence of fibrosis or cirrhosis, sensitivity, and specificity and compared calcu- We synthesized the overall quality of each body of lated measures of diagnostic accuracy from the tables with evidence on the basis of the type and quality of studies reported results. We focused on results for clinically signif- (good, fair, or poor); the precision of the estimate of diag- icant fibrosis (defined as a score of 3 to 6 on the Ishak scale nostic accuracy or the estimate of effect, based on the num- or F2 to F4 on the Meta-analysis of Histologic Data in ber and size of studies and the CI (high, moderate, or low); Viral Hepatitis [METAVIR], Knodell, Hytiroglou, Batts– the consistency of results among studies (high, moderate, Ludwig, Scheuer, or Desmet scale, as determined from or low); and the directness of the evidence linking the biopsy specimen) and cirrhosis (defined as a score of 5 or 6 intervention and health outcomes (direct or indirect). We on the Ishak scale or F4 on the METAVIR or similar scale) rated the strength of evidence for each blood test with 1 of (see Appendix Table 2, available at www.annals.org, for
4 grades (high, moderate, low, or insufficient), in accor- further descriptions of METAVIR and Ishak stages) (46, dance with the AHRQ Methods Guide for Effectiveness 47). We also abstracted the reported area under the and Comparative Effectiveness Reviews (52).
receiver-operating characteristic curve (AUROC) (48, 49), Role of the Funding Source
which is based on sensitivities and specificities across a This research was funded by AHRQ’s Effective Health range of test results and is a measure of discrimination, or Care Program. Investigators worked with AHRQ staff to the ability of a test to distinguish persons with a condition develop and refine the review protocol. AHRQ staff had no from those without it. An AUROC of 1.0 indicates perfect role in conducting the review, and the investigators are discrimination, and an AUROC of 0.5 indicates complete solely responsible for the content of the manuscript and the lack of discrimination. Interpretation of values between 0.5 decision to submit it for publication.
and 1.0 is somewhat arbitrary, but a value of 0.90 to lessthan 1.0 has been classified as excellent, 0.80 to less than0.90 as good, 0.70 to less than 0.80 as fair, and less than Detailed results of the search and study selection pro- We did not pool results because of differences across cess through May 2012 are shown in the full report (42).
studies in populations evaluated, differences in how fibrosis We reviewed a total of 8736 citations related to HCV and cirrhosis were defined, and methodological limitations screening in nonpregnant persons (including an update in the studies. Instead, we created descriptive statistics with search done in January 2013) and included 172 studies on the median sensitivity and specificity at specific cutoffs and the accuracy of blood tests versus liver biopsy for diagnos- reported AUROCs and their associated ranges. The total ing fibrosis or cirrhosis (Table 1 of the Supplement, avail-
range rather than the interquartile range was chosen to able at www.annals.org) (12–16, 18 – 40, 53–196). Diag- highlight the greater variability and uncertainty in the es- nostic accuracy was also reported in 4 subsequent reports timates, some of which were based on few studies. We (197–200) from 3 of these studies (29, 132, 151). The calculated likelihood ratios based on the median sensitivi- studies varied with respect to inclusion criteria, such as ties and specificities and reported the range of likelihood presence of elevated aminotransferase levels, exposure to www.annals.org
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Appendix Table 1. Search Strategy
Ovid MEDLINE without Revisions (1996 to week 1 of January 2013)
Ovid MEDLINE In-Process & Other Non-Indexed Citations (12 January
2013)
1. Hepatitis C/ or Hepatitis C, Chronic/ or Hepacivirus/ or Hepatitis C.mp. or hepacivirus$.mp. or HCV.mp. (50979) 2. Hepatitis C/di, pa, ra, us or Immunoenzyme Techniques/ or Enzyme-Linked Immunosorbent Assay/ or Immunoblotting/ orPolymerase Chain Reaction/ or Reverse Transcriptase PolymeraseChain Reaction/ or Liver function tests/ or blood test$.mp. or bloodmarker$.mp. or Breath Tests/ or Diagnostic Imaging/ or MagneticResonance Imaging/ or exp Tomography, X-ray Computed/ orAlanine Transaminase/ or “sensitivity and specificity”/ or FalseNegative Reactions/ or False Positive Reactions/ or Hepatitis CAntibodies/ or HCV Antibodies.mp. or anti hcv.mp. oranti-hcv.mp. (970174) 3. (“Age-Platelet Index” or “AST-platelet ratio index” or apri or “Cirrhosis Discriminant Score” or “Bonacini Index” or “EuropeanLiver Fibrosis” or elf or “simplified elf” or “FIB-4 of Firbo-alphaScore” or “FibroIndex” or fibrometer or “FibroQ Index” or“Fibrosis-Cirrhosis Index” or “Fibrosis Probability Index” or “SudIndex” or “Fibrosis-Protein Index” or “FibroSpect II” or Fibrotest orFibrosure or “Forns Index” or “Globulin/albumin ratio” or“Goteborg University Cirrhosis Index” or “HALT-C Model” or“Hepascore” or “King’s Score” or “Lok Index” or “MP3 Score” or“Pohl Index” or “Sabadell NIHCED Index” or “Significant FibrosisIndex” or “Zeng Index”).mp. [mpϭtitle, abstract, original title,name of substance word, subject heading word, protocolsupplementary concept, rare disease supplementary concept,unique identifier] (2125) 4. 1 and 2 (16541)5. 1 and 3 (320)6. 4 or 5 (16689)7. (201205$ or 201206$ or 201207$ or 201208$ or 201209$ or 8. 6 and 7 (549)9. limit 8 to english language (519)10. limit 8 to abstracts (518)11. 9 or 10 (544)12. limit 11 to humans (432)13. limit 12 to “all adult (19 plus years)” (243) Appendix Table 2. METAVIR and Ishak Scoring Systems for Hepatic Fibrosis*
Description
Stellate enlargement of portal tract without septa Enlargement of portal tract with rare septa Fibrous expansion of some portal areas with or without short fibrous septa Fibrous expansion of most portal areas with or without short fibrous septa Fibrous expansion of most portal areas with occasional portal-to-portal bridging Fibrous expansion of portal areas with marked portal-to-portal bridging and portal-to-central bridging Marked bridging (portal-to-portal and/or portal-to-central), with occasional nodules (incomplete cirrhosis) METAVIR ϭ Meta-analysis of Histologic Data in Viral Hepatitis.
* Clinically significant fibrosis is usually defined as METAVIR stages F2 to F4 or Ishak stages 3 to 6. Cirrhosis is typically defined as METAVIR stage F4 or Ishak stages 5or 6; however, METAVIR stage F3 includes patients with early or developing cirrhosis.
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Blood Tests for Fibrosis or Cirrhosis in HCV Infection Review (ELF) index score greater than 8.75 to greater than 9.78 ranged from 0.25 to 0.55. A Go¨teborg University Cirrhosis and a Forns index score greater than 4.2 to greater than Index (GUCI) score greater than 1.0, 1.11, or 1.5 and a 4.57 were associated with slightly lower sensitivity (0.85 Lok index score of at least 0.5 or greater than 0.6 were and 0.88, respectively) but similar negative likelihood ra- associated with similar specificities and slightly lower pos- itive likelihood ratios (4.8 and 4.4, respectively). A Lok The median AUROC for fibrosis (METAVIR score of index score of 0.20 or greater was associated with a median F2 to F4, Ishak score of 3 to 6, or equivalent) was 0.80 or sensitivity of 0.90 for diagnosing cirrhosis, for a negative greater (range, 0.81 to 0.86) for the ELF index, Fibro- likelihood ratio of 0.21 (range, 0 to 0.94) (6 studies) and a meter, and FIBROSpect II. The median AUROC was 0.70 positive likelihood ratio of 1.8 (range, 1.0 to 4.8).
to less than 0.80 for platelet counts, hyaluronic acid, age– The median AUROC for cirrhosis (METAVIR score platelet index, APRI, the FIB-4 index, FibroIndex, of F4, Ishak score of 5 or 6, or equivalent) was 0.80 or FibroTest, the Forns index, and Hepascore.
greater (range, 0.80 to 0.91) for platelet counts, hyaluronic For cirrhosis, an APRI score greater than 2.0 was as- acid, age–platelet index, APRI, the ELF index, the FIB-4 sociated with a specificity of 0.94 (range, 0.65 to 0.99) index, FibroIndex, Fibrometer, FibroTest, the Forns index, (18 studies), and platelet counts less than 140 to less than 155 ϫ 109 cells/L, an age–platelet index score of 6.0 or Excluding poor-quality studies, studies that reported greater, and a Hepascore greater than 0.801 to 0.84 or discrepant results, results from the original sample and greater were each associated with median specificities of analysis used to develop an index, studies restricted to pa- 0.86 to 0.88 (Table 3). Associated positive likelihood ra-
tients with normal aminotransferase levels (135, 153, 171), tios ranged from 5.1 to 8.0, and negative likelihood ratios and results from similar or overlapping population samples Table 3. Diagnostic Accuracy of Blood Tests for Cirrhosis*
Cutoff for
Sensitivity
Specificity
Positive
Negative
Sensitivity and
Likelihood
Likelihood
Specificity
Ratio (Range)†
Median (Range)‡
Samples,
Median (Range)‡
Samples,
Median (Range)‡
Samples,
(Range)†
ALT ϭ alanine aminotransferase; APRI ϭ AST–platelet ratio index; AST ϭ aspartate aminotransferase; AUROC ϭ area under the receiver-operating characteristic curve; ELF ϭ enhanced liver fibrosis; GUCI ϭ Göteborg University Cirrhosis Index; METAVIRϭ Meta-analysis of Histologic Data in Viral Hepatitis.
* Defined as METAVIR stage F4, Ishak stages 3 to 6, or equivalent.
† Ratios based on median sensitivity and specificity at the specified cutoff; ranges based on values from individual studies.
‡ Not calculated for groups of Ͻ3 studies (results from individual studies provided).
§ Some studies reported results for Ͼ1 population sample.
࿣ Excludes 1 study with positive likelihood ratio of ϱ due to specificity of 1.
¶ Positive likelihood ratio of ϱ in 2 studies due to specificity of 1.
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Review Blood Tests for Fibrosis or Cirrhosis in HCV Infection Table 4. Direct Comparisons of Blood Tests for Diagnosing Fibrosis
Studies, n
Median AUROC for
Median AUROC for
Median Difference
Test A (Range)
Test B (Range)
ALT ϭ alanine aminotransferase; APRI ϭ AST–platelet ratio index; AST ϭ aspartate aminotransferase; AUROC ϭ area under the receiver-operating characteristic curve; * One study reported results for 2 separate samples.
had little effect on summary estimates. Studies found no differences between the APRI or FibroTest and other consistent association between shorter biopsy specimen blood tests were small; median differences ranged from 0 length (36, 91, 134, 155, 169) or presence of elevated aminotransferase levels (19, 170, 171) and measures of di- Combinations of Indices
Nine studies evaluated combinations of indices (31, For other blood tests and indices, a median AUROC 71, 77, 82, 90, 123, 169, 173, 179). The Sequential Algo- less than 0.70 for fibrosis and less than 0.80 for cirrhosis rithm for Fibrosis Evaluation, which incorporates the was reported (alanine aminotransferase [ALT], the aspar- APRI and FibroTest, was evaluated in 4 studies (77, 82, tate aminotransferase [AST]–ALT ratio, the cirrhosis dis- 169, 173). For fibrosis, it was associated with an AUROC criminant score, and the Pohl index) or the AUROC was of 0.90 and 0.94 in 2 studies (82, 169). Median sensitivity evaluated in too few studies to reliably estimate.
was 1.0 (range, 1.0 to 1.0) and median specificity was 0.82 Direct Comparisons
(range, 0.77 to 0.88) in 4 studies (77, 82, 169, 173). For Sixty-eight studies directly compared the AUROC for cirrhosis, the algorithm was associated with a median 2 or more blood indices in the same population (Tables 4
AUROC of 0.87 (range, 0.87 to 0.92) in 3 studies (82, and 5). The most frequently evaluated indices in head-to-
169, 173). Median sensitivity was 0.84 (range, 0.62 to head studies were the APRI and FibroTest. The APRI was 0.90) and median specificity was 0.92 (range, 0.90 to 0.93) associated with a slightly lower AUROC than FibroTest in 4 studies (77, 82, 169, 173). In single studies, the Leroy for fibrosis (18 studies; median difference, Ϫ0.03; range, and Fibropaca algorithms and various combinations of the Ϫ0.10 to 0.07), but there was no difference for cirrhosis (7 APRI, FIBROSpect II, FibroTest, the FIB-4 index, and studies; median difference, 0.0; range, Ϫ0.04 to 0.06). The Fibrometer were also associated with diagnostic accuracy APRI was associated with a substantially higher AUROC somewhat higher than that observed for single indices (90, than the AST–ALT ratio for fibrosis (13 studies; median difference, 0.17; range, Ϫ0.06 to 0.23) and cirrhosis (11studies; median difference, 0.19; range, Ϫ0.18 to 0.23).
For fibrosis, the APRI was also associated with a higher DISCUSSION
AUROC than the cirrhosis discriminant score (4 studies; Although liver biopsy is still regarded as the most ac- median difference, 0.08; range, 0.07 to 0.09) and platelet curate method for assessing the histologic stage of HCV count (8 studies; median difference, 0.08; range, Ϫ0.06 to infection, it has limitations and is an invasive test with 0.53) and a lower AUROC than Fibrometer (8 studies; some risk for serious harms (201, 202). This has spurred median difference, Ϫ0.06; range, Ϫ0.07 to 0.02), al- interest in noninvasive tests as a potential alternative to though differences were smaller. The FibroTest was asso- biopsy. We found many blood tests associated with an ciated with a higher AUROC than FibroIndex for diagnos- AUROC of 0.70 or greater (range, 0.70 to 0.86) for fibro- ing fibrosis (median difference, 0.08; range, 0.02 to 0.10), sis (generally classified as fair to good [48, 49]) and 0.80 or but results were based on only 3 studies. For cirrhosis, greater (range, 0.80 to 0.91) for cirrhosis (generally classi- 812 4 June 2013 Annals of Internal Medicine Volume 158 • Number 11
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Blood Tests for Fibrosis or Cirrhosis in HCV Infection Review fied as good to excellent) when compared with liver biopsy bias, although some studies have found that restricting sys- (the strength-of-evidence ratings are summarized in Ap-
tematic reviews of noncomplementary medicine interven- pendix Table 3, available at www.annals.org). Among tests
tions to English-language studies has little effect on the meeting these AUROC thresholds, those that were associ- conclusions (203, 204). We did not attempt to pool the ated with positive likelihood ratios of 5 to 10 (generally studies because of methodological limitations and variabil- classified as moderately useful [50]) at commonly used cut- ity in populations and how fibrosis and cirrhosis were de- offs were platelet counts, age–platelet index, APRI, Fibro- fined. Many of the blood tests were evaluated in few stud- Index, FibroTest, and the Forns index for fibrosis and ies, thus precluding reliable conclusions about diagnostic platelet counts, age–platelet index, APRI, and Hepascore accuracy. Liver biopsy is subject to sampling error, inade- for cirrhosis. For diagnosing cirrhosis, GUCI and the Lok quate specimens, and interobserver variability interpreta- index had positive likelihood ratios just below the thresh- tion, which could result in underestimates of diagnostic old. Only FibroIndex and FibroTest were also associated accuracy due to misclassification (9, 205, 206). Our results with negative likelihood ratios for fibrosis in the moder- may not apply to specific populations of HCV-infected ately useful range (0.10 to 0.20) at commonly used cutoffs, patients that were excluded from our review, such as pa- suggesting that blood tests may be somewhat more useful tients co-infected with hepatitis B virus or HIV (who may for ruling in than ruling out fibrosis.
be at higher risk for progression to cirrhosis) and those In direct comparisons based on the AUROC, the receiving hemodialysis. We also did not include results for APRI performed only slightly worse than FibroTest for imaging tests, such as those used to assess liver stiffness, diagnosing fibrosis and the tests did not differ for cirrhosis.
that are addressed in the full report (42).
The APRI performed substantially better than the AST– Results of our study should also be interpreted in the ALT ratio for diagnosing fibrosis or cirrhosis and moder- context of the analytic methods used. Estimates of diagnos- ately better than platelet count for diagnosing fibrosis. Dif- tic accuracy were based on a binary reference standard di- ferences between the APRI or FibroTest and other blood agnosis (absence or presence of clinically significant fibro- tests were relatively small, particularly for cirrhosis. This sis). However, fibrosis grading systems are multilevel, with suggests that simple indices based on a small number of higher grades associated with progressively worse progno- commonly available blood tests and straightforward sis. Measures that incorporate the accuracy of tests at each calculations—such as the age–platelet index (based on age fibrosis stage would therefore be more informative than and platelet count) and the APRI (based on AST level and estimates based on dichotomized classifications. Tech- platelet count)—may perform similarly to measures based niques for calculating an AUROC based on a multilevel on more blood tests, including indices requiring tests not reference standard, such as the Obuchowski method (207) routinely obtained or involving proprietary formulas or (which also weights the degree of discordance between pre- panels of tests. Some evidence suggests that using multiple dicted and observed findings), are available. However, only indices in combination or in an algorithmic approach is 2 studies reported the Obuchowski measure (115, 196), associated with somewhat higher diagnostic accuracy than and other studies did not provide data to calculate it. We were also unable to determine the diagnostic accuracy of Our study has limitations. We excluded non–English- blood tests for less severe stages of fibrosis independent language articles, which could have resulted in language from the diagnostic accuracy for cirrhosis because almost Table 5. Direct Comparisons of Blood Tests for Diagnosing Cirrhosis
Studies, n
Median AUROC for
Median AUROC for
Median Difference
Test A (Range)
Test B (Range)
ALT ϭ alanine aminotransferase; APRI ϭ AST–platelet ratio index; AST ϭ aspartate aminotransferase; AUROC ϭ area under the receiver-operating characteristic curve; ELF ϭ enhanced liver fibrosis; GUCI ϭ Göteborg University Cirrhosis Index.
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Review Blood Tests for Fibrosis or Cirrhosis in HCV Infection all studies grouped less severe fibrosis (for example, Science University, Mail Code BICC, 3181 Southwest Sam Jackson Park METAVIR stage F2 or F3) with cirrhosis. In addition, Road, Portland, OR 97239-3098; e-mail, [email protected].
estimates of diagnostic accuracy could have been affectedby variability in the distribution and severity of fibrosis in Current author addresses and author contributions are available at www different study populations. Methods for calculating “ad- justed” AUROCs based on a standardized distribution offibrosis stages have been proposed to enhance the compa- References
rability of diagnostic estimates across studies (208, 209).
1. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter
We did not use such methods, which are based on assump- MJ. The prevalence of hepatitis C virus infection in the United States, 1999
tions about the underlying prevalence of each fibrosis stage through 2002. Ann Intern Med. 2006;144:705-14. [PMID: 16702586] and the effects of stage on diagnostic accuracy and require 2. Busch MP. Insights into the epidemiology, natural history and pathogenesis of
further statistical validation. Rather, we separately analyzed hepatitis C virus infection from studies of infected donors and blood productrecipients. Transfus Clin Biol. 2001;8:200-6. [PMID: 11499958] head-to-head studies on diagnostic accuracy—thus, in 3. El-Serag HB. Hepatocellular carcinoma: recent trends in the United States.
principle, reducing spectrum effects because comparative Gastroenterology. 2004;127:S27-34. [PMID: 15508094] estimates from each study are based on the application of 4. Kim WR. The burden of hepatitis C in the United States. Hepatology. 2002;
different blood tests in the same population.
36:S30-4. [PMID: 12407574]
5. Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The
Our study has other strengths. Unlike other reviews, increasing burden of mortality from viral hepatitis in the United States between our analysis included all blood tests rather than 1 or several 1999 and 2007. Ann Intern Med. 2012;156:271-8. [PMID: 22351712] tests (209 –212). We restricted our analysis to HCV- 6. Yano M, Kumada H, Kage M, Ikeda K, Shimamatsu K, Inoue O, et al. The
infected patients, potentially resulting in a more homoge- long-term pathological evolution of chronic hepatitis C. Hepatology. 1996;23:1334-40. [PMID: 8675148] neous population. Finally, our findings were robust in sen- 7. Niederau C, Lange S, Heintges T, Erhardt A, Buschkamp M, Hu¨rter D,
sitivity analyses related to study quality, study methods, et al. Prognosis of chronic hepatitis C: results of a large, prospective cohort study.
Hepatology. 1998;28:1687-95. [PMID: 9828236] Our results suggest that blood tests can help to iden- 8. National Institutes of Health Consensus Development Conference Panel state-ment: management of hepatitis C. Hepatology. 1997;26:2S-10S. [PMID: tify HCV-infected patients with clinically significant fibro- sis, with somewhat greater accuracy for identifying 9. Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT,
cirrhosis than less advanced fibrosis. In addition to the et al. Sampling error and intraobserver variation in liver biopsy in patients with
chronic HCV infection. Am J Gastroenterol. 2002;97:2614-8. [PMID:
cross-sectional studies included in our review, longitudinal studies support the usefulness of blood tests in providing 10. Seeff LB, Everson GT, Morgan TR, Curto TM, Lee WM, Ghany MG,
prognostic information, although data are more limited et al; HALT–C Trial Group. Complication rate of percutaneous liver biopsies
(213). Factors that may affect use or selection of blood among persons with advanced chronic liver disease in the HALT-C trial. ClinGastroenterol Hepatol. 2010;8:877-83. [PMID: 20362695] tests include availability and cost, given the variability in 11. Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for
component blood tests, the number of tests required, and the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis
proprietary status. Studies that evaluate the virologic and C: an update. Hepatology. 2009;49:1335-74. [PMID: 19330875] clinical outcomes of antiviral treatment in HCV-infected 12. Poynard T, Bedossa P. Age and platelet count: a simple index for predicting
the presence of histological lesions in patients with antibodies to hepatitis C virus.
patients who have not had liver biopsy are needed (214) to METAVIR and CLINIVIR Cooperative Study Groups. J Viral Hepat. 1997;4: further define optimum work-up strategies.
199-208. [PMID: 9181529]
13. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conje-
From Oregon Health & Science University, Portland, Oregon.
evaram HS, et al. A simple noninvasive index can predict both significant fibrosis
and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518-26.
[PMID: 12883497]
Disclaimer: The findings and conclusions in this article are those of the
14. Williams AL, Hoofnagle JH. Ratio of serum aspartate to alanine aminotrans-
authors, who are responsible for its content, and do not necessarily rep- ferase in chronic hepatitis. Relationship to cirrhosis. Gastroenterology. 1988;95: resent the views of AHRQ. No statement in this report should be con- strued as an official position of AHRQ or the U.S. Department of 15. Bonacini M, Hadi G, Govindarajan S, Lindsay KL. Utility of a discriminant
score for diagnosing advanced fibrosis or cirrhosis in patients with chronic hepa-titis C virus infection. Am J Gastroenterol. 1997;92:1302-4. [PMID: 9260794] Acknowledgment: The authors thank Tracy Dana, MLS; AHRQ Task
16. Rosenberg WM, Voelker M, Thiel R, Becka M, Burt A, Schuppan D, et al;
European Liver Fibrosis Group. Serum markers detect the presence of liver
Order Officer Christine Chang, MD, MPH; and USPSTF Medical Of- fibrosis: a cohort study. Gastroenterology. 2004;127:1704-13. [PMID: ficer Iris Mabry-Hernandez, MD, MPH.
15578508]
17. Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, et al;
Grant Support: By AHRQ (contract 290-2007-10057-I, task order 8),
APRICOT Clinical Investigators. Development of a simple noninvasive index to
predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology.
2006;43:1317-25. [PMID: 16729309] Potential Conflicts of Interest: Disclosures can be viewed at www
18. Omran MM, Farid K, Emran TM, Attallah AA. Fibro-a score as a simple
and useful non-invasive test for predicting significant liver fibrosis in chronic
.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNumϭM12 hepatitis C patients. Arab J Gastroenterol. 2011;12:74-9. [PMID: 21684477] 19. Koda M, Matunaga Y, Kawakami M, Kishimoto Y, Suou T, Murawaki Y.
FibroIndex, a practical index for predicting significant fibrosis in patients with
Requests for Single Reprints: Roger Chou, MD, Oregon Health &
chronic hepatitis C. Hepatology. 2007;45:297-306. [PMID: 17256741] 814 4 June 2013 Annals of Internal Medicine Volume 158 • Number 11
www.annals.org
Downloaded From: http://annals.org/ by a Oxford University User on 06/04/2013
Blood Tests for Fibrosis or Cirrhosis in HCV Infection Review 20. Cale`s P, Oberti F, Michalak S, Hubert-Fouchard I, Rousselet MC, Konate´
39. Obrador BD, Prades MG, Go´mez MV, Domingo JP, Cueto RB, Rue´ M,
A, et al. A novel panel of blood markers to assess the degree of liver fibrosis.
et al. A predictive index for the diagnosis of cirrhosis in hepatitis C based on
Hepatology. 2005;42:1373-81. [PMID: 16317693] clinical, laboratory, and ultrasound findings. Eur J Gastroenterol Hepatol. 2006; 21. Attallah AM, Abdallah SO, Attallah AA, Omran MM, Farid K, Nasif WA,
et al. Diagnostic value of fibronectin discriminant score for predicting liver fibro-
40. Cheong JY, Um SH, Seo YS, Kim DJ, Hwang SG, Lee YJ, et al. Non-
sis stages in chronic hepatitis C virus patients. Ann Hepatol. 2013;12:44-53.
invasive index for predicting significant liver fibrosis: comparison of diagnostic performances in patients with chronic hepatitis B and C. Dig Dis Sci. 2011;56: 22. Hsieh YY, Tung SY, Lee IL, Lee K, Shen CH, Wei KL, et al. FibroQ: an
easy and useful noninvasive test for predicting liver fibrosis in patients with 41. Zeng MD, Lu LG, Mao YM, Qiu DK, Li JQ, Wan MB, et al. Prediction
chronic viral hepatitis. Chang Gung Med J. 2009;32:614-22. [PMID: of significant fibrosis in HBeAg-positive patients with chronic hepatitis B by a noninvasive model. Hepatology. 2005;42:1437-45. [PMID: 16317674] 23. Ahmad W, Ijaz B, Javed FT, Gull S, Kausar H, Sarwar MT, et al. A
42. Chou R, Cottrell E, Wasson N, Rahman B, Guise JM. Screening for Hep-
comparison of four fibrosis indexes in chronic HCV: development of new atitis C Virus Infection in Adults. Comparative Effectiveness Review no. 69.
fibrosis-cirrhosis index (FCI). BMC Gastroenterol. 2011;11:44. [PMID: (Prepared by the Oregon Evidence-based Practice Center under contract 290- 2007-10057-I.) Rockville, MD: Agency for Healthcare Research and Quality; 24. Ohta T, Sakaguchi K, Fujiwara A, Fujioka S, Iwasaki Y, Makino Y, et al.
2012. Accessed at www.effectivehealthcare.ahrq.gov/reports/final.cfm on 26 Simple surrogate index of the fibrosis stage in chronic hepatitis C patients using platelet count and serum albumin level. Acta Med Okayama. 2006;60:77-84.
43. Downs SH, Black N. The feasibility of creating a checklist for the assessment
of the methodological quality both of randomised and non-randomised studies of 25. Sud A, Hui JM, Farrell GC, Bandara P, Kench JG, Fung C, et al. Improved
health care interventions. J Epidemiol Community Health. 1998;52:377-84.
prediction of fibrosis in chronic hepatitis C using measures of insulin resistance in a probability index. Hepatology. 2004;39:1239-47. [PMID: 15122752] 44. Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM,
26. Cheung KJ, Tilleman K, Deforce D, Colle I, Moreno C, Gustot T, et al.
et al; Methods Work Group, Third US Preventive Services Task Force. Current
Usefulness of a novel serum proteome-derived index FI-PRO (fibrosis-protein) in methods of the US Preventive Services Task Force: a review of the process. Am the prediction of fibrosis in chronic hepatitis C. Eur J Gastroenterol Hepatol.
J Prev Med. 2001;20:21-35. [PMID: 11306229] 45. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB,
27. Attallah AM, Omran MM, Farid K, El-Bendary M, Emran TM, Albannan
et al; QUADAS-2 Group. QUADAS-2: a revised tool for the quality assessment
MS, et al. Development of a novel score for liver fibrosis staging and comparison
of diagnostic accuracy studies. Ann Intern Med. 2011;155:529-36. [PMID: with eight simple laboratory scores in large numbers of HCV-monoinfected pa- tients. Clin Chim Acta. 2012;413:1725-30. [PMID: 22759976] 46. Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, et al.
28. Patel K, Gordon SC, Jacobson I, He´zode C, Oh E, Smith KM, et al.
Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22:696-9.
Evaluation of a panel of non-invasive serum markers to differentiate mild from moderate-to-advanced liver fibrosis in chronic hepatitis C patients. J Hepatol.
47. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic
hepatitis C. The METAVIR Cooperative Study Group. Hepatology. 1996;24: 29. Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard
T; MULTIVIRC Group. Biochemical markers of liver fibrosis in patients with
48. Altman DG, Bland JM. Diagnostic tests 3: receiver operating characteristic
hepatitis C virus infection: a prospective study. Lancet. 2001;357:1069-75.
plots. BMJ. 1994;309:188. [PMID: 8044101] 49. Zweig MH, Campbell G. Receiver-operating characteristic (ROC) plots: a
30. Forns X, Ampurdane`s S, Llovet JM, Aponte J, Quinto´ L, Martı´nez-Bauer
fundamental evaluation tool in clinical medicine. Clin Chem. 1993;39:561-77.
E, et al. Identification of chronic hepatitis C patients without hepatic fibrosis by
a simple predictive model. Hepatology. 2002;36:986-92. [PMID: 12297848] 50. Jaeschke R, Guyatt GH, Sackett DL. Users’ guides to the medical literature.
31. Luo JC, Hwang SJ, Chang FY, Chu CW, Lai CR, Wang YJ, et al. Simple
III. How to use an article about a diagnostic test. B. What are the results and will blood tests can predict compensated liver cirrhosis in patients with chronic hep- they help me in caring for my patients? The Evidence-Based Medicine Working atitis C. Hepatogastroenterology. 2002;49:478-81. [PMID: 11995477] Group. JAMA. 1994;271:703-7. [PMID: 8309035] 32. Islam S, Antonsson L, Westin J, Lagging M. Cirrhosis in hepatitis C virus-
51. Deeks JJ, Altman DG. Diagnostic tests 4: likelihood ratios. BMJ. 2004;329:
infected patients can be excluded using an index of standard biochemical serum markers. Scand J Gastroenterol. 2005;40:867-72. [PMID: 16109665] 52. Agency for Healthcare Research and Quality. Methods Guide for Effective-
33. Fontana RJ, Goodman ZD, Dienstag JL, Bonkovsky HL, Naishadham D,
ness and Comparative Effectiveness Reviews. AHRQ publication no. 10(12)- Sterling RK, et al; HALT-C Trial Group. Relationship of serum fibrosis markers
EHC063-EF. Rockville, MD: Agency for Healthcare Research and Quality; with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C. Hepatology. 2008;47:789-98. [PMID: 18175357] 53. Adler M, Gulbis B, Moreno C, Evrard S, Verset G, Golstein P, et al. The
34. Adams LA, Bulsara M, Rossi E, DeBoer B, Speers D, George J, et al.
predictive value of FIB-4 versus FibroTest, APRI, FibroIndex and Forns index to Hepascore: an accurate validated predictor of liver fibrosis in chronic hepatitis C noninvasively estimate fibrosis in hepatitis C and nonhepatitis C liver diseases infection. Clin Chem. 2005;51:1867-73. [PMID: 16055434] [Letter]. Hepatology. 2008;47:762-3. [PMID: 18220307] 35. Cross TJ, Rizzi P, Berry PA, Bruce M, Portmann B, Harrison PM. King’s
54. Alsatie M, Kwo PY, Gingerich JR, Qi R, Eckert G, Cummings OW, et al.
Score: an accurate marker of cirrhosis in chronic hepatitis C. Eur J Gastroenterol A multivariable model of clinical variables predicts advanced fibrosis in chronic hepatitis C. J Clin Gastroenterol. 2007;41:416-21. [PMID: 17413613] 36. Lok AS, Ghany MG, Goodman ZD, Wright EC, Everson GT, Sterling
55. Amorim TG, Staub GJ, Lazzarotto C, Silva AP, Manes J, Ferronato Mda
RK, et al. Predicting cirrhosis in patients with hepatitis C based on standard
G, et al. Validation and comparison of simple noninvasive models for the pre-
laboratory tests: results of the HALT-C cohort. Hepatology. 2005;42:282-92.
diction of liver fibrosis in chronic hepatitis C. Ann Hepatol. 2012;11:855-61.
37. Leroy V, Monier F, Bottari S, Trocme C, Sturm N, Hilleret MN, et al.
56. Anderson FH, Zeng L, Rock NR, Yoshida EM. An assessment of the clinical
Circulating matrix metalloproteinases 1, 2, 9 and their inhibitors TIMP-1 and utility of serum ALT and AST in chronic hepatitis C. Hepatol Res. 2000;18:63- TIMP-2 as serum markers of liver fibrosis in patients with chronic hepatitis C: comparison with PIIINP and hyaluronic acid. Am J Gastroenterol. 2004;99: 57. Arabul M, Aslan F, Alper E, Akpinar Z, C
¸ elik M, Kandemir A, et al. Simple
non-invasive markers as a predictor of fibrosis and viral response in chronic hep- 38. Pohl A, Behling C, Oliver D, Kilani M, Monson P, Hassanein T. Serum
atitis C patients. Turk J Gastroenterol. 2012;23:538-45. [PMID: 23161299] aminotransferase levels and platelet counts as predictors of degree of fibrosis in 58. Arain SA, Meo SA, Jamal Q. Serum hyaluronic acid level does not reliably
chronic hepatitis C virus infection. Am J Gastroenterol. 2001;96:3142-6.
differentiate minimal and significant liver disease in chronic hepatitis C. Saudi www.annals.org
4 June 2013 Annals of Internal Medicine Volume 158 • Number 11 815
Downloaded From: http://annals.org/ by a Oxford University User on 06/04/2013
Review Blood Tests for Fibrosis or Cirrhosis in HCV Infection 59. Attallah AM, Toson el-SA, El-Waseef AM, Abo-Seif MA, Omran MM,
diagnosis of liver fibrosis stages in chronic hepatitis C. Am J Gastroenterol. 2011; Shiha GE. Discriminant function based on hyaluronic acid and its degrading
enzymes and degradation products for differentiating cirrhotic from non-cirrhotic 77. Boursier J, de Ledinghen V, Zarski JP, Fouchard-Hubert I, Gallois Y,
liver diseased patients in chronic HCV infection. Clin Chim Acta. 2006;369:66- Oberti F, et al; multicentric groups from SNIFF 32, VINDIAG 7, and ANRS/
HC/EP23 FIBROSTAR studies. Comparison of eight diagnostic algorithms for
60. Attallah AM, Shiha GE, Omran MM, Zalata KR. A discriminant score
liver fibrosis in hepatitis C: new algorithms are more precise and entirely nonin- based on four routine laboratory blood tests for accurate diagnosis of severe fibro- vasive. Hepatology. 2012;55:58-67. [PMID: 21898504] sis and/or liver cirrhosis in Egyptian patients with chronic hepatitis C. Hepatol 78. Burton MJ, Sunesara I, Penman A, Pham H, Oliver N, Young CA, et al.
Comparing the aspartate aminotransferase (AST) to platelet ratio index (APRI) 61. Attallah AM, Mosa TE, Omran MM, Abo-Zeid MM, El-Dosoky I, Shaker
between African American and white veterans with chronic hepatitis C. South YM. Immunodetection of collagen types I, II, III, and IV for differentiation of
liver fibrosis stages in patients with chronic HCV. J Immunoassay Immunochem.
79. Cale`s P, de Ledinghen V, Halfon P, Bacq Y, Leroy V, Boursier J, et al.
Evaluating the accuracy and increasing the reliable diagnosis rate of blood tests for 62. Attallah AM, Zahran F, Ismail H, Omran MM, El-Dosoky I, Shiha GE.
liver fibrosis in chronic hepatitis C. Liver Int. 2008;28:1352-62. [PMID: Immunochemical identification and detection of serum fibronectin in liver fibro- sis patients with chronic hepatitis C. J Immunoassay Immunochem. 2007;28: 80. Cale`s P, Boursier J, Bertrais S, Oberti F, Gallois Y, Fouchard-Hubert I,
et al; multicentric groups (SNIFF 14 & 17, ANRS HC EP 23 Fibrostar).
63. Attallah AM, Abdallah SO, El Sayed AS, Omran MM, El-Bendary M,
Optimization and robustness of blood tests for liver fibrosis and cirrhosis. Clin Farid K, et al. Non-invasive predictive score of fibrosis stages in chronic hepatitis
Biochem. 2010;43:1315-22. [PMID: 20713037] C patients based on epithelial membrane antigen in the blood in combination 81. Castera L. Transient elastography and other noninvasive tests to assess hepatic
with routine laboratory markers. Hepatol Res. 2011;41:1075-84. [PMID: fibrosis in patients with viral hepatitis. J Viral Hepat. 2009;16:300-14. [PMID: 64. Attallah AM, Badr El-Din NK, Omran MM, Farid K, El-Wahab AH,
82. Caste´ra L, Sebastiani G, Le Bail B, de Le´dinghen V, Couzigou P, Alberti A.
El-Bendary M, et al. Assessment of matrix metalloproteinase-1 for marking liver
Prospective comparison of two algorithms combining non-invasive methods for cirrhosis in chronic hepatitis C patients. Egypt J Immunol. 2011;18:33-42.
staging liver fibrosis in chronic hepatitis C. J Hepatol. 2010;52:191-8. [PMID: 65. Bain VG, Bonacini M, Govindarajan S, Ma M, Sherman M, Gibas A, et al.
83. Caste´ra L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, et al.
A multicentre study of the usefulness of liver biopsy in hepatitis C. J Viral Hepat.
Prospective comparison of transient elastography, Fibrotest, APRI, and liver bi- opsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology. 2005; 66. Becker L, Salameh W, Sferruzza A, Zhang K, ng Chen R, Malik R, et al.
Validation of hepascore, compared with simple indices of fibrosis, in patients with 84. Cheung RC, Currie S, Shen H, Bini EJ, Ho SB, Anand BS, et al; VA
chronic hepatitis C virus infection in United States. Clin Gastroenterol Hepatol.
HCV-001 Study Group. Can we predict the degree of fibrosis in chronic hepa-
titis C patients using routine blood tests in our daily practice? J Clin Gastroen- 67. Bejarano G, Vergara M, Dalmau B, Puig J, Bella MR, Sua´rez D, et al.
Prospective evaluation of liver fibrosis in chronic viral hepatitis C infection using 85. Christensen C, Bruden D, Livingston S, Deubner H, Homan C, Smith K,
the Sabadell NIHCED (Non-Invasive Hepatitis-C-Related Cirrhosis Early De- et al. Diagnostic accuracy of a fibrosis serum panel (FIBROSpect II) compared
tection) index. Rev Esp Enferm Dig. 2009;101:325-35. [PMID: 19527078] with Knodell and Ishak liver biopsy scores in chronic hepatitis C patients. J Viral 68. Ben Jazia E, Kaabia N, Benabdelkader A, Khalifa M, Harrabi I, Braham A,
et al. Noninvasive fibrosis markers for the prediction of significant fibrosis in
86. Chrysanthos NV, Papatheodoridis GV, Savvas S, Kafiri G, Petraki K,
patients with chronic hepatitis C virus infection in Tunisia. Infect Dis Clin Pract Manesis EK, et al. Aspartate aminotransferase to platelet ratio index for fibrosis
(Baltim Md). 2009;17:385-7.
69. Berg T, Sarrazin C, Hinrichsen H, Buggisch P, Gerlach T, Zachoval R,
evaluation in chronic viral hepatitis. Eur J Gastroenterol Hepatol. 2006;18:389- et al. Does noninvasive staging of fibrosis challenge liver biopsy as a gold standard
in chronic hepatitis C? [Letter]. Hepatology. 2004;39:1456-7. [PMID: 87. Cobbold JF, Crossey MM, Colman P, Goldin RD, Murphy PS, Patel N,
et al. Optimal combinations of ultrasound-based and serum markers of disease
70. Boeker KH, Haberkorn CI, Michels D, Flemming P, Manns MP, Licht-
severity in patients with chronic hepatitis C. J Viral Hepat. 2010;17:537-45.
inghagen R. Diagnostic potential of circulating TIMP-1 and MMP-2 as markers
of liver fibrosis in patients with chronic hepatitis C. Clin Chim Acta. 2002;316: 88. Colletta C, Smirne C, Fabris C, Toniutto P, Rapetti R, Minisini R, et al.
Value of two noninvasive methods to detect progression of fibrosis among HCV 71. Borroni G, Ceriani R, Cazzaniga M, Tommasini M, Roncalli M, Mal-
carriers with normal aminotransferases. Hepatology. 2005;42:838-45. [PMID: tempo C, et al. Comparison of simple tests for the non-invasive diagnosis of
clinically silent cirrhosis in chronic hepatitis C. Aliment Pharmacol Ther. 2006; 89. Colli A, Colucci A, Paggi S, Fraquelli M, Massironi S, Andreoletti M, et al.
Accuracy of a predictive model for severe hepatic fibrosis or cirrhosis in chronic 72. Bota S, Sirli R, Sporea I, Focsa M, Popescu A, Danila M, et al. A new
hepatitis C. World J Gastroenterol. 2005;11:7318-22. [PMID: 16437635] scoring system for prediction of fibrosis in chronic hepatitis C. Hepat Mon.
90. Crisan D, Radu C, Lupsor M, Sparchez Z, Grigorescu MD, Grigorescu M.
Two or more synchronous combination of noninvasive tests to increase accuracy 73. Bourliere M, Penaranda G, Ouzan D, Renou C, Botta-Fridlund D, Tran
of liver fibrosis assessement in chronic hepatitis C; results from a cohort of 446 A, et al. Optimized stepwise combination algorithms of non-invasive liver fibrosis
patients. Hepat Mon. 2012;12:177-84. [PMID: 22550525] scores including Hepascore in hepatitis C virus patients. Aliment Pharmacol 91. Cross TJ, Calvaruso V, Maimone S, Carey I, Chang TP, Pleguezuelo M,
et al. Prospective comparison of Fibroscan, King’s score and liver biopsy for the
74. Bourliere M, Penaranda G, Renou C, Botta-Fridlund D, Tran A, Portal I,
assessment of cirrhosis in chronic hepatitis C infection. J Viral Hepat. 2010;17: et al. Validation and comparison of indexes for fibrosis and cirrhosis prediction in
chronic hepatitis C patients: proposal for a pragmatic approach classification 92. Deghady A, Abdou A, El-Neanaey WA, Diab I. Association of genetic
without liver biopsies. J Viral Hepat. 2006;13:659-70. [PMID: 16970597] polymorphism -670AϾG in the Fas gene and serum markers AST platelet ratio 75. Boursier J, Bacq Y, Halfon P, Leroy V, de Ledinghen V, de Muret A, et al.
index, AST/ALT with significant fibrosis and cirrhosis in chronic hepatitis C.
Improved diagnostic accuracy of blood tests for severe fibrosis and cirrhosis in Genet Test Mol Biomarkers. 2012;16:531-5. [PMID: 22352690] chronic hepatitis C. Eur J Gastroenterol Hepatol. 2009;21:28-38. [PMID: 93. Dinesen L, Caspary WF, Chapman RW, Dietrich CF, Sarrazin C, Braden
B. 13C-methacetin-breath test compared to also noninvasive biochemical blood
76. Boursier J, de Ledinghen V, Zarski JP, Rousselet MC, Sturm N, Foucher J,
tests in predicting hepatic fibrosis and cirrhosis in chronic hepatitis C. Dig Liver et al. A new combination of blood test and fibroscan for accurate non-invasive
816 4 June 2013 Annals of Internal Medicine Volume 158 • Number 11
www.annals.org
Downloaded From: http://annals.org/ by a Oxford University User on 06/04/2013
Blood Tests for Fibrosis or Cirrhosis in HCV Infection Review 94. Ehsan N, Badr M, Raouf A, Gamal B. Correlation between liver biopsy
112. Gue´chot J, Poupon RE, Giral P, Balkau B, Giboudeau J, Poupon R.
findings and different serum biochemical tests in staging fibrosis in Egyptian Relationship between procollagen III aminoterminal propeptide and hyaluronan patients with chronic hepatitis C virus infection. Arab J Gastroenterol. 2008;9:7- serum levels and histological fibrosis in primary biliary cirrhosis and chronic viral hepatitis C. J Hepatol. 1994;20:388-93. [PMID: 8014451] 95. El-Gindy I, El Rahman AT, El-Alim MA, Zaki SS. Diagnostic potential of
113. Gue´chot J, Laudat A, Loria A, Serfaty L, Poupon R, Giboudeau J. Diag-
serum matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as nostic accuracy of hyaluronan and type III procollagen amino-terminal peptide non-invasive markers of hepatic fibrosis in patients with HCV related chronic serum assays as markers of liver fibrosis in chronic viral hepatitis C evaluated by liver disease. Egypt J Immunol. 2003;10:27-35. [PMID: 15719620] ROC curve analysis. Clin Chem. 1996;42:558-63. [PMID: 8605673] 96. El-mezayen HA, Toson el-SA, Shiha GE. Role of hyaluronic acid, its de-
114. Gue´chot J, Lasnier E, Sturm N, Paris A, Zarski JP; ANRS HC EP 23
grading enzymes, degradation products, and ferritin in the assessment of fibrosis Fibrostar Study Group. Automation of the Hepascore and validation as a bio-
stage in Egyptian patients with chronic hepatitis C. Eur J Gastroenterol Hepatol.
chemical index of liver fibrosis in patients with chronic hepatitis C from the ANRS HC EP 23 Fibrostar cohort. Clin Chim Acta. 2010;411:86-91. [PMID: 97. El-Sayed R, Fahmy M, El Koofy N, El-Raziky M, El-Hawary M, Helmy H,
et al. Can aspartate aminotransferase to platelet ratio index replace liver biopsy in
115. Gue´chot J, Trocme´ C, Renversez JC, Sturm N, Zarski JP; ANRS HC EP
chronic hepatitis C? Trop Gastroenterol. 2011;32:267-72. [PMID: 22696906] 23 Fibrostar Study Group. Independent validation of the Enhanced Liver Fibro-
98. el-Shorbagy E, Afefy AF, Ibrahem IA, Mangoud AM, Eissa MH, Sabee EI,
sis (ELF) score in the ANRS HC EP 23 Fibrostar cohort of patients with chronic et al. Non-invasive markers and predictors of severity of hepatic fibrosis in HCV
hepatitis C. Clin Chem Lab Med. 2012;50:693-9. [PMID: 22505560] patients at Sharkia Governorate, Egypt. J Egypt Soc Parasitol. 2004;34:459-78.
116. Gu¨zelbulut F, C
¸ etinkaya ZA, Sezikli M, Yasar B, Ozkara S, O
¨ vu¨nc¸ AO.
AST-platelet ratio index, Forns index and FIB-4 in the prediction of significant 99. Fabris C, Smirne C, Toniutto P, Colletta C, Rapetti R, Minisini R, et al.
fibrosis and cirrhosis in patients with chronic hepatitis C. Turk J Gastroenterol.
Usefulness of six non-proprietary indirect markers of liver fibrosis in patients with chronic hepatitis C. Clin Chem Lab Med. 2008;46:253-9. [PMID: 18324909] 117. Halfon P, Bourlie`re M, Pe´naranda G, Deydier R, Renou C, Botta-
100. Ferraioli G, Tinelli C, Malfitano A, Dal Bello B, Filice G, Filice C, et al;
Fridlund D, et al. Accuracy of hyaluronic acid level for predicting liver fibrosis
Liver Fibrosis Study Group. Performance of real-time strain elastography, tran-
stages in patients with hepatitis C virus. Comp Hepatol. 2005;4:6. [PMID: sient elastography, and aspartate-to-platelet ratio index in the assessment of fibro- sis in chronic hepatitis C. AJR Am J Roentgenol. 2012;199:19-25. [PMID: 118. Halfon P, Bourliere M, Deydier R, Botta-Fridlund D, Renou C, Tran A,
et al. Independent prospective multicenter validation of biochemical markers
101. Fontanges T, Bailly F, Trepo E, Chevallier M, Maynard-Muet M, Nalet
(Fibrotest-Actitest) for the prediction of liver fibrosis and activity in patients with B, et al. Discordance between biochemical markers of liver activity and fibrosis
chronic hepatitis C: the Fibropaca study. Am J Gastroenterol. 2006;101:547-55.
(Actitest-Fibrotest) and liver biopsy in patients with chronic hepatitis C. Gastro- enterol Clin Biol. 2008;32:858-65. [PMID: 18775614] 119. Halfon P, Bacq Y, De Muret A, Penaranda G, Bourliere M, Ouzan D,
102. Fouad SA, Esmat S, Omran D, Rashid L, Kobaisi MH. Noninvasive
et al. Comparison of test performance profile for blood tests of liver fibrosis in
assessment of hepatic fibrosis in Egyptian patients with chronic hepatitis C virus chronic hepatitis C. J Hepatol. 2007;46:395-402. [PMID: 17156890] infection. World J Gastroenterol. 2012;18:2988-94. [PMID: 22736923] 120. Halfon P, Penaranda G, Renou C, Bourliere M. External validation of
103. Friedrich-Rust M, Rosenberg W, Parkes J, Herrmann E, Zeuzem S,
FibroIndex [Letter]. Hepatology. 2007;46:280-1. [PMID: 17596884] Sarrazin C. Comparison of ELF, FibroTest and FibroScan for the non-invasive
121. Hsieh YY, Tung SY, Lee K, Wu CS, Wei KL, Shen CH, et al. Routine
assessment of liver fibrosis. BMC Gastroenterol. 2010;10:103. [PMID: blood tests to predict liver fibrosis in chronic hepatitis C. World J Gastroenterol.
104. Gabrielli GB, Capra F, Casaril M, Squarzoni S, Tognella P, Dagradi R,
122. Iacobellis A, Fusilli S, Mangia A, Clemente R, Festa V, Giacobbe A, et al.
et al. Serum laminin and type III procollagen in chronic hepatitis C. Diagnostic
Ultrasonographic and biochemical parameters in the non-invasive evaluation of value in the assessment of disease activity and fibrosis. Clin Chim Acta. 1997;265:21-31. [PMID: 9352126] liver fibrosis in hepatitis C virus chronic hepatitis. Aliment Pharmacol Ther.
105. Gara N, Zhao X, Kleiner DE, Liang TJ, Hoofnagle JH, Ghany MG.
Discordance among transient elastography, aspartate aminotransferase to platelet 123. Iacobellis A, Mangia A, Leandro G, Clemente R, Festa V, Attino V, et al.
ratio index, and histologic assessments of liver fibrosis in patients with chronic External validation of biochemical indices for noninvasive evaluation of liver fi- hepatitis C. Clin Gastroenterol Hepatol. 2013;11:303-308.e1. [PMID: brosis in HCV chronic hepatitis. Am J Gastroenterol. 2005;100:868-73. [PMID: 106. Giannini E, Risso D, Botta F, Chiarbonello B, Fasoli A, Malfatti F, et al.
124. Ichino N, Osakabe K, Nishikawa T, Sugiyama H, Kato M, Kitahara S,
Validity and clinical utility of the aspartate aminotransferase-alanine aminotrans- et al. A new index for non-invasive assessment of liver fibrosis. World J Gastro-
ferase ratio in assessing disease severity and prognosis in patients with hepatitis C enterol. 2010;16:4809-16. [PMID: 20939109] virus-related chronic liver disease. Arch Intern Med. 2003;163:218-24. [PMID: 125. Imperiale TF, Said AT, Cummings OW, Born LJ. Need for validation of
clinical decision aids: use of the AST/ALT ratio in predicting cirrhosis in chronic 107. Giannini E, Testa R. Noninvasive diagnosis of fibrosis: the truth is rarely
hepatitis C. Am J Gastroenterol. 2000;95:2328-32. [PMID: 11007237] pure and never simple [Letter]. Hepatology. 2003;38:1312-3. [PMID: 126. Jeffers LJ, Cortes RA, Bejarano PA, Oh E, Regev A, Smith KM, et al.
Prospective evaluation of FIBROSpect II for fibrosis detection in hepatitis C and 108. Giannini EG, Zaman A, Ceppa P, Mastracci L, Risso D, Testa R. A
B patients undergoing laparoscopic biopsy. Gastroenterol Hepatol (N Y). 2007; simple approach to noninvasively identifying significant fibrosis in chronic hepa- titis C patients in clinical practice. J Clin Gastroenterol. 2006;40:521-7. [PMID: 127. Kalantari H, Hoseini H, Babak A, Yaran M. Validation of hepascore as a
predictor of liver fibrosis in patients with chronic hepatitis C infection. Hepat Res 109. Silva Jr RG, Fakhouri R, Nascimento TV, Santos IM, Barbosa LM.
Treat. 2011;2011:972759. [PMID: 22254137] Aspartate aminotransferase-to-platelet ratio index for fibrosis and cirrhosis predic- 128. Kaul V, Friedenberg FK, Braitman LE, Anis U, Zaeri N, Fazili J, et al.
tion in chronic hepatitis C patients. Braz J Infect Dis. 2008;12:15-9. [PMID: Development and validation of a model to diagnose cirrhosis in patients with hepatitis C. Am J Gastroenterol. 2002;97:2623-8. [PMID: 12385450] 110. Gordon A, Bailey MJ, Gibson PR, Roberts SK. Comprehensive clinical
129. Khairy M, Abdel-Rahman M, El-Raziky M, El-Akel W, Zayed N, Khatab
assessment improves the accuracy of predicting cirrhosis in chronic hepatitis C.
H, et al. Non-invasive prediction of hepatic fibrosis in patients with chronic
J Gastroenterol Hepatol. 2005;20:825-32. [PMID: 15946128] HCV based on the routine pre-treatment workup. Hepat Mon. 2012;12:e6718.
111. Grigorescu M, Rusu M, Neculoiu D, Radu C, Serban A, Catanas M, et al.
The FibroTest value in discriminating between insignificant and significant fibro- 130. Khan DA, Fatima-Tuz-Zuhra, Khan FA, Mubarak A. Evaluation of diag-
sis in chronic hepatitis C patients. The Romanian experience. J Gastrointestin nostic accuracy of APRI for prediction of fibrosis in hepatitis C patients. J Ayub Liver Dis. 2007;16:31-7. [PMID: 17410286] Med Coll Abbottabad. 2008;20:122-6. [PMID: 19999223] www.annals.org
4 June 2013 Annals of Internal Medicine Volume 158 • Number 11 817
Downloaded From: http://annals.org/ by a Oxford University User on 06/04/2013
Review Blood Tests for Fibrosis or Cirrhosis in HCV Infection 131. Khokhar N. Serum aminotransferase levels and platelet count as predictive
A non-invasive algorithm accurately predicts advanced fibrosis in hepatitis C: a factor of fibrosis and cirrhosis in patients with chronic hepatitis C infection. J Pak comparison using histology with internal-external validation. J Hepatol. 2008;49: Med Assoc. 2003;53:101-4. [PMID: 12779023] 132. Lackner C, Struber G, Liegl B, Leibl S, Ofner P, Bankuti C, et al. Com-
150. Parise ER, Oliveira AC, Figueiredo-Mendes C, Lanzoni V, Martins J,
parison and validation of simple noninvasive tests for prediction of fibrosis in Nader H, et al. Noninvasive serum markers in the diagnosis of structural liver
chronic hepatitis C. Hepatology. 2005;41:1376-82. [PMID: 15915455] damage in chronic hepatitis C virus infection. Liver Int. 2006;26:1095-9.
133. Leroy V, Halfon P, Bacq Y, Boursier J, Rousselet MC, Bourlie`re M, et al.
Diagnostic accuracy, reproducibility and robustness of fibrosis blood tests in 151. Park GJ, Lin BP, Ngu MC, Jones DB, Katelaris PH. Aspartate amino-
chronic hepatitis C: a meta-analysis with individual data. Clin Biochem. 2008; transferase: alanine aminotransferase ratio in chronic hepatitis C infection: is it a useful predictor of cirrhosis? J Gastroenterol Hepatol. 2000;15:386-90. [PMID: 134. Leroy V, Hilleret MN, Sturm N, Trocme C, Renversez JC, Faure P, et al.
Prospective comparison of six non-invasive scores for the diagnosis of liver fibrosis 152. Park SH, Kim CH, Kim DJ, Suk KT, Park JH, Cheong JY, et al. Diag-
in chronic hepatitis C. J Hepatol. 2007;46:775-82. [PMID: 17321634] nostic value of multiple biomarker panel for prediction of significant fibrosis in 135. Liu CH, Lin JW, Tsai FC, Yang PM, Lai MY, Chen JH, et al. Noninva-
chronic hepatitis C. Clin Biochem. 2011;44:1396-9. [PMID: 21971609] sive tests for the prediction of significant hepatic fibrosis in hepatitis C virus 153. Park JJ, Park JY, Kim do Y, Park YN, Ahn SH, Chon CY, et al. Prediction
carriers with persistently normal alanine aminotransferases. Liver Int. 2006;26: of significant fibrosis in chronic hepatitis C patients with normal ALT. Hepato- gastroenterology. 2011;58:1321-7. [PMID: 21937403] 136. Lo Iacono O, Garcı´a-Monzo´n C, Almasio P, Garcı´a-Buey L, Craxı´ A,
154. Parkes J, Guha IN, Roderick P, Harris S, Cross R, Manos MM, et al.
Moreno-Otero R. Soluble adhesion molecules correlate with liver inflammation
Enhanced Liver Fibrosis (ELF) test accurately identifies liver fibrosis in patients and fibrosis in chronic hepatitis C treated with interferon-alpha. Aliment Phar- with chronic hepatitis C. J Viral Hepat. 2011;18:23-31. [PMID: 20196799] macol Ther. 1998;12:1091-9. [PMID: 9845398] 155. Patel K, Benhamou Y, Yoshida EM, Kaita KD, Zeuzem S, Torbenson M,
137. Loaeza-del-Castillo A, Paz-Pineda F, Oviedo-Ca´rdenas E, Sa´nchez-Avila F,
et al. An independent and prospective comparison of two commercial fibrosis
Vargas-Vora´ckova´ F. AST to platelet ratio index (APRI) for the noninvasive
marker panels (HCV FibroSURE and FIBROSpect II) during albinterferon evaluation of liver fibrosis. Ann Hepatol. 2008;7:350-7. [PMID: 19034235] alfa-2b combination therapy for chronic hepatitis C. J Viral Hepat. 2009;16:178- 138. Lu SN, Wang JH, Liu SL, Hung CH, Chen CH, Tung HD, et al.
Thrombocytopenia as a surrogate for cirrhosis and a marker for the identification 156. Plevris JN, Haydon GH, Simpson KJ, Dawkes R, Ludlum CA, Harrison
of patients at high-risk for hepatocellular carcinoma. Cancer. 2006;107:2212-22.
DJ, et al. Serum hyaluronan—a non-invasive test for diagnosing liver cirrhosis.
Eur J Gastroenterol Hepatol. 2000;12:1121-7. [PMID: 11057458] 139. Martinez SM, Ferna´ndez-Varo G, Gonza´lez P, Sampson E, Bruguera M,
157. Poynard T, Imbert-Bismut F, Ratziu V, Chevret S, Jardel C, Moussalli J,
Navasa M, et al. Assessment of liver fibrosis before and after antiviral therapy by
et al; GERMED cyt04 group. Biochemical markers of liver fibrosis in patients
different serum marker panels in patients with chronic hepatitis C. Aliment Phar- infected by hepatitis C virus: longitudinal validation in a randomized trial. J Viral macol Ther. 2011;33:138-48. [PMID: 21083589] 140. McHutchison JG, Blatt LM, de Medina M, Craig JR, Conrad A, Schiff
158. Poynard T, McHutchison J, Manns M, Myers RP, Albrecht J. Biochem-
ER, et al. Measurement of serum hyaluronic acid in patients with chronic hep-
ical surrogate markers of liver fibrosis and activity in a randomized trial of pegin- atitis C and its relationship to liver histology. Consensus Interferon Study Group.
terferon alfa-2b and ribavirin. Hepatology. 2003;38:481-92. [PMID: 12883493] J Gastroenterol Hepatol. 2000;15:945-51. [PMID: 11022838] 159. Pradat P, Alberti A, Poynard T, Esteban JI, Weiland O, Marcellin P, et al.
141. Metwally MA, Zein CO, Zein NN. Predictors and noninvasive identifica-
Predictive value of ALT levels for histologic findings in chronic hepatitis C: a tion of severe liver fibrosis in patients with chronic hepatitis C. Dig Dis Sci.
European collaborative study. Hepatology. 2002;36:973-7. [PMID: 12297846] 160. Reedy DW, Loo AT, Levine RA. AST/ALT ratio Ͼ or ϭ 1 is not diag-
142. Morali G, Maor Y, Klar R, Braun M, Ben Ari Z, Bujanover Y, et al.
nostic of cirrhosis in patients with chronic hepatitis C. Dig Dis Sci. 1998;43: Fibrotest-Actitest: the biochemical marker of liver fibrosis—the Israeli experience.
Isr Med Assoc J. 2007;9:588-91. [PMID: 17877064] 161. Renou C, Muller P, Jouve E, Bertrand JJ, Raoult A, Benderriter T, et al.
143. Morra R, Munteanu M, Bedossa P, Dargere D, Janneau JL, Paradis V,
Revelance of moderate isolated thrombopenia as a strong predictive marker of et al. Diagnostic value of serum protein profiling by SELDI-TOF ProteinChip
cirrhosis in patients with chronic hepatitis C virus [Letter]. Am J Gastroenterol.
compared with a biochemical marker, FibroTest, for the diagnosis of advanced fibrosis in patients with chronic hepatitis C. Aliment Pharmacol Ther. 2007;26: 162. Romagnuolo J, Jhangri GS, Jewell LD, Bain VG. Predicting the liver
histology in chronic hepatitis C: how good is the clinician? Am J Gastroenterol.
144. Mossong J, Bill S, Hawotte K, Gilson G, Knolle U, Weber J, et al.
Predicting significant fibrosis in hepatitis C patients in Luxembourg using sero- 163. Romera M, Corpas R, Romero Go´mez M. Insulin resistance as a non-
logical markers. Bull Soc Sci Med Grand Duche Luxemb. 2011:19-30. [PMID: invasive method for the assessment of fibrosis in patients with hepatitis C: a comparative study of biochemical methods. Rev Esp Enferm Dig. 2006;98: 145. Murawaki Y, Ikuta Y, Okamoto K, Koda M, Kawasaki H. Diagnostic
value of serum markers of connective tissue turnover for predicting histological 164. Rossi E, Adams L, Prins A, Bulsara M, de Boer B, Garas G, et al. Vali-
staging and grading in patients with chronic hepatitis C. J Gastroenterol. 2001; dation of the FibroTest biochemical markers score in assessing liver fibrosis in hepatitis C patients. Clin Chem. 2003;49:450-4. [PMID: 12600957] 146. Murawaki Y, Koda M, Okamoto K, Mimura K, Kawasaki H. Diagnostic
165. Saadeh S, Cammell G, Carey WD, Younossi Z, Barnes D, Easley K. The
value of serum type IV collagen test in comparison with platelet count for pre- role of liver biopsy in chronic hepatitis C. Hepatology. 2001;33:196-200.
dicting the fibrotic stage in patients with chronic hepatitis C. J Gastroenterol Hepatol. 2001;16:777-81. [PMID: 11446886] 166. Said Y, Salem M, Mouelhi L, Mekki H, Houissa F, Ben Rejeb M, et al.
147. Myers RP, De Torres M, Imbert-Bismut F, Ratziu V, Charlotte F, Poy-
Correlation between liver biopsy and fibrotest in the evaluation of hepatic fibrosis nard T; MULTIVIRC Group. Biochemical markers of fibrosis in patients with
in patients with chronic hepatitis C. Tunis Med. 2010;88:573-8. [PMID: chronic hepatitis C: a comparison with prothrombin time, platelet count, and age-platelet index. Dig Dis Sci. 2003;48:146-53. [PMID: 12645802] 167. Saitou Y, Shiraki K, Yamanaka Y, Yamaguchi Y, Kawakita T, Yamamoto
148. Myers RP, Ratziu V, Imbert-Bismut F, Charlotte F, Poynard T;
N, et al. Noninvasive estimation of liver fibrosis and response to interferon ther-
MULTIVIRC Group; Groupe d’Etude Multidisciplinaire sur les Pathologies
apy by a serum fibrogenesis marker, YKL-40, in patients with HCV-associated Lie´es au Virus C. Biochemical markers of liver fibrosis: a comparison with his-
liver disease. World J Gastroenterol. 2005;11:476-81. [PMID: 15641129] torical features in patients with chronic hepatitis C. Am J Gastroenterol. 2002; 168. Schneider AR, Teuber G, Paul K, Nikodem A, Duesterhoeft M, Caspary
WF, et al. Patient age is a strong independent predictor of 13C-aminopyrine
149. Paggi S, Colli A, Fraquelli M, Vigano` M, Del Poggio P, Facciotto C, et al.
breath test results: a comparative study with histology, duplex-Doppler and a 818 4 June 2013 Annals of Internal Medicine Volume 158 • Number 11
www.annals.org
Downloaded From: http://annals.org/ by a Oxford University User on 06/04/2013
Blood Tests for Fibrosis or Cirrhosis in HCV Infection Review laboratory index in patients with chronic hepatitis C virus infection. Clin Exp 188. Walsh KM, Fletcher A, MacSween RN, Morris AJ. Comparison of assays
Pharmacol Physiol. 2006;33:300-4. [PMID: 16620291] for N-amino terminal propeptide of type III procollagen in chronic hepatitis C by 169. Sebastiani G, Halfon P, Castera L, Pol S, Thomas DL, Mangia A, et al.
using receiver operating characteristic analysis. Eur J Gastroenterol Hepatol.
SAFE biopsy: a validated method for large-scale staging of liver fibrosis in chronic hepatitis C. Hepatology. 2009;49:1821-7. [PMID: 19291784] 189. Walsh KM, Fletcher A, MacSween RN, Morris AJ. Basement membrane
170. Sebastiani G, Vario A, Guido M, Alberti A. Performance of noninvasive
peptides as markers of liver disease in chronic hepatitis C. J Hepatol. 2000;32: markers for liver fibrosis is reduced in chronic hepatitis C with normal transami- nases. J Viral Hepat. 2008;15:212-8. [PMID: 18179453] 190. Walsh KM, Timms P, Campbell S, MacSween RN, Morris AJ. Plasma
171. Sebastiani G, Vario A, Guido M, Noventa F, Plebani M, Pistis R, et al.
levels of matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of metallo- Stepwise combination algorithms of non-invasive markers to diagnose significant proteinases -1 and -2 (TIMP-1 and TIMP-2) as noninvasive markers of liver fibrosis in chronic hepatitis C. J Hepatol. 2006;44:686-93. [PMID: 16490278] disease in chronic hepatitis C: comparison using ROC analysis. Dig Dis Sci.
172. Sebastiani G, Castera L, Halfon P, Pol S, Mangia A, Di Marco V, et al.
The impact of liver disease aetiology and the stages of hepatic fibrosis on the 191. Westin J, Ydreborg M, Islam S, Alsio¨ A, Dhillon AP, Pawlotsky JM, et al;
performance of non-invasive fibrosis biomarkers: an international study of 2411 DITTO-HCV Study Group. A non-invasive fibrosis score predicts treatment
cases. Aliment Pharmacol Ther. 2011;34:1202-16. [PMID: 21981787] outcome in chronic hepatitis C virus infection. Scand J Gastroenterol. 2008;43: 173. Sebastiani G, Halfon P, Castera L, Mangia A, Di Marco V, Pirisi M, et al.
Comparison of three algorithms of non-invasive markers of fibrosis in chronic 192. Wilson LE, Torbenson M, Astemborski J, Faruki H, Spoler C, Rai R,
hepatitis C. Aliment Pharmacol Ther. 2012;35:92-104. [PMID: 22035045] et al. Progression of liver fibrosis among injection drug users with chronic hepa-
174. Sheth SG, Flamm SL, Gordon FD, Chopra S. AST/ALT ratio predicts
titis C. Hepatology. 2006;43:788-95. [PMID: 16557548] cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol.
193. Wong VS, Hughes V, Trull A, Wight DG, Petrik J, Alexander GJ. Serum
hyaluronic acid is a useful marker of liver fibrosis in chronic hepatitis C virus 175. Shlomai A, Halfon P, Goldiner I, Zelber-Sagi S, Halpern Z, Oren R, et al.
infection. J Viral Hepat. 1998;5:187-92. [PMID: 9658372] Serum bile acid levels as a predictor for the severity of liver fibrosis in patients 194. Yilmaz Y, Yonal O, Kurt R, Bayrak M, Aktas B, Ozdogan O. Noninvasive
with chronic hepatitis C. J Viral Hepat. 2013;20:95-102. [PMID: 23301544] assessment of liver fibrosis with the aspartate transaminase to platelet ratio index 176. Silva IS, Ferraz ML, Perez RM, Lanzoni VP, Figueiredo VM, Silva AE.
(APRI): Usefulness in patients with chronic liver disease: APRI in chronic liver Role of gamma-glutamyl transferase activity in patients with chronic hepatitis C disease. Hepat Mon. 2011;11:103-6. [PMID: 22087126] virus infection. J Gastroenterol Hepatol. 2004;19:314-8. [PMID: 14748879] 195. Zaman A, Rosen HR, Ingram K, Corless CL, Oh E, Smith K. Assessment
of FIBROSpect II to detect hepatic fibrosis in chronic hepatitis C patients. Am
177. Sirli R, Sporea I, Bota S, Popescu A, Cornianu M. A comparative study of
J Med. 2007;120:280.e9-14. [PMID: 17349453] non-invasive methods for fibrosis assessment in chronic HCV infection. Hepat 196. Zarski JP, Sturm N, Guechot J, Paris A, Zafrani ES, Asselah T, et al;
ANRS HCEP 23 Fibrostar Group. Comparison of nine blood tests and transient
178. Snyder N, Gajula L, Xiao SY, Grady J, Luxon B, Lau DT, et al. APRI: an
elastography for liver fibrosis in chronic hepatitis C: the ANRS HCEP-23 study.
easy and validated predictor of hepatic fibrosis in chronic hepatitis C. J Clin J Hepatol. 2012;56:55-62. [PMID: 21781944] Gastroenterol. 2006;40:535-42. [PMID: 16825937] 197. Lackner C, Struber G, Bankuti C, Bauer B, Stauber RE. Noninvasive
179. Snyder N, Nguyen A, Gajula L, Soloway R, Xiao SY, Lau DT, et al. The
diagnosis of cirrhosis in chronic hepatitis C based on standard laboratory tests APRI may be enhanced by the use of the FIBROSpect II in the estimation of [Letter]. Hepatology. 2006;43:378-9. [PMID: 16440344] fibrosis in chronic hepatitis C. Clin Chim Acta. 2007;381:119-23. [PMID: 198. Le Calvez S, Thabut D, Messous D, Munteanu M, Ratziu V, Imbert-
Bismut F, et al. The predictive value of Fibrotest vs. APRI for the diagnosis of
180. Stibbe KJ, Verveer C, Francke J, Hansen BE, Zondervan PE, Kuipers EJ,
fibrosis in chronic hepatitis C [Letter]. Hepatology. 2004;39:862-3. [PMID: et al. Comparison of non-invasive assessment to diagnose liver fibrosis in chronic
hepatitis B and C patients. Scand J Gastroenterol. 2011;46:962-72. [PMID: 199. Park G, Jones DB, Katelaris P. Value of AST/ALT ratio as fibrotic predic-
tor in chronic hepatitis C [Letter]. Am J Gastroenterol. 2005;100:1623-4.
181. Testa R, Testa E, Giannini E, Borro P, Milazzo S, Isola L, et al. Nonin-
vasive ratio indexes to evaluate fibrosis staging in chronic hepatitis C: role of 200. Thabut D, Simon M, Myers RP, Messous D, Thibault V, Imbert-Bismut
platelet count/spleen diameter ratio index. J Intern Med. 2006;260:142-50.
F, et al. Noninvasive prediction of fibrosis in patients with chronic hepatitis C
[Letter]. Hepatology. 2003;37:1220-1. [PMID: 12717403] 182. Trocme C, Leroy V, Sturm N, Hilleret MN, Bottari S, Morel F, et al.
201. Seeff LB, Everson GT, Morgan TR, Curto TM, Lee WM, Ghany MG,
Longitudinal evaluation of a fibrosis index combining MMP-1 and PIIINP com- et al; HALT-C Trial Group. Complication rate of percutaneous liver biopsies
pared with MMP-9, TIMP-1 and hyaluronic acid in patients with chronic hep- among persons with advanced chronic liver disease in the HALT-C trial. Clin atitis C treated by interferon-alpha and ribavirin. J Viral Hepat. 2006;13:643-51.
Gastroenterol Hepatol. 2010;8:877-83. [PMID: 20362695] 202. West J, Card TR. Reduced mortality rates following elective percutaneous
183. Usluer G, Erben N, Aykin N, Dagli O, Aydogdu O, Barut S, et al; Study
liver biopsies. Gastroenterology. 2010;139:1230-7. [PMID: 20547160] Group. Comparison of non-invasive fibrosis markers and classical liver biopsy in
203. Morrison A, Polisena J, Husereau D, Moulton K, Clark M, Fiander M,
chronic hepatitis C. Eur J Clin Microbiol Infect Dis. 2012;31:1873-8. [PMID: et al. The effect of English-language restriction on systematic review-based meta-
analyses: a systematic review of empirical studies. Int J Technol Assess Health 184. Uyar C, Akcam FZ, Ciris M, Kaya O, Kockar C, Isler M. Comparison of
FibroTest-ActiTest with histopathology in demonstrating fibrosis and necroin- 204. Pham B, Klassen TP, Lawson ML, Moher D. Language of publication
flammatory activity in chronic hepatitis B and C. Indian J Pathol Microbiol.
restrictions in systematic reviews gave different results depending on whether the intervention was conventional or complementary. J Clin Epidemiol. 2005;58: 185. Vallet-Pichard A, Mallet V, Nalpas B, Verkarre V, Nalpas A, Dhalluin-
Venier V, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV
205. Schiano TD, Azeem S, Bodian CA, Bodenheimer HC Jr, Merati S, Thung
infection. comparison with liver biopsy and fibrotest. Hepatology. 2007;46:32-6.
SN, et al. Importance of specimen size in accurate needle liver biopsy evaluation
of patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2005;3:930-5.
186. Verbaan H, Bondeson L, Eriksson S. Non-invasive assessment of inflam-
matory activity and fibrosis (grade and stage) in chronic hepatitis C infection.
206. Colloredo G, Guido M, Sonzogni A, Leandro G. Impact of liver biopsy size
Scand J Gastroenterol. 1997;32:494-9. [PMID: 9175214] on histological evaluation of chronic viral hepatitis: the smaller the sample, the 187. Borsoi Viana MS, Takei K, Collarile Yamaguti DC, Guz B, Strauss E. Use
milder the disease. J Hepatol. 2003;39:239-44. [PMID: 12873821] of AST platelet ratio index (APRI Score) as an alternative to liver biopsy for 207. Obuchowski NA. Estimating and comparing diagnostic tests’ accuracy
treatment indication in chronic hepatitis C. Ann Hepatol. 2009;8:26-31.
when the gold standard is not binary. Acad Radiol. 2005;12:1198-204. [PMID: www.annals.org
4 June 2013 Annals of Internal Medicine Volume 158 • Number 11 819
Downloaded From: http://annals.org/ by a Oxford University User on 06/04/2013
Review Blood Tests for Fibrosis or Cirrhosis in HCV Infection 208. Lambert J, Halfon P, Penaranda G, Bedossa P, Cacoub P, Carrat F. How
hepatitis C-related fibrosis: an updated meta-analysis. Hepatology. 2011;53:726- to measure the diagnostic accuracy of noninvasive liver fibrosis indices: the area under the ROC curve revisited. Clin Chem. 2008;54:1372-8. [PMID: 213. Poynard T, Ngo Y, Munteanu M, Thabut D, Massard J, Moussalli J,
et al. Biomarkers of liver injury for hepatitis clinical trials: a meta-analysis of
209. Poynard T, Halfon P, Castera L, Munteanu M, Imbert-Bismut F, Ratziu
longitudinal studies. Antivir Ther. 2010;15:617-31. [PMID: 20587855] V, et al; FibroPaca Group. Standardization of ROC curve areas for diagnostic
214. Andriulli A, Persico M, Iacobellis A, Maio G, Di Salvo D, Spadaccini A,
evaluation of liver fibrosis markers based on prevalences of fibrosis stages. Clin et al. Treatment of patients with HCV infection with or without liver biopsy.
J Viral Hepat. 2004;11:536-42. [PMID: 15500554] 210. Shaheen AA, Wan AF, Myers RP. FibroTest and FibroScan for the pre-
diction of hepatitis C-related fibrosis: a systematic review of diagnostic test accu-
215. Park JW. [Hepatocellular carcinoma in Korea: introduction and overview].
racy. Am J Gastroenterol. 2007;102:2589-600. [PMID: 17850410] Korean J Gastroenterol. 2005;45:217-26. [PMID: 15843747] 211. Shaheen AA, Myers RP. Diagnostic accuracy of the aspartate
216. Caste´ra L, Le Bail B, Roudot-Thoraval F, Bernard PH, Foucher J, Mer-
aminotransferase-to-platelet ratio index for the prediction of hepatitis C-related rouche W, et al. Early detection in routine clinical practice of cirrhosis and
fibrosis: a systematic review. Hepatology. 2007;46:912-21. [PMID: 17705266] oesophageal varices in chronic hepatitis C: comparison of transient elastography 212. Lin ZH, Xin YN, Dong QJ, Wang Q, Jiang XJ, Zhan SH, et al. Perfor-
(FibroScan) with standard laboratory tests and non-invasive scores. J Hepatol.
mance of the aspartate aminotransferase-to-platelet ratio index for the staging of ANNALS OF INTERNAL MEDICINE JUNIOR INVESTIGATOR AWARDS
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Current Author Addresses: Drs. Chou and Wasson: Oregon Health &
Final approval of the article: R. Chou.
Science University, Mail Code BICC, 3181 Southwest Sam Jackson Park Provision of study materials or patients: R. Chou.
Statistical expertise: R. Chou.
Obtaining of funding: R. Chou.
Author Contributions: Conception and design: R. Chou.
Administrative, technical, or logistic support: R. Chou, N. Wasson.
Analysis and interpretation of the data: R. Chou.
Collection and assembly of data: R. Chou, N. Wasson.
Drafting of the article: R. Chou.
Critical revision of the article for important intellectual content:R. Chou.
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Appendix Table 1. Search Strategy
Ovid MEDLINE without Revisions (1996 to week 1 of January 2013)
Ovid MEDLINE In-Process & Other Non-Indexed Citations (12 January
2013)
1. Hepatitis C/ or Hepatitis C, Chronic/ or Hepacivirus/ or Hepatitis C.mp. or hepacivirus$.mp. or HCV.mp. (50979) 2. Hepatitis C/di, pa, ra, us or Immunoenzyme Techniques/ or Enzyme-Linked Immunosorbent Assay/ or Immunoblotting/ orPolymerase Chain Reaction/ or Reverse Transcriptase PolymeraseChain Reaction/ or Liver function tests/ or blood test$.mp. or bloodmarker$.mp. or Breath Tests/ or Diagnostic Imaging/ or MagneticResonance Imaging/ or exp Tomography, X-ray Computed/ orAlanine Transaminase/ or “sensitivity and specificity”/ or FalseNegative Reactions/ or False Positive Reactions/ or Hepatitis CAntibodies/ or HCV Antibodies.mp. or anti hcv.mp. oranti-hcv.mp. (970174) 3. (“Age-Platelet Index” or “AST-platelet ratio index” or apri or “Cirrhosis Discriminant Score” or “Bonacini Index” or “EuropeanLiver Fibrosis” or elf or “simplified elf” or “FIB-4 of Firbo-alphaScore” or “FibroIndex” or fibrometer or “FibroQ Index” or“Fibrosis-Cirrhosis Index” or “Fibrosis Probability Index” or “SudIndex” or “Fibrosis-Protein Index” or “FibroSpect II” or Fibrotest orFibrosure or “Forns Index” or “Globulin/albumin ratio” or“Goteborg University Cirrhosis Index” or “HALT-C Model” or“Hepascore” or “King’s Score” or “Lok Index” or “MP3 Score” or“Pohl Index” or “Sabadell NIHCED Index” or “Significant FibrosisIndex” or “Zeng Index”).mp. [mpϭtitle, abstract, original title,name of substance word, subject heading word, protocolsupplementary concept, rare disease supplementary concept,unique identifier] (2125) 4. 1 and 2 (16541)5. 1 and 3 (320)6. 4 or 5 (16689)7. (201205$ or 201206$ or 201207$ or 201208$ or 201209$ or 8. 6 and 7 (549)9. limit 8 to english language (519)10. limit 8 to abstracts (518)11. 9 or 10 (544)12. limit 11 to humans (432)13. limit 12 to “all adult (19 plus years)” (243) Appendix Table 2. METAVIR and Ishak Scoring Systems for Hepatic Fibrosis*
Description
Stellate enlargement of portal tract without septa Enlargement of portal tract with rare septa Fibrous expansion of some portal areas with or without short fibrous septa Fibrous expansion of most portal areas with or without short fibrous septa Fibrous expansion of most portal areas with occasional portal-to-portal bridging Fibrous expansion of portal areas with marked portal-to-portal bridging and portal-to-central bridging Marked bridging (portal-to-portal and/or portal-to-central), with occasional nodules (incomplete cirrhosis) METAVIR ϭ Meta-analysis of Histologic Data in Viral Hepatitis.
* Clinically significant fibrosis is usually defined as METAVIR stages F2 to F4 or Ishak stages 3 to 6. Cirrhosis is typically defined as METAVIR stage F4 or Ishak stages 5or 6; however, METAVIR stage F3 includes patients with early or developing cirrhosis.
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Appendix Table 3. Strength-of-Evidence Domains and Overall Ratings
Studies,
Quality*
Consistency†
Directness‡
Precision§
Patients, nሻ
Strength of
Evidence
ALT ϭ alanine aminotransferase; APRI ϭ AST–platelet ratio index; AST ϭ aspartate aminotransferase; ELF ϭ enhanced liver fibrosis; GUCI ϭ Göteborg University Cirrhosis Index.
* Rated good, fair, or poor.
† Rated high, moderate, or low.
‡ Rated direct or indirect.
§ Rated high, moderate, or low.
࿣ For studies of diagnostic accuracy that report the area under the receiver-operating characteristic curve.
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Source: http://promesi.med.auth.gr/LessonResources/mathimata_a/3_Ann_InternMed2013_Hepatic_Dx.pdf