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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, chour@ohsu.edu.
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
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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