Noninvasive Methods to Assess Liver Disease in Patients With Hepatitis B or C

The prognosis and management of patients with chronic viral hepatitis B and C depend on the amount and progression of liver fibrosis and the risk for cirrhosis. Liver biopsy, traditionally considered to be the reference standard for staging of fibrosis, has been challenged over the past decade by the development of noninvasive methodologies. These methods rely on distinct but complementary approaches: a biologic approach, which quantifies serum levels of biomarkers of fibrosis, and a physical approach, which measures liver stiffness by ultrasound or magnetic resonance elastography. Noninvasive methods were initially studied and validated in patients with chronic hepatitis C but are now used increasingly for patients with hepatitis B, reducing the need for liver biopsy analysis. We review the advantages and limitations of the noninvasive methods used to manage patients with chronic viral hepatitis B or C infection. The prognosis and management of patients with chronic viral hepatitis B and C depend on the amount and progression of liver fibrosis and the risk for cirrhosis. Liver biopsy, traditionally considered to be the reference standard for staging of fibrosis, has been challenged over the past decade by the development of noninvasive methodologies. These methods rely on distinct but complementary approaches: a biologic approach, which quantifies serum levels of biomarkers of fibrosis, and a physical approach, which measures liver stiffness by ultrasound or magnetic resonance elastography. Noninvasive methods were initially studied and validated in patients with chronic hepatitis C but are now used increasingly for patients with hepatitis B, reducing the need for liver biopsy analysis. We review the advantages and limitations of the noninvasive methods used to manage patients with chronic viral hepatitis B or C infection. It is important to assess liver disease in patients with viral hepatitis B or C, not only to determine prognosis but to identify patients who require antiviral therapy.1EASL clinical practice guidelines: management of chronic hepatitis B.J Hepatol. 2009; 50: 227-242Abstract Full Text Full Text PDF PubMed Scopus (972) Google Scholar, 2Lok A.S. McMahon B.J. Chronic hepatitis B: update 2009.Hepatology. 2009; 50: 661-662Crossref PubMed Scopus (683) Google Scholar, 3Ghany M.G. Strader D.B. Thomas D.L. et al.Diagnosis, management, and treatment of hepatitis C: an update.Hepatology. 2009; 49: 1335-1374Crossref PubMed Scopus (1126) Google Scholar, 4Ghany M.G. Nelson D.R. 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It is an invasive procedure that is prone to sampling errors and to intra- and interobserver variation.9Maharaj B. Maharaj R.J. Leary W.P. et al.Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver.Lancet. 1986; 1: 523-525Abstract PubMed Google Scholar, 10Regev A. Berho M. Jeffers L.J. et al.Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection.Am J Gastroenterol. 2002; 97: 2614-2618Crossref PubMed Google Scholar Recent American Association for the Study of Liver Diseases guidelines recommended a biopsy of at least 2–3 cm in length, obtained with a 16-gauge needle, that contains more than 11 complete portal tracts for adequate staging and grading of diffuse parenchymal disease.11Rockey D.C. Caldwell S.H. Goodman Z.D. et al.Liver biopsy.Hepatology. 2009; 49: 1017-1044Crossref PubMed Scopus (218) Google Scholar However, in clinical practice, few percutaneous needle biopsies meet these criteria. These limitations, as well as powerful virologic tools for determining genotypes and viral load and new antiviral drugs, have rapidly reduced the use of liver biopsy in management of patients with viral hepatitis. The development of noninvasive methods to assess liver fibrosis over the past decade has advanced the practice of hepatology.12Castera L. Pinzani M. Noninvasive assessment of liver fibrosis: are we ready?.Lancet. 2010; 375: 1419-1420Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Apart from assessing liver fibrosis, these noninvasive methods could be used in deciding whether to treat a patient or defer antiviral treatment, in monitoring patients' response to treatment and progression of disease, and in determining prognosis. We review methods for noninvasive evaluation of liver fibrosis and discuss their advantages and limitations in managing patients with viral hepatitis B or C. The performance of a noninvasive diagnostic method is evaluated by calculation of the area under the receiver operator characteristic curve (AUROC), taking liver biopsy as the reference standard. However, biopsy analysis is an imperfect reference standard: taking into account a range of accuracies of the biopsy, even in the best possible scenario, an AUROC >0.90 cannot be achieved even for a perfect marker of liver disease.13Mehta S.H. Lau B. Afdhal N.H. et al.Exceeding the limits of liver histology markers.J Hepatol. 2009; 50: 36-41Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar The AUROC can vary based on the prevalence of each stage of fibrosis, described as spectrum bias.14Ransohoff D.F. Feinstein A.R. Problems of spectrum and bias in evaluating the efficacy of diagnostic tests.N Engl J Med. 1978; 299: 926-930Crossref PubMed Google Scholar Spectrum bias has important implications for the study of noninvasive methods, particularly in comparisons of methods across different study populations. If extreme stages of fibrosis (F0 and F4) are over-represented in a population, the sensitivity and specificity of a diagnostic will be higher than in a population of patients that has middle stages of fibrosis (F1 and F2). Several ways of preventing the “spectrum bias” have been proposed including the adjustment of AUROC using the DANA method (standardization according to the prevalence of fibrosis stages; Difference in Advanced [F2-F3-F4] and Nonadvanced [F0-F1] fibrosis) and nonadvanced (F0-F1) fibrosis)15Poynard T. Halfon P. 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Fibrosis can be measured noninvasively, based on a “biological” approach (quantifying biomarkers in serum samples) or based on a “physical” approach (measuring liver stiffness). Although these approaches are complementary, they are based on a different rationale. Liver stiffness corresponds to a genuine and intrinsic physical property of liver parenchyma, whereas serum biomarkers indicate several, not strictly liver-specific features of blood that have been associated with fibrosis stage, as assessed by liver biopsy. Many serum biomarkers have been evaluated for their ability to determine stage of liver fibrosis, mainly in patients with chronic hepatitis C (for review, see Pinzani et al,18Pinzani M. Vizzutti F. Arena U. et al.Technology insight: noninvasive assessment of liver fibrosis by biochemical scores and elastography.Nat Clin Pract Gastroenterol Hepatol. 2008; 5: 95-106Crossref PubMed Scopus (91) Google Scholar Manning and Afdhal,19Manning D.S. Afdhal N.H. Diagnosis and quantitation of fibrosis.Gastroenterology. 2008; 134: 1670-1681Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar and Castera20Castera L. Transient elastography and other noninvasive tests to assess hepatic fibrosis in patients with viral hepatitis.J Viral Hepat. 2009; 16: 300-314Crossref PubMed Scopus (61) Google Scholar). Among the proposed markers, the so–called direct markers reflect the deposition or removal of extracellular matrix in the liver. These include glycoproteins such as serum hyaluronate, laminin, and YKL-40 and collagens such as procollagen III N-peptide and type IV collagen, collagenases, and their inhibitors such as matrix metalloproteases and tissue inhibitory metalloprotease-1. So–called indirect markers include factors that can be measured in routine blood tests, such as the prothrombin index, platelet count, and ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT), which indicate alterations in hepatic function. Results from measurements of direct and indirect markers can be combined and used in diagnosis; the FibroTest (proprietary formula; Biopredictive, Paris, France) was the first algorithm that combined these data.21Imbert-Bismut F. Ratziu V. Pieroni L. et al.Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study.Lancet. 2001; 357: 1069-1075Abstract Full Text Full Text PDF PubMed Scopus (884) Google Scholar Several other scores22Forns X. Ampurdanes S. Llovet J.M. et al.Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model.Hepatology. 2002; 36: 986-992PubMed Google Scholar, 23Wai C.T. Greenson J.K. 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Bilonick R. et al.Modeling hepatic fibrosis in African American and Caucasian American patients with chronic hepatitis C virus infection.Hepatology. 2006; 44: 925-935Crossref PubMed Scopus (25) Google Scholar, 35Koda M. Matunaga Y. Kawakami M. et al.FibroIndex, a practical index for predicting significant fibrosis in patients with chronic hepatitis C.Hepatology. 2007; 45: 297-306Crossref PubMed Scopus (88) Google Scholar, 36Vallet-Pichard A. Mallet V. Nalpas B. et al.FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection Comparison with liver biopsy and Fibrotest.Hepatology. 2007; 46: 32-36Crossref PubMed Scopus (172) Google Scholar, 37Fontana R.J. Goodman Z.D. Dienstag J.L. et al.Relationship of serum fibrosis markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C.Hepatology. 2008; 47: 789-798Crossref PubMed Scopus (78) Google Scholar have been proposed: 4 are protected by patents and are commercially available (Table 1). Nonproprietary methods use published models, based on routinely available laboratory tests.Table 1Currently Available Noninvasive Methods to Assess Liver Disease in Patients With Hepatitis B or CSerum biomarkersHCV Fibrotest (Biopredictive, Paris, France) patented formula combining α-2-macroglobulin, γGT, apolipoprotein A1, haptoglobin, total bilirubin, age, and gender Forn index = 7.811 − 3.131 × In(platelet count) + 0.781 × In(GGT) + 3.467 × In(age) − 0.014 × (cholesterol) AST to platelet ratio (APRI) = AST (/ULN)/platelet (109/L) × 100 FibroSpectII (Promotheus Laboratory Inc, San Diego, CA) patented formula combining α-2-macroglobulin, hyaluronate, and TIMP-1 MP3 = 0.5903 × log⁡ PIIINP (ng/mL) − 0.1749 × log⁡ MMP-1 (ng/mL) Enhanced liver fibrosis score (ELF) (iQur Ltd, Southampton, UK) patented formula combining age, hyaluronate, MMP-3, and TIMP-1 Fibrosis probability index (FPI) = 10.929 + (1.827 × LnAST) + (0.081 × age) + (0.768 × past alcohol usea) + (0.385 × HOMA-IR) − (0.447 × cholesterol) Hepascore (PathWest, University of Western Australia, Perth, Australia) patented formula combining bilirubin, γGT, hyaluronate, α-2-macroglobulin, age, and gender Fibrometers (BioLiveScale, Angers, France) patented formula combining platelet count, prothrombin index, AST, α-2-macroglobulin, hyaluronate, urea, and age Lok index = −5.56 − 0.0089 × platelet (103/mm3) + 1.26 × AST/ALT ratio + 5.27 × INR Goteborg University cirrhosis index (GUCI) = AST × prothrombin-INR × 100/platelet Virahep−c mod⁡el = 5.17 + 0.20 × race + 0.07 × age (years) + 1.19 In (AST [IU/L]) − 1.76 In (platelet count [103/mL]) + 1.38 In (alkaline phosphatase [IU/L] Fibroindex = 1.738 − 0.064 × (platelets [104/mm3]) + 0.005 × (AST [IU/L]) + 0.463 × (γ−globulin [g/dL]) FIB-4 = age (years) × AST [U/L]/(platelets [109/L] × (ALT [U/L])1/2 HALT-C mod⁡el = −3.66 − 0.00995 × platelets (103/mL) + 0.008 × serum × TIMP-1 + 1.42 × log⁡ (hyaluronate) HBV Hui score = 3.148 + 0.167 × BMI + 0.088 × bilirubin − 0.151 × albumin⁡ − 0.019 × platelet Zeng score = 13.995 + 3.220 log⁡ (α-2-macroglobulin) + 3.096 (age) + 2.254 log⁡ (GGT) + 2.437 log⁡ (hyaluronate)Measurement of liver stiffness Transient elastography: FibroScan (Echosens, Paris, France) (results ranging from 2.5 to 75 kPa) Acoustic radiation force impulse imaging: Acuson 2000 Virtual Touch Tissue Quantification (Siemens Healthcare, Erlangen, Germany) (results ranging from 0.5 to 4.4 meters/sec) Magnetic resonance elastography (results ranging from 0.5 to 10 kPa)a Graded as 0–2. Open table in a new tab The practical advantages of analyzing serum biomarkers to measure fibrosis include their high applicability (>95%) and interlaboratory reproducibility38Cales P. Veillon P. Konate A. et al.Reproducibility of blood tests of liver fibrosis in clinical practice.Clin Biochem. 2008; 41: 10-18Crossref PubMed Scopus (30) Google Scholar, 39Imbert-Bismut F. Messous D. Thibaut V. et al.Intra-laboratory analytical variability of biochemical markers of fibrosis (Fibrotest) and activity (Actitest) and reference ranges in healthy blood donors.Clin Chem Lab Med. 2004; 42: 323-333PubMed Scopus (0) Google Scholar and their potential widespread availability (Table 2). However, none are liver specific—their results can be influenced by comorbid conditions, and they require critical interpretation of results. For instance, FibroTest and Hepascore produce false-positive results in patients with Gilbert's syndrome or hemolysis because these patients have hyperbilirubinemia.40Poynard T. Munteanu M. Imbert-Bismut F. et al.Prospective analysis of discordant results between biochemical markers and biopsy in patients with chronic hepatitis C.Clin Chem. 2004; 10: 10Google Scholar Similarly, acute hepatitis can produce false-positive results in the aspartate-to-platelet ratio index (APRI), Forns index, FIB-4, or Fibrometer tests, which all measure levels of aminotransferases.Table 2Respective Advantages and Disadvantages of Currently Available Noninvasive Methods in Patients With Hepatitis B or CSerum biomarkersMeasurement of liver stiffnessTransient elastographyARFIMR elastographyAdvantages• Good reproducibility• High applicability (95%)• Low cost and wide availability(nonpatented)• Well validated• Liver stiffness is a genuinephysical property of liver tissue• Good reproducibility• Well validated• High performance for cirrhosis• User-friendly (rapid, resultsimmediately available; short learning curve)• Can be performed in the outpatient clinic• Prognostic value in cirrhosis• Liver stiffness is a genuinephysical property of liver tissue• Performance likely equivalent to that of TE• Region of interest smaller than TE but chosen bythe operator• Can be implemented on a regular ultrasound machine• High applicability: overcomes the limitationsof TE (ascites and obesity)• Liver stiffness is a genuinephysical property of liver tissue• Performance may be higher than TE for significant fibrosis• Examination of the whole liver• Can be implemented on a regular MRI machine• High applicability: overcomes the limitations of TE (ascites and obesity)Disadvantages• Nonspecific of the liver• Unable to discriminate between intermediate stages of fibrosis• Performance not as good as TE for cirrhosis• Results not immediately available• Cost and limited availability (proprietary)• Limitations (hemolysis, Gilbert syndrome, inflammation…) <5%• Requires a dedicated device• Region of interest cannot be chosen• Unable to discriminate between intermediate stages of fibrosis• Low applicability (80%, obesity, ascites, limited operator experience)• False positive in case of acute hepatitis, extra-hepatic cholestasis, and congestion• Ongoing validation• Unable to discriminate between intermediate stages of fibrosis• Narrow range of values• Quality criteria not well defined• Prognostic value in cirrhosis?• Further validation warranted• Not applicable in case of iron overload• Requires an MRI facility• Time-consuming• Costly Open table in a new tab Liver fibrosis can be staged using 1-dimensional ultrasound transient elastography (TE),41Sandrin L. Fourquet B. Hasquenoph J.M. et al.Transient elastography: a new noninvasive method for assessment of hepatic fibrosis.Ultrasound Med Biol. 2003; 29: 1705-1713Abstract Full Text Full Text PDF PubMed Scopus (790) Google Scholar which measures the velocity of a low-frequency (50 Hz) elastic shear wave propagating through the liver. This velocity is directly related to tissue stiffness, called the elastic modulus (expressed as E = 3ρv2, where v is the shear velocity, and ρ is the density of tissue, assumed to be constant). The stiffer the tissue, the faster the shear wave propagates. TE measures liver stiffness in a volume that approximates a cylinder that is 1-cm wide and 4-cm long, 25–65 mm below skin surface. The results are expressed in kilopascals (kPa) and range from 2.5 to 75 kPa; a normal value is around 5 kPa.42Roulot D. Czernichow S. Le Clesiau H. et al.Liver stiffness values in apparently healthy subjects: influence of gender and metabolic syndrome.J Hepatol. 2008; 48: 606-613Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 43Kim S.U. Choi G.H. Han W.K. et al.What are “true normal” liver stiffness values using FibroScan? A prospective study in healthy living liver and kidney donors in South Korea.Liver Int. 2010; 30: 268-274Crossref PubMed Scopus (21) Google Scholar, 44Colombo S. Belloli L. Zaccanelli M. et al.Normal liver stiffness and its determinants in healthy blood donors.Dig Liver Dis. 2011; 43: 231-236Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Advantages to TE include a short procedure time (<5 minutes), immediate results, and the ability to perform the test at the bedside or in an outpatient clinic: it is not a difficult procedure to learn (Table 2). However, accurate results45Lucidarme D. Foucher J. Le Bail B. et al.Factors of accuracy of transient elastography (Fibroscan) for the diagnosis of liver Fibrosis in chronic hepatitis C.Hepatology. 2009; : 1083-1089Crossref PubMed Scopus (87) Google Scholar, 46Myers R.P. Crotty P. Pomier-Layrargues G. et al.Prevalence, risk factors and causes of discordance in fibrosis staging by transient elastography and liver biopsy.Liver Int. 2010; 30: 1471-1480Crossref PubMed Scopus (21) Google Scholar require careful interpretation of data, based on at least 10 validated measurements, a success rate (the ratio of valid measurements to the total number of measurement) above 60%, and an interquartile range (IQR; reflects variations among measurements) of less than 30% of the median value (IQR/M, ≤30%).47Castera L. Forns X. Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography.J Hepatol. 2008; 48: 835-847Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar Although TE analysis has excellent inter- and intraobserver agreement,48Fraquelli M. Rigamonti C. Casazza G. et al.Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease.Gut. 2007; 56: 968-973Crossref PubMed Scopus (317) Google Scholar, 49Boursier J. Konate A. Gorea G. et al.Reproducibility of liver stiffness measurement by ultrasonographic elastometry.Clin Gastroenterol Hepatol. 2008; 6: 1263-1269Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar its applicability (80%) is not as good as that of serum biomarkers. Failure to obtain any measurement has been reported in 3% of cases, and unreliable results (not meeting manufacturer's recommendations) have been reported for 16%,50Castera L. Foucher J. Bernard P.H. et al.Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations.Hepatology. 2010; 51: 828-835PubMed Google Scholar mostly because of patient obesity or limited operator experience. A new probe (XL probe; Echosens, Paris, France) has been proposed to overcome these limitations for overweight and obese patients.51Myers R.P. Pomier-Layrargues G. Kirsch R. et al.Feasibility and diagnostic performance of the FibroScan XL probe for liver stiffness measurement in overweight and obese patients.Hepatology. 2012; 55: 199-208Crossref PubMed Scopus (43) Google Scholar Apart from obese patients, TE results can also be difficult to obtain from patients with narrow intercostal space and are impossible to obtain from patients with ascites.41Sandrin L. Fourquet B. Hasquenoph J.M. et al.Transient elastography: a new noninvasive method for assessment of hepatic fibrosis.Ultrasound Med Biol. 2003; 29: 1705-1713Abstract Full Text Full Text PDF PubMed Scopus (790) Google Scholar The liver is an organ wrapped in a distensible but nonelastic envelope (Glisson's capsula), so additional space-occupying tissue abnormalities, such as edema, inflammation, extrahepatic cholestasis, or congestion, can interfere with measurements of liver stiffness, independently of fibrosis.52Castera L. Pinzani M. Biopsy and non-invasive methods for the diagnosis of liver fibrosis: does it take two to tango?.Gut. 2010; 59: 861-866Crossref PubMed Scopus (56) Google Scholar The influence of steatosis is a matter of debate.53Arena U. Vizzutti F. Abraldes J.G. et al.Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C.Gut. 2008; 57: 1288-1293Crossref PubMed Scopus (96) Google Scholar, 54Fraquelli M. Rigamonti C. Casazza G. et al.Etiology-related determinants of liver stiffness values in chronic viral hepatitis B or C.J Hepatol. 2011; 54: 621-628Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Several other liver elasticity-based imaging techniques are being developed, including (2-D) acoustic radiation force impulse imaging (ARFI) and 3-D magnetic resonance (MR) elastography. ARFI involves mechanical excitation of tissue using short-duration (∼262 μsec) acoustic pulses that propagate shear waves and generate localized, μ-scale displacements in tissue.55Nightingale K. Soo M.S. Nightingale R. et al.Acoustic radiation force impulse imaging: in vivo demonstration of clinical feasibility.Ultrasound Med Biol. 2002; 28: 227-235Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar The shear-wave velocity (expressed in meters/sec) is measured in a smaller region than in TE (10-mm long and 6-mm wide) but can be chosen by the operator. The major advantage of ARFI is that it can be easily implemented on a modified commercial ultrasound machine (Acuson 2000 Virtual Touch Tissue Quantification; Siemens Healthcare, Erlangen, Germany). However, ARFI values, in contrast to TE values, have a narrow range (0.5–4.4 meters/sec). This limits definitions of cut-off values for patient management decisions. MR elastography uses a modified phase-contrast method to image the propagation characteristics of the shear wave in the liver.56Muthupillai R. Lomas D.J. Rossman P.J. et al.Magnetic resonance elastography by direct visualization of propagating acoustic strain waves.Science. 1995; 269: 1854-1857Crossref PubMed Google Scholar Elasticity is quantified by MR elastography (expressed in kilopascals) using a formula that determines the shear modulus, which is equivalent to one-third the Young's modulus used with TE.57Talwalkar J.A. Yin M. Fidler J.L. et al.Magnetic resonance imaging of hepatic fibrosis: emerging clinical applications.Hepatology. 2008; 47: 332-342Crossref PubMed Scopus (120) Google Scholar The theoretical advantages of MR elastography include its ability to analyze almost the entire liver and its applicability to patients with obesity or ascites. However, MR elastography cannot be performed in livers of patients with iron overload because of signal-to-noise limitations and it is too costly and time-consuming to use in routine practice. The diagnostic performances of serum biomarkers of fibrosis for significant fibrosis and cirrhosis are summarized in Table 3. Overall, biomarkers are less accurate in detecting intermediate stages of fibrosis than cirrhosis. The most widely used and validated are the APRI (a free nonpatented index) and the FibroTest (a patented test that is not widely available). A meta-analysis by the developer58Poynard T. Morra R. Halfon P. et al.Meta-analyses of Fibrotest diagnostic value in chronic liver disease.BMC Gastroenterol. 2007; 7: 40Crossref PubMed Scopus (123) Google Scholar that analyzed data from 6378 subjects (individual data from 3282 subjects) who received the FibroTest and biopsies (3501 with hepatitis C virus [HCV] infection and 1457 with hepatitis B virus [HBV]) found that the mean standardized AUROC for diagno