- Email: [email protected]
Staging of Liver Disease
S t a g i n g o f Li v e r D i s e a s e Which Option is Right for My Patient? Harjit Bhogal,
MD,
Richard K. Sterling,
MD, MSc*
KEYWORDS Hepatitis C Noninvasive staging Liver fibrosis KEY POINTS It is important to assess the stage of liver fibrosis in chronic hepatitis C to guide treatment decisions. Liver biopsy has limitations in staging fibrosis, including sampling error and intraobserver and interobserver variability. Several blood tests, algorithms, and imaging tests have been studied as noninvasive markers to stage fibrosis in hepatitis C. In patients without suspicion for cirrhosis, 2 noninvasive methods can be used to predict presence of absence of significant liver fibrosis; however, liver biopsy remains the gold standard. It is imperative not to miss the diagnosis of cirrhosis, because this has further implications for screening of hepatocellular carcinoma and varices.
INTRODUCTION
Chronic hepatitis C virus (HCV) affects more than 4 million Americans. HCV can progress to cirrhosis after decades of infection and result in complications related to portal hypertension, including hepatic encephalopathy, development of varices, and ascites. Cirrhosis also increases the risk of hepatocellular carcinoma (HCC). As a result, HCV is the leading indication for liver transplantation. Consequently, the accurate identification of advanced fibrosis in those with HCV is important in the management of infected patients. With recent advances in HCV therapy, identification of those with cirrhosis also affects duration of therapy. STAGING LIVER DISEASE IN HCV FOR TREATMENT CONSIDERATIONS: CURRENT RECOMMENDATIONS
Until the advent of the direct antiviral agents (DAA), boceprevir and telaprevir, the management of chronic viral hepatitis C included pegylated interferon (PEG-IFN) in Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA * Corresponding author. Section of Hepatology, VCU Medical Center, West Hospital, Room 1478, 1200 East Broad Street, Richmond, VA 23298-0341. E-mail address: [email protected] Infect Dis Clin N Am 26 (2012) 849–861 http://dx.doi.org/10.1016/j.idc.2012.08.002 0891-5520/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
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combination with ribavirin. In patients with genotype 2 and 3, a liver biopsy was not often necessary because sustained virologic response (SVR) is 70% to 80% with PEG-IFN and ribavirin compared with 40% to 50% in those with genotype 1. Given the suboptimal response in genotype 1, liver biopsy was often used to identify those with advanced fibrosis who might benefit from therapy and avoid treatment side effects in those with more mild disease.1 With the advent of triple therapy and higher SVR rates (60%–75%), the recommendations for liver biopsy have now become debatable in those with genotype 1. THE LIVER BIOPSY IN STAGING HCV: BENEFITS AND RISKS
Histologic assessment of a liver biopsy specimen is the gold standard diagnostic test to assess liver inflammation, fibrosis, and presence of steatosis, which can guide the physician in identifying whether the patient requires treatment more immediately, or whether treatment can be delayed, and perhaps leaving more room for further developments in therapies for HCV. The presence of advanced fibrosis, bridging fibrosis, or cirrhosis indicates that the patient is at an increased risk of hepatic decompensation and HCC, which require periodic surveillance with ultrasound scans and endoscopy for varices. However, the liver biopsy is an invasive procedure and the risks and benefits should be carefully evaluated. Liver biopsies can be performed either percutaneously via ultrasound guidance at the bedside or through a transjugular approach under fluoroscopy by an interventional radiologist. The transjugular approach also allows measurement of the hepatic vein pressure gradient. Histologic assessment identifies the degree of inflammation, steatosis, and importantly fibrosis. The risks of undergoing a liver biopsy include pain, bleeding, infection, and perforation.2–4 Patients with end-stage renal disease and hemophilia may be at higher risk of bleeding, and desmopressin or factors, respectively, are often administered to minimize this risk in these patient populations.5,6 In addition to the risks of the procedure, there are also limitations of the liver biopsy, including the size of the liver biopsy specimen, interobserver and intraobserver variability in histologic assessment, and sampling error. In a study of liver biopsy samples taken from both the right and left lobes of the liver, there was a difference in inflammation grade in one-quarter of the patients and a difference in fibrosis staging in one-third of patients, showing the significant variability in HCV-related disease, which can be seen within the same individual.7 Studies of interobserver variability among pathologists have shown good concordance in assessing early or advanced liver disease (ie, portal fibrosis vs cirrhosis). However, when they assessed several other histologic features, there was a wide range of concordance.8 Intraobserver variability is another limitation of liver biopsy. Various lengths of liver biopsy specimens have been assessed at 5 mm, 10 mm, 15 mm, and greater than 20 mm and as the size of the biopsy specimen is increased there is less intraobserver variability.9 It has been suggested that liver biopsy specimens for assessment of fibrosis in HCV should be 25 mm long and contain 8 to 10 portal tracts.10 Therefore, although liver biopsy remains the gold standard, sampling error and interobserver and intraobserver variability in histologic assessment are limitations to accurate grading and staging of liver inflammation and fibrosis. NONINVASIVE MARKERS OF STAGING LIVER DISEASE
Because of the limitations of liver biopsy and patient acceptance, there has been intense interest in developing accurate noninvasive markers to stage liver disease in
Accurate Assessment for Staging Liver Disease in HCV
HCV, including blood tests, transient elastography (TE), imaging studies, and breath tests. Blood Tests
Several routine and nonroutine blood tests have been evaluated in isolation or in combination to identify an optimal biomarker or model to stage liver disease in HCV. Some models use common tests that are readily available, whereas others include more specific tests of collagen production or degradation. The key blood tests and models are discussed in this review. Table 1 includes a summary of blood tests and models not discussed that have also been studied as biomarkers in staging liver disease in HCV. Aspartate Aminotransferase/Platelet Ratio Index
The aspartate aminotransferase/platelet ratio index (APRI) was developed and validated as a noninvasive tool to predict fibrosis in HCV.11 In the retrospective singlecenter study that developed the APRI, significant fibrosis was defined as an Ishak score of 3 or more, whereas many other studies define significant fibrosis as F 2 or more. In this study, platelet count (PLT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were independent predictors of fibrosis, and PLT, AST, ALP, AST/alanine aminotransferase (ALT) ratio and white blood cell count were independent predictors of cirrhosis.11 The investigators created models with these variables and concluded that a model with PLT and AST was a simple accurate method to predict advanced fibrosis or cirrhosis. The final model created was termed the APRI, defined as AST (/upper limit of normal [ULN])/PLT (109) *100. The area under the receiver operating characteristic curve (AUROC) was used to assess diagnostic accuracy. The AUROC for APRI to predict significant fibrosis was 0.8, and for prediction of cirrhosis, the AUROC was 0.89.11 Threshold values were identified to predict the absence or presence of significant fibrosis. If APRI was 0.5 or less, significant fibrosis is absent, and if APRI is greater than 1.5, significant fibrosis is present (Table 2). In this study, it was estimated that 51% of patients could be accurately predicted to have significant fibrosis or to have absence of significant fibrosis.11 To
Table 1 Additional blood tests and models that have been evaluated to stage liver disease in HCV Blood Tests
Models
Albumin/total protein47 PT47 Immunoglobulins48 Insulinlike growth factor 149 a2-Macroglobulin50 Amino-terminal propeptide of type II collagen26 Matrix metalloproteinase26 Tissue inhibitor of matrix metalloproteinase51 Hyaluronic acid52 High-sensitivity C-reactive protein52 Type IV collagen53 Caspase activity54 Plasma amino acids55 Proteomic markers50 Complement components50
FIBROSpect II56 Fibroindex57 Hepascore20 SHASTA58 Hospital Gregorio Maran˜o´n index59 Enhanced liver fibrosis test60
Abbreviation: PT, prothrombin time.
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Table 2 Threshold values for assessment of fibrosis biomarkers in the setting of HCV
a
Test
No Significant Fibrosis (F<2)
Significant Fibrosis (‡F2)
APRIa
0.5
1.5
FibroTest
0.1
0.6
Forn index
<4.2
>6.9
FIB-4
1.45
3.25
FibroScan
5 kPa
7.6 kPa
APRI study defined significant fibrosis as F3.
identify cirrhosis with the APRI, threshold values were identified with APRI of 1.00 or less, indicating absence of cirrhosis and APRI greater than 2 detects cirrhosis. With these threshold values, 81% of patients can be correctly classified as cirrhotic or noncirrhotic.11 This model was validated in a validation cohort and by other investigators.12–14 In a recent meta-analysis of studies assessing the usefulness of APRI in HCV, it was concluded that the APRI was best used to rule out significant fibrosis.14 Forns Index
The Forns index was created in a prospective study of patients with hepatitis C undergoing liver biopsy, and a model including demographic variables and laboratory tests was identified to predict presence or absence of fibrosis (stage 2 based on the Scheuer classification).15 The Forns model includes 4 independent predictors of fibrosis, including age, g-glutamyltransferase (GGT), PLT, and cholesterol level. The Forns index formula is 7.811–3.131.ln(PLT) 1 0.781.ln(GGT) 1 3.467.ln(age)–0.014.(cholesterol). An AUROC for the Forns index for fibrosis was 0.86 in the test cohort and 0.81 in a validation cohort. Using this model, a cutoff of less than 4.21 was established to predict absence of fibrosis and more than 6.9 significant fibrosis (see Table 2). In patients with a score less than 4.21, only 4% had significant fibrosis on the liver biopsy, representing a 96% negative predictive value (NPV). With the application of the Forns index, in patients with a value greater than 6.9, 44% of patients with significant fibrosis in the liver biopsy group were correctly identified; however, this number decreased in the validation cohort. Similar to APRI, the Forns index is more appropriate to use to exclude fibrosis rather than to identify fibrosis. FIB-4
FIB-4 is a noninvasive marker of fibrosis that was initially developed as a marker of fibrosis in patients with human immunodeficiency virus (HIV)/HCV coinfection.16 In this retrospective analysis of liver histology and routine blood test results, multivariate logistic regression revealed that age, platelet, and AST were associated with significant fibrosis (Ishak 4–6). These variables were fashioned into a model, termed FIB-4 (age(year) AST (U/L)/(PLT (109) x ALT (U/L). Based on this model, one can estimate the degree of liver fibrosis. Using the FIB-4 model, a value of less than 1.45 has an NPV of 90% to exclude advanced fibrosis (Ishak 4–6). For a value greater than 3.25, the FIB-4 had a positive predictive value (PPV) of advanced fibrosis of 65%. Therefore, in most patients with values less than 1.45 or greater than 3.25, a liver biopsy may be avoided16 (see Table 2). Although the FIB-4 was developed in an HIV/HCVcoinfected population, a subsequent study by Vallet-Pichard and colleagues17 showed that FIB-4 can be applied to HCV-monoinfected patients as well.
Accurate Assessment for Staging Liver Disease in HCV
FibroTest
Unlike the models that use routine tests, the FibroTest is a noninvasive model that includes several nonroutine tests, including a2-macroglobulin, apolipoprotein A1, g-glutamyltranspeptidase, haptoglobin, g-globulin in addition to total bilirubin. In development of this model, liver biopsies were assessed based on the METAVIR system for substantial fibrosis, F2 or greater, and biopsy specimens were given an activity score (A0–A1 not much activity and A2 or A3 substantial activity), and together with the fibrosis stage, 3 categories were created: (1) without important histologic features (A<2 and F<2), (2) important lesions (A2 and F2 or both), and (3) widespread fibrosis or cirrhosis (F3 or F4).18 The AUROC for this model, the FibroTest, was 0.836, and this was replicated in a second group with similar ROC at 0.870. For a score of 0 to 0.1, the NPV was 100% to exclude the presence of significant fibrosis and at scores of 0.60 to 1.00 had a high PPV of more than 90% in identifying the presence of significant fibrosis.18 COMPARISONS BETWEEN NONINVASIVE MARKERS OF STAGING FOR HCV
Several studies have compared the performance of noninvasive markers to stage liver disease. In 1 study that compared 9 noninvasive markers, including PLT count, AST/ALT, cirrhosis discriminate score, FIB-4, APRI, age-platelet index (API), Go¨teborg University cirrhosis index (GUCI), FibroTest, and ActiTest with liver biopsy, FibroTest, FIB-4, APRI, and API all had NPV of greater than 80% to exclude significant fibrosis (compare F0–F2 vs F3–F4)19 and are better used to exclude significant fibrosis. Vallet-Pichard and colleagues17 compared FIB-4 and FibroTest in patients with HCV and there was concordance between tests for FIB-4 values less than 1.45 and greater than 3.25. This study showed that FIB-4 can be used in an HCV-monoinfected cohort.17 In another study, 9 blood tests (FibroTest, FibroMeter, Forns index, APRI, MP3, the European Liver Fibrosis Group score, Hepascore, FIB-4, and hyaluronate) and TE with FibroScan for liver fibrosis were compared with liver biopsy. FibroScan, FibroMeter, FibroTest, and Hepascore were the optimal tests to detect significant fibrosis and cirrhosis.20 In an analysis of 5 study populations, the performance of several markers of fibrosis were assessed including FibroMeter, FibroTest, Hepascore, and APRI. These tests were designed to detect significant fibrosis of F2 or greater.21 In this study, investigators applied new target end points, including significant fibrosis (F21F31F4), severe fibrosis (F31F4), and cirrhosis (F4). In detection of severe fibrosis, FibroMeter had the highest AUROC, and for cirrhosis, FibroMeter and Hepascore had the highest AUROCs. The AUROCs and accuracies for all tests were higher for cirrhosis than severe fibrosis. This study highlights that the results of blood test or noninvasive marker are dependent on the population studied, the cutoff used, and the diagnostic end point chosen.21 Therefore, although the absence of fibrosis can be detected with a reasonable degree of accuracy, in patients with test results in the gray zone, further evaluation is required. FUTURE DEVELOPMENT OF BIOMARKERS FOR FIBROSIS IN HCV
Although the use of biomarkers based on laboratory tests to classify patients with significant fibrosis may reduce the need for liver biopsy, 1 criticism is that these markers are often indeterminate and may not detect those patients with mild to moderate fibrosis or predict those with more rapidly progressive disease.22 Furthermore, most
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noninvasive models have similar AUROC values; however, these are compared with the liver biopsy, which, although we consider it a gold standard test to stage liver disease, also has its limitations23 In addition, because many patients fall in between the upper and lower cutoff values, giving indeterminate results, liver biopsy is still needed in many patients. Because most of the discussed biomarkers are based on retrospective data to identify biomarkers, including liver function tests as markers of fibrosis, a more accurate assessment of fibrosis based on intermediates or end products of proteins and enzymes involved in the fibrosis pathways may be more accurate. Liver fibrosis involves stellate cell activation and extracellular matrix turnover; therefore, there is interest in development of biomarkers of fibrosis specifically identifying key cytokines and proteins involved in this process. Several biomarkers involved in the fibrosis pathway have already been investigated and include hyaluronic acid, type III procollagen, matrix metalloproteinases, and tissue inhibitors of metalloproteinase.24–26 Future noninvasive fibrosis tests will likely be based on biomarkers that are functionally related to the pathophysiology of fibrosis development in HCV.22 These noninvasive markers of fibrosis have also been used to predict histologic progression and clinical outcomes such as hepatic decompensation in patients with HCV cirrhosis.27 IMAGING STUDIES
Imaging modalities including magnetic resonance imaging (MRI) and ultrasonography have been studied as noninvasive methods in staging liver disease in the setting of chronic HCV. ULTRASOUND-BASED MODALITIES FibroScan
The FibroScan is a portable device that can capture the elasticity of the liver as a marker of fibrosis. The probe has an ultrasound transducer and a vibrator, which is placed in the intercostal space over the right lobe of the liver. A vibration is sent to the tissue to produce a wave that traverses the liver. The ultrasound follows this wave and measures its velocity, which is a measure of tissue stiffness.28 TE has been studied to determine the degree of fibrosis in liver disease.29 FibroScan (Echosens, Paris, France) has been studied and compared with liver biopsy results in patients with HCV. The FibroScan probe measures elasticity of the liver, and these results were compared with the activity, steatosis, and fibrosis as assessed on the liver biopsy. There was a high correlation between TE measurements and fibrosis, with a partial correlation coefficient of 0.71 (P<.001). In patients with elasticity of 5 kPa or less, 93% had fibrosis stage F0 or F1 and in those with an elasticity of 7.6 kPa or greater, 94% had fibrosis of F2 or greater (see Table 2).29 The FibroScan has limitations in patients with ascites, obesity, or those with narrow intercostal spaces.29 A prospective study in cirrhotic patients, which assessed factors that negatively affected the performance of FibroScan, found that increased patient age and obesity resulted in lower success rates.28 Operators who have performed at least 50 previous FibroScan examinations had a higher success rate in capturing shots. It has been suggested that a median of 5 successful measurements with the FibroScan is sufficient to assess for stage of fibrosis in an individual patient.28 In addition to FibroScan, acoustic radiation force impulse (ARFI) and supersonic shear imaging (SSI) are ultrasound-based modalities that have been investigated in HCV staging. ARFI uses an ultrasound beam that locally deforms the parenchyma
Accurate Assessment for Staging Liver Disease in HCV
and triggers a shear wave to give a measure of liver stiffness.30 In a comparison of FibroScan and ARFI with liver biopsy in patients with chronic hepatitis C, the performance of ARFI was superior to FibroScan for diagnosing significant fibrosis (F2) and severe fibrosis (F3–F4); however, for cirrhosis, the test performance was equivalent between the 2 modalities.30 SSI is also an ultrasound-based modality and compared with FibroScan, the SSI technology was more accurate for F2 and greater and F3 and greater; however, they were similar for detecting F 5 4 fibrosis.31 SSI measures a larger area than FibroScan and therefore may be better able to detect fibrosis.31 MRI
MRI has been studied in HCV staging with different MRI protocols, including unenhanced MRI, magnetic resonance elastography (MRE), MRI with diffusion-weighted imaging (DWI) and MR spectroscopy. In a study of unenhanced MRI comparing liver biopsy in patients with HCV, although there was a high correlation on MR and certain features of fibrosis and hepatic activity index, the combination of MR features together with laboratory data was superior in detecting inflammation and fibrosis.32 This study excluded patients with clinical features of portal hypertension, and therefore cannot be applied to patients with cirrhosis.32 MRI with DWI has been studied and compared with MRE and it has been shown that MRE is superior in predicting fibrosis stage compared with MRI with DWI.33 MRE has also been compared with ultrasound elastography using FibroScan and APRI for staging liver disease in patients with chronic liver disease.34 The AUROC for each stage of fibrosis (F>2, F>3, F 5 4) was greater for MRE compared with FibroScan, APRI, and FibroScan and APRI together, when comparing accuracy of diagnostic tool with liver biopsy specimens. This study was not performed exclusively in patients with HCV. The benefits of MRE over FibroScan include that this modality can be performed in obese patients and those with ascites.34 However, MRE is more expensive than FibroScan, which may limit its use. Breath Tests
Breath tests assess how the liver metabolizes an ingested substance and have been studied as a marker of liver fibrosis in the setting of HCV. The methacetin breath test is based on the fact that 13C-methacetin is metabolized in the liver by cytochrome p450 1A2 into acetaminophen and 13CO2 and can therefore be studied as a test of liver function. The methacetin breath test was studied in patients with HCV and control patients.35 The breath test was able to classify patients as cirrhotic versus noncirrhotic; however, it was unable to differentiate between the various stages of fibrosis.35 However, by using an algorithm to include breath test parameters, age, and other patient data for both inflammation and fibrosis, in patients with HCV and normal ALT (defined as 2 ULN), these algorithms were able to differentiate between high and low inflammation and to differentiate between significant and nonsignificant fibrosis in this setting.36 An additional breath test that has been studied in HCV is the 13C-aminopyrine breath test. This breath test was able to distinguish control patients from those with chronic hepatitis from patients with Child A cirrhosis early in the breath test.37 However, at longer time points, there was no difference between patients with hepatitis and cirrhosis. In addition, this breath test was not able to distinguish between high fibrosis scores and cirrhosis.37 Although breath tests may be able to identify those with cirrhosis at risk for decompensation, they have limited usefulness for accurate assessment of varying degrees of fibrosis.38
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ALGORITHMS
Several algorithms have been proposed to combine blood tests, models, or FibroScan to improve the accuracy of detecting liver fibrosis and cirrhosis.39–41 The SAFE Biopsy
The SAFE (sequential algorithm for fibrosis evaluation) biopsy algorithm has been validated as an algorithm for assessment of fibrosis in HCV.39 In an international multicenter retrospective study, patients with chronic hepatitis C who underwent liver biopsies also had blood tests for the APRI and FibroTest drawn on the same day. In the SAFE biopsy algorithm, patients have the APRI as an initial screening test, followed by the FibroTest to assess for significant fibrosis of F2 or greater and cirrhosis F4. Application of this algorithm correctly identified most patients, and only 2.6% were misclassified.39 Fibropaca Algorithm
The Fibropaca algorithm detects significant fibrosis and cirrhosis based on the use of FibroTest with the APRI and Forns index.42 With the use of all 3 tests to detect significant fibrosis (F2–F4) and cirrhosis F4, 81.3% of patients were correctly identified comparing their noninvasive markers to liver biopsy.42 This algorithm suggests performing the FibroTest, the APRI, and Forns index to assess for concordance; if there is no concordance, proceed with a liver biopsy. With this method, 81.3% of patients are correctly identified solely with the combination of noninvasive markers.42 Leroy Algorithm
The Leroy algorithm uses APRI and FibroTest simultaneously. This algorithm is useful to detect significant fibrosis (F2–F4) or extensive fibrosis or cirrhosis (F3–F4) using threshold values of FibroTest greater than 0.59 and APRI greater than 2, with a PPV of 96.7% and 92.2%, respectively. The algorithm excluded significant fibrosis (F2–F4) using threshold values of FibroTest less than 0.22 and APRI less than 0.5, with an NPV of 94.1%.43 This algorithm is useful to discriminate between early and advanced fibrosis. However, there is inadequate information about staging with this algorithm among patients with test values that do not fall within these cutoffs.43 In comparing the SAFE biopsy, Fibropaca, and Leroy algorithms, the most accurate algorithm was the Leroy algorithm.40 However, more biopsies were avoided with Fibropaca, followed by the SAFE biopsy algorithm. The SAFE biopsy and Fibropaca algorithms would be useful in the clinical setting.40 IMPLICATIONS OF STAGING VIRAL HEPATITIS C Treatment Duration
In those with cirrhosis, 48 weeks of treatment with PEG-IFN, ribavirin, and a DAA (boceprevir or telaprevir) is recommended, regardless of virologic response.44 In contrast, patients without cirrhosis and treatment-naive patients can be treated with response-guided therapy. Therefore, an accurate diagnosis of cirrhosis is imperative in determining treatment duration and counseling about treatment success rates. Implications of Management
It is imperative not to miss the diagnosis of cirrhosis, because this has important implications. Patients with cirrhosis are at an increased risk of developing HCC and surveillance liver ultrasonography is recommended every 6 months. Patients with cirrhosis are also at risk of developing varices, and these thin-walled veins are at risk of rupture.
Accurate Assessment for Staging Liver Disease in HCV
An esophagogastroduodenoscopy (EGD) is recommended once a patient is diagnosed with cirrhosis. If the patient develops decompensated cirrhosis, the EGD should be repeated annually.45 Therefore, it is important to accurately diagnose cirrhosis, because it changes the patient’s management and surveillance strategies. SUMMARY
Accurate assessment of liver fibrosis is essential in the management of those with HCV. It allows identification of those with advanced fibrosis who require periodic surveillance for HCC and esophageal varices. It also identifies those who are not
Chronic HCV
If patient has obvious features of cirrhosis, including HE, Ascites, Varices:
Screening: HCC:US every 6 months Esophageal Varices : EGD
Non-invasive model (APRI, FibroTest, Forn's index, FIB-4), Fibroscan
Confirm with a second non-invasive marker of fibrosis
< F2
Treatment is optional
Intedeterminate results
Liver biopsy
Fig. 1. Algorithm for evaluation of fibrosis in HCV.
F >= 2
Antiviral therapy, if no contraindications present
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candidates for response-guided therapy with DAA. To determine the best option for your patient with chronic HCV requires an understanding of the accuracy and limitations of the models and tests described earlier. We recommend the algorithm depicted in Fig. 1.46 In those with obvious signs of advanced fibrosis (ascites, hepatic encephalopathy, coagulopathy, or significant thrombocytopenia), a biopsy is usually not required. These patients can proceed directly to periodic surveillance for HCC and varices. In those without obvious clinical signs of cirrhosis, we recommend a noninvasive model used alone or in conjunction with a second model for confirmation (ie, APRI, FIB-4, or FibroTest plus FibroScan if available). In those with mild disease (
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Accurate Assessment for Staging Liver Disease in HCV
12. Snyder N, Gajula L, Xiao SY, et al. APRI: an easy and validated predictor of hepatic fibrosis in chronic hepatitis C. J Clin Gastroenterol 2006;40:535–42. 13. Al-Mohri H, Cooper C, Murphy T, et al. Validation of a simple model for predicting liver fibrosis in HIV/hepatitis C virus-coinfected patients. HIV Med 2005;6: 375–8. 14. Shaheen AA, Myers RP. Diagnostic accuracy of the aspartate aminotransferaseto-platelet ratio index for the prediction of hepatitis C-related fibrosis: a systematic review. Hepatology 2007;46:912–21. 15. Forns X, Ampurdanes S, Llovet JM, et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology 2002;36:986–92. 16. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43:1317–25. 17. Vallet-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;46:32–6. 18. Imbert-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: 1069–75. 19. Usluer G, Erben N, Aykin N, et al. Comparison of non-invasive fibrosis markers and classical liver biopsy in chronic hepatitis C. Eur J Clin Microbiol Infect Dis 2012;31(8):1873–8. 20. Zarski JP, Sturm N, Guechot J, et al. Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: the ANRS HCEP-23 study. J Hepatol 2012;56:55–62. 21. Boursier J, Bacq Y, Halfon P, et al. Improved diagnostic accuracy of blood tests for severe fibrosis and cirrhosis in chronic hepatitis C. Eur J Gastroenterol Hepatol 2009;21:28–38. 22. Martinez SM, Crespo G, Navasa M, et al. Noninvasive assessment of liver fibrosis. Hepatology 2011;53:325–35. 23. Mehta SH, Lau B, Afdhal NH, et al. Exceeding the limits of liver histology markers. J Hepatol 2009;50:36–41. 24. Rosenberg WM, Voelker M, Thiel R, et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology 2004;127:1704–13. 25. Fontana RJ, Goodman ZD, Dienstag JL, et al. Relationship of serum fibrosis markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C. Hepatology 2008;47:789–98. 26. Leroy V, Monier F, Bottari S, et al. Circulating matrix metalloproteinases 1, 2, 9 and their inhibitors TIMP-1 and TIMP-2 as serum markers of liver fibrosis in patients with chronic hepatitis C: comparison with PIIINP and hyaluronic acid. Am J Gastroenterol 2004;99:271–9. 27. Fontana RJ, Dienstag JL, Bonkovsky HL, et al. Serum fibrosis markers are associated with liver disease progression in non-responder patients with chronic hepatitis C. Gut 2010;59:1401–9. 28. Kettaneh A, Marcellin P, Douvin C, et al. Features associated with success rate and performance of FibroScan measurements for the diagnosis of cirrhosis in HCV patients: a prospective study of 935 patients. J Hepatol 2007;46:628–34. 29. Sandrin L, Fourquet B, Hasquenoph JM, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003;29:1705–13.
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30. Rizzo L, Calvaruso V, Cacopardo B, et al. Comparison of transient elastography and acoustic radiation force impulse for non-invasive staging of liver fibrosis in patients with chronic hepatitis C. Am J Gastroenterol 2011;106:2112–20. 31. Bavu E, Gennisson JL, Couade M, et al. Noninvasive in vivo liver fibrosis evaluation using supersonic shear imaging: a clinical study on 113 hepatitis C virus patients. Ultrasound Med Biol 2011;37:1361–73. 32. Mitchell DG, Navarro VJ, Herrine SK, et al. Compensated hepatitis C: unenhanced MR imaging correlated with pathologic grading and staging. Abdom Imaging 2008;33:58–64. 33. Wang Y, Ganger DR, Levitsky J, et al. Assessment of chronic hepatitis and fibrosis: comparison of MR elastography and diffusion-weighted imaging. AJR Am J Roentgenol 2011;196:553–61. 34. Huwart L, Sempoux C, Vicaut E, et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology 2008;135:32–40. 35. Braden B, Faust D, Sarrazin U, et al. 13C-methacetin breath test as liver function test in patients with chronic hepatitis C virus infection. Aliment Pharmacol Ther 2005;21:179–85. 36. Lalazar G, Pappo O, Hershcovici T, et al. A continuous 13C methacetin breath test for noninvasive assessment of intrahepatic inflammation and fibrosis in patients with chronic HCV infection and normal ALT. J Viral Hepat 2008;15:716–28. 37. Giannini E, Fasoli A, Chiarbonello B, et al. 13C-aminopyrine breath test to evaluate severity of disease in patients with chronic hepatitis C virus infection. Aliment Pharmacol Ther 2002;16:717–25. 38. Everson GT, Shiffman ML, Hoefs JC, et al. Quantitative liver function tests improve the prediction of clinical outcomes in chronic hepatitis C: results from the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial. Hepatology 2012;55: 1019–29. 39. Sebastiani G, Halfon P, Castera L, et al. SAFE biopsy: a validated method for large-scale staging of liver fibrosis in chronic hepatitis C. Hepatology 2009;49: 1821–7. 40. Sebastiani G, Halfon P, Castera L, et al. Comparison of three algorithms of noninvasive markers of fibrosis in chronic hepatitis C. Aliment Pharmacol Ther 2012; 35:92–104. 41. Castera L, Sebastiani G, Le Bail B, et al. Prospective comparison of two algorithms combining non-invasive methods for staging liver fibrosis in chronic hepatitis C. J Hepatol 2010;52:191–8. 42. Bourliere M, Penaranda G, Renou C, et al. Validation and comparison of indexes for fibrosis and cirrhosis prediction in chronic hepatitis C patients: proposal for a pragmatic approach classification without liver biopsies. J Viral Hepat 2006; 13:659–70. 43. Leroy V, Hilleret MN, Sturm N, et al. Prospective comparison of six non-invasive scores for the diagnosis of liver fibrosis in chronic hepatitis C. J Hepatol 2007; 46:775–82. 44. Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011;54:1433–44. 45. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46:922–38. 46. Smith JO, Sterling RK. Systematic review: non-invasive methods of fibrosis analysis in chronic hepatitis C. Aliment Pharmacol Ther 2009;30:557–76.
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47. Benlloch S, Heredia L, Barquero C, et al. Prospective validation of a noninvasive index for predicting liver fibrosis in hepatitis C virus-infected liver transplant recipients. Liver Transpl 2009;15:1798–807. 48. Watt K, Uhanova J, Gong Y, et al. Serum immunoglobulins predict the extent of hepatic fibrosis in patients with chronic hepatitis C virus infection. J Viral Hepat 2004;11:251–6. 49. Lorenzo-Zuniga V, Bartoli R, Masnou H, et al. Serum concentrations of insulin-like growth factor-I (igf-I) as a marker of liver fibrosis in patients with chronic hepatitis C. Dig Dis Sci 2007;52:3245–50. 50. Gangadharan B, Antrobus R, Dwek RA, et al. Novel serum biomarker candidates for liver fibrosis in hepatitis C patients. Clin Chem 2007;53:1792–9. 51. Larrousse M, Laguno M, Segarra M, et al. Noninvasive diagnosis of hepatic fibrosis in HIV/HCV-coinfected patients. J Acquir Immune Defic Syndr 2007;46: 304–11. 52. Yilmaz S, Bayan K, Tuzun Y, et al. Replacement of histological findings: serum hyaluronic acid for fibrosis, high-sensitive C-reactive protein for necroinflammation in chronic viral hepatitis. Int J Clin Pract 2007;61:438–43. 53. Murawaki Y, Koda M, Okamoto K, et al. Diagnostic value of serum type IV collagen test in comparison with platelet count for predicting the fibrotic stage in patients with chronic hepatitis C. J Gastroenterol Hepatol 2001;16:777–81. 54. Bantel H, Lugering A, Poremba C, et al. Caspase activation correlates with the degree of inflammatory liver injury in chronic hepatitis C virus infection. Hepatology 2001;34:758–67. 55. Zhang Q, Takahashi M, Noguchi Y, et al. Plasma amino acid profiles applied for diagnosis of advanced liver fibrosis in patients with chronic hepatitis C infection. Hepatol Res 2006;34:170–7. 56. Zaman A, Rosen HR, Ingram K, et al. Assessment of FIBROSpect II to detect hepatic fibrosis in chronic hepatitis C patients. Am J Med 2007;120(280):e9–14. 57. Koda M, Matunaga Y, Kawakami M, et al. FibroIndex, a practical index for predicting significant fibrosis in patients with chronic hepatitis C. Hepatology 2007;45:297–306. 58. Kelleher TB, Mehta SH, Bhaskar R, et al. Prediction of hepatic fibrosis in HIV/HCV co-infected patients using serum fibrosis markers: the SHASTA index. J Hepatol 2005;43:78–84. 59. Berenguer J, Bellon JM, Miralles P, et al. Identification of liver fibrosis in HIV/HCVcoinfected patients using a simple predictive model based on routine laboratory data. J Viral Hepat 2007;14:859–69. 60. Parkes J, Guha IN, Roderick P, et al. Enhanced Liver Fibrosis (ELF) test accurately identifies liver fibrosis in patients with chronic hepatitis C. J Viral Hepat 2011;18:23–31.
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MD,
Richard K. Sterling,
MD, MSc*
KEYWORDS Hepatitis C Noninvasive staging Liver fibrosis KEY POINTS It is important to assess the stage of liver fibrosis in chronic hepatitis C to guide treatment decisions. Liver biopsy has limitations in staging fibrosis, including sampling error and intraobserver and interobserver variability. Several blood tests, algorithms, and imaging tests have been studied as noninvasive markers to stage fibrosis in hepatitis C. In patients without suspicion for cirrhosis, 2 noninvasive methods can be used to predict presence of absence of significant liver fibrosis; however, liver biopsy remains the gold standard. It is imperative not to miss the diagnosis of cirrhosis, because this has further implications for screening of hepatocellular carcinoma and varices.
INTRODUCTION
Chronic hepatitis C virus (HCV) affects more than 4 million Americans. HCV can progress to cirrhosis after decades of infection and result in complications related to portal hypertension, including hepatic encephalopathy, development of varices, and ascites. Cirrhosis also increases the risk of hepatocellular carcinoma (HCC). As a result, HCV is the leading indication for liver transplantation. Consequently, the accurate identification of advanced fibrosis in those with HCV is important in the management of infected patients. With recent advances in HCV therapy, identification of those with cirrhosis also affects duration of therapy. STAGING LIVER DISEASE IN HCV FOR TREATMENT CONSIDERATIONS: CURRENT RECOMMENDATIONS
Until the advent of the direct antiviral agents (DAA), boceprevir and telaprevir, the management of chronic viral hepatitis C included pegylated interferon (PEG-IFN) in Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA * Corresponding author. Section of Hepatology, VCU Medical Center, West Hospital, Room 1478, 1200 East Broad Street, Richmond, VA 23298-0341. E-mail address: [email protected] Infect Dis Clin N Am 26 (2012) 849–861 http://dx.doi.org/10.1016/j.idc.2012.08.002 0891-5520/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
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combination with ribavirin. In patients with genotype 2 and 3, a liver biopsy was not often necessary because sustained virologic response (SVR) is 70% to 80% with PEG-IFN and ribavirin compared with 40% to 50% in those with genotype 1. Given the suboptimal response in genotype 1, liver biopsy was often used to identify those with advanced fibrosis who might benefit from therapy and avoid treatment side effects in those with more mild disease.1 With the advent of triple therapy and higher SVR rates (60%–75%), the recommendations for liver biopsy have now become debatable in those with genotype 1. THE LIVER BIOPSY IN STAGING HCV: BENEFITS AND RISKS
Histologic assessment of a liver biopsy specimen is the gold standard diagnostic test to assess liver inflammation, fibrosis, and presence of steatosis, which can guide the physician in identifying whether the patient requires treatment more immediately, or whether treatment can be delayed, and perhaps leaving more room for further developments in therapies for HCV. The presence of advanced fibrosis, bridging fibrosis, or cirrhosis indicates that the patient is at an increased risk of hepatic decompensation and HCC, which require periodic surveillance with ultrasound scans and endoscopy for varices. However, the liver biopsy is an invasive procedure and the risks and benefits should be carefully evaluated. Liver biopsies can be performed either percutaneously via ultrasound guidance at the bedside or through a transjugular approach under fluoroscopy by an interventional radiologist. The transjugular approach also allows measurement of the hepatic vein pressure gradient. Histologic assessment identifies the degree of inflammation, steatosis, and importantly fibrosis. The risks of undergoing a liver biopsy include pain, bleeding, infection, and perforation.2–4 Patients with end-stage renal disease and hemophilia may be at higher risk of bleeding, and desmopressin or factors, respectively, are often administered to minimize this risk in these patient populations.5,6 In addition to the risks of the procedure, there are also limitations of the liver biopsy, including the size of the liver biopsy specimen, interobserver and intraobserver variability in histologic assessment, and sampling error. In a study of liver biopsy samples taken from both the right and left lobes of the liver, there was a difference in inflammation grade in one-quarter of the patients and a difference in fibrosis staging in one-third of patients, showing the significant variability in HCV-related disease, which can be seen within the same individual.7 Studies of interobserver variability among pathologists have shown good concordance in assessing early or advanced liver disease (ie, portal fibrosis vs cirrhosis). However, when they assessed several other histologic features, there was a wide range of concordance.8 Intraobserver variability is another limitation of liver biopsy. Various lengths of liver biopsy specimens have been assessed at 5 mm, 10 mm, 15 mm, and greater than 20 mm and as the size of the biopsy specimen is increased there is less intraobserver variability.9 It has been suggested that liver biopsy specimens for assessment of fibrosis in HCV should be 25 mm long and contain 8 to 10 portal tracts.10 Therefore, although liver biopsy remains the gold standard, sampling error and interobserver and intraobserver variability in histologic assessment are limitations to accurate grading and staging of liver inflammation and fibrosis. NONINVASIVE MARKERS OF STAGING LIVER DISEASE
Because of the limitations of liver biopsy and patient acceptance, there has been intense interest in developing accurate noninvasive markers to stage liver disease in
Accurate Assessment for Staging Liver Disease in HCV
HCV, including blood tests, transient elastography (TE), imaging studies, and breath tests. Blood Tests
Several routine and nonroutine blood tests have been evaluated in isolation or in combination to identify an optimal biomarker or model to stage liver disease in HCV. Some models use common tests that are readily available, whereas others include more specific tests of collagen production or degradation. The key blood tests and models are discussed in this review. Table 1 includes a summary of blood tests and models not discussed that have also been studied as biomarkers in staging liver disease in HCV. Aspartate Aminotransferase/Platelet Ratio Index
The aspartate aminotransferase/platelet ratio index (APRI) was developed and validated as a noninvasive tool to predict fibrosis in HCV.11 In the retrospective singlecenter study that developed the APRI, significant fibrosis was defined as an Ishak score of 3 or more, whereas many other studies define significant fibrosis as F 2 or more. In this study, platelet count (PLT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were independent predictors of fibrosis, and PLT, AST, ALP, AST/alanine aminotransferase (ALT) ratio and white blood cell count were independent predictors of cirrhosis.11 The investigators created models with these variables and concluded that a model with PLT and AST was a simple accurate method to predict advanced fibrosis or cirrhosis. The final model created was termed the APRI, defined as AST (/upper limit of normal [ULN])/PLT (109) *100. The area under the receiver operating characteristic curve (AUROC) was used to assess diagnostic accuracy. The AUROC for APRI to predict significant fibrosis was 0.8, and for prediction of cirrhosis, the AUROC was 0.89.11 Threshold values were identified to predict the absence or presence of significant fibrosis. If APRI was 0.5 or less, significant fibrosis is absent, and if APRI is greater than 1.5, significant fibrosis is present (Table 2). In this study, it was estimated that 51% of patients could be accurately predicted to have significant fibrosis or to have absence of significant fibrosis.11 To
Table 1 Additional blood tests and models that have been evaluated to stage liver disease in HCV Blood Tests
Models
Albumin/total protein47 PT47 Immunoglobulins48 Insulinlike growth factor 149 a2-Macroglobulin50 Amino-terminal propeptide of type II collagen26 Matrix metalloproteinase26 Tissue inhibitor of matrix metalloproteinase51 Hyaluronic acid52 High-sensitivity C-reactive protein52 Type IV collagen53 Caspase activity54 Plasma amino acids55 Proteomic markers50 Complement components50
FIBROSpect II56 Fibroindex57 Hepascore20 SHASTA58 Hospital Gregorio Maran˜o´n index59 Enhanced liver fibrosis test60
Abbreviation: PT, prothrombin time.
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Table 2 Threshold values for assessment of fibrosis biomarkers in the setting of HCV
a
Test
No Significant Fibrosis (F<2)
Significant Fibrosis (‡F2)
APRIa
0.5
1.5
FibroTest
0.1
0.6
Forn index
<4.2
>6.9
FIB-4
1.45
3.25
FibroScan
5 kPa
7.6 kPa
APRI study defined significant fibrosis as F3.
identify cirrhosis with the APRI, threshold values were identified with APRI of 1.00 or less, indicating absence of cirrhosis and APRI greater than 2 detects cirrhosis. With these threshold values, 81% of patients can be correctly classified as cirrhotic or noncirrhotic.11 This model was validated in a validation cohort and by other investigators.12–14 In a recent meta-analysis of studies assessing the usefulness of APRI in HCV, it was concluded that the APRI was best used to rule out significant fibrosis.14 Forns Index
The Forns index was created in a prospective study of patients with hepatitis C undergoing liver biopsy, and a model including demographic variables and laboratory tests was identified to predict presence or absence of fibrosis (stage 2 based on the Scheuer classification).15 The Forns model includes 4 independent predictors of fibrosis, including age, g-glutamyltransferase (GGT), PLT, and cholesterol level. The Forns index formula is 7.811–3.131.ln(PLT) 1 0.781.ln(GGT) 1 3.467.ln(age)–0.014.(cholesterol). An AUROC for the Forns index for fibrosis was 0.86 in the test cohort and 0.81 in a validation cohort. Using this model, a cutoff of less than 4.21 was established to predict absence of fibrosis and more than 6.9 significant fibrosis (see Table 2). In patients with a score less than 4.21, only 4% had significant fibrosis on the liver biopsy, representing a 96% negative predictive value (NPV). With the application of the Forns index, in patients with a value greater than 6.9, 44% of patients with significant fibrosis in the liver biopsy group were correctly identified; however, this number decreased in the validation cohort. Similar to APRI, the Forns index is more appropriate to use to exclude fibrosis rather than to identify fibrosis. FIB-4
FIB-4 is a noninvasive marker of fibrosis that was initially developed as a marker of fibrosis in patients with human immunodeficiency virus (HIV)/HCV coinfection.16 In this retrospective analysis of liver histology and routine blood test results, multivariate logistic regression revealed that age, platelet, and AST were associated with significant fibrosis (Ishak 4–6). These variables were fashioned into a model, termed FIB-4 (age(year) AST (U/L)/(PLT (109) x ALT (U/L). Based on this model, one can estimate the degree of liver fibrosis. Using the FIB-4 model, a value of less than 1.45 has an NPV of 90% to exclude advanced fibrosis (Ishak 4–6). For a value greater than 3.25, the FIB-4 had a positive predictive value (PPV) of advanced fibrosis of 65%. Therefore, in most patients with values less than 1.45 or greater than 3.25, a liver biopsy may be avoided16 (see Table 2). Although the FIB-4 was developed in an HIV/HCVcoinfected population, a subsequent study by Vallet-Pichard and colleagues17 showed that FIB-4 can be applied to HCV-monoinfected patients as well.
Accurate Assessment for Staging Liver Disease in HCV
FibroTest
Unlike the models that use routine tests, the FibroTest is a noninvasive model that includes several nonroutine tests, including a2-macroglobulin, apolipoprotein A1, g-glutamyltranspeptidase, haptoglobin, g-globulin in addition to total bilirubin. In development of this model, liver biopsies were assessed based on the METAVIR system for substantial fibrosis, F2 or greater, and biopsy specimens were given an activity score (A0–A1 not much activity and A2 or A3 substantial activity), and together with the fibrosis stage, 3 categories were created: (1) without important histologic features (A<2 and F<2), (2) important lesions (A2 and F2 or both), and (3) widespread fibrosis or cirrhosis (F3 or F4).18 The AUROC for this model, the FibroTest, was 0.836, and this was replicated in a second group with similar ROC at 0.870. For a score of 0 to 0.1, the NPV was 100% to exclude the presence of significant fibrosis and at scores of 0.60 to 1.00 had a high PPV of more than 90% in identifying the presence of significant fibrosis.18 COMPARISONS BETWEEN NONINVASIVE MARKERS OF STAGING FOR HCV
Several studies have compared the performance of noninvasive markers to stage liver disease. In 1 study that compared 9 noninvasive markers, including PLT count, AST/ALT, cirrhosis discriminate score, FIB-4, APRI, age-platelet index (API), Go¨teborg University cirrhosis index (GUCI), FibroTest, and ActiTest with liver biopsy, FibroTest, FIB-4, APRI, and API all had NPV of greater than 80% to exclude significant fibrosis (compare F0–F2 vs F3–F4)19 and are better used to exclude significant fibrosis. Vallet-Pichard and colleagues17 compared FIB-4 and FibroTest in patients with HCV and there was concordance between tests for FIB-4 values less than 1.45 and greater than 3.25. This study showed that FIB-4 can be used in an HCV-monoinfected cohort.17 In another study, 9 blood tests (FibroTest, FibroMeter, Forns index, APRI, MP3, the European Liver Fibrosis Group score, Hepascore, FIB-4, and hyaluronate) and TE with FibroScan for liver fibrosis were compared with liver biopsy. FibroScan, FibroMeter, FibroTest, and Hepascore were the optimal tests to detect significant fibrosis and cirrhosis.20 In an analysis of 5 study populations, the performance of several markers of fibrosis were assessed including FibroMeter, FibroTest, Hepascore, and APRI. These tests were designed to detect significant fibrosis of F2 or greater.21 In this study, investigators applied new target end points, including significant fibrosis (F21F31F4), severe fibrosis (F31F4), and cirrhosis (F4). In detection of severe fibrosis, FibroMeter had the highest AUROC, and for cirrhosis, FibroMeter and Hepascore had the highest AUROCs. The AUROCs and accuracies for all tests were higher for cirrhosis than severe fibrosis. This study highlights that the results of blood test or noninvasive marker are dependent on the population studied, the cutoff used, and the diagnostic end point chosen.21 Therefore, although the absence of fibrosis can be detected with a reasonable degree of accuracy, in patients with test results in the gray zone, further evaluation is required. FUTURE DEVELOPMENT OF BIOMARKERS FOR FIBROSIS IN HCV
Although the use of biomarkers based on laboratory tests to classify patients with significant fibrosis may reduce the need for liver biopsy, 1 criticism is that these markers are often indeterminate and may not detect those patients with mild to moderate fibrosis or predict those with more rapidly progressive disease.22 Furthermore, most
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noninvasive models have similar AUROC values; however, these are compared with the liver biopsy, which, although we consider it a gold standard test to stage liver disease, also has its limitations23 In addition, because many patients fall in between the upper and lower cutoff values, giving indeterminate results, liver biopsy is still needed in many patients. Because most of the discussed biomarkers are based on retrospective data to identify biomarkers, including liver function tests as markers of fibrosis, a more accurate assessment of fibrosis based on intermediates or end products of proteins and enzymes involved in the fibrosis pathways may be more accurate. Liver fibrosis involves stellate cell activation and extracellular matrix turnover; therefore, there is interest in development of biomarkers of fibrosis specifically identifying key cytokines and proteins involved in this process. Several biomarkers involved in the fibrosis pathway have already been investigated and include hyaluronic acid, type III procollagen, matrix metalloproteinases, and tissue inhibitors of metalloproteinase.24–26 Future noninvasive fibrosis tests will likely be based on biomarkers that are functionally related to the pathophysiology of fibrosis development in HCV.22 These noninvasive markers of fibrosis have also been used to predict histologic progression and clinical outcomes such as hepatic decompensation in patients with HCV cirrhosis.27 IMAGING STUDIES
Imaging modalities including magnetic resonance imaging (MRI) and ultrasonography have been studied as noninvasive methods in staging liver disease in the setting of chronic HCV. ULTRASOUND-BASED MODALITIES FibroScan
The FibroScan is a portable device that can capture the elasticity of the liver as a marker of fibrosis. The probe has an ultrasound transducer and a vibrator, which is placed in the intercostal space over the right lobe of the liver. A vibration is sent to the tissue to produce a wave that traverses the liver. The ultrasound follows this wave and measures its velocity, which is a measure of tissue stiffness.28 TE has been studied to determine the degree of fibrosis in liver disease.29 FibroScan (Echosens, Paris, France) has been studied and compared with liver biopsy results in patients with HCV. The FibroScan probe measures elasticity of the liver, and these results were compared with the activity, steatosis, and fibrosis as assessed on the liver biopsy. There was a high correlation between TE measurements and fibrosis, with a partial correlation coefficient of 0.71 (P<.001). In patients with elasticity of 5 kPa or less, 93% had fibrosis stage F0 or F1 and in those with an elasticity of 7.6 kPa or greater, 94% had fibrosis of F2 or greater (see Table 2).29 The FibroScan has limitations in patients with ascites, obesity, or those with narrow intercostal spaces.29 A prospective study in cirrhotic patients, which assessed factors that negatively affected the performance of FibroScan, found that increased patient age and obesity resulted in lower success rates.28 Operators who have performed at least 50 previous FibroScan examinations had a higher success rate in capturing shots. It has been suggested that a median of 5 successful measurements with the FibroScan is sufficient to assess for stage of fibrosis in an individual patient.28 In addition to FibroScan, acoustic radiation force impulse (ARFI) and supersonic shear imaging (SSI) are ultrasound-based modalities that have been investigated in HCV staging. ARFI uses an ultrasound beam that locally deforms the parenchyma
Accurate Assessment for Staging Liver Disease in HCV
and triggers a shear wave to give a measure of liver stiffness.30 In a comparison of FibroScan and ARFI with liver biopsy in patients with chronic hepatitis C, the performance of ARFI was superior to FibroScan for diagnosing significant fibrosis (F2) and severe fibrosis (F3–F4); however, for cirrhosis, the test performance was equivalent between the 2 modalities.30 SSI is also an ultrasound-based modality and compared with FibroScan, the SSI technology was more accurate for F2 and greater and F3 and greater; however, they were similar for detecting F 5 4 fibrosis.31 SSI measures a larger area than FibroScan and therefore may be better able to detect fibrosis.31 MRI
MRI has been studied in HCV staging with different MRI protocols, including unenhanced MRI, magnetic resonance elastography (MRE), MRI with diffusion-weighted imaging (DWI) and MR spectroscopy. In a study of unenhanced MRI comparing liver biopsy in patients with HCV, although there was a high correlation on MR and certain features of fibrosis and hepatic activity index, the combination of MR features together with laboratory data was superior in detecting inflammation and fibrosis.32 This study excluded patients with clinical features of portal hypertension, and therefore cannot be applied to patients with cirrhosis.32 MRI with DWI has been studied and compared with MRE and it has been shown that MRE is superior in predicting fibrosis stage compared with MRI with DWI.33 MRE has also been compared with ultrasound elastography using FibroScan and APRI for staging liver disease in patients with chronic liver disease.34 The AUROC for each stage of fibrosis (F>2, F>3, F 5 4) was greater for MRE compared with FibroScan, APRI, and FibroScan and APRI together, when comparing accuracy of diagnostic tool with liver biopsy specimens. This study was not performed exclusively in patients with HCV. The benefits of MRE over FibroScan include that this modality can be performed in obese patients and those with ascites.34 However, MRE is more expensive than FibroScan, which may limit its use. Breath Tests
Breath tests assess how the liver metabolizes an ingested substance and have been studied as a marker of liver fibrosis in the setting of HCV. The methacetin breath test is based on the fact that 13C-methacetin is metabolized in the liver by cytochrome p450 1A2 into acetaminophen and 13CO2 and can therefore be studied as a test of liver function. The methacetin breath test was studied in patients with HCV and control patients.35 The breath test was able to classify patients as cirrhotic versus noncirrhotic; however, it was unable to differentiate between the various stages of fibrosis.35 However, by using an algorithm to include breath test parameters, age, and other patient data for both inflammation and fibrosis, in patients with HCV and normal ALT (defined as 2 ULN), these algorithms were able to differentiate between high and low inflammation and to differentiate between significant and nonsignificant fibrosis in this setting.36 An additional breath test that has been studied in HCV is the 13C-aminopyrine breath test. This breath test was able to distinguish control patients from those with chronic hepatitis from patients with Child A cirrhosis early in the breath test.37 However, at longer time points, there was no difference between patients with hepatitis and cirrhosis. In addition, this breath test was not able to distinguish between high fibrosis scores and cirrhosis.37 Although breath tests may be able to identify those with cirrhosis at risk for decompensation, they have limited usefulness for accurate assessment of varying degrees of fibrosis.38
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ALGORITHMS
Several algorithms have been proposed to combine blood tests, models, or FibroScan to improve the accuracy of detecting liver fibrosis and cirrhosis.39–41 The SAFE Biopsy
The SAFE (sequential algorithm for fibrosis evaluation) biopsy algorithm has been validated as an algorithm for assessment of fibrosis in HCV.39 In an international multicenter retrospective study, patients with chronic hepatitis C who underwent liver biopsies also had blood tests for the APRI and FibroTest drawn on the same day. In the SAFE biopsy algorithm, patients have the APRI as an initial screening test, followed by the FibroTest to assess for significant fibrosis of F2 or greater and cirrhosis F4. Application of this algorithm correctly identified most patients, and only 2.6% were misclassified.39 Fibropaca Algorithm
The Fibropaca algorithm detects significant fibrosis and cirrhosis based on the use of FibroTest with the APRI and Forns index.42 With the use of all 3 tests to detect significant fibrosis (F2–F4) and cirrhosis F4, 81.3% of patients were correctly identified comparing their noninvasive markers to liver biopsy.42 This algorithm suggests performing the FibroTest, the APRI, and Forns index to assess for concordance; if there is no concordance, proceed with a liver biopsy. With this method, 81.3% of patients are correctly identified solely with the combination of noninvasive markers.42 Leroy Algorithm
The Leroy algorithm uses APRI and FibroTest simultaneously. This algorithm is useful to detect significant fibrosis (F2–F4) or extensive fibrosis or cirrhosis (F3–F4) using threshold values of FibroTest greater than 0.59 and APRI greater than 2, with a PPV of 96.7% and 92.2%, respectively. The algorithm excluded significant fibrosis (F2–F4) using threshold values of FibroTest less than 0.22 and APRI less than 0.5, with an NPV of 94.1%.43 This algorithm is useful to discriminate between early and advanced fibrosis. However, there is inadequate information about staging with this algorithm among patients with test values that do not fall within these cutoffs.43 In comparing the SAFE biopsy, Fibropaca, and Leroy algorithms, the most accurate algorithm was the Leroy algorithm.40 However, more biopsies were avoided with Fibropaca, followed by the SAFE biopsy algorithm. The SAFE biopsy and Fibropaca algorithms would be useful in the clinical setting.40 IMPLICATIONS OF STAGING VIRAL HEPATITIS C Treatment Duration
In those with cirrhosis, 48 weeks of treatment with PEG-IFN, ribavirin, and a DAA (boceprevir or telaprevir) is recommended, regardless of virologic response.44 In contrast, patients without cirrhosis and treatment-naive patients can be treated with response-guided therapy. Therefore, an accurate diagnosis of cirrhosis is imperative in determining treatment duration and counseling about treatment success rates. Implications of Management
It is imperative not to miss the diagnosis of cirrhosis, because this has important implications. Patients with cirrhosis are at an increased risk of developing HCC and surveillance liver ultrasonography is recommended every 6 months. Patients with cirrhosis are also at risk of developing varices, and these thin-walled veins are at risk of rupture.
Accurate Assessment for Staging Liver Disease in HCV
An esophagogastroduodenoscopy (EGD) is recommended once a patient is diagnosed with cirrhosis. If the patient develops decompensated cirrhosis, the EGD should be repeated annually.45 Therefore, it is important to accurately diagnose cirrhosis, because it changes the patient’s management and surveillance strategies. SUMMARY
Accurate assessment of liver fibrosis is essential in the management of those with HCV. It allows identification of those with advanced fibrosis who require periodic surveillance for HCC and esophageal varices. It also identifies those who are not
Chronic HCV
If patient has obvious features of cirrhosis, including HE, Ascites, Varices:
Screening: HCC:US every 6 months Esophageal Varices : EGD
Non-invasive model (APRI, FibroTest, Forn's index, FIB-4), Fibroscan
Confirm with a second non-invasive marker of fibrosis
< F2
Treatment is optional
Intedeterminate results
Liver biopsy
Fig. 1. Algorithm for evaluation of fibrosis in HCV.
F >= 2
Antiviral therapy, if no contraindications present
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candidates for response-guided therapy with DAA. To determine the best option for your patient with chronic HCV requires an understanding of the accuracy and limitations of the models and tests described earlier. We recommend the algorithm depicted in Fig. 1.46 In those with obvious signs of advanced fibrosis (ascites, hepatic encephalopathy, coagulopathy, or significant thrombocytopenia), a biopsy is usually not required. These patients can proceed directly to periodic surveillance for HCC and varices. In those without obvious clinical signs of cirrhosis, we recommend a noninvasive model used alone or in conjunction with a second model for confirmation (ie, APRI, FIB-4, or FibroTest plus FibroScan if available). In those with mild disease (
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