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Diagnosis of Liver Fibrosis: Present and Future Keyur Patel, MD1

Pierre Bedossa, MD, PhD2

Laurent Castera, MD, PhD3

1 Division of Gastroenterology, Duke University Medical Center, Duke

Clinical Research Institute, Durham, North Carolina 2 Department of Pathology, Physiology and Imaging, Hôpital Beaujon, Clichy, France 3 Department of Hepatology, Hôpital Beaujon, Clichy, France

Address for correspondence Laurent Castera, MD, PhD, Department of Hepatology, Hôpital Beaujon, Clichy, France (e-mail: [email protected]).

Abstract

Keywords

► ► ► ► ► ►

noninvasive liver fibrosis biopsy serum biomarkers imaging liver stiffness

The diagnostic assessment of liver fibrosis, a major determinant of disease severity, is an important step in the management of patients with chronic liver diseases. Liver biopsy is still considered the gold standard for the assessment of necroinflammation and fibrosis; however, recent technical advances have resulted in the development of numerous serum biomarkers and imaging tools as noninvasive alternatives to biopsy. These tests include biological (serum biomarker algorithms), physical (imaging assessment of tissue stiffness), and physiological (breath test) methods. Accumulating evidence shows that noninvasive tests provide prognostic information of clinical relevance, which has led to their incorporation into clinical guidelines and everyday practice. Here, the authors review and compare invasive and noninvasive tests for the diagnosis of liver fibrosis. They discuss emerging functional genomic, microparticle, protein-profiling, and bioimaging tools, focusing on novel sensitive tools that are able to assess the dynamic nature of fibrogenesis, a key requirement for the assessment of the efficacy of antifibrotic compounds in the future.

Histologic assessment of liver disease severity has been a cornerstone for therapeutic decisions and predicting prognosis in chronic liver disease (CLD), and been a foundation for much of modern hepatology. Although liver biopsy is still regarded as the gold standard for assessment of injury, inflammation, and fibrosis stage, its clinical application has significantly decreased over the past two decades. At the same time, noninvasive approaches that avoid the risks and possibly overcome limitations of liver biopsy have been under development for the past two decades. Noninvasive assessment of liver fibrosis has been increasingly incorporated into clinical studies and into everyday clinical practice. As such, semiquantitative categorical grading systems for histopathologic analysis, such as METAVIR, were developed to standardize and improve observer variability to determine thresholds for therapy in viral hepatitis, but do not quantify linearity of fibrosis deposition or actual matrix content. Moreover, the

Issue Theme Liver Fibrosis; Guest Editors, Robert Schwabe, MD, and Ramon Bataller, MD, PhD

rapid evolution of simplified noninterferon (IFN) direct acting antiviral therapeutic regimens, with high efficacy and tolerability amongst all hepatitis C virus (HCV) genotypes, suggest that the need for a liver biopsy for staging disease prior to antiviral therapy may be limited. Many noninvasive approaches, initially developed for disease staging in chronic hepatitis C (CHC), continue to be refined for diagnostic use in other CLD such as nonalcoholic fatty liver disease (NAFLD). One of the main goals in developing noninvasive measures of fibrosis has been to overcome the diagnostic limitations of a liver biopsy—which include the only semiquantitative assessment of matrix content as well as sampling error. Many of the existing serum biomarker panels and imaging tools were developed in relation to a cross-sectional, binary assessment of categorical histopathologic scores, and not to specifically reflect the dynamic nature of liver fibrogenesis. As we consider how to best monitor efficacy measures for

Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0035-1550059. ISSN 0272-8087.

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Semin Liver Dis 2015;35:166–183.

Diagnosis of Liver Fibrosis: Present and Future

Liver Biopsy The Reference Tool for Evaluation of Liver Fibrosis Hepatic fibrosis consists of the deposition of extracellular matrix (ECM) components in highly stable and optically visible structures (usually fibers) within the liver parenchyma.3 Because histological examination allows for direct visualization of the liver parenchyma, it is still considered as the reference tool for evaluation of fibrosis. However, liver biopsy has some disadvantages.4,5 Liver biopsy is an invasive procedure associated with morbidity (such as pain in 84%, and bleeding risk in 1 of 2,500 to 1 of 10,000 of patients), and mortality rates of 1 of 10,000. Moreover, the cost of a liver biopsy is high with conservative estimates at $1,032 and $2,745 for biopsies without and with complications, respectively.6 Actual costs may be higher depending on the type of complication, the need for further imaging, patient admission, and hospital facility fee. Because the liver specimen contained in a biopsy only represents a very small portion of the whole organ, there is a risk of sampling error due to heterogeneity in fibrosis distribution.7–9 Increasing the length of liver biopsy decreases the risk of such sampling error. Except for cirrhosis, for which microfragments may be sufficient, a 25-mm-long biopsy is considered an optimal specimen for an accurate evaluation, although 15 mm is considered sufficient in most studies.10–13 These thresholds have been set up in viral chronic hepatitis. Because of the variable fibrosis pattern depending on the etiology, it is possible that the recommended lengths may vary from disease to disease. Interobserver variation is another potential limit related to the discordance between pathologists in the interpretation of the biopsy.14 The use of histopathological semiquantitative scoring systems for evaluation of liver fibrosis (staging) may increase reproducibility because several studies have shown that different scoring systems provide more-consistent fibrosis evaluation especially when used by experienced liver pathologists.15–19 In this regard, specific fibrous tissue stains such as Masson’s trichrome or Sirius red are of great value for pathologists and may explain why fibrosis staging is one of the most reliable feature with the lowest interobserver variation. 18,20,21

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Thus, although liver biopsy has limitations, appropriate precautions may reduce the flaws inherent to this technique.

Liver Biopsy and Patterns of Fibrosis Although fibrosis is the mainstay in CLD, the histological pattern of fibrosis is not unique. The extent and distribution of hepatic fibrosis have different patterns depending on the underlying disease, and can be useful in the identification of the cause of the liver disease. Excess fibrous tissue often develops within the portal tracts and expands into the adjacent parenchyma. This pattern is seen in conditions associated with persistent portal inflammation, including chronic viral hepatitis, inflammatory cholangiopathy, etc. Periportal fibrosis thus represent the first stage in the evolution to bridging fibrosis.22,23 Bridging fibrosis, also known as septal fibrosis, designates the presence of fibrous septa that extend across lobules and connect mesenchymal structures (portal tracts and central veins) in various arrangements. It is an important indicator of prognosis and marks the shift from minimal fibrosis to significant fibrosis.24 Based on the vascular structures involved, bridging fibrosis can be separated into portal-portal, portal-central, and central-central types. Although this classification is conceptually relevant, the nature of a fibrous bridge can be difficult to determine in biopsy specimens, especially in the precirrhosis stage. Cirrhosis is histologically defined as a diffuse process characterized by annular fibrosis and a conversion of normal architecture into structurally abnormal hepatocyte-containing nodules.25 Cirrhosis is associated with the development of intrahepatic portohepatic vascular shunts. Regeneration of hepatocytes may occur, but is impaired in patients with advanced cirrhosis. Currently, histopathologists do not consider cirrhosis as a unique entity, but a spectrum of disease with different degrees of severity.26,27 Pericellular fibrosis is characterized by collagen fibers that extend along the sinusoids and surround single or small groups of hepatocytes. On special stains, pericellular fibrosis has a chicken-wire appearance and because of its distribution, it is also referred as perisinusoidal fibrosis. The most prominent causes of pericellular fibrosis are alcoholic and nonalcoholic fatty liver diseases.28,29 In diabetes, pericellular fibrosis spreads across entire lobules, producing a pattern of diffuse intralobular fibrosis (diabetic hepatopathy).30

Liver Biopsy and Scoring Fibrosis (Staging) The development of scoring systems to quantify the degree of fibrosis has increased the reliability of histological assessment. Indeed, using accurate guidelines that include the presence and association of elementary lesions, most pathologists are able to accurately assess the degree of fibrosis. By categorizing patients into homogeneous groups with the same extent and severity of a disease, histological scores have helped to perform large, multicentric studies as well as clinical trials. These reasons explain why histological scores of fibrosis have been widely accepted for more than 40 years. Scoring systems of fibrosis exist not only for viral chronic hepatitis, but also for other CLD such as NAFLD and biliary Seminars in Liver Disease

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antifibrotic therapeutic development (see “Antifibrotic Therapies in the Liver” by Mehal and Schuppan in this issue), current noninvasive tests do not yet provide sufficiently reliable and sensitive assessment of quantitative changes in fibrosis. Although clinical practice guidelines for CHC and NAFLD now include noninvasive tests for assessing the presence or absence of advanced fibrosis, liver biopsy is still recommended for prognostic and therapeutic decisions.1,2 However, this is likely to change with increased availability, validation, and greater acceptance of noninvasive tests as an alternative to biopsy for diagnosis of advanced stage disease and determination of prognosis (►Table 1). Moreover, further developments will undoubtedly lead to noninvasive tests that will allow for reliable and sensitive assessment of quantitative changes, even in early stages of liver fibrosis.

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•Unable to discriminate between intermediate stages of fibrosis •Units (m/s) different from that of TE (kPa) •Narrow range of values (0.5–4.4 m/s) •Quality criteria not well defined •Prognostic value in cirrhosis?

•Can be implemented on a regular US machine •ROI smaller than TE but chosen by the operator •Higher applicability than TE (ascites and obesity) •Performance equivalent to that of TE

ARFI

•Further validation warranted •Unable to discriminate between intermediate stages of fibrosis •Quality criteria not well defined •Learning curve? •Influence of inflammation?

•Can be implemented on a regular US machine •ROI can be adjusted in size and location and chosen by the operator •Measures liver stiffness in real-time •High range of values (2–150 kPa) •Good applicability •High performance for cirrhosis

SWE

•Further validation warranted especially in comparison with TE •Not applicable in case of iron overload •Requires a MRI facility •Time-consuming •Costly

•Can be implemented on a regular MRI machine •Examination of the whole liver •High applicability: overcomes the limitations of TE (ascites and obesity) •High performance for cirrhosis

MR elastography

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Abbreviations: ARFI, acoustic radiation force impulse imaging; AUROC, area under ROC curve; MR, magnetic resonance; MRI, magnetic resonance imaging; ROI, region of interest; SWE, ShearWave elastography; TE, transient elastography; US, ultrasound.

•Requires a dedicated device •ROI cannot be chosen •Unable to discriminate between intermediate stages of fibrosis •Applicability (80%) lower than serum biomarker: (obesity, ascites, operator experi ence) •False-positive in case of acute hepatitis, extrahepatic cholestasis and congestion

•Most widely used and validated technique: standard to be beaten •User-friendly (performed at bedside; rapid, easy to learn) •High range of values (2–75 kPa) •Quality criteria well defined •Good reproducibility •High performance for cirrhosis (AUROC > 0.9) •Prognostic value in cirrhosis

Transient elastography

Measurement of liver stiffness

Diagnosis of Liver Fibrosis: Present and Future

•Nonspecific of the liver •Unable to discriminate between intermediate stages of fibrosis •Performance not as good as TE for cirrhosis •Cost and limited availability (proprietary) •Limitations (hemolysis, Gilbert’s syndrome, inflammation…)

Disadvantages

•Good reproducibility •High applicability (95%) •No cost and wide availability (nonpatented) •Well validated •Can be performed in the outpatient clinic

Advantages

Serum biomarkers

Table 1 Respective advantages and disadvantages of currently available noninvasive methods in patients with chronic liver disease

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Liver Biopsy and Fibrosis Regression It is now well accepted that fibrosis and even cirrhosis may regress after successful treatment of the underlying disease.37,38 The landmark article by Wanless et al showed histological evidence from serial biopsies of patients who showed apparent shift from fully developed cirrhosis to incomplete septal cirrhosis.39 The most fascinating demonstration of the reversibility of fibrosis/cirrhosis came from studies analyzing large cohorts of patients with HCV or hepatitis B virus (HBV) effectively treated with new antiviral drugs and sequential biopsies with sufficient time interval.40–44 After viral suppression or eradication, most patients show regression of fibrosis, and regression of cirrhosis is observed in 50 to 60% of patients with a baseline diagnosis of cirrhosis. Cirrhosis regression is associated with a marked decrease in the amount of fibrosis that can easily be demonstrated by morphometric measurement of the area of fibrosis.45,46 One characteristic feature is the major thinning of fibrous septa, which may be reduced to a few collagen fibers. Associated with septa thinning is the disappearance of neovascular shunting. Indeed, thin septa in regressing cirrhosis usually lack vessels, or contain only few residual capillaries that may not function as shunting vessels anymore. Thereafter, septa become incomplete or may totally disappear.39 Regression of fibrosis is associated with a partial or full restoration of the lobular organization. However, nodular organization may partially persist despite disappearance of fibrous septa leading to a pattern that resembles vaguely to nodular regenerative hyperplasia. Whether perisinusoidal fibrosis and sinusoidal capillarization regress with the acqui-

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sition of a normal sinusoidal phenotype remains unclear. Indeed, recent studies suggest that this pattern may regress more inconsistently. However, ductular proliferation, a feature associated with fibrosis progression, quickly disappears in regressing cirrhosis. In addition, though the metabolic zonation is usually lost in cirrhosis, reversion is associated with the normalization of the lobular enzymatic zonation.46

New Technologies for Assessing Fibrosis in Liver Biopsy In the field of fibrosis, liver biopsy can provide information that is more than a semiquantitative score. Indeed, to get more accuracy and objectivity in the quantification of fibrosis, pathologists have developed a more sophisticated approach (i.e., morphometry), which is based on image analysis. The principles are obtaining a digitized image from a histological slide through high-definition digital cameras, thresholding the digitized image according to greyscale values, segment the image into the region that contains objects of interest for analysis (e.g., fibrous tissue) and background tissue, and measuring the structure of interest using image analysis software. This approach provides a very high level of accuracy for fibrous tissue quantitation (collagen percentage area [CPA]), which has been shown to be clinically relevant.47–50 More sophisticated approaches include measurement of form factors (size, shape, or other more complex measurements). For this approach, fractal geometry is the technique of choice.51 The development of easy-to-use systems and high-performance algorithms has made morphometry more accessible and useful to pathologists. It should be noted that, even when using fully automated techniques, morphometry remains time consuming and is not recommended for routine practice. A major advantage of morphometry is to provide a finite quantitative scale, which is linear and much more accurate than those determined by semiquantitative scoring methods.52 This approach has been used in clinical trials in the context of chronic viral hepatitis and NAFLD.52–54 Interestingly, these studies have shown the nonlinearity relationship between CPA and semiquantitative stages of fibrosis, a further demonstration that a fibrosis score does not equate to amount of fibrosis.11,48,55 Immunohistochemistry, although not a new tool, is a potential complementary approach that may allow a more dynamic assessment of fibrosis. It can be used for the labeling of activated hepatic stellate cells (mainly with α-smooth muscle antibody) or capillarization and/or neoangiogenesis (with CD34) or ductular proliferation (with cytokeratin 7), which are markers potentially associated with the progression of fibrosis in CHC or NAFLD.46,56,57 These tools are simple, relatively cheap, and reproducible. Biopsy can also provide useful information on the texture of fibrosis, which might have clinical relevance. Indeed, nonlinear optical microscopy enables the observation of endogenous signals such as two-photon excitation fluorescence (TPEF) and second harmonic generation (SHG) in unstained samples and deep within the tissue.58 In short, although TPEF allows for the visualization of the liver background and lobular organization, the SHG displays the threedimensional (3D) architecture of fibrillar collagen, a Seminars in Liver Disease

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diseases.20,21,31 Most of these scoring systems are clinically relevant because they are able to predict prognosis in most CLD.32,33 Recently, and in addition to score of fibrosis, several histological subscoring systems of cirrhosis have been proposed. They are all based on the size of parenchymal nodules and the width of fibrous septa such as the newly developed Laennec scoring system dividing cirrhosis into three groups (4a, 4b, 4c), a subclassification that correlates well both with hepatic venous pressure gradient (HVPG) and clinical outcome.34–36 Histological scores have also some drawbacks that have to be considered by both clinicians and pathologists. Histological staging of fibrosis is a reductive approach to the evaluation of liver damage. Fibrosis is a complex biological process with different patterns, which are not always reflected in the staging systems. In addition, fibrosis is usually present in combination with other histopathological features (inflammation, liver cell necrosis, steatosis, iron overload) that can influence the rate of progression, and the evolution to cirrhosis. Therefore, scoring systems should complement, but not replace the complete descriptive report of the pathologist. An important issue is that scores are semiquantitative values. The consequence is that scores should not be handled statistically as linear values, but as categories with adapted statistical tests. Unfortunately, many studies including clinical trials have missed this point, which limits the value of their scientific conclusions.

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Table 2 Diagnostic performance of serum biomarkers of fibrosis for significant fibrosis (F
2) and cirrhosis (F4) in patients with chronic liver diseases Biomarkers

Year

Etiologies

Patients (n)

F
2 (%)

FibroTest81

2001

HCV

339

77

F4 (%)

Cutoffs

AUROC

Se (%)

Sp (%)

CC (%)

80

>0.48

0.87

75

85

46

2002

HCV

476

26

6.9

0.81

30–94

51–95

45

APRI64

2003

HCV

270

50

0.5 >1.5 0.36

0.83

77

73

75

2004

HCV

194

45

0.4

0.82

35–65

85–96

NA

2004

Mixed

1021

40

0.102 NA

0.78 0.89

87 NA

51 NA

NA NA

Forns Index

17 MP3 ELF

65

83

12 66

2005

HCV

302

48

0.2
0.8

0.77

42–85

48–98

40–49

Hepascore84

2005

HCV

211

57


0.5 >0.84

0.82 0.89

63 71

89 89

92 NA

Fibrometer85

2005

Mixed

598

56

NA

0.89

80

84

82

0.1

0.85

80

70

NA

Hui Score69

2005

HBV

235

25

0.15 >0.5

0.79

37–88

50–88

49

Zeng Score70

GUCI

ViraHep-C

38 12

2005

HBV

372

58

8.7

0.77

40–98

28–90

35

71

2006

HCV

398

37

0.22 >0.55

0.83

51–90

54–90

52

72

50

2007

HCV

360

1.25
2.25

0.83

30–40

97–97

35

FIB-478

2007

HCV

847

17a

3.25

0.85

38–74

81–98

68

NFS75

2007

NAFLD

733

30a

0.676

0.82

43–77

97–97

68

2008

NAFLD

669

38


2

0.81





NA

2008

HCV

512

38

69,000 differentially methylated CpG sites between mild and advanced NAFLD disease. Pathway analysis implicated differential methylation profiles in genes regulating several processes such as fatty acid metabolism, stellate cell activation, tissue repair, and carcinogenesis.122 An important caveat is that miRNA or epigenetic biomarkers may provide differing results within the same individual depending on methods or sample type such as urine, circulating white cells, within microvesicles, or circulating free in serum or plasma. At this stage, the identification of biomarkers based on miRNA transcripts that are detectable in blood or urine, and provide viable clinical diagnostic or prognostic utility, are still awaited. Long noncoding RNA transcripts (> 200 nucleotides), genomic and proteomic profiling of circulating extracellular vesicles (such as microvesicles, membrane particles, exosomes or apoptotic bodies) implicated in disease pathogenesis and intercellular signaling, represent novel approaches that hold promise for refined “liquid biopsy” biomarker development in the future.115,123,124

Imaging Assessment of Fibrosis Currently Available Methods Imaging techniques, particularly ultrasound (US), have been used for many years for the workup of patients with CLD because of their ease of use and wide availability.125 A major advance has been the introduction for liver fibrosis staging of liver stiffness measurement by using a variety of US or magnetic resonance- (MR-) based techniques. Monodimensional ultrasound transient elastography (TE; FibroScan), was the first introduced technique in the early 2000s.126 Its principle relies on the measurement of the velocity of a low-frequency (50 Hz) elastic shear wave propagating through the liver, that is directly related to tissue stiffness, called the elastic modulus (expressed as E ¼ 3ρv2, where v is the shear velocity and ρ is the density of tissue, assumed to be Seminars in Liver Disease

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Diagnosis of Liver Fibrosis: Present and Future

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Table 3 Diagnostic performance of transient elastography for significant fibrosis (F
2) and cirrhosis (F4) in chronic liver diseases Authors

Year

Etiologies

Patient

F
2 (n)

Castera et al132

2005

HCV

183

74

Ziol et al133

2005

HCV

251

65

F4 (%)

25 19 134

AUROC (kPa)

Se (%)

Sp (%)

7.1

0.83

67

89

12.5

0.95

87

91

8.6

0.79

56

91

14.6

0.87

86

96

7.3

0.92

84

87

2006

PBC-PSC

95

16

17.3

0.96

93

95

Ganne-Carrie et al135

2006

Mixed

775

15

14.6

0.95

79

95

Foucher et al136

2007

Mixed

354

13

17.6

0.96

77

97

137

2007

Mixed

200

7.9

0.86

72

84

11.9

0.90

91

89

8.3

0.93

85

91

14.0

0.96

78

98

7.8

0.91

83

82

14.8

0.98

94

92

6.6

0.86

88

74

Corpechot et al

Fraquelli et al

60

Cutoffs (%)

50 12

Coco et al

138

2007

HCV/HBV

228

62

2008

HCV

150

56

50 Arena et al139

19 140

2008

NAFLD

97

50

17.0

0.99

100

97

Nobili et al141

2008

NAFLD

50

24

7.4

0.99

100

92

Nguyen-Khac et al142

2008

ALD

103

75

7.8

0.91

80

91

Nahon et al143

2008

ALD

147

Marcellin et al144

2009

HBV

173

Yoneda et al

9

32

19.5

0.92

86

84

54

22.7

0.87

84

83

7.2

0.81

70

83

0.93

93

87

50 8

Chan et al

145

Wong et al146 Degos et al

147

2009

HBV

161

2010

NAFLD

246

2010

HCV/HBV

25

1307

Petta et al Gaia et al

148

149

0.93

98

75

0.84

79

76

10

10.3

0.95

92

88

5.2

0.75

90

32

14

12.9

0.90

72

89

7.25

0.79

69

70

7.0

0.80

76

80

10.5

0.94

78

96

5.2

0.82

97

35

14

12.9

0.93

77

90

7.2

0.87

74

88

8

11.0

0.93

75

90

7.8

0.86

84

79

57

2011

NAFLD

169

47

2011

NAFLD

72

46 12.5

Zarski et al

150

Cardoso et al

2012

151

2012

HCV HBV

382

47

202

42

152

2012

NAFLD

75

NA

Wong et al153

2012

NAFLD

193

45

Myers et al

NA

Afdhal et al

154

2015

HCV/HBV

560

a

12–13.4

a

7.0

41

HCV-HIV

11.0

22.3

0.88

80

91

7.0

0.83

79

64

13

10.3

0.89

81

83

8.4

0.73

58

75

14.8

12.8

0.90

76

85

67

Abbreviations: AUROC, area under ROC curve; HBV, chronic hepatitis B; HCV, chronic hepatitis C; NA, not available; NAFLD, nonalcoholic fatty liver disease; Se, sensitivity; Sp, specificity. a Validation cohort.

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respective advantages and disadvantages are shown in ►Table 1. Finally, liver stiffness can be measured by means of MR elastography using a modified phase-contrast method to image the propagation characteristics of the shear wave in the liver.131 Elasticity is quantified by MR elastography (expressed in kPa) using a formula that determines the shear modulus, which is equivalent to one-third the Young’s modulus used with TE. 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 is so far too costly and time-consuming to be used in routine practice (►Table 1).

Diagnostic Algorithms for Staging Liver Fibrosis Viral Hepatitis The high efficacy of new HCV treatments (with SVR > 90%) as well as the increased tolerability of IFN-free regimens has made exact staging of disease less important. The most important knowledge derived from staging fibrosis in HCV is identifying those patients with bridging fibrosis and especially cirrhosis who should be screened for esophageal varices and hepatocellular carcinoma (HCC). The results of TE in the diagnosis of significant fibrosis and cirrhosis are summarized in ►Table 3.132–154 The value of TE in the assessment of liver fibrosis has been initially suggested in patients with chronic hepatitis C.132,133 These results have since been confirmed by many other groups both in hepatitis C139,147,150,154,155 and B.138,144,145,147,156 Transient elastography more accurately detects cirrhosis (AUROC values, 0.87– 0.99) than significant fibrosis (AUROC values, 0.73–0.93) (►Table 3). Several meta-analyses have confirmed the better diagnostic performance of TE for cirrhosis than for fibrosis, with mean AUROC values of 0.94 and 0.84, respectively.157 In

Fig. 1 Confounders of liver stiffness measurement with transient elastography. (Adapted from Tapper et al130). ALT, alanine transaminase; BMI, Body Mass Index. Seminars in Liver Disease

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constant). The stiffer the tissue, the faster the shear wave propagates. Transient elastography measures liver stiffness in a volume that approximates a cylinder (10 mm wide, 40 mm long), 25 to 65 mm below skin surface. Its results are expressed in kilopascals (kPa), and range from 2.5 to 75 kPa, with normal value around 5 kPa.127 Accurate results 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) > 60%, and an interquartile range (IQR; reflects variations among measurements) < 30% of the median value (IQR/LSM  30%).128 Transient elastography is a fast (5 minutes), safe, and reproducible procedure that can be performed at the bedside with immediate results (point of care). For these reasons, TE is currently the most widely used and best validated technique for noninvasive assessment of liver fibrosis worldwide. However, its main limitation in clinical practice is its limited applicability (80%) mostly due to obesity, ascites, or limited operator experience.129 Apart from obesity, important liver stiffness measurement confounders include inflammation, cholestasis, congestion, and food intake. Thus, TE should be performed by an experienced operator (> 100 examinations) in fasting patients (for at least 6 hours) and taking into account ALT levels (< 100 IU) (►Fig. 1).130 More recently, 2D-elastography techniques incorporated into conventional US machines (sonoelastography), based on the measurement of the velocity of shear waves generated by mechanically exciting liver tissue by ultrasound pushes have been introduced. The first described was acoustic radiation force impulse imaging (ARFI; Acuson 2000 Virtual Touch Tissue Quantification, Siemens Healthcare) followed by ShearWave elastography (SWE; Aixplorer, Supersonic Imagine).125 ShearWave elastography results are measured in kPa, whereas ARFI results are measured in meters/second. Their

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a meta-analysis of 40 studies (32 papers and 8 abstracts), sensitivity and specificity values were 0.83 and 0.89 for patients with cirrhosis and 0.79 and 0.78 for patients with significant fibrosis.158 However, only nine studies (comprising 1,364 patients) had acceptable standards for liver biopsy and TE, which limit the conclusions. In a recent meta-analysis of 18 studies including 2,772 HBV patients,159 mean AUROC values for diagnosing cirrhosis and significant fibrosis were 0.93 and 0.86, respectively. However, we are still lacking a meta-analysis of data from individual patients. When compared, the performances of TE have been shown to be similar between patients with HBV and HCV.151 However, serum levels of aminotransferases should be taken into account in interpreting results from TE in patients with hepatitis B.160 To avoid the risk of false-positive results, some authors have proposed to adapt TE cutoffs based on levels of ALT,145 a strategy that might not apply to patients with fluctuating levels of ALT or hepatitis flares. Conversely, in hepatitis e antigen- (HBeAg-) negative patients with normal levels of ALT, TE could be used as an adjunct tool in the measurement of HBV DNA, to follow inactive carriers or better identify patients who require liver biopsy (those with ongoing disease activity or significant fibrosis, despite normal levels of ALT).156,161,162 Although performances of TE and serum biomarkers have been shown to be equivalent for diagnosing significant fibrosis in patients with chronic viral hepatitis,132,147 TE has been shown to outperform serum biomarkers for diagnosing cirrhosis.147 Also a strategy combining TE with serum biomarkers has been shown to increase diagnostic accuracy, particularly for significant fibrosis in chronic hepatitis C.132 In HCV treatment-naïve patients without comorbidities, TE combined with a serum biomarker can be used as first-line assessment of liver fibrosis, with liver biopsy performed only in case of unexplained discordance between TE and the biomarker.127 In HBV treatment-naïve patients, TE could be used as first-line for patients with levels of ALT < twofold the upper limit of normal and levels of HBV DNA > 20,000 IU/mL (for HBeAg-positive patients) or > 2,000 IU/mL (for HBeAgnegative patients). The benefit of combining TE with a serum biomarker remains to be demonstrated in hepatitis B. Similar to TE, ARFI more accurately detects cirrhosis (mean AUROC value: 0.91) than significant fibrosis (mean AUROC value: 0.84).163 In a meta-analysis164 including 13 studies (n ¼ 1,163 patients) comparing ARFI with TE, no significant difference were found between ARFI and TE: summary sensitivities and specificities for the diagnosis of significant fibrosis were 0.74 and 0.83 for ARFI and 0.78 and 0.84 for TE, respectively, and 0.87 and 0.87 for ARFI and 0.89 and 0.87 for TE for the diagnosis of cirrhosis, respectively. Preliminary studies comparing SWE to TE, suggest that it may perform better than TE for significant fibrosis.165–167 These results need to be further validated.

Nonalcoholic Fatty Liver Disease Transient elastography has also been investigated in NAFLD patients, but in a smaller number of studies.140,141,146,148,149,152,153,168 Like in viral hepatitis, Seminars in Liver Disease

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TE performances are better for cirrhosis than for significant fibrosis with AUROCs ranging from 0.94 to 0.99 and from 0.79 to 0.99, respectively (►Table 3). However, these results deserve several comments. First, these studies have been conducted in heterogeneous or peculiar populations such as Asian patients or children with low Body Mass Index (BMI; < 28 kg/m2); second, most of them are underpowered with small sample size (< 100 patients) and very few patients with cirrhosis; third, the scoring systems (Brunt or Kleiner) and endpoints (significant fibrosis or severe fibrosis) are heterogeneous. These differences among the studies are likely the explanation for the observed differences among proposed cutoffs for a given endpoint, known as the spectrum bias.169,170 Finally, it should be stressed that all these studies have been conducted in tertiary referral centers where the proportion of patients with severe fibrosis is higher than that in the general population, making it difficult to extrapolate the performance of TE in detecting cirrhosis in large populations. The major challenge for the use of TE in patients with NAFLD in clinical practice is the high rate of failure (no valid shot) or unreliable results (valid shots < 10, success rate < 60%, or IQR/LSM > 30%) using the regular (M) probe, ranging from 3.8 to 50%.93 Such a wide range could be explained by the differences in the definitions used (failure vs. unreliable results) as well as in the BMI of the studied populations (higher rates in the populations with higher BMI). The so-called XL probe has been proposed to overcome these limitations for overweight and obese patients. Myers et al152 have shown, in 276 patients with chronic liver disease (42% viral hepatitis, 46% NAFLD) and a BMI > 28 kg/m2, that failure was significantly less frequent with the XL probe than the M probe (1.1% vs. 16%; P < 0.00005). However, unreliable results were still observed with the XL probe in 25% of cases compared with 50% of cases with the M probe (P < 0.00005). In another series of 193 patients with NAFLD,153 the failure rate of XL probe was significantly lower than that of M probe (2% vs. 10%, respectively; p ¼ 0.002), but the unreliable result rate, although lower, did not differ significantly (25% vs. 33%, respectively; p ¼ 0.093). The overall diagnostic accuracy of M probe and XL probe was similar for significant fibrosis. However, by intention-to-diagnose the performance of M probe was unsatisfactory due to the high rate of unreliable results (AUROCs) compared with the XL probe. Among 155 patients with 10 valid measurements by both M probe and XL probe, 124 (80%) patients had lower liver stiffness values by XL probe than M probe. Pairwise examination showed that LSM by XL probe was 1.7  2.3 kPa lower than that by M probe. Altogether, these results indicate that the use of TE could be of interest to exclude severe fibrosis and cirrhosis in NAFLD patients with confidence, but the high rate of unreliable results remains the main challenge. The XL probe could be used as second line in the subset of patients (30%) in whom the regular M probe fails. However, appropriate cutoff values for the XL probe remain to be defined and validated. Algorithms combining TE with a serum biomarker remain to be validated.

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Diagnosis of Liver Fibrosis: Present and Future As for ARFI, SWE, and MRE, results are too preliminary to draw any firm conclusions.

Other Liver Diseases Transient elastography has also been evaluated in cholestatic liver diseases,134,171 in a variety of chronic liver diseases135–137,172 as well as in ALD (►Table 3).142,143 For this latter condition, cutoffs for cirrhosis diagnosis have been reported to be higher than in viral hepatitis (> 20 kPa). However, it has been suggested by several groups that the presence of alcoholic hepatitis may lead to overestimation of liver stiffness results173–175 thus, TE should be performed after alcohol withdrawal to improve accuracy.

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1,457 HCV patients, liver stiffness values and FibroTest had the highest 5-year predictive values for predicting survival and liver-related death, which did not change after adjustment for treatment response, patient age, and estimates of necroinflammatory grade.108 Interestingly, Corpechot et al192 have shown in 168 patients with PSC that, not only those with high baseline but also those with increase in liver stiffness values (> 1.5 kPa/y) were at very high risk (10 times the risk estimated in the other group) of death, liver transplantation, or hepatic complications within a 4-year period. Thus, the potential of liver stiffness values for predicting clinical outcomes seems to be greater than that of liver biopsy, probably liver stiffness measures ongoing pathophysiological processes and functions that a biopsy cannot.

Prognostic Role Future Imaging Methods Among US-based elastography challenging TE, ARFI, and SWE are the most advanced and promising with performances at least similar or even better than TE.167 Their use is becoming more common in practice although their exact place remains to be defined. Compared with US-based elastography techniques, MR elastography has the advantage of analyzing a substantially larger liver volume, allowing a precise analysis of the viscoelastic properties of the liver via a full 3D assessment of the displacement of the wave. However, studies comparing MR elastography with TE have been limited so far and have shown conflicting results.194,195 In addition, MRelastography procedure remains too cumbersome and not standardized enough for widespread use in routine practice. Several novel imaging technologies, including perfusion, MR diffusion-weighted imaging, intravoxel incoherent motion or acoustic structure quantification, are being developed, but their use remains limited so far to research settings.196

Abbreviations 3D APRI ARFI AST AUROC BMI CHB CHC CPA CRS ECM ELF GMCSF GWAS HBV HCC HCV HVPG IL MBT MELD miRNA

three-dimensional AST to Platelet Ratio Index acoustic radiation force impulse imaging aspartate aminotransferase area under ROC curve Body Mass Index chronic hepatitis B chronic hepatitis C collagen percentage area Cirrhosis Risk Score extracellular matrix Enhanced Liver Fibrosis granulocyte monocyte colony stimulating factor genome-wide association studies hepatitis B virus hepatocellular carcinoma hepatitis C virus hepatic venous pressure gradient interleukin 13 C-Methacetin Breath Test Model for End-Stage Liver Disease microRNA Seminars in Liver Disease

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Liver stiffness can be used to identify patients with cirrhosis who are at risk of disease progression because it correlates with the severity of liver disease,136 portal pressure,176,177 which accurately predicts clinical events, as well as with the presence of esophageal varices. A recent meta-analysis found pooled positive and negative predictive values of 88% for the ability of TE to predict the presence of significant portal hypertension (HVPG > 10 mm Hg).178 However, the diagnostic accuracy of TE (specificity below 60%) is too low for identification of patients with esophageal varices in clinical practice.179 More recently, spleen stiffness has received much attention as a potential better predictor of portal hypertension than liver stiffness.180–183 However, results remain conflicting and ARFI or SWE might be more suited for the measurement of spleen stiffness with better applicability then TE.184–186 Finally, it has been recently suggested that spleen stiffness could predict the occurrence of complications.187 Further studies to better define the most appropriate technique to measure spleen stiffness as well as its limitations are needed before spleen stiffness can be used in clinical practice. Liver stiffness, measured using TE, can also be used in determining prognosis. Large, prospective cohort studies in Asia of patients with hepatitis B or C correlated liver stiffness values with HCC occurrence.188–190 Among 866 Japanese patients with HCV infection, the cumulative incidence of HCC within 3 years was as high as 38.5%, among patients with baseline liver stiffness values > 25 kPa, compared with 0.4% among patients with values  10 kPa.188 Although measurements of liver stiffness could be used to identify patients at risk of developing HCC, more data are needed before they could be integrated into an HCC surveillance program. Several recent studies have shown that in patients with chronic liver disease, liver stiffness could also predict clinical decompensation as well as survival.108,191–193 For instance, Robic et al191 found that TE was as effective as HVPG in predicting clinical decompensations in 100 patients with chronic liver disease with a 2-year follow-up. Both HVPG
10 mm Hg and liver stiffness
21.1 kPa had 100% NPV for portal-hypertensive complications. Similarly, in a cohort of 128 Korean patients with active HBV cirrhosis, liver stiffness at a cutoff of 19 kPa, had a hazard ratio of 7 for development of clinical decompensation.193 In a cohort of

Diagnosis of Liver Fibrosis: Present and Future MMP MR MRI NAFLD SHG SNP SWE TE TPEF US

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matrix metalloproteinase magnetic resonance magnetic resonance imaging nonalcoholic fatty liver disease second harmonic generation single-nucleotide polymorphism ShearWave elastography transient elastography two-photon excitation fluorescence ultrasound

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