Journal of Hepatology
Volume 48, Issue 5 , Pages 835-847, May 2008

Non-invasive evaluation of liver fibrosis using transient elastography☆

  • Laurent Castera

      Affiliations

    • Departments of Hepatology, Hospital Saint-André & Haut Lévêque, University Hospital of Bordeaux, Bordeaux, France
    • Corresponding Author InformationCorresponding author. Address: Service d’Hépato-Gastroentérologie, C.H.U. Bordeaux, Hôpital Haut Lévêque, Avenue Magellan, 33604 Pessac, France. Tel.: +33 5 57 65 64 39; fax: +33 5 57 65 64 45.
    • ,
  • Xavier Forns

      Affiliations

    • Liver Unit, Hospital Clinic, IDIBAPS, Ciberehd, Barcelona, Spain
    • ,
  • Alfredo Alberti

      Affiliations

    • Department of Clinical and Experimental Medicine and Venetian Institute of Molecular Medicine (VIMM), University of Padova, Padova, Italy

published online 26 February 2008.

Associate Editor: M. Colombo

Article Outline

Transient elastography (TE, FibroScan®) is a novel non-invasive method that has been proposed for the assessment of hepatic fibrosis in patients with chronic liver diseases, by measuring liver stiffness. TE is a rapid and user-friendly technique that can be easily performed at the bedside or in the outpatient clinic with immediate results and good reproducibility. Limitations include failure in around 5% of cases, mainly in obese patients. So far, TE has been mostly validated in chronic hepatitis C, with diagnostic performance equivalent to that of serum markers for the diagnosis of significant fibrosis. Combining TE with serum markers increases diagnostic accuracy and as a result, liver biopsy could be avoided for initial assessment in most patients with chronic hepatitis C. This strategy warrants further evaluation in other aetiological types of chronic liver diseases. TE appears to be an excellent tool for early detection of cirrhosis and may have prognostic value in this setting. As TE has excellent patient acceptance it could be useful for monitoring fibrosis progression and regression in the individual case, but more data are awaited for this application. Guidelines are needed for the use of TE in clinical practice.

Abbreviations: TE, transient elastography, ALT, alanine aminotransferase levels, HBV, hepatitis B virus, AUROC, area under the ROC curve, CI, confidence interval

Keywords: Transient elastography, FibroScan, Liver fibrosis, Reproducibility

 

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1. Introduction 

The prognosis and management of chronic liver diseases largely depend on the extent and the progression of liver fibrosis. For instance, in patients with chronic hepatitis C, the leading cause of chronic liver disease worldwide, precise staging of hepatic fibrosis is paramount as fibrosis is the most important predictor of disease outcome and influences the indication for antiviral therapy [1], [2]. Histopathological examination of a liver specimen obtained by percutaneous biopsy has traditionally been considered as the gold standard for evaluating hepatic fibrosis [3]. However, liver biopsy is an invasive and painful procedure, often with poor patient acceptance and also carries a significant, although small risk of life-threatening complications [4], [5]. The accuracy of liver biopsy for assessing fibrosis has also been questioned, due to sampling errors and intra- and inter-observer variability that may lead to over or underestimation of fibrosis stage [6], [7]. Even when an experienced physician performs liver biopsy and an expert pathologist interprets the results, liver biopsy has up to a 20% error rate in disease staging [8]. In addition, it is certainly not the ideal procedure for serially repeated assessment of disease progression.

These findings thus emphasize the need for non-invasive tools that accurately measure the degree of liver fibrosis. Ideally, a non-invasive marker of liver fibrosis should be liver-specific, easy to perform, reliable and inexpensive. In addition, it should be accurate not only for the grading of fibrosis, but also for monitoring disease progression and treatment efficacy. A variety of surrogate markers have been evaluated for their ability to assess liver fibrosis, mostly in patients with chronic hepatitis C [9], [10], [11], [12]. The latest technological advance in this setting is the measurement of liver stiffness by means of transient elastography (TE).

This special article aims at reviewing the data currently available regarding TE performance in assessing stage and progression of liver fibrosis, and compares it to the other non-invasive methods that have become available for this purpose. This review will also discuss the advantages and limits of TE and perspectives for its rational use in clinical practice.

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2. Transient elastography 

2.1. Principle 

TE, using FibroScan® (Echosens, Paris, France), is a novel non-invasive method that has been proposed for assessment of liver fibrosis by measuring liver stiffness [13]. Briefly, an ultrasound transducer probe is mounted on the axis of a vibrator (Fig. 1A). Vibrations of mild amplitude and low frequency (50Hz) are transmitted by the transducer, inducing an elastic shear wave that propagates through the underlying tissues. Pulse-echo ultrasound acquisition is used to follow the propagation of the shear wave and to measure its velocity, which is directly related to tissue stiffness (the elastic modulus E expressed as E=3ρV2, where V is the shear velocity and ρ is the mass density (constant for tissues)): the stiffer the tissue, the faster the shear wave propagates (Fig. 1B). TE measures liver stiffness in a volume that approximates a cylinder 1cm wide and 4cm long, between 25mm and 65mm below the skin surface. This volume is at least 100 times bigger than a biopsy sample, and is therefore far more representative of the hepatic parenchyma.

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  • Fig. 1. 

    (A) Position of probe and explored volume (Imaging from Echosens). (B) Shear wave propagation velocity according to the severity of hepatic fibrosis (Metavir score). The elastic modulus E expressed as E=3ρV2, where V is the shear velocity and ρ is the mass density (constant for tissues): the stiffer the tissue, the faster the shear wave propagates. Hence, for absent fibrosis (F0), velocity is 1.0m/s and elasticity is 3kPa, whereas for cirrhosis (F4) velocity is 3.0m/s and elasticity is 27kPa. Adapted from Sandrin et al. [13].

2.2. Interpretation of results 

TE is painless, rapid (less than 5min) and easy to perform at the bedside or in the outpatient clinic. The examination is performed on a non-fasting patient lying flat on his/her back, with the right arm tucked behind the head to facilitate access to the right upper quadrant. The tip of the probe transducer is placed on the skin between the rib bones at the level of the right lobe of the liver where liver biopsy would be performed. Once the measurement area has been located, the operator presses the probe button (shot) to start an acquisition. The software determines whether each measurement is successful or not. When a shot is unsuccessful, the machine does not give any reading. Results are expressed in kiloPascals (kPa) and correspond, according to the manufacturer’s recommendations, to the median of 10 validated measurements. Liver stiffness values range from 2.5 to 75kPa. The results are immediately available and are operator-independent [14]. The examination can be performed by a nurse after a short learning curve (about 100 examinations) [15].

The validity of TE results also depends on two important parameters: (1) the interquartile range (IQR), which reflects the variability of the validated measures, and should not exceed 30% of the median value [16]; (2) the success rate (the ratio of the number of successful measurements to the total number of acquisitions) should be at least 60%.

The clinical interpretation of TE results should be always in the hands of an expert clinician and should be made having information regarding patient demographics, disease aetiology and essential laboratory parameters at his/her disposal.

2.3. Limitations and reproducibility 

Liver stiffness measurements can be difficult in obese patients or in those with narrow intercostal space and impossible in patients with ascites [13]. Failure rates range between 2.4% and 9.4% in the different studies [13], [14], [17], [18], [19], [20], [21]. According to our experience in 2114 examinations, liver stiffness could not be measured in 4.5% of cases [22]. In multivariate analysis, the only factor associated with failure was a body mass index above 28 (odds ratio 10.0; 95% confidence interval 5.7–17.9, P=0.001). However, with more experience, we think that rather than body mass index, a fatty thoracic belt is a limiting factor for the success rate. Indeed, in overweight or obese patients, the fatty thoracic belt attenuates both elastic waves and ultrasound making liver stiffness measurement impossible. Specific probes are being developed for obese patients.

Three recent studies suggested that TE results may be influenced by ALT flares [21], [23], [24]. Coco et al. [21] reported a 1.3- to 3-fold increase in liver stiffness values at the time of ALT flares with a progressive return to baseline values afterwards in 10 patients with chronic viral hepatitis and acute exacerbations (9 with hepatitis B). Arena et al. [23] reported similar results in 18 patients with acute viral hepatitis without a history of liver disease. Also in this study, progressive normalization of liver stiffness values was observed in parallel with the decrease of aminotransferase levels. Finally, Sagir et al. [24] reported high liver stiffness values suggestive of cirrhosis in 15 out of 20 patients with acute liver damage without any signs or liver cirrhosis at physical examination, ultrasound examination, or liver histology (performed in 11 patients). In six patients in whom a follow-up was available, liver stiffness values decreased to values below the cut-off for cirrhosis at the time of normalization of aminotransferase levels.

It should be kept in mind, however, that apart from the setting of acute viral hepatitis and of acute reactivation of chronic HBV, liver stiffness values have not been shown to be correlated with histological activity in multivariate analysis in patients with chronic hepatitis C in whom ALT flares are unusual [17], [18].

Reproducibility of TE is also an important prerequisite for its widespread application in clinical practice. In the initial study by Sandrin et al. [13], reproducibility was deemed good (with low intra- and inter-operator standardized coefficient of variation: 3.2% and 3.3%, respectively). However, this study was obviously underpowered in terms of sample size (15 subjects) thus making it impossible to draw firm conclusions on host- and disease-related covariates that may interfere with TE performances. Two independent groups [14], [25], recently addressed this issue with similar results. In the study by Fraquelli et al. [14], where 800 TE examinations were performed by two operators in 200 patients with various chronic liver diseases, TE reproducibility was excellent for both inter-observer and intra-observer agreement, with intraclass correlation coefficients (ICC) of 0.98. However, interobserver agreement was significantly reduced in patients with lower degrees of hepatic fibrosis (ICC for F0–F1 0.60 vs. 0.99 for F⩾2), with hepatic steatosis (ICC for steatosis ⩾25% of hepatocytes 0.90 vs. 0.98 for <25%) and with increased body mass index (ICC for BMI ⩾25kg/m2 0.94 vs. 0.98 for <25kg/m2). Similar results have been reported by Konate et al. [25] in 100 patients, suggesting that the ideal candidate for TE is a lean patient with severe fibrosis.

2.4. Normal values 

“Normal” liver stiffness values have recently been examined in 429 healthy subjects, without overt causes of liver disease and normal liver enzymes, undergoing a medical check-up [26]. The mean liver stiffness value in these patients was 5.5±1.6kPa. Age had no influence but as suggested previously [27], liver stiffness values were higher in men than in women (5.8+1.5 vs. 5.2+1.6kPa, respectively; p=0.0002), and in subjects with BMI>30kg/m2 (6.3+1.9 vs. 5.4+1.5kPa, respectively; p=0.0003). However, even after adjustment for gender and BMI, liver stiffness values remained higher in subjects with metabolic syndrome (n=59; 13.7%) than in those without (6.5+1.6 vs. 5.3+1.5kPa, respectively; p<0.0001) (Fig. 2). Interestingly, among 7 subjects with metabolic syndrome who had liver stiffness values above 8kPa, 4 underwent liver biopsy. All had NASH lesions with portal fibrosis but mild or absent steatosis, suggesting, in agreement with another recent study in healthy subjects who underwent a liver biopsy as potential liver donors [28], that liver stiffness values are not influenced by steatosis and that TE may be a sensitive tool for the detection of fibrosis. Further studies are needed to determine whether the monitoring of liver stiffness values in patients with metabolic syndrome may predict the evolution towards cirrhosis.

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  • Fig. 2. 

    Distribution of liver stiffness values in 429 healthy subjects without overt causes of liver disease and normal liver enzymes, according to the presence or the absence of metabolic syndrome. Adapted from Roulot et al. [25].

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3. Diagnostic performance of transient elastography 

3.1. Diagnosis of significant fibrosis 

The first issue in the evaluation of a novel diagnostic tool for measuring liver fibrosis is its validation against the current clinical gold standard (liver biopsy) to determine sensitivity, specificity, and predictive values [29]. The standard expression of the effectiveness of a test is to look at the area under the receiver operator characteristic curve (AUROC), which plots the sensitivity over 1 – specificity. The perfect test will score 1.0. This has been done for transient elastography in large-scale prospective studies, initially in patients with chronic hepatitis C [17], [18].

3.1.1. Hepatitis C 

The results show that liver stiffness values correlated strongly with Metavir fibrosis stages (Fig. 3). AUROCs ranged from 0.79 to 0.83 for significant fibrosis (F⩾2) and cut-off values with optimal diagnostic accuracy were defined for each stage of fibrosis (Table 1). It should be stressed, however, that despite high AUROC values, a substantial overlap of liver stiffness values was observed between adjacent stages of hepatic fibrosis, particularly for lower fibrosis stages.

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  • Fig. 3. 

    Box-plots of liver stiffness values for each fibrosis stage (Metavir). Because of the wide range of FS values for F4, the vertical axis is in logarithmic scale. Adapted from (A) Ziol et al. [18] and (B) Castera et al. [17].

Table 1. Diagnostic performance of transient elastography in patients with chronic hepatitis C
Fibrosis score (Metavir)Significant fibrosis F⩾2Severe fibrosis F⩾3Cirrhosis F=4
Authors [17], [18]ZiolCasteraZiolCasteraZiolCastera
Number of patients163/251136/18376/25183/18349/25146/183
(%)657430451925
Cut-off (kPa)8.87.19.69.514.612.5
Sensitivity (%)566786738687
Specificity (%)918985919691
Negative predictive value (%)564893819795
Positive predictive value (%)889571877877
Positive likelihood ratio6.636.095.768.1123.059.66
Negative likelihood ratio0.480.370.160.290.140.14
Area under the ROC curve0.790.830.910.900.970.95

The correlation between liver stiffness and fibrosis stage did not seem to be affected by steatosis [13], [18]. However, none of the patients in these studies had massive steatosis, and further specific studies assessing liver stiffness values in patients stratified according to the degree of steatosis are needed.

3.1.2. Other aetiologies 

TE has been assessed also in a number of chronic liver diseases other than hepatitis C to identify significant fibrosis [14], [30], including chronic hepatitis B [21], [31], HIV-HCV co-infection [32], [33], cholestatic diseases (PBC and PSC) [34], and NASH [35], [36] with AUROCs ranging from 0.74 to 0.93 and cut-offs from 4.0 to 8.7kPa (Table 2).

Table 2. Diagnostic performance of transient elastography for the diagnosis of significant fibrosis according to liver disease aetiology
AuthorsGomez-Dominguez et al. [30]de Ledinghen et al. [32]Yoneda et al. [36]Marcellin et al. [31]Vergara et al. [33]Corpechot et al. [34]Rigamonti et al [60]Fraquelli et al. [14]Coco et al. [21]Carrion et al. [53]Kelleher et al. [35]
Number of patients947267170169a9595200228b124c129
Prevalence significant fibrosis (F⩾2)82%61%49%58%62%60%36%50%61.8%43%50.4%
AetiologiesAllHCV–HIVNAFLDHBVHCV–HIVPBC & PSCHCV–LTAllHCV & HBVHCV–LTNASH
Proposed cut-offs (kPa)4.04.56.67.07.27.37.97.98.38.58.7
Sensitivity (%)9493.282.7668884817285.29081
Specificity (%)3317.981.3836687768490.78178
Negative predictive value (%)506159.1657579887078.892–
Positive predictive value (%)886593.5848891658293.879–
Positive likelihood ratio1.221.354.423.882.596.463.374.589.164.733.68
Negative likelihood ratio0.180.380.210.410.180.180.250.330.160.120.24
AUROC0.740.720.870.810.830.920.850.860.930.900.86

aHundred and fifty-nine patients underwent liver biopsy.

bHundred and twenty-three patients underwent liver biopsy.

cHundred and twenty-four patients underwent 169 liver biopsies.

In a recent meta-analysis based on 7 studies [37], the pooled estimates for the diagnosis of significant fibrosis were good: sensitivity 70% (95% CI, 67%–73%), specificity 84% (95% CI, 80%–88%), positive likelihood ratio 4.2 (95% CI, 2.4 –7.2), and negative likelihood ratio 0.31 (95% CI, 0.23–0.43).

In patients with hepatitis B, TE showed similar performance to those reported in hepatitis C with 84% and 65% positive and negative predictive values, respectively, for a cut-off of 7.0kPa [31]. However, more precise staging may be required in patients with chronic HBV infection who are candidates for antiviral treatment, since the decision to start therapy and also the type of drugs to be used may be influenced by fibrosis stage. For instance, differentiating between F1 and F2 stage may be critical not to start long-term therapy with analogs with the risk of developing resistance. Thus, more data are needed before TE can be used in patients with hepatitis B and liver biopsy should still be recommended before starting antiviral therapy in these patients. Similarly in patients with NASH, although preliminary data suggest that performances of TE are close to those observed in hepatitis C [35], [36], the staging of disease severity is still a matter of debate and the distinction between bland steatosis and steatohepatitis can only be made on liver biopsy.

Finally, the imperfection of liver biopsy, used as the reference standard, can also influence the diagnostic property of TE. Thus the inclusion criteria of the studies should be very strict and include only cases with adequate histological samples fulfilling the recommended guidelines for liver histology [6].

3.2. Diagnosis of cirrhosis 

TE is a very promising tool for the early detection of cirrhosis. In the 2 initial studies in patients with chronic hepatitis C [17], [18], the best performances were observed for severe fibrosis (F⩾3) (with AUROCs of 0.90 and 0.91, respectively) and cirrhosis (F=4) (with AUROCs of 0.95 and 0.97, respectively) (Table 1). A cut-off value of 12.5kPa yielded positive and negative predictive values of 77% and 95%, respectively, for the diagnosis of cirrhosis, whereas a cut-off value of 14.6 yielded positive and negative predictive values of 78% and 97%, respectively. When compared with standard laboratory tests and non-invasive scores, TE had the best diagnostic performance for early detection of cirrhosis in patients with chronic hepatitis C, avoiding liver biopsy in 90% of cases versus 82% with platelet count, 80% with FibroTest, 78% with prothrombin index, 76% with prothrombin time or AST/ALT ratio, 70% with APRI and 45% with Lok index, respectively [38]. Interestingly, in patients without clinical or biological signs suggestive of cirrhosis, diagnosis could have been made in 70% with TE, versus 42% with FibroTest, 24% with APRI and 8% with AST/ALT ratio and 4% with the Lok index.

In a recent meta-analysis based on 9 studies [37], the pooled estimates for the diagnosis of cirrhosis were excellent: sensitivity 87% (95% CI, 84%–90%), specificity 91% (95% CI, 89%–92%), positive likelihood ratio 11.7 (95% CI, 7.9–17.1), and negative likelihood ratio 0.14 (95% CI, 0.10–0.20). A “cut-off effect” was identified as an important cause of heterogeneity for pooled results. Indeed, an optimal TE cut-off for cirrhosis remains debated. Reported TE cut-offs for cirrhosis range from 10.3kPa in chronic hepatitis B [31] to 17.3kPa in chronic cholestatic diseases [34] (Table 3). In the largest series to date in 1007 patients with chronic liver diseases of various causes [20], it has been suggested that TE cut-off values could be optimized if specifically defined for each aetiology. Because HBV is the main cause of macronodular cirrhosis, it is possible that the amount of fibrosis is lower in the cirrhotic liver of patients with HBV infection than in that of patients with cholestatic diseases. However, it must be kept in mind that these cut-off values have been defined using ROC curves in order to maximize sensitivity and specificity. Difference between cut-offs may be simply related to difference in cirrhosis prevalence in the studied populations as recently suggested for other non-invasive methods [39]. Indeed, prevalence of cirrhosis varied widely across the different studies ranging from 7.5% to 38.5% (Table 3). Although a cut-off value defined in a given population may be relevant, it may not be applicable to another population where the prevalence is different. Also, one might speculate that in patients with NASH or in patients with hepatitis C and massive steatosis (such as those infected with HCV genotype 3), steatosis could influence the cut-offs. Thus, further studies are needed to address this issue.

Table 3. Diagnostic performance of transient elastography for the diagnosis of cirrhosis according to liver disease aetiology
AuthorsMarcellin et al. [31]de Ledinghen et al. [32]Fraquelli et al. [14]Rigamonti et al. [60]Carrion et al. [53]Coco et al. [21]Vergara et al. [33]Ganne-Carrie et al. [20]Gomez-Dominguez et al. [30]Yoneda et al. [36]Corpechot et al. [34]Foucher et al. [19]
Number of patients1707220095124a228b169c775946795354
Prevalence of cirrhosis (F4)8%23.6%12%17%11%20.2%38.5%15.5 %17%7.5%16%13.3%
AetiologiesHBVHCV-HIVAllHCV-LTHCV-LTHCV & HBVHCV-HIVAllAllNAFLDPBC & PSCAll
Proposed cut-offs (kPa)10.311.811.91212.514.014.614.616.017.017.317.6
Sensitivity (%)831009193100789379891009377
Specificity (%)9692.789938798889596989597
Negative predictive value (%)9782989910082949698969992
Positive predictive value (%)4810053745098867480647891
Positive likelihood ratio20.7513.708.27147.70397.7515.8022.255018.625.66
Negative likelihood ratio0.1700.10.0700.220.080.110.1100.070.23
AUROC0.920.970.900.900.980.960.950.950.940.990.960.96

aHundred and twenty-four patients underwent 169 liver biopsies.

bHundred and fifty-nine patients underwent liver biopsy.

cHundred and twenty-three patients underwent liver biopsy.

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4. Comparison and combination with serum markers of fibrosis 

TE has certain advantages over indices based on laboratory tests, in that it provides a more direct measurement of fibrosis, is not affected by intercurrent health disorders, and is theoretically applicable to all chronic liver diseases. In a study of 183 patients with chronic hepatitis C, we prospectively compared TE with serum fibrosis markers (FibroTest and APRI) and liver biopsy, all performed on the same day [17]. The combination of TE and FibroTest offered the best diagnostic performance, both for significant fibrosis (F⩾2) and for severe fibrosis-cirrhosis (F3–F4). When TE and FibroTest matched, which was the case in 70–80% of cases, the results also matched with those of liver biopsy in 84% of cases of significant fibrosis (Metavir F⩾2), in 95% of cases of severe fibrosis (F⩾3) and in 94% of cases of cirrhosis (F=4). A clinical management algorithm, using the combination of FibroScan and FibroTest as part of the first-line work-up, was inferred from these results (Fig. 4). Using this algorithm, liver biopsy would have been avoided in 140 (77%) of the 183 patients. In contrast, 19 patients (10%) who qualified for treatment on the basis of liver biopsy would have been offered follow-up instead, and three patients (1.5%) would have been offered treatment instead of follow-up. However, before this algorithm can be implemented in clinical practice, the issue of discordance between FibroScan and FibroTest results needs to be solved. In the 2 studies which addressed this problem, more false-negatives were observed with FibroScan than Fibrotest [40] and it seems that FibroScan more often underestimated, whereas FibroTest more frequently overestimated liver biopsy results [41].

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  • Fig. 4. 

    Proposed algorithm for clinical practice combining FibroScan and Fibrotest as first-line assessment of hepatic fibrosis in patients with chronic hepatitis C. Adapted from Castera et al. [17].

Interestingly, the use of either TE or Fibrotest has been recently recommended in France by the Haute Autorité de Santé (HAS) for the first-line assessment of liver fibrosis in patients with hepatitis C without comorbidities [42].

Combination of either TE and serum markers [43] or 2 non-invasive serum markers (APRI and FibroTest) sequentially [44] appears to increase diagnostic accuracy in patients with hepatitis C for the detection of both significant fibrosis and cirrhosis. Recently, two algorithms (FibroScan+FibroTest versus APRI+FibroTest) in the same population of patients with chronic hepatitis C were compared [45]. The results suggest that both algorithms are effective and that their use in clinical practice would result in a reduction of liver biopsies in 48 to 71% of cases for the diagnosis of significant fibrosis and in 74 to 78% of cases for cirrhosis.

The combination of FibroScan with FibroTest [46], [47] or other serum markers [48] may also be of interest in HCV-infected patients with normal ALT values and in chronic hepatitis B inactive carriers [49]. Indeed in the Bordeaux experience in 266 HBV positive patients, the combination of FibroScan and FibroTest allowed to exclude significant fibrosis (⩾F2) in nearly 80% of 100 inactive carriers of HBV.

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5. Monitoring of disease progression 

5.1. Screening for complications of cirrhosis 

One promising and most attractive application of TE concerns the monitoring of liver fibrosis progression. In cirrhotic patients with chronic hepatitis C, liver stiffness values range from 12.5 to 75kPa. It is obviously of great interest to understand whether cut-offs of clinical value exist across this wide range of measurements. Preliminary results from our group [19] suggest that liver stiffness values in cirrhotic patients may increase as liver disease becomes more advanced. In this retrospective study of 711 patients with chronic liver diseases (95 with histologically proven cirrhosis), liver stiffness values significantly correlated not only with the Child-Pugh score but also with clinical parameters (past history of bleeding varices or ascites, hepatocellular carcinoma), biological parameters (platelets, prothrombin time, factor V, albumin and bilirubin) and other relevant parameters (esophageal varices stage 2/3, splenomegaly on sonography, nodular surface, heterogeneous parenchyma) of liver disease severity. For instance, the cut-off values of 27.5, 37.5, 49.1, 53.7 and 62.7kPa had >90% negative predictive value for the presence of esophageal varices stage 2/3, child-Pugh scores B or C, past history of ascites, hepatocellular carcinoma and oesophageal bleeding, respectively. However, these preliminary findings need to be confirmed in long-term prospective follow-up studies to see whether liver stiffness values can predict the occurrence of clinical events in patients with compensated cirrhosis. If so, TE could be used as a rapid screening tool to allocate cirrhotic patients to a specific risk category [50].

5.2. Screening for portal hypertension 

Several recent studies have reported a correlation between liver stiffness values and portal hypertension, assessed either by the presence of oesophageal varices (OV) on upper GI endoscopy [38], [51], [52] or by the measurement of hepatic venous pressure gradient (HVPG) (the gold standard for the diagnosis and staging of portal hypertension) [52], [53], [54], [55] (Table 4). Carrion et al. [53] were the first to report a close direct correlation between liver stiffness values and HVPG (Pearson coefficient, 0.84; P<0.001) in 124 HCV-infected liver transplant recipients [56] (Fig. 5A). More recently, Vizzutti et al. [52] reported similar results in 61 patients with HCV-related severe chronic liver disease (Metavir F3–F4) (Fig. 5B). However, although the correlation was excellent for HVPG values less than 10 or 12mmHg (r=0.81, P<0.0003 and r=0.91, P<0.0001, respectively), linear regression analysis was not optimal for HVPG values >10mmHg (the threshold value of the HVPG for the formation of varices) (r2=0.35, P<0.0001) or >12mmHg (the threshold for the appearance of other complications, such as variceal bleeding and ascites) (r2=0.17, P<0.02). This important observation is consistent with the pathophysiology of portal hypertension where several extrahepatic factors such as the hyperdynamic circulation, the splanchnic vasodilatation, and the resistance opposed to portal blood flow by the portosystemic collaterals contribute to the rise in portal pressure. It suggests that although TE may reflect a progressive rise in portal pressure, mainly due to an increase in hepatic vascular resistance from the accumulation of fibrillar extracellular matrix, it cannot measure the complex hemodynamic changes characteristics of late portal hypertension [57]. Accordingly, TE is unlikely to be useful in the monitoring the hemodynamic response to drug therapy, the effect of which is mediated primarily by alterations in splanchnic blood flow.

Table 4. Diagnostic performance of transient elastography for the detection of portal hypertension
AuthorsCarrion et al. [53]Bureau et al. [54]Lemoine et al. [55]Vizutti et al. [52]Kazemi et al. [51]Castera et al. [38]
Number of patients124150914716577
AetiologiesHCVHCV/alcoholHCV/alcoholHCVAllHCV
Prevalence of oesophageal varices (OV)–––66%45%38%
Proposed cut-offs (kPa) (HVPG)8.7a21b20b17.6c–––––
Proposed cut-offs (kPa) (presence of OV)––––17.613.9–21.3–
Proposed cut-offs (kPa) (OV grade 2–3)––––––19.0–30.5
Sensitivity (%)909088949095917976
Specificity (%)819361814343607080
Negative predictive value (%)909381916691958492
Positive predictive value (%)819172867757486454
AUROC0.920.940.870.920.760.840.830.820.85

aHepatic venous pressure gradient (HVPG)⩾6mmHg.

bHVPG⩾10mmHg.

cHVPG⩾12mmHg.

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  • Fig. 5. 

    (A) Relationship between liver stiffness and portal pressure in a cohort of 124 HCV-infected liver transplant recipients who underwent 129 paired hepatic venous pressure gradient (HVPG) and liver stiffness measurements. Patients are grouped according to the HVPG value (x axis): normal portal pressure (HVPG<6mmHg), mild portal hypertension (HVPG=6–9.9mmHg), and clinically significant portal hypertension (HVPG⩾10mmHg). Adapted from Garcia-Samanego & Forns [56]. (B) Linear regression analysis between HVPG and liver stiffness values in 61 HCV patients. Adapted from Vizzutti et al. [52].

Regarding the relationship between liver stiffness and the presence of varices, AUROCs of TE for the prediction of OV ranged from 0.76 to 0.84 [38], [51], [52] (Table 4). Using cut-offs of 13.9, 17.6 and 21.3kPa, sensitivity for the prediction of the presence of OV was high (95%, 90%, and 79%, respectively) but specificity was rather low (43%, 43%, and 70%, respectively) [38], [51], [52]. A correlation between liver stiffness values and variceal size was observed in 2 studies [38], [51], whereas it was not in another [52]. Using cut-offs of 19 and 30.5kPa, sensitivity for the prediction of the presence of large OV (grade 2 and 3) was high (91% and 76%, respectively) but specificity (60% and 80%, respectively) and positive predictive value (48% and 54%, respectively) were rather low [38], [51]. These results give rise to several comments [58]. First, the assessment of size of varices is rather subjective, and no details were provided in these studies regarding the quality of this assessment (double observers for each endoscopy, assessment of the degree of agreement between the endoscopists). Second, these findings were not validated prospectively in an independent sample. Third, as for cirrhosis, the optimal cut-off for predicting varices remains to be defined. Finally, the specificity and positive predictive value reported so far are much too low for a reliable use in clinical practice. Thus, from the data currently available, measurement of liver stiffness may not be accurate enough at detecting varices as to delay endoscopy in patients diagnosed to have cirrhosis [58]. However, even if not that accurate in predicting size of varices, liver stiffness measurement may still reflect the risk of bleeding [59]. Further studies are needed to address this issue.

5.3. Hepatitis C recurrence after liver transplantation 

TE could be also valuable for assessing the severity of recurrent hepatitis C after liver transplantation, reducing the need for follow-up liver biopsies [53], [60]. In the study by Carrion [53], at a cut-off value of 8.5kPa, the sensitivity, specificity and negative and positive predictive values for significant fibrosis (F⩾2) were 90%, 81%, 79% and 92%, respectively (Table 2). Importantly, none of the patients with liver stiffness below the cut-off value had severe fibrosis (F3) or cirrhosis (F4), or significant portal hypertension (HVPG⩾10mmHg). Moreover, only 6 (10%) of 62 patients with liver stiffness below the cut-off value had portal hypertension, and in all of them portal hypertension was mild (6mmHg in 2, 6.5mmHg in 2 and 8mmHg in 2) (Fig. 5A).

Interestingly, in the study by Rigamonti et al. [60], during post-liver transplantation follow-up in 40 patients with paired liver biopsies (6 to 21 months), TE results changed in parallel with fibrosis staging (r=0.71), showing 86% sensitivity and 92% specificity in predicting staging increases.

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6. How to interpret transient elastography in clinical practice and recommendations for a rational use 

TE is a very promising non-invasive method for the assessment of hepatic fibrosis in patients with chronic liver diseases with the best diagnostic performances for severe fibrosis and cirrhosis. However, several important questions remain to be solved including: To what extent does hepatic steatosis influence liver stiffness values? Which cut-offs should be used in patients of different liver disease aetiologies? How can TE be used for monitoring disease progression? Is TE sensitive enough to detect changes in fibrosis over time in relation with response to antiviral treatment or anti-fibrotic therapy?

TE will probably be soon widely adopted in clinical practice, even though no specific guidelines are currently available. Indeed, the results of a national survey in France clearly showed that TE and serum markers of liver fibrosis are widely used in routine clinical practice, despite the absence of guidelines [61]. However, it is likely that these non-invasive fibrosis tools will reduce but not substitute the need for liver biopsy [12]. While guidelines are awaited, the following recommendations can be made for the rational use of TE in clinical practice:

(a)For TE results to be considered reliable strict adherence to quality criterial should be followed while performing the TE examination. The interquartile range (IQR) should not exceed 30% of the median value and the success rate (the ratio of the number of successful measurements to the total number of acquisitions) should be at least 60% for the TE result to be deemed valid.

(b)Results should always be interpreted by an expert clinician according to the clinical context (taking demographics, disease aetiology and laboratory parameters into account).

(c)TE should be repeated when results are discordant with clinical context and a liver biopsy should be performed when discordance is unexplained.

(d)To predict severity of fibrosis the use of ranges of values rather than a single cut-off value should be used (Fig. 6). For instance, when liver stiffness values range between 2.5 and 7kPa, mild or absent fibrosis is likely, whereas cirrhosis is likely when values are above 12.5kPa.
  • View full-size image.
  • Fig. 6. 

    Clinical significance of liver stiffness cut-offs in chronic liver diseases. When liver stiffness values range between 2.5 and 7kPa, mild or absent fibrosis is likely, whereas when liver stiffness values are above 12.5kPa, cirrhosis is likely.


e)Apart from the initial evaluation of patients with chronic hepatitis C, a decision should not be made on the sole results of TE in other settings.

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7. Future perspectives 

Although there is growing evidence that TE will become an important tool in the future practice of hepatology, there is still work to be done to further define its correct place. The focus should now shift from cross-sectional diagnosis to the utilization of TE in longitudinal studies to look at disease progression, regression and clinical outcomes and priority should be given to large scale validation studies. Indeed, longitudinal monitoring of fibrosis in treated and untreated patients may be a very exciting application for TE. Preliminary results suggest that a significant decrease of liver stiffness values is observed in patients with chronic hepatitis C after sustained viral eradication as compared with untreated or non-responder patients [62], [63], [64]. TE, together with serum markers, should therefore be included in future clinical trials and cohort studies.

Given its excellent patient acceptance and its simplicity, TE may also be an interesting tool for the screening of high-risk populations (excessive alcohol drinkers, IV drug users, etc.) to identify patients with liver disease. Further studies are needed on that specific issue. TE could also be used for diagnosing liver disease in children in whom a specific probe is currently under evaluation [65].

Finally, new alternative imaging techniques may also become available: magnetic resonance (MR) elastography that can be implemented readily on standard MR imaging systems with additional hardware; diffusion weighted magnetic resonance imaging (DWMRI), which measures the apparent diffusion coefficient of water (ADC), a parameter that is dependent on the tissue structure, and sonography-based real-time elastography, which can be performed with conventional ultrasound probes during a routine sonography examination. Preliminary studies in human subjects have confirmed the feasibility of these techniques for quantitative assessment of hepatic fibrosis [66], [67], [68], [69], [70]. Although these techniques may overcome some limitations of TE such as obesity and ascites, they are currently not ready for implementation in clinical practice for screening hepatic fibrosis because of their limited cost-effectiveness and patient acceptance.

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☆ The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript.

PII: S0168-8278(08)00123-2

doi:10.1016/j.jhep.2008.02.008

Journal of Hepatology
Volume 48, Issue 5 , Pages 835-847, May 2008

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