**4. Performance of TE for the noninvasive evaluation of liver fibrosis HCV patients**

The first condition that benefited from unidimensional transient elastography was chronic hepatitis type C [21, 26].

#### **4.1. The diagnosis of liver fibrosis stages**

aminer and the recommandations of the producer [19]. It is not known whether this variabil‐ ity is encountered only in the diseased liver or whether it is present in the healthy liver as well and to what degree this affects the interpretation of the results. The cause of this prob‐ lem can be an inadequate technique or the liver pathology itself (for example, in macronod‐ ular cirrhosis, liver stiffness can be different in different areas of the liver). When there is a high variability of the results, it is important to check whether the probe is placed perfectly perpendicular on the thoracic wall, if the transmited vibration does not encounter the ribs and if the waves are transmited vertically, strictly between the ribs. If the generated wave is large, bifid or angulated, than the software of the machine will reconstruct the velocity curve in different points of the wave and therefore lead to variations of the acquired values. In order to obtain an accurate elastogram the transducer must be placed in the middle area of the right lobe, avoiding contact with the ribs that may lead to vibration distorsion and

The technique measures the stiffness of a volume that is equivalent with that of a cilinder of 1 cm in diameter and 4 cm in length (the measurement can be performed on a distance of 25 to 45 cm from the skin). This volume, representing about 1/500 of the liver volume, is at least a 100 times larger than the one obtained through liver biopsy and it is therefore more repre‐

The examination can be performed by a technician following a short period of training (ap‐ proximately 100 cases) [22-23], while the clinical interpretation of the results must always be done by an expert who would consider the demographic data, the etiology of the disease

A multivariate analysis of the relationship between liver stiffness and fibrosis, necroinflam‐ matory activity and steatosis Showed, in some studies, that there is a significant correlation with fibrosis, but no correlation with necroinflammatory activity and steatosis [16, 24]. Nev‐ ertheless, the authors of the initial concept acknowledged, following in vitro studies, that it is unlikely that a single physical parameter (liver stiffness) would describe entirely a com‐

A prospective assessment of the role of the histopathological parameters seen in LB in ex‐ plaining the variance of liver stiffness was performed on 345 chronic hepatitis C patients that all underwent liver biopsy [25]. First, LS correlated highly with the degree of fibrosis assessed by liver biopsy,, but we also found a weak correlation with hepatic iron deposition and steatosis and a mild correlation with activity. In multiple regression analysis, fibrosis, activity, and steatosis independently influenced LSM. Iron deposition does not seem to in‐ fluence the liver stiffness in CHC patients. Fibrosis, activity, and steatosis together explained 62.4% of the variance of the LS. The three significant parameters uniquely explained 45.95% of the amount of LS, with fibrosis making the most unique contribution (44.49%); the differ‐ ence of 16.25% (62.4%-45.95%) was accounted for by the joint contribution of the three pa‐ rameters. The size and the direction of the relationships suggest that higher LS values are obtained for patients with advanced fibrosis, increased necroinflammatory activity and in‐ creased steatosis. Among these three, however, the stage of fibrosis is the single most impor‐

and the biochemical profile of the patient at the moment of the examination [21].

absorbtion [19].

212 Liver Biopsy – Indications, Procedures, Results

sentative for the whole liver parenchyma [20, 21].

plex biological system in which fibrosis is only a part [15].

tant predictor, as suggested by the squared partial correlation [25].

Studies performed on a large number of HCV patients indicate that the LS value is highly correlated with the stage of fibrosis. The practical utility of the method is based on establish‐ ing cutoff values for each stage of fibrosis. A diagnosis of stage F ≥2, F ≥3 and F4 (cirrhosis) is based on measurements of liver stiffness that vary, according to some studies, from 6.2 to 8.8 Kpa, 7.7 to 10.8 kPa and from 11 to 14.8 kPa (Table 1) [24, 26-30].

There are some meta-analyses addressing the issue of diagnosis performance of TE. Fifty studies were included in the analysis performed by Friedrich Rust et al. The mean AUROC for the diagnosis of significant fibrosis, severe fibrosis, and cirrhosis were 0.84, 0.89 and 0.94, respectively [31]. In Stebbing's meta-analysis, a total of 22 studies were selected, comprising 4430 patients, most of them suffering from a virus C liver infection. The pooled estimates for significant fibrosis (≥F2) measured 7.71 kPa (LSM cutoff value) with a sensitivity of 71.9% and a specificity of 82.4%, whereas for cirrhosis (F4) the results showed a cutoff of 15.08 kPa with a sensitivity of 84.45% and a specificity of 94.69% [32].

It must be underlined that, in spite of the very good areas under the ROC curves, overlaps of the stiffness values were registered in adjacent stages, especially for early fibrosis [33]. The increase of liver stiffness is higher between stage F2 (6.6 kPa) and F3 (10.3 kPa) of fibro‐ sis than between F1 (5.5 kPa) and F2 (6.6 kPa), a fact that is in agreement with the morpho‐ logical data according to which the increase in fibrotic tissue is more significant from F2 to F3 than from F1 to F2 [12].

The diagnosis accuracy of TE is much better in predicting cirrhosis. In Friedrich-Rust metaa‐ nalysis [31], the AUROC mean for the diagnosis of cirrhosis was 0.94 and the performance estimated by Talwalkar [34] was also very good: sensitivity 87%, specificity 91%, positive probability rate 11.7, and negative probability rate 0.14 (95% CI 0.10-0.20).


fined for a certain population may be relevant, they may not be applicable in another population where the incidence of fibrosis is different. Because of this, it is indicated that each centre establishes its own cutoff values, in agreement with the prevalence of fibrosis stages in that particular population, and calculates the performance of the method in rela‐ tion with those cutoff values. According to our experience on a number of 1138 HCV pa‐ tients that underwent liver biopsy, the predictive cutoff values for stages F1, F2, F3 and F4 are: 5.1kPa, 7.5kPa, 9.1kPa and 13,2kPa, with an AUROC of 0.836, 0.826, 0.933 and 0.973, and diagnosis accuracy between 77 and 92.8% [35]. In table 2 are presented the liver stiffness cut‐ off values that predict each stage of fibrosis for the Romanian patients suffering from viral C chronic hepatitis. The table also presents the sensitivity (Se), specificity (Sp), positive predic‐ tive value (PPV) and negative predicting value (NPV), false positive (FPR) and false nega‐ tive rate (FNR) the area under the ROC curve (AUROC) as well as the diagnosis accuracy (DA) of these cutoff values. In our study, the adjusted AUROC according to the prevalence of each individual stage of fibrosis did not significantly differ from the observed ones (0.847 for F≥1, p=1.00; 0.893 for F≥2, p=0.06; 0.945 for F≥3, p=0.34; 0.983 for F4, p=0.312), therefore

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the cutoff values that we obtained may have a large applicability.

hepatocarcinoma and 62.7 kPa for bleeding esophageal varices.

tal gradient (HVPG) is the best surrogate marker to assess its presence.

*4.2.1. Diagnosis of liver cirrhosis. Prediction of portal hypertension and related complications*

TE has a very good diagnosis accuracy in predicting cirrhosis (stage F4 Metavir), with areas under ROC varying from 0.90 to 0.99 and cutoff values between 9-26.6 kPa [31], but there is a high interest to determine whether the use of the machine's entire specter of measure‐ ments (up to 75 kPa) can predict the clinical events characteristic to the evolution of cirrho‐ sis. Some authors [36] indicated, with a negative predictive value of over 90%, that the suggestive values for predicting the presence of various complications are: 27.5 kPa for large esophageal varices; 37.5 kPa for Child B and C cirrhosis; 49.1 kPa for ascites; 53.7 kPa for

Portal hypertension is the main characteristic of liver cirrhosis, and the hepatic venous por‐

A positive strong correlation between liver stiffness and HVPG was reported in HCV pa‐ tients [37] and, afterwards, independently confirmed in another group of patients with se‐ vere fibrosis (Metavir F3-F4) [38]. The correlation was excellent for HVPG values lower than 10 or 12 mm Hg, but the linear regression analysis did not reveal exceptional results for HVPG values >10 mm Hg or >12 mm Hg. This means that, even though TU may detect a progressive elevation of the portal pressure, mainly because of an increase in intrahepatic vascular resistance caused by the accumulation of extracellular fibrillar matrix, this method can not entirely determine the extremely complex hemodynamic alterations that character‐ ize the delayed phase of portal hypertension [39]. As a result, some authors believe it is un‐ likely that elastography can be useful in monitoring the hemodynamic therapeutic response, as the effect of the treatment is mainly mediated by the splanchnic circulatory changes [40].

**4.2. Monitoring disease progression**

**Table 1.** Liver stiffness cutoff values for staging liver fibrosis using TE in HCV patients. Sensibility (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) for each fibrosis stage (using Metavir scorring system).

But it must not be forgotten that the cutoff values for predicting the stages of fibrosis were chosen using the ROC curves in such a way that the sum of sensitivity and specificity is maximum. The country where the study was performed was among the factors that influ‐ enced the diagnosis performance of TE [31]. Therefore, even though the cutoff values de‐ fined for a certain population may be relevant, they may not be applicable in another population where the incidence of fibrosis is different. Because of this, it is indicated that each centre establishes its own cutoff values, in agreement with the prevalence of fibrosis stages in that particular population, and calculates the performance of the method in rela‐ tion with those cutoff values. According to our experience on a number of 1138 HCV pa‐ tients that underwent liver biopsy, the predictive cutoff values for stages F1, F2, F3 and F4 are: 5.1kPa, 7.5kPa, 9.1kPa and 13,2kPa, with an AUROC of 0.836, 0.826, 0.933 and 0.973, and diagnosis accuracy between 77 and 92.8% [35]. In table 2 are presented the liver stiffness cut‐ off values that predict each stage of fibrosis for the Romanian patients suffering from viral C chronic hepatitis. The table also presents the sensitivity (Se), specificity (Sp), positive predic‐ tive value (PPV) and negative predicting value (NPV), false positive (FPR) and false nega‐ tive rate (FNR) the area under the ROC curve (AUROC) as well as the diagnosis accuracy (DA) of these cutoff values. In our study, the adjusted AUROC according to the prevalence of each individual stage of fibrosis did not significantly differ from the observed ones (0.847 for F≥1, p=1.00; 0.893 for F≥2, p=0.06; 0.945 for F≥3, p=0.34; 0.983 for F4, p=0.312), therefore the cutoff values that we obtained may have a large applicability.

#### **4.2. Monitoring disease progression**

**Fibrosis Stage**

214 Liver Biopsy – Indications, Procedures, Results

system).

**Author Cutoff (kPa) Se(%) Sp(%) PPV(%) NPV(%) +LR -LR AUROC**

Castera [26] - - - - - - - - Sporea [27] - - - - - - - - Nitta [28] - - - - - - - - Arena [29] - - - - - - - - Kim SU [30] - - - - - - - -

F≥1 Ziol [24] - - - - - - - -

F≥2 Ziol [24] 8.8 56 91 56 88 0.63 0.48 0.79

F≥3 Ziol [24] 9.6 86 85 93 71 5.76 0.16 0.91

F4 Ziol [24] 14.6 86 96 97 78 23.05 0.14 0.97

**Table 1.** Liver stiffness cutoff values for staging liver fibrosis using TE in HCV patients. Sensibility (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) for each fibrosis stage (using Metavir scorring

But it must not be forgotten that the cutoff values for predicting the stages of fibrosis were chosen using the ROC curves in such a way that the sum of sensitivity and specificity is maximum. The country where the study was performed was among the factors that influ‐ enced the diagnosis performance of TE [31]. Therefore, even though the cutoff values de‐

Castera [26] 12.5 87 91 95 77 9.66 0.14 0.95 Sporea [27] - - - - - - - - Nitta [28] 11.6 91.7 78 41.5 98.2 4.2 - 0.90 Arena [29] 14.8 94 92 73 98 11.27 0.07 0.98 Kim SU [30] 11 77.8 93.9 58.3 97.5 12.8 0.2 0.970

Castera [26] 9.5 73 91 81 87 8.11 0.29 0.90 Sporea [27] - - - - - - - - Nitta [28] 9.6 87.7 82.4 72.5 92.7 5 - 0.90 Arena [29] 10.8 91 94 92 73 11.27 0.07 0.99 Kim SU [30] 7.7 100 95.7 87.5 100 0 23.3 0.993

Castera [26] 7.1 67 89 48 95 6.09 0.37 0.83 Sporea [27] 6.8 59.6 93.3 98 30.1 - - 0.773 Nitta [28] 7.1 82.8 80.3 86 73.6 4.1 0.88 Arena [29] 7.8 83 82 83 79 4.58 0.20 0.91 Kim SU [30] 6.2 76 97.5 97.4 80 30.4 0.3 0.909

#### *4.2.1. Diagnosis of liver cirrhosis. Prediction of portal hypertension and related complications*

TE has a very good diagnosis accuracy in predicting cirrhosis (stage F4 Metavir), with areas under ROC varying from 0.90 to 0.99 and cutoff values between 9-26.6 kPa [31], but there is a high interest to determine whether the use of the machine's entire specter of measure‐ ments (up to 75 kPa) can predict the clinical events characteristic to the evolution of cirrho‐ sis. Some authors [36] indicated, with a negative predictive value of over 90%, that the suggestive values for predicting the presence of various complications are: 27.5 kPa for large esophageal varices; 37.5 kPa for Child B and C cirrhosis; 49.1 kPa for ascites; 53.7 kPa for hepatocarcinoma and 62.7 kPa for bleeding esophageal varices.

Portal hypertension is the main characteristic of liver cirrhosis, and the hepatic venous por‐ tal gradient (HVPG) is the best surrogate marker to assess its presence.

A positive strong correlation between liver stiffness and HVPG was reported in HCV pa‐ tients [37] and, afterwards, independently confirmed in another group of patients with se‐ vere fibrosis (Metavir F3-F4) [38]. The correlation was excellent for HVPG values lower than 10 or 12 mm Hg, but the linear regression analysis did not reveal exceptional results for HVPG values >10 mm Hg or >12 mm Hg. This means that, even though TU may detect a progressive elevation of the portal pressure, mainly because of an increase in intrahepatic vascular resistance caused by the accumulation of extracellular fibrillar matrix, this method can not entirely determine the extremely complex hemodynamic alterations that character‐ ize the delayed phase of portal hypertension [39]. As a result, some authors believe it is un‐ likely that elastography can be useful in monitoring the hemodynamic therapeutic response, as the effect of the treatment is mainly mediated by the splanchnic circulatory changes [40].


The literature data available on this topic are synthetized in table 3

HVPG ≥ 6 mm Hg; <sup>b</sup> HVPG ≥ 10 mm Hg; <sup>c</sup>

**Table 3.** TE performance in EV diagnosis and HVPG prediction in liver cirrhosis patiens.

in the selection of the patients who will not experiment clinical events.

*4.2.2. Optimization of liver stiffness performance in the diagnosis of liver cirrhosis or its*

Based on the principle enounced by Pinzani et al, which states that a concordance between two distinct noninvasive tests is needed for an accurate diagnosis [52], an association be‐ tween LS and serum noninvasive tests for liver fibrosis was used to improve the diagnostic accuracy. Such an algorithm was proposed by the Bordeaux group [53] and it is based on the concordance between FibroScan and FibroTest. Using this approach, cirrhosis could be diag‐ nosed with an accuracy of 93% and liver biopsy could be avoided for the diagnosis of cirrho‐

pressure gradient (a

*complications*

sis in almost 80% of cases.

Author etiology prev EV cutoff (kPa) Se Sp VPP VPN AUROC HVPG VE VEM Carion[37] HCV - 8.7a - - 90 81 90 81 0.92 Bureau[43] toate - 21b - - 90 93 91 90 0.94 Lemoine [48] HCV - 20.5b - - 63 70 35 88 0.76

Vizutti [38] HCV 66% 17.6c - - 94 81 91 86 0.92

Kazemi [42] toate 45% - 13.9 - 95 43 91 57 0.84

Castera [41] HCV 36% - 21.5 - 76 78 84 68 0.82

HCV = hepatits C virus; -OH = etanol; EV = esophageal varices; LEV =large esophageal varices; Se = sensibility; Sp = specificity; P/NPV =positive/negative predictive value; AUROC = area under the ROC curve; HVPG = Hepatic venous

The huge potential of TE for cirrhosis patients was acknowledged ever since the method was introduced, as it can serve as a fast and non-invasive screening toll in the assessment of actual complications, it can estimate the long term risk and thus place the patient in a certain risk category [49]. The first signs of this possibility were the outcome of a retrospective study which found that the risk of a patient with hepatitis C for developing hepatocellular carcinoma is 5 times higher in patients with a LS value above 25 kPa, at the moment of the diagnosis [50]. Even more, a recent prospective study [51], that evaluated the role of liver stiffness in predicting complications related to portal hypertension in cirrhosis patients, demonstrated that a LS value < 21.1 kPa at diagnosis was as valuable as a HVPG<12 mmHg


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HVPG ≥ 12 mm Hg).

**Table 2.** Diagnostic performance of different cutoff values of liver stiffness in staging liver fibrosis in HCV Romanian patients [35].

Regarding the relationship between liver stiffness and the presence of esophageal varices, the area under the ROC curve for predicting the presence of varices varied between 0.76 and 0.84 [38, 41, 42]. Using cutoff values of 13.9 kPa, 17.6 kPa and 21.3 kPa, the sensitivity for varices prediction was high (95%, 90% and 79%), but the specificity was relatively low (43%, 43% and 70%) [38, 41, 42]. There are studies that demonstrated a relationship between the value of liver stiffness and the size of the varices [41, 42, 43], while other studies were not able to demonstrate this correlation [38]. Using cutoff values of 19 and 30.5 kPa, the sensitiv‐ ity of TE for varices prediction was higher, but the specificity and the positive predictive value were modest [41, 42]. TE did not provide better results than the serological markers (like prothrombin time, thrombocytes [44] or FibroTest [45]), neither for varice detection (re‐ gardless of their grade), nor for the diagnosis of significant varices [41]. Yet, a predictive role of liver stiffness in anticipating variceal bleeding cannot be excluded [43, 46].

These contradicting results may be caused by the heterogeneity of the studied populations, the variable prevalence of varices (in general, but also of the large ones), the lack of prospec‐ tive validation (all the cited studies were cross-sectional studies) and the variability of the cutoff values [47]. In conclusion, the evaluation of liver stiffness is not safe enough for the detection and grading of esophageal varices in such a manner that it may replace upper di‐ gestive tract endoscopy in patients with cirrhosis, since the specificity and positive predic‐ tive value reported until now are too low to allow for a regular use of the method in clinical practice.


### The literature data available on this topic are synthetized in table 3

**≥ F1; F0vsF1234 ≥ F2; F01vsF234 ≥ F3; F012vsF34 F4; F0123vsF4**

0.847 0.893 0.945 0.983

value (kPa) 5.1 7.5 9.1 13.2 Se (%) 85.09 74.27 86.99 93.59 Sp (%) 65.45 82.95 88.51 92.71 +LR 2.46 4.36 7.57 12.84 -LR 0.23 0.31 0.15 0.07 PPV (%) 97.9 88.8 83.2 83.4 NPV (%) 18.7 63.9 91.2 97.4 FPR (%) 36.36 17.30 12.23 7.41 FNR (%) 13.86 25.59 12.55 6.41 Diagnosis accuracy (%) 85.01 77.34 87.63 92.87 Observed AUROC 0.836 0.860 0.933 0.973

obs vs adj AUROC) 1.00 0.06 0.34 0.312

**Table 2.** Diagnostic performance of different cutoff values of liver stiffness in staging liver fibrosis in HCV Romanian

Regarding the relationship between liver stiffness and the presence of esophageal varices, the area under the ROC curve for predicting the presence of varices varied between 0.76 and 0.84 [38, 41, 42]. Using cutoff values of 13.9 kPa, 17.6 kPa and 21.3 kPa, the sensitivity for varices prediction was high (95%, 90% and 79%), but the specificity was relatively low (43%, 43% and 70%) [38, 41, 42]. There are studies that demonstrated a relationship between the value of liver stiffness and the size of the varices [41, 42, 43], while other studies were not able to demonstrate this correlation [38]. Using cutoff values of 19 and 30.5 kPa, the sensitiv‐ ity of TE for varices prediction was higher, but the specificity and the positive predictive value were modest [41, 42]. TE did not provide better results than the serological markers (like prothrombin time, thrombocytes [44] or FibroTest [45]), neither for varice detection (re‐ gardless of their grade), nor for the diagnosis of significant varices [41]. Yet, a predictive role

These contradicting results may be caused by the heterogeneity of the studied populations, the variable prevalence of varices (in general, but also of the large ones), the lack of prospec‐ tive validation (all the cited studies were cross-sectional studies) and the variability of the cutoff values [47]. In conclusion, the evaluation of liver stiffness is not safe enough for the detection and grading of esophageal varices in such a manner that it may replace upper di‐ gestive tract endoscopy in patients with cirrhosis, since the specificity and positive predic‐ tive value reported until now are too low to allow for a regular use of the method in clinical

of liver stiffness in anticipating variceal bleeding cannot be excluded [43, 46].

Liver stiffness cutoff

216 Liver Biopsy – Indications, Procedures, Results

Adjusted AUROC according to the prevalence of the fibrosis stages

*p* (difference between

patients [35].

practice.

HCV = hepatits C virus; -OH = etanol; EV = esophageal varices; LEV =large esophageal varices; Se = sensibility; Sp = specificity; P/NPV =positive/negative predictive value; AUROC = area under the ROC curve; HVPG = Hepatic venous pressure gradient (a HVPG ≥ 6 mm Hg; <sup>b</sup> HVPG ≥ 10 mm Hg; <sup>c</sup> HVPG ≥ 12 mm Hg).

**Table 3.** TE performance in EV diagnosis and HVPG prediction in liver cirrhosis patiens.

The huge potential of TE for cirrhosis patients was acknowledged ever since the method was introduced, as it can serve as a fast and non-invasive screening toll in the assessment of actual complications, it can estimate the long term risk and thus place the patient in a certain risk category [49]. The first signs of this possibility were the outcome of a retrospective study which found that the risk of a patient with hepatitis C for developing hepatocellular carcinoma is 5 times higher in patients with a LS value above 25 kPa, at the moment of the diagnosis [50]. Even more, a recent prospective study [51], that evaluated the role of liver stiffness in predicting complications related to portal hypertension in cirrhosis patients, demonstrated that a LS value < 21.1 kPa at diagnosis was as valuable as a HVPG<12 mmHg in the selection of the patients who will not experiment clinical events.

#### *4.2.2. Optimization of liver stiffness performance in the diagnosis of liver cirrhosis or its complications*

Based on the principle enounced by Pinzani et al, which states that a concordance between two distinct noninvasive tests is needed for an accurate diagnosis [52], an association be‐ tween LS and serum noninvasive tests for liver fibrosis was used to improve the diagnostic accuracy. Such an algorithm was proposed by the Bordeaux group [53] and it is based on the concordance between FibroScan and FibroTest. Using this approach, cirrhosis could be diag‐ nosed with an accuracy of 93% and liver biopsy could be avoided for the diagnosis of cirrho‐ sis in almost 80% of cases.

On the other hand, our group managed to demonstrate that the Lok Score and LS used to‐ gether as part of a noninvasive algorithm (see figure 1) can improve (78% diagnostic accura‐ cy) the noninvasive estimation of large esophageal varices in cirrhotic patients [54].

needed. Nevertheless, increased LS seems to be a determinant of advanced cirrhosis, being associated with decompensating episodes (high grade esophageal varices, bleeding, devel‐ opment of ascites) as well as with the presence of HCC [62], proving that increased LS alone

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219

On the other hand, Japanese studies also suggest that TE could be used as an indicator for the de‐ velopment of hepatocellular carcinoma in patients with virus C hepatitis [58, 63], the risk being 5 times higher in patients with a liver stiffness of over 25 kPa. Yet, these results must be confirmed in prospective studies performed on larger groups of patients, in order to see whether liver stiff‐ ness can trully predict complication development in patients with compensated cirrhosis [21]. If this fact is confirmed, elastography may serve as a non-invasive, quick screening modality which

ETU is useful in the appreciation of the severity of hepatitis C recurrence after transplanta‐ tion, thus reducing the number of liver biopsies [65]. In Carrion's study, for a cutoff value of 8.5 kPa, the sensitivity, specificity, negative predictive value and positive predictive value in anticipating significant fibrosis were 90%, 81%, 79% and 92%. The important thing is that none of the patients with a liver stiffness below that value presented severe fibrosis (F3), cir‐ rhosis (F4) or significant portal hypertension (HVPG ≥10 mm Hg). Furthermore only 6 (10%) out of the 62 patients, having LS below the established threshold limit value,, did develop

In Rigamonti's study [66], during the follow-up after transplantation, in 40 patients with double biopsies (at 6 and 21 months), the liver stiffness changed in parallel with the stage of fibrosis, having a sensitivity of 86 % and a specificity of 92% in predicting an increase in the

A recently published meta-analysis [67] showed that in patients undergoing transplantation for HCV-related disease, TE appears to be a reliable diagnostic test for the exclusion of liver cirrho‐ sis. Furthermore, low TE values can reliable exclude cirrhosis in patients with recurrent HCV af‐ ter liver transplantation and liver biopsy may even be avoided in these situations. Among the studies that evaluated significant fibrosis due to a recurrent HCV infection after liver transplan‐ tation, the pooled estimates were 83% for sensitivity, 83% for specificity, 4.95 for the positive like‐ lihood ratio, 0.17 for negative likelihood ratio and 30.5 for diagnostic odds ratio. For the studies that assessed cirrhosis, the pooled estimates were 98% for sensitivity, 84% for specificity, 7 for positive likelihood ratio, 0.06 for negative likelihood ratio, and 130 for diagnostic odds ratio[67].

**5. Confounding factors influencing the interpretation of liver stiffness**

Since the liver is self-contained in the non extensible Glisson's capsule, stiffness is definitive‐ ly influenced by pressure that can be either hydrostatic or osmotic [68]. There are a few con‐

cannot be a good predictor of HCC.

stage of fibrosis.

**values**

could place the cirrhosis patient in a certain risk category [64].

portal hypertension, but in all cases it was a mild hypertension.

*4.2.4. Hepatitis C infection recurrence after liver transplant*

**Figure 1.** Proposition for a non-invasive algorithm for the assessment of esophageal varices in patients with liver cir‐ rhosis.

#### *4.2.3. TE efficacy in hepatocellular carcinoma risk assessment*

Early detection of hepatocellular carcinoma (HCC) in HCV patients represents an emerging health problem. As a common practice, alpha-fetoprotein (AFP) is widely used for the diag‐ nosis of HCC, despite its low sensitivity and specificity [55]. Tateyama et al report AFP above normal levels as a risk factor for the development of hepatocellular carcinoma in pa‐ tients infected with hepatitis C virus [56].

Besides AFP, it has been proven that LS values increase as the liver disease progresses, the highest values being specific for cirrhotic patients with associated HCC [36]. The evidence prove that the individual role of increased LS measurements and serological markers are predictive biomarkers of HCC [57, 58]. The first risk evaluation of HCC development in HCV patients using TE was first performed by Foucher et al in 2006, reporting a cut-off val‐ ue of 53.7 kPa [36]. Also, according to Akima T et al [59] liver stiffness as measured by TE is a good predictor of HCC development in viral hepatitis, with serum total bilirubin ≥1.0 mg/dL significantly correlated with tumor development. The latest published results report good diagnostic accuracy of LS in HCC prediction, for cut-off values ranging between 12.5 and 53.7 kPa [57,59,60]. However none of these studies have been designed to evaluate the accuracy of more predictive parameters, others than LS. On the other hand, adding bio‐ markers and other variables (such as variance) to LS measurement could represent con‐ founding factors in the assessment of patients with liver cirrhosis and HCC [61]. This may lead to an over- or under-estimation of the risk assessed by TE, so a new accuracy testing is needed. Nevertheless, increased LS seems to be a determinant of advanced cirrhosis, being associated with decompensating episodes (high grade esophageal varices, bleeding, devel‐ opment of ascites) as well as with the presence of HCC [62], proving that increased LS alone cannot be a good predictor of HCC.

On the other hand, Japanese studies also suggest that TE could be used as an indicator for the de‐ velopment of hepatocellular carcinoma in patients with virus C hepatitis [58, 63], the risk being 5 times higher in patients with a liver stiffness of over 25 kPa. Yet, these results must be confirmed in prospective studies performed on larger groups of patients, in order to see whether liver stiff‐ ness can trully predict complication development in patients with compensated cirrhosis [21]. If this fact is confirmed, elastography may serve as a non-invasive, quick screening modality which could place the cirrhosis patient in a certain risk category [64].

### *4.2.4. Hepatitis C infection recurrence after liver transplant*

On the other hand, our group managed to demonstrate that the Lok Score and LS used to‐ gether as part of a noninvasive algorithm (see figure 1) can improve (78% diagnostic accura‐

**Figure 1.** Proposition for a non-invasive algorithm for the assessment of esophageal varices in patients with liver cir‐

Early detection of hepatocellular carcinoma (HCC) in HCV patients represents an emerging health problem. As a common practice, alpha-fetoprotein (AFP) is widely used for the diag‐ nosis of HCC, despite its low sensitivity and specificity [55]. Tateyama et al report AFP above normal levels as a risk factor for the development of hepatocellular carcinoma in pa‐

Besides AFP, it has been proven that LS values increase as the liver disease progresses, the highest values being specific for cirrhotic patients with associated HCC [36]. The evidence prove that the individual role of increased LS measurements and serological markers are predictive biomarkers of HCC [57, 58]. The first risk evaluation of HCC development in HCV patients using TE was first performed by Foucher et al in 2006, reporting a cut-off val‐ ue of 53.7 kPa [36]. Also, according to Akima T et al [59] liver stiffness as measured by TE is a good predictor of HCC development in viral hepatitis, with serum total bilirubin ≥1.0 mg/dL significantly correlated with tumor development. The latest published results report good diagnostic accuracy of LS in HCC prediction, for cut-off values ranging between 12.5 and 53.7 kPa [57,59,60]. However none of these studies have been designed to evaluate the accuracy of more predictive parameters, others than LS. On the other hand, adding bio‐ markers and other variables (such as variance) to LS measurement could represent con‐ founding factors in the assessment of patients with liver cirrhosis and HCC [61]. This may lead to an over- or under-estimation of the risk assessed by TE, so a new accuracy testing is

*4.2.3. TE efficacy in hepatocellular carcinoma risk assessment*

tients infected with hepatitis C virus [56].

218 Liver Biopsy – Indications, Procedures, Results

rhosis.

cy) the noninvasive estimation of large esophageal varices in cirrhotic patients [54].

ETU is useful in the appreciation of the severity of hepatitis C recurrence after transplanta‐ tion, thus reducing the number of liver biopsies [65]. In Carrion's study, for a cutoff value of 8.5 kPa, the sensitivity, specificity, negative predictive value and positive predictive value in anticipating significant fibrosis were 90%, 81%, 79% and 92%. The important thing is that none of the patients with a liver stiffness below that value presented severe fibrosis (F3), cir‐ rhosis (F4) or significant portal hypertension (HVPG ≥10 mm Hg). Furthermore only 6 (10%) out of the 62 patients, having LS below the established threshold limit value,, did develop portal hypertension, but in all cases it was a mild hypertension.

In Rigamonti's study [66], during the follow-up after transplantation, in 40 patients with double biopsies (at 6 and 21 months), the liver stiffness changed in parallel with the stage of fibrosis, having a sensitivity of 86 % and a specificity of 92% in predicting an increase in the stage of fibrosis.

A recently published meta-analysis [67] showed that in patients undergoing transplantation for HCV-related disease, TE appears to be a reliable diagnostic test for the exclusion of liver cirrho‐ sis. Furthermore, low TE values can reliable exclude cirrhosis in patients with recurrent HCV af‐ ter liver transplantation and liver biopsy may even be avoided in these situations. Among the studies that evaluated significant fibrosis due to a recurrent HCV infection after liver transplan‐ tation, the pooled estimates were 83% for sensitivity, 83% for specificity, 4.95 for the positive like‐ lihood ratio, 0.17 for negative likelihood ratio and 30.5 for diagnostic odds ratio. For the studies that assessed cirrhosis, the pooled estimates were 98% for sensitivity, 84% for specificity, 7 for positive likelihood ratio, 0.06 for negative likelihood ratio, and 130 for diagnostic odds ratio[67].
