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Non invasive evaluation of portal hypertension using transient elastography

  • Laurent Castera
    Correspondence
    Corresponding author. Address: Service d’Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Université Denis Diderot-Paris VII, 100 boulevard du General Leclerc, 92110 Clichy, France.
    Affiliations
    Service d’Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Université Denis Diderot Paris VII, Clichy, France
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  • Massimo Pinzani
    Affiliations
    Dipartimento di Medicina Interna, Center for Research, High Education and Transfer “DENOThe”, Università degli Studi di Firenze, Firenze, Italy
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  • Jaime Bosch
    Affiliations
    Hepatic Hemodynamic Laboratory, Hospital Clínic-IDIBAPS, University of Barcelona and CIBERehd, Barcelona, Spain
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Open AccessPublished:July 18, 2011DOI:https://doi.org/10.1016/j.jhep.2011.07.005

      Summary:

      The development of portal hypertension is a common consequence of chronic liver diseases leading to the formation of esophageal and gastric varices responsible for variceal bleeding, associated with a high mortality rate, as well as other severe complications such as portosystemic encephalopathy and sepsis. Measurement of hepatic venous pressure gradient (HVPG) and upper GI endoscopy are considered the gold standards for portal hypertension assessment in patients with cirrhosis. However, both types of investigation are invasive and HVPG measurement is routinely available and/or performed with adequate standards only in expert centres. There is thus a need for non invasive methods able to predict, with acceptable diagnostic accuracy, the progression of portal hypertension toward the levels of clinically significant (i.e. HVPG ⩾10 mmHg) and severe (HVPG ⩾12 mmHg) as well as the presence and the size of oesophageal varices. Transient elastography (TE) is a novel non invasive technology that allows measuring liver stiffness and that has gained popularity over the past few years. Although TE has been initially proposed to assess liver fibrosis, a good correlation has been reported between liver stiffness values and HVPG as well as the presence of oesophageal varices, suggesting that it could be an interesting tool for the non invasive evaluation of portal hypertension. This review is aimed at discussing the advantages and limits of TE and the perspectives for its rationale use in clinical practice for the management of patients with portal hypertension.

      Keywords

      Introduction

      The development of portal hypertension is a common consequence of chronic liver diseases (CLD) characterized by progressive liver tissue fibrogenesis and extensive vascular changes occurring both within the liver and in the splanchnic compartment [
      • Sanyal A.J.
      • Bosch J.
      • Blei A.
      • Arroyo V.
      Portal hypertension and its complications.
      ]. Established evidence indicates that CLD are characterized by a progressive intrahepatic vascular remodelling with capillarization of sinusoids, fibrogenesis, neo-angiogenesis, and development of intrahepatic shunts, which would lead to increased hepatic resistance leading to increased portal pressure and decreased effective hepatocyte perfusion leading to liver failure. It is also well established that increased hepatic vascular resistance in cirrhosis is not only a mechanical consequence of the hepatic architectural disorder (so-called “static component”). Indeed, the extensive accumulation of fibrillar extracellular matrix is associated with the active contraction of myofibroblasts, activated hepatic stellate cells, and vascular smooth-muscle cells of the intrahepatic veins in a tissue microenvironment characterized by a net predominance of vasoconstrictors (so-called “dynamic component”) [
      • Iwakiri Y.
      • Groszmann R.J.
      The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule.
      ]. An additional determinant of portal hypertension is the progressive increase in blood flow in the portal veins, which is established through splanchnic arteriolar vasodilatation caused by an excessive release of endogenous vasodilators. The increase in portal blood flow aggravates the increase in portal pressure and contributes to the formation of an extensive network of portosystemic collaterals that may divert as much as 80% of portal blood flow. These are responsible for the formation of esophageal and gastric varices, involved in variceal bleeding, associated with a high mortality rate [
      • Garcia-Tsao G.
      • Bosch J.
      Management of varices and variceal hemorrhage in cirrhosis.
      ]. In addition, collateral vessels result in shunting of portal blood into the systemic circulation, causing high systemic concentrations of several substances normally metabolized by the liver. These in turn contribute to severe complications of cirrhosis, such as portosystemic encephalopathy.
      An increase in portal pressure (i.e. >6 mmHg) can be already detected by the measurement of the hepatic vein pressure gradient (HVPG) in patients with histologically defined advanced fibrosis. However, complications of portal hypertension, i.e. development of esophageal varices, may start when HVPG increases over 10 mmHg, which defines what is known as “clinically significant portal hypertension” (Baveno IV) and clinical decompensation in form of bleeding, ascites, hepatic encephalopathy, and renal impairment, may develop when HVPG increases over a threshold value of 10–12 mmHg [
      • Ripoll C.
      • Groszmann R.
      • Garcia-Tsao G.
      • Grace N.
      • Burroughs A.
      • Planas R.
      • et al.
      Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis.
      ].
      Beyond these classic clinical concepts, the detection of increased portal pressure in the context of chronic fibrogenic diseases of the liver has profound implications and currently represents a key reference standard for the development of a pathophysiological classification of cirrhosis [
      • Garcia-Tsao G.
      • Friedman S.
      • Iredale J.
      • Pinzani M.
      Now there are many (stages) where before there was one: in search of a pathophysiological classification of cirrhosis.
      ]. At present the stage of “cirrhosis” is either defined by the histopathological evidence of METAVIR stage F4 or ISHAK S5–S6 or more in general by the presence of the so-called “regenerative” or “cirrhotic nodules”. In routine clinical practice, such definition does not allow making the distinction between a fibrogenic process that is still in progress but potentially reversible from a more advanced stage of the liver disease that becomes irreversible. Indeed, cirrhosis encompasses a pathological spectrum which is neither static nor uncompromisingly progressive but rather dynamic and bidirectional, especially when treatment against the causative agent of tissue damage can be introduced with success at this stage of the disease. Thus, there is a pressing need to redefine cirrhosis in a manner that better recognizes its underlying relationship to portal hypertension and tissue fibrosis, and more faithfully reflects its progression, reversibility, and prognosis. The need becomes particularly appropriate given the increasing use of effective antiviral treatments in patients with HBV and HCV cirrhosis and the possibility of introducing effective antifibrotic agents. In this context, it is essential to define favorable or unfavorable endpoints that correlate with a distinct clinical outcome in patients with cirrhosis.
      All these considerations apply particularly to the stage of cirrhosis defined as “compensated”, characterized by the paucity or absence of clinical signs. Currently, compensated cirrhosis is subclassified in two stages: without varices (stage 1) or with varices (stage 2). In addition, this distinction could be further refined as (a) no portal hypertension; (b) portal hypertension that is not clinically-significant (HVPG <10 mmHg); and (c) clinically significant portal hypertension (HVPG ⩾10 mmHg) [
      • de Franchis R.
      Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension.
      ]. Regardless, in most cases presenting in clinical practice, it is practically impossible to allocate a patient with compensated cirrhosis in one of these substages without performing HVPG measurement and upper GI endoscopy. Both types of investigation are invasive and HVPG measurement is routinely available and/or performed with adequate standards only in expert centres. Along these lines, the need of non invasive methods able to predict with acceptable diagnostic accuracy the progression of portal hypertension toward the levels of clinically significant (i.e. ⩾10 mmHg) and severe (i.e. ⩾12 mmHg) becomes absolutely relevant. In this context, it would be also useful to have non invasive methodologies able to predict the presence or absence of esophageal and gastric varices. However, it should be stressed that the available non invasive methods are not expected to replace either HVPG measurement or upper GI endoscopy, but rather to offer a mean for the rapid discrimination of different steps of progression within the stage of compensated cirrhosis. This will greatly help allocating cirrhotic patients in different categories of risk and guide the need of further evaluation with HVPG measurement and upper GI endoscopy.

      How to evaluate portal hypertension

      Is HVPG measurement a relevant gold standard for portal hypertension assessment?

      HVPG is an accurate, reproducible and safe way of measuring portal pressure in patients with cirrhosis of any aetiology (with the exception of primary biliary cirrhosis) [
      • Bosch J.
      • Abraldes J.G.
      • Berzigotti A.
      • Garcia-Pagan J.C.
      The clinical use of HVPG measurements in chronic liver disease.
      ]. HVPG is considered to be the best surrogate indicator of prognosis in patients with cirrhosis [
      • Gluud C.
      • Henriksen J.H.
      • Nielsen G.
      Prognostic indicators in alcoholic cirrhotic men.
      ]. This is due to the fact that HVPG elevation has been found in multiple studies to carry independent prognostic value for most relevant events in the course of cirrhosis (Table 1). Briefly, HVPG has been found to correlate with the risk of formation of varices, of clinical decompensation and of development of hepatocellular carcinoma (HCC) in patients with “Stage 1” compensated cirrhosis [
      • Ripoll C.
      • Groszmann R.
      • Garcia-Tsao G.
      • Grace N.
      • Burroughs A.
      • Planas R.
      • et al.
      Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis.
      ,
      • Groszmann R.J.
      • Garcia-Tsao G.
      • Bosch J.
      • Grace N.D.
      • Burroughs A.K.
      • Planas R.
      • et al.
      Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.
      ,
      • Ripoll C.
      • Groszmann R.J.
      • Garcia-Tsao G.
      • Bosch J.
      • Grace N.
      • Burroughs A.
      • et al.
      Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis.
      ]. Measurement of HVPG can distinguish sub-stages within compensated cirrhosis, according to whether HVPG is <10 or ⩾10 mmHg, the latter having an increased risk of decompensation, HCC and death. Based on this, it has been proposed that preventive therapies may be started when HVPG is ⩾10 mmHg, since lowering portal pressure below 10 mmHg is likely to result in prevention of clinical decompensation, and death [
      • Garcia-Tsao G.
      • Bosch J.
      Management of varices and variceal hemorrhage in cirrhosis.
      ]. Relevance of HVPG measurements is further emphasized by the findings that HVPG above 16 mmHg correlates with increased risk of death [
      • Bosch J.
      • Abraldes J.G.
      • Berzigotti A.
      • Garcia-Pagan J.C.
      The clinical use of HVPG measurements in chronic liver disease.
      ,
      • Bosch J.
      • Garcia-Pagan J.C.
      • Berzigotti A.
      • Abraldes J.G.
      Measurement of portal pressure and its role in the management of chronic liver disease.
      ,
      • Merkel C.
      • Bolognesi M.
      • Bellon S.
      • Zuin R.
      • Noventa F.
      • Finucci G.
      • et al.
      Prognostic usefulness of hepatic vein catheterization in patients with cirrhosis and esophageal varices.
      ], that during acute variceal bleeding, HVPG >20 mmHg is the best independent prognostic marker [
      • Abraldes J.G.
      • Tarantino I.
      • Turnes J.
      • Garcia-Pagan J.C.
      • Rodes J.
      • Bosch J.
      Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis.
      ,
      • Abraldes J.G.
      • Villanueva C.
      • Banares R.
      • Aracil C.
      • Catalina M.V.
      • Garci A.P.J.C.
      • et al.
      Hepatic venous pressure gradient and prognosis in patients with acute variceal bleeding treated with pharmacologic and endoscopic therapy.
      ,
      • Moitinho E.
      • Escorsell A.
      • Bandi J.C.
      • Salmeron J.M.
      • Garcia-Pagan J.C.
      • Rodes J.
      • et al.
      Prognostic value of early measurements of portal pressure in acute variceal bleeding.
      ,
      • Monescillo A.
      • Martinez-Lagares F.
      • Ruiz-del-Arbol L.
      • Sierra A.
      • Guevara C.
      • Jimenez E.
      • et al.
      Influence of portal hypertension and its early decompression by TIPS placement on the outcome of variceal bleeding.
      ] and that measurement of changes in HVPG during the treatment of portal hypertension allow to define a group of patients with an optimal outcome (the hemodynamic “responders”) [
      • Bosch J.
      • Masti R.
      • Kravetz D.
      • Bruix J.
      • Gaya J.
      • Rigau J.
      • et al.
      Effects of propranolol on azygos venous blood flow and hepatic and systemic hemodynamics in cirrhosis.
      ,
      • Thalheimer U.
      • Bosch J.
      • Burroughs A.K.
      How to prevent varices from bleeding: shades of grey – the case for nonselective beta blockers.
      ,
      • Turnes J.
      • Garcia-Pagan J.C.
      • Abraldes J.G.
      • Hernandez-Guerra M.
      • Dell’Era A.
      • Bosch J.
      Pharmacological reduction of portal pressure and long-term risk of first variceal bleeding in patients with cirrhosis.
      ,
      • D’Amico G.
      • Garcia-Pagan J.C.
      • Luca A.
      • Bosch J.
      Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review.
      ,
      • Feu F.
      • Garcia-Pagan J.C.
      • Bosch J.
      • Luca A.
      • Teres J.
      • Escorsell A.
      • et al.
      Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis.
      ] (Table 1). Recent studies further suggest that patients showing a drop in HVPG ⩾10% of baseline 15 min after the IV administration of propranolol (0.15 mg/kg) (“acute hemodynamic responders”) [
      • La Mura V.
      • Abraldes J.G.
      • Raffa S.
      • Retto O.
      • Berzigotti A.
      • Garcia-Pagan J.C.
      • et al.
      Prognostic value of acute hemodynamic response to i.v. propranolol in patients with cirrhosis and portal hypertension.
      ,
      • Villanueva C.
      • Aracil C.
      • Colomo A.
      • Hernandez-Gea V.
      • Lopez-Balaguer J.M.
      • Alvarez-Urturi C.
      • et al.
      Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding.
      ] also have a lower risk of bleeding and death. Finally, a pre-operative HVPG ⩾10 mmHg denotes a poor prognostic of liver resection in patients with small HCC; HVPG ⩾6 mmHg 1-year after liver transplantation, is the best indicator of a poor outcome [
      • Blasco A.
      • Forns X.
      • Carrion J.A.
      • Garcia-Pagan J.C.
      • Gilabert R.
      • Rimola A.
      • et al.
      Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation.
      ] and successful treatment of viral cirrhosis [
      • Carrion J.A.
      • Navasa M.
      • Garcia-Retortillo M.
      • Garcia-Pagan J.C.
      • Crespo G.
      • Bruguera M.
      • et al.
      Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study.
      ,
      • Manolakopoulos S.
      • Triantos C.
      • Theodoropoulos J.
      • Vlachogiannakos J.
      • Kougioumtzan A.
      • Papatheodoridis G.
      • et al.
      Antiviral therapy reduces portal pressure in patients with cirrhosis due to HBeAg-negative chronic hepatitis B and significant portal hypertension.
      ,
      • Rincon D.
      • Ripoll C.
      • Lo Iacono O.
      • Salcedo M.
      • Catalina M.V.
      • Alvarez E.
      • et al.
      Antiviral therapy decreases hepatic venous pressure gradient in patients with chronic hepatitis C and advanced fibrosis.
      ], and alcohol withdrawal [
      • Vorobioff J.
      • Groszmann R.J.
      • Picabea E.
      • Gamen M.
      • Villavicencio R.
      • Bordato J.
      • et al.
      Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis: a 10-year prospective study.
      ] are associated with a significant decrease in HVPG. Because of this, it has been proposed that serial measurements of HVPG could be used for assessing progression/regression of fibrosis/cirrhosis in chronic liver diseases of any aetiology [
      • Bosch J.
      • Abraldes J.G.
      • Berzigotti A.
      • Garcia-Pagan J.C.
      The clinical use of HVPG measurements in chronic liver disease.
      ]. Details on the technique and precautions for accurate measurements are described in depth in recent reviews [
      • Bosch J.
      • Abraldes J.G.
      • Berzigotti A.
      • Garcia-Pagan J.C.
      The clinical use of HVPG measurements in chronic liver disease.
      ,
      • Bosch J.
      • Garcia-Pagan J.C.
      • Berzigotti A.
      • Abraldes J.G.
      Measurement of portal pressure and its role in the management of chronic liver disease.
      ].
      Table 1Correlation between HVPG and complications of portal hypertension in patients with cirrhosis.
      Chronic HVPG response (change in HVPG after 3–12 weeks on therapy); the criteria for a “good” HVPG response after acute IV propranolol is a decrease in HVPG ⩾10% of baseline values.
      SBP, spontaneous bacterial peritonitis.

      Is upper GI endoscopy a relevant gold standard for portal hypertension assessment?

      Another “gold standard” in the evaluation of portal hypertension is the use of upper GI endoscopy for the detection of varices [
      • de Franchis R.
      Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension.
      ]. By far, endoscopy is the best way of assessing the presence of oesophageal varices (OV), where its accuracy is much greater than that of radiology (including multidetector CT-angiography) [
      • de Franchis R.
      Non-invasive (and minimally invasive) diagnosis of oesophageal varices.
      ,
      • de Franchis R.
      Cirrhosis: screening for esophageal varices.
      ,
      • Perri R.E.
      • Chiorean M.V.
      • Fidler J.L.
      • Fletcher J.G.
      • Talwalkar J.A.
      • Stadheim L.
      • et al.
      A prospective evaluation of computerized tomographic (CT) scanning as a screening modality for esophageal varices.
      ]. Endoscopy has to be complemented sometimes with endoscopic ultrasonography, especially in cases with suspected isolated gastric varices. Endoscopy has the further advantage of allowing to detect indicators of increased bleeding risk (the red colour signs and “wale” marks) that cannot be detected accurately by other imaging techniques [
      The North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study.
      ]. Because of this, it is recommended that any patient with cirrhosis should undergo screening endoscopy at diagnosis, and repeat follow-up examinations if no varices are found or if no preventive treatment is initiated in patients with “low-risk” varices (small varices without red colour signs in a Child A patient) [
      • de Franchis R.
      Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension.
      ].
      Both HVPG measurements and upper GI endoscopy are safe but minimally invasive diagnostic techniques that carry patient discomfort, increase the burden for medical providers and increased cost of medical care. Because of this, there is a clinical need for non-invasive ways of assessing portal hypertensive patients that could substitute for the need of hemodynamic measurements and endoscopy. Let us state upfront that despite new technological developments, all the efforts done up to now have not resulted in such a substitute. However, as discussed in this review, there have been substantial advances that may result in a much better definition of patients in whom these procedures are indicated, decreasing the number of patients that have to be submitted to HVPG/endoscopy. Specifically, there is substantial evidence indicating that transient elastography (TE) can be quite effective in detecting patients with a high risk of having (or not having) developed clinically significant elevations of HVPG or varices. Details on the principle and technique of TE have been previously described [
      • Sandrin L.
      • Fourquet B.
      • Hasquenoph J.M.
      • Yon S.
      • Fournier C.
      • Mal F.
      • et al.
      Transient elastography: a new noninvasive method for assessment of hepatic fibrosis.
      ,
      • Castera L.
      • Forns X.
      • Alberti A.
      Non-invasive evaluation of liver fibrosis using transient elastography.
      ].

      Diagnostic performance of transient elastography for portal hypertension

      Detection of clinically significant portal hypertension

      The performances of TE for detection of clinically significant portal hypertension are shown in Table 2. A good correlation between liver stiffness values and HVPG has been initially reported by Carrion et al. in 124 HCV patients with HCV recurrence after liver transplantation (Pearson coefficient, 0.84; p <0.001) [
      • Carrion J.A.
      • Navasa M.
      • Bosch J.
      • Bruguera M.
      • Gilabert R.
      • Forns X.
      Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation.
      ]. The AUROCs for the diagnosis of portal hypertension (HVPG ⩾6 mmHg) and clinically significant portal hypertension were 0.93 and 0.94, respectively (Table 2). Several other groups have confirmed these results since in patients with chronic hepatitis C [
      • Vizzutti F.
      • Arena U.
      • Romanelli R.G.
      • Rega L.
      • Foschi M.
      • Colagrande S.
      • et al.
      Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis.
      ] or with other chronic liver diseases [
      • Bureau C.
      • Metivier S.
      • Peron J.M.
      • Selves J.
      • Robic M.A.
      • Gourraud P.A.
      • et al.
      Transient elastography accurately predicts presence of significant portal hypertension in patients with chronic liver disease.
      ,
      • Lemoine M.
      • Katsahian S.
      • Ziol M.
      • Nahon P.
      • Ganne-Carrie N.
      • Kazemi F.
      • et al.
      Liver stiffness measurement as a predictive tool of clinically significant portal hypertension in patients with compensated hepatitis C virus or alcohol-related cirrhosis.
      ,
      • Sanchez-Conde M.
      • Montes-Ramirez M.L.
      • Miralles P.
      • Alvarez J.M.
      • Bellon J.M.
      • Ramirez M.
      • et al.
      Comparison of transient elastography and liver biopsy for the assessment of liver fibrosis in HIV/hepatitis C virus-coinfected patients and correlation with noninvasive serum markers.
      ], with AUROCs for detecting clinically significant portal hypertension ranging from 0.76 to 0.99 and TE cut-offs from 13.6 to 34.9 kPa (Table 2). Interestingly, in the only study that analysed the results according to the liver disease etiology [
      • Lemoine M.
      • Katsahian S.
      • Ziol M.
      • Nahon P.
      • Ganne-Carrie N.
      • Kazemi F.
      • et al.
      Liver stiffness measurement as a predictive tool of clinically significant portal hypertension in patients with compensated hepatitis C virus or alcohol-related cirrhosis.
      ], cut-offs were higher in alcoholic cirrhosis than in viral cirrhosis (34.9 and 20.5 kPa, respectively). Although these results are in keeping with findings suggesting that cut-offs for cirrhosis diagnosis may be higher in alcoholic liver disease [
      • Nahon P.
      • Kettaneh A.
      • Tengher-Barna I.
      • Ziol M.
      • de Ledinghen V.
      • Douvin C.
      • et al.
      Assessment of liver fibrosis using transient elastography in patients with alcoholic liver disease.
      ,
      • Nguyen-Khac E.
      • Chatelain D.
      • Tramier B.
      • Decrombecque C.
      • Robert B.
      • Joly J.P.
      • et al.
      Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with 7 non-invasive laboratory tests.
      ], they need to be further confirmed in other series.
      Table 2Diagnostic performance of transient elastography for the detection of clinically significant portal hypertension (HVPG ⩾10 mmHg).
      Hepatic venous pressure gradient (HVPG) ⩾6 mmHg; ∗∗severe portal hypertension HVPG ⩾12 mmHg.
      AUC, area under ROC curve; Se, sensitivity; Sp, specificity; +LR, positive likelihood ratio; −LR, negative likelihood ratio; HCV, chronic hepatitis C; HCV-LT, liver transplant for hepatitis C; CLD, chronic liver diseases; Pro. mono., prospective monocentric; Retro. mono., retrospective monocentric.
      Another interesting finding is the fact that, although the correlation was excellent for HVPG values below 10–12 mmHg, it hardly reached statistical significance for values above 12 mmHg [
      • Vizzutti F.
      • Arena U.
      • Romanelli R.G.
      • Rega L.
      • Foschi M.
      • Colagrande S.
      • et al.
      Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis.
      ]. This important observation suggests that beyond a certain degree of portal pressure (i.e. above 10–12 mmHg), the development of portal hypertension becomes at least partially independent from the simple accumulation of fibrillar extracellular matrix responsible for the increase in liver stiffness. It is consistent with the pathophysiology of portal hypertension where several extra-hepatic 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 [
      • Bosch J.
      • Abraldes J.G.
      • Berzigotti A.
      • Garcia-Pagan J.C.
      The clinical use of HVPG measurements in chronic liver disease.
      ,
      • Lim J.K.
      • Groszmann R.J.
      Transient elastography for diagnosis of portal hypertension in liver cirrhosis: is there still a role for hepatic venous pressure gradient measurement?.
      ]. Accordingly, TE is unlikely to be useful in the monitoring the hemodynamic response to drug therapy, the effect of which is mediated primarily by decreasing the splanchnic blood flow [
      • Ripoll C.
      • Groszmann R.
      • Garcia-Tsao G.
      • Grace N.
      • Burroughs A.
      • Planas R.
      • et al.
      Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis.
      ].
      Conversely, repeated liver stiffness measurements over time could be of interest during the first year after liver transplantation to identify patients with severe hepatitis C recurrence at an early stage [
      • Carrion J.A.
      • Torres F.
      • Crespo G.
      • Miquel R.
      • Garcia-Valdecasas J.C.
      • Navasa M.
      • et al.
      Liver stiffness identifies two different patterns of fibrosis progression in patients with hepatitis C virus recurrence after liver transplantation.
      ]. Indeed, liver stiffness values together with donor age and bilirubin levels were independent predictors in multivariate analysis of portal hypertension (HVPG ⩾6 mmHg) and fibrosis progression (fibrosis stage >2) in HCV-infected liver transplant recipients. These preliminary results are promising but need to be validated by other groups [
      • Rigamonti C.
      • Donato M.F.
      • Colombo M.
      Transient elastography in the early prediction of progressive recurrent hepatitis C following liver transplantation.
      ] before implementation in clinical practice.

      Detection of oesophageal varices

      A correlation between liver stiffness values and the presence of OV has also been reported [
      • Vizzutti F.
      • Arena U.
      • Romanelli R.G.
      • Rega L.
      • Foschi M.
      • Colagrande S.
      • et al.
      Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis.
      ,
      • Bureau C.
      • Metivier S.
      • Peron J.M.
      • Selves J.
      • Robic M.A.
      • Gourraud P.A.
      • et al.
      Transient elastography accurately predicts presence of significant portal hypertension in patients with chronic liver disease.
      ,
      • Kazemi F.
      • Kettaneh A.
      • N’Kontchou G.
      • Pinto E.
      • Ganne-Carrie N.
      • Trinchet J.C.
      • et al.
      Liver stiffness measurement selects patients with cirrhosis at risk of bearing large oesophageal varices.
      ,
      • Castera L.
      • Le Bail B.
      • Roudot-Thoraval F.
      • Bernard P.H.
      • Foucher J.
      • Merrouche W.
      • et al.
      Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores.
      ,
      • Pineda J.A.
      • Recio E.
      • Camacho A.
      • Macias J.
      • Almodovar C.
      • Gonzalez-Serrano M.
      • et al.
      Liver stiffness as a predictor of esophageal varices requiring therapy in HIV/hepatitis C virus-coinfected patients with cirrhosis.
      ,
      • Pritchett S.
      • Cardenas A.
      • Manning D.
      • Curry M.
      • Afdhal N.H.
      The optimal cut-off for predicting large oesophageal varices using transient elastography is disease specific.
      ,
      • Nguyen-Khac E.
      • Saint-Leger P.
      • Tramier B.
      • Coevoet H.
      • Capron D.
      • Dupas J.L.
      Noninvasive diagnosis of large esophageal varices by fibroscan: strong influence of the cirrhosis etiology.
      ,
      • Malik R.
      • Lai M.
      • Sadiq A.
      • Farnan R.
      • Mehta S.
      • Nasser I.
      • et al.
      Comparison of transient elastography, serum markers and clinical signs for the diagnosis of compensated cirrhosis.
      ]. AUROCs of TE for diagnosing the presence of OV ranged from 0.74 to 0.85 and cut-offs from 13.9 to 21.5 kPa (Table 3). Sensitivity for the prediction of the presence of OV was high (76–95%) but specificity was much lower (43–78%).
      Table 3Diagnostic performance of transient elastography for the detection of oesophageal varices (OV and LOV) in cirrhotic patients.
      CROV: clinically relevant OV requiring primary prophylaxis of bleeding, i.e. patients carrying LOV or OV with red signs or Child-Pugh class C.
      CLD, chronic liver diseases; HCV, chronic hepatitis C; HIV-HCV, co-infection with human deficiency virus and hepatitis C virus; HBV, hepatitis B virus; AUC, area under ROC curve; Se, sensitivity; Sp, specificity; PPV & NPV, positive and negative predictive values; +LR & −LR, positive and negative likelihood ratios; Pro. mono., prospective monocentric; Pro. multi., prospective multicentric; Retro. mono., retrospective monocentric.
      The percentage of saved endoscopy was calculated as the percentage of correctly classified patients by pooling true negative and true positive.
      A correlation between liver stiffness values and variceal size was observed in some studies [
      • Bureau C.
      • Metivier S.
      • Peron J.M.
      • Selves J.
      • Robic M.A.
      • Gourraud P.A.
      • et al.
      Transient elastography accurately predicts presence of significant portal hypertension in patients with chronic liver disease.
      ,
      • Kazemi F.
      • Kettaneh A.
      • N’Kontchou G.
      • Pinto E.
      • Ganne-Carrie N.
      • Trinchet J.C.
      • et al.
      Liver stiffness measurement selects patients with cirrhosis at risk of bearing large oesophageal varices.
      ,
      • Castera L.
      • Le Bail B.
      • Roudot-Thoraval F.
      • Bernard P.H.
      • Foucher J.
      • Merrouche W.
      • et al.
      Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores.
      ,
      • Pritchett S.
      • Cardenas A.
      • Manning D.
      • Curry M.
      • Afdhal N.H.
      The optimal cut-off for predicting large oesophageal varices using transient elastography is disease specific.
      ] whereas it was not in others [
      • Vizzutti F.
      • Arena U.
      • Romanelli R.G.
      • Rega L.
      • Foschi M.
      • Colagrande S.
      • et al.
      Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis.
      ,
      • Pineda J.A.
      • Recio E.
      • Camacho A.
      • Macias J.
      • Almodovar C.
      • Gonzalez-Serrano M.
      • et al.
      Liver stiffness as a predictor of esophageal varices requiring therapy in HIV/hepatitis C virus-coinfected patients with cirrhosis.
      ,
      • Nguyen-Khac E.
      • Saint-Leger P.
      • Tramier B.
      • Coevoet H.
      • Capron D.
      • Dupas J.L.
      Noninvasive diagnosis of large esophageal varices by fibroscan: strong influence of the cirrhosis etiology.
      ,
      • Malik R.
      • Lai M.
      • Sadiq A.
      • Farnan R.
      • Mehta S.
      • Nasser I.
      • et al.
      Comparison of transient elastography, serum markers and clinical signs for the diagnosis of compensated cirrhosis.
      ]. Cut-offs for the prediction of the presence of large OV (LOV) were higher ranging from 19 to 48.0 kPa (Table 3). Sensitivity of TE for detecting LOV was also high (77–100%) with much lower specificity (32–85%) (Table 3). In the only study that analysed the results according to the etiology of the underlying liver disease [
      • Nguyen-Khac E.
      • Saint-Leger P.
      • Tramier B.
      • Coevoet H.
      • Capron D.
      • Dupas J.L.
      Noninvasive diagnosis of large esophageal varices by fibroscan: strong influence of the cirrhosis etiology.
      ], cut-offs for detection of LOV were higher in patients with alcoholic cirrhosis than in those with viral cirrhosis (47.2 and 19.8 kPa, respectively), a finding consistent with what has been reported for clinically significant portal hypertension [
      • Lemoine M.
      • Katsahian S.
      • Ziol M.
      • Nahon P.
      • Ganne-Carrie N.
      • Kazemi F.
      • et al.
      Liver stiffness measurement as a predictive tool of clinically significant portal hypertension in patients with compensated hepatitis C virus or alcohol-related cirrhosis.
      ]. Further studies are needed to confirm these findings.
      Overall, these results deserve several comments. First, most of these studies have been conducted retrospectively in single centers on heterogeneous populations (mixing viral hepatitis- and alcohol-related liver diseases) with small sample size (<100 in most cases). Second, the prevalence of disease severity (proportion of Child-Pugh A patients ranging from 34% to 100%) and varices (proportion of patients with OV or LOV ranging from 36% to 72% and 19% to 48%, respectively) was highly variable from one study to another. Third, the judgement criteria markedly differed between studies: presence of OV only in two of them [
      • Vizzutti F.
      • Arena U.
      • Romanelli R.G.
      • Rega L.
      • Foschi M.
      • Colagrande S.
      • et al.
      Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis.
      ,
      • Malik R.
      • Lai M.
      • Sadiq A.
      • Farnan R.
      • Mehta S.
      • Nasser I.
      • et al.
      Comparison of transient elastography, serum markers and clinical signs for the diagnosis of compensated cirrhosis.
      ], presence of LOV only in one of them [
      • Nguyen-Khac E.
      • Saint-Leger P.
      • Tramier B.
      • Coevoet H.
      • Capron D.
      • Dupas J.L.
      Noninvasive diagnosis of large esophageal varices by fibroscan: strong influence of the cirrhosis etiology.
      ] and presence of both in four [
      • Bureau C.
      • Metivier S.
      • Peron J.M.
      • Selves J.
      • Robic M.A.
      • Gourraud P.A.
      • et al.
      Transient elastography accurately predicts presence of significant portal hypertension in patients with chronic liver disease.
      ,
      • Kazemi F.
      • Kettaneh A.
      • N’Kontchou G.
      • Pinto E.
      • Ganne-Carrie N.
      • Trinchet J.C.
      • et al.
      Liver stiffness measurement selects patients with cirrhosis at risk of bearing large oesophageal varices.
      ,
      • Castera L.
      • Le Bail B.
      • Roudot-Thoraval F.
      • Bernard P.H.
      • Foucher J.
      • Merrouche W.
      • et al.
      Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores.
      ,
      • Pritchett S.
      • Cardenas A.
      • Manning D.
      • Curry M.
      • Afdhal N.H.
      The optimal cut-off for predicting large oesophageal varices using transient elastography is disease specific.
      ]. However, according to the latest Baveno V recommendations [
      • de Franchis R.
      Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension.
      ], primary prophylaxis for variceal bleeding is indicated in patients with clinically relevant OV (CROV) (i.e. patients with LOV or with small OV and red wale marks or Child C class), a criteria that has been taken into account in one study only [
      • Pineda J.A.
      • Recio E.
      • Camacho A.
      • Macias J.
      • Almodovar C.
      • Gonzalez-Serrano M.
      • et al.
      Liver stiffness as a predictor of esophageal varices requiring therapy in HIV/hepatitis C virus-coinfected patients with cirrhosis.
      ]. Also the assessment of OV size was rather subjective: no details were provided in most of these studies regarding the quality of this assessment even though endoscopy is known to be an imperfect gold standard with considerable inter-observer variability for detecting and grading varices [
      • Thabut D.
      • Moreau R.
      • Lebrec D.
      Screening for esophageal varices: endoscopy, other tools, or endoscopy and other tools?.
      ]. Fourth, the proposed cut-offs for detecting OV or LOV were discrepant between studies, thus the optimal cut-off remains to be defined. Finally, the diagnostic accuracy (specificity and likelihood ratios) reported so far is much too low for a reliable use in clinical practice.
      Thus, from the data currently available, diagnostic performances of TE are acceptable for the prediction of clinically significant portal hypertension but far from satisfactory to confidently predict the presence of OV in clinical practice and to screen cirrhotic patients without endoscopy.

      Comparison of transient elastography with other non invasive tools

      Detection of portal hypertension

      Several biological parameters have been proposed for the non invasive detection of clinically significant portal hypertension including prothrombin time [
      • Bureau C.
      • Metivier S.
      • Peron J.M.
      • Selves J.
      • Robic M.A.
      • Gourraud P.A.
      • et al.
      Transient elastography accurately predicts presence of significant portal hypertension in patients with chronic liver disease.
      ], a score combining platelet count and total bilirubin [
      • Park S.H.
      • Park T.E.
      • Kim Y.M.
      • Kim S.J.
      • Baik G.H.
      • Kim J.B.
      • et al.
      Non-invasive model predicting clinically-significant portal hypertension in patients with advanced fibrosis.
      ], and FibroTest® [
      • Thabut D.
      • Imbert-Bismut F.
      • Cazals-Hatem D.
      • Messous D.
      • Muntenau M.
      • Valla D.C.
      • et al.
      Relationship between the Fibrotest and portal hypertension in patients with liver disease.
      ]. In a population of 61 Korean patients, Park et al. [
      • Park S.H.
      • Park T.E.
      • Kim Y.M.
      • Kim S.J.
      • Baik G.H.
      • Kim J.B.
      • et al.
      Non-invasive model predicting clinically-significant portal hypertension in patients with advanced fibrosis.
      ] have shown that a score combining platelet count and total bilirubin had an AUROC of 0.91 for predicting clinically significant portal hypertension with a 88% sensitivity and 86% specificity at a cut-off of −1.0. In 92 French patients with cirrhosis, the FibroTest® had an AUROC of 0.79 for predicting severe portal hypertension (HVPG ⩾12 mmHg) [
      • Thabut D.
      • Imbert-Bismut F.
      • Cazals-Hatem D.
      • Messous D.
      • Muntenau M.
      • Valla D.C.
      • et al.
      Relationship between the Fibrotest and portal hypertension in patients with liver disease.
      ]. In the only study comparing TE to other non invasive tests, performance of TE and prothrombin time did not differ (AUROC 0.95 vs. 0.89, respectively) [
      • Bureau C.
      • Metivier S.
      • Peron J.M.
      • Selves J.
      • Robic M.A.
      • Gourraud P.A.
      • et al.
      Transient elastography accurately predicts presence of significant portal hypertension in patients with chronic liver disease.
      ]. Combining TE (at a cut-off of 21 kPa) and prothrombin time (at a cut-off of 82.5%) allowed classifying correctly 73% of patients.

      Detection of oesophageal varices

      Several non invasive tools have been proposed for the detection of OV including routine biological parameters [
      • Sebastiani G.
      • Tempesta D.
      • Fattovich G.
      • Castera L.
      • Halfon P.
      • Bourliere M.
      • et al.
      Prediction of oesophageal varices in hepatic cirrhosis by simple serum non-invasive markers: results of a multicenter, large-scale study.
      ], FibroTest® [
      • Thabut D.
      • Trabut J.B.
      • Massard J.
      • Rudler M.
      • Muntenau M.
      • Messous D.
      • et al.
      Non-invasive diagnosis of large oesophageal varices with FibroTest in patients with cirrhosis: a preliminary retrospective study.
      ], combination of simple biological and ultrasound parameters [
      • Giannini E.G.
      • Zaman A.
      • Kreil A.
      • Floreani A.
      • Dulbecco P.
      • Testa E.
      • et al.
      Platelet count/spleen diameter ratio for the noninvasive diagnosis of esophageal varices: results of a multicenter, prospective, validation study.
      ], and more recently oesophageal capsule endoscopy [
      • de Franchis R.
      • Eisen G.M.
      • Laine L.
      • Fernandez-Urien I.
      • Herrerias J.M.
      • Brown R.D.
      • et al.
      Esophageal capsule endoscopy for screening and surveillance of esophageal varices in patients with portal hypertension.
      ,
      • Lapalus M.G.
      • Ben Soussan E.
      • Gaudric M.
      • Saurin J.C.
      • D’Halluin P.N.
      • Favre O.
      • et al.
      Esophageal capsule endoscopy vs. EGD for the evaluation of portal hypertension: a French prospective multicenter comparative study.
      ]. The performances of these tools are summarized in Table 4. The AUROCs of serum markers ranged from 0.57 to 0.86, with higher sensitivity (51–92%) than specificity (53–76%). In the largest study to date comparing retrospectively a panel of serum markers (platelet count, AST/ALT ratio, APRI, Forns index, Lok index, FIB-4, and Fibroindex) in more than 500 patients with chronic liver diseases, the combination of Lok index (cut-off = 1.5) and Forns index (cut-off = 8.8) had the best diagnostic performance (AUROC of 0.80 and negative predictive value of 90%) for predicting clinically relevant OV [
      • Sebastiani G.
      • Tempesta D.
      • Fattovich G.
      • Castera L.
      • Halfon P.
      • Bourliere M.
      • et al.
      Prediction of oesophageal varices in hepatic cirrhosis by simple serum non-invasive markers: results of a multicenter, large-scale study.
      ].
      Table 4Diagnostic performance of other non invasive tools for the detection of oesophageal varices (OV and LOV) in cirrhotic patients.
      CROV, clinically relevant OV requiring primary prophylaxis of bleeding, i.e. patients carrying LOV or OV with red signs or Child-Pugh class C.
      CLD, chronic liver diseases; AUC, area under ROC curve; Se, sensitivity; Sp, specificity; PPV & NPV, positive and negative predictive values; +LR & −LR, positive and negative likelihood ratios; Pro. multi., prospective multicentric; Retro. mono., retrospective monocentric; Retro. multi., retrospective multicentric.
      The percentage of saved endoscopy was calculated as the percentage of correctly classified patients by pooling true negative and true positive.
      Sensitivity of oesophageal capsule endoscopy for the detection of LOV ranged from 77% to 78% and specificity from 88% to 96% [
      • de Franchis R.
      • Eisen G.M.
      • Laine L.
      • Fernandez-Urien I.
      • Herrerias J.M.
      • Brown R.D.
      • et al.
      Esophageal capsule endoscopy for screening and surveillance of esophageal varices in patients with portal hypertension.
      ,
      • Lapalus M.G.
      • Ben Soussan E.
      • Gaudric M.
      • Saurin J.C.
      • D’Halluin P.N.
      • Favre O.
      • et al.
      Esophageal capsule endoscopy vs. EGD for the evaluation of portal hypertension: a French prospective multicenter comparative study.
      ] (Table 4). These preliminary results suggest that oesophageal capsule endoscopy is a promising tool for the detection of OV. However, further studies comparing this technology to other available non invasive tools such as TE are awaited.
      Three studies only compared TE with other non invasive tools thus far [
      • Kazemi F.
      • Kettaneh A.
      • N’Kontchou G.
      • Pinto E.
      • Ganne-Carrie N.
      • Trinchet J.C.
      • et al.
      Liver stiffness measurement selects patients with cirrhosis at risk of bearing large oesophageal varices.
      ,
      • Castera L.
      • Le Bail B.
      • Roudot-Thoraval F.
      • Bernard P.H.
      • Foucher J.
      • Merrouche W.
      • et al.
      Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores.
      ,
      • Kim B.K.
      • Han K.H.
      • Park J.Y.
      • Ahn S.H.
      • Kim J.K.
      • Paik Y.H.
      • et al.
      A liver stiffness measurement-based, noninvasive prediction model for high-risk esophageal varices in B-viral liver cirrhosis.
      ]. TE did not perform better for the detection of OV and LOV in patients with chronic hepatitis C than serum markers [
      • Castera L.
      • Le Bail B.
      • Roudot-Thoraval F.
      • Bernard P.H.
      • Foucher J.
      • Merrouche W.
      • et al.
      Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores.
      ]. For instance, at a cut-off of 30.5 kPa, TE predicted the presence of LOV with 79% accuracy as compared with 79% for prothrombin time, 77% for Lok index, 76% for AST/ALT ratio and platelet count, 64% for FibroTest®, and 63% for APRI, respectively. Similarly, in another study [
      • Kazemi F.
      • Kettaneh A.
      • N’Kontchou G.
      • Pinto E.
      • Ganne-Carrie N.
      • Trinchet J.C.
      • et al.
      Liver stiffness measurement selects patients with cirrhosis at risk of bearing large oesophageal varices.
      ], TE performances did not differ from those of platelet count/spleen diameter ratio for detection of LOV. In a cohort of 401 Korean patients with chronic hepatitis B (training set 280; validation set 121), TE had similar diagnostic performances than spleen diameter and platelet count for detection of clinically relevant OV [
      • Kim B.K.
      • Han K.H.
      • Park J.Y.
      • Ahn S.H.
      • Kim J.K.
      • Paik Y.H.
      • et al.
      A liver stiffness measurement-based, noninvasive prediction model for high-risk esophageal varices in B-viral liver cirrhosis.
      ]. However, the combination of liver stiffness with spleen diameter and platelet count (referred as LSPS for LSM-Spleen diameter to Platelet ratio Score) increased diagnostic accuracy. Indeed, LSPS had a significantly better AUROC than TE alone (0.95 vs. 0.88, respectively; p <0.001). At a cut-off <3.5, LSPS had a 94.0% negative predictive value and a 94.2% positive predictive value at a cut-off >5.5. Overall, upper GI endoscopy could be saved in 90.3% patients. These promising results suggest that like for the diagnosis of liver fibrosis [
      • Castera L.
      • Vergniol J.
      • Foucher J.
      • Le Bail B.
      • Chanteloup E.
      • Haaser M.
      • et al.
      Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C.
      ], combining two unrelated methods such as TE and serum markers or ultrasonography may increase accuracy for detecting OV but need to be further validated.

      Prediction of clinical outcome

      Since the initial report [
      • Foucher J.
      • Chanteloup E.
      • Vergniol J.
      • Castera L.
      • Le Bail B.
      • Adhoute X.
      • et al.
      Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study.
      ], suggesting that liver stiffness may be of prognostic value in patients with cirrhosis, other groups have confirmed these findings [
      • Castera L.
      Liver stiffness and hepatocellular carcinoma: liaisons dangereuses?.
      ,
      • Masuzaki R.
      • Tateishi R.
      • Yoshida H.
      • Goto E.
      • Sato T.
      • Ohki T.
      • et al.
      Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography.
      ,
      • Jung K.S.
      • Kim S.U.
      • Ahn S.H.
      • Park Y.N.
      • Kim do Y.
      • Park J.Y.
      • et al.
      Risk assessment of hepatitis B virus-related hepatocellular carcinoma development using liver stiffness measurement (FibroScan).
      ]. Very recently, a French study conducted in 100 patients with chronic liver diseases and a 2-year follow-up, reported that liver stiffness values may be as effective as HVPG in predicting clinical decompensation and portal hypertension-related complications [
      • Robic M.A.
      • Procopet B.
      • Metivier S.
      • Peron J.M.
      • Selves J.
      • Vinel J.P.
      • et al.
      Liver stiffness accurately predicts portal hypertension related complications in patients with chronic liver disease: a prospective study.
      ]. For instance, at a cut-off of 21.1 kPa, TE had a 100% negative predictive value for the occurrence of portal hypertension related complications, suggesting that if such results are further confirmed, TE could be used as a screening test for clinical outcome [
      • Bosch J.
      Soft technique, hard end-points.
      ].

      Limitations of transient elastography

      Liver stiffness measurements can be difficult in obese patients or with narrow intercostal space and impossible in patients with ascites [
      • Sandrin L.
      • Fourquet B.
      • Hasquenoph J.M.
      • Yon S.
      • Fournier C.
      • Mal F.
      • et al.
      Transient elastography: a new noninvasive method for assessment of hepatic fibrosis.
      ]. Although TE reproducibility has been shown to be excellent for inter-observer and intra-observer agreement [
      • Fraquelli M.
      • Rigamonti C.
      • Casazza G.
      • Conte D.
      • Donato M.F.
      • Ronchi G.
      • et al.
      Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease.
      ,
      • Boursier J.
      • Konate A.
      • Guilluy M.
      • Gorea G.
      • Sawadogo A.
      • Quemener E.
      • et al.
      Learning curve and interobserver reproducibility evaluation of liver stiffness measurement by transient elastography.
      ], its applicability may not be as good as initially thought. Indeed, in our experience over 5 years in more than 13,000 examinations, liver stiffness measurements were not interpretable in nearly one in five cases (failure to obtain any measurement in 4% and unreliable results not meeting manufacturer’s recommendations in 17%) [
      • Castera L.
      • Foucher J.
      • Bernard P.H.
      • Carvalho F.
      • Allaix D.
      • Merrouche W.
      • et al.
      Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations.
      ]. The principal reasons were obesity, particularly increased waist circumference, and limited operator experience. These results emphasize the need for adequate operator training and for technological improvements in specific patient populations such as those with non alcoholic fatty liver disease.
      Finally, as the liver is an organ wrapped in a distensible but non-elastic envelope (Glisson’s capsula), additional space-occupying tissue abnormalities, such as oedema and inflammation, cholestasis and congestion, may interfere with liver stiffness measurement (LSM), independently of fibrosis. Indeed, as previously mentioned, the extent of necro-inflammatory activity has been shown to influence TE measurements in patients with viral hepatitis with a steady increase of liver stiffness values in parallel with the degree of histological activity [
      • Fraquelli M.
      • Rigamonti C.
      • Casazza G.
      • Conte D.
      • Donato M.F.
      • Ronchi G.
      • et al.
      Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease.
      ,
      • Arena U.
      • Vizzutti F.
      • Abraldes J.G.
      • Corti G.
      • Stasi C.
      • Moscarella S.
      • et al.
      Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C.
      ,
      • Chan H.L.
      • Wong G.L.
      • Choi P.C.
      • Chan A.W.
      • Chim A.M.
      • Yiu K.K.
      • et al.
      Alanine aminotransferase-based algorithms of liver stiffness measurement by transient elastography (Fibroscan) for liver fibrosis in chronic hepatitis B.
      ]. Consistent with these results, the risk of overestimating liver stiffness values has been reported in case of ALT flares in patients with acute viral hepatitis or chronic hepatitis B [
      • Coco B.
      • Oliveri F.
      • Maina A.M.
      • Ciccorossi P.
      • Sacco R.
      • Colombatto P.
      • et al.
      Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases.
      ,
      • Sagir A.
      • Erhardt A.
      • Schmitt M.
      • Haussinger D.
      Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage.
      ,
      • Arena U.
      • Vizzutti F.
      • Corti G.
      • Ambu S.
      • Stasi C.
      • Bresci S.
      • et al.
      Acute viral hepatitis increases liver stiffness values measured by transient elastography.
      ] as well as in cases of extrahepatic cholestasis [
      • Millonig G.
      • Reimann F.M.
      • Friedrich S.
      • Fonouni H.
      • Mehrabi A.
      • Buchler M.W.
      • et al.
      Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis.
      ] or congestive heart failure [
      • Millonig G.
      • Friedrich S.
      • Adolf S.
      • Fonouni H.
      • Golriz M.
      • Mehrabi A.
      • et al.
      Liver stiffness is directly influenced by central venous pressure.
      ]. Also TE measurements need to be standardized, since in patients with cirrhosis its values increased by over 25% after a light meal, as compared with fasting patients [
      • Berzigotti A.
      • de Gottardi A.
      • Delgado M.G.
      • Seijo S.
      • Abraldes J.G.
      • Garcia-Pagan J.C.
      • et al.
      Liver stiffness increases after a meal in patients with cirrhosis but its change does not correlate with the changes in HVPG (abstract).
      ].

      Conclusions and perspectives

      TE is currently insufficient to confidently predict the presence of oesophageal varices in clinical practice but rather, given its likely prognostic value in cirrhosis, to offer a mean for rapid discrimination of different steps of progression within the stage of compensated cirrhosis. This will greatly help allocating cirrhotic patients in different categories of risk and guide the need for further evaluation with HVPG measurement and upper GI endoscopy.
      TE is not expected to replace HVPG measurement in assessing the response to the treatment of portal hypertension and the prognosis of acute variceal bleeding. This will remain the domain of invasive procedures and future developments should be aimed at making easier to obtain repeated measurements along the follow-up. There is insufficient data as to whether TE may substitute HVPG in indications such as prognosis of liver resection for HCC, although it is likely that patients with high TE values (i.e. >14 kPa) may be reasonably excluded as candidates for liver resection and may not need and HVPG measurement to confidently identify severe recurrence of HCV after liver transplantation.
      Also studies comparing TE with other non invasive methods for the detection of OV are awaited. However, when designing future studies, the weaknesses of the existing gold standard should probably be taken into account. In particular, attention should be paid to improving the interpretation of endoscopy and reducing the variability of results.
      Finally, other techniques such as the measurement of spleen stiffness [
      • Talwalkar J.A.
      • Yin M.
      • Venkatesh S.
      • Rossman P.J.
      • Grimm R.C.
      • Manduca A.
      • et al.
      Feasibility of in vivo MR elastographic splenic stiffness measurements in the assessment of portal hypertension.
      ] may also become available and deserved to be further evaluated in comparison or in combination with TE.

      Conflict of interest

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

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