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...+++ + + + + +++ +++ hypertension Ultrasound Abdominal CT-scan + (*) + ++ ++ +++ + ++ Abdominal MRI ++ + ++ ++ +++ + ++ *Cumulative radiation exposure and subsequent risk should be carefully evaluated =-=[78]-=-. Fig. 1. Proposed algorithm for the non-invasive diagnosis of cirrhosis and portal hypertension. As shown, in indeterminate cases requiring liver biopsy the transjugular modality has to be preferred ...

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... Berzigotti et al. / Non-invasive diagnostic and prognostic evaluation of liver cirrhosis and portal hypertension dividual histology scores in 1000 patients with a wide range of chronic liver disease =-=[21]-=-. Overall, the algorithm discriminant score allowed a good differentiation between patients with and without cirrhosis at biopsy and might be a promising approach in the future. 3.3. Panels combining ...

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...ss, TE has been used to assess the presence of fibrosis and cirrhosis, and has proved an excellent tool in this setting [28]. Liver stiffness has been shown to correlate with fibrosis severity in HCV =-=[29]-=-, and in other chronic liver disease [30]. The best cut-off to detect cirrhosis is not exactly defined since it appears to vary according to the etiology of liver disease; however, in a recent prospec...

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...er sampling error. Since fibrosis within the liver increases the organ’s stiffness, TE has been used to assess the presence of fibrosis and cirrhosis, and has proved an excellent tool in this setting =-=[28]-=-. Liver stiffness has been shown to correlate with fibrosis severity in HCV [29], and in other chronic liver disease [30]. The best cut-off to detect cirrhosis is not exactly defined since it appears ...

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...that express liver matrix constituents or enzymes involved in their regulation,which allow a quantitative assessment of the total amount of hepatic extracellular matrix, and its deposition or removal =-=[19]-=-. Their determination is expensive, and the ability of single markers in the assessment of the severity and progression of liver fibrosis is poor. A systematic review of serummarkers of liver fibrosis...

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... since it appears to vary according to the etiology of liver disease; however, in a recent prospective study performed in patients with liver disease values over 12.5 kPa strongly suggested cirrhosis =-=[31]-=-. The value of TE in the non-invasive prediction of portal hypertension has also been evaluated. In a study performed in patients with hepatitis C recurrence after liver transplantation, liver stiffne...

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...ce and grade of esophageal varices in several studies [16,17], and platelet count to spleen diameter ratio> 909 had a 100%negative predictive value for the presence of esophageal varices in one study =-=[18]-=- suggesting that it could be of help in avoiding unnecessary endoscopies; however in subsequent series its predictive value was lower, and should be further investigated before being accepted in clini...

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...d indirect noninvasive markers to diagnose significant fibrosis or cirrhosis. For example, Fibrometer [22] includes platelets, prothrombin time, AST, α2M, age, urea and hyaluronan (HA), and Hepascore =-=[23]-=- includes bilirubin, γGT, TIMP-1, α2M, age, and sex. Prospective evaluation [24] has shown improved accuracy of Fibrometer compared to Fibrotest, in particular in diagnosing severe fibrosis and cirrho...

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... of severe fibrosis/cirrhosis in patients with chronic hepatitis C (AUC: 0.80) [11]. However, a recent meta-analysis of 14 studies examining 10 panels of indirect blood markers in chronic hepatitis C =-=[12]-=-, including Fibrotest and APRI, demonstrated that in individual patients they cannot reliably differentiate stages of fibrosis. This makes noninvasive markers of fibrosis still insufficient to “monito...

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...diagnosis of HVPG over 12 mmHg. In two additional studies the cut-off values of respectively 23 and 13.6 kPa had a good capacity to predict the presence of CSPH in patients with chronic liver disease =-=[35,36]-=-. It should be underlined that in the study by Vizzutti et al. [35], it was shown that above the threshold value of 13.6 kPa there was not a good correlation between liver stiffness and HVPG, probably...

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...hy (MRE) is a novel method proposed to evaluate liver stiffness. The measurement is obtained by synchronizing motion-sensitive imaging sequences with the application of acoustic waves in tissue media =-=[73]-=-. It has been tested in human subjects, and the preliminary results support its practicability in predicting the stage of fibrosis in patients with chronic liver disease [74]. MRE is repeatable and ch...

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...redict the presence of severe fibrosis/cirrhosis with an AUC of 0.92. APRI has also been found to be a reliable predictor of severe fibrosis/cirrhosis in patients with chronic hepatitis C (AUC: 0.80) =-=[11]-=-. However, a recent meta-analysis of 14 studies examining 10 panels of indirect blood markers in chronic hepatitis C [12], including Fibrotest and APRI, demonstrated that in individual patients they c...

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...formed in 129 unselected cirrhotic patients [63], probably since porto-systemic collaterals are signs of clinically significant portal hypertension, which is independently related with HCC occurrence =-=[64]-=-. US is highly sensitive in diagnosing ascites, which is the most common clinical decompensation of cirrhosis and holds a severe prognostic significance. The increase of intrarenal arteriolar RI in pa...

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...isms due to portal hypertension (i.e. platelet count). These parameters may also be surrogates of inflammation and steatosis, which have a significant predictive value for the progression of fibrosis =-=[4,5]-=-. About 20 numerical scores or indices are reported for parameters which are mostly routine laboratory tests and frequently multiparametric. Among them, Fibrotest and AST to Platelet ratio index (APRI...

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...vein catheterization is not available a percutaneous liver biopsy should be obtained. Platelet count is independently correlated with the prevalence and grade of esophageal varices in several studies =-=[16,17]-=-, and platelet count to spleen diameter ratio> 909 had a 100%negative predictive value for the presence of esophageal varices in one study [18] suggesting that it could be of help in avoiding unnecess...

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...vein catheterization is not available a percutaneous liver biopsy should be obtained. Platelet count is independently correlated with the prevalence and grade of esophageal varices in several studies =-=[16,17]-=-, and platelet count to spleen diameter ratio> 909 had a 100%negative predictive value for the presence of esophageal varices in one study [18] suggesting that it could be of help in avoiding unnecess...

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...o correlate with the presence of large esophageal varices; specifically, in the study by Kazemi and colleagues, a liver stiffness value above 19 kPa predicted the presence of large esophageal varices =-=[33]-=-. In another study published as an abstract [34] the authors found a good direct correlation between HVPG and liver stiffness in a population of uncomplicated alcoholic and HCV-related cirrhotic patie...

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...hageal varices at endoscopy, and with the risk of bleeding from varices. Portal fraction of liver perfusion and mean transit time at MRI have been recently showed to have a good correlation with HVPG =-=[72]-=-. Whether any of these sophisticated and expensive techniques add to clinical, biochemical, US or transient elastography parameters should be evaluated in future studies. MR elastography (MRE) is a no...

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...diagnosis of HVPG over 12 mmHg. In two additional studies the cut-off values of respectively 23 and 13.6 kPa had a good capacity to predict the presence of CSPH in patients with chronic liver disease =-=[35,36]-=-. It should be underlined that in the study by Vizzutti et al. [35], it was shown that above the threshold value of 13.6 kPa there was not a good correlation between liver stiffness and HVPG, probably...

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...orted for parameters which are mostly routine laboratory tests and frequently multiparametric. Among them, Fibrotest and AST to Platelet ratio index (APRI) have been proposed for clinical application =-=[6,7]-=-. The FibroTest, which is a combination of α2-macroglobulin (α2M), ApoA1, Bilirubin, γGT, Haptoglobinmeasurements, is the most validated indirect test for liver fibrosis [8–10]. It has been shown to a...

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...orted for parameters which are mostly routine laboratory tests and frequently multiparametric. Among them, Fibrotest and AST to Platelet ratio index (APRI) have been proposed for clinical application =-=[6,7]-=-. The FibroTest, which is a combination of α2-macroglobulin (α2M), ApoA1, Bilirubin, γGT, Haptoglobinmeasurements, is the most validated indirect test for liver fibrosis [8–10]. It has been shown to a...

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...sensitivity of F3-F4 fibrosis at enrolment in the prediction of liver-related mortality at 8 years was 80.7%, while that of serummarkers was 84.0%. In a study in patients with alcoholic liver disease =-=[25]-=-,Nojgaard reported that YKL-40 and collagen propetidePIIINPwere predictive of short survival and increased relative risk of death. In a cohort of patients with primary biliary cirrhosis treated with U...

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... prognostic evaluation of liver cirrhosis and portal hypertension The most accurate single sign for the diagnosis of cirrhosis, which can be found even in early phases, is nodularity of liver surface =-=[42]-=-; this should be specifically investigated. The use of high frequency transducers increases the diagnostic performance of conventional abdominal US probes, and should be preferred. Few false positive ...

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...ges in tissue fibrosis [75]. MRE has been successfully applied to measure spleen stiffness, which was highly correlated with hepatic stiffness and might have a closer correlation with portal pressure =-=[76]-=-. Although MR elastography has some technical advantage over Fibroscan (no need an acoustical window, a freely-oriented field of view, lack of sensitivity to body habitus) it is more expensive and tim...

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...nation of nodular liver surface and portal vein mean velocity below 12 cm/s holds 80% accuracy for discriminating between patients with chronic hepatitis with severe fibrosis and those with cirrhosis =-=[44]-=-. In patients with clinical suspicion of cirrhosis and confounding conditions the detection of nodular liver surface is an excellent non-invasive method to rulein cirrhosis, while the combination of U...

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...rdynamic circulation found in patients with cirrhosis. All these findings can be found in decompensated disease with features of portal hypertension, and are obviously highly specific of the syndrome =-=[2]-=-. However, decompensated cirrhosis does not represent the population where non-invasive diagnosis is more needed, and unfortunately, the sensitivity of physical signs in patients with compensated cirr...

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...ic venous Doppler pattern [50]; increased intraparenchymal hepatic and splenic artery impedance [51–53]; increased intraparenchymal renal artery impedance [54] and reduced mesenteric artery impedance =-=[55]-=-. HVPG significantly correlates with some US parameters such as portal vein velocity and volume of blood flow [55], hepatic artery resistance index, splenic and renal artery resistance and pulsatility...

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...]. Congestion index of the portal vein (ratio between the cross-sectional area and blood flow velocity) independently predicted first variceal bleeding in a prospective study in patients with varices =-=[61]-=-. As for the prediction of first clinical decompensation of any kind, spleen enlargement (> 1 cm) on followup might be associated with a higher probability of developing the first clinical decompensat...

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...n a recent prospective study [62]. The presence of porto-systemic collateral circulation predicted hepatocellular carcinoma appearance in a recent study performed in 129 unselected cirrhotic patients =-=[63]-=-, probably since porto-systemic collaterals are signs of clinically significant portal hypertension, which is independently related with HCC occurrence [64]. US is highly sensitive in diagnosing ascit...

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...nsity versus time curves for magnetic resonance images of the liver after injection of a gadolinium chelate), and phase contrastMR angiographyallow a quantitativemeasurement of portal [70] and azygos =-=[71]-=- blood flow. Azygos blood flow, as measured by MRI, correlates with the presence of esophageal varices at endoscopy, and with the risk of bleeding from varices. Portal fraction of liver perfusion and ...

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...hosis in which HVPG was measured, none of the physical signs was useful to identify patients with HVPG over 10 mmHg. On the other hand spider naevi were independently predictive of esophageal varices =-=[3]-=-. 3. Laboratory tests Serum markers of fibrosis have the advantage over liver biopsy of offering a sampling of the all liver,allowing frequent repetition, being far less invasive and having less depen...

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... of fibrosis in patients with cirrhosis. Guechot and colleagues looked at the predictive value of Hyaluronic acid (HA) in a series of patients with HCVcirrhosis, followed-up for a median of 38 months =-=[27]-=-. In this study, HA had a predictive value equivalent to Child-Pugh score for the prediction of severe complications of cirrhosis or death. 4. Transient Elastography (TE) Transient elastography (measu...

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...varices of any size or of large varices include portal vein diameter or spleen size in combination with blood tests (platelet count and prothrombin time). Prospective studies in compensated cirrhosis =-=[56,57]-=- initially suggested a good discriminating ability. Nonetheless, validation studies in subsequent series failed to confirm an adequate accuracy for varices prediction. Porto-systemic collaterals such ...

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...uracy for varices prediction. Porto-systemic collaterals such as left gastric vein > 3 mm and short gastic veins (collaterals at upper spleen half) strongly suggest the presence of esophageal varices =-=[58]-=-, and their development/increase in number have been associated with a greater proportion of variceal formation and growth [59]. Similarly, progressive spleen enlargement may predict variceal formatio...

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...e of intrarenal arteriolar RI in patients with cirrhosis is related to arterial vasoconstriction; it is observed in about 40% of patients with ascites, is accurate for detecting hepato-renal syndrome =-=[65]-=-. A small liver size, spleen size over 14.5 cm, mean portal vein velocity below 10 cm/s and loss of pulsatility of hepatic veins have been associated to higher A. Berzigotti et al. / Non-invasive diag...

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...isms due to portal hypertension (i.e. platelet count). These parameters may also be surrogates of inflammation and steatosis, which have a significant predictive value for the progression of fibrosis =-=[4,5]-=-. About 20 numerical scores or indices are reported for parameters which are mostly routine laboratory tests and frequently multiparametric. Among them, Fibrotest and AST to Platelet ratio index (APRI...

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...severity and progression of liver fibrosis is poor. A systematic review of serummarkers of liver fibrosis concluded that panels of markers evaluated in combination are more accurate than single tests =-=[20]-=-. The European Liver Fibrosis (ELF) study evaluated the relationship between different algorithms incorporating serum levels of a panel of direct markers and in132 A. Berzigotti et al. / Non-invasive ...

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...gaard reported that YKL-40 and collagen propetidePIIINPwere predictive of short survival and increased relative risk of death. In a cohort of patients with primary biliary cirrhosis treated with UDCA =-=[26]-=-, HA was the only independent predictor of poor outcome. Some studies evaluated the prognostic value of serum markers of fibrosis in patients with cirrhosis. Guechot and colleagues looked at the predi...

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...ce of fibrosis and cirrhosis, and has proved an excellent tool in this setting [28]. Liver stiffness has been shown to correlate with fibrosis severity in HCV [29], and in other chronic liver disease =-=[30]-=-. The best cut-off to detect cirrhosis is not exactly defined since it appears to vary according to the etiology of liver disease; however, in a recent prospective study performed in patients with liv...

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...s on conventional US include changes in liver morphology and signs of portal hypertension (Table 2). US findings are usually highly specific, and can be considered sufficient to confirm the diagnosis =-=[41]-=-, so a positive result “rules-in” cirrhosis. On the other hand, the sensitivity of individual US findings is low, indicating that a negative result cannot fully rule-out cirrhosis. 134 A. Berzigotti e...

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...0% specific US signs of CSPH. Other US signs of CSPH include dilatation of portal vein (diameter > 13 mm) [46]; lack or reduced respiratory variations of splenic and superior mesenteric vein diameter =-=[47]-=-; reduced portal vein velocity (maximal and mean velocimetry of portal vein flow, respectively < 16 cm/s and < 10–12 cm/s) [48]; increased congestion index of portal vein [49]; altered hepatic venous ...

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... respiratory variations of splenic and superior mesenteric vein diameter [47]; reduced portal vein velocity (maximal and mean velocimetry of portal vein flow, respectively < 16 cm/s and < 10–12 cm/s) =-=[48]-=-; increased congestion index of portal vein [49]; altered hepatic venous Doppler pattern [50]; increased intraparenchymal hepatic and splenic artery impedance [51–53]; increased intraparenchymal renal...

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...tion index of portal vein [49]; altered hepatic venous Doppler pattern [50]; increased intraparenchymal hepatic and splenic artery impedance [51–53]; increased intraparenchymal renal artery impedance =-=[54]-=- and reduced mesenteric artery impedance [55]. HVPG significantly correlates with some US parameters such as portal vein velocity and volume of blood flow [55], hepatic artery resistance index, spleni...

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...d readily available information to detect cirrhosis and/or of portal hypertension is that obtained by physical examination (Fig. 1). Physical stigmata of liver cirrhosis are: a firm left hepatic lobe =-=[1]-=-, gynaecomastia, testicular atrophy, parotidomegaly, features of hepato-cellular failure such as jaundice, vascular spiders, leuconykia, palmar erythema or of hepatic encephalopathy, presence of abdom...

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...ach in the future. 3.3. Panels combining direct and indirect markers Some scores combine direct and indirect noninvasive markers to diagnose significant fibrosis or cirrhosis. For example, Fibrometer =-=[22]-=- includes platelets, prothrombin time, AST, α2M, age, urea and hyaluronan (HA), and Hepascore [23] includes bilirubin, γGT, TIMP-1, α2M, age, and sex. Prospective evaluation [24] has shown improved ac...

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...r example, Fibrometer [22] includes platelets, prothrombin time, AST, α2M, age, urea and hyaluronan (HA), and Hepascore [23] includes bilirubin, γGT, TIMP-1, α2M, age, and sex. Prospective evaluation =-=[24]-=- has shown improved accuracy of Fibrometer compared to Fibrotest, in particular in diagnosing severe fibrosis and cirrhosis, but further external validation is needed. 3.4. Prognostic value of serum m...

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...rtension has also been evaluated. In a study performed in patients with hepatitis C recurrence after liver transplantation, liver stiffness showed an excellent correlation with fibrosis and with HVPG =-=[32]-=-. In this study, a liver stiffness value 8.74 kPa had a sensitivity and specificity of 90% and 81% for the diagnosis of any grade of portal hypertension (HVPG 6 mm Hg). In addition, in the setting o...

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...l varices; specifically, in the study by Kazemi and colleagues, a liver stiffness value above 19 kPa predicted the presence of large esophageal varices [33]. In another study published as an abstract =-=[34]-=- the authors found a good direct correlation between HVPG and liver stiffness in a population of uncomplicated alcoholic and HCV-related cirrhotic patients; a cut-off value of 17 kPa had a sensitivity...

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...oma. The results suggested that TE is not an ideal method to rule-out or confirm CSPH in this population, and should not be used as a non-invasive surrogate for indicating or contraindicating surgery =-=[37]-=-. Given these observations, it can be suggested that even if high values of liver stiffness at TE are strongly predictive of cirrhosis and of the presence of CSPH, the technique is not accurate enough...

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...onditions the detection of nodular liver surface is an excellent non-invasive method to rulein cirrhosis, while the combination of US and transient elastography allows the best diagnostic performance =-=[45]-=-. As for the assessment of portal hypertension in cirrhosis, all US signs of portal hypertension are very specific, while their sensitivity is low, especially in compensated cirrhosis; therefore, whil...

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...ilated left and short gastric veins, and the inversion of flow within the portal system are 100% specific US signs of CSPH. Other US signs of CSPH include dilatation of portal vein (diameter > 13 mm) =-=[46]-=-; lack or reduced respiratory variations of splenic and superior mesenteric vein diameter [47]; reduced portal vein velocity (maximal and mean velocimetry of portal vein flow, respectively < 16 cm/s a...

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...mesenteric vein diameter [47]; reduced portal vein velocity (maximal and mean velocimetry of portal vein flow, respectively < 16 cm/s and < 10–12 cm/s) [48]; increased congestion index of portal vein =-=[49]-=-; altered hepatic venous Doppler pattern [50]; increased intraparenchymal hepatic and splenic artery impedance [51–53]; increased intraparenchymal renal artery impedance [54] and reduced mesenteric ar...

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... vein velocity (maximal and mean velocimetry of portal vein flow, respectively < 16 cm/s and < 10–12 cm/s) [48]; increased congestion index of portal vein [49]; altered hepatic venous Doppler pattern =-=[50]-=-; increased intraparenchymal hepatic and splenic artery impedance [51–53]; increased intraparenchymal renal artery impedance [54] and reduced mesenteric artery impedance [55]. HVPG significantly corre...

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...varices of any size or of large varices include portal vein diameter or spleen size in combination with blood tests (platelet count and prothrombin time). Prospective studies in compensated cirrhosis =-=[56,57]-=- initially suggested a good discriminating ability. Nonetheless, validation studies in subsequent series failed to confirm an adequate accuracy for varices prediction. Porto-systemic collaterals such ...

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...t upper spleen half) strongly suggest the presence of esophageal varices [58], and their development/increase in number have been associated with a greater proportion of variceal formation and growth =-=[59]-=-. Similarly, progressive spleen enlargement may predict variceal formation and growth [60]. Congestion index of the portal vein (ratio between the cross-sectional area and blood flow velocity) indepen...

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...evelopment/increase in number have been associated with a greater proportion of variceal formation and growth [59]. Similarly, progressive spleen enlargement may predict variceal formation and growth =-=[60]-=-. Congestion index of the portal vein (ratio between the cross-sectional area and blood flow velocity) independently predicted first variceal bleeding in a prospective study in patients with varices [...

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... cirrhosis [60]. A portal vein averaged maximum velocity <15 cm/s was the only variable independently associated with a high risk of non-malignant portal vein thrombosis in a recent prospective study =-=[62]-=-. The presence of porto-systemic collateral circulation predicted hepatocellular carcinoma appearance in a recent study performed in 129 unselected cirrhotic patients [63], probably since porto-system...

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...ociated to higher A. Berzigotti et al. / Non-invasive diagnostic and prognostic evaluation of liver cirrhosis and portal hypertension 135 mortality on follow-up in patients with compensated cirrhosis =-=[66]-=-. Monitoring of treatment of portal hypertension. There is currently no room for performingUS-Doppler monitoring of HVPG response to medical therapy of portal hypertension, since changes of Doppler pa...

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... splanchnic vasodilatation (as indicated by a low pulsatility and resistance index in splenic, mesenteric and hepatic artery) in HVPG non-responders than in responders after chronic nadolol treatment =-=[67]-=-, and overall the high negative predictive value of Doppler parameters may help to detect non-responders. On the other hand, US-Doppler is useful in the noninvasive follow-up of transjugular intrahepa...

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...esponders. On the other hand, US-Doppler is useful in the noninvasive follow-up of transjugular intrahepatic portosystemic shunt (TIPS), and allows saving unnecessary invasive hemodynamics procedures =-=[68]-=-. 6. Second line imaging techniques and new methods needing validation Computed tomographic scan (CT) and magnetic resonance (MRI) allow an accurate visualization of the liver parenchyma and the porta...

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...analysis of intensity versus time curves for magnetic resonance images of the liver after injection of a gadolinium chelate), and phase contrastMR angiographyallow a quantitativemeasurement of portal =-=[70]-=- and azygos [71] blood flow. Azygos blood flow, as measured by MRI, correlates with the presence of esophageal varices at endoscopy, and with the risk of bleeding from varices. Portal fraction of live...

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...tic waves in tissue media [73]. It has been tested in human subjects, and the preliminary results support its practicability in predicting the stage of fibrosis in patients with chronic liver disease =-=[74]-=-. MRE is repeatable and changes correlate well with changes in tissue fibrosis [75]. MRE has been successfully applied to measure spleen stiffness, which was highly correlated with hepatic stiffness a...

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...minary results support its practicability in predicting the stage of fibrosis in patients with chronic liver disease [74]. MRE is repeatable and changes correlate well with changes in tissue fibrosis =-=[75]-=-. MRE has been successfully applied to measure spleen stiffness, which was highly correlated with hepatic stiffness and might have a closer correlation with portal pressure [76]. Although MR elastogra...