Noninvasive Assessment of Portal Hypertension in Advanced Chronic Liver Disease: An Update.
Portal hypertension (PH) is defined as an increased hepatic venous pressure gradient (HVPG) and represents a common complication of liver cirrhosis. It develops whenever resistance to portal blood flow increases because of hepatic (i.e., liver diseases), prehepatic (i.e., schistosomiasis), or posthepatic causes (i.e., Budd-Chiari syndrome). In western countries, liver cirrhosis is the most frequent cause of portal hypertension. Portal hypertension is initially asymptomatic in the vast majority of patients (around 80-90%), but when complications develop it may lead to variceal bleeding, ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome among other clinical manifestations.
A review of the pathophysiology and natural history of portal hypertension is beyond the scopes of the present manuscript that focuses on noninvasive assessment of the portal pressure gradient (HVPG). However, reminding that variceal hemorrhage, ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome are among the possible complications of PH is enough to underline the clinical relevance of this syndrome. Consequently, the assessment of clinically significant portal hypertension (CSPH) in cirrhotic patients is of utmost importance. Until today, the gold standard for the evaluation of HVPG is represented by transvenous catheterization of the hepatic vein.
The evaluation of portal hypertension includes, as previously suggested , the assessment of the pathogenic factors and of the clinical complications of portal hypertension. Among the various possible evaluations, in clinical practice, the assessment of the presence of varices and of the extent of fibrosis in the liver and spleen are certainly the most important. Recently, the Baveno VI consensus workshop  highlighted the diagnostic role of noninvasive techniques (NITs) such as liver stiffness measurement (LSM) in defining the presence of CSPH and EV and proposed the new term "compensated advanced chronic liver disease (cACLD)" to better define patients who present severe fibrosis and initial cirrhosis. This review will focus on these topics with a special attention to NITs.
1.1. Hepatic Venous Pressure Gradient (HVPG). HVPG represents the current gold standard of HVPG evaluation and is obviously an invasive technique requiring venous catheterization. HVPG is usually within the 1-5mmHg range and becomes clinically significant when it reaches values of 10mmHg or above [1, 3-5]. The technique is considered safe with no fatalities reported in experienced centers and with a rate of complications of less than 1% of cases mainly represented by transient cardiac arrhythmias and local injury at the venous puncture site. It is also a technique with very few relative contraindications represented by allergy to iodinated contrast and insufficient coagulation parameters (platelets < 20,000; PT < 30%) [1, 3]. Despite this, and besides being invasive, the procedure is costly, requires expertise, and is not widely available. Therefore, noninvasive and reproducible techniques capable of substituting HVPG would be very useful in clinical practice.
HVPG is one of the best prognostic indicators so far in patients with liver cirrhosis. Several studies have highlighted the value of this technique in predicting the clinical history or the appearance of events in cirrhotic patients. The first important threshold is 10mmHg, which defined as a cutoff of CSPH, beyond which the development of ascites, varices, and hepatorenal syndrome may be observed [6-8]. Furthermore, patients with an HVPG > 10 mmHg are at increased risk of developing hepatocellular carcinoma  and decompensation after hepatic resection . On the other hand, an HVPG below 10 mmHg is associated with a high probability (approximately 90%) of remaining compensated over a period of 4 years .
When HVPG rises above 12 mmHg, the patient is at risk of variceal bleeding and ascitic decompensation [7, 11, 12]. Another important threshold is 16 mmHg that is associated with decompensation and mortality [13, 14]. Other thresholds associated with failure to control bleeding varices (20 mmHg), mortality from acute alcoholic hepatitis or alcoholic cirrhosis (22 mmHg), or spontaneous bacterial peritonitis (30 mmHg) have been identified in decompensated cirrhosis [15-18].
Apart from the abovementioned thresholds in cirrhotic patients, HVPG measurement is of relevance in evaluating the response to treatment with beta-blockers and after transjugular intrahepatic portosystemic shunt (TIPS) placement [19, 20]. In fact, a reduction of HVPG below 12 mmHg or of 20% from the baseline value equals to a reduction in the risk of development of complications and to an improved survival . Failure to obtain an HVPG below 12mmHg after TIPS placement corresponds to a dysfunction of the TIPS, and a revision of the stent is indicated [20, 22, 23]. Moreover, several studies have demonstrated a significant reduction in HVPG after achieving sustained virological response (SVR), both after an interferon-based regimen [24-26] and a DAA-based regimen [27-31], though, at the moment it is unknown which threshold can be considered as a point of "no return."
1.2. Endoscopy. Upper GI endoscopy (EGD) remains the gold standard for the evaluation of the presence of esophageal and gastric varices (GEV) [32, 33]. It allows the assessment of a number of characteristics (variceal size, presence of red signs or spots, and site) that associate with the specific risk of bleeding resulting from the combination of these endoscopic characteristics, in particular to define patients with high risk varices (HRV) [34-36]. Furthermore, EGD allows the evaluation of other findings such as portal hypertensive gastropathy that may benefit from beta blockers and gastric antral vascular ectasia (GAVE) that is not specific of cirrhosis. Recommendations on the use of EGD for the detection of HRV in all cirrhotic patients have been issued since the first Baveno consensus workshop in 1992 . Until the last Baveno consensus, all patients with a new diagnosis of cirrhosis must be referred to endoscopic screening to exclude the presence of GEV and in particular HRV . However, a large proportion of cirrhotic patients do not present HRV, thus making endoscopy a redundant test, that is, on the other hand, associated with significant costs and patient discomfort . Accordingly, in the last decade increased attention has been dedicated to identify sufficiently accurate NITs able to rule in and rule out patients who present CSPH and HRV and thus to reduce or avoid the use of invasive methods such as HVPG measurement and EGD [7, 8]. Accordingly, the so-called Baveno VI criteria stated that patients with LSM < 20kPa (assessed by transient elastography (TE)) and with normal platelet count (PLT > 150,000/[m.sup.3]) can be considered very unlikely to have HVR (based on a reasonable risk of 5% of missed varices requiring treatment). These criteria can also be applied for longitudinal follow-up, prompting screening endoscopy if LSM increases or PLT decreases . Several papers with the aim at validating the Baveno VI criteria have been published concluding that the above criteria can be safely used in clinical practice allowing to spare around 45-55% of unnecessary EGD [37, 38]. In the past year, in order to further improve the rate of spared EGD, different authors have proposed new criteria combining Baveno VI criteria with other NITs [39, 40].
1.3. Videocapsule. Different types of video capsules have been developed to overcome the invasiveness of classic upper GI endoscopy. However, this procedure is very expensive and the assessment of varices with this device is difficult, not comparable to the classic esophagogastroduodenoscopy and not accurate for the evaluation of gastric varices [41-45]. Therefore, this technique is not commonly used in current clinical practice to evaluate esophageal varices. Recently, Cales et al. developed an algorithm called VariScreen (a sequential combination of esophageal capsule endoscopy (ECE) with the patented CirrhoMeter test) which safely spared the missed HRV rate by 87% . However, video-capsule endoscopy is not widely available and is much more expensive than conventional EGD.
2. Noninvasive Tests (NITs)
2.1. Serum Biomarkers. Many attempts have been made to detect and quantify liver fibrosis using serum biomarkers, and a series of models for fibrosis detection have been proposed. There are two main groups of tests, namely indirect and direct biomarker tests. Indirect biomarker tests are based on several serum and blood parameters that reflect liver function and progression of fibrosis to cirrhosis. Direct biomarkers are based on the measurement of factors involved in extracellular matrix turnover, which are increased in the course of liver fibrogenesis.
While serum biomarkers have been well validated for the evaluation of fibrosis in chronic viral hepatitis , their correlation with portal hypertension is not optimal.
Previous attempts to correlate portal hypertension or the risk of variceal bleeding with the serum levels of direct biomarkers such as laminin, type III procollagen, and hyaluronic acid did not provide affordable results [48-50]. More recently, promising results have been obtained by the measurement of the serum levels of degraded extracellular matrix (ECM) products .
Concerning indirect biomarkers, the performance of the majority of these scores are well investigated and validated for the diagnosis of cirrhosis rather than for the assessment of portal hypertension. Among indirect biomarkers, platelet count is probably the routinely used test able to identify patients with portal hypertension in cACLD .
A recent study compared the predictive value for portal hypertension of transient elastography (TE) and different indirect biomarker test panels, both as individual tests and in combination . In this study, TE was compared with the AST-Platelet Ratio Index (ApRi) , Fibroindex (a test based on platelet count, AST, and GGT) , and Fibrosis-4 (FIB4) (a panel based on age, AST, platelet count, and ALT) , both individually and in combinations of two or three of them. When individual tests were compared, TE had the best performance in terms of sensitivity (83.87%), specificity (72.53%), and accuracy (77.1%), while the association of TE associated with FIB4 had the best specificity (74.73%) and accuracy (78.8%) when a combination of 2-3 tests were considered. These results do not seem to be better than the performance of a score combining platelet count and total bilirubin reaching an 88% sensitivity and 86% specificity for the diagnosis of CSPH . Similar efforts have been made by other authors who identified a good performance (AuROC > 0.70) of APRI, FIB4, and LOK score to predict CSPH .
Some of these serum biomarkers, alone [59, 60] or in combination with ultrasonographic parameters [61-63], have been proposed for the detection of esophageal varices. The most promising seems to be a simple score derived from the combination of acoustic radiation force impulse (ARFI) velocity and spleen diameter/platelet count . This score has been developed in a training set of compensated cirrhotic patients and then validated in an external set of similar patients from a different hospital. The proposed score reached a negative predictive value of 98.3% and a positive predictive value of 100% in the validation set of patients for the prediction of the presence of high-risk esophageal varices in patients with compensated cirrhosis .
2.2. Ultrasonography. Ultrasonography (US) is a mainstay in the assessment of patients with chronic liver disease; a noninvasive, widely available, and inexpensive technique that allows the evaluation of liver morphology as well as of functional parameters with Doppler US [64-66].
Gray scale ultrasonography allows the evaluation of various elements including the liver size and its surface, the coarseness of the parenchyma, portal vein dilatation (diameter > 13 mm) and thrombosis, and the presence of signs of portal hypertension. The main signs (pathognomonic) of portal hypertension are the presence of portosystemic collaterals (flow in paraumbilical vein and development of splenorenal collaterals) and the reversal of portal vein flow. Doppler US can evaluate several parameters related with blood hemodynamics, such as portal vein velocity, congestion index, pulsatility index, and hepatic vein Doppler US pattern [64, 65, 67, 68]. However, none of these parameters allowed the grading of portal hypertension. It is clear that the findings of collaterals or of ascites associate with severe PH and a worse prognosis, however, the abovementioned US parameters show a poor correlation with HVPG and cannot, at the present time, substitute HVPG measurement . Furthermore, US is operator dependent and Doppler measurement may be influenced by a number of factors such as respiration, timing of meals, steatosis, collaterals, inflammation, and equipment [69-72].
With the availability of contrast agents, other US evaluations have become possible. The measurement of hepatic vein transit times evaluated with contrast enhanced ultrasound (CEUS) have been suggested to be correlated with PH [73-76]. Of particular interest, in a study on cirrhotic compensated patients, the authors have shown a good correlation of the hepatic vein arrival time (< 14 seconds) at CEUS with HVPG ; the AUROC for the diagnosis of clinically significant portal hypertension was 0.973 with a positive predictive value of 90% and a negative predictive value of 87-89%. Furthermore, this data is associated with the presence of large esophageal varices. Despite the promise of such good performance, the evaluation of hepatic vein arrival time has not cleared the way to routine clinical use. An explanation may come from a failure rate of about 11.5% and the variations due to the kind of software, equipment, and contrast agent used.
Another proposed parameter is the regional hepatic perfusion described by Berzigotti et al.  that was increased in cirrhotic patients; however, its correlation with HVPG was only weak. Conventional and Doppler US are useful in the diagnosis and follow-up of patients with liver disease, however, US signs and parameters of portal hypertension do not satisfactorily correlate with HVPG and cannot be used in place of HVPG.
2.3. Ultrasound Elastography Techniques. More attractive is the measurement of tissue elastography which may be accomplished by transient elastography [79-81] (TE, FibroScan[R], Echosens, Paris, France) or different shear-wave-based techniques, such as point-shear wave elastography  (p-SWE) and two-dimensional shear wave elastography [83, 84] (2D-SWE) that have been developed and incorporated in ultrasound equipment [3, 84]. Both p-SWE and 2D-SWE are based on acoustic radiation force impulse imaging (ARFI).
Elastography techniques are commonly used for the evaluation of liver fibrosis and in the evaluation of portal hypertension . A meta-analysis, performed on 18 studies, showed that liver stiffness measurement (LSM) has high accuracy (90% sensitivity, 79% specificity, and an AUC of 0.93) for the detection of CSPH .
Recently, the Baveno VI Consensus Conference recommended LSM values of 20-25 kPa as an accurate cutoff to identify patients with CSPH ; in fact, patients with LSM values > 10 kPa at TE were considered suggestive of cACLD and values of LSM [greater than or equal to] 21 kPa were defined to rule in CSPH [86-88]. Despite the good results described in different studies, the main drawbacks of liver TE are the low accuracy in obese patients (an extra large XL probe is now available) and the overestimation of liver stiffness in patients with elevated ALT serum values .
Several studies have shown that the accuracy of p-SWE for the evaluation of liver fibrosis is comparable to that of TE [80, 89-93]. Similar to TE, p-SWE has been studied as a noninvasive tool to evaluate PH. However, studies published until now have reported conflicting results about the correlation of p-SWE and HVPG [94-96].
As expected, 2D-SWE performed as well as TE in assessing liver fibrosis with a higher accuracy in the diagnosis of mild and severe fibrosis and with a greater applicability [83, 97-99]. More recently, studies from different groups have reported a moderate or good correlation of 2D-SWE with HVPG suggesting that it might be a useful tool in the assessment of PH [100-104].
In conclusion, it is important to remember that it could be difficult to compare, mainly in terms of thresholds, the results obtained with different elastographic techniques, as was recently documented for LSM .
2.4. Spleen Stiffness Measurement. Together with significant distortions in liver and vascular architecture, alterations in spleen size and morphology are usually observed in patients with liver cirrhosis complicated by PH. It is well known that splenomegaly is a common finding in patients with cirrhosis; however, studies demonstrating a robust linear correlation between spleen size (diameter) and portal pressure are lacking . Increased congestion of the splenic venous system leads to increased splenic red pulp volume and changes in histology, such as histiocyte hyperplasia, lengthening of arterial terminals, increased white pulp volume, and finally trabecular fibrosis [107, 108]. Based on these findings and the presumed consequent alteration in parenchymal strain, in the last years various groups focused their attention on the evaluation of spleen stiffness measurement (SSM) and its correlation with PH. Colecchia et al. first demonstrated a clear and reproducible correlation between SSM by TE and the presence and degree of PH assessed by HVPG . With a cutoff value of <40 kPa, the authors were able to rule out the presence of CSPH with a sensitivity of 98.5%; with a cutoff value of [greater than or equal to] 52.8 kPa, they were able to rule in the presence of CSPH with a specificity of 97.1%. Moreover, similar cutoff values have been identified to rule out and rule in the presence of EV (<41.3 kPa; sensitivity 98.1% and [greater than or equal to] 55 kPa; specificity 95.7%, resp.) . Later, many other authors found similar results also with p-SWE and 2DSWE [94, 95, 101, 110-114]. In this setting, a recent metaanalysis of studies comparing SSM with endoscopy found suboptimal pooled diagnostic accuracy for the diagnosis of EV (pooled sensitivity 88%; pooled specificity 78%) concluding that SSM is superior to LSM (pooled sensitivity 83%; pooled specificity 66%) for predicting EV in chronic liver disease . Despite these well-defined evidence, SSM has not routinely been used yet due to its technical limitation, that is, low applicability in normal-sized spleen and ceiling effect at 75 kPa impairing risk stratification of patients . Technical implementations are looming: the development of a dedicated device for SSM able to detect stiffness greater than 75 kPa will be released soon .
Recent studies showed that SSM also has a prognostic value for decompensation events in patients with cACLD [117, 118]. Colecchia et al., followed-up for a mean of 30 months a cohort of 92 patients with HCV-related cirrhosis and found that MELD values and SSM were independently correlated to the risk of decompensation. The authors identified a SSM cutoff value of 54 kPa able to identify patients with a low risk of decompensation (negative predictive value 0.975) and proposed the use of SSM as a noninvasive prognostic factor in patients with compensated HCV cirrhosis . Up to now, the MELD model score and the Child Pugh score are mainly used in clinical practice as independent predictive scores of mortality. Recently, Takuma et al.  assessed SSM by SWE to predict mortality as a primary end point; the authors found that SSM had the best discriminative value among all other clinical variables; each SS unit (m/s) of increase by p-SWE was associated with a 14.5-fold increase in the risk of death, and the cutoff of 3.43 m/s had a 75.8% accuracy in predicting mortality after a median follow-up of 44.6 months. Recently, a small but intriguing study demonstrated a rapid reduction of SS in patients before and after liver transplantation (LT); the authors investigated 21 patients awaiting for LT and 11 patients after LT. They hypothesized that the resolution of PH consequent to LT could reflect into significant changes in SSM. Patients awaiting for LT showed a SS measurement significantly higher compared to posttransplant patients (75 versus 28.4 kPa; P <0.0001). The authors demonstrated that SS noninvasively reflects changes in PH after LT, even in the early phases post-LT . In a similar setting, SSM was demonstrated to be a valid tool for the assessment of early changes of portal hemodynamics: two different studies evaluate changes of SSM after transjugular intrahepatic portosystemic shunt (TIPS) creation. The authors found nonunivocal results: while Gao et al. found a significant reduction of SSM in 10 patients after TIPS placement (3.65 m/s versus 3.27m/s; P <0.001), Novelli et al. found an increase in SS in 42% (8 out of 19) of patients and a reduction in the remaining 58%. Concurrent coil embolization of portal collateral was correlated to the increase of SSM, but the small study population does not allow performing detailed correlation (resulting in an underpowered multivariate analysis) [120, 121].
Finally, the application of NITs for the diagnosis and grading of PH and its complication is even more important in a pediatric population, in which the performance of invasive procedures (i.e., upper endoscopy) have to be performed under deep sedation, with a significant increase in cost and related morbidity. In this field, some authors evaluated the application of SSM as a reliable tool to spare unnecessary maneuvers. Goldschmidt et al. performed SSM in 99 children with different degrees of chronic liver disease; in the pediatric population, SS measurement using TE was feasible in 90.5% of children with splenomegaly (versus 70.2% in children without). The authors found a significant increase of SS in patients with varices (75 versus 24kPa) and found that patients with SSM < 60 kPa had no risk of upper variceal bleeding .
2.5. Indocyanine Green Clearance. Several serum markers of the liver function test have been developed and evaluated in order to obtain detailed and reliable information on functional reserve. Indeed, in this field, the routine application of liver function tests (i.e., serum albumin, bilirubin, INR, etc.) or even composite score (i.e., MELD, Na-MELD, etc.) is usually quite insensitive and nonspecific. Dye test, measurement of total serum bile acid concentration, breath tests, and metabolic clearance tests (i.e., caffeine) have been tested and demonstrated able to estimate hepatic excretory capacity. Despite known clinical potential applications, these tools are more complex to perform and to reproduce and thus rarely used in clinical practice [123, 124].
The estimation of liver function reserve by a clearance test is based on the assessment of the synthetic capacity through the administration of a known substrate with the measurement of a known product or clearance of an exogenous drug, which is mostly removed and/or metabolized by the liver. Metabolic clearance depends upon three major factors, hepatic perfusion, sinusoidal exchange, and functional hepatic mass. Thus, clearance of substrates dependent upon microsomial function (i.e., aminopyrine or caffeine) reflects functional reserve, while a substrate with high extraction (i.e., indocyanine green) depends mostly on blood flow [125, 126].
Indocyanine green (ICG) is a water-soluble organic dye that binds to albumin and alpha-1 lipoproteins; after an active uptake from hepatocytes, it is secreted unchanged into the bile. ICG is removed exclusively from the liver and does not undergo enterohepatic circulation. Finally, ICG clearance is modified by acute changes in vascular liver perfusion . ICG clearance is a quantitative liver function test representing both parenchymal function and hepatic blood flow. Based on its characteristics, ICG clearance is routinely used, especially in Eastern countries, for the assessment of liver function in patients undergoing hepatic surgery (hepatocellular carcinoma or biliary cancer resection) [128, 129].
Our group evaluated the ability of ICG clearance to evaluate the presence and degree of PH and its complications (EV) among patients with compensated cirrhosis. We hypothesized that, among patients with a well-preserved liver function, the ICG-retention test will directly reflect liver blood flow and thus, indirectly, the presence of PH. In a homogeneous group of well-compensated (child A) cirrhotic patients, we observed a good direct correlation between the ICG-retention test at 15 minutes (namely ICG-r15) and HVPG measurement . Among noninvasive serum markers tested, ICG-r15 showed the best diagnostic performance for the assessment of portal hypertension, CSPH, and SPH; indeed, according to ROC curve analyses, we identified two cutoff values (<6.7% and <6.9%) able to rule out the presence of CSPH and SPH with a very good sensitivity (95.9% and 96.6%, resp.). These preliminary data have been further validated by an independent Danish group .
Moreover, ICG-r15 seems to be a valid noninvasive tool for ruling out the presence of EV; we identified two cutoff points: ICG-r15 < 10% able to rule out the presence of EV (sensitivity 97.8%, NPV 96.3%, and negative LR 0.042) and ICG-r15 > 22.9% to rule in the presence of EV (specificity 90.0%, PPV 83.8%, and positive LR 5.43). We also observed that 45 out of 46 patients with EV were correctly identified by the proposed cutoff, which is able to exclude the presence of large EV with a sensitivity of 100% and a negative likelihood ratio of 0.0 .
It is well known that quantitative liver function tests are able to detect early changes in liver blood flow and function with good reproducibility; their ability to show functional impairment reflects on the usefulness as prognostic factors for short-term clinical outcomes . To date, a relevant study confirmed that the incorporation of ICG clearance into MELD (MELD-ICG) increases accuracy on the prediction of 1-year survival in patients with intermediate-advanced liver cirrhosis (area under ROC curve for MELD: 0.58-0.71 versus MELD-ICG: 0.65-0.73). The authors hypothesized that the integrated information on blood flow to liver function leads to the increased accuracy as a prognostic factor .
Liver disease progression is characterized by hemodynamic alterations occurring together with liver functional impairment; we recently evaluated if ICG-r15 could be a long-term prognostic factor in patients with compensated disease because of its demonstrated ability to provide information that integrates the assessment of liver blood flow and hepatic functional reserve.
We longitudinally observed 134 patients for a mean of 29 months. Our preliminary observation showed that ICG-r15 (OR 1.068; 95% CI 1.038-1.098), HVPG measurement (OR 1.100; 95% CI 1.017-1.190), and presence of EV (OR 2.544; 95% CI 1.141-5.673) are independently correlated with the development of decompensation. Kaplan-Meyer curves confirmed ICG-r15 [greater than or equal to] 22.9% (HR 5.491; 95% CI 2.681-11.245), HVPG [greater than or equal to] 12mmHg (HR 2.686; 95% CI 1.456-4.954), and presence of OV (HR 5.050; 95% CI 2.184-7.511) as risk factors for decompensation .
2.6. Magnetic Resonance (MR) and Computed Tomography (CT). In clinical practice, at least in Europe, MR and CT are not frequently used just to evaluate PH. The reason relies on costs and ease of access, particularly for MRI. In fact, in the United States, CT scan is cost-effective for the diagnosis of gastroesophageal varices , but the technique is less costly than in Europe, where endoscopy is usually cheaper. About CT, scan irradiation represents another factor weighing on its use.
This radiologic technique can give an accurate representation of the morphology of the portal venous system and on the presence and extent of thrombosis as well as on the presence of collaterals. This accurate imaging may be particularly useful before TIPS placement in patients with posthepatic portal hypertension such as in the Budd-Chiari syndrome. With regard to varix detection, the performance of CT and MRI are good for large varices, but lower for small varices [3, 136-138].
Another application of MR is the elastography of the liver (MRE) . Recent meta-analyses have reported good results for MRE in the evaluation of fibrosis [140, 141]. Differently from US-based methods, MRE allows the evaluation of the entire liver and is not limited by body habitus or meteorism [142, 143]. However, long-term studies are not available yet and, as abovementioned, its use is limited by costs.
Promising results have been reported also for the evaluation of spleen stiffness elastography using a MRE protocol comparing healthy controls and patients with chronic liver disease (CLD) . MRE was successfully performed in all patients, and the authors found a significant SSM difference among healthy volunteers and patients with liver fibrosis (3.6 [+ or -] 0.3 versus 5.6 [+ or -] 5.0 kPa; P <0.001). Interestingly, the authors identified a SS cutoff value of [greater than or equal to] 10.5 kPa able to identify the presence of esophageal varices in patients with compensated cirrhosis with a specificity of 100% . These preliminary data have been recently confirmed by other groups; in particular, Shin et al. showed that MRE was highly reproducible and could be integrated with double contrast-enhanced MRI to increase the sensitivity and overall accuracy for the diagnosis of EV . Multiparametric liver and spleen MRE have been correlated with HVPG measurement and endoscopy . The authors calculated three parameters, namely storage, loss, and shear moduli. Among them, spleen loss modulus appears to be the best parameter for identifying patients with severe portal hypertension (AUC 0.81) or high-risk varices (AUC 0.93).
The armamentarium available to hepatologists for the assessment of PH has increased in recent years with the advent of several NITs beside the classical and invasive measurement performed by HVPG and endoscopy. The availability of each technique is not universal since some of them are quite expensive and require specific expertise. In this scenario, the availability of easily reproducible techniques with acceptable costs is certainly welcome.
While HVPG measurement and endoscopy remain the gold standard for the evaluation of PH and varices, NITs will likely optimize their use. We think that in a patient with a newly diagnosed cACLD, a screening with NITs is preferable in order to define the best timing to perform endoscopy or other invasive techniques unless we are facing a decompensated patient. The real point is when to perform these procedures in patients with an initial-stage ACLD that are unlikely to have already developed CSPH.
With regard to the techniques described in the present paper, we believe they have the potential to partially satisfy this request either alone (i.e., indocyanine green and SSM) or in combination (i.e., Baveno VI criteria and other NITs). The choice of the technique, excluding significant differences in accuracy that may arise as our knowledge expands, will likely be dependent on local availability and expertise. For example, since ultrasonography is already current practice for liver patients, it is likely that the implementation of elastographic techniques on already available ultrasound machines will have a larger diffusion than TE. Furthermore, it allows performing ultrasound and elastometric examination at the same time and has a higher success rate.
In times during which we have to face with monetary budgets, choosing the right time to perform an appropriate procedure is advisable in order not to waste money.
Conflicts of Interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
 D. Thabut, R. Moreau, and D. Lebrec, "Noninvasive assessment of portal hypertension in patients with cirrhosis," Hepatology, vol. 53, no. 2, pp. 683-694, 2011.
 P. S. Kamath and R. P. Mookerjee, "Individualized care for portal hypertension: not quite yet," Journal of Hepatology, vol. 63, no. 3, pp. 543-545, 2015.
 A. Berzigotti, S. Seijo, E. Reverter, and J. Bosch, "Assessing portal hypertension in liver diseases," Expert Review of Gastroenterology & Hepatology, vol. 7, no. 2, pp. 141-155, 2013.
 M. Y. Kim, W. K. Jeong, and S. K. Baik, "Invasive and noninvasive diagnosis of cirrhosis and portal hypertension," World Journal of Gastroenterology, vol. 20, no. 15, pp. 4300-4315, 2014.
 R. Khanna and S. K. Sarin, "Non-cirrhotic portal hypertension--diagnosis and management," Journal of Hepatology, vol. 60, no. 2, pp. 421-441, 2014.
 R. J. Groszmann, G. Garcia-Tsao, J. Bosch et al., "Betablockers to prevent gastroesophageal varices in patients with cirrhosis," The New England Journal of Medicine, vol. 353, no. 21, pp. 2254-2261, 2005.
 G. Garcia-Tsao, R. J. Groszmann, R. L. Fisher, H. O. Conn, C. E. Atterbury, and M. Glickman, "Portal pressure, presence of gastroesophageal varices and variceal bleeding," Hepatology, vol. 5, no. 3, pp. 419-424, 1985.
 C. Ripoll, R. Groszmann, G. Garcia-Tsao et al., "Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis," Gastroenterology, vol. 133, no. 2, pp. 481-488, 2007.
 C. Ripoll, R. J. Groszmann, G. Garcia-Tsao et al., "Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis," Journal of Hepatology, vol. 50, no. 5, pp. 923-928, 2009.
 A. Berzigotti, M. Reig, J. G. Abraldes, J. Bosch, and J. Bruix, "Portal hypertension and the outcome of surgery for hepatocellular carcinoma in compensated cirrhosis: a systematic review and meta-analysis," Hepatology, vol. 61, no. 2, pp. 526-536, 2015.
 C. Merkel, M. Bolognesi, S. Bellon et al., "Prognostic usefulness of hepatic vein catheterization in patients with cirrhosis and esophageal varices," Gastroenterology, vol. 102, no. 3, pp. 973-979, 1992.
 C. Gluud and J. H. Henriksen, "Prognostic indicators in alcoholic cirrhotic men," Hepatology, vol. 8, no. 2, pp. 222-227, 1988.
 A. Berzigotti, V. Rossi, C. Tiani et al., "Prognostic value of a single HVPG measurement and Doppler-ultrasound evaluation in patients with cirrhosis and portal hypertension," Journal of Gastroenterology, vol. 46, no. 5, pp. 687695, 2011.
 A. J. Stanley, I. Robinson, E. H. Forrest, A. L. Jones, and P. C. Hayes, "Haemodynamic parameters predicting variceal haemorrhage and survival in alcoholic cirrhosis," QJM, vol. 91, no. 1, pp. 19-25, 1998.
 J. G. Abraldes, C. Villanueva, R. Banares et al., "Hepatic venous pressure gradient and prognosis in patients with acute variceal bleeding treated with pharmacologic and endoscopic therapy," Journal of Hepatology, vol. 48, no. 2, pp. 229-236, 2008.
 E. Moitinho, A. Escorsell, J.-C. Bandi et al., "Prognostic value of early measurements of portal pressure in acute variceal bleeding," Gastroenterology, vol. 117, no. 3, pp. 626-631, 1999.
 D. Rincon, O. Lo Iacono, C. Ripoll et al., "Prognostic value of hepatic venous pressure gradient for in-hospital mortality of patients with severe acute alcoholic hepatitis," Alimentary Pharmacology & Therapeutics, vol. 25, no. 7, pp. 841-848, 2007.
 T. Serste, N. Bourgeois, D. Lebrec, S. Evrard, J. Deviere, and O. Le Moine, "Relationship between the degree of portal hypertension and the onset of spontaneous bacterial peritonitis in patients with cirrhosis," Acta Gastro-enterologica Belgica, vol. 69, pp. 355-360, 2006.
 T. D. Boyer and Z. J. Haskal, "American Association for the Study of Liver Diseases practice guidelines: the role of transjugular intrahepatic portosystemic shunt creation in the management of portal hypertension," Journal of Vascular and Interventional Radiology, vol. 16, no. 5, pp. 615-629, 2005.
 T. D. Boyer, Z. J. Haskal, and American Association for the Study of Liver Diseases, "The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension: update 2009," Hepatology, vol. 51, no. 1, pp. 306-306, 2010.
 C. Merkel, M. Bolognesi, D. Sacerdoti et al., "The hemodynamic response to medical treatment of portal hypertension as a predictor of clinical effectiveness in the primary prophylaxis of variceal bleeding in cirrhosis," Hepatology, vol. 32, no. 5, pp. 930-934, 2000.
 C. Bureau, J.. Garcia-Pagan, P. Otal et al., "Improved clinical outcome using polytetrafluoroethylene-coated stents for TIPS: results of a randomized study," Gastroenterology, vol. 126, no. 2, pp. 469-475, 2004.
 A. Blasco, X. Forns, J. A. Carrion et al., "Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation," Hepatology, vol. 43, no. 3, pp. 492-499, 2006.
 D. Rincon, C. Ripoll, O. L. Iacono et al., "Antiviral therapy decreases hepatic venous pressure gradient in patients with chronic hepatitis C and advanced fibrosis," The American Journal of Gastroenterology, vol. 101, no. 10, pp. 2269-2274, 2006.
 S. Roberts, A. Gordon, C. McLean et al., "Effect of sustained viral response on hepatic venous pressure gradient in hepatitis C-related cirrhosis," Clinical Gastroenterology and Hepatology, vol. 5, no. 8, pp. 932-937, 2007.
 T. Reiberger, B. A. Payer, A. Ferlitsch et al., "A prospective evaluation of pulmonary, systemic and hepatic haemodynamics in HIV-HCV-coinfected patients before and after antiviral therapy with pegylated interferon and ribavirin," Antiviral Therapy, vol. 17, no. 7, pp. 1327-1334, 2012.
 M. Mandorfer, K. Kozbial, P. Schwabl et al., "Sustained virologic response to interferon-free therapies ameliorates HCV-induced portal hypertension," Journal of Hepatology, vol. 65, no. 4, pp. 692-699, 2016.
 E. Mauro, G. Crespo, C. Montironi et al., "Portal pressure and liver stiffness measurements in the prediction of fibrosis regression after sustained virological response in recurrent hepatitis C," Hepatology, vol. 67, no. 5, pp. 1683-1694, 2018.
 N. Afdhal, G. T. Everson, J. L. Calleja et al., "Effect of viral suppression on hepatic venous pressure gradient in hepatitis C with cirrhosis and portal hypertension," Journal of Viral Hepatitis, vol. 24, no. 10, pp. 823-831, 2017.
 S. Lens, E. Alvarado-Tapias, Z. Marino et al., "Effects of alloral anti-viral therapy on HVPG and systemic hemodynamics in patients with hepatitis C virus-associated cirrhosis," Gastroenterology, vol. 153, no. 5, pp. 1273-1283.e1, 2017.
 P. Schwabl, M. Mandorfer, S. Steiner et al., "Interferon-free regimens improve portal hypertension and histological necroinflammation in HIV/HCV patients with advanced liver disease," Alimentary Pharmacology & Therapeutics, vol. 45, no. 1, pp. 139-149, 2017.
 G. Garcia-Tsao, J. K. Lim, and Members of Veterans Affairs Hepatitis C Resource Center Program, "Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program," The American Journal of Gastroenterology, vol. 104, no. 7, pp. 1802-1829, 2009.
 J. H. Hwang, A. K. Shergill, R. D. Acosta et al., "The role of endoscopy in the management of variceal hemorrhage," Gastrointestinal Endoscopy, vol. 80, no. 2, pp. 221-227, 2014.
 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," The New England Journal of Medicine, vol. 319, no. 15, pp. 983-989, 1988.
 K. Beppu, K. Inokuchi, N. Koyanagi et al., "Prediction of variceal hemorrhage by esophageal endoscopy," Gastrointestinal Endoscopy, vol. 27, no. 4, pp. 213-218, 1981.
 S. K. Sarin, D. Lahoti, S. P. Saxena, N. S. Murthy, and U. K. Makwana, "Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients," Hepatology, vol. 16, no. 6, pp. 1343-1349, 1992.
 A. Marot, E. Trepo, C. Doerig, A. Schoepfer, C. Moreno, and P. Deltenre, "Liver stiffness and platelet count for identifying patients with compensated liver disease at low risk of variceal bleeding," Liver International, vol. 37, no. 5, pp. 707-716, 2017.
 C. Moctezuma-Velazquez and J. G. Abraldes, "Non-invasive diagnosis of esophageal varices after Baveno VI," Turkish Journal of Gastroenterology, vol. 28, no. 3, pp. 159-165, 2017.
 P. Jangouk, L. Turco, A. De Oliveira, F. Schepis, E. Villa, and G. Garcia-Tsao, "Validating, deconstructing and refining Baveno criteria for ruling out high-risk varices in patients with compensated cirrhosis," Liver International, vol. 37, no. 8, pp. 1177-1183, 2017.
 A. Colecchia, F. Ravaioli, G. Marasco et al., "A combined model based on spleen stiffness measurement and Baveno VI criteria to rule out high-risk varices in advanced chronic liver disease," Journal of Hepatology, 2018.
 R. de Franchis, G. M. Eisen, L. Laine et al., "Esophageal capsule endoscopy for screening and surveillance of esophageal varices in patients with portal hypertension," Hepatology, vol. 47, no. 5, pp. 1595-1603, 2008.
 E. Rondonotti, F. Villa, A. Dell' Era, G. E. Tontini, and R. de Franchis, "Capsule endoscopy in portal hypertension," Clinics in Liver Disease, vol. 14, no. 2, pp. 209-220, 2010.
 D. Chavalitdhamrong, D. M. Jensen, B. Singh et al., "Capsule endoscopy is not as accurate as esophagogastroduodenoscopy in screening cirrhotic patients for varices," Clinical Gastroenterology and Hepatology, vol. 10, no. 3, pp. 254-258.e1, 2012.
 A. Laurain, A. de Leusse, R. Gincul et al., "Oesophageal capsule endoscopy versus oesophago-gastroduodenoscopy for the diagnosis of recurrent varices: a prospective multicentre study," Digestive and Liver Disease, vol. 46, no. 6, pp. 535-540, 2014.
 S. Sacher-Huvelin, P. Cales, C. Bureau et al., "Screening of esophageal varices by esophageal capsule endoscopy: results of a French multicenter prospective study," Endoscopy, vol. 47, no. 6, pp. 486-492, 2015.
 P. Cales, S. Sacher-Huvelin, D. Valla et al., "Large oesophageal varice screening by a sequential algorithm using a cirrhosis blood test and optionally capsule endoscopy," Liver International, vol. 38, no. 1, pp. 84-93, 2018.
 European Association for Study of Liver and Asociacion Latinoamericana para el Estudio del Higado, "EASL-ALEH Clinical Practice Guidelines: non-invasive tests for evaluation of liver disease severity and prognosis," Journal of Hepatology, vol. 63, no. 1, pp. 237-264, 2015.
 J. Kropf, A. M. Gressner, and W. Tittor, "Logistic-regression model for assessing portal hypertension by measuring hyaluronic acid (hyaluronan) and laminin in serum," Clinical Chemistry, vol. 37, no. 1, pp. 30-35, 1991.
 A. M. Gressner, W. Tittor, A. Negwer, and K. H. Pick-Kober, "Serum concentrations of laminin and aminoterminal propeptide of type III procollagen in relation to the portal venous pressure of fibrotic liver diseases," Clinica Chimica Acta, vol. 161, no. 3, pp. 249-258, 1986.
 M. Kondo, S. J. Miszputen, M. M. Leite-mor, and E. R. Parise, "The predictive value of serum laminin for the risk of variceal bleeding related to portal pressure levels," Hepato-Gastroenterology, vol. 42, no. 5, pp. 542-545, 1995.
 D. J. Leeming, M. A. Karsdal, I. Byrjalsen et al., "Novel serological neo-epitope markers of extracellular matrix proteins for the detection of portal hypertension," Alimentary Pharmacology & Therapeutics, vol. 38, no. 9, pp. 1086-1096, 2013.
 A. Berzigotti, S. Seijo, U. Arena et al., "Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis," Gastroenterology, vol. 144, no. 1, pp. 102-111.e1, 2013.
 R. Chou and N. Wasson, "Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review," Annals of Internal Medicine, vol. 158, no. 11, pp. 807-820, 2013.
 A. Loaeza-del-Castillo, F. Paz-Pineda, E. Oviedo-Cardenas, F. Sanchez-Avila, and F. Vargas-Vorackova, "AST to platelet ratio index (APRI) for the noninvasive evaluation of liver fibrosis," Annals of Hepatology, vol. 7, no. 4, pp. 350-357, 2008.
 M. Koda, Y. Matunaga, M. Kawakami, Y. Kishimoto, T. Suou, and Y. Murawaki, "FibroIndex, a practical index for predicting significant fibrosis in patients with chronic hepatitis C," Hepatology, vol. 45, no. 2, pp. 297-306, 2007.
 S. McPherson, S. F. Stewart, E. Henderson, A. D. Burt, and C. P. Day, "Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease," Gut, vol. 59, no. 9, pp. 1265-1269, 2010.
 S. H. Park, T. E. Park, Y. M. Kim et al., "Non-invasive model predicting clinically-significant portal hypertension in patients with advanced fibrosis," Journal of Gastroenterology and Hepatology, vol. 24, no. 7, pp. 1289-1293, 2009.
 B. Procopet, V. M. Cristea, M. A. Robic et al., "Serum tests, liver stiffness and artificial neural networks for diagnosing cirrhosis and portal hypertension," Digestive and Liver Disease, vol. 47, no. 5, pp. 411-416, 2015.
 D. Thabut, J. B. Trabut, J. Massard et al., "Non-invasive diagnosis of large oesophageal varices with FibroTest in patients with cirrhosis: a preliminary retrospective study," Liver International, vol. 26, no. 3, pp. 271-278, 2006.
 G. Sebastiani, D. Tempesta, G. Fattovich et al., "Prediction of oesophageal varices in hepatic cirrhosis by simple serum non-invasive markers: results of a multicenter, large-scale study," Journal of Hepatology, vol. 53, no. 4, pp. 630-638, 2010.
 E. G. Giannini, A. Zaman, A. Kreil et al., "Platelet count/ spleen diameter ratio for the noninvasive diagnosis of esophageal varices: results of a multicenter, prospective, validation study," The American Journal of Gastroenterology, vol. 101, no. 11, pp. 2511-2519, 2006.
 E. Giannini, F. Botta, P. Borro et al., "Platelet count/spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis," Gut, vol. 52, no. 8, pp. 1200-1205, 2003.
 Y. Park, S. U. Kim, S. Y. Park et al., "A novel model to predict esophageal varices in patients with compensated cirrhosis using acoustic radiation force impulse elastography," PLoS One, vol. 10, no. 3, article e0121009, 2015.
 A. Berzigotti and F. Piscaglia, "Ultrasound in portal hypertension--part 1," Ultraschall in der Medizin, vol. 32, no. 6, pp. 548-571, 2011.
 A. Berzigotti, F. Piscaglia, and and the EFSUMB Education and Professional Standards Committee, "Ultrasound in portal hypertension--part 2--and EFSUMB recommendations for the performance and reporting of ultrasound examinations in portal hypertension," Ultraschall in der Medizin, vol. 33, no. 1, pp. 8-32, 2012.
 A. Colecchia, G. Marasco, M. Taddia et al., "Liver and spleen stiffness and other noninvasive methods to assess portal hypertension in cirrhotic patients: a review of the literature," European Journal of Gastroenterology & Hepatology, vol. 27, no. 9, pp. 992-1001, 2015.
 G. Zironi, S. Gaiani, D. Fenyves, A. Rigamonti, L. Bolondi, and L. Barbara, "Value of measurement of mean portal flow velocity by Doppler flowmetry in the diagnosis of portal hypertension," Journal of Hepatology, vol. 16, no. 3, pp. 298-303, 1992.
 K. Haag, M. Rossle, A. Ochs et al., "Correlation of duplex sonography findings and portal pressure in 375 patients with portal hypertension," American Journal of Roentgenology, vol. 172, no. 3, pp. 631-635, 1999.
 T. Kok, E. J. van der Jagt, E. B. Haagsma, C. M. A. Bijleveld, P. L. M. Jansen, and W. J. Boeve, "The value of Doppler ultrasound in cirrhosis and portal hypertension," Scandinavian Journal of Gastroenterology, vol. 34, no. 230, pp. 82-88,1999.
 A. Colli, M. Cocciolo, N. Mumoli, N. Cattalini, M. Fraquelli, and D. Conte, "Hepatic artery resistance in alcoholic liver disease," Hepatology, vol. 28, no. 5, pp. 1182-1186, 1998.
 T. Bernatik, D. Strobel, E. G. Hahn, and D. Becker, "Doppler measurements: a surrogate marker of liver fibrosis?," European Journal of Gastroenterology & Hepatology, vol. 14, no. 4, pp. 383-387, 2002.
 A. K. P. Lim, N. Patel, R. J. Eckersley et al., "Can Doppler sonography grade the severity of hepatitis C-related liver disease?," American Journal of Roentgenology, vol. 184, no. 6, pp. 1848-1853, 2005.
 A. K. Lim, S. D. Taylor-Robinson, N. Patel et al., "Hepatic vein transit times using a microbubble agent can predict disease severity non-invasively in patients with hepatitis C," Gut, vol. 54, no. 1, pp. 128-133, 2005.
 A. K. P. Lim, N. Patel, R. J. Eckersley et al., "Hepatic vein transit time of SonoVue: a comparative study with Levovist," Radiology, vol. 240, no. 1, pp. 130-135, 2006.
 T. Albrecht, M. J. K. Blomley, D. O. Cosgrove et al., "Noninvasive diagnosis of hepatic cirrhosis by transit-time analysis of an ultrasound contrast agent," The Lancet, vol. 353, no. 9164, pp. 1579-1583, 1999.
 M. J. Blomley, A. K. Lim, C. J. Harvey et al., "Liver microbubble transit time compared with histology and Child-Pugh score in diffuse liver disease: a cross sectional study," Gut, vol. 52, no. 8, pp. 1188-1193, 2003.
 M. Y. Kim, K. T. Suk, S. K. Baik et al., "Hepatic vein arrival time as assessed by contrast-enhanced ultrasonography is useful for the assessment of portal hypertension in compensated cirrhosis," Hepatology, vol. 56, no. 3, pp. 1053-1062, 2012.
 A. Berzigotti, C. Nicolau, P. Bellot et al., "Evaluation of regional hepatic perfusion (RHP) by contrast-enhanced ultrasound in patients with cirrhosis," Journal of Hepatology, vol. 55, no. 2, pp. 307-314, 2011.
 T. Shiina, K. R. Nightingale, M. L. Palmeri et al., "WFUMB guidelines and recommendations for clinical use of ultrasound elastography: part 1: basic principles and terminology," Ultrasound in Medicine & Biology, vol. 41, no. 5, pp. 1126-1147, 2015.
 M. Friedrich-Rust, K. Wunder, S. Kriener et al., "Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography," Radiology, vol. 252, no. 2, pp. 595-604, 2009.
 D. Cosgrove, F. Piscaglia, J. Bamber et al., "EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 2: clinical applications," Ultraschall in der Medizin, vol. 34, no. 3, pp. 238-253, 2013.
 R. Goertz, Y. Zopf, V. Jugl et al., "Measurement of liver elasticity with acoustic radiation force impulse (ARFI) technology: an alternative noninvasive method for staging liver fibrosis in viral hepatitis," Ultraschall in der Medizin, vol. 31, no. 2, pp. 151-155, 2010.
 T. Poynard, M. Munteanu, E. Luckina et al., "Liver fibrosis evaluation using real-time shear wave elastography: applicability and diagnostic performance using methods without a gold standard," Journal of Hepatology, vol. 58, no. 5, pp. 928-935, 2013.
 C. F. Dietrich, J. Bamber, A. Berzigotti et al., "EFSUMB guidelines and recommendations on the clinical use of liver ultrasound elastography, update 2017 (long version)," Ultraschall in der Medizin, vol. 38, no. 4, pp. e16-e47, 2017.
 K.-Q. Shi, Y. C. Fan, Z. Z. Pan et al., "Transient elastography: a meta-analysis of diagnostic accuracy in evaluation of portal hypertension in chronic liver disease," Liver International, vol. 33, no. 1, pp. 62-71, 2013.
 E. Llop, A. Berzigotti, M. Reig et al., "Assessment of portal hypertension by transient elastography in patients with compensated cirrhosis and potentially resectable liver tumors," Journal of Hepatology, vol. 56, no. 1, pp. 103-108, 2012.
 F. Vizzutti, U. Arena, R. G. Romanelli et al., "Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis," Hepatology, vol. 45, no. 5, pp. 1290-1297, 2007.
 M.-W. You, K. W. Kim, J. Pyo et al., "A meta-analysis for the diagnostic performance of transient elastography for clinically significant portal hypertension," Ultrasound in Medicine & Biology, vol. 43, no. 1, pp. 59-68, 2017.
 S. Bota, H. Herkner, I. Sporea et al., "Meta-analysis: ARFI elastography versus transient elastography for the evaluation of liver fibrosis," Liver International, vol. 33, no. 8, pp. 1138-1147, 2013.
 J. Nierhoff, A. A. Chavez Ortiz, E. Herrmann, S. Zeuzem, and M. Friedrich-Rust, "The efficiency of acoustic radiation force impulse imaging for the staging of liver fibrosis: a meta-analysis," European Radiology, vol. 23, no. 11, pp. 3040-3053, 2013.
 M. Friedrich-Rust, J. Nierhoff, M. Lupsor et al., "Performance of acoustic radiation force impulse imaging for the staging of liver fibrosis: a pooled meta-analysis," Journal of Viral Hepatitis, vol. 19, no. 2, pp. e212-e219, 2012.
 I. Sporea, S. Bota, M. Peck-Radosavljevic et al., "Acoustic radiation force impulse elastography for fibrosis evaluation in patients with chronic hepatitis C: an international multicenter study," European Journal of Radiology, vol. 81, no. 12, pp. 4112-4118, 2012.
 F. Piscaglia, V. Salvatore, R. di Donato et al., "Accuracy of VirtualTouch acoustic radiation force impulse (ARFI) imaging for the diagnosis of cirrhosis during liver ultrasonography," Ultraschall in der Medizin, vol. 32, no. 2, pp. 167-175, 2011.
 D. Attia, B. Schoenemeier, T. Rodt et al., "Evaluation of liver and spleen stiffness with acoustic radiation force impulse quantification elastography for diagnosing clinically significant portal hypertension," Ultraschall in der Medizin, vol. 36, no. 6, pp. 603-610, 2015.
 Y. Takuma, Y. Morimoto, H. Takabatake et al., "Measurement of spleen stiffness with acoustic radiation force impulse imaging predicts mortality and hepatic decompensation in patients with liver cirrhosis," Clinical Gastroenterology and Hepatology, vol. 15, no. 11, pp. 1782-1790.e4, 2017.
 P. Salzl, T. Reiberger, M. Ferlitsch et al., "Evaluation of portal hypertension and varices by acoustic radiation force impulse imaging of the liver compared to transient elastography and AST to platelet ratio index," Ultraschall in der Medizin, vol. 35, no. 6, pp. 528-533, 2014.
 G. Ferraioli, C. Tinelli, B. Dal Bello et al., "Accuracy of realtime shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study," Hepatology, vol. 56, no. 6, pp. 2125-2133, 2012.
 E. Bavu, J. L. Gennisson, M. Couade et al., "Noninvasive in vivo liver fibrosis evaluation using supersonic shear imaging: a clinical study on 113 hepatitis C virus patients," Ultrasound in Medicine & Biology, vol. 37, no. 9, pp. 1361-1373, 2011.
 C. Cassinotto, B. Lapuyade, A. Mouries et al., "Non-invasive assessment of liver fibrosis with impulse elastography: comparison of supersonic shear imaging with ARFI and FibroScan[R]," Journal of Hepatology, vol. 61, no. 3, pp. 550-557, 2014.
 S. Y. Choi, W. K. Jeong, Y. Kim, J. Kim, T. Y. Kim, and J. H. Sohn, "Shear-wave elastography: a noninvasive tool for monitoring changing hepatic venous pressure gradients in patients with cirrhosis," Radiology, vol. 273, no. 3, pp. 917-926, 2014.
 L. Elkrief, P. E. Rautou, M. Ronot et al., "Prospective comparison of spleen and liver stiffness by using shear-wave and transient elastography for detection of portal hypertension in cirrhosis," Radiology, vol. 275, no. 2, pp. 589-598, 2015.
 B. Procopet, A. Berzigotti, J. G. Abraldes et al., "Real-time shear-wave elastography: applicability, reliability and accuracy for clinically significant portal hypertension," Journal of Hepatology, vol. 62, no. 5, pp. 1068-1075, 2015.
 T. Y. Kim, W. K. Jeong, J. H. Sohn, J. Kim, M. Y. Kim, and Y. Kim, "Evaluation of portal hypertension by real-time shear wave elastography in cirrhotic patients," Liver International, vol. 35, no. 11, pp. 2416-2424, 2015.
 C. Jansen, C. Bogs, W. Verlinden et al., "Algorithm to rule out clinically significant portal hypertension combining shearwave elastography of liver and spleen: a prospective multicentre study," Gut, vol. 65, no. 6, pp. 1057-1058, 2016.
 F. Piscaglia, V. Salvatore, L. Mulazzani et al., "Differences in liver stiffness values obtained with new ultrasound elastography machines and Fibroscan: a comparative study," Digestive and Liver Disease, vol. 49, no. 7, pp. 802-808, 2017.
 S. H. Shah, P. C. Hayes, P. L. Allan, J. Nicoll, and N. D. Finlayson, "Measurement of spleen size and its relation to hypersplenism and portal hemodynamics in portal hypertension due to hepatic cirrhosis," The American Journal of Gastroenterology, vol. 91, no. 12, pp. 2580-2583, 1996.
 G. Re, A. M. Casali, D. Cavalli, G. Guida, R. Cau, and G. Cavalli, "Histometric analysis of white pulp arterial vessels in congestive splenomegaly," Applied Pathology, vol. 4, no. 1-2, pp. 98-103, 1986.
 G. Cavalli, G. Re, and A. M. Casali, "Red pulp arterial terminals in congestive splenomegaly: a morphometric study," Pathology-Research and Practice, vol. 178, no. 6, pp. 590-594, 1984.
 A. Colecchia, L. Montrone, E. Scaioli et al., "Measurement of spleen stiffness to evaluate portal hypertension and the presence of esophageal varices in patients with HCV-related cirrhosis," Gastroenterology, vol. 143, no. 3, pp. 646-654, 2012.
 P. Sharma, V. Kirnake, P. Tyagi et al., "Spleen stiffness in patients with cirrhosis in predicting esophageal varices," The American Journal of Gastroenterology, vol. 108, no. 7, pp. 1101-1107, 2013.
 V. Calvaruso, F. Bronte, E. Conte, F. Simone, A. Craxi, and V. di Marco, "Modified spleen stiffness measurement by transient elastography is associated with presence of large oesophageal varices in patients with compensated hepatitis C virus cirrhosis," Journal of Viral Hepatitis, vol. 20, no. 12, pp. 867-874, 2013.
 H. Stefanescu, M. Grigorescu, M. Lupsor, B. Procopet, A. Maniu, and R. Badea, "Spleen stiffness measurement using Fibroscan for the noninvasive assessment of esophageal varices in liver cirrhosis patients," Journal of Gastroenterology and Hepatology, vol. 26, no. 1, pp. 164-170, 2011.
 C. Cassinotto, A. Charrie, A. Mouries et al., "Liver and spleen elastography using supersonic shear imaging for the noninvasive diagnosis of cirrhosis severity and oesophageal varices," Digestive and Liver Disease, vol. 47, no. 8, pp. 695-701, 2015.
 C. Jansen, C. Bogs, W. Verlinden et al., "Shear-wave elastography of the liver and spleen identifies clinically significant portal hypertension: a prospective multicentre study," Liver International, vol. 37, no. 3, pp. 396-405, 2017.
 X. Ma, L. Wang, H. Wu et al., "Spleen stiffness is superior to liver stiffness for predicting esophageal varices in chronic liver disease: a meta-analysis," PLoS ONE, vol. 11, no. 11, article e0165786, 2016.
 H. Stefanescu, P. Cales, M. Fraquelli et al., "Performance of FibroScan[R] to detect large esophageal varices in chronic liver diseases is improved by a novel spleen-dedicated examination," Journal of Hepatology, vol. 66, no. 1, article S374, 2017.
 A. Colecchia, A. Colli, G. Casazza et al., "Spleen stiffness measurement can predict clinical complications in compensated HCV-related cirrhosis: a prospective study," Journal of Hepatology, vol. 60, no. 6, pp. 1158-1164, 2014.
 I. Grgurevic, T. Bokun, S. Mustapic et al., "Real-time twodimensional shear wave ultrasound elastography of the liver is a reliable predictor of clinical outcomes and the presence of esophageal varices in patients with compensated liver cirrhosis," Croatian Medical Journal, vol. 56, no. 5, pp. 470-481,2015.
 J. L. Chin, G. Chan, J. D. Ryan, and P. A. McCormick, "Spleen stiffness can non-invasively assess resolution of portal hypertension after liver transplantation," Liver International, vol. 35, no. 2, pp. 518-523, 2015.
 J. Gao, H. T. Ran, X. P. Ye, Y. Y. Zheng, D. Z. Zhang, and Z. G. Wang, "The stiffness of the liver and spleen on ARFI imaging pre and post TIPS placement: a preliminary observation," Clinical Imaging, vol. 36, no. 2, pp. 135-141, 2012.
 P. M. Novelli, K. Cho, and J. M. Rubin, "Sonographic assessment of spleen stiffness before and after transjugular intrahepatic portosystemic shunt placement with or without concurrent embolization of portal systemic collateral veins in patients with cirrhosis and portal hypertension: a feasibility study," Journal of Ultrasound in Medicine, vol. 34, no. 3, pp. 443-449, 2015.
 I. Goldschmidt, C. Brauch, T. Poynard, and U. Baumann, "Spleen stiffness measurement by transient elastography to diagnose portal hypertension in children," Journal of Pediatric Gastroenterology and Nutrition, vol. 59, no. 2, pp. 197-203, 2014.
 J. Bircher, "Quantitative assessment of deranged hepatic function: a missed opportunity?," Seminars in Liver Disease, vol. 3, no. 4, pp. 275-284, 1983.
 D. Festi, A. M. Morselli Labate, A. Roda et al., "Diagnostic effectiveness of serum bile acids in liver diseases as evaluated by multivariate statistical methods," Hepatology, vol. 3, no. 5, pp. 707-713, 1983.
 J. F. Schneider, A. L. Baker, N. W. Haines, G. Hatfield, and J. L. Boyer, "Aminopyrine N-demethylation: a prognostic test of liver function in patients with alcoholic liver disease," Gastroenterology, vol. 79, no. 6, pp. 1145-1150, 1980.
 G. R. Cherrick, S. W. Stein, C. M. Leevy, and C. S. Davidson, "Indocyanine green: observations on its physical properties, plasma decay, and hepatic extraction," The Journal ofClinical Investigation, vol. 39, no. 4, pp. 592-600, 1960.
 F. J. Burczynski, K. L. Pushka, D. S. Sitar, and C. V. Greenway, "Hepatic plasma flow: accuracy of estimation from bolus injections of indocyanine green," American Journal of Physiology-Heart and Circulatory Physiology, vol. 252, 5, Part 2, pp. H953-H962, 1987.
 M. Makuuchi, T. Kosuge, T. Takayama et al., "Surgery for small liver cancers," Seminars in Surgical Oncology, vol. 9, no. 4, pp. 298-304, 1993.
 Y. Yokoyama, H. Nishio, T. Ebata, T. Igami, G. Sugawara, and M. Nagino, "Value of indocyanine green clearance of the future liver remnant in predicting outcome after resection for biliary cancer," The British Journal of Surgery, vol. 97, no. 8, pp. 1260-1268, 2010.
 A. Lisotti, F. Azzaroli, F. Buonfiglioli et al., "Indocyanine green retention test as a noninvasive marker of portal hypertension and esophageal varices in compensated liver cirrhosis," Hepatology, vol. 59, no. 2, pp. 643-650, 2014.
 M. L. L. Pind, S. M0ller, N. Faqir, and F. Bendtsen, "Predictive value of indocyanine green retention test and indocyanine green clearance in Child-Pugh class A patients," Hepatology, vol. 61, no. 6, pp. 2112-2113, 2015.
 F. Salerno, G. Borroni, P. Moser et al., "Prognostic value of the galactose test in predicting survival of patients with cirrhosis evaluated for liver transplantation. A prospective multicenter Italian study," Journal of Hepatology, vol. 25, no. 4, pp. 474-480, 1996.
 A. Zipprich, O. Kuss, S. Rogowski et al., "Incorporating indocyanin green clearance into the model for end stage liver disease (MELD-ICG) improves prognostic accuracy in intermediate to advanced cirrhosis," Gut, vol. 59, no. 7, pp. 963968, 2010.
 A. Lisotti, F. Azzaroli, A. Cucchetti et al., "Relationship between indocyanine green retention test, decompensation and survival in patients with Child-Pugh A cirrhosis and portal hypertension," Liver International, vol. 36, no. 9, pp. 1313-1321,2016.
 A. K. Lotfipour, M. Douek, S. V. Shimoga et al., "The cost of screening esophageal varices: traditional endoscopy versus computed tomography," Journal of Computer Assisted Tomography, vol. 38, no. 6, pp. 963-967, 2014.
 H. Kim, D. Choi, G. Y. Gwak et al., "Evaluation of esophageal varices on liver computed tomography: receiver operating characteristic analyses of the performance of radiologists and endoscopists," Journal of Gastroenterology and Hepa tology, vol. 24, no. 9, pp. 1534-1540, 2009.
 S. H. Kim, Y. J. Kim, J. M. Lee et al., "Esophageal varices in patients with cirrhosis: multidetector CT esophagography--comparison with endoscopy," Radiology, vol. 242, no. 3, pp. 759-768, 2007.
 N. C. Yu, D. Margolis, M. Hsu, S. S. Raman, and D. S. K. Lu, "Detection and grading of esophageal varices on liver CT: comparison of standard and thin-section multiplanar reconstructions in diagnostic accuracy," American Journal of Roentgenology, vol. 197, no. 3, pp. 643-649, 2011.
 A. Manduca, T. E. Oliphant, M. A. Dresner et al., "Magnetic resonance elastography: non-invasive mapping of tissue elasticity," Medical Image Analysis, vol. 5, no. 4, pp. 237-254, 2001.
 Q. B. Wang, H. Zhu, H. L. Liu, and B. Zhang, "Performance of magnetic resonance elastography and diffusion-weighted imaging for the staging of hepatic fibrosis: a meta-analysis," Hepatology, vol. 56, no. 1, pp. 239-247, 2012.
 S. Singh, S. K. Venkatesh, Z. Wang et al., "Diagnostic performance of magnetic resonance elastography in staging liver fibrosis: a systematic review and meta-analysis of individual participant data," Clinical Gastroenterology and Hepatology, vol. 13, no. 3, pp. 440-451.e6, 2015.
 L. Huwart and B. E. van Beers, "MR elastography," Gastroenterologie Clinique et Biologique, vol. 32, no. 6, Supplement 1, pp. 68-72, 2008.
 L. Huwart, C. Sempoux, E. Vicaut et al., "Magnetic resonance elastography for the noninvasive staging of liver fibrosis," Gastroenterology, vol. 135, no. 1, pp. 32-40, 2008.
 J. A. Talwalkar, M. Yin, S. Venkatesh et al., "Feasibility of in vivo MR elastographic splenic stiffness measurements in the assessment of portal hypertension," American Journal of Roentgenology, vol. 193, no. 1, pp. 122-127, 2009.
 S. U. Shin, J. M. Lee, M. H. Yu et al., "Prediction of esophageal varices in patients with cirrhosis: usefulness of threedimensional MR elastography with echo-planar imaging technique," Radiology, vol. 272, no. 1, pp. 143-153, 2014.
 M. Ronot, S. Lambert, L. Elkrief et al., "Assessment of portal hypertension and high-risk oesophageal varices with liver and spleen three-dimensional multifrequency MR elastography in liver cirrhosis," European Radiology, vol. 24, no. 6, pp. 1394-1402, 2014.
Federico Ravaioli (iD), (1) Marco Montagnani (iD), (1) Andrea Lisotti (iD), (2) Davide Festi (iD), (1) Giuseppe Mazzella, (1) and Francesco Azzaroli (iD) (1)
(1) Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
(2) Gastroenterology Unit, Ospedale S. Maria della Scaletta, Imola, Italy
Correspondence should be addressed to Francesco Azzaroli; email@example.com
Received 13 February 2018; Accepted 30 April 2018; Published 7 June 2018
Academic Editor: Tatsuya Toyokawa
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|Author:||Ravaioli, Federico; Montagnani, Marco; Lisotti, Andrea; Festi, Davide; Mazzella, Giuseppe; Azzaroli,|
|Publication:||Gastroenterology Research and Practice|
|Article Type:||Clinical report|
|Date:||Jan 1, 2018|
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